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What changed in ALNYLAM PHARMACEUTICALS, INC.'s 10-K — 2022 vs 2023

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Paragraph-level year-over-year comparison of ALNYLAM PHARMACEUTICALS, INC.'s 2022 and 2023 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2023 report.

+905 added−927 removedSource: 10-K (2024-02-15) vs 10-K (2023-02-23)

Top changes in ALNYLAM PHARMACEUTICALS, INC.'s 2023 10-K

905 paragraphs added · 927 removed · 681 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

276 edited+112 added−94 removed238 unchanged
Biggest changeKey 2022 and Recent Highlights TTR Franchise • ONPATTRO (patisiran) and AMVUTTRA (vutrisiran)– hATTR Amyloidosis with Polyneuropathy ◦ Achieved global net product revenues for ONPATTRO and AMVUTTRA for the full year 2022 of $558 million and $94 million, respectively ◦ Attained over 2,975 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2022 ◦ Received 760 Start Forms in the U.S. for AMVUTTRA from launch through December 31, 2022 • Patisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Reported positive results from the APOLLO-B Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy ◦ Submitted and received acceptance of the sNDA for ONPATTRO (patisiran) for the treatment of the cardiomyopathy of ATTR amyloidosis ▪ The FDA has set an action date of October 8, 2023 under the PDUFA ▪ In their file acceptance letter, the FDA stated that they have not identified any review issues, and also noted that they are planning to hold an advisory committee meeting to discuss the application • Vutrisiran – hATTR Amyloidosis with Polyneuropathy ◦ Received FDA approval of AMVUTTRA for the treatment of the polyneuropathy of hATTR amyloidosis in adults ◦ Received marketing authorization for AMVUTTRA for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy in Europe and the UK, as well as approval for TTR type familial amyloidosis with polyneuropathy in Japan ◦ Received approval from the Brazilian Health Regulatory Agency (ANVISA) for AMVUTTRA for the treatment of hATTR amyloidosis in adults • Vutrisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Announced that we do not plan to conduct the optional interim analysis for the HELIOS-B Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy; the study remains on track for topline results in early 2024 7 Table of Contents Commercial/Late-Stage Pipeline • GIVLAARI (givosiran) – Acute Hepatic Porphyria ◦ Recognized GIVLAARI global net revenue of $173.1 million for the year ended December 31, 2022 ◦ Attained over 520 patients worldwide on commercial GIVLAARI treatment as of December 31, 2022 • OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1 ◦ Recognized OXLUMO global net revenue of $69.8 million for the year ended December 31, 2022 ◦ Attained over 280 patients worldwide on commercial OXLUMO treatment as of December 31, 2022, up from over 230 commercial patients as of September 30, 2022 • Leqvio (inclisiran) – Hypercholesterolemia (in collaboration with Novartis) ◦ Our partner, Novartis, continued the launch of Leqvio, with focus on patient on-boarding, removing access hurdles and enhancing medical education • Lumasiran – Primary Hyperoxaluria Type 1 ◦ Based on the successful outcome of the ILLUMINATE-C study in children and adults with advanced PH1, received approval from the FDA of an sNDA for OXLUMO, expanding the indication for the treatment of PH1 to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients, and received approval from the EMA of a Type II variation to include the ILLUMINATE-C data in the label Early-Stage and Pre-Clinical Pipeline • Zilebesiran (ALN-AGT) for the treatment of hypertension; completed enrollment in the KARDIA-1 Phase 2 monotherapy study of zilebesiran in patients with mild-to-moderate hypertension • ALN-APP for the treatment of cerebral amyloid angiopathy and autosomal dominant Alzheimer’s Disease; enrollment and dose escalation continue in the Phase 1 study of ALN-APP in patients with early onset Alzheimer’s Disease, in collaboration with Regeneron, with initial topline results expected in early 2023 • ALN-TTRsc04 for the treatment of ATTR amyloidosis; submitted a CTA application and initiated dosing in a Phase 1 study Corporate Highlights • Finance ◦ Ended 2022 with $2.19 billion in cash, cash equivalents and marketable securities • Business ◦ Issued $1.04 billion convertible senior notes with proceeds primarily used to pay down Blackstone $700 million credit facility and approximately $200 million in prepayment premiums under the credit facility, the purchase of capped call transactions, and underwriter fees 8 Table of Contents RNAi Therapeutics – A New Class of Innovative Medicines Overview of RNAi Therapeutics In recent years, a tremendous amount of progress has been made in effectively delivering RNAi therapeutics to targeted organs and cells, and we believe Alnylam has been the leader of this advancement.
Biggest changeKey 2023 and Recent Highlights TTR Franchise • ONPATTRO (patisiran) and AMVUTTRA (vutrisiran)– hATTR Amyloidosis with Polyneuropathy ◦ Achieved global net product revenues for ONPATTRO and AMVUTTRA for the full year 2023 of $354.5 million and $557.8 million, respectively ◦ Attained over 4,060 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2023 • Vutrisiran – hATTR Amyloidosis with Polyneuropathy ◦ Presented nine-month results from the randomized treatment extension period of the HELIOS-A study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy • Patisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Presented 18-month results from the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy ◦ Presented new 24-month results from an interim analysis of the open-label extension period of the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy ◦ Received CRL from the FDA for the sNDA for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis • Vutrisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Announced updates to the statistical analysis plan for the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy, including updates to the primary and secondary endpoint structure, as well as study exposure; Topline results expected to be available in late June or early July 2024 • ALN-TTRsc04 – ATTR Amyloidosis ◦ Presented positive initial topline results from the Phase 1 study in healthy volunteers Commercial/Late-Stage Pipeline • GIVLAARI (givosiran) – Acute Hepatic Porphyria ◦ Recognized GIVLAARI global net revenue of $219.3 million for the year ended December 31, 2023 7 Table of Con tents ◦ Attained over 650 patients worldwide on commercial GIVLAARI treatment as of December 31, 2023 • OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1 ◦ Recognized OXLUMO global net revenue of $109.8 million for the year ended December 31, 2023 ◦ Attained over 430 patients worldwide on commercial OXLUMO treatment as of December 31, 2023 • Leqvio (inclisiran) – Hypercholesterolemia (in collaboration with Novartis) ◦ Our collaborator, Novartis, continued the launch of Leqvio, with focus on patient on-boarding, removing access hurdles and enhancing medical education • Fitusiran – Hemophilia (in collaboration with Sanofi) ◦ Our collaborator, Sanofi, reported positive data from the Phase 3 ATLAS-OLE study of fitusiran, in development for the treatment of hemophilia A or B, with or without inhibitors, and an NDA submission with the FDA is expected in 2024 Early-Stage and Pre-Clinical Pipeline • Zilebesiran – Hypertension ◦ Completed enrollment in the KARDIA-2 Phase 2 study, evaluating the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of another antihypertensive medication ◦ Reported positive topline results from the KARDIA-1 Phase 2 dose-ranging study of zilebesiran • ALN-APP – Cerebral Amyloid Angiopathy and Autosomal Dominant Alzheimer’s Disease ◦ Reported positive interim results from the ongoing single ascending dose part of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease ◦ Announced that the FDA has provided clearance to initiate the multiple-dose part (Part B) of the ongoing Phase 1 study of ALN-APP Corporate Highlights • Finance ◦ Ended 2023 with $2.44 billion in cash, cash equivalents and marketable securities • Business ◦ Entered into global strategic collaboration with Roche for the co-development and co-commercialization of zilebesiran 8 Table of Con tents RNAi Therapeutics – A New Class of Innovative Medicines Overview of RNAi Therapeutics In recent years, a tremendous amount of progress has been made in effectively delivering RNAi therapeutics to targeted organs and cells, and we believe Alnylam has been the leader of this advancement.
ONPATTRO is approved by the United States Food and Drug Administration, or the FDA, for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis, in adults and has also been approved in the European Union, or EU, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries, including Brazil.
ONPATTRO is approved by the United States Food and Drug Administration, or the FDA, for the treatment of hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis, with polyneuropathy in adults and has also been approved in the European Union, or EU, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries, including Brazil.
In August 2022, we reported positive results from the APOLLO-B Phase 3 study of patisiran (the non-branded name of ONPATTRO) in patients with ATTR amyloidosis with cardiomyopathy, and in December 2022, we submitted a supplemental New Drug Application, or sNDA, to the FDA for ONPATTRO as a potential treatment of the cardiomyopathy of ATTR amyloidosis.
In August 2022, we reported positive results from the APOLLO-B Phase 3 study of patisiran (the non-branded name of ONPATTRO) in patients with ATTR amyloidosis with cardiomyopathy, and in December 2022, we submitted a supplemental New Drug Application, or sNDA, to the FDA for patisiran as a potential treatment for the ATTR amyloidosis with cardiomyopathy.
We and Regeneron will alternate leadership on CNS and liver programs, with the lead party retaining global development and commercial responsibility. With respect to the programs directed to C5 complement-mediated diseases, we retain control of cemdisiran monotherapy development, and Regeneron is leading combination product development.
We and Regeneron will alternate leadership on CNS and liver programs, with the lead party retaining global development and commercial responsibility. With respect to the programs directed to C5 complement-mediated diseases, we retain control of cemdisiran monotherapy development, and Regeneron is leading cemdisiran-combination product development.
Additional granted and pending patents in the U.S., Europe and other countries may be available. ** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.
Additional granted and pending patents in the U.S., Europe and other countries may be available. ** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.
The competitive landscape continues to expand, and we expect that additional companies will initiate programs focused on the development of RNAi therapeutic products using the approaches described above as well as potentially new approaches that may result in the more rapid development of RNAi therapeutics or more effective technologies for RNAi drug development or delivery.
The competitive landscape continues to expand, and we expect that additional companies will initiate programs focused on the development of RNAi therapeutic products using the approaches described above as well as potentially new approaches that may result in more rapid development of RNAi therapeutics or more effective technologies for RNAi drug development or delivery.
The FDA may waive the review of an advisory committee and is not bound by the recommendation of an advisory committee, but it often follows such recommendations.
The FDA may waive the review by an advisory committee and is not bound by the recommendation of an advisory committee, but it often follows such recommendations.
In connection with the collaboration, Blackstone agreed to provide us up to $2.0 billion in financing, including $1.0 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran (formerly ALN-AGT) pursuant to the funding agreement finalized in August 2020.
In connection with the collaboration, Blackstone agreed to provide us up to $2.00 billion in financing, including $1.00 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran (formerly ALN-AGT) pursuant to the funding agreement finalized in August 2020.
By harnessing the RNAi pathway, we have developed a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics are comprised of small interfering RNA, or siRNA, and function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made.
By harnessing the RNAi pathway, we have developed a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics are comprised of small interfering RNA, or siRNA, that function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made.
As part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative prevalent disease medicines. In addition to Leqvio, we are advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension.
As part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative medicines to treat prevalent disease. In addition to Leqvio, we are advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension.
Orphan Drug Designation must be requested before submitting an NDA or an sNDA for the orphan indication. After the FDA grants Orphan Drug Designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. We intend to request Orphan Drug Designation for our product candidates, if applicable.
Orphan Drug Designation must be requested before submitting an NDA or an sNDA for the orphan indication. After the FDA grants Orphan Drug Designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. We intend to request Orphan Drug Designation for certain of our product candidates, if applicable.
KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually, whereas KARDIA-2 is evaluating the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by a standard of care antihypertensive medication.
KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually, and KARDIA-2 is evaluating the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by a standard of care antihypertensive medication.
The FDA normally conducts a pre-approval inspection to gain assurance that the manufacturing facility or facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, purity and stability, and are in compliance with regulations governing current good manufacturing practice, or cGMP, requirements.
The FDA normally conducts a pre-approval inspection to gain assurance that the manufacturing facility or facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity, and are in compliance with regulations governing current good manufacturing practice, or cGMP, requirements.
HELIOS-B Phase 3 Study The HELIOS-B Phase 3 trial, initiated in late 2019, is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vutrisiran in patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy.
HELIOS-B Phase 3 Study The HELIOS-B Phase 3 study, initiated in late 2019, is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vutrisiran in patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy.
The time required may differ from that required for FDA approval and may be longer than that required to obtain FDA approval. Thus, there can be substantial delays in obtaining required approvals from foreign regulatory authorities after the relevant applications are filed.
The time required may differ from that required for FDA approval and may be longer than that required to obtain FDA approval. Thus, there can be substantial delays in obtaining required marketing approvals from foreign regulatory authorities after the relevant applications are filed.
Fast Track designation provides opportunities for frequent interactions with FDA to expedite drug development and review as well as the opportunity for rolling review of the NDA. We intend to request Fast Track designation for our product candidates, if applicable.
Fast Track designation provides opportunities for frequent interactions with FDA to expedite drug development and review as well as the opportunity for rolling review of the NDA. We intend to request Fast Track designation for certain of our product candidates, if applicable.
Drugs approved in this way are commonly referred to as generic equivalents to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.
Drugs approved in this way are commonly referred to as generic equivalents to the listed product and can often be substituted by pharmacists under prescriptions written for the original listed drug.
For example, the FDA granted Fast Track designation to patisiran for the treatment of hATTR amyloidosis, which was approved in August 2018 for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and also granted Fast Track designation to vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis, which was approved in June 2022.
For example, the FDA granted Fast Track designation to patisiran for the treatment of hATTR amyloidosis, which was approved in August 2018 for the treatment of the hATTR amyloidosis with polyneuropathy in adults, and also granted Fast Track designation to vutrisiran for the treatment of the hATTR amyloidosis with polyneuropathy, which was approved in June 2022.
As a condition of NDA approval, the FDA may require post-approval evaluations, sometimes referred to as Phase 4 trials, or other surveillance to monitor the drug’s safety or effectiveness and may impose other conditions, including labeling restrictions, such as a Boxed Warning, and/or distribution and use restrictions through a Risk Evaluation and Mitigation Strategy, or REMS, all of which can materially affect the potential market and profitability of the drug.
As a condition of NDA approval, the FDA may require post-approval evaluations, sometimes referred to as Phase 4 trials, or other surveillance to monitor the drug’s safety or effectiveness and may impose other conditions, including labeling restrictions, such as a Boxed Warning, and/or distribution and use restrictions through a Risk Evaluation and Mitigation Strategy, or REMS, all of which can materially affect the potential market and profitability of the product.
To the extent that we rely on previously unapproved drug delivery systems, we may be subject to additional testing and approval requirements from the FDA above and beyond those described above.
To the extent we rely on previously unapproved drug delivery systems, we may be subject to additional testing and approval requirements from the FDA above and beyond those described above.
In connection with our EMA approval on August 26, 2018, the EMA granted ONPATTRO Marketing Exclusivity and ODE until August 26, 2028. 22 Table of Contents AMVUTTRA Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9370581 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9399775 United States Compositions of Matter & Methods of Use 11/16/2032 Alnylam 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 10208307 United States Compositions of Matter & Methods of Use 7/28/2036 Alnylam 10570391 United States Compositions of Matter 11/16/2032 Alnylam 10612024 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 10683501 United States Methods of Use 7/28/2036 Alnylam 10806791 United States Compositions of Matter 12/4/2028 Alnylam 11286486 United States Methods of Use 7/28/2036 Alnylam 11401517 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 3301177 Europe Compositions of Matter & Methods of Use 11/16/2032 Alnylam 3329002 Europe Compositions of Matter & Methods of Use 7/28/2036 Alnylam _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
In connection with our EMA approval on August 26, 2018, the EMA granted ONPATTRO Marketing Exclusivity and ODE until August 26, 2028. 22 Table of Con tents AMVUTTRA Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9370581 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9399775 United States Compositions of Matter & Methods of Use 11/16/2032 Alnylam 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 10208307 United States Compositions of Matter & Methods of Use 7/28/2036 Alnylam 10570391 United States Compositions of Matter 11/16/2032 Alnylam 10612024 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 10683501 United States Methods of Use 7/28/2036 Alnylam 10806791 United States Compositions of Matter 12/4/2028 Alnylam 11286486 United States Methods of Use 7/28/2036 Alnylam 11401517 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 3301177 Europe Compositions of Matter & Methods of Use 11/16/2032 Alnylam 3329002 Europe Compositions of Matter & Methods of Use 7/28/2036 Alnylam _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
Pediatric Study Plans The FDCA requires that a sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.
Pediatric Study Plans The FDCA requires that a sponsor planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.
We believe this success will enable us to achieve our Alnylam P 5 x25 strategy under which we expect to sustainably and organically create and commercialize transformative rare and prevalent disease medicines benefiting patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.
We believe this success will enable us to achieve our Alnylam P 5 x25 strategy under which we expect to sustainably and organically create and commercialize transformative rare, specialty and select prevalent disease medicines benefiting patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.
In connection with our EMA approval on March 2, 2020, the EMA granted GIVLAARI Marketing Exclusivity and ODE until March 2, 2030. 24 Table of Contents OXLUMO Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9828606 United States Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 10435692 United States Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10465195 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10478500 United States Compositions of Matter & Methods of Use 10/9/2035 Alnylam 10487330 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10612024 United States Compositions of Matter 8/14/2035 Alnylam 10612027 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 3087184 Europe Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
In connection with our EMA approval on March 2, 2020, the EMA granted GIVLAARI Marketing Exclusivity and ODE until March 2, 2030. 24 Table of Con tents OXLUMO Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9828606 United States Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 10435692 United States Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10465195 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10478500 United States Compositions of Matter & Methods of Use 10/9/2035 Alnylam 10487330 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals 10612024 United States Compositions of Matter 8/14/2035 Alnylam 10612027 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam 3087184 Europe Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products in exchange for a previously disclosed technology access fee, participation in fees for our partnering programs and future milestone and royalty payments from us for programs that incorporate Ionis’ intellectual property.
Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products in exchange for a previously disclosed technology access fee, participation in fees for our collaboration programs and future milestone and royalty payments from us for programs that incorporate Ionis’ intellectual property.
Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the NDA also includes a non-orphan indication. The FDA conducts a preliminary review of all NDAs within the first 60 days after submission before accepting them for filing to determine whether they are sufficiently complete to permit substantive review.
Additionally, no application fees are assessed on NDAs for products designated as orphan drugs, unless the NDA also includes a non-orphan indication. The FDA conducts a preliminary review of all NDAs within the first 60 days after submission before accepting them for filing to determine whether they are sufficiently complete to permit substantive review.
Nonclinical Tests and Clinical Trials Nonclinical tests include laboratory evaluation of product chemistry and formulation, as well as animal testing to assess the potential safety and efficacy of the product.
Nonclinical Tests and Clinical Trials Nonclinical tests include laboratory evaluation of product chemistry and formulation, as well as animal testing to assess the potential safety and efficacy of the product candidate.
Clinical trials to support NDAs are typically conducted in three sequential phases, which may overlap or be combined. • In Phase 1, the initial introduction of the drug into healthy human subjects or patients, the drug is tested primarily to assess safety, tolerability, pharmacokinetics, pharmacological actions and metabolism associated with increasing doses. • Phase 2 usually involves trials in a limited patient population, to assess the optimum dosage and dose regimen, identify possible adverse effects and safety risks, and provide preliminary support for the efficacy of the drug in the indication being studied. • Phase 3 clinical trials further evaluate the drug’s clinical efficacy, side effects and safety in an expanded patient population, typically at geographically dispersed clinical trial sites, to establish the overall benefit-risk relationship of the drug and to provide adequate information for the labeling of the drug.
Clinical trials to support NDAs are typically conducted in three sequential phases, which may overlap or be combined. • In Phase 1, the initial introduction of the drug into healthy human subjects or patients, the drug is tested primarily to assess safety, tolerability, pharmacokinetics, pharmacological actions and metabolism associated with increasing doses. • Phase 2 usually involves trials in a limited patient population, to assess the optimum dosage and dose regimen, identify possible adverse effects and safety risks, and provide preliminary support for the efficacy of the drug in the indication being studied. 27 Table of Con tents • Phase 3 clinical trials further evaluate the drug’s clinical efficacy, side effects and safety in an expanded patient population, typically at geographically dispersed clinical trial sites, to establish the overall benefit-risk relationship of the drug and to provide adequate information for the labeling of the drug.
We value diversity at all levels of the organization and continue to focus on extending our diversity, equity and inclusion initiatives across our entire 43 Table of Contents workforce, from: working with managers to develop strategies for building diverse, high performing teams; to ensuring that we attract, develop and retain diverse talent from all backgrounds; to increasing awareness within our company of unconscious biases, and supporting affinity groups comprised of individuals who are underrepresented in our company, industry or society, such as women, members of the LGBTQ community and people of color.
We value diversity at all levels of the organization and continue to focus on extending our diversity, equity and inclusion initiatives across our entire workforce, from: working with managers to develop strategies for building diverse, high performing teams; to ensuring that we attract, develop and retain diverse talent from all backgrounds; to increasing awareness within our company of unconscious biases, and supporting affinity groups comprised of individuals who are underrepresented in our company, industry or society, such as women, members of the LGBTQ+ community and people of color.
We received additional marketing authorizations for GIVLAARI for the treatment of AHP in adults in Brazil, Canada, and marketing authorizations for GIVLAARI for the treatment of AHP in adults and adolescents in Japan, Argentina, Switzerland and Taiwan.
We received additional marketing authorizations for GIVLAARI for the treatment of AHP in adults in Brazil, Canada, and marketing authorizations for GIVLAARI for the treatment of AHP in adults and adolescents in Japan, Argentina, Australia, Switzerland and Taiwan.
Success in early-stage clinical trials does not necessarily assure success in later-stage clinical trials. Data obtained from clinical activities, including but not limited to the data derived from our clinical trials for drug candidates, are not always conclusive and may be subject to alternative interpretations that could delay, limit or even prevent regulatory approval.
Success in early-stage clinical trials does not necessarily assure success in later-stage clinical trials. Data obtained from clinical activities, including but not limited to the data derived from our clinical trials for product candidates, are not always conclusive and may be subject to alternative interpretations that could delay, limit or even prevent regulatory approval.
If the FDA’s evaluation of an NDA submission or GCP inspections or inspection of the manufacturing facilities for the product are not favorable or cannot be completed due to COVID-19 related restrictions, the FDA may defer action on an application or refuse to approve the NDA and issue a complete response letter.
If the FDA’s evaluation of an NDA submission or GCP inspections or inspection of the manufacturing facilities for the product are not favorable or cannot be completed due restrictions (including, for example, restrictions related to COVID-19), the FDA may defer action on an application or refuse to approve the NDA and issue a complete response letter.
In all cases, however, the clinical trials must be conducted in accordance with GCP, which have their origin in the World Medical Association’s Declaration of Helsinki, the applicable regulatory requirements, and guidelines developed by the ICH for GCP in clinical trials. The approval procedure also varies among countries and can involve requirements for additional testing.
In all cases, however, the clinical trials must be conducted in accordance with GCP, which have their origin in the World Medical Association’s Declaration of Helsinki, the applicable regulatory requirements, and guidelines developed by the ICH for GCP in clinical trials. The marketing approval procedure for pharmaceuticals also varies among countries and can involve requirements for additional testing.
Patients were randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months. The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular events at 30 months.
Patients were randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months. The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular events.
Breakthrough Therapy Designation A drug or biological product can be designated as a breakthrough therapy if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that it may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
Breakthrough Therapy Designation A drug or biological product can be designated as a breakthrough therapy if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that it may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints.
Over the last several years, we have been building commercial capability and leveraging the internal knowledge we have accumulated as well as hiring talented people with broad industry experience to enable us to commercialize our products ourselves and with collaborators in key countries globally.
Over the last several years, we have been building commercial capabilities and leveraging the internal knowledge we have accumulated as well as hiring talented people with broad industry experience to enable us to commercialize our products ourselves and with collaborators in key countries globally.
To demonstrate a drug is “clinically superior” to the previously approved orphan drug, a sponsor must show that the drug provides a significant therapeutic advantage over and above the previously already approved drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.
To demonstrate a drug is “clinically superior” to the previously approved orphan drug, a sponsor must show that the drug provides a significant therapeutic advantage over and above the previously approved product in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.
Under the new EU Regulation on Clinical Trials, which became applicable on January 31, 2022, there is a centralized application procedure where one national authority leads the scientific review of the application leading to increased 37 Table of Contents information-sharing and decision-making between member states (as compared to the previous EU Directive on Clinical Trials, where a separate application to the competent authority in each EU member state in which the trial was conducted was required).
Under the new EU Regulation on Clinical Trials, which became applicable on January 31, 2022, there is a centralized application procedure where one national authority leads the scientific review of the application leading to increased information-sharing and decision-making between member states (as compared to the previous EU Directive on Clinical Trials, where a separate application to the competent authority in each EU member state in which the trial was conducted was required).
Even if a product receives regulatory approval, later discovery of previously unknown problems with a product, including new safety risks from clinical or nonclinical data or manufacturing issues, may result in restrictions on the product or even complete withdrawal of the product from the market.
Even if a product receives regulatory approval, later discovery of previously unknown problems with a product, including new safety risks from commercial use, clinical or nonclinical data or manufacturing issues, may result in restrictions on the product or even complete withdrawal of the product from the market.
Under this program, the sponsor of an application for a rare pediatric disease drug may be eligible to obtain a voucher that can be used to obtain a priority review for a subsequent human drug application. The FDA recommends that a sponsor request rare pediatric disease designation before submission of the rare pediatric disease product application.
Under this program, the sponsor of an application for a rare pediatric disease drug may be eligible to obtain a voucher that can be used to obtain a priority review for a subsequent human drug application. The FDA recommends that a sponsor request rare pediatric disease designation before filing of the rare pediatric disease product application.
The safety and efficacy of ALN-HBV02 are currently being investigated in an ongoing Phase 2 trial, and in June 2022, Vir reported preliminary results that demonstrated that a six-dose regimen provided greater and more durable reductions in hepatitis B surface antigen than a two-dose regimen, with all participants achieving a >1 log10 IU/mL reduction during the trial.
The safety and efficacy of elebsiran are currently being investigated in an ongoing Phase 2 trial, and in June 2022, Vir reported preliminary results that demonstrated that a six-dose regimen provided greater and more durable reductions in hepatitis B surface antigen than a two-dose regimen, with all participants achieving a >1 log10 IU/mL reduction during the trial.
Our reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, including our annual reports on Form 10-K, our quarterly reports on Form 10-Q and our current reports on Form 8-K, and amendments to those reports, are accessible through our website, free of charge, as soon as reasonably practicable after these reports are filed electronically with, or otherwise furnished to, the United States Securities and Exchange Commission, or SEC.
Our reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, including our annual reports on Form 10-K, our quarterly reports on Form 10-Q and our current reports on Form 8-K, and amendments to those reports, are accessible through our website, free of charge, as soon as reasonably practicable after these reports are filed electronically with, or otherwise furnished to, the SEC.
If a product that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to Orphan Drug Exclusivity, which means that the FDA may not approve for seven years any other applications, including a full NDA, to market the “same drug” for the same indication, except in limited circumstances.
If a product that has Orphan Drug Designation subsequently receives the first FDA approval for that product for the disease for which it has such designation, the product is entitled to Orphan Drug Exclusivity, which means that the FDA may not approve for seven years any other applications, including a full NDA, from another sponsor to market the “same drug” for the same indication, except in limited circumstances.
Pursuant to the Novartis License Agreement, we received an upfront fee, and may also receive milestone payments upon the achievement of certain development, regulatory and commercial milestones, as well as tiered royalties on the net sales of licensed products ranging from high-single-digit to sub-teen double-digit percentages.
Pursuant to the Novartis License Agreement, we received an upfront fee, and may also receive milestone payments upon the achievement of certain development, regulatory and commercial milestones, as well as tiered royalties on the net sales of licensed products ranging from high-single-digit to sub-teen double-digit percentages. Ionis Pharmaceuticals, Inc.
Obtaining such additional approvals or clearances, and cooperation of other companies, when necessary, could significantly delay, and increase the cost of obtaining marketing approval, which could reduce the commercial viability of a product candidate.
Obtaining such additional approvals or clearances, and cooperation of other companies, when necessary, could significantly delay, and increase the cost of obtaining marketing approval, which in turn could reduce the commercial viability of a product candidate.
FDA approval of an 30 Table of Contents NDA is required before commercial distribution of a new drug may begin in the U.S. An NDA must include the results of extensive nonclinical, clinical and other testing, as described above, a compilation of data relating to the product’s pharmacology, CMC, proposed labeling and other information.
FDA approval of an NDA is required before commercial distribution of a new drug may begin in the U.S. An NDA must include the results of extensive nonclinical, clinical and other testing, as described above, a compilation of data relating to the product’s pharmacology, CMC information, proposed labeling and other information.
A number of states also have false claims laws, and some of these laws may apply to claims for items or services reimbursed under Medicaid and/or commercial insurance. Sanctions under these federal and state fraud and abuse laws may include civil monetary penalties and criminal fines, exclusion from government healthcare programs and imprisonment.
A number of states also have false claims laws, and some of these laws may apply to claims for items or services reimbursed under Medicaid and/or commercial insurance. Sanctions under these federal and state fraud and abuse laws may include civil monetary penalties and criminal fines, exclusion from government healthcare programs and imprisonment. The U.S.
Agilent is required to reserve 41 Table of Contents sufficient capacity to ensure that it can supply our commercial and clinical products in the amounts specified under such firm orders, including a certain percentage of the remaining, non-binding portions of each forecast, as well as a specified number of batches each year.
Agilent is required to reserve sufficient capacity to ensure that it can supply our commercial and clinical products in the amounts specified under such firm orders, including a certain percentage of the remaining, non-binding portions of each forecast, as well as a specified number of batches each year.
Early-Stage Clinical Development Programs Zilebesiran (formerly ALN-AGT) — Hypertension Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension in high unmet need populations.
Early-Stage Clinical Development Programs Zilebesiran (formerly ALN-AGT) — Hypertension Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting AGT, in development for the treatment of hypertension in high unmet need populations.
During 2020, we completed construction and qualification of our cGMP manufacturing facility in Norton, Massachusetts where we currently manufacture drug substance for clinical programs and, eventually, intend to manufacture drug substance for commercial use.
During 2020, we completed construction and qualification of our GMP manufacturing facility in Norton, Massachusetts where we currently manufacture drug substance for clinical programs and, eventually, intend to manufacture drug substance for commercial use.
The conduct of these commercial activities will continue to be dependent upon regulatory approvals and on agreements that we have made or may make in the future with strategic collaborators, currently as follows with respect to our first five approved products and our late-stage clinical programs: • With respect to our ATTR amyloidosis franchise, we have global rights to develop and commercialize both ONPATTRO and AMVUTTRA; • For GIVLAARI and OXLUMO, we have global rights to develop and commercialize; • For Leqvio, we granted MDCO, which was acquired by Novartis in January 2020, global rights to develop and commercialize; and • For fitusiran, Sanofi has global rights to develop and commercialize fitusiran and any back-ups as a result of the 2018 amendment to the Sanofi collaboration and the related product-specific license terms.
The conduct of these commercial activities will continue to be dependent upon regulatory approvals and on agreements that we have made or may make in the future with strategic collaborators, currently as follows with respect to our first five approved products and our late-stage clinical programs: • With respect to our ATTR amyloidosis franchise, we have global rights to develop and commercialize both ONPATTRO and AMVUTTRA; • With respect to our Ultra Rare franchise, we have global rights to develop and commercialize GIVLAARI and OXLUMO; 41 Table of Con tents • For Leqvio, we granted MDCO, which was acquired by Novartis in January 2020, global rights to develop and commercialize; and • For fitusiran, Sanofi has global rights to develop and commercialize fitusiran and any back-ups as a result of the 2018 amendment to the Sanofi collaboration and the related product-specific license terms.
The cap price of the capped call transactions will initially be $424.00 per share, which represents a premium of approximately 100% based on the last reported sale price of our common stock of $212.00 per share on September 12, 2022, 6 Table of Contents and is subject to certain adjustments under the terms of the capped call transactions.
The cap price of the capped call transactions will initially be $424.00 per share, which represents a premium of approximately 100% based on the last reported sale price of our common stock of $212.00 per share on September 12, 2022, and is subject to certain adjustments under the terms of the capped call transactions.
In addition, Orphan Drug Exclusivity may be lost if the FDA later determines that the Orphan Drug Designation request was materially defective or if the manufacturer is unable to assure sufficient quantities of the drug to meet the needs of patients with the rare disease or condition, or if the manufacturer chooses to provide consent to approval of other applications.
In addition, Orphan Drug Exclusivity may be lost if the FDA later determines that the Orphan Drug Designation request was materially defective or if the manufacturer is unable to ensure the availability of sufficient quantities of the drug to meet the needs of patients with the rare disease or condition, or if the manufacturer chooses to provide consent to approval of other applications.
Our collaboration strategy is to form alliances that create significant value for ourselves and our collaborators in the advancement of RNAi therapeutics as a new class of innovative medicines.
Our collaboration strategy is to form collaborations that create significant value for ourselves and our collaborators in the advancement of RNAi therapeutics as a new class of innovative medicines.
For medicines that do not fall within these categories, an applicant may voluntarily submit an application for a centralized marketing authorisation to the EMA, as long as the CHMP agrees that (i) the medicine concerned contains a new active substance, (ii) the medicine is a significant therapeutic, scientific, or technical innovation, or (iii) the authorisation of the medicine under the centralized procedure would be in the interest of public health.
For 36 Table of Con tents medicines that do not fall within these categories, an applicant may voluntarily submit an application for a centralized marketing authorisation to the EMA, as long as the CHMP agrees that (i) the medicine concerned contains a new active substance, (ii) the medicine is a significant therapeutic, scientific, or technical innovation, or (iii) the authorisation of the medicine under the centralized procedure would be in the interest of public health.
In January 2014, we entered into a global, strategic collaboration with Sanofi to discover, develop and commercialize RNAi therapeutics as Genetic Medicines to treat orphan diseases, referred to as the 2014 Sanofi collaboration.
Sanofi. In January 2014, we entered into a global, strategic collaboration with Sanofi to discover, develop and commercialize RNAi therapeutics to treat orphan diseases, referred to as the 2014 Sanofi collaboration.
PeptiDream will select, optimize, and synthesize peptides for each receptor. We will then generate peptide-siRNA conjugates and perform in vitro and in vivo studies to support final peptide selection.
PeptiDream will select, optimize, and synthesize peptides for each receptor. We will then generate peptide-siRNA conjugates and perform in vitro and in vivo studies to support final peptide selection. Novartis AG.
Once granted, product approvals may be further limited or withdrawn if compliance with regulatory standards is not maintained or safety or other problems are identified following initial marketing.
Once granted, product approvals may be further limited or withdrawn if compliance with regulatory requirements is not maintained or safety or other problems are identified following initial marketing.
Coupled with our proven ability to uncover novel gene targets, we believe our approach, investments and commitment to genetically validated targets has the potential to increase our success rate, streamline clinical trials and speed the development of precision medicines for patients with both rare and prevalent diseases.
Coupled with our proven ability to uncover novel gene targets, we believe our approach, investments and commitment to genetically validated targets has the potential to increase our success rate, streamline clinical trials and speed the development of precision medicines for patients with rare, specialty and select prevalent diseases.
In October 2017, we and Vir entered into a collaboration and license agreement, or the Vir Agreement, pursuant to which we granted to Vir an exclusive license to develop, manufacture and commercialize ALN-HBV02 (VIR-2218), for all uses and purposes other than certain excluded fields, as set forth in the agreement.
In October 2017, we and Vir entered into a collaboration and license agreement, or the Vir Agreement, pursuant to which we granted to Vir an exclusive license to develop, manufacture and commercialize elebsiran (formerly ALN-HBV02), for all uses and purposes other than certain excluded fields, as set forth in the Vir Agreement.
AMVUTTRA (vutrisiran) – hATTR Amyloidosis with Polyneuropathy 12 Table of Contents In June 2022, AMVUTTRA was approved by the FDA for the treatment of the polyneuropathy of hATTR amyloidosis in adults based on positive 9-month results from the HELIOS-A Phase 3 study that evaluated the efficacy and safety of AMVUTTRA in patients with hATTR amyloidosis with polyneuropathy.
AMVUTTRA (vutrisiran) – hATTR Amyloidosis with Polyneuropathy In June 2022, AMVUTTRA was approved by the FDA for the treatment of hATTR amyloidosis with polyneuropathy in adults based on positive 9-month results from the HELIOS-A Phase 3 study that evaluated the efficacy and safety of AMVUTTRA in patients with hATTR amyloidosis with polyneuropathy.
The collaboration amendment entered into in April 2019 described below made no changes to the terms described in clauses (i)-(iii) above, which remain in full force and effect.
The collaboration amendment entered into in April 2019 described below made no changes to the terms described in clauses (i)-(ii) above, which remain in full force and effect.
In December 2020, we began cGMP operations, and we believe this facility will enable us to initiate manufacturing for multiple new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support our late-stage and commercial programs in the future.
In December 2020, we began GMP operations, and we believe this facility will enable us to initiate manufacturing for multiple new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support our late-stage and select commercial programs in the future.
These programs include our wholly owned programs: patisiran (the non-branded drug name for ONPATTRO) for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, (wild-type or hereditary) with cardiomyopathy; vutrisiran (the non-branded drug name for AMVUTTRA) for the treatment of ATTR (wild-type or hereditary) amyloidosis with cardiomyopathy; as well as fitusiran for the treatment of hemophilia, which is being advanced by our partner Genzyme Corporation, a Sanofi Company, or Sanofi; and cemdisiran for the treatment of complement-mediated diseases, where our partner Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with pozelimab in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria.
These programs include our wholly owned programs: vutrisiran (the non-branded drug name for AMVUTTRA) for the treatment of ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy; as well as fitusiran for the treatment of hemophilia, which is being advanced by our collaborator Genzyme Corporation, a Sanofi Company, or Sanofi; and cemdisiran for the treatment of complement-mediated diseases, where our collaborator Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with pozelimab in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria.
The manufacturer or importer must have a qualified person 39 Table of Contents who is responsible for certifying that each batch of product has been manufactured in accordance with EU standards of cGMP before releasing the product for commercial distribution in the EU or for use in a clinical trial.
The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with EU standards of cGMP before releasing the product for commercial distribution in the EU or for use in a clinical trial.
If the patent holder then initiates a suit for patent infringement within 45 days of receipt of the notice, the FDA cannot grant effective approval of the ANDA or 505(b)(2) application until either 30 months have passed (which may be extended or shortened in certain cases) or there has been a court decision or settlement order holding or stating that the patents in question are invalid, unenforceable or not infringed.
If a suit for patent infringement is initiated within 45 days of receipt of the notice, the FDA cannot grant effective approval of the ANDA or 505(b)(2) application until either 30 months have passed (which may be extended or shortened in certain cases) or there has been a court decision or settlement order holding or stating that the patents in question are invalid, unenforceable or not infringed.
Competition for Our Business in General The competition we face can be grouped into three broad categories: • other companies working to develop RNAi and microRNA therapeutic products; • companies developing technology known as antisense, which, like RNAi, attempts to silence the activity of specific genes by targeting the mRNAs copied from them; and • marketed products and development programs for therapeutics that treat the same diseases for which we may also be developing treatments.
Competition for Our Business in General The competition we face can be grouped into three broad categories: • other companies working to develop RNAi and microRNA therapeutic products; • companies developing technology known as antisense, which, like RNAi, attempts to silence the activity of specific genes by targeting the mRNAs copied from them; and • marketed products and development programs for therapeutics that treat the same diseases for which we are marketing products or developing treatments.
We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our alliance partners’ currently anticipated needs.
We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our collaborators’ currently anticipated needs.
AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.
AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established 16 Table of Con tents anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.
Standard treatment for people with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or on-demand 15 Table of Contents therapy, which can lead to a temporary restoration of thrombin generation capacity.
Standard treatment for people with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or on-demand therapy, which can lead to a temporary restoration of thrombin generation capacity.
In addition, in 2022, Vir continued to progress a Phase 2 combination trial of ALN-HBV02 with pegylated interferon-alpha, as well as a triple combination with VIR-3434 and interferon, each to evaluate the potential for the combination to result in a functional cure of HBV.
In addition, in 2022, Vir continued to progress a Phase 2 combination trial of elebsiran with pegylated interferon-alpha, as well as a triple combination with VIR-3434 and interferon, each to evaluate the potential for the combination to result in a functional cure of HBV.
Thereafter, Sanofi will fund all potential future development and commercialization costs for such asset. If this asset is approved, we will be eligible to receive tiered double-digit royalties on global net sales. Novartis AG.
Thereafter, Sanofi will fund all potential future development and commercialization costs for such asset. If this asset is approved, we will be eligible to receive tiered double-digit royalties on global net sales. Vir.
(acquired by Novo Nordisk A/S, or Novo Nordisk, in December 2021), or Dicerna, and PeptiDream, Inc., or PeptiDream. Convertible Senior Notes In September 2022, we issued $1.04 billion aggregate principal amount of 1.00% Convertible Senior Notes due 2027, or Notes. The Notes will mature on September 15, 2027, unless earlier converted, redeemed or repurchased.
(acquired by Novo Nordisk A/S, or Novo Nordisk, in December 2021), or Dicerna, and PeptiDream, Inc., or PeptiDream . 6 Table of Con tents Convertible Senior Notes In September 2022, we issued $1.04 billion aggregate principal amount of 1.00% Convertible Senior Notes due 2027, or Notes. The Notes will mature on September 15, 2027, unless earlier converted, redeemed or repurchased.
C16 conjugates provide robust CNS knockdown with wide biodistribution and long duration of action, and this technology enabled our landmark collaboration with Regeneron for the advancement of RNAi therapeutics for a broad range of diseases by addressing therapeutic targets in the eye and CNS, in addition to a select number of targets in the liver.
C16 conjugates provide 9 Table of Con tents robust CNS knockdown with wide biodistribution and long duration of action, and this technology enabled our landmark collaboration with Regeneron for the advancement of RNAi therapeutics for a broad range of diseases by addressing therapeutic targets in the eye and CNS, in addition to a select number of targets in the liver.
Through this collaboration, the companies will collaborate to select and optimize peptides for targeted delivery of small siRNA molecules to a wide range of cell types and tissues via specific interactions with receptors expressed on the target cells. Under the terms of the alliance, we will select a set of receptors for PeptiDream’s peptide discovery platform.
Through this collaboration, the companies are collaborating to select and optimize peptides for targeted delivery of small siRNA molecules to a wide range of cell types and tissues via specific interactions with receptors expressed on the target cells. Under the terms of the collaboration, we will select a set of receptors for PeptiDream’s peptide discovery platform.
The sponsor of a new drug or biological product may request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of the product, but ideally no later than the pre-NDA or pre–biologics license application meeting because many of the features of Fast Track designation will not apply after that time.
The sponsor of a new drug or biological product may request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of the product, but ideally no later than the pre-NDA or pre–BLA meeting because many of the features of Fast Track designation will not apply after that time.
Specifically, under the process set forth by the statute, the ANDA or 505(b)(2) applicant must provide notice of its patent challenge to the NDA sponsor and the patent holder within certain time limits.
Specifically, under the process set forth by the statute, the ANDA or 505(b)(2) applicant must provide notice of its patent challenge to the listed product sponsor and the patent holder within certain time limits.
We believe that for most or all of our drug development programs, there will be one or more competing programs under development at other companies. In some cases, the companies with competing programs will have access to greater resources and expertise than we do and may be more advanced in those programs.
We believe that for most or all of our drug development programs, there will be one or more competing programs being marketed and/or under development at other companies. In some cases, the companies with competing programs will have access to greater resources and expertise and may be more advanced in those programs than we are.
The new employees were hired to support a variety of functions and key initiatives, including extending our research, clinical and pre-clinical pipeline development, as well as our medical affairs, manufacturing and commercialization capabilities, with hires in commercial, compliance, legal, clinical development and operations, research, medical affairs, manufacturing, and general and administrative functions.
The new employees were hired to support a variety of functions and key initiatives, including extending our research, clinical and pre-clinical pipeline development, as well as our medical affairs, manufacturing and commercialization capabilities, with hires in commercial, compliance, legal, clinical development and operations, research, medical affairs, manufacturing, and general and 42 Table of Con tents administrative functions.
The FDA granted breakthrough therapy designation for patisiran, approved in August 2018, givosiran, approved in November 2019, as well as lumasiran, approved in November 2020. We intend to request breakthrough therapy designation for our other product candidates, if applicable.
The FDA granted breakthrough therapy designation for patisiran, approved in August 2018, givosiran, approved in November 2019, as well as lumasiran, approved in November 2020. We intend to request breakthrough therapy designation for certain of our other product candidates, as applicable.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeIndustry Related Risks – Risks Related to Development, Clinical Testing and Regulatory Approval of Our Product Candidates and the Commercialization of Our Approved Products • Any product candidates we or our partners develop may fail in development or be delayed to a point where they do not become commercially viable. • We or our partners may be unable to obtain U.S. or foreign regulatory approval for our or our partnered product candidates, or if approved, may fail to obtain desired labeling for such products. • Even if we or our partners obtain regulatory approvals, our marketed drugs will be subject to ongoing regulatory oversight. • Even if we receive regulatory approval to market our product candidates, and our collaborators receive regulatory approval to market product candidates discovered by us or developed with our technology, the market may not be receptive to such product candidates upon their commercial introduction, which could prevent us from becoming profitable. • We are a multi-product commercial company and expect to continue to invest significant financial and management resources to continue to scale our marketing, sales, market access and distribution capabilities and further establish our global commercial and compliance infrastructure, and our commercial efforts may not be successful. • We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities or promoting our commercially approved products in a way that violates applicable regulations, including in connection with the ongoing DOJ investigation. • Any drugs we develop may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, thereby harming our business.
Biggest changeIndustry Related Risks – Risks Related to Development, Clinical Testing and Regulatory Approval of Our Product Candidates and the Commercialization of Our Approved Products • Any product candidate we or our collaborators develop may fail in development or be delayed to a point where such product candidate does not become commercially viable. • We or our collaborators may be unable to obtain U.S. or foreign regulatory approval for our or our collaborated product candidates, and, as a result, we or our collaborators may be unable to commercialize such product candidates. • Even if we or our collaborators obtain regulatory approvals, our products will be subject to ongoing regulatory oversight. • We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities with respect to our unapproved product candidates or promoting our commercially approved products in a way that violates applicable regulations. • Even if we or our collaborators receive regulatory approval to market our product candidates, the market may not be receptive to such product candidates upon their commercial introduction, which could prevent us from becoming profitable. • We are a multi-product commercial company and expect to continue to invest significant financial and management resources to continue to build our marketing, sales, market access and distribution capabilities and further establish our global infrastructure, and our efforts may not be successful. • Any drugs we currently market or may develop in the future may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, thereby harming our business. 44 Table of Con tents Risks Related to Patents, Licenses and Trade Secrets • If we are not able to obtain and enforce patent protection for our discoveries, our ability to develop and commercialize our product candidates will be harmed. • We license patent rights from third-party owners.
Further, from time to time we issue financial guidance relating to our expectations regarding our combined product sales, collaboration and royalty revenues, and GAAP and non-GAAP combined research and development and selling, general and administrative expenses, which guidance is based on estimates and the judgment of management.
Further, from time to time we issue financial guidance relating to our expectations regarding our combined product sales, collaboration and royalty revenues, and GAAP and non-GAAP combined research and development and selling, general and administrative expenses, which guidance is based on estimates and the judgment of our management.
Additionally, the Organization for Economic Co-operation and Development, or OECD, the EC, and individual taxing jurisdictions where we and our affiliates do business have recently focused on issues related to the taxation of multinational corporations. The OECD has released its comprehensive plan to create an agreed set of international rules for fighting base erosion and profit shifting.
Additionally, the Organization for Economic Co-operation and Development, or the OECD, the EC, and individual taxing jurisdictions where we and our affiliates do business have recently focused on issues related to the taxation of multinational corporations. The OECD has released its comprehensive plan to create an agreed set of international rules for fighting base erosion and profit shifting.
The loss of the service of any of the members of our senior management could significantly delay or prevent the achievement of product development and commercialization, and other business objectives, and adversely impact our stock price. Our employment arrangements with our key personnel are terminable without notice. We do not carry key person life insurance on any of our employees.
The loss of the service of any members of our senior management could significantly delay or prevent the achievement of product development and commercialization, and other business objectives, and adversely impact our stock price. Our employment arrangements with our key personnel are terminable without notice. We do not carry key person life insurance on any of our employees.
This growth has placed a strain on our administrative and operational infrastructure and, as a result, we will need to continue to develop additional and/or new infrastructure and capabilities to support our growth and obtain additional space to conduct our global operations in the U.S., the EU, Japan, Latin America and other geographies.
This growth has placed a strain on our administrative and operational infrastructure and, as a result, we will need to continue to develop additional and/or new infrastructure and capabilities to support our growth and obtain additional space to conduct our global operations in the U.S., EU, Japan, Latin America and other geographies.
We are increasingly dependent on our information technology systems and infrastructure for our business. We collect, store and transmit sensitive information including intellectual property, proprietary business information, including highly sensitive clinical trial data, and personal information in connection with business operations. The secure maintenance of this information is critical to our operations and business strategy.
We are increasingly dependent on our information technology systems and infrastructure for our business. We collect, store and transmit sensitive information including intellectual property, proprietary business information, including highly sensitive clinical trial data, and personal information in connection with our business operations. The secure maintenance of this information is critical to our operations and business strategy.
The goal of these agreements is to ensure that we are paid based on the ability of our commercially approved products to deliver results in the real world setting comparable to those demonstrated in clinical trials, and the agreements are structured to link the performance of our approved products in real-world use to financial terms.
The goal of these agreements is to ensure that we are paid based on the ability of our commercially approved products to deliver results in the real world setting comparable to those demonstrated in our clinical trials, and the agreements are structured to link the performance of our approved products in real-world use to financial terms.
In order to protect our proprietary technology and processes, we rely in part on confidentiality agreements with our collaborators, employees, consultants, CMOs, outside scientific collaborators and sponsored researchers, and other advisors. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information.
In order to protect our proprietary technology and processes, we rely in part on confidentiality agreements with our collaborators, employees, consultants, scientific advisors, CMOs, outside scientific collaborators and sponsored researchers, and other advisors. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information.
In addition, even if holders do not elect to convert their Notes, we could be required under applicable accounting rules to reclassify all or a portion of the outstanding principal of the Notes as a current rather than long-term liability, which would result in a material reduction of our net working capital.
In addition, even if holders do not elect to convert their Notes, we could be required under applicable accounting rules to reclassify all or a portion of the outstanding principal of the Notes as a current liability, rather than long-term liability, which would result in a material reduction of our net working capital.
Transactions relating to our Notes may affect the value of our common stock. The conversion of some or all of the Notes would dilute the ownership interests of existing stockholders to the extent we satisfy our conversion obligation by delivering shares of our common stock upon any conversion of such Notes.
Transactions relating to the Notes may affect the value of our common stock. The conversion of some or all of the Notes would dilute the ownership interests of existing stockholders to the extent we satisfy our conversion obligation by delivering shares of our common stock upon any conversion of such Notes.
Our Notes may become in the future convertible at the option of their holders under certain circumstances. If holders of our Notes elect to convert their notes, we may settle our conversion obligation by delivering to them a significant number of shares of our common stock, which would cause dilution to our existing stockholders.
The Notes may become in the future convertible at the option of their holders under certain circumstances. If holders of the Notes elect to convert their notes, we may settle our conversion obligation by delivering to them a significant number of shares of our common stock, which would cause dilution to our existing stockholders.
In addition, we, the FDA or other applicable regulatory authorities, or an IRB, or similar foreign review board or committee, may delay initiation of or suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks.
In addition, we, the FDA or other applicable regulatory authorities, or an institutional review board, or IRB, or similar foreign review board or committee, may delay initiation of or suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks.
If we are unsuccessful in accomplishing the objectives set forth above, we may not be able to develop product candidates, successfully commercialize our approved products or any future products, raise capital, if needed, repay our indebtedness, achieve financial self-sustainability or continue our operations. We have a history of losses and may never become and remain consistently profitable.
If we are unsuccessful in accomplishing the objectives set forth above, we may not be able to develop product candidates, successfully commercialize our approved products or any future products, raise capital, if needed, repay our indebtedness, achieve financial self-sustainability or continue our operations. We have a history of losses and may never become and remain profitable.
The cost to us of any litigation or other proceeding relating to intellectual property rights, even if resolved in our favor, could be substantial, and litigation would divert our management’s efforts. Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources.
The cost to us of any litigation or other proceeding relating to such intellectual property rights, even if resolved in our favor, could be substantial, and litigation would divert our management’s efforts. Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources.
If the payment we receive for our products, or the reimbursement provided for such products, is inadequate in light of our development and other costs, or if reimbursement is denied, our return on investment could be adversely affected. In addition, we have stated publicly that we intend to grow through continued scientific innovation rather than arbitrary price increases.
If the payment we receive for our products, or the reimbursement provided for such products, is inadequate in light of our significant development and other costs, or if reimbursement is denied, our return on investment could be adversely affected. In addition, we have stated publicly that we intend to grow through continued scientific innovation rather than arbitrary price increases.
In addition, as a result of agreements that we have entered into, Takeda has obtained a non-exclusive license, and Arrowhead, as the assignee of Novartis, has obtained specific exclusive licenses for 30 gene targets, that include access to certain aspects of our technology. We also compete with companies working to develop antisense-based drugs.
In addition, as a result of agreements that we have entered into, Takeda has obtained a non-exclusive license, and Arrowhead, as the assignee of Novartis, has obtained specific exclusive licenses for 30 gene targets, that include access to certain aspects of our technology. We and our collaborators also compete with companies working to develop antisense-based drugs.
While we believe 2019 was our peak operating loss year, we expect to continue to incur annual operating losses, and will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve self-sustainability by the end of 2025.
While we believe 2019 was our peak operating loss year, we expect to continue to incur annual operating losses, and will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve financial self-sustainability by the end of 2025.
Such competitors could also recruit our employees, which could negatively impact our level of expertise and the ability to execute on our business plan. Furthermore, we also face competition from existing and new treatment methods that reduce or eliminate the need for drugs, such as the use of advanced medical devices.
Such competitors could also recruit our employees, which could negatively impact our level of expertise and our ability to execute on our business plan. Furthermore, we and our collaborators also face competition from existing and new treatment methods that reduce or eliminate the need for drugs, such as the use of advanced medical devices.
Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the current U.S. presidential administration may reverse or otherwise change these measures, both the current U.S. presidential administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.
Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the current U.S. presidential administration may reverse or otherwise change these measures, both the current U.S. presidential administration and Congress have indicated that they will continue to seek new measures to control drug costs.
Accordingly, we have developed internal marketing, sales, market access and distribution capabilities as part of our core product strategy initially in the U.S., Europe and Japan, with expansion ongoing globally, which has, and will continue to, require significant financial and management resources.
Accordingly, we have developed internal marketing, sales, market access and distribution capabilities as part of our core product strategy initially in the U.S., Europe and Japan, with expansion ongoing globally, which has required, and will continue to require, significant financial and management resources.
Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. Open-label clinical trials may be subject to a “patient bias” where patients perceive their symptoms to have improved merely due to their awareness of receiving an experimental treatment.
Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. Accordingly, open-label clinical trials may be subject to a “patient bias” where patients perceive their symptoms to have improved merely due to their awareness of receiving an experimental treatment.
In July 2021, Novartis announced that the resubmission to the FDA of the inclisiran NDA to address the complete response letter was filed, and the FDA approved Leqvio (which is the trade name under which inclisiran is marketed in the U.S.) in December 2021. The delay in the approval of Leqvio resulted in delayed milestone and royalty revenue to us.
In July 2021, Novartis announced that the resubmission to the FDA of the inclisiran NDA to address the complete response letter was filed, and the FDA approved Leqvio (the trade name under which inclisiran is marketed in the U.S.) in December 2021. This delay in the approval of Leqvio resulted in delayed milestone and royalty revenue to us.
As our approved products are used commercially, we or others could identify previously unknown side effects or known side effects could be observed as being more frequent or severe than in clinical studies or earlier post-marketing periods, in which case: • sales of our approved products may be more modest than originally anticipated; • regulatory approvals for our approved products may be restricted or withdrawn; • we may decide, or be required, to send product warning letters or field alerts to physicians, pharmacists and hospitals; • additional nonclinical or clinical studies, changes in labeling, adoption of a REMS plan, or changes to manufacturing processes, specifications and/or facilities may be required; and • government investigations or lawsuits, including class action suits, may be brought against us.
As our approved products are used commercially, we or others could identify previously unknown side effects or known side effects could be observed as being more frequent or severe than in clinical studies or earlier post-marketing periods, in which case: • sales of our approved products may be lower than originally anticipated; • regulatory approvals for our approved products may be restricted or withdrawn; • we may decide, or be required, to send product warning letters or field alerts to physicians, pharmacists and hospitals; • additional nonclinical or clinical studies, changes in labeling, adoption of a REMS plan, or changes to manufacturing processes, specifications and/or facilities may be required; and/or • government investigations or lawsuits, including class action suits, may be brought against us.
There are many issued and pending patents that claim aspects of oligonucleotide chemistry and modifications that we may need for our siRNA products marketed by us or our licensees, our late-stage therapeutic candidates being developed by us or our licensees, including zilebesiran and fitusiran, as well as our other pipeline products.
There are many issued and pending patents that claim aspects of oligonucleotide chemistry and modifications that we may need for our siRNA products marketed by us or our licensees, our late-stage therapeutic candidates being developed by us or our collaborators, including zilebesiran and fitusiran, as well as our other pipeline products.
We have used substantial funds to develop our RNAi technologies and will require substantial funds to conduct further research and development, including pre-clinical testing and clinical trials of our product candidates, and to manufacture, market and sell our four approved products and any other products that are approved for commercial sale.
We have used substantial funds to develop our RNAi technologies and will require substantial funds to conduct further research and development activities, including pre-clinical testing and clinical trials of our product candidates, and to manufacture, market and sell our four approved products and any other products that are approved for commercial sale.
Moreover, any threatened or actual government enforcement actions or lawsuits by third parties could also generate adverse publicity, which could decrease demand for our products and require that we devote substantial resources that could be used productively on other aspects of our business.
Moreover, any threatened or actual government enforcement actions or lawsuits by third parties could also generate adverse publicity, which could decrease demand for our products and require that we devote substantial resources that otherwise could be used productively on other aspects of our business.
We are subject to governmental regulation and other legal obligations, particularly related to privacy, data protection and information security, and we are subject to consumer protection laws that regulate our marketing practices and prohibit unfair or deceptive acts or practices. Our actual or perceived failure to comply with such obligations could harm our business.
We are subject to governmental regulation and other legal obligations related to privacy, data protection and information security, and we are subject to consumer protection laws that regulate our marketing practices and prohibit unfair or deceptive acts or practices. Our actual or perceived failure to comply with such obligations could harm our business.
Moreover, eligibility for coverage does not imply that any drug will be reimbursed in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution or that covers a particular provider’s cost of acquiring the drug.
Moreover, eligibility for coverage does not imply that any drug will be reimbursed in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution or that covers a particular provider’s cost of acquiring the product.
Subsequent guidance published by the European Data Protection Board in June 2021 described what such supplementary measures must be, and stated that businesses should avoid or cease transfers of personal data if, in the absence of supplementary measures, equivalent protections cannot be afforded.
Subsequent guidance published by the European Data Protection Board, or EDPB, in June 2021 described what such supplementary measures must be, and stated that businesses should avoid or cease transfers of personal data if, in the absence of supplementary measures, equivalent protections cannot be afforded.
Our success will depend in part on the ability of our licensors to obtain, maintain and enforce patent protection for our licensed intellectual property, in particular, those patents to which we have secured exclusive rights. Our licensors may not successfully prosecute the patent applications to which we are licensed.
Our success will depend in part on the ability of our licensors to obtain, maintain and enforce patent protection for our licensed intellectual property, in particular, those patents to which we have secured exclusive rights. Our licensors may not successfully prosecute the patent applications we have licensed.
Misconduct by employees could include intentional failures to comply with governmental regulations, comply with healthcare fraud and abuse and anti-kickback laws and regulations in the U.S. and abroad, or failure to report financial information or data accurately or disclose unauthorized activities to us.
Misconduct by employees could include intentional failures to comply with governmental regulations, including healthcare fraud and abuse and anti-kickback laws and regulations in the U.S. and abroad, or failure to report financial information or data accurately or disclose unauthorized activities to us.
If, for any reason, our revenues and/or expenses differ materially from our guidance, we may have to adjust our publicly announced financial guidance. For example, in April 2022, we decreased our 2022 guidance range for combined net product revenues, and in October 2022, we decreased our guidance range for our collaboration and royalty revenue.
If, for any reason, our product sales, revenues and/or expenses differ materially from our guidance, we may have to adjust our publicly announced financial guidance. For example, in April 2022, we decreased our 2022 guidance range for combined net product revenues, and in October 2022, we decreased our guidance range for our collaboration and royalty revenue.
In developing manufacturing capabilities by building our own manufacturing facilities, we have incurred substantial expenditures, and expect to incur significant additional expenditures in the future. Also, we have had to, and will likely need to continue to, hire and train qualified employees to staff our facilities.
In developing manufacturing capabilities by building our own manufacturing facilities, we have incurred substantial expenditures, and expect to incur significant additional expenditures in the future. Also, we have had to, and will likely need to continue to, recruit, hire, and train qualified employees to staff our facilities.
However, donations to patient assistance programs have received some negative publicity and have been the subject of multiple government enforcement actions, related to allegations regarding their use to promote branded pharmaceutical products over other less costly alternatives.
However, donations to patient assistance programs have received negative publicity and have been the subject of multiple government enforcement actions, related to allegations regarding their use to promote branded pharmaceutical products over other less costly alternatives.
If our significant stockholders, or we or our officers and directors, sell substantial amounts of our common stock in the public market, or there is a perception that such sales may occur, the market price of our common stock could be adversely affected.
If we, our officers or directors, or our significant stockholders sell substantial amounts of our common stock in the public market, or there is a perception that such sales may occur, the market price of our common stock could be adversely affected.
State and foreign laws also govern the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
State and foreign laws also govern the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating our compliance efforts.
For certain product candidates, we have formed collaborations to fund all or part of the costs of drug development and commercialization, such as our collaborations with Regeneron, Novartis, Vir, Dicerna and Sanofi.
For certain product candidates, we have formed collaborations to fund all or part of the costs of drug development and commercialization, such as our collaborations with Regeneron, Roche, Novartis, Vir, Dicerna and Sanofi.
In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, plan as part of an NDA, or after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll in a registry.
In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, plan as part of its review of an NDA, or after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll in a registry.
If our present or future collaborators fail to file and prosecute all necessary and desirable patent applications at a reasonable cost and in a timely manner, our business may be adversely affected.
If we or our present or future collaborators fail to file and prosecute all necessary and desirable patent applications at a reasonable cost and in a timely manner, our business may be adversely affected.
Specifically, we have a portfolio of patents, patent applications and other intellectual property covering: fundamental aspects of the structure and uses of siRNAs, including their use as therapeutics, and RNAi-related mechanisms; chemical modifications to siRNAs that improve their suitability for therapeutic and other uses; siRNAs directed to specific targets as treatments for particular diseases; delivery technologies, such as in the fields of carbohydrate conjugates and cationic liposomes; and all aspects of our specific development candidates.
Specifically, we have a portfolio of patents, patent applications and other intellectual property covering, among other things: fundamental aspects of the structure and uses of siRNAs, including their use as therapeutics, and RNAi-related mechanisms; chemical modifications to siRNAs that improve their suitability for therapeutic and other uses; siRNAs directed to specific targets as treatments for particular diseases; delivery technologies, such as in the fields of carbohydrate conjugates and cationic liposomes; and all aspects of our specific development candidates.
While Leqvio was approved by the FDA in December 2021, the resolution of the complete response letter resulted in a delay in the payment of an approval milestone and potential U.S. royalties.
While Leqvio was ultimately approved by the FDA in December 2021, the resolution of the complete response letter resulted in a delay in the payment of an approval milestone and potential U.S. royalties.
We also have very limited experience in such scale-up and manufacturing, requiring us to depend on a limited number of third parties, who might not be able to deliver in a timely manner, or at all. Failure by manufacturers to properly manufacture our delivery technology and/or formulate our siRNAs for delivery could result in unusable product, supply delays and shortages.
We also have limited experience in such scale-up and manufacturing, requiring us to depend on a limited number of third parties, who might not be able to deliver in a timely manner, or at all. Failure by manufacturers to properly manufacture our delivery technology and/or formulate our siRNAs for delivery could result in unusable product, supply delays and drug shortages.
In addition, there may be issued and pending patent applications that may be asserted against us in a court proceeding or otherwise based upon the asserting party’s belief that we may need such patents for our siRNA therapeutic candidates or marketed products, or to further develop and commercialize future products, or to continue to develop candidates in our pipeline that are being developed by us or our licensees.
In addition, there may be issued and pending patent applications that may be asserted against us in a court proceeding or otherwise based upon the asserting party’s belief that we may need such patents for our siRNA therapeutic candidates or marketed products, or to further develop and commercialize future products, or to continue to develop candidates in our pipeline that are being developed by us or our collaborators.
For example, in October 2017 Silence sued us in the UK alleging that ONPATTRO and other investigational RNAi therapeutics we or MDCO are developing infringed one or more Silence patents. In December 2018 we and Silence settled all ongoing litigation between us. A third party may also claim that we have improperly obtained or used its confidential or proprietary information.
For example, in October 2017 Silence sued us in the UK alleging that ONPATTRO and other investigational RNAi therapeutics we or MDCO were developing infringed one or more Silence patents. In December 2018 we and Silence settled all ongoing litigation between us. A third party may also claim that we have improperly obtained or used its confidential or proprietary information.
We might obtain regulatory approval for a product, including one or more of our approved products, in a particular country, but then be subject to price regulations that delay our commercial launch of the product and negatively impact the revenues we are able to generate from the sale of the product in that country and potentially in other countries due to reference pricing.
We might also obtain regulatory approval for a product, including one or more of our approved products, in a particular country, but then be subject to price regulations or price controls that delay our commercial launch of the product and/or negatively impact the revenues we are able to generate from the sale of the product in that country and potentially in other countries due to reference pricing.
If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S. or foreign jurisdictions in which we may seek to market our products, we or they may be subject to, among other 60 Table of Contents things, fines, warning letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.
If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S. or foreign jurisdictions in which we seek to market our products, we or they may be subject to, among other things, fines, warning letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.
Nonclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome, and the historical failure rate for product candidates is high. We currently have multiple programs in clinical development, including internal and partnered programs in Phase 3 development, as well as several earlier-stage clinical programs.
Nonclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome, and the historical failure rate for product candidates is high. We currently have multiple programs in clinical development, including internal and collaborated programs in Phase 3 development, as well as several earlier-stage clinical programs.
We remain focused on these laws and the activities they regulate and, as detailed above, maintain a global compliance program designed to empower our business to operate in compliance with their requirements. Governments outside the U.S. may impose strict price controls, which may adversely affect our revenues.
We remain focused on these laws and the activities they regulate and, as detailed below, maintain a global compliance program designed to empower our business to operate in compliance with their requirements. Governments outside the U.S. may impose strict price controls, which may adversely affect our revenues.
If we are unable to obtain additional funding on a timely basis, we may be required to significantly delay or curtail one or more of our research or development programs, or delay or curtail the further development of our global commercial infrastructure, and our ability to achieve our long-term strategic goals may be delayed or diminished.
If we require additional funding and are unable to obtain such funding on a timely basis, we may be required to significantly delay or curtail one or more of our research or development programs, or delay or curtail the further development of our global commercial infrastructure, and our ability to achieve our long-term strategic goals may be delayed or diminished.
For example, during 2017 and 2018, Silence filed claims in several jurisdictions, including the High Court of England and Wales, and named us and our wholly owned subsidiary Alnylam UK Ltd. as co-defendants. Silence alleged various claims, including that ONPATTRO infringed one or more Silence patents.
For example, during 2017 and 2018, Silence Therapeutics, plc, or Silence, filed claims in several jurisdictions, including the High Court of England and Wales, and named us and our wholly owned subsidiary Alnylam UK Ltd. as co-defendants. Silence alleged various claims, including that ONPATTRO infringed one or more Silence patents.
Although we depend heavily on these parties, we control only certain aspects of their activity and therefore, we cannot be assured that these third parties will adequately perform all of their contractual obligations to us in compliance with regulatory and other legal requirements and our internal policies and procedures.
Although we depend heavily on these parties, we control only limited aspects of their activity and therefore, we cannot be assured that these third parties will adequately perform all of their contractual obligations to us in compliance with regulatory and other legal requirements and our internal policies and procedures.
Although our investigational RNAi therapeutics have been generally well-tolerated in our clinical trials to date, new safety findings may emerge.
Although our RNAi therapeutics have been generally well-tolerated in our clinical trials to date, new safety findings may emerge.
For example, in June 2018, Ionis sent us a notice claiming that it was owed payments under our second amended and restated strategic collaboration and license agreement as a result of the January 2018 amendment of our collaboration agreement with Sanofi and the related Exclusive TTR License and AT3 License Terms.
For example, in June 2018, Ionis sent us a notice claiming that it was owed payments under our second amended and restated strategic collaboration and license agreement as a result of the January 2018 restructuring of our collaboration agreement with Sanofi and the related Exclusive TTR License and AT3 License Terms.
The arbitration panel issued its final award in December 2020, which ruled in favor of Ionis’s request for a TAF on certain rights the panel determined we received in the Sanofi restructuring (but rejecting the TAF amount sought by Ionis), and in favor of us in denying Ionis’s request for a TAF on a milestone payment received by us in the same restructuring.
The arbitration panel issued its final award in December 2020, which ruled in favor of Ionis’s request for a TAF on certain rights the panel determined we received in the Sanofi restructuring (but rejected the TAF amount sought by Ionis), and in favor of us in denying Ionis’s request for a TAF on a milestone payment received by us in the same restructuring.
For example, it could: • make us more vulnerable to adverse changes in general U.S. and worldwide economic, industry and competitive conditions and adverse changes in government regulation; • limit our flexibility in planning for, or reacting to, changes in our business and our industry; • place us at a disadvantage compared to our competitors who have less debt; 79 Table of Contents • limit our ability to borrow additional amounts to fund acquisitions, for working capital and for other general corporate purposes; and • make an acquisition of our company less attractive or more difficult.
For example, it could: • make us more vulnerable to adverse changes in general U.S. and worldwide economic, industry and competitive conditions and adverse changes in government regulation; • limit our flexibility in planning for, or reacting to, changes in our business and our industry; • place us at a disadvantage compared to our competitors who have less debt; • limit our ability to borrow additional amounts to fund acquisitions, for working capital and for other general corporate purposes; and • make an acquisition of our company less attractive or more difficult.
We or our partners may also encounter unexpected delays or increased costs due to new government regulations, for example, from future legislation or administrative action, or from changes in FDA policy during the period of product development, clinical trials and FDA regulatory review.
We or our collaborators may also encounter unexpected delays or increased costs due to new government regulations, for example, from future legislation or administrative action, or from changes in FDA policy during the period of product development, clinical trials and FDA regulatory review.
Although to date we have launched four products in the U.S., EU and various other countries globally, and expect to launch our commercially approved products in additional countries during 2023 and beyond, we may never attain profitability or positive cash flow from operations.
Although to date we have launched four products in the U.S., EU and various other countries globally, and expect to launch our commercially approved products in additional countries during 2024 and beyond, we may never attain profitability or positive cash flow from operations.
Specifically, we have stated that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers (approximately 6.4% currently) absent a significant value driver.
Specifically, we have stated that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers (approximately 3.4% currently) ) absent a significant value driver.
Some state laws also require pharmaceutical manufacturers to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, in addition to requiring manufacturers to report information related to payments to physicians and other healthcare provides or marketing expenditures and pricing information.
Some state laws also require pharmaceutical manufacturers to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, in addition to requiring manufacturers to report information related to payments to physicians and other healthcare providers or marketing expenditures and pricing information.
EEA Member States have adopted implementing national laws to implement the GDPR which may partially deviate from the GDPR and the competent authorities in the EEA Member States may interpret GDPR obligations slightly differently from country to country, so that we do not expect to operate in a uniform legal landscape in the EU.
EEA Member States have adopted implementing national laws to implement the GDPR which may partially deviate from the GDPR and the competent authorities in the EEA Member States may interpret GDPR obligations slightly differently from country to country, and we do not expect to operate in a uniform legal landscape in the EU.
Some of these companies are seeking, as we are, to develop chemically synthesized siRNAs as drugs. Others are following a gene therapy approach, with the goal of treating patients not with synthetic siRNAs but with synthetic, exogenously-introduced genes designed to produce siRNA-like molecules within cells.
Some of these companies are seeking, as we are, to develop chemically synthesized siRNAs as drugs. Others are following a gene therapy approach, with the goal of treating patients with synthetic, exogenously-introduced genes designed to produce siRNA-like molecules within cells.
Our estimates regarding the potential market size for ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or any future products at the time we commence commercialization, may be materially different from the actual market size, including as a result of the indication approved by regulatory authorities, which could result in significant changes in our business plan and may have a material adverse effect on our results of operations and financial condition.
Our estimates regarding the potential market size for ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or any future products at the time we commence commercialization, may be materially different from the actual market size, including as a result of the indication approved by regulatory authorities, which could result in significant changes in our business plan and may have a material adverse effect on our business, prospects, operating results and financial condition.
Other factors that we believe will materially affect market acceptance of our product candidates include: • the timing of our receipt of any marketing approvals, the terms of any approvals and the countries in which approvals are obtained; 61 Table of Contents • the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • relative convenience and ease of administration of our product candidates; • the willingness of patients to accept potentially new routes of administration or new or different therapeutic approaches and mechanisms of action; • the success of our physician education programs; • the availability of adequate government and third-party payor reimbursement; • the pricing of our products, particularly as compared to alternative treatments, and the market perception of such prices and any price increase that we may implement in the future; and • availability of alternative effective treatments for the diseases that product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
Other factors we believe will materially affect market acceptance of our products include: • the timing of our receipt of any marketing approvals, the terms of any approvals and the countries in which approvals are obtained; • the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • relative convenience, dosing regimen and ease of administration of our product candidates; • the willingness of patients to accept potentially new routes of administration or new or different therapeutic approaches and mechanisms of action; • the success of our physician education programs; • the availability of adequate government and third-party payor reimbursement; • the pricing of our products, particularly as compared to alternative treatments, and the market perception of such prices and any price increase that we may implement in the future; and • availability of alternative effective treatments for the diseases that our product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
If such owners do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, our competitive position and business prospects may be harmed. • Other companies or organizations may challenge our patent rights or may assert patent rights that prevent us from developing and commercializing our products. • If we become involved in intellectual property litigation or other proceedings related to a determination of rights, including our ongoing patent infringement litigation against Pfizer, Inc., or Pfizer, and Moderna, Inc., we could incur 45 Table of Contents substantial costs and expenses, and in the case of such litigation or proceedings against us, substantial liability for damages or be required to stop our product development and commercialization efforts. • If we fail to comply with our obligations under any licenses or related agreements, we may be required to pay damages and could lose license or other rights that are necessary for developing, commercializing and protecting our RNAi technology.
If such owners do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, our competitive position may be harmed. • Other companies or organizations may challenge our patent rights or may assert patent rights that prevent us from developing and commercializing our products. • If we become involved in intellectual property litigation or other proceedings related to a determination of rights, including our ongoing patent infringement litigation against Pfizer, Inc., or Pfizer, and Moderna, Inc., or Moderna, we could incur substantial costs and expenses, and in the case of such litigation or proceedings against us, substantial liability for damages or be required to stop our product development and commercialization efforts. • If we fail to comply with our obligations under any licenses or related agreements, we may be required to pay damages and could lose license or other rights that are necessary for developing, commercializing and protecting our RNAi technology.
In addition to the competition we face from competing drugs in general, we also face competition from other companies working to develop novel drugs using technology that competes more directly with our own. We are aware of several other companies that are working to develop RNAi therapeutic products.
In addition to the competition we face from competing drugs in general, we and our collaborators also face competition from other companies working to develop novel drugs using technology that competes more directly with our own. We are aware of several other companies that are working to develop RNAi therapeutic products.
For example, in April 2022, due to an amendment to our existing regulatory submission to address a pending inspection classification at a third-party secondary packaging and labeling facility, the FDA extended the review timeline of the NDA for vutrisiran.
For example, in April 2022, due to an amendment to our vutrisiran NDA submission to address a pending inspection classification at a third-party secondary packaging and labeling facility, the FDA extended the review timeline of the NDA.
Utah was seeking correction of inventorship of the Tuschl patents, unspecified damages and other relief. After several years of court proceedings and discovery, the court granted our motions for summary judgment, and dismissed Utah’s state law damages claims as well.
Utah was seeking correction of inventorship of the Tuschl patents, unspecified damages and other relief. After several years of court proceedings and discovery, the court granted our motions for summary judgment and dismissed Utah’s state law damages claims.
During the pendency of this litigation, as well as the Dicerna litigation described above, we incurred significant costs, and in each case, the litigation diverted the attention of our management and other resources that would otherwise have been engaged in other activities.
During the pendency of this litigation, as well as the Dicerna litigation described below, we incurred significant costs, and in each case, the litigation diverted the attention of our management and other resources that would otherwise have been engaged in other activities.
Under that method, diluted earnings per share would generally be calculated assuming that all the Notes were converted solely into shares of common stock at the beginning of the reporting period, unless the result would be anti-dilutive.
Under this method, diluted earnings per share is generally calculated assuming that all the Notes were converted solely into shares of common stock at the beginning of the reporting period, unless the result would be anti-dilutive.
Our and our partnered product candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, pricing, marketing and distribution of drugs.
Our and our collaborated product candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, pricing, marketing and distribution of drugs.
The lack of policies, practices or guidelines may hinder or slow review by the FDA of any regulatory filings that we or our partners may submit. Moreover, the FDA may respond to these submissions by defining requirements we or our partners may not have anticipated.
The lack of policies, practices or guidelines may hinder or slow review by the FDA of any regulatory filings that we or our collaborators may submit. Moreover, the FDA may respond to these submissions by defining requirements we or our collaborators may not have anticipated.
For those products for which we will perform marketing, sales, market access and distribution functions ourselves, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and for future products we successfully develop where we may retain certain product development and commercialization rights, we could face a number of additional risks, including: • scaling and retaining our global sales, marketing and administrative infrastructure and capabilities; • hiring, training, managing and supervising our personnel worldwide; • the cost of further developing, or leveraging an established, marketing or sales force, which may not be justifiable in light of the revenues generated by any particular product and/or in any specific geographic region; and • our direct sales and marketing efforts may not be successful.
For those products for which we will perform marketing, sales, market access and distribution functions ourselves, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and for future products we successfully develop with respect to which we retain development and commercialization rights, we could face a number of additional risks, including: • scaling and retaining our global sales, marketing and administrative infrastructure and capabilities; • hiring, training, managing and supervising our personnel worldwide; • the cost of further developing, or leveraging an established, marketing or sales force, which may not be justifiable in light of the revenues generated by any particular product and/or in any specific geographic region; and • our direct sales and marketing efforts may not be successful.
Corporate notes may also include foreign bonds denominated in U.S. dollars. These investments are subject to general credit, liquidity, market and interest rate risks. We may realize losses in the fair value of these investments or a complete loss of these investments, which would have a negative effect on our consolidated financial statements.
Corporate notes may also include foreign bonds denominated in U.S. dollars. These investments are subject to general credit, liquidity, market and interest rate risks. We may realize losses in the fair value of these investments or a complete loss of these investments, which would have a negative effect on our financial condition.
While the e-Privacy Regulation was originally intended to be adopted on May 25, 2018 (alongside the GDPR), it is still going through the European legislative process. Draft regulations were rejected by the Permanent Representatives Committee of the Council of EU on November 22, 2019; it is not clear when new regulations will be adopted.
While the e-Privacy Regulation was originally intended to be adopted on May 25, 2018 (alongside the GDPR), it is still going through the European legislative process. Draft regulations were rejected by the Permanent Representatives Committee of the Council of EU on November 22, 2019; it is not clear when, or even if, new regulations will be adopted.
If we or any of our CROs fail to comply with applicable GCP requirements, or fail to take any such corrective action, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, the EMA, the PMDA in Japan or comparable foreign regulatory authorities may require us to take additional action or perform additional clinical trials before approving our marketing applications.
If we or any of our CROs fail to comply with applicable GCP requirements, or fail to take any such corrective action, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, EMA, PMDA or other foreign regulatory authorities may require us to take additional action or perform additional clinical trials before approving our marketing applications.
Failure to obtain and maintain all available regulatory exclusivities, broad patent scope and to maximize patent term restoration or extension on patents covering our products may lead to loss of exclusivity and early generic entry resulting in a loss of market share and/or revenue. We license patent rights from third-party owners.
Failure to obtain and maintain broad patent scope and all available regulatory exclusivities and to maximize patent term restoration or extension on patents covering our product candidates and products may lead to loss of exclusivity and generic entry resulting in a loss of market share and/or revenue. We license patent rights from third-party owners.
These laws and regulations include: • The U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, the purchase, lease, order, arrangement, or recommendation of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs.
Restrictions under applicable federal and state healthcare laws and regulations include the following: • The U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, the purchase, lease, order, arrangement, or recommendation of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs.
In either instance, these limitations and restrictions may limit the size of the market for the product and affect reimbursement by third-party payors. We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement.
In either instance, these limitations and restrictions may limit the size of the market for our products and affect reimbursement by third-party payors. We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement.
For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical study or to report an alleged AE.
For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical study or to report an alleged adverse event, or AE.
If we or our collaborators, CMOs or service providers fail to comply with healthcare laws and regulations, or legal obligations related to privacy, data protection and information security, we or they could be subject to enforcement actions, which could affect our ability to develop, market and sell our products and may harm our reputation.
If we or our collaborators, CMOs or service providers fail to comply with healthcare laws and regulations, or legal obligations related to privacy, data protection and information security, we or they could be subject to enforcement actions, which could negatively impact our ability to develop, market and sell our products and may harm our reputation.

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Item 2. Properties

Properties — owned and leased real estate

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Biggest changeIn addition, we have a separate lease agreement for the 10th floor at 101 Main Street, which expires in March 2024. ** We manufacture ONPATTRO (patisiran) formulated bulk drug product at this location. In addition to the locations above, we also occupy small offices in multiple locations in and outside of the U.S. to support our operations and growth.
Biggest changeIn addition, we have a separate lease agreement for the 10th floor at 101 Main Street, which expires in March 2024 and will not be extended. ** We manufacture ONPATTRO (patisiran) formulated bulk drug product at this location.
ITEM 2. PROPERTIES Our operations are based primarily in Cambridge, Massachusetts; Zug, Switzerland; Maidenhead, United Kingdom; Amsterdam, Netherlands; and Tokyo, Japan. A description of certain of the facilities we lease or own as of January 31, 2023 is included in the table below. Location Primary Use Approximate Square Footage Lease Expiration Date Renewal Option 675 West Kendall Street Henri A.
ITEM 2. PROPERTIES Our operations are based primarily in Cambridge, Massachusetts; Zug, Switzerland; Maidenhead, United Kingdom; Amsterdam, Netherlands; and Tokyo, Japan. A description of certain of the facilities we lease or own as of January 31, 2024 is included in the table below. Location Primary Use Approximate Square Footage Lease Expiration Date Renewal Option 675 West Kendall Street Henri A.
Termeer Square Cambridge, Massachusetts Corporate headquarters and primary research facility 295,000 January 2034 Two five-year terms 300 Third Street Cambridge, Massachusetts Office space and additional research facility 129,000 January 2034 Two five-year terms 101 Main Street Cambridge, Massachusetts Office space* 61,000 March 2024 and June 2026 One five-year term on each lease 20 Commerce Way Norton, Massachusetts cGMP manufacturing 200,000 Not applicable Not applicable 665 Concord Avenue Cambridge, Massachusetts cGMP manufacturing** 15,000 September 2027 One five-year term Grafenauweg 4 6300 Zug, Switzerland International headquarters 14,500 March 2028 One five-year term Braywick Gate Braywick Road, Maidenhead Berkshire, United Kingdom Office space 21,500 May 2026 None Wisdom Cross Tower Antonio Vivaldistraat 150 Amsterdam, Netherlands Office space 12,500 April 2025 One five-year term Pacific Century Place 1-Chome-11-1 Marunouchi Chiyoda-ku Tokyo, Japan Office space 16,900 May 2025 None _________________________________________ 81 Table of Contents * We lease office space located on the 12th and 13th floors at 101 Main Street, Cambridge, Massachusetts under a non-cancelable real property lease agreement by and between the Company and RREEF America REIT II CORP.
Termeer Square Cambridge, Massachusetts Corporate headquarters and primary research facility 295,000 January 2034 Two five-year terms 300 Third Street Cambridge, Massachusetts Office space and additional research facility 129,000 January 2034 Two five-year terms 101 Main Street Cambridge, Massachusetts Office space* 61,000 March 2024 and June 2026 One five-year term on each lease 20 Commerce Way Norton, Massachusetts GMP manufacturing 200,000 Not applicable Not applicable 665 Concord Avenue Cambridge, Massachusetts GMP manufacturing** 15,000 September 2027 One five-year term Grafenauweg 4 6300 Zug, Switzerland International headquarters 14,500 March 2028 One five-year term Braywick Gate Braywick Road, Maidenhead Berkshire, United Kingdom Office space 21,500 May 2026 None Wisdom Cross Tower Antonio Vivaldistraat 150 Amsterdam, Netherlands Office space 12,500 April 2025 One five-year term Pacific Century Place 1-Chome-11-1 Marunouchi Chiyoda-ku Tokyo, Japan Office space 16,900 May 2025 None _________________________________________ * We lease office space located on the 12th and 13th floors at 101 Main Street, Cambridge, Massachusetts under a non-cancelable real property lease agreement by and between the Company and RREEF America REIT II CORP.
In the future, we may lease, operate, purchase or construct additional facilities in which to conduct expanded research, development and manufacturing activities and support future commercial operations.
In addition to the locations above, we also occupy small offices in multiple locations in and outside of the U.S. to support our operations and growth. In the future, we may lease, operate, purchase or construct additional facilities in which to conduct expanded research, development and manufacturing activities and support future commercial operations.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeITEM 3. LEGAL PROCEEDINGS For a discussion of material pending legal proceedings, please read the section titled "Litigation" within Note 14, Commitments and Contingencies, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this Annual Report on Form 10-K, which is incorporated into this item by reference. ITEM 4.
Biggest changeITEM 3. LEGAL PROCEEDINGS For a discussion of material pending legal proceedings, please read the section titled “Litigation” within Note 13, Commitments and Contingencies, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K, which is incorporated into this item by reference. ITEM 4.
MINE SAFETY DISCLOSURES Not applicable. 82 Table of Contents PART II
MINE SAFETY DISCLOSURES Not applicable. 81 Table of Con tents PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeIssuer Purchases of Equity Securities The following table provides information about our purchases of shares of Alnylam common stock during the three-month period ended December 31, 2022: Period Total Number of Shares Purchased (1) Average Price per Share Total Number of Shares Purchased as Part of Publicly Announced Plans or Programs Maximum Number (or Approximated Dollar Value) of Shares that May Yet Be Purchased Under the Plans or Programs October 1, 2022 - October 31, 2022 — $ — — — November 1, 2022 - November 30, 2022 — — — — December 1, 2022 - December 31, 2022 3,182 231.84 — — Total 3,182 $ 231.84 — — (1) Share repurchases reported in this column consist of shares of Alnylam's common stock tendered by employees in December 2022 to cover the exercise price of certain stock options exercised by those employees. 83 Table of Contents Stock Performance Graph The following performance graph and related information shall not be deemed “soliciting material” or to be “filed” with the SEC, nor shall such information be incorporated by reference into any future filing under the Securities Act of 1933 or Securities Exchange Act of 1934, each as amended, except to the extent that we specifically incorporate it by reference into such filing.
Biggest changeStock Performance Graph The following performance graph and related information shall not be deemed “soliciting material” or to be “filed” with the Securities and Exchange Commission, or SEC, nor shall such information be incorporated by reference into any future filing under the Securities Act of 1933 or Securities Exchange Act of 1934, each as amended, except to the extent that we specifically incorporate it by reference into such filing.
ITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES Market Information Our common stock trades on The Nasdaq Global Select Market under the symbol “ALNY.” Holders of Record At January 31, 2023, there were 24 holders of record of our common stock.
ITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES Market Information Our common stock trades on The Nasdaq Global Select Market under the symbol “ALNY.” Holders of Record At January 31, 2024, there were 24 holders of record of our common stock.
The comparative stock performance graph below compares the five-year cumulative total stockholder return (assuming reinvestment of dividends, if any) from investing $100 on the last trading day of 2017, to the close of the last trading day of 2022, in each of our common stock and the selected indices.
The comparative stock performance graph below compares the five-year cumulative total stockholder return (assuming reinvestment of dividends, if any) from investing $100 on the last trading day of 2018, to the close of the last trading day of 2023, in each of our common stock and the selected indices.
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The stock price performance reflected in the graph below is not necessarily indicative of future price performance.
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The stock price performance reflected in the graph below is not necessarily indicative of future price performance. 82 Table of Con tents Comparison of Five-Year Cumulative Total Return Among Alnylam Pharmaceuticals, Inc., Nasdaq Composite Total Return and Nasdaq Biotechnology Total Return 12/31/2018 12/31/2019 12/31/2020 12/31/2021 12/30/2022 12/29/2023 Alnylam Pharmaceuticals, Inc. $ 100.00 $ 157.96 $ 178.26 $ 232.59 $ 325.95 $ 262.53 Nasdaq Composite Total Return $ 100.00 $ 136.69 $ 198.10 $ 242.03 $ 163.28 $ 236.17 Nasdaq Biotechnology Total Return $ 100.00 $ 125.11 $ 158.17 $ 158.20 $ 142.19 $ 148.72 ITEM 6.
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Comparison of Five-Year Cumulative Total Return Among Alnylam Pharmaceuticals, Inc., Nasdaq Composite Total Return and Nasdaq Biotechnology Total Return 12/29/2017 12/31/2018 12/31/2019 12/31/2020 12/31/2021 12/30/2022 Alnylam Pharmaceuticals, Inc. $ 100.00 $ 57.39 $ 90.65 $ 102.30 $ 133.48 $ 187.05 Nasdaq Composite Total Return $ 100.00 $ 97.16 $ 132.81 $ 192.47 $ 235.15 $ 158.65 Nasdaq Biotechnology Total Return $ 100.00 $ 91.14 $ 114.02 $ 144.15 $ 144.18 $ 129.59 ITEM 6.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeDiscussion of Results of Operations Revenues Total revenues consist of the following: Years Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Net product revenues $ 894,329 $ 662,138 $ 361,520 $ 232,191 35 % $ 300,618 83 % Net revenues from collaborations 134,912 180,953 131,333 (46,041) (25) % 49,620 38 % Royalty revenue 8,177 1,196 — 6,981 584 % 1,196 N/A Total $ 1,037,418 $ 844,287 $ 492,853 $ 193,131 23 % $ 351,434 71 % 85 Table of Contents Net Product Revenues Net product revenues consist of the following, by product and region: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change ONPATTRO United States $ 246,748 $ 213,210 $ 151,574 $ 33,538 16 % $ 61,636 41 % Europe 224,063 190,435 107,755 33,628 18 % 82,680 77 % Rest of World 86,797 71,092 46,752 15,705 22 % 24,340 52 % Total 557,608 474,737 306,081 82,871 17 % 168,656 55 % AMVUTTRA United States 82,521 — — 82,521 N/A — N/A Europe 4,214 — — 4,214 N/A — N/A Rest of World 7,060 — — 7,060 N/A — N/A Total 93,795 — — 93,795 N/A — N/A GIVLAARI United States 115,659 92,747 42,797 22,912 25 % 49,950 117 % Europe 48,670 30,895 12,000 17,775 58 % 18,895 157 % Rest of World 8,815 4,173 309 4,642 111 % 3,864 1,250 % Total 173,144 127,815 55,106 45,329 35 % 72,709 132 % OXLUMO United States 27,698 18,876 — 8,822 47 % 18,876 N/A Europe 37,915 38,949 333 (1,034) (3) % 38,616 11,596 % Rest of World 4,169 1,761 — 2,408 137 % 1,761 N/A Total 69,782 59,586 333 10,196 17 % 59,253 17,794 % Total net product revenues $ 894,329 $ 662,138 $ 361,520 $ 232,191 35 % $ 300,618 83 % Net product revenues increased during the year ended December 31, 2022, compared to the year ended December 31, 2021, primarily as a result of increased patients across our commercial portfolio of products, including the initial launch of AMVUTTRA.
Biggest changeDiscussion of Results of Operations Revenues Total revenues consist of the following: Years Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Net product revenues $ 1,241,474 $ 894,329 $ 662,138 $ 347,145 39 % $ 232,191 35 % Net revenues from collaborations 546,185 134,912 180,953 411,273 305 % (46,041) (25) % Royalty revenue 40,633 8,177 1,196 32,456 397 % 6,981 * Total $ 1,828,292 $ 1,037,418 $ 844,287 $ 790,874 76 % $ 193,131 23 % * Indicates the percentage change period over period is greater than 500%. 84 Table of Con tents Net Product Revenues Net product revenues consist of the following, by product and region: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change ONPATTRO United States $ 97,739 $ 246,748 $ 213,210 $ (149,009) (60) % $ 33,538 16 % Europe 210,916 224,063 190,435 (13,147) (6) % 33,628 18 % Rest of World 45,891 86,797 71,092 (40,906) (47) % 15,705 22 % Total 354,546 557,608 474,737 (203,062) (36) % 82,871 17 % AMVUTTRA United States 411,169 82,521 — 328,648 398 % 82,521 N/A Europe 70,898 4,214 — 66,684 * 4,214 N/A Rest of World 75,771 7,060 — 68,711 * 7,060 N/A Total 557,838 93,795 — 464,043 495 % 93,795 N/A GIVLAARI United States 141,954 115,659 92,747 26,295 23 % 22,912 25 % Europe 57,498 48,670 30,895 8,828 18 % 17,775 58 % Rest of World 19,799 8,815 4,173 10,984 125 % 4,642 111 % Total 219,251 173,144 127,815 46,107 27 % 45,329 35 % OXLUMO United States 38,159 27,698 18,876 10,461 38 % 8,822 47 % Europe 60,025 37,915 38,949 22,110 58 % (1,034) (3) % Rest of World 11,655 4,169 1,761 7,486 180 % 2,408 137 % Total 109,839 69,782 59,586 40,057 57 % 10,196 17 % Total net product revenues $ 1,241,474 $ 894,329 $ 662,138 $ 347,145 39 % $ 232,191 35 % Net product revenues increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to the launch of AMVUTTRA in the third quarter of 2022, partially offset by a decrease of demand for ONPATTRO due to patient switches to AMVUTTRA.
However, our ongoing development efforts may not be successful and we may not be able to commence sales of any other products or successfully expand the indications for our approved products, including ONPATTRO and AMVUTTRA in the future.
However, our ongoing development efforts may not be successful and we may not be able to commence sales of any other products or successfully expand the approved indications for our approved products, including AMVUTTRA, in the future.
Third-party forecasts are updated periodically as new data is obtained with regards to Leqvio's global launch progress or as sales information becomes available. Increases, decreases or a shift in timing of estimated revenues affects the interest rate utilized in the calculation of the liability related to the sale of future royalties.
Third-party forecasts are updated periodically as new data is obtained with respect to Leqvio’s global launch progress or as sales information becomes available. Increases, decreases or a shift in timing of estimated revenues affects the interest rate utilized in the calculation of the liability related to the sale of future royalties.
We use the expected value method to estimate variable consideration for chargebacks, certain rebates, and other incentives and we use the most likely amount method for certain rebates and trade discounts and allowances. A 10% increase or decrease in these estimates impacts net sales by a corresponding increase or decrease of approximately $7.0 million.
We use the expected value method to estimate variable consideration for chargebacks, certain rebates, and other incentives and we use the most likely amount method for certain rebates and trade discounts and allowances. A 10% increase or decrease in these estimates impacts net sales by a corresponding increase or decrease of approximately $13.0 million.
Due to numerous factors described in more detail under the caption Part I, Item 1A, "Risk Factors" of this Annual Report on Form 10-K, we may require significant additional funds earlier than we currently expect in order to continue to commercialize ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and to develop, conduct clinical trials for, manufacture and, if approved, commercialize additional product candidates.
Due to numerous factors described in more detail under the caption Part I, Item 1A, “Risk Factors” of this Annual Report on Form 10-K, we may require significant additional funds earlier than we currently expect in order to continue to commercialize ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and to develop, conduct clinical trials for, manufacture and, if approved, commercialize additional product candidates.
Recognition of our combined net revenues from collaborations and royalty revenue is dependent on a variety of factors including the level of work reimbursed by partners, achievement of milestones under our collaboration agreements, and royalties associated with sales of Leqvio.
Recognition of our combined net revenues from collaborations and royalty revenue is dependent on a variety of factors including the level of work reimbursed by collaborators, achievement of milestones under our collaboration agreements, and royalties associated with sales of Leqvio.
The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to the customer who directly purchases from us, and rebates that represent discount obligations under government programs, including Medicaid in the U.S. and similar programs in certain other countries, 90 Table of Contents including countries in which we are accruing for estimated rebates because final pricing has not yet been negotiated.
The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to the customer who directly purchases from us, and rebates that represent discount obligations under government programs, including Medicaid in the U.S. and similar programs in certain other countries, including countries in which we are accruing for estimated rebates because final pricing has not yet been negotiated.
In addition to revenues from the commercial sales of our approved products and potentially from sales of future products, we expect our sources of potential funding for the next several years to continue to be derived in part from existing and new strategic alliances.
In addition to revenues from the commercial sales of our approved products and potentially from sales of future products, we expect our sources of potential funding for the next several years to continue to be derived in part from existing and new strategic collaborations.
During the years ended December 31, 2022 and 2021, in connection with advancing activities under our collaboration agreements, we incurred research and development expenses, primarily related to external development and clinical expenses, including the manufacture of clinical product.
During the years ended December 31, 2023 and 2022, in connection with advancing activities under our collaboration agreements, we incurred research and development expenses, primarily related to external development and clinical expenses, including the manufacture of clinical product.
A 10% increase or decrease in the total forecasted costs to be incurred over the period the transfer of goods or services occurs impacts net revenues from collaborators by a corresponding decrease or increase of approximately $32.0 million.
A 10% increase or decrease in the total forecasted costs to be incurred over the period the transfer of goods or services occurs impacts net revenues from collaborators by a corresponding decrease or increase of approximately $39.0 million.
For elements of collaboration arrangements that are accounted for pursuant to ASC Topic 606, Revenue from Contracts with Customers, or ASC 606, we identify the performance obligations and allocate the total consideration we expect to receive on a relative standalone selling price basis to each performance obligation.
For elements of collaboration arrangements that are accounted for pursuant to Accounting Standards Codification Topic 606, Revenue from Contracts with Customers, or ASC 606, we identify the performance obligations and allocate the total consideration we expect to receive on a relative standalone selling price basis to each performance obligation.
Based on our current operating plan, we believe that our cash, cash equivalents and marketable securities as of December 31, 2022, together with the cash we expect to generate from product sales and under our current alliances, will be sufficient to satisfy our near-term capital and operating needs for at least the next 12 months from the filing of this Annual Report on Form 10-K.
Based on our current operating plan, we believe that our cash, cash equivalents and marketable securities as of December 31, 2023, together with the cash we expect to generate from product sales and under our current collaborations, will be sufficient to satisfy our near-term capital and operating needs for at least the next 12 months from the filing of this Annual Report on Form 10-K.
Net Revenues from Collaborations We earn revenue in connection with collaboration agreements which allow our collaboration partners to utilize our technology platforms and develop product candidates.
Net Revenues from Collaborations We earn revenue in connection with collaboration agreements which allow our collaborators to utilize our technology platforms and develop product candidates.
We currently have programs focused on a number of therapeutic areas and, as of December 31, 2022, we generate worldwide product revenues from four commercialized products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, primarily in the U.S., Europe and Japan.
We currently have programs focused on a number of therapeutic areas and, as of December 31, 2023, we generate worldwide product revenues from four commercialized products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, primarily in the U.S. and Europe.
A 10% increase or decrease in the transaction price impacts net revenues from collaborators by a corresponding increase or decrease of approximately $35.0 million.
A 10% increase or decrease in the transaction price impacts net revenues from collaborators by a corresponding increase or decrease of approximately $43.0 million.
We recognize revenue associated with each performance obligation as the control over the promised goods or services transfer to our collaboration partner which occurs either at a point in time or over time.
We recognize revenue associated with each performance obligation as the control over the promised goods or services transfer to our collaborator which occurs either at a point in time or over time.
"Business," of this Annual Report on Form 10-K, we currently have five products that have received marketing approval, including one partnered product, and multiple late-stage investigational programs advancing towards potential commercialization. In Part I, Item 1.
“Business” of this Annual Report on Form 10-K, we currently have five products that have received marketing approval, including one collaborated product, and multiple late-stage investigational programs advancing towards potential commercialization. In Part I, Item 1.
Please read Note 3 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this Annual Report on Form 10-K for balances and activity in each product revenue allowance and reserve category for the years ended December 31, 2022 and 2021.
Please see Note 3 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for balances and activity in each product revenue allowance and reserve category for the years ended December 31, 2023 and 2022.
Since we commenced operations in 2002, we have generated significant losses and as of December 31, 2022, we had an accumulated deficit of $6.57 billion. As of December 31, 2022, we had cash, cash equivalents and marketable securities of $2.19 billion, compared to $2.44 billion as of December 31, 2021.
Since we commenced operations in 2002, we have generated significant losses and as of December 31, 2023, we had an accumulated deficit of $7.01 billion. As of December 31, 2023, we had cash, cash equivalents and marketable securities of $2.44 billion, compared to $2.19 billion as of December 31, 2022.
"Business" you can also find a summary of key events in 2022 and 2023 to-date related to our marketed products and our clinical development programs. We have incurred significant losses since we commenced operations in 2002 and as of December 31, 2022, we had an accumulated deficit of $6.57 billion.
“Business” you can also find a summary of key events in 2023 and 2024 to-date related to our marketed products and our clinical development programs. We have incurred significant losses since we commenced operations in 2002 and as of December 31, 2023, we had an accumulated deficit of $7.01 billion.
Actual results could vary materially from these estimates. 91 Table of Contents Recent Accounting Pronouncements Please read Note 2 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this Annual Report on Form 10-K for a description of recent accounting pronouncements applicable to our business.
Actual results could vary materially from these estimates. 90 Table of Con tents Recent Accounting Pronouncements Please read Note 2 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for a description of recent accounting pronouncements.
A substantial portion of our total revenues in recent years has been derived from collaboration revenues from strategic alliances with Regeneron, Vir and Novartis.
A substantial portion of our total revenues in recent years has been derived from collaboration revenues from collaborations with Roche, Regeneron and Novartis.
As a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the establishment of late-stage clinical and commercial capabilities, including global commercial operations, continued management and growth of our patent portfolio, collaborations and general corporate activities, we expect to incur additional operating losses, however we expect 2019 represents our peak operating loss year as we transition towards a self-sustainable financial profile.
As a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the establishment of late-stage clinical and commercial capabilities, including global commercial operations, continued management and growth of our patent portfolio, collaborations and general corporate activities, we expect to incur additional operating losses.
We expect cost of goods sold will increase during 2023, as compared to 2022, primarily as a result of an expected increase in net product sales as well as increased royalties.
We anticipate variability in our cost of goods sold as a percentage of net product revenues in 2024, as compared to 2023. We expect our cost of goods sold will increase during 2024, as compared to 2023, primarily as a result of an expected increase in net product sales as well as increased royalties.
An increase or decrease of 5% to the interest rate would result in an increase or decrease to our liability related to the sale of future royalties of approximately $15.8 million.
An increase or decrease of 10% to the interest rate would result in an increase or decrease to our liability related to the sale of future royalties of approximately $33.9 million.
We expect that research and development expenses combined with selling, general and administrative expenses will increase during 2023, as compared to 2022, as we continue to advance and develop our platform and pipeline, advance our product candidates, including partnered programs, into later-stage development, prepare regulatory submissions and continue to build-out our global commercial and compliance infrastructure and field team to support ONPATTRO, GIVLAARI, OXLUMO, and the launch of AMVUTTRA in the U.S. and EU, as well as launch these products into additional markets, assuming regulatory approvals.
We expect that research and development expenses combined with selling, general and administrative expenses will increase during 2024, as compared to 2023, as we continue to advance and develop our platform and pipeline, advance our product candidates, including collaborated programs, into later-stage development, prepare regulatory submissions and continue to build-out our global commercial and compliance infrastructure as well as launch our commercial products into additional 87 Table of Con tents markets, assuming regulatory approvals.
We expect capital expenditures to increase in 2022 to support the increase in our manufacturing and production capacity needs. • Amounts related to future long-term debt total $1.02 billion, of which we do not expect to make payments on principal within the next 12 months. • Payments associated with the liability related to the sale of future royalties were approximately $3.4 million in 2022, with $40.3 million to be paid within the next 12 months.
We expect capital expenditures to increase in 2024 to support the increase in our manufacturing and production capacity needs. • Amounts related to future long-term debt total $1.02 billion, of which we do not expect to make payments on principal within the next 12 months. • Payments associated with the liability related to the sale of future royalties were approximately $21.6 million in 2023, with an estimated $58.2 million to be paid within the next 12 months. • Amount associated with the achievement of a development milestone payable to Blackstone was $84.5 million as of December 31, 2023, with $21.1 million to be paid within the next 12 months.
We use the expected value method, which is the sum of probability-weighted amounts in a range of possible consideration amounts, or the most likely amount method, which is the single most likely amount in a range of possible considerations, to estimate variable consideration related to our product revenues.
We are also subject to potential rebates in connection with our value-based agreements, or VBAs, with certain commercial payors. 89 Table of Con tents We use the expected value method, which is the sum of probability-weighted amounts in a range of possible consideration amounts, or the most likely amount method, which is the single most likely amount in a range of possible considerations, to estimate variable consideration related to our product revenues.
Recent and expected working and other capital requirements, in addition to the above matters, also include the items described below: • Amounts related to future lease payments for operating lease obligations at December 31, 2022 totaled $460.1 million, with $43.0 million expected to be paid within the next 12 months. • Our cash operating expenditures were $541.3 million in 2022 and $641.7 million in 2021, and we expect to increase our investment in operations in 2023. • Cash outflows for capital expenditures were $72.1 million in 2022 and $76.4 million in 2021.
Recent and expected working and other capital requirements, in addition to the above matters, also include the items described below: • Amounts related to future lease payments for operating lease obligations at December 31, 2023 totaled $418.0 million, with $43.6 million expected to be paid within the next 12 months.
The following table summarizes research and development expenses incurred, for which we recognize net revenue, that are directly attributable to our collaboration agreements, by collaboration partner: Year Ended December 31, (In thousands) 2022 2021 2020 Regeneron Pharmaceuticals $ 43,002 $ 73,411 $ 57,833 Other 1,172 15,575 35,300 Total $ 44,174 $ 88,986 $ 93,133 Selling, General and Administrative Selling, general and administrative expenses consist of the following: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Compensation and related $ 273,262 $ 224,237 $ 200,071 $ 49,025 22 % $ 24,166 12 % Consulting and professional services 226,941 201,841 176,097 25,100 12 % 25,744 15 % Stock-based compensation 138,488 97,302 79,409 41,186 42 % 17,893 23 % Occupancy and all other costs 131,967 97,259 132,843 34,708 36 % (35,584) (27) % Total $ 770,658 $ 620,639 $ 588,420 $ 150,019 24 % $ 32,219 5 % Selling, general and administrative expenses increased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to the following: • Increased compensation and related expenses as a result of increased headcount and other strategic investments in support of the global launch of AMVUTTRA and other expenses to support our strategic growth; • Increased stock-based compensation expense primarily due to the accounting for certain performance-based awards; and • Increased consulting and professional services expenses to support our commercial portfolio.
The following table summarizes research and development expenses incurred, for which we recognize revenue, that are directly attributable to our collaboration agreements, by collaborator: Year Ended December 31, (In thousands) 2023 2022 2021 Roche $ 44,620 $ — $ — Regeneron Pharmaceuticals 77,444 43,002 73,411 Other 4,951 1,172 15,575 Total $ 127,015 $ 44,174 $ 88,986 Selling, General and Administrative Selling, general and administrative expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Compensation and related $ 298,888 $ 273,262 $ 224,237 $ 25,626 9 % $ 49,025 22 % Consulting and professional services 226,664 226,941 201,841 (277) — % 25,100 12 % Occupancy and all other costs 145,687 131,967 97,259 13,720 10 % 34,708 36 % Stock-based compensation 124,407 138,488 97,302 (14,081) (10) % 41,186 42 % Total $ 795,646 $ 770,658 $ 620,639 $ 24,988 3 % $ 150,019 24 % Selling, general and administrative expenses increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased headcount and other investments supporting our strategic growth including the global launch of AMVUTTRA.
Investing Activities Net cash provided by investing activities increased during the year ended December 31, 2022, compared to the year ended December 31, 2021, primarily due to net activities related to our marketable debt securities.
Investing Activities Net cash used in investing activities increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to net activities related to our marketable debt securities as a result of an increase of cash invested in marketable debt securities.
Cost of collaborations and royalties Cost of collaborations and royalties increased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to timing and demand of GalNAc material supply to our collaboration partners to support certain product manufacturing and ongoing clinical trials.
Cost of collaborations and royalties Cost of collaborations and royalties increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased demand of GalNAc material supplied to our collaborators to support certain product manufacturing and ongoing clinical trials and increased royalties payable to third parties on the net sales of licensed products by Novartis.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS 84 Table of Contents Overview We are a global commercial-stage biopharmaceutical company that discovers, develops, manufactures and commercializes novel therapeutics based on RNAi.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS Overview We are a global commercial-stage biopharmaceutical company that discovers, develops, manufactures and commercializes novel therapeutics based on RNAi. Our commercial products and broad pipeline of investigational RNAi therapeutics are focused in rare, specialty and select prevalent indications. As described in Part I, Item 1.
Operating Costs and Expenses Operating costs and expenses consist of the following: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Cost of goods sold $ 140,174 $ 115,005 $ 74,185 $ 25,169 22 % $ 40,820 55 % Cost of goods sold as a percentage of net product revenues 15.7 % 17.4 % 20.5 % Cost of collaborations and royalties 28,643 25,139 3,867 3,504 14 % 21,272 550 % Research and development 883,015 792,156 654,819 90,859 11 % 137,337 21 % Selling, general and administrative 770,658 620,639 588,420 150,019 24 % 32,219 5 % Total $ 1,822,490 $ 1,552,939 $ 1,321,291 $ 269,551 17 % $ 231,648 18 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues decreased to 15.7% for the year ended December 31, 2022, as compared to 17.4% for the year ended December 31, 2021, primarily due to an increase in sales of products with a lower cost to manufacture.
Operating Costs and Expenses Operating costs and expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Cost of goods sold $ 268,216 $ 140,174 $ 115,005 $ 128,042 91 % $ 25,169 22 % Cost of goods sold as a percentage of net product revenues 21.6 % 15.7 % 17.4 % Cost of collaborations and royalties 42,190 28,643 25,139 13,547 47 % 3,504 14 % Research and development 1,004,415 883,015 792,156 121,400 14 % 90,859 11 % Selling, general and administrative 795,646 770,658 620,639 24,988 3 % 150,019 24 % Total $ 2,110,467 $ 1,822,490 $ 1,552,939 $ 287,977 16 % $ 269,551 17 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues increased to 21.6% for the year ended December 31, 2023, as compared to 15.7% for the year ended December 31, 2022, primarily due to the following: • Increased volume and rate of royalties payable on net sales of AMVUTTRA.
Research and Development Research and development expenses consist of the following: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Clinical research and outside services $ 438,418 $ 418,985 $ 307,378 $ 19,433 5 % $ 111,607 36 % Compensation and related 225,589 196,134 190,705 29,455 15 % 5,429 3 % Occupancy and all other costs 126,847 108,622 96,272 18,225 17 % 12,350 13 % Stock-based compensation 92,161 68,415 60,464 23,746 35 % 7,951 13 % Total $ 883,015 $ 792,156 $ 654,819 $ 90,859 11 % $ 137,337 21 % Research and development expenses increased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to the following: 87 Table of Contents • Increased compensation and related expenses as a result of increased headcount to support our R&D pipeline and development expenses; • Increased stock-based compensation expense primarily due to the accounting for certain performance-based awards; and • Increased clinical research and outside services expenses primarily due to increase in clinical batches manufactured and development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran phase 2 studies.
We expect our cost of collaborations and royalties will decrease during 2024, as compared to 2023, primarily due to a decrease in demand of GalNAc material supplied to our collaborators in support of certain product manufacturing as our collaborators begin to transition to producing the material independently. 86 Table of Con tents Research and Development Research and development expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Clinical research and outside services $ 485,732 $ 438,418 $ 418,985 $ 47,314 11 % $ 19,433 5 % Compensation and related 260,423 225,589 196,134 34,834 15 % 29,455 15 % Occupancy and all other costs 160,987 126,847 108,622 34,140 27 % 18,225 17 % Stock-based compensation 97,273 92,161 68,415 5,112 6 % 23,746 35 % Total $ 1,004,415 $ 883,015 $ 792,156 $ 121,400 14 % $ 90,859 11 % Research and development expenses increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to the following: • Increased compensation and related expenses as a result of increased headcount to support our R&D pipeline and development expenses; • Increased clinical research and outside services primarily associated with zilebesiran as we reached full enrollment for our KARDIA-1 and KARDIA-2 clinical studies and additional costs associated with manufacturing batches associated with those clinical activities.
Results of Operations The following data summarizes the results of our operations: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Total revenues $ 1,037,418 $ 844,287 $ 492,853 $ 193,131 23 % $ 351,434 71 % Operating costs and expenses $ 1,822,490 $ 1,552,939 $ 1,321,291 $ 269,551 17 % $ 231,648 18 % Loss from operations $ (785,072) $ (708,652) $ (828,438) $ (76,420) 11 % $ 119,786 (14) % Net loss $ (1,131,156) $ (852,824) $ (858,281) $ (278,332) 33 % $ 5,457 (1) % For discussion of our 2021 results and a comparison with 2020 results please refer to "Management's Discussion and Analysis of Financial Conditions and Results of Operations" in our Annual Report on Form 10-K for the fiscal year ended December 31, 2021 that was filed with the SEC on February 10, 2022.
Such collaborations include, or may include in the future, license and other fees, funded research and development, milestone payments and royalties on product sales by our licensors, including royalties on sales of Leqvio made by our collaborator, Novartis, as well as proceeds from the sale of equity or debt. 83 Table of Con tents Results of Operations The following data summarizes the results of our operations: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Total revenues $ 1,828,292 $ 1,037,418 $ 844,287 $ 790,874 76 % $ 193,131 23 % Operating costs and expenses $ 2,110,467 $ 1,822,490 $ 1,552,939 $ 287,977 16 % $ 269,551 17 % Loss from operations $ (282,175) $ (785,072) $ (708,652) $ 502,897 (64) % $ (76,420) 11 % Net loss $ (440,242) $ (1,131,156) $ (852,824) $ 690,914 (61) % $ (278,332) 33 % For discussion of our 2022 results and a comparison with 2021 results please refer to “Management’s Discussion and Analysis of Financial Conditions and Results of Operations” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2022 that was filed with the SEC on February 23, 2023.
Financing Activities Net cash provided by financing activities decreased during the year ended December 31, 2022, compared to the year ended December 31, 2021, primarily due to greater cash received in 2021, including $500.0 million received from our sale of one-half of our royalty interest under the Novartis agreement in September 2021 and $500.0 million received in connection with the second and final drawdowns on our credit agreement in June 2021 and December 2021, respectively, offset by $136.2 million 89 Table of Contents received from the issuance of convertible debt, net of repayment of credit facility and purchase of capped call transactions in September 2022.
Financing Activities Net cash provided by financing activities decreased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to greater cash received in 2022, including $136.2 million received from the issuance of convertible debt, net of repayment of the credit facility held with Blackstone and purchase of capped call transactions in September 2022, and greater net proceeds from the issuance of common stock in connection with stock option exercises and other types of equity. 88 Table of Con tents Additional Capital Requirements We currently have programs focused on a number of therapeutic areas and, as of December 31, 2023, have received regulatory approval and commercially launched four products.
Net Revenues from Collaborations and Royalty Revenue Net revenues from collaborations consist of the following: Years Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Regeneron Pharmaceuticals $ 87,844 $ 113,226 $ 74,072 $ (25,382) (22) % $ 39,154 53 % Novartis AG 43,159 49,120 22,208 (5,961) (12) % 26,912 121 % Vir Biotechnology 1,755 16,897 31,396 (15,142) (90) % (14,499) (46) % Other 2,154 1,710 3,657 444 26 % (1,947) (53) % Total $ 134,912 $ 180,953 $ 131,333 $ (46,041) (25) % $ 49,620 38 % Net revenues from collaborations decreased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to a decrease in revenue recognized in connection with our collaboration agreements with Regeneron and Vir, attributed to reduced research and manufacturing activities and timing of reimbursable activities. 86 Table of Contents Royalty revenue increased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to increased global net sales of Leqvio by our partner, Novartis.
Net Revenues from Collaborations and Royalty Revenue Net revenues from collaborations and royalty revenue consist of the following: Years Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Roche $ 337,802 $ — $ — $ 337,802 N/A $ — N/A Regeneron Pharmaceuticals 100,468 87,844 113,226 12,624 14 % (25,382) (22) % Novartis AG 86,727 43,159 49,120 43,568 101 % (5,961) (12) % Other 21,188 3,909 18,607 17,279 442 % (14,698) (79) % Total net revenues from collaborations $ 546,185 $ 134,912 $ 180,953 $ 411,273 305 % $ (46,041) (25) % Royalty revenue $ 40,633 $ 8,177 $ 1,196 $ 32,456 397 % $ 6,981 * Net revenues from collaborations increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to revenue recognized under our agreements with Roche and Novartis.
However, we expect that certain expenses will be variable depending on the timing of manufacturing batches, clinical trial enrollment and results, regulatory review of our product candidates and programs, and stock-based compensation expenses due to our determination regarding the probability of vesting for performance-based awards. 88 Table of Contents Other (Expense) Income Other (expense) income consists of the following: Year Ended December 31, 2022 vs 2021 2021 vs 2020 (In thousands, except percentages) 2022 2021 2020 $ Change % Change $ Change % Change Interest expense $ (155,968) $ (143,021) $ (84,496) $ (12,947) 9 % $ (58,525) 69 % Other (expense) income, net Interest income 24,808 1,579 11,809 23,229 1,471 % (10,230) (87) % Realized and unrealized (losses) gains on marketable equity securities (33,312) 55,695 54,042 (89,007) (160) % 1,653 3 % Change in fair value of development derivative liability (94,659) (38,433) (17,185) (56,226) 146 % (21,248) 124 % Other (6,204) (19,312) 8,668 13,108 (68) % (27,980) (323) % Loss on the extinguishment of debt (76,586) — — (76,586) N/A — N/A Total $ (341,921) $ (143,492) $ (27,162) $ (198,429) 138 % $ (116,330) 428 % Total other expense increased during the year ended December 31, 2022, as compared to the year ended December 31, 2021, primarily due to a $76.6 million loss on the extinguishment of the Blackstone credit agreement, increased realized and unrealized losses on our marketable equity securities holdings, and increased loss as a result of a mark-to-market adjustment related to the development derivative liability.
Other (Expense) Income Other (expense) income consists of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Interest expense $ (121,221) $ (155,968) $ (143,021) $ 34,747 (22) % $ (12,947) 9 % Other expense, net Interest income 95,561 24,808 1,579 70,753 285 % 23,229 * Realized and unrealized (losses) gains on marketable equity securities (16,944) (33,312) 55,695 16,368 (49) % (89,007) (160) % Change in fair value of development derivative liability (90,997) (94,659) (38,433) 3,662 (4) % (56,226) 146 % Other (17,741) (6,204) (19,312) (11,537) 186 % 13,108 (68) % Loss on the extinguishment of debt — (76,586) — 76,586 (100) % (76,586) N/A Total $ (151,342) $ (341,921) $ (143,492) $ 190,579 (56) % $ (198,429) 138 % * Indicates the percentage change period over period is greater than 500%.
We expect variability in net revenues from collaboration and royalty revenue in 2023, as compared to 2022, due to the timing of manufacturing activities, achievement of milestones under our collaboration agreements and royalties associated with sales of Leqvio.
Royalty revenue increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, due to increased royalties earned from global net sales of Leqvio by our collaborator, Novartis.
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Our commercial products and broad pipeline of investigational RNAi therapeutics are focused in four STArs: Genetic Medicines, Cardio-Metabolic Diseases, Hepatic Infectious Diseases and CNS/Ocular Diseases. As described in Part I, Item 1.
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While we believe 2019 was our peak operating loss year, we expect to continue to incur annual operating losses, and will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve financial self-sustainability by the end of 2025.
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Such alliances include, or may include in the future, license and other fees, funded research and development, milestone payments and royalties on product sales by our licensors, including royalties on sales of Leqvio made by our partner Novartis, as well as proceeds from the sale of equity or debt.
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Additional growth was related to an increase in patients on GIVLAARI and OXLUMO.
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We expect net product revenues to increase during 2023, as compared to 2022, as we continue to add new patients onto our commercial products, as well as launch these products into additional markets, assuming regulatory approvals.
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During 2023, we recognized $337.8 million of revenue under our Collaboration and License Agreement with Roche, which was executed in July 85 Table of Con tents 2023, and under our Novartis Collaboration Agreement we recognized an additional $30.0 million of revenue, compared to 2022, associated with the achievement of specified commercialization and regulatory milestones.
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In December 2020, Leqvio received marketing authorization from the EC for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, and in December 2021, Leqvio was approved by the FDA for the treatment of adults with HeFH or ASCVD.
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We expect net revenues from collaboration will decrease in 2024, as compared to 2023, primarily driven by a reduction in the revenues recognized under our Roche Collaboration and License Agreement.
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We anticipate variability in our cost of goods sold as a percentage of net product revenues due to the timing of manufacturing runs and utilization and the depletion of zero-cost inventories, as well as future product launches.
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We expect our royalty revenues will increase in 2024, as compared to 2023, due to the continued growth of royalties earned from global net sales of Leqvio by our collaborator, Novartis. The amount of revenue from collaborations that we recognize, in part, is based on estimates of total costs to be incurred.
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We anticipate variability in the cost of collaborations and royalties during 2023, as compared to 2022, due to the timing and demand of GalNAc material to be supplied to our collaboration partners.
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These estimates reflect our historical experiences, current contractual requirements, and forecasted plans of development or manufacturing activities. We adjust these estimates for changes in actual costs incurred, contractual terms, and further forecasts. Such changes in estimates could have a significant impact on revenue and earnings in the period of the adjustment.
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Liquidity and Capital Resources The following table summarizes our cash flow activities: Year Ended December 31, (In thousands) 2022 2021 2020 Net loss $ (1,131,156) $ (852,824) $ (858,281) Non-cash adjustments to reconcile net loss to net cash used in operating activities: 625,435 373,954 256,021 Changes in operating assets and liabilities: (35,553) (162,823) (12,701) Net cash used in operating activities (541,274) (641,693) (614,961) Net cash provided by (used in) investing activities 169,354 (273,300) (435,518) Net cash provided by financing activities 425,753 1,247,118 994,979 Effect of exchange rate changes on cash, cash equivalents and restricted cash (7,430) (9,018) 4,918 Net increase (decrease) in cash, cash equivalents and restricted cash 46,403 323,107 (50,582) Cash, cash equivalents and restricted cash, beginning of period 822,153 499,046 549,628 Cash, cash equivalents and restricted cash, end of period $ 868,556 $ 822,153 $ 499,046 Operating Activities Net cash used in operating activities decreased during the year ended December 31, 2022, compared to the year ended December 31, 2021, primarily due to decreased cash disbursements related to working capital payments and stronger cash receipts from increased product sales.
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Our collaborator is eligible to receive tiered royalties of 15% to 30% based on global annual net sales and therefore the growth in AMVUTTRA net sales during 2023 resulted in more net sales and a higher tier rate for the applicable royalties payable; and • Increased excess and obsolete charges primarily due to cancelling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the use of patisiran for the treatment of patients with ATTR amyloidosis with cardiomyopathy for which we did not receive regulatory approval in the U.S.
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Additional Capital Requirements We currently have programs focused on a number of therapeutic areas and, as of December 31, 2022, have received regulatory approval and commercially launched four products.
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Costs associated with clinical trials of other programs such as ALN-TTRsc04 and our ongoing early development studies also were higher when compared to 2022; and • Increased occupancy and all other costs as a result of higher costs related to infrastructure and other professional services to support our growing clinical footprint.
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We are also subject to potential rebates in connection with our VBAs with certain commercial payors.
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However, we expect that certain expenses will be variable depending on the timing of manufacturing batches, clinical trial enrollment and results, regulatory review of our product candidates and programs, and stock-based compensation expenses due to our determination regarding the probability of vesting for performance-based awards.
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Total other expense decreased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased interest income driven by higher market interest rates on our marketable debt securities, decreased interest expense as a result of a more favorable interest rate under the Convertible Senior Notes compared with the interest rate under the credit facility previously held with Blackstone and a $76.6 million loss on the extinguishment of the Blackstone credit agreement recognized in 2022.
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Liquidity and Capital Resources The following table summarizes our cash flow activities: Year Ended December 31, $ Change (In thousands) 2023 2022 2021 2023 vs 2022 2022 vs 2021 Net cash provided by (used in): Operating activities $ 104,156 $ (541,274) $ (641,693) $ 645,430 $ 100,419 Investing activities $ (336,350) $ 169,354 $ (273,300) $ (505,704) $ 442,654 Financing activities $ 172,131 $ 425,753 $ 1,247,118 $ (253,622) $ (821,365) Operating Activities Net cash provided by operating activities increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to receipt of a $310.0 million up-front payment received in connection with the Roche Collaboration and License Agreement and $100.0 million payment from Regeneron in connection with achieving certain criteria during early clinical development for our CNS program, ALN-APP, in addition to cash receipts from increased product sales, offset by cash disbursements related to working capital payments.
Added
Cash outflows for capital expenditures were $62.2 million in 2023 and $72.1 million in 2022.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK Interest Rate Risk - Investment Portfolio. We invest a portion of our cash in a number of diversified fixed- and floating-rate securities consisting of cash equivalents, marketable debt securities, debt funds and derivative instruments related to our investment portfolio that are subject to interest rate risk.
Biggest changeITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK Interest Rate Risk - Investment Portfolio. We invest a portion of our cash in a number of diversified fixed- and floating-rate securities consisting of cash equivalents and marketable debt securities related to our investment portfolio that are subject to interest rate risk.
As sales outside the United States continue to grow, and as we expand our international operations, we will continue to assess potential steps, including foreign currency hedging and other strategies, to mitigate our foreign exchange risk. 92 Table of Contents
As sales outside the United States continue to grow, and as we expand our international operations, we will continue to assess potential steps, including foreign currency hedging and other strategies, to mitigate our foreign exchange risk. 91 Table of Contents
As of December 31, 2022 and 2021, a hypothetical increase in interest rates of 50 basis points across the entire yield curve on our holdings would have resulted in an immaterial decrease to the fair value of our holdings. Foreign Currency Exchange Risk.
As of December 31, 2023 and December 31, 2022, a hypothetical increase in interest rates of 100 basis points across the entire yield curve on our holdings would have resulted in an immaterial decrease to the fair value of our holdings. Foreign Currency Exchange Risk.

Other ALNY 10-K year-over-year comparisons