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What changed in Protalix BioTherapeutics, Inc.'s 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of Protalix BioTherapeutics, Inc.'s 2023 and 2024 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 2024 report.

+395 added−420 removedSource: 10-K (2025-03-17) vs 10-K (2024-03-14)

Top changes in Protalix BioTherapeutics, Inc.'s 2024 10-K

395 paragraphs added · 420 removed · 275 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

125 edited+69 added−41 removed224 unchanged
Biggest changeWe hosted an informational booth at the symposium. ● On March 21, 2023, the first patient was dosed in our phase I First-in-Human (FIH) clinical trial of PRX-115. ● Our decision to voluntarily delist our common stock from the Tel Aviv Stock Exchange took effect on March 22, 2023. ● On May 5, 2023, we announced that the EC had granted marketing authorization to Elfabrio in the European Union for the treatment of adult patients with Fabry disease. ● On May 10, 2023, we announced that the FDA had approved Elfabrio in the United States for the treatment of adult patients with Fabry disease. ● On June 28, 2023, we held our Annual Meeting of Stockholders at which our stockholders: (1) elected the seven persons nominated by our Board of Directors to serve as directors of our Company; (2) approved, on a non-binding, advisory basis, the compensation of our named executive officers; (3) approved, on a non-binding, advisory basis, one year as the frequency at which we will solicit stockholder approval of the compensation of our named executive officers; (4) adopted amendments to our Amended and Restated 2006 Stock Incentive Plan, as amended , to increase the number of shares of common stock available under such plan from 8,475,171 shares to 12,475,171 shares and to amend certain other terms of the plan; and (5) ratified the appointment of Kesselman & Kesselman, Certified Public Accountants (Isr.), a member of PricewaterhouseCoopers International Limited, as our independent registered public accounting firm for the fiscal year ending December 31, 2023.
Biggest changeOur proprietary modified DNase I, which we have designed for long and customized systemic circulation in the bloodstream, may potentially enable effective treatment for these conditions. 2024 Company Developments 2024 Developments ● In May 2024, we announced our decision to expand our phase I First-in-Human clinical trial of PRX-115 by adding an eighth cohort with eight new patients and to commence preparations for a phase II clinical trial of PRX-115. 7 Table of Contents ● On June 27, 2024, we held our Annual Meeting of Stockholders at which our stockholders: (1) elected the seven persons nominated by our Board of Directors to serve as directors of the Company; (2) approved, on a non-binding, advisory basis, the compensation of our named executive officers; (3) adopted amendments to the Protalix BioTherapeutics, Inc. 2006 Stock Incentive Plan, as amended, to increase the number of shares of the Company’s common stock available under such plan from 12,475,171 shares to 17,475,171 shares and adopted certain other terms of said plan and (4) ratified the appointment of Kesselman & Kesselman, Certified Public Accountants (Isr.), a member firm of PricewaterhouseCoopers International Limited, as our independent registered public accounting firm for the fiscal year ending December 31, 2024. ● In September 2024, we repaid in full all of the outstanding principal and interest payable under our 2024 Notes.
The FDA review team also concluded that the BALANCE study met its primary efficacy endpoint, which assessed the annualized rate of change in eGFR (estimated glomerular filtration rate) over 104 weeks.
The FDA review team also concluded that the BALANCE study met its primary efficacy endpoint, which assessed the annualized rate of change in eGFR (estimated glomerular filtration rate) over 104 weeks.
These regulations include: ● the federal healthcare program anti-kickback law, which prohibits, among other things, persons from soliciting, receiving or providing remuneration, directly or indirectly, to induce either the referral of an individual, for an item or service or the purchasing or ordering of a good or service, for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs; 26 Table of Contents ● federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other government reimbursement programs that are false or fraudulent; ● the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters and which also imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information; ● the federal transparency requirements under the Health Care Reform Law requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Department of Health and Human Services information related to physician payments and other transfers of value and physician ownership and investment interests; ● the FFDCA, which among other things, strictly regulates drug and biologic product marketing, prohibits manufacturers from marketing drug products for off-label use and regulates the distribution of drug samples; and ● state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by federal laws, thus complicating compliance efforts.
These regulations include: ● the federal healthcare program anti-kickback law, which prohibits, among other things, persons from soliciting, receiving or providing remuneration, directly or indirectly, to induce either the referral of an individual, for an item or service or the purchasing or ordering of a good or service, for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs; ● federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other government reimbursement programs that are false or fraudulent; ● the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters and which also imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information; ● the federal transparency requirements under the Health Care Reform Law requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Department of Health and Human Services information related to physician payments and other transfers of value and physician ownership and investment interests; ● the FFDCA, which among other things, strictly regulates drug and biologic product marketing, prohibits manufacturers from marketing drug products for off-label use and regulates the distribution of drug samples; and ● state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by federal laws, thus complicating compliance efforts.
NETs are composed of DNA, histones, antimicrobial and pro-inflammatory proteins. Excessive formation or ineffective clearance of NETs can cause different pathological effects. NETs formation has been observed in various autoimmune, inflammatory and fibrotic conditions, diverse forms of thrombosis, cancer and metastasis. According to scientific literature, animal studies have demonstrated that DNase I treatment reduce NETs toxicity.
NETs are composed of DNA, histones, antimicrobial and pro-inflammatory proteins. Excessive formation or ineffective clearance of NETs can cause different pathological effects. NETs formation has been observed in various autoimmune, inflammatory and fibrotic conditions, diverse forms of thrombosis, cancer and metastasis. According to scientific literature, animal studies have demonstrated that DNase treatment reduce NETs toxicity.
Gout leads to substantial morbidity, severe pain, reduced quality of life, decreased physical function, increased healthcare costs, and lost economic productivity. Furthermore, gout is strongly associated with a number of comorbidities, including hypertension, cardiovascular disease, renal impairment, diabetes, obesity, hyperlipidaemia and frequently in a combination known as the metabolic syndrome.
Gout leads to substantial morbidity, severe pain, reduced quality of life, decreased physical function, increased healthcare costs, and lost economic productivity. Furthermore, gout is strongly associated with a number of comorbidities, including hypertension, cardiovascular disease, renal impairment, diabetes, obesity, hyperlipidaemia and frequently occurs in a combination known as the metabolic syndrome.
Gout results from sustained elevation of serum urate levels (hyperuricaemia). Urate levels may increase due to diet, genetic predisposition and environmental factors leading to the deposition of monosodium urate crystals, tophi, in joints, tendons and other tissues, which triggers recurrent episodes of pronounced acute inflammation, known as gout flares.
Gout results from sustained elevation of serum urate levels (hyperuricaemia). Urate levels may increase due to diet, genetic predisposition and environmental factors leading to the deposition of monosodium urate crystals and\or tophi in joints, tendons and other tissues, which triggers recurrent episodes of pronounced acute inflammation, known as gout flares.
In addition, the amendment provides that if the purchaser of the know-how gives the selling Israeli company the right to exploit the know-how by way of an exclusive, irrevocable and unlimited license, the research committee may approve such transfer in special cases without requiring a cash payment. ● in the event of a sale of a company which is the owner of know-how, pursuant to which the company ceases to be an Israeli company, provided that upon such sale, the owner of the know-how makes a cash payment to NATI as set forth in the Research Law (and the regulations promulgated thereunder). ● in the event of an exchange of know-how such that in exchange for the transfer of know-how outside of Israel, the recipient of the know-how transfers other know-how to the company in Israel in a manner in 30 Table of Contents which NATI is convinced that the Israeli economy realizes a greater, overall benefit from the exchange of know-how.
In addition, the amendment provides that if the purchaser of the know-how gives the selling Israeli company the right to exploit the know-how by way of an exclusive, irrevocable and unlimited license, the research committee may approve such transfer in special cases without requiring a cash payment. ● in the event of a sale of a company which is the owner of know-how, pursuant to which the company ceases to be an Israeli company, provided that upon such sale, the owner of the know-how makes a cash payment to NATI as set forth in the Research Law (and the regulations promulgated thereunder). ● in the event of an exchange of know-how such that in exchange for the transfer of know-how outside of Israel, the recipient of the know-how transfers other know-how to the company in Israel in a manner in which NATI is convinced that the Israeli economy realizes a greater, overall benefit from the exchange of know-how.
Each of these documents is also available in print, free of charge, to any stockholder who requests a copy by addressing a request to: Protalix BioTherapeutics, Inc. 2 University Plaza, Suite 100 Hackensack, NJ 07601 Attn: Mr. Eyal Rubin, Sr. Vice President and Chief Financial Officer ​ 32 Table of Contents
Each of these documents is also available in print, free of charge, to any stockholder who requests a copy by addressing a request to: Protalix BioTherapeutics, Inc. 2 University Plaza, Suite 100 Hackensack, NJ 07601 Attn: Mr. Eyal Rubin, Sr. Vice President and Chief Financial Officer ​ 34 Table of Contents
A company that has elected to participate in the alternative benefits program and that subsequently pays a dividend out of the income derived from the portion of its facilities that have been granted Approved Enterprise status during the tax exemption period will be subject to corporate tax in respect of the amount of dividend distributed at the rate that would 28 Table of Contents have been applicable had the company not elected the alternative benefits program (generally 10% to 23%, depending on the extent to which non-Israeli shareholders hold such company’s shares).
A company that has elected to participate in the alternative benefits program and that subsequently pays a dividend out of the income derived from the portion of its facilities that have been granted Approved Enterprise status during the tax exemption period will be subject to corporate tax in respect of the amount of dividend distributed at the rate that would have been applicable had the company not elected the alternative benefits program (generally 10% to 23%, depending on the extent to which non-Israeli shareholders hold such company’s shares).
On May 5, 2023, the European Commission, or EC, announced that it had approved the Marketing Authorization Application, or MAA, for Elfabrio and on May 9, 2023, the FDA announced that it had approved the Biologics License Application, or BLA, for Elfabrio (pegunigalsidase alfa-iwxj) injection BLA 761161, each for adult patients with a confirmed diagnosis of Fabry disease.
On May 5, 2023, the European Commission, or EC, announced that it had approved the MAA for Elfabrio and on May 9, 2023, the FDA announced that it had approved the Biologics License Application, or BLA, for Elfabrio (pegunigalsidase alfa-iwxj) injection BLA 761161, each for adult patients with a confirmed diagnosis of Fabry disease.
With respect to severe gout, we face competition from Horizon Therapeutics Public Limited Company (Krsytexxa), which is indicated for treatment of chronic gout in adult patients refractory to conventional therapy. In addition, we are aware of other clinical stage, early clinical stage and experimental refractory or chronic gout treatments.
With respect to uncontrolled gout, we face competition from Horizon Therapeutics Public Limited Company (Krsytexxa), which is indicated for treatment of chronic gout in adult patients refractory to conventional therapy. In addition, we are aware of other clinical stage, early clinical stage and experimental refractory or chronic gout treatments.
In June 2012, the EMA’s Committee for Medicinal Products for Human Use, or the CHMP, issued a positive opinion regarding the benefit of Elelyso but did not immediately grant marketing authorization because of the ten-year market exclusivity granted to Vpriv ® (Takeda Shire) in August 2010 for the same condition, which was extended for an additional two years, and expired in August 2022.
In June 2012, the EMA’s Committee for Medicinal Products for Human Use, or the CHMP, issued a positive opinion regarding the benefit of Elelyso but did not immediately grant marketing authorization because of the ten-year market exclusivity granted to Vpriv ® (Takeda Shire) in August 2010 for 6 Table of Contents the same condition, which was extended for an additional two years, and expired in August 2022.
Phase III BRIDGE Study The BRIDGE study (PB-102-F30, NCT03018730) was a 12-month open-label, single arm switch-over study evaluating the safety and efficacy of PRX-102, 1 mg/kg infused every two weeks, in up to 22 Fabry patients previously treated with 11 Table of Contents agalsidase alfa for at least two years and on a stable dose for at least six months.
Phase III BRIDGE Study The BRIDGE study (PB-102-F30, NCT03018730) was a 12-month open-label, single arm switch-over study evaluating the safety and efficacy of PRX-102, 1 mg/kg infused every two weeks, in up to 22 Fabry patients previously treated with agalsidase alfa for at least two years and on a stable dose for at least six months.
Pre-clinical data demonstrates long half-life, reduced immunogenic risk and high specific activity which supports the potential of PRX-115 to be a safe and effective treatment for patients with gout. One-month multiple dosing toxicity studies in two species and 6-month multiple dosing toxicity study in one species were conducted to support single and multiple dose studies is humans.
Pre-clinical data demonstrates long half-life, reduced immunogenic risk and high specific activity supports the potential of PRX-115 to be a safe and effective treatment for patients with gout. One-month multiple dosing toxicity studies in two animal species and a 6-month multiple dosing toxicity study in one animal species were conducted to support single- and multiple-dose studies in humans.
We are also entitled to a non-exclusive worldwide license to make and have made other proteins expressed by using Icon’s technology. As consideration for the license, we are obligated to make royalty payments equal to varying low, single-digit percentages of net sales of products by us, our affiliates, or any 17 Table of Contents sublicensees under the agreement.
We are also entitled to a non-exclusive worldwide license to make and have made other proteins expressed by using Icon’s technology. As consideration for the license, we are obligated to make royalty payments equal to varying low, single-digit percentages of net sales of products by us, our affiliates, or any sublicensees under the agreement.
To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.
To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that 28 Table of Contents compare the cost-effectiveness of a particular product candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.
The ultimate consequences of Gb 3 deposition 8 Table of Contents range from episodes of pain and impaired peripheral sensation to end-organ failure, particularly of the kidneys, but also of the heart and the cerebrovascular system. Fabry disease occurs in one person per 40,000 to 60,000 males. The standard of care for Fabry disease is ERT.
The ultimate consequences of Gb 3 deposition range from episodes of pain and impaired peripheral sensation to end-organ failure, particularly of the kidneys, but also of the heart and the cerebrovascular system. Fabry disease occurs in one person per 40,000 to 60,000 males. The standard of care for Fabry disease is ERT.
Orphan drug designation is generally given to medicinal products that treat conditions for which no current therapy exists or are expected to bring a significant benefit to patients over existing therapies. 25 Table of Contents Third Party Payor Coverage and Reimbursement Coverage and reimbursement status of any approved therapy carries uncertainty and risk.
Orphan drug designation is generally given to medicinal products that treat conditions for which no current therapy exists or are expected to bring a significant benefit to patients over existing therapies. Third Party Payor Coverage and Reimbursement Coverage and reimbursement status of any approved therapy carries uncertainty and risk.
Cardiac parameters, including LVM, LVMI and EF, remained stable with no cardiac fibrosis development detected. In conclusion, an improvement of over 40% in disease severity was shown as measured by the Mainz Severity Score Index, or MSSI, a score compiling the different elements of the disease severity 13 Table of Contents including neurological, renal and cardiovascular parameters.
Cardiac parameters, including LVM, LVMI and EF, remained stable with no cardiac fibrosis development detected. In conclusion, an improvement of over 40% in disease severity was shown as measured by the Mainz Severity Score Index, or MSSI, a score compiling the different elements of the disease severity including neurological, renal and cardiovascular parameters.
The three basic criteria for the registration of pharmaceuticals in Israel is quality, safety and efficacy of the pharmaceutical product and the Israeli Ministry of Health requires pharmaceutical companies to conform to international developments and standards. Regulatory requirements are constantly changing in accordance with scientific advances as well as social and ethical values.
The three basic criteria for the registration of pharmaceuticals in Israel is quality, safety and efficacy of the 27 Table of Contents pharmaceutical product and the Israeli Ministry of Health requires pharmaceutical companies to conform to international developments and standards. Regulatory requirements are constantly changing in accordance with scientific advances as well as social and ethical values.
Drug Development Process The FDA regulates drugs under the U.S. Federal Food, Drug, and Cosmetic Act, or the FFDCA, and its implementing regulations. Drugs are also subject to other federal, state and local statutes and regulations.
Drug Development Process The FDA regulates drugs under the U.S. Federal Food, Drug, and Cosmetic Act, or the FFDCA, and the implementing regulations thereto. Drugs are also subject to other federal, state and local statutes and regulations.
As of December 31, 2023, NATI approved grants in respect of Protalix Ltd.’s continuing operations totaling approximately $53.2 million (before interest, as described below), measured from inception.
As of December 31, 2024, NATI approved grants in respect of Protalix Ltd.’s continuing operations totaling approximately $53.2 million (before interest, as described below), measured from inception.
To date, two variants of recombinant uricases are approved for marketing: (i) Krystexxa ® (pegloticase) for treatment of chronic gout refractory to conventional therapy (gout patients who have contraindication/failure of other lowering uric acid treatments) and (ii) Elitek ® , indicated for the treatment of tumor lysis syndrome but not gout.
To date, two variants of recombinant uricases are approved for marketing: (i) Krystexxa ® (pegloticase) for treatment of chronic gout refractory to conventional therapy (gout patients who have contraindication/failure of other lowering urate treatments) and (ii) Elitek ® , indicated for the treatment of tumor lysis syndrome but not gout.
According to the EMA, overall, the benefit/risk balance of Elfabrio is positive in the claimed indication (Fabry disease). The FDA publicly released the internal review documents for Elfabrio. These documents provide previously unavailable additional information regarding the basis for the FDA’s May 2023 approval decision.
According to the EMA, overall, the benefit/risk balance of Elfabrio is positive in the claimed indication (Fabry disease). 3 Table of Contents The FDA publicly released the internal review documents for Elfabrio. These documents provide previously unavailable additional information regarding the basis for the FDA’s May 2023 approval decision.
Protalix Ltd. received an upfront, non-refundable, non-creditable payment of $25.0 million from 19 Table of Contents Chiesi and was entitled to additional payments of up to a maximum of $20.0 million to cover development costs for PRX-102, capped at $7.5 million per year.
Protalix Ltd. received an upfront, non-refundable, non-creditable payment of $25.0 million from Chiesi and was entitled to additional payments of up to a maximum of $20.0 million to cover development costs for PRX-102, capped at $7.5 million per year.
The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.
The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and 25 Table of Contents the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.
We developed ProCellEx based on our plant cell culture technology for the development, expression and manufacture of recombinant proteins which are the essential foundation of modern biotechnology.
We developed ProCellEx based on our plant cell culture technology for the development, expression and manufacture of recombinant proteins that are the essential foundation of modern biotechnology.
In order to qualify for these incentives, an Approved Enterprise is required to comply with the requirements of the Investment Law, and Letter of approval received by Protalix Ltd. 27 Table of Contents Protalix Ltd. will continue to enjoy the tax benefits under the pre-revision provisions of the Investment Law.
In order to qualify for these incentives, an Approved Enterprise is required to comply with the requirements of the Investment Law, and Letter of approval received by Protalix Ltd. Protalix Ltd. will continue to enjoy the tax benefits under the pre-revision provisions of the Investment Law.
To be lawfully marketed in interstate commerce, a biologic product must be the subject of a BLA issued by the FDA on the basis of a demonstration that the product is safe, pure and potent, and that the facility in which the product is manufactured meets standards to assure that the product continues to be safe, pure and potent.
To be lawfully marketed in 22 Table of Contents interstate commerce, a biologic product must be the subject of a BLA issued by the FDA on the basis of a demonstration that the product is safe, pure and potent, and that the facility in which the product is manufactured meets standards to assure that the product continues to be safe, pure and potent.
In addition, changes to the manufacturing process generally 24 Table of Contents require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.
In addition, changes to the manufacturing process generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.
Some parts of this discussion are based on new tax legislation that has not been subject to judicial or administrative interpretation. Therefore, the views expressed in the discussion may not be accepted by the tax authorities in question.
Some parts of this discussion are based on new tax legislation that has not been subject to judicial or administrative interpretation. Therefore, the views expressed in the 29 Table of Contents discussion may not be accepted by the tax authorities in question.
Overall, 126 subjects who participated in our PRX-102 clinical program initially opted, with the advice of the treating physician, to enroll in one of our long-term, open label, extension studies of PRX-102: 97 patients in the 1 mg/kg every two weeks extension study (PB-102-F60, NCT03566017) (10 subjects who completed an extension study from the phase I/II study, 18 subjects who completed the BRIDGE study; 69 subjects who completed the BALANCE study), and 29 subjects who completed the BRIGHT study in the 2 mg/kg every four weeks extension study (PB-102-F51, NCT03614234).
Overall, 126 patients who participated in our PRX-102 clinical program initially opted, with the advice of the treating physician, to enroll in one of the extension studies: 97 patients in the 1 mg/kg every two weeks extension study (PB-102-F60, NCT03566017) (10 patients who completed an extension study from the phase I/II study, 18 patients who completed the BRIDGE study; 69 patients who completed the BALANCE study), and 29 patients who completed the BRIGHT study in the 2 mg/kg every four weeks extension study (PB-102-F51, NCT03614234).
Phase III BRIGHT Study The BRIGHT study (PB-102-F50, NCT03180840) was a multicenter, multinational open-label, switch-over study designed to evaluate the safety, efficacy and pharmacokinetics of treatment with 2 mg/kg of PRX-102 administered every four weeks for 52 weeks (a total of 14 infusions). The study was completed in June 2020.
Phase III BRIGHT Study The BRIGHT study (PB-102-F50, NCT03180840) was a multicenter, multinational open-label, switch-over study designed to evaluate the safety, efficacy and pharmacokinetics of treatment with 2 mg/kg of PRX-102 administered every four weeks for 52 weeks (a total of 14 infusions).
Global Pending Jurisdictions Granted Jurisdictions Nominal Expiry Production of High Mannose Proteins in Plant Culture/PCT/ Il2004 000181 N/A Japan, Israel, Canada, Russian Federation, Mexico, India, Australia, South Africa, Republic of Korea, Singapore, Europe, Hong Kong, Ukraine, China, USA, Brazil 2024(1) (3) Plant Cell/Tissue Culturing Device, System and Method/PCT/Il2005/ 000228 N/A Israel 2025 Large Scale Disposable Bioreactor/PCT/Il2008/000614 N/A Australia, Canada, China, Europe, Hong Kong, India, Israel, Republic of Korea, Russian Federation, Singapore, South Africa, USA, Brazil 2028(2) Stabilized Alpha-galactosidase and uses thereof/PCT/Il2011/ 000209 Brazil Canada, South Africa, Russian Federation, Singapore, Israel, India, New Zealand, Republic of Korea, Australia, 2031(3) 16 Table of Contents China, Japan, USA, Europe, Hong Kong, India, Brazil Nucleic Acid Construct for Expression of Alpha-galactosidase in Plants and Plant Cells/PCT/ Il2011/000719 N/A India, China, Republic of Korea, Japan, Israel, Europe, Hong Kong, USA, Brazil 2024(2) Therapeutic Regimen For The Treatment of Fabry Using Stabilized Alpha-galactosidase/ PCT/Il2018/050018 USA, Europe, Brazil, Japan, Canada, Australia, Chile, Israel, Republic of Korea, China, Mexico, Hong Kong South Africa, New Zealand, Russian Federation 2038 Dry Powder Formulations of DNase 1/PCT/Il2013/050094 N/A Israel, USA 2033 DNase I Polypeptides, Polynucleotides Encoding Same, Methods of Producing DNase I and uses thereof in Therapy/PCT/ Il2013/050097 N/A Europe, Israel, Brazil 2033 Inhalable Liquid Formulations of DNase I/PCT/Il2013/050096 N/A Israel, USA 2033 Modified DNase and uses thereof/ PCT/Il2016/050003 Europe, Canada, China, Hong Kong USA, Australia, Mexico, Israel, New Zealand, South Africa 2036 Use of Plant Cells Expressing a TNF Alpha Polypeptide Inhibitor in Therapy/PCT/IL2014/050231 N/A Israel 2034 Removal of Constructs from Transformed Cells/PCT/IL2019/ 051266 USA, Israel, Japan, New Zealand, Australia N/A N/A Long-Acting DNase/PCT/IL2021/051207 Canada, Israel, USA, Japan, Europe, Hong Kong, Republic of Korea, China N/A N/A Dicer-Like Knock-Out Plant Cells/ PCT/IL2021/051194 Israel, USA, Japan, Europe, Hong Kong, Republic of Korea, China N/A N/A Modified Uricase and Uses Thereof/PCT/IL2021/051305 Japan, Canada, Brazil, USA, Israel, Mexico, Europe, Republic of Korea, China N/A N/A Methods of treating diseases associated with elevated uric acid N/A N/A N/A ​ (1) Patent granted in Australia expires in 2029.
Global Pending Jurisdictions Granted Jurisdictions Nominal Expiry Production of High Mannose Proteins in Plant Culture/PCT/ Il2004 000181 N/A Russian Federation, Australia, USA 2025(1) (3) Plant Cell/Tissue Culturing Device, System and Method/PCT/Il2005/000228 N/A Israel 2025 Large Scale Disposable Bioreactor/PCT/Il2008/000614 N/A Australia, Canada, China, Europe, Hong Kong, India, Israel, Republic of Korea, Russian Federation, Singapore, South Africa, USA, Brazil 2028(2) Stabilized Alpha-galactosidase and uses thereof/PCT/Il2011/ 000209 Brazil Canada, South Africa, Russian Federation, Singapore, Israel, India, New Zealand, Republic of Korea, Australia, China, Japan, USA, Europe, Hong Kong, India, Brazil 2031(3) Nucleic Acid Construct for Expression of Alpha-galactosidase in Plants and Plant Cells/PCT/ Il2011/000719 N/A India, China, Republic of Korea, Japan, Israel, Europe, Hong Kong, USA, Brazil 2031(2) Therapeutic Regimen For The Treatment of Fabry Using Stabilized Alpha-galactosidase/ PCT/Il2018/050018 Europe, Brazil, Japan, Canada, Israel, Republic of Korea, China, Hong Kong South Africa, New Zealand, Russian Federation, USA, Chile, Mexico, Australia 2038 18 Table of Contents Dry Powder Formulations of DNase 1/PCT/Il2013/050094 N/A Israel, USA 2033 DNase I Polypeptides, Polynucleotides Encoding Same, Methods of Producing DNase I and uses thereof in Therapy/PCT/ Il2013/050097 N/A Europe, Israel, Brazil 2033 Inhalable Liquid Formulations of DNase I/PCT/Il2013/050096 N/A Israel, USA 2033 Modified DNase and uses thereof/ PCT/Il2016/050003 Europe, Canada, China, Hong Kong USA, Australia, Mexico, Israel, New Zealand, South Africa 2036 Removal of Constructs from Transformed Cells/PCT/IL2019/ 051266 USA, Israel, New Zealand, Australia Japan, 2040 Long-Acting DNase/PCT/IL2021/051207 Canada, Israel, USA, Japan, Europe, Hong Kong, Republic of Korea, China N/A 2041 Dicer-Like Knock-Out Plant Cells/ PCT/IL2021/051194 Israel, USA, Japan, Europe, Hong Kong, Republic of Korea, China N/A 2041 Modified Uricase and Uses Thereof/PCT/IL2021/051305 Japan, Canada, Brazil, USA, Israel, Mexico, Europe, Republic of Korea, China N/A 2041 Methods of treating diseases associated with elevated uric acid USA N/A N/A (1) Patent granted in Australia expires in 2029.
The phase III program was preceded by the phase I/II clinical trial, a dose range finding study in ERT-naïve adult patients with Fabry disease, which was completed in 2016.
The phase III program was preceded by the phase I/II clinical trial, a dose range finding study in ERT-naïve adult patients with Fabry disease.
Phase I/II Study The phase I/II clinical trial of PRX-102 (NCT01678898) was a worldwide, multi-center, open-label, dose ranging study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and efficacy parameters of PRX-102 in adult patients with Fabry disease. It was completed in 2015.
No Fabry clinical events were reported during the study. Phase I/II Study The phase I/II clinical trial of PRX-102 (NCT01678898) was a worldwide, multi-center, open-label, dose ranging study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and efficacy parameters of PRX-102 in adult patients with Fabry disease. It was completed in 2015.
In particular, the FDA determined that substantial evidence of effectiveness for Elfabrio in Fabry patients was established with one adequate and well-controlled study, our phase I\II clinical trial of Fabry disease, with confirmatory evidence provided by the BALANCE study.
The FDA noted its determination that substantial evidence of effectiveness for Elfabrio in Fabry patients was established with one adequate and well-controlled study, our phase I\II clinical trial of Fabry disease, with confirmatory evidence provided by the BALANCE study.
In August 2014, the FDA approved Elelyso for injection for pediatric patients. Elelyso is the first plant cell derived recombinant protein to be approved by the FDA for the treatment of Gaucher disease and is now approved in 23 markets including the United States, Brazil, Israel and others.
Elelyso is the first plant cell derived recombinant protein to be approved by the FDA for the treatment of Gaucher disease and is now approved in 23 markets including the United States, Brazil, Israel and others.
The Brazilian MoH clinical treatment guidelines (PCDT) state that BioManguinhos alfataliglicerase is the therapy of choice for newly diagnosed patients. BioManguinhos alfataliglicerase is currently estimated to be used by approximately 25% of Gaucher patients in Brazil.
Gaucher patients in Brazil are entitled to receive ERT paid for by the Brazilian MoH. The Brazilian MoH clinical treatment guidelines (PCDT) state that BioManguinhos alfataliglicerase is the therapy of choice for newly diagnosed patients. BioManguinhos alfataliglicerase is currently estimated to be used by approximately 25% of Gaucher patients in Brazil.
The current standard of care for Gaucher disease is ERT, which is a medical treatment where recombinant enzymes are injected into patients to replace the lacking or dysfunctional enzyme. In Gaucher disease, recombinant GCD is infused to replace the mutated or deficient natural GCD enzyme.
The current standard of care for Gaucher disease is ERT, which is a medical treatment where recombinant enzymes are injected into patients to replace the lacking or dysfunctional enzyme. In Gaucher disease, recombinant GCD is infused to replace the mutated or deficient natural GCD enzyme. Elelyso is the only alternative ERT treatment of Gaucher disease to Cerezyme and Vpriv.
Regulatory Background On November 9, 2022, we, together with Chiesi, resubmitted to the FDA a BLA for PRX-102, the name we assigned to Elfabrio internally prior to its approvals, for the potential treatment of adult patients with Fabry disease.
Regulatory Background On November 9, 2022, we, together with Chiesi, resubmitted to the FDA a BLA for PRX-102, the name we assigned to Elfabrio internally prior to its approvals, for the potential treatment of adult patients with Fabry disease. The initial BLA for PRX-102 was submitted to the FDA in May 2020.
We also agreed to negotiate certain manufacturing related matters. On August 29, 2022, we entered into the F/F Agreement and the Letter Agreement.
We also agreed to negotiate certain manufacturing related matters. 21 Table of Contents On August 29, 2022, we entered into the F/F Agreement and the Letter Agreement.
PRX-102 was well-tolerated in the BRIDGE study, with all adverse events being transient in nature without sequelae. Of the 22 patients enrolled in the BRIDGE study, the majority of TEAEs were mild or moderate in severity, with two patients (9.1%) withdrawing from the therapy due to hypersensitivity reaction that was resolved.
PRX-102 was well-tolerated in the BRIDGE study, with all adverse events being transient in nature without sequelae. The majority of TEAEs were mild or moderate in severity, with two patients (9.1%) withdrawing from the therapy due to hypersensitivity reaction that was resolved. The most common moderate TEAEs were nasopharyngitis, headache and dyspnea.
In the study, patients were screened and evaluated over three months while continuing agalsidase alfa treatment. The study was completed in December 2019. Final results of the data generated in the BRIDGE study showed substantial improvement in renal function as measured by mean annualized eGFR slope in both male and female patients.
In the study, patients were screened and evaluated over three months while continuing agalsidase alfa treatment. Final results of the data generated in the BRIDGE study showed substantial improvement in renal function as measured by mean annualized eGFR slope in both male and female patients. Twenty of 22 patients completed the 12-month treatment duration.
BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA. We used the Rolling Review option for our taliglucerase alfa NDA, which we completed in April 2010. Accelerated Approval Section 901 of the U.S.
BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA. We used the Rolling Review option for our taliglucerase alfa NDA, which we completed in April 2010.
Excessive formation or ineffective clearance of NETs can cause different pathological effects. NETs formation has been observed in various autoimmune, inflammatory and fibrotic conditions, diverse forms of thrombosis, cancer and metastasis. According to scientific literature, animal studies have demonstrated that DNase treatment reduces NETs toxicity.
NETs are composed of DNA, histones, antimicrobial and pro-inflammatory proteins. Excessive formation or ineffective clearance of NETs can cause different pathological effects. NETs formation has been observed in various autoimmune, inflammatory and fibrotic conditions, diverse forms of thrombosis, cancer and metastasis. According to scientific literature, animal studies have demonstrated that DNase treatment reduce NETs toxicity.
There were no serious or severe treatment-related TEAEs and no TEAEs led to death or study withdrawal. Of the treatment-related TEAEs, 27 were infusion-related reactions (IRRs) and the remainder were single events of diarrhea, erythema, fatigue, influenza-like illness, increases urine protein/creatinine ratio, and urine positive for white blood cells. The 27 IRRs were reported in five (16.7%) patients, all male.
Of the treatment-related TEAEs, 27 were infusion-related reactions (IRRs) and the remainder were single events of diarrhea, erythema, fatigue, influenza-like illness, increases urine protein/creatinine ratio, and urine positive for white blood cells. The 27 IRRs were reported in five (16.7%) patients, all male.
Under the Research Law and the regulations promulgated thereunder, the NATI Council may allow the transfer outside of Israel of know-how derived from an approved program and the related manufacturing rights in limited circumstances which are currently as follows: ● in the event of a sale of know-how itself to a non-affiliated third party, provided that upon such sale the owner of the know-how pays to NATI an amount, in cash, as set forth in the Research Law (and the regulations promulgated thereunder).
No assurance can be made that approval to any such transfer, if requested, will be granted. 32 Table of Contents Under the Research Law and the regulations promulgated thereunder, the NATI Council may allow the transfer outside of Israel of know-how derived from an approved program and the related manufacturing rights in limited circumstances which are currently as follows: ● in the event of a sale of know-how itself to a non-affiliated third party, provided that upon such sale the owner of the know-how pays to NATI an amount, in cash, as set forth in the Research Law (and the regulations promulgated thereunder).
Competition The biotechnology and pharmaceutical industries are characterized by rapidly evolving technology and significant competition. Competition from numerous existing companies and others entering the fields in which we operate is intense and expected to increase. Most of these companies have substantially greater research and development, manufacturing, marketing, financial, technological personnel and managerial resources than we do.
Competition from numerous existing companies and others entering the fields in which we operate is intense and expected to increase. Most of these companies have substantially greater research and development, manufacturing, marketing, financial, technological personnel and managerial resources than we do.
Our first product, Elelyso ® (taliglucerase alfa, except in Brazil where it is marketed as BioManguinhos alfataliglicerase), an ERT for the treatment of patients with Gaucher disease was first approved by the FDA in May 2012 and is now approved for marketing in 23 markets including Brazil, Israel and others.
Our first product, Elelyso ® , an ERT for the treatment of patients with Gaucher disease, was first approved by the FDA in May 2012 and is now approved for marketing in 23 markets including Brazil, Israel and others.
If Protalix Ltd. does not fulfill these conditions in whole or in part, the benefits can be canceled and Protalix Ltd. may be required to refund the benefits received, linked to the Israeli consumer price index with interest. We believe that Protalix Ltd. currently operates in compliance with all applicable conditions and criteria.
If Protalix Ltd. does not fulfill these conditions in whole or in part, the benefits can be canceled and Protalix Ltd. may be required to refund the benefits received, linked to the Israeli consumer price index with interest.
The process required by the FDA before a biological product or drug may be marketed in the United States generally involves the following: ● Completion of preclinical laboratory tests, animal studies and formulation studies according to Good Laboratory Practices or other regulations; ● Submission to the FDA of an investigational new drug application, or IND, which must become effective before human clinical trials may begin; ● Performance of adequate and well-controlled clinical trials according to Good Clinical Practices, or GCP, to establish the safety and efficacy of the proposed biological product or drug for its intended use; 21 Table of Contents ● Submission to the FDA of a BLA for a new biological product or a new drug application, or NDA, for a new drug; ● Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with cGMP to assure that the facilities, methods and controls are adequate to preserve the drug’s or biologic’s identity, strength, quality and purity; and ● FDA review and approval of the BLA or NDA.
The process required by the FDA before a biological product or drug may be marketed in the United States generally involves the following: ● Completion of preclinical laboratory tests, animal studies and formulation studies , with certain studies conducted in accordance with Good Laboratory Practice regulations, or GLPs, and other applicable regulations ; ● Submission to the FDA of an investigational new drug application, or IND, which must become effective before human clinical trials may begin; ● Approval by an independent institutional review board, or IRB, or ethics committee at each clinical site before each trial may be initiated; ● Performance of adequate and well-controlled clinical trials according to Good Clinical Practices, or GCPs, to establish the safety and efficacy of a proposed drug candidate, and the safety, purity and potency of a proposed biological product candidate, for its intended use ; ● Submission to the FDA of a BLA for a new biological product or a new drug application, or NDA, for a new drug; ● Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with cGMP to assure that the facilities, methods and controls are adequate to preserve the drug’s or biologic’s identity, strength, quality and purity; ● satisfactory completion of potential inspection of selected clinical investigation sites to assess compliance with GCPs; and ● FDA review and approval of the BLA or NDA.
In the study, the mean annualized eGFR slope of the study participants improved from -5.90 mL/min/1.73m 2 /year while on agalsidase alfa to -1.19 mL/min/1.73m 2 /year on PRX-102 in all patients. Male patients improved from -6.36 mL/min/1.73m 2 /year to -1.73mL/min/1.73m 2 /year and female patients improved from -5.03 mL/min/1.73m 2 /year to -0.21 mL/min/1.73m 2 /year.
In the study, the mean annualized eGFR slope of the study participants improved from -5.90 mL/min/1.73m 2 /year while on agalsidase alfa to -1.19 mL/min/1.73m 2 /year on PRX-102 in all patients.
We have undergone successful inspections by the FDA, the Irish Medicines Board (under the EMA’s centralized marketing authorization procedure), the Brazilian National Health Surveillance Agency (ANVISA), the Israeli Ministry of Health, the Turkish Ministry of Health, the Australian Therapeutic Goods Administration (TGA) and Health Canada.
Our manufacturing facilities are subject to inspections by various regulatory authorities from time to time. We have undergone successful inspections by the FDA, the Irish Medicines Board (under the EMA’s centralized marketing authorization procedure), the Brazilian National Health Surveillance Agency (ANVISA), the Israeli Ministry of Health, the Turkish Ministry of Health, the Australian Therapeutic Goods Administration (TGA) and Health Canada.
Both approvals cover the 1 mg/kg every two weeks dosage. Overall, the FDA review team concluded that in the context of Fabry disease as a rare, serious disease with limited therapeutic options that may not be suitable to all individual patients, the benefit-risk of Elfabrio is favorable for the treatment of adults with confirmed Fabry disease.
Similarly, the FDA review team concluded that in the context of Fabry disease as a rare, serious disease with limited therapeutic options that may not be suitable to all individual patients, the benefit-risk of Elfabrio is favorable for the treatment of adults with confirmed Fabry disease.
A total of 77 patients were treated; 52 with PRX-102 and 25 with agalsidase beta. Approximately 40% of the enrolled patients were female. Forty-seven (90.4%) patients in the PRX-102 arm experienced at least one treatment-emergent adverse event (TEAE) compared to 24 (96.0%) in the agalsidase beta arm.
Approximately 40% of the enrolled patients were female. 10 Table of Contents Forty-seven (90.4%) patients in the PRX-102 arm experienced at least one treatment-emergent adverse event (TEAE) compared to 24 (96.0%) in the agalsidase beta arm.
The global market for Fabry disease, that includes agalsidase beta, Sanofi’s Fabrazyme ® , agalsidase alfa, Shire’s (acquired by Takeda Pharmaceutical Company Limited) Replagal ® and Amicus Therapeutics’ Galafold ® , among others, is forecasted to be approximately $2.0 billion in 2023 and is forecasted to grow at a CAGR of 6.8% from 2023-2029 reaching approximately $3.1 billion in annual sales at the end of the decade.
The global market for Fabry disease, that includes agalsidase beta, Sanofi’s Fabrazyme ® , agalsidase alfa, Shire’s Replagal ® and Amicus Therapeutics’ Galafold ® , among others, is forecasted to be approximately $2.3 billion in 2025 and is forecasted to grow at a CAGR of 6.6% from 2024-2030 reaching approximately $3.1 billion in annual sales in 2030.
A company that qualifies as a foreign investors’ company and has an Approved Enterprise program is eligible for tax benefits for a 10-year benefit period and may enjoy a reduced corporate tax rate of 10% to 23%, depending on the amount of the company’s shares held by non-Israeli shareholders.
A company that qualifies as a foreign investors’ company and has an Approved Enterprise program is eligible for tax benefits for a 10-year benefit period and may enjoy a reduced corporate tax rate of 10% to 23%, depending on the amount of the company’s shares held by non-Israeli shareholders. 30 Table of Contents If a company that has an Approved Enterprise program is a wholly-owned subsidiary of another company, the percentage of foreign investments is determined based on the percentage of foreign investment in the parent company.
On February 7, 2022, the PRX-102 MAA was submitted to, and subsequently validated by, the EMA. The submission was made after the October 8, 2021 meeting we held, together with Chiesi, with the Rapporteur and Co-Rapporteur of the EMA regarding PRX-102.
A Marketing Authorization Application, or MAA, was submitted to the EMA on February 7, 2022, after the October 8, 2021 meeting we held, together with Chiesi, with the Rapporteur and Co-Rapporteur of the EMA regarding PRX-102.
These companies base their product development on transgenic plants or whole plants. 18 Table of Contents Agreements and Partnerships Elelyso – Pfizer We have licensed to Pfizer the global rights to Elelyso in all markets, excluding Brazil, pursuant to an Amended and Restated Exclusive License and Supply Agreement, or the Amended Pfizer Agreement, which we entered into with Pfizer in October 2015 to amend and restate our initial Exclusive License and Supply Agreement with Pfizer, or the Pfizer Agreement.
Agreements and Partnerships Elelyso – Pfizer We have licensed to Pfizer the global rights to Elelyso in all markets, excluding Brazil, pursuant to an Amended and Restated Exclusive License and Supply Agreement, or the Amended Pfizer Agreement, which we entered into with Pfizer in October 2015 to amend and restate our initial Exclusive License and Supply Agreement with Pfizer, or the Pfizer Agreement.
As of December 31, 2023, Protalix Ltd. either paid or accrued royalties payable of $17.7 million, and Protalix Ltd.’s contingent liability to NATI with respect to grants received was approximately $35.5 million.
As of December 31, 2024, Protalix Ltd. either paid or accrued royalties payable of $19.3 million, and Protalix Ltd.’s contingent liability to NATI with respect to grants received was approximately $33.9 million.
The most common moderate TEAEs were nasopharyngitis, headache and dyspnea. An immunogenicity assessment indicated that four out of 20 patients (20%) developed persistent ADAs over the course of the study, of which two had neutralizing activity.
An immunogenicity assessment indicated that four out of 20 patients (20%) developed persistent ADAs over the course of the study, of which two had neutralizing activity.
In addition, our technology is subject to certain restrictions with respect to the transfer of technology and manufacturing rights. 20 Table of Contents Raw Materials and Suppliers We believe that the raw materials that we require throughout the manufacturing process of Elfabrio and Elelyso, and our current and potential drug product candidates, are widely available from numerous suppliers and are generally considered to be generic industrial biological supplies.
Raw Materials and Suppliers We believe that the raw materials that we require throughout the manufacturing process of Elfabrio and Elelyso, and our current and potential drug product candidates, are widely available from numerous suppliers and are generally considered to be generic industrial biological supplies.
These conditions include, inter alia, the following: ● the Benefitted Enterprise’s revenues from any single country or a separate customs territory may not exceed 75% of the Benefitted Enterprise’s total revenues; or ● at least 25% of the Benefitted Enterprise’s revenues during the benefits period must be derived from sales into a single country or a separate customs territory with a population of at least 14 million people (starting from January 1, 2012, 1.4% must be added for each year).
These conditions include, inter alia, the following: ● the Benefitted Enterprise’s revenues from any single country or a separate customs territory may not exceed 75% of the Benefitted Enterprise’s total revenues; or ● at least 25% of the Benefitted Enterprise’s revenues during the benefits period must be derived from sales into a single country or a separate customs territory with a population of at least 14 million people (starting from January 1, 2012, 1.4% must be added for each year). 31 Table of Contents There can be no assurance that Protalix Ltd. will comply with the above conditions in the future or that Protalix Ltd. will be entitled to any additional benefits under the Investment Law.
PRX-119 PRX-119 is our plant cell-expressed PEGylated recombinant human DNase I product candidate being designed to elongate half-life in the circulation for NETs-related diseases. NETs, Neutrophil extracellular traps, are web-like structures, released by activated neutrophils that trap and kill a variety of microorganisms. NETs are composed of DNA, histones, antimicrobial and pro-inflammatory proteins.
PRX-119 PRX-119 is our plant cell-expressed PEGylated recombinant human DNase I product candidate which we are designing to have an elongated half-life in the circulation for the potential treatment of NETs-related diseases. NETs, or Neutrophil extracellular traps, are web-like structures released by activated neutrophils that trap and kill a variety of microorganisms.
Our strategy moving forward is to develop proprietary recombinant proteins designed to address high, unmet needs in the genetic and non-genetic rare disease space that are therapeutically superior to existing recombinant proteins currently marketed for the same indications.
Our strategy moving forward is to develop proprietary recombinant proteins designed to address high, unmet needs in the genetic and non-genetic rare disease space that are therapeutically superior to existing recombinant proteins currently marketed for the same indications. Consistent with this strategy, we have a number of product candidates in varying stages of the clinical development process.
Zeev Bronfeld, the former Chairman of our Board retired for personal reasons, effective as of the same date. 7 Table of Contents Our Marketed Products Elelyso for the Treatment of Gaucher Disease Elelyso (taliglucerase alfa), our first commercial product, was approved by the FDA in 2012 for injection as an ERT for the long-term treatment of adult patients with a confirmed diagnosis of type 1 Gaucher disease.
Our Marketed Products Elelyso for the Treatment of Gaucher Disease Elelyso (taliglucerase alfa), our first commercial product, was approved by the FDA in 2012 for injection as an ERT for the long-term treatment of adult patients with a confirmed diagnosis of type 1 Gaucher disease. In August 2014, the FDA approved Elelyso for injection for pediatric patients.
However, low adherence, under dosing and disease progression that cause high patient burden require new, effective and safe therapies to treat these severe, underserved gout patients.
However, factors such as low adherence, under dosing, disease progression that cause high patient burden or patients that are not suitable for available therapy, require new, effective and safe therapies to treat these underserved uncontrolled gout patients.
The FDA label of krystexxa was amended in 2022 to include co-treatment of metrotrexate to prolong efficacy and increases tolerability in patients with refractory gout. Krystexxa is no longer marketed in the European Union.
Both have a black box warning for anaphylaxis and other major side-effects. The FDA label of Krystexxa was amended in 2022 to include co-treatment of methotrexate to prolong efficacy and increases tolerability in patients with refractory gout. Krystexxa is no longer marketed in the European Union.
Extension Studies Patients who completed the BALANCE , BRIDGE and BRIGHT studies, and the extension of the phase I/II study, were offered the opportunity to continue PRX-102 treatment in one of two long-term open-label extension studies.
Extension Studies Two long-term open-label extension studies were available for patients who completed the BALANCE , BRIDGE and BRIGHT studies, and the extension of the phase I/II study.
Our unique expression system represents a new method for developing recombinant proteins in an industrial-scale manner. To date, we have successfully developed two commercial products.
Our unique expression system represents a new method for developing recombinant proteins in an industrial-scale manner.
In 202 3 , we generated $12.5 million from sales of Elelyso to Pfizer and $10.4 million from sales of BioManguinhos alfataliglicerase to the Brazilian MoH.
In 2024, we generated $12.6 million from sales of Elelyso to Pfizer and $11.0 million from sales of BioManguinhos alfataliglicerase to the Brazilian MoH.
The uricase enzyme converts uric acid to allantoin, which is easily eliminated through urine and does not exist naturally in humans. This recombinant enzyme, expressed via our ProCellEx system, is designed to lower uric acid levels and improve clinical manifestation of the disease while having low immunogenicity and increased half-life of the drug in the blood.
This recombinant enzyme, expressed via our ProCellEx system, is designed to lower urate levels and improve clinical manifestation of the disease while having low immunogenicity and increased half-life of the drug in the blood.
Due to travel restrictions during the COVID-19 pandemic, the FDA was unable to conduct the required pre-approval inspection during the review cycle. In addition to the foregoing, the FDA noted that agalsidase beta had recently been converted to full approval, a change in regulatory circumstances which had to be addressed in the resubmitted BLA for PRX-102.
In addition to the foregoing, the FDA noted that agalsidase beta had recently been converted to full approval, a change in regulatory circumstances which had to be addressed in the resubmitted BLA for PRX-102.
The phase III clinical program included three individual studies; the BALANCE study, the BRIDGE study the BRIGHT study, all of which have been completed.
The phase III clinical program included three individual studies; the BALANCE study, the BRIDGE study and the BRIGHT study.
Icon may also terminate the exclusivity granted to us by written notice if we fail to reach certain milestones within a designated period of time. Notwithstanding the termination date of the agreement, our obligation to pay royalties to Icon under the agreement may expire prior to the termination of the agreement, subject to certain conditions.
Icon may also terminate the exclusivity granted to us by written notice if we fail to reach certain milestones within a designated period of time.
We anticipate that we will apply for restorations of the patent term for certain of patents covering our product candidates. 23 Table of Contents Fast Track Designation The FDA has a fast track program that is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need, the purpose being to make important new drugs available to patients earlier.
Fast Track Designation; Breakthrough Therapy Designation The FDA has a fast track program that is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need, the purpose being to make important new drugs available to patients earlier.
In addition, we are developing PEGylated uricase, or PRX-115, for the treatment of severe gout, Long Acting (LA) DNase I, or PRX-119, for the treatment of NETs-related diseases, and a number of other technologies and preclinical assets. Our proprietary ProCellEx platform is being used to manufacture both of our approved and marketed products as well as PRX-115 and PRX-119.
In addition, we are developing PEGylated uricase, or PRX-115, for the treatment of uncontrolled gout, Long Acting (LA) DNase I, or PRX-119, for the treatment of NETs-related diseases, and a number of other technologies and preclinical assets.
Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the applicable product candidate does not undergo unacceptable deterioration over its shelf life. 22 Table of Contents The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the product candidate, proposed labeling and other relevant information, are submitted to the FDA as part of an NDA or BLA, requesting approval to market the product.
The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the product candidate, proposed labeling and other relevant information, are 24 Table of Contents submitted to the FDA as part of an NDA or BLA, requesting approval to market the product.
The global market for Gaucher disease, that includes Sanofi’s Cerezyme ® , Shire’s Vpriv ® and Sanofi’s Cerdelga ® , among others, was $1.6 billion in 2023, is forecasted to be approximately $1.6 billion in 2024 and is forecasted to grow at a CAGR of approximately 1% from 2023-2029.
The global market for Gaucher disease, that includes Sanofi’s Cerezyme ® , Shire’s (acquired by Takeda Pharmaceutical Company Limited) Vpriv ® and Sanofi’s Cerdelga ® , among others, was $1.7 billion in 2024, is forecasted to be approximately $1.7 billion in 2025 and is forecasted to grow at a compound annual growth rate (CAGR) of approximately -0.46% from 2024-2030.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeThe securities of life sciences companies often experience significant volatility in connection with clinical trial and regulatory announcements. 57 Table of Contents We anticipate that the market price of our common stock is likely to continue to fluctuate significantly in response to numerous factors, some of which are beyond our control, such as: ● sales of Elfabrio by Chiesi; ● our sale of shares of our common stock under our ATM program, or market expectations that such sales are to be executed; ● purchases of BioManguinhos alfataliglicerase in Brazil; ● the progress and results of the studies of our product candidates under development; ● the announcement of new products or product enhancements by us or our competitors; ● developments concerning intellectual property rights and regulatory approvals; ● variations in our and our competitors’ results of operations; ● changes in earnings estimates or recommendations by securities analysts; ● developments in the biotechnology industry; and ● general market conditions and other factors, including factors unrelated to our operating performance, such as the Israel-Hamas war.
Biggest changeWe anticipate that the market price of our common stock is likely to continue to fluctuate significantly in response to numerous factors, some of which are beyond our control, such as: ● sales of Elfabrio by Chiesi; ● purchases of BioManguinhos alfataliglicerase in Brazil; ● the progress and results of the studies of our product candidates under development; ● the announcement of new products or product enhancements by us or our competitors; 58 Table of Contents ● developments concerning intellectual property rights and regulatory approvals; ● variations in our and our competitors’ results of operations; ● changes in earnings estimates or recommendations by securities analysts; ● developments in the biotechnology industry; and ● general market conditions and other factors, including factors unrelated to our operating performance, such as the Israel-Hamas war.
In October 2023, terrorists from the Hamas organization infiltrated Israel’s southern border from the Gaza Strip and in other areas within the State of Israel attacking a number of civilian and military targets while simultaneously launching extensive rocket attacks on the Israeli population and industrial centers. At the same time, clashes between Israel and Hezbollah in Lebanon have increased.
In October 2023, terrorists from the Hamas organization infiltrated Israel’s southern border from the Gaza Strip and in other areas within the State of Israel attacking a number of civilian and military targets while simultaneously launching extensive rocket attacks on the Israeli population and industrial centers. At the same time, clashes between Israel and Hezbollah in Lebanon increased.
Future acceptance and use of any of our products will depend upon a number of factors including: ● perceptions by physicians, patients, third party payors and others in the medical community about the safety and effectiveness of Elfabrio or Elelyso, or any future product, if any; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; 36 Table of Contents ● the prevalence and severity of any side effects, including any limitations or warnings contained in our products’ approved labeling, including the boxed warning associated with Elfabrio in the United States; ● pharmacological benefits of Elfabrio or Elelyso, or any future product, if any relative to competing products and products under development; ● the efficacy and potential advantages relative to competing products and products under development; ● relative convenience and ease of administration; ● effectiveness of education, marketing and distribution efforts by Chiesi, Pfizer and any other relevant licensees and distributors; ● publicity concerning Elfabrio or Elelyso, or any future product, if any, or concerning competing products and treatments; and ● the price for our products and competing products.
Future acceptance and use of any of our products will depend upon a number of factors including: ● perceptions by physicians, patients, third party payors and others in the medical community about the safety and effectiveness of Elfabrio or Elelyso, or any future product, if any; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ● the prevalence and severity of any side effects, including any limitations or warnings contained in our products’ approved labeling, including the boxed warning associated with Elfabrio in the United States; 38 Table of Contents ● pharmacological benefits of Elfabrio or Elelyso, or any future product, if any relative to competing products and products under development; ● the efficacy and potential advantages relative to competing products and products under development; ● relative convenience and ease of administration; ● effectiveness of education, marketing and distribution efforts by Chiesi, Pfizer and any other relevant licensees and distributors; ● publicity concerning Elfabrio or Elelyso, or any future product, if any, or concerning competing products and treatments; and ● the price for our products and competing products.
Failure to comply with applicable requirements of the FDA or comparable foreign regulatory authorities could result in, among other things, any of the following actions: ● warning letters; ● fines and other monetary penalties; ● unanticipated expenditures; ● delays in the FDA’s or other foreign regulatory authorities’ approving, or the refusal of any regulatory authority to approve, any drug candidate; ● product recall or seizure; ● interruption of manufacturing or clinical trials; ● operating restrictions; ● injunctions; and ● criminal prosecutions. 46 Table of Contents In addition to the approval requirements, other numerous and pervasive regulatory requirements apply, both before and after approval, to us, our drug candidates, our suppliers, contract manufacturers, and contract testing laboratories.
Failure to comply with applicable requirements of the FDA or comparable foreign regulatory authorities could result in, among other things, any of the following actions: ● warning letters; ● fines and other monetary penalties; ● unanticipated expenditures; ● delays in the FDA’s or other foreign regulatory authorities’ approving, or the refusal of any regulatory authority to approve, any drug candidate; ● product recall or seizure; ● interruption of manufacturing or clinical trials; ● operating restrictions; ● injunctions; and ● criminal prosecutions. 48 Table of Contents In addition to the approval requirements, other numerous and pervasive regulatory requirements apply, both before and after approval, to us, our drug candidates, our suppliers, contract manufacturers, and contract testing laboratories.
We have agreed to sell drug substance to Pfizer and Chiesi for the production of Elelyso and Elfabrio. With respect to Elelyso, our drug substance supply commitment is for a 15-year period after the execution of the Amended Pfizer Agreement, subject to certain terms and conditions.
We have agreed to sell drug substance to Pfizer and Chiesi for the production of Elelyso and Elfabrio, respectively. With respect to Elelyso, our drug substance supply commitment is for a 15-year period after the execution of the Amended Pfizer Agreement, subject to certain terms and conditions.
If we or any of our current or future partners breach or terminate the agreements that make up such arrangements, our partners otherwise fail to conduct their obligations under such arrangements in a timely 39 Table of Contents manner, there is a dispute about their obligations or if either party terminates the applicable agreement or elects not to continue the arrangement, we may not enjoy the benefits of the agreements or receive a sufficient amount of royalty or milestone payments from them, if any, which may have a material adverse effect on our business, results of operations and financial condition.
If we or any of our current or future partners breach or terminate the agreements that make up such arrangements, our partners otherwise fail to conduct their obligations under such arrangements in a timely manner, there is a dispute about their obligations or if either party terminates the applicable agreement or elects not to continue the arrangement, we may not enjoy the benefits of the agreements or receive a sufficient amount of royalty or 41 Table of Contents milestone payments from them, if any, which may have a material adverse effect on our business, results of operations and financial condition.
In-licensing additional drug candidates may significantly increase our capital requirements, and 41 Table of Contents place a strain on the time of our existing personnel, which may delay or otherwise adversely affect the development of our existing drug candidates or cause us to re-prioritize our drug pipeline if we do not have the necessary capital resources to develop all of our drug candidates, which may have a material adverse effect on our business, results of operations and financial condition.
In-licensing additional drug candidates may significantly increase our capital requirements, and place a strain on the time of our existing personnel, which may delay or otherwise adversely affect the development of our existing drug candidates or cause us to re-prioritize our drug pipeline if we do not have the necessary capital 43 Table of Contents resources to develop all of our drug candidates, which may have a material adverse effect on our business, results of operations and financial condition.
Human clinical trials are very expensive and difficult to design and implement, in part because they are subject to rigorous regulatory requirements. Preliminary and initial results from a clinical trial do not necessarily predict final results, and failure can occur at any stage of the trial.
Preclinical and clinical trials are very expensive and difficult to design and implement, in part because they are subject to rigorous regulatory requirements. Preliminary and initial results from a clinical trial do not necessarily predict final results, and failure can occur at any stage of the trial.
Any failure or perceived failure by us to comply with local or foreign laws or regulation, our internal policies and procedures or our contracts governing our processing of personal information could result in negative publicity, government investigations 43 Table of Contents and enforcement actions, claims by third parties and damage to our reputation, any of which could have a material adverse effect on our business, results of operation and financial condition.
Any failure or perceived failure by us to comply with local or foreign laws or regulation, our internal policies and procedures or our contracts governing our processing of personal information could result in negative publicity, government investigations and enforcement actions, claims by third parties and damage to our reputation, any of which could have a material adverse effect on our business, results of operation and financial condition.
The distribution of those earnings or advances or other distributions of funds by our subsidiary to us, as well as our receipt of such funds, are contingent upon the earnings of Protalix Ltd. and are subject to various business considerations and U.S. and Israeli laws.
The distribution of those earnings or advances or other distributions of funds by our subsidiaries to us, as well as our receipt of such funds, are contingent upon the earnings of Protalix Ltd. and are subject to various business considerations and U.S. and Israeli laws.
Furthermore, the approval of pharmaceutical products generally includes requirements related to the preparation of a Risk Evaluation and Mitigation Strategy, or REMS, or a risk 35 Table of Contents management plan as required by the EMA, which could include a medication guide outlining the risks of such side effects for distribution to patients, a communication plan for healthcare providers and/or other elements to assure safe use.
Furthermore, the approval of pharmaceutical products generally includes requirements related to the preparation of a Risk Evaluation and Mitigation Strategy, or REMS, or a risk management plan as required by the EMA, which could include a medication guide outlining the risks of such side effects for distribution to patients, a communication plan for healthcare providers and/or other elements to assure safe use.
Effective in 2022, the TCJA requires all U.S. companies to capitalize and subsequently amortize R&D expenses that fall within the scope of Section 174 over five years for research activities conducted in the United States and over 15 years for research activities conducted outside of the United States rather than deducting such costs in the year incurred for tax purposes.
Effective in 2022, the TCJA requires all U.S. companies to capitalize and subsequently amortize R&D expenses that fall within the scope of Section 174 over five years for research activities conducted in the United States and over 15 years for research activities conducted outside of the United States rather 46 Table of Contents than deducting such costs in the year incurred for tax purposes.
If a dispute arises, a court may determine that the right belongs to a third party, and enforcement of our rights can be costly and unpredictable. In addition, we rely on trade secrets and proprietary know-how that we seek to protect in part by confidentiality agreements with our employees, contractors, consultants, advisors and others.
If a dispute arises, a court may determine that the right belongs to a third party, and enforcement of our rights can be costly and unpredictable. In addition, we rely on trade secrets and proprietary know-how that we seek 54 Table of Contents to protect in part by confidentiality agreements with our employees, contractors, consultants, advisors and others.
Even if we do receive approval to manufacture products developed 56 Table of Contents with government grants outside of Israel, we may be required to pay an increased total amount of royalties (possibly up to 600% of the grant amounts plus interest), depending on the manufacturing volume that is performed outside of Israel, as well as a possibly increased royalty rate.
Even if we do receive approval to manufacture products developed with government grants outside of Israel, we may be required to pay an increased total amount of royalties (possibly up to 600% of the grant amounts plus interest), depending on the manufacturing volume that is performed outside of Israel, as well as a possibly increased royalty rate.
Our failure to adhere to or successfully implement processes in response to changing regulatory requirements in this area could result in legal liability or impairment to our reputation in the marketplace, which could have a material adverse effect on our business, financial condition and results of operations. We could be subject to securities class action litigation.
Our failure to adhere to or successfully implement processes in response to changing regulatory requirements in this area could result in legal liability or impairment to our reputation in the marketplace, which could have a material adverse effect on our business, financial condition and results of operations. 45 Table of Contents We could be subject to securities class action litigation.
Delays in the approval process for any drug candidate may have a material adverse effect upon our prospects, business, results of operations and financial condition. 47 Table of Contents Clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs, which may have a material adverse effect on our business, results of operations and financial condition.
Delays in the approval process for any drug candidate may have a material adverse effect upon our prospects, business, results of operations and financial condition. 49 Table of Contents Preclinical and clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs, which may have a material adverse effect on our business, results of operations and financial condition.
The results of our clinical trials with respect to any drug candidate might not support our claims of safety or efficacy, the results of our clinical trials may fail to conclusively show superiority over other commercially available treatments for the same or similar indications, the effects of our drug candidates may not be the desired effects or may include undesirable side effects or the drug candidates may have other unexpected characteristics.
The results of our clinical trials with respect to any drug candidate might not support our claims of safety or efficacy, the results of our clinical trials may fail to conclusively show superiority over other commercially available treatments for the same or similar indications, the effects of our drug candidates may not be the desired effects or may include 50 Table of Contents undesirable side effects or the drug candidates may have other unexpected characteristics.
The successful worldwide commercialization of Elfabrio and Elelyso depends on several factors, including the following: ● Chiesi’s efforts under the Chiesi Agreements and the effectiveness of Chiesi’s commercial strategy and its execution of that strategy, including its pricing strategy and the effectiveness of its efforts to obtain adequate third-party reimbursements and, to a lesser extent, Pfizer’s and Fiocruz’s efforts; ● expanding the scope of the countries in which our products are approved for marketing; ● maintaining the cGMP compliance of our manufacturing facility or establishing manufacturing arrangements with third parties; ● Chiesi’s development and maintenance of successful sales and marketing organizations for Elfabrio; ● the availability of coverage or reimbursement to patients from relevant healthcare payors for Elfabrio and Elelyso; ● the willingness of patients with Fabry disease and Gaucher disease to switch from other treatments to Elfabrio or Elelyso, as the case may be; ● competition from other approved treatments of Fabry disease and Gaucher disease; ● the continued acceptable safety and efficacy profile of Elfabrio and Elelyso; and ● other risks described in these Risk Factors.
The successful worldwide commercialization of Elfabrio and Elelyso depends on several factors, including the following: ● Chiesi’s efforts under the Chiesi Agreements and the effectiveness of Chiesi’s commercial strategy and its execution of that strategy, including its pricing strategy, its development and maintenance of successful sales and marketing organizations and the effectiveness of its efforts to obtain adequate third-party reimbursements and, to a lesser extent, Pfizer’s and Fiocruz’s efforts; ● expanding the scope of the countries in which our products are approved for marketing; ● maintaining the cGMP compliance of our manufacturing facility or establishing manufacturing arrangements with third parties; ● the willingness of patients with Fabry disease and Gaucher disease to switch from other treatments to Elfabrio or Elelyso, as the case may be; ● competition from other approved treatments of Fabry disease and Gaucher disease; ● the continued acceptable safety and efficacy profile of Elfabrio and Elelyso; and ● other risks described in these Risk Factors.
Any costs incurred in connection with such events or the inability to sell our products may have a material adverse effect on our business, results of operations and financial condition. 54 Table of Contents If we cannot meet requirements under our license agreements, we could lose the rights to our products, which could have a material adverse effect on our business.
Any costs incurred in connection with such events or the inability to sell our products may have a material adverse effect on our business, results of operations and financial condition. If we cannot meet requirements under our license agreements, we could lose the rights to our products, which could have a material adverse effect on our business.
Members of our Board of Directors and our executive officers, could face an increased risk of personal liability in connection with the performance of their duties. As a result, we may have difficulty attracting and retaining qualified directors and executive officers, which could have a material adverse effect on our business.
Members of our Board of Directors and our executive officers, could face an increased risk of personal liability in 59 Table of Contents connection with the performance of their duties. As a result, we may have difficulty attracting and retaining qualified directors and executive officers, which could have a material adverse effect on our business.
Our collaborators may also have relationships with other commercial entities, some of whom may compete with us. If our collaborators also assist our competitors, our competitive position could be harmed. 49 Table of Contents We have only limited experience in regulatory affairs, and some of our drug candidates may be based on new technologies.
Our collaborators may also have relationships with other commercial entities, some of whom may compete with us. If our collaborators also assist our competitors, our competitive position could be harmed. We have only limited experience in regulatory affairs, and some of our drug candidates may be based on new technologies.
For example, Chiesi must follow a risk management plan agreed upon with the EMA with respect to Elfabrio, which includes risk minimization measures in connection with risks associated with hypersensitivity reactions and possible medication errors in the home infusion setting. Our product candidates, if approved, may also be subject to certain post-authorization reporting requirements.
For example, Chiesi must follow a risk management plan agreed upon with the EMA with respect to Elfabrio, which 37 Table of Contents includes risk minimization measures in connection with risks associated with hypersensitivity reactions and possible medication errors in the home infusion setting. Our product candidates, if approved, may also be subject to certain post-authorization reporting requirements.
Protalix Ltd. may not receive the required approvals for any proposed transfer and, if received, Protalix Ltd. may be required to pay NATI a portion of the consideration that it receives upon any sale of such technology by a non-Israeli entity.
Protalix Ltd. may not receive the required approvals for any proposed transfer and, if received, Protalix Ltd. may be required to pay NATI a portion of the consideration that it 57 Table of Contents receives upon any sale of such technology by a non-Israeli entity.
We are highly dependent upon the principal members of our management team, especially our President and Chief Executive Officer, Dror Bashan, as well as the Chairman of our Board of Directors, Eliot Forster, our other directors, consultants and collaborating scientists.
We are highly dependent upon the principal members of our management team, especially our President and Chief Executive Officer, Dror Bashan, as well as the Chairman of our Board of Directors, Eliot R. Forster, Ph.D., our other directors, consultants and collaborating scientists.
Thus, any patents we own or license from or to third parties may not provide any protection against our competitors and those who infringe upon our patents. 53 Table of Contents Furthermore, the life of our patents is limited.
Thus, any patents we own or license from or to third parties may not provide any protection against our competitors and those who infringe upon our patents. Furthermore, the life of our patents is limited.
If physicians, patients, third party payors and others in the medical community do not accept and use Elfabrio, Elelyso or any other future products, our ability to generate revenue from product sales will be materially impaired. Physicians and patients, and other healthcare providers, may not accept and use Elfabrio, Elelyso or any other future of our other product candidates.
If physicians, patients, third party payors and others in the medical community do not accept and use Elfabrio, Elelyso or any other future products, our ability to generate revenue from product sales will be materially impaired. Physicians and patients, and other healthcare providers, may not accept and use Elfabrio, Elelyso or any other products we may develop in the future.
In addition, full reimbursement may not be available for high priced products. Moreover, eligibility for coverage does not imply that any approved product will be reimbursed in all cases or at a rate 37 Table of Contents that allows us to make a profit or even cover our costs.
In addition, full reimbursement may not be available for high priced products. Moreover, eligibility for coverage does not imply that any approved product will be reimbursed in all cases or at a rate that allows us to make a profit or even cover our costs.
As of December 31, 2023, we held, or had license rights to, approximately 90 patents. If patent rights covering our products or technologies are not sufficiently broad, they may not provide us with sufficient proprietary protection or competitive advantages against competitors with similar products and technologies.
As of December 31, 2024, we held, or had license rights to, approximately 75 patents. If patent rights covering our products or technologies are not sufficiently broad, they may not provide us with sufficient proprietary protection or competitive advantages against competitors with similar products and technologies.
Currently, our source of potential revenues will be from royalties and commercial milestone payments generated from Pfizer, Fiocruz and Chiesi. We have also generated revenues from research and development services and milestone and other payments we received in connection with our agreements with our commercialization partners, and generated capital from equity and debt offerings and other sources.
Currently, our sources of potential revenues are royalties and commercial milestone payments generated from Pfizer, Fiocruz and Chiesi. We have also generated revenues from research and development services and milestone and other payments we received in connection with our agreements with our commercialization partners, and generated capital from equity and debt offerings and other sources.
To date, we have not suffered any disruptions to our operations from the absence of employees in connection with the current military action.
To date, we have not suffered any disruptions to our operations from the 56 Table of Contents absence of employees in connection with the current military action.
In addition, more than one drug can have orphan designation for the same indication. Although we may seek orphan drug designation for other product candidates, we might not receive such designations.
In addition, more than one drug can have orphan 52 Table of Contents designation for the same indication. Although we may seek orphan drug designation for other product candidates, we might not receive such designations.
Risks Related to Clinical Trials and Regulatory Matters ● We may not obtain the necessary U.S., EMA or other worldwide regulatory approvals to commercialize our drug candidates in a timely manner, if at all. 33 Table of Contents ● We may experience delays in obtaining regulatory approvals with respect to any drug candidate. ● Clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs. ● If the results of our clinical trials do not support our claims relating to a drug candidate, or if serious side effects are identified, the completion of development of such drug candidate may be significantly delayed or we may be forced to abandon development altogether. ● We may find it difficult to enroll patients in our clinical trials or patients may discontinue their participation in our clinical trials. ● Dependence upon third-party service providers in connection with our clinical trials expose us to risks.
Risks Related to Clinical Trials and Regulatory Matters ● We may not obtain the necessary U.S., EMA or other worldwide regulatory approvals to commercialize our drug candidates in a timely manner, if at all. 35 Table of Contents ● We may experience delays in obtaining regulatory approvals with respect to any drug candidate. ● Preclinical and clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs. ● If the results of our clinical trials do not support our claims relating to a drug candidate, or if serious side effects are identified, the completion of development of such drug candidate may be significantly delayed or we may be forced to abandon development altogether. ● We may find it difficult to enroll patients in our clinical trials or patients may discontinue their participation in our clinical trials. ● Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions. ● Dependence upon third-party service providers in connection with our clinical trials expose us to risks.
While our assessment of our internal control over financial reporting resulted in our conclusion that as of December 31, 2023, our internal control over financial reporting was effective, we cannot predict the outcome of our testing or any subsequent testing by our auditor in future periods.
While our assessment of our internal control over financial reporting resulted in our 44 Table of Contents conclusion that as of December 31, 2024, our internal control over financial reporting was effective, we cannot predict the outcome of our testing or any subsequent testing by our auditor in future periods.
Any failure to commercialize Elfabrio, or the experience of significant delays in doing so, will have a material adverse effect on our business, results of operations and financial condition. We have invested a significant portion of our efforts and financial resources in the development of Elfabrio, and in the past, on the development of Elelyso.
Any failure to successfully commercialize Elfabrio will have a material adverse effect on our business, results of operations and financial condition. We have invested a significant portion of our efforts and financial resources in the development of Elfabrio, and in the past, on the development of Elelyso.
Our NOL carryforwards as of December 31, 2023, are equal to approximately $234.8 million, of which approximately $24.4 million may be restricted under Section 382 of the Internal Revenue Code, or the IRC. IRC Section 382 applies whenever a corporation with NOLs experiences an ownership change.
Our NOL carryforwards as of December 31, 2024, are equal to approximately $227.2 million, of which approximately $22.2 million may be restricted under Section 382 of the Internal Revenue Code, or the IRC. IRC Section 382 applies whenever a corporation with NOLs experiences an ownership change.
Limited reimbursement amounts may reduce the demand for, or the price of, Elfabrio, Elelyso or any other future products. If coverage and reimbursement are not available or are available only to limited levels, the sales of Elfabrio, Elelyso or other future products, if any, may be diminished or we may not be able to sell such products profitably.
If coverage and reimbursement are not available or are 39 Table of Contents available only to limited levels, the sales of Elfabrio, Elelyso or other future products, if any, may be diminished or we may not be able to sell such products profitably.
Any failure to identify and maintain fill and finish service providers could delay our preclinical and clinical trials, the approval, if any, of our potential drug candidates by the FDA and other regulatory authorities, or the commercialization of our drug candidates, or could result in higher product costs or otherwise deprive us of potential product revenues.
In addition, the FDA and other regulatory authorities, as applicable, must approve any manufacturer and/or replacement manufacturer, including us. 42 Table of Contents Any failure to identify and maintain fill and finish service providers could delay our preclinical and clinical trials, the approval, if any, of our potential drug candidates by the FDA and other regulatory authorities, or the commercialization of our drug candidates, or could result in higher product costs or otherwise deprive us of potential product revenues.
The TCJA, among other things, includes changes to U.S. federal tax rates, imposes significant additional limitations on the deductibility of certain expenses and adds certain limitations to the use of net operating loss carryforwards arising after December 31, 2017.
Tax Cuts and Jobs Act, or the TCJA, that significantly reforms the IRC was enacted. The TCJA, among other things, includes changes to U.S. federal tax rates, imposes significant additional limitations on the deductibility of certain expenses and adds certain limitations to the use of net operating loss carryforwards arising after December 31, 2017.
However, the filing of a patent application does not mean that we will be issued a patent, or that any patent eventually issued will be as broad as requested in the patent application or sufficient to protect our technology.
As of December 31, 2024, we had approximately 50 pending patent applications. However, the filing of a patent application does not mean that we will be issued a patent, or that any patent eventually issued will be as broad as requested in the patent application or sufficient to protect our technology.
These inefficiencies may require us to use more of our NOLs than we otherwise might and may result in a tax liability without a corresponding distribution from our subsidiary which could have a material adverse effect on our business, results of operations and financial condition. 44 Table of Contents In addition, on December 22, 2017, the U.S.Tax Cuts and Jobs Act, or the TCJA, that significantly reforms the IRC was enacted.
These inefficiencies may require us to use more of our NOLs than we otherwise might and may result in a tax liability without a corresponding distribution from our subsidiaries which could have a material adverse effect on our business, results of operations and financial condition. In addition, on December 22, 2017, the U.S.
The market for our common stock relies in part on the research and reports that industry or financial analysts publish about us or our business. We do not control these analysts.
If securities analysts stop publishing research or reports about us or our business or if they downgrade our common stock, the market price of our common stock could decline. The market for our common stock relies in part on the research and reports that industry or financial analysts publish about us or our business. We do not control these analysts.
In response, Israel’s security cabinet declared war against the Hamas and a military campaign against these terrorist organizations commenced in parallel to their continued rocket and terror attacks.
In response, Israel’s security cabinet declared war against the Hamas and a military campaign against these terrorist organizations commenced in parallel to their continued rocket and terror attacks. Moreover, the attacks by Hamas and Hezbollah, and Israel’s defensive measures, may result in a greater regional conflict.
Our Board of Directors may, at any time, authorize the issuance of a series of preferred stock that would grant to holders the preferred right to our assets upon liquidation, the right to receive dividend payments before dividends are distributed to the holders of common stock and the right to the redemption of the shares, together with a premium, before the redemption of our common stock, which may have a material adverse effect on the rights of the holders of our common stock.
Any series of such preferred stock, could, for example, grant to holders, among other terms, the preferred right to our assets upon liquidation, the right to receive dividend payments before dividends are distributed to the holders of our common stock and the right to the redemption of the preferred shares, together with a premium, before the redemption of our common stock, which may have a material adverse effect on the rights of the holders of our common stock.
We suffered minimal damages during a rocket attack in 2006. Our insurance policies do not cover damages incurred in connection with these conflicts or for any resulting disruption in our operations.
Our insurance policies do not cover damages incurred in connection with these conflicts or for any resulting disruption in our operations.
In addition, several countries, principally in the Middle East, restrict doing business with Israel, and additional countries may impose restrictions on doing business with Israel and Israeli companies whether as a result of hostilities in the region or otherwise.
In addition, several countries, principally in the Middle East, restrict doing business with Israel, and additional countries may impose restrictions on doing business with Israel and Israeli companies whether as a result of hostilities in the region or otherwise. Moreover, there have been increased efforts by organizations and movements to cause companies and consumers to boycott Israeli goods.
The issuance and sale of substantial amounts of common stock, or the perception that such issuances and sales may occur, could adversely affect the market price of our common stock and impair our ability to raise capital through the sale of additional equity securities. 58 Table of Contents If securities analysts stop publishing research or reports about us or our business or if they downgrade our common stock, the market price of our common stock could decline.
The issuance and sale of substantial amounts of common stock, or the perception that such issuances and sales may occur, could adversely affect the market price of our common stock and impair our ability to raise capital through the sale of additional equity securities.
The results of clinical trials of our product candidates may fail to demonstrate that the candidates are safe and effective for their intended uses. Companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in advanced or late-stage clinical trials, even after obtaining promising earlier trial results or in preliminary findings or other comparable authorities for such clinical trials.
Companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in advanced or late-stage clinical trials, even after obtaining promising earlier trial results or in preliminary findings or other comparable authorities for such clinical trials.
Risks Related to Investing in our Common Stock ● The market price of our common stock may fluctuate significantly; future sales of our common stock could reduce our stock price. ● Compliance with changing regulation of corporate governance and public disclosure may result in additional expenses or divert management’s attention. * * * 34 Table of Contents Risks Related to the Commercialization and Continued Approval of our Products We currently depend heavily on the generation of revenues from the sales of Elfabrio and Elelyso.
Risks Related to Investing in our Common Stock ● The market price of our common stock may fluctuate significantly; future sales of our common stock could reduce our stock price. ● Compliance with changing regulation of corporate governance and public disclosure may result in additional expenses or divert management’s attention. ● Delaware law and our organizational documents contain certain anti-takeover provisions. ● Our Amended and Restated Bylaws provide for limits on our stockholders ’ ability to obtain a favorable judicial forum. * * * 36 Table of Contents Risks Related to the Commercialization and Continued Approval of our Products We currently depend heavily on the generation of revenues from the sales of Elfabrio and Elelyso.
Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations.
Effective internal control over financial reporting is necessary for us to provide reliable financial reports. Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations.
If we cannot enforce our employees’ non-compete agreements, we may be unable to prevent our competitors from benefiting from the expertise of our former employees, which may have a material adverse effect on our business, results of operations and financial condition. 42 Table of Contents If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial results or prevent fraud.
If we cannot enforce our employees’ non-compete agreements, we may be unable to prevent our competitors from benefiting from the expertise of our former employees, which may have a material adverse effect on our business, results of operations and financial condition.
Also at December 31, 2023, there were 633,409 shares of common stock available for future for issuance in connection with future grants of incentives under our Amended and Restated Protalix BioTherapeutics, Inc. 2006 Stock Incentive Plan, as amended , approximately 15.2 million shares of common stock reserved for issuance upon conversion of our outstanding 2024 Notes and approximately 13.4 million shares of common stock reserved for issuance upon the exercise of our outstanding warrants.
Also at December 31, 2024, there were 4,139,412 shares of common stock available for future for issuance in connection with future grants of incentives under our Amended and Restated Protalix BioTherapeutics, Inc. 2006 Stock Incentive Plan, as amended .
If we do not meet our obligations under our license agreements in a timely manner, we could lose the rights to our proprietary technology which could have a material adverse effect on our business, results of operations and financial condition.
If we do not meet our obligations under our license agreements in a timely manner, we could lose the rights to our proprietary technology which could have a material adverse effect on our business, results of operations and financial condition. 55 Table of Contents Risks Relating to our Operations in Israel Significant parts of our operations are located in Israel and, therefore, our results may be adversely affected by political, economic and military conditions in Israel.
Risks Related to Clinical Trials and Regulatory Matters We may not obtain the necessary U.S., EMA or other worldwide regulatory approvals to commercialize our drug candidates in a timely manner, if at all, which would have a material adverse effect on our business, results of operations and financial condition.
Failure to uphold, meet or make timely forward progress against our public commitments and goals related to climate action could adversely affect our reputation with suppliers and customers, financial performance or the ability to recruit and retain talent. 47 Table of Contents Risks Related to Clinical Trials and Regulatory Matters We may not obtain the necessary U.S., EMA or other worldwide regulatory approvals to commercialize our drug candidates in a timely manner, if at all, which would have a material adverse effect on our business, results of operations and financial condition.
Any delay in, or termination of, our clinical trials will delay the filing of BLAs and NDAs with the FDA, or other filings with other foreign regulatory authorities, and, ultimately, significantly impair our ability to commercialize our drug candidates and generate product revenues which would have a material adverse effect on our business, results of operations and financial condition. 48 Table of Contents Interim, top-line or preliminary data from clinical trials that we announce or publish may change as more patient data becomes available and are subject to audit and verification procedures that could result in material changes in the final data.
Any delay in, or termination of, our clinical trials will delay the filing of BLAs and NDAs with the FDA, or other filings with other foreign regulatory authorities, and, ultimately, significantly impair our ability to commercialize our drug candidates and generate product revenues which would have a material adverse effect on our business, results of operations and financial condition.
The health care fraud statute prohibits knowingly and willfully executing a scheme to defraud any health care benefit program, including private third-party payers.
HIPAA created several new federal crimes, including health care fraud, and false statements relating to health care matters. The health care fraud statute prohibits knowingly and willfully executing a scheme to defraud any health care 40 Table of Contents benefit program, including private third-party payers.
The number of potential fill and finish services providers is limited and we face the risk of being unable to identify manufacturers and/or replacement manufacturers on acceptable 40 Table of Contents terms or at all. In addition, the FDA and other regulatory authorities, as applicable, must approve any manufacturer and/or replacement manufacturer, including us.
The number of potential fill and finish services providers is limited and we face the risk of being unable to identify manufacturers and/or replacement manufacturers on acceptable terms or at all.
Any failure or delay in commencement or completion of any clinical trials of our product candidates will have a material adverse effect on our business, results of operations and financial condition.
Our product candidates may fail to show the required safety and effectiveness through clinical trials despite positive results in preclinical studies or having successfully advanced through initial clinical trials. Any failure or delay in commencement or completion of any clinical trials of our product candidates will have a material adverse effect on our business, results of operations and financial condition.
We may need to raise additional capital to operate our business, which may not be available on favorable terms, or at all, and which will have a dilutive effect on our stockholders.
We may need to raise additional capital to operate our business, which may not be available on favorable terms, or at all, and which will have a dilutive effect on our stockholders. For the years ended December 31, 2023 and 2024, we had net incomes of $8.3 million and $2.9 million, respectively.
At December 31, 2023, there were outstanding options to purchase common stock issued covering approximately 7.0 million shares of our common stock with a weighted average exercise price of $ 2.13 per share.
In addition, we may sell additional shares of our common stock in the future to raise capital. At December 31, 2024, there were outstanding options to purchase common stock issued covering approximately 7.4 million shares of our common stock with a weighted average exercise price of $1.98 per share.
Risks Related to Investing in our Common Stock The market price of our common stock may fluctuate significantly. The market price of our common stock has experienced significant volatility.
Risks Related to Investing in our Common Stock The market price of our common stock may fluctuate significantly. The market price of our common stock has experienced significant volatility. The securities of life sciences companies often experience significant volatility in connection with clinical trial and regulatory announcements.
Accordingly, economic, geopolitical and military conditions in Israel and the surrounding region could directly affect our business. Any armed conflicts, political instability, terrorism, cyberattacks or any other hostilities involving Israel or the interruption or curtailment of trade between Israel and its present trading partners could adversely affect our operations.
Any armed conflicts, political instability, terrorism, cyberattacks or any other hostilities involving Israel or the interruption or curtailment of trade between Israel and its present trading partners could adversely affect our operations. Since the establishment of Israel in 1948, a number of armed conflicts have occurred between Israel and its Arab neighbors, Hamas and Hezbollah.
Future sales of our common stock could reduce our stock price. If our stockholders sell substantial amounts of our common stock, including shares of our common stock underlying our outstanding convertible notes and warrants, or if we sell a substantial amount of our common stock under our ATM program, the market price of our common stock could decrease significantly.
Future sales of our common stock could reduce our stock price. If our stockholders sell substantial amounts of our common stock or if we sell a substantial amount of our common stock in any public or private offering, the market price of our common stock could decrease significantly.
As a result, stockholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our common stock. Effective internal control over financial reporting is necessary for us to provide reliable financial reports.
If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our common stock.
Moreover, there have been 55 Table of Contents increased efforts by organizations and movements to cause companies and consumers to boycott Israeli goods based on Israeli government policies. Our operations may be disrupted by the obligations of our personnel to perform military service which could have a material adverse effect on our business.
Our operations may be disrupted by the obligations of our personnel to perform military service which could have a material adverse effect on our business.
We may incur losses in future fiscal years as we continue to execute on our strategic goals as drug development and commercialization is very capital intensive.
Our net losses were primarily the result of expenses incurred through a combination of research and development activities and expenses supporting those activities, which includes share-based compensation expense. We may incur losses in future fiscal years as we continue to execute on our strategic goals as drug development and commercialization is very capital intensive.
Many of these state laws apply where a claim is submitted to any third-party payer and not merely a federal healthcare program.
Many of these state laws apply where a claim is submitted to any third-party payer and not merely a federal healthcare program. Violations of the federal False Claims Act and the analogous state laws may result in substantial financial penalties, some as much as three times the actual damages sustained by the government.
This feature may have the effect of delaying or preventing a takeover of our company that would otherwise be beneficial to our stockholders. We may fail to meet the continued market capitalization-based listing requirement or other continued listing requirements of the NYSE American.
Risks Related to our Financial Condition and Capital Requirements We may fail to meet the continued market capitalization-based listing requirement or other continued listing requirements of the NYSE American.
If we fail to adequately protect or enforce our intellectual property rights or secure rights to third party patents, the value of our intellectual property rights would diminish and our business, competitive position and results of operations would suffer. As of December 31, 2023, we had approximately 50 pending patent applications.
Furthermore, any additional source of financing will likely involve the issuance of our equity securities, which will have a dilutive effect on our stockholders. 53 Table of Contents Risks Related to Intellectual Property Matters If we fail to adequately protect or enforce our intellectual property rights or secure rights to third party patents, the value of our intellectual property rights would diminish and our business, competitive position and results of operations would suffer.
Risks Relating to our Operations in Israel Significant parts of our operations are located in Israel and, therefore, our results may be adversely affected by political, economic and military conditions in Israel. Our executive office and operations are located in the State of Israel.
Our executive office and operations are located in the State of Israel. Accordingly, economic, geopolitical and military conditions in Israel and the surrounding region could directly affect our business.
We may not be able to engage in any of these activities or engage in these activities on desirable terms, which could result in a default on our debt obligations. Any default on our debt will have a material adverse effect on our business, results of operations and financial condition.
If we fail to comply with the regulatory requirements in international markets and/or receive applicable marketing approvals, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed, which may have a material adverse effect on our prospects, business, results of operations and financial condition.
Risks Related to Intellectual Property Matters ● The intellectual property and assets owned by our subsidiaries are subject to security agreements that secure our payment and other obligations under our convertible notes. ● We may fail to adequately protect or enforce our intellectual property rights or secure rights to third party patents.
Risks Related to our Financial Condition and Capital Requirements ● We may need to raise additional capital to operate our business, which may not be available on favorable terms, or at all. Risks Related to Intellectual Property Matters ● We may fail to adequately protect or enforce our intellectual property rights or secure rights to third party patents.
Removed
Risks Related to our Financial Condition and Capital Requirements ● We have a significant level of indebtedness and servicing our debt and settling conversion requests may require a significant amount of cash.
Added
Limited reimbursement amounts may reduce the demand for, or the price of, Elfabrio, Elelyso or any other future products.
Removed
Furthermore, restrictive covenants governing our indebtedness may restrict our ability to raise additional capital. ● Any conversion of our outstanding 2024 Notes into common stock will dilute the ownership interest of our existing stockholders. ● We may need to raise additional capital to operate our business, which may not be available on favorable terms, or at all.
Added
Approvals of BLAs, NDAs, MAAs and comparable marketing authorization applications worldwide requires that we demonstrate that the subject drug candidate is safe and effective for its intended use which requires significant research, animal or preclinical trials and human or clinical tests trials.
Removed
Violations of the federal False Claims Act and the analogous state laws may result in substantial financial penalties, some as much as three times the actual damages sustained by the government. 38 Table of Contents HIPAA created several new federal crimes, including health care fraud, and false statements relating to health care matters.
Added
The results of preclinical and clinical trials of our product candidates may fail to demonstrate that the candidates are safe and effective for their intended uses.
Removed
Failure to uphold, meet or make timely forward progress against our public commitments 45 Table of Contents and goals related to climate action could adversely affect our reputation with suppliers and customers, financial performance or the ability to recruit and retain talent.
Added
PRX-115 and PRX-119 are still in clinical development and their risk of failure is high. Failure or delay can occur at any time during the preclinical or clinical trial process.
Removed
In order to obtain FDA approval of any of our drug candidates, we must submit to the FDA a BLA or an NDA demonstrating that the drug candidate is safe and effective for its intended use.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeManagement is involved with our efforts to prevent, detect, and mitigate cybersecurity incidents by overseeing preparation of cybersecurity policies and procedures, testing incident response plans and engaging vendors to conduct penetration tests. Management participates in cybersecurity incident response efforts by being a member of the incident response team and helping direct our response to cybersecurity incidents.
Biggest changeIn addition, the company’s incident response processes include reporting to our Board of Directors for certain cybersecurity incidents. Management is involved with our efforts to prevent, detect, and mitigate cybersecurity incidents by overseeing preparation of cybersecurity policies and procedures, testing incident response plans and engaging vendors to conduct penetration tests.
See “Risk Factors – Our internal computer systems, or those used by our third-party contractors or consultants, may fail or suffer security breaches, resulting in liability and harm to our reputation, which could negatively affect our business, results of operation and financial condition.
See “ Risk Factors – Our internal computer systems, or those used by our third-party contractors or consultants, may fail or suffer security breaches, resulting in liability and harm to our reputation, which could negatively affect our business, results of operation and financial condition.
We may face liability if we breach our obligations related to the protection, 60 Table of Contents security, nondisclosure of confidential information or disclosure of sensitive data or fail or are perceived to fail to comply with applicable data protection laws and regulations, or consumer protection laws, regulations and standards. ”
We may face liability if we breach our obligations related to the protection, security, nondisclosure of confidential information or disclosure of sensitive data or fail or are perceived to fail to comply with applicable data protection laws and regulations, or consumer protection laws, regulations and standards. ”
To protect this 59 Table of Contents information, we use managed detection and response services to monitor our network infrastructure and associated endpoints for possible cybersecurity threats on a constant basis. In addition, we use multi-factor authentication (MFA) for external use, perform penetration testing and engage third parties to assess the effectiveness of our cybersecurity practices.
To protect this information, we use external and internal services to managed detection and response services to monitor our network infrastructure and associated endpoints for possible cybersecurity threats on a constant basis. In addition, we use multi-factor authentication (MFA) for external use, perform penetration testing and engage third parties to assess the effectiveness of our cybersecurity practices.
It applies to all entities who are using our equipment and resources, including but not limited to, employees and temporary workers. Our Senior Director, Information Technology, is primarily responsible for implementing and overseeing the DPP and identifying, measuring, monitoring, and reporting on key enterprise-wide risks, including cybersecurity risks.
It applies to all entities who are using our equipment and resources, including but not limited to, employees and temporary workers. Our Senior Director, Information Technology, is a certified information security officer (CISO). He is primarily responsible for implementing and overseeing the DPP and identifying, measuring, monitoring, and reporting on key enterprise-wide risks, including cybersecurity risks.
No risks from cybersecurity threats have occurred that have affected our business, results of operations or financial condition. Governance Our cybersecurity risk assessment and management processes are implemented and maintained by certain members of our management, including our Senior Director, Information Technology, who reports to our Sr. Vice President, Operations.
No risks from cybersecurity threats have occurred that have materially affected or are reasonably likely to materially affect our business, results of operations or financial condition. 61 Table of Contents Governance Our cybersecurity risk assessment and management processes are implemented and maintained by certain members of our management, including our Senior Director, Information Technology, who reports to our Sr.
Our Board of Directors addresses our cybersecurity risk management as part of its general oversight function. Our Chief Financial Officer and IT consultant provide periodic briefings to the Board of Directors regarding our cybersecurity risks and activities, including any recent cybersecurity incidents and related responses, if any, cybersecurity systems testing, activities of third parties, and the like.
Our Chief Financial Officer and IT consultant provide periodic briefings to the Board of Directors regarding our cybersecurity risks and activities, including any recent cybersecurity incidents and related responses, if any, cybersecurity systems testing, activities of third parties, and the like.
He is expected to become a certified Information Security Officer in March 2024. Our DPP includes an incident response process that includes reporting thresholds and follows standardized identification and authentication practices. If an incident is identified, it is documented by our Senior Director, Information Technology, who is required to report the incident to management.
Our DPP includes an incident response process that includes reporting thresholds and follows standardized identification and authentication practices. If an incident is identified, it is documented by our Senior Director, Information Technology, who is required to report the incident to management.
Management is also responsible for hiring appropriate personnel, integrating cybersecurity considerations into our overall risk management strategy, and for communicating key priorities to employees, as well as for approving budgets, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-related reports. Our incident response process involves management, who participates in our disclosure controls and procedures.
Vice President, Operations. Management is also responsible for hiring appropriate personnel, integrating cybersecurity considerations into our overall risk management strategy, and for communicating key priorities to employees, as well as for approving budgets, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-related reports.
Our incident response process is designed to escalate certain cybersecurity incidents and vulnerabilities to members of management depending on the circumstances, including work with our incident response team to help the company mitigate and remediate cybersecurity incidents of which they are notified. In addition, the company’s incident response processes include reporting to our Board of Directors for certain cybersecurity incidents.
Our incident response process involves management, who participates in our disclosure controls and procedures. Our incident response process is designed to escalate certain cybersecurity incidents and vulnerabilities to members of management depending on the circumstances, including work with our incident response team to help the company mitigate and remediate cybersecurity incidents of which they are notified.
Added
Management participates in cybersecurity incident response efforts by being a member of the incident response team and helping direct our response to cybersecurity incidents. Our Board of Directors addresses our cybersecurity risk management as part of its general oversight function.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeOur facilities are equipped with the requisite laboratory services required to conduct our business, and we believe that the existing facilities are adequate to meet our needs for the foreseeable future. Our original lease for the facility was in effect until 2016 and we have exercised two of three options to extend the term, each for an additional five-year period.
Biggest changeOur original lease for the facility was in effect until 2016 and we have exercised two of three options to extend the term, each for an additional five-year period. The lease is currently in effect until 2026 and we retain an additional option to extend the term for another five-year period thereafter.
Our facilities in Israel currently contain approximately 14,700 sq/ft of manufacturing space and 3,400 sq/ft for a pilot plant, 11,700 sq/ft for offsite warehouse space and approximately 43,100 sq/ft of laboratories, front warehouse and office space, and are leased at a rate of approximately $83,000 per month.
Our facilities in Israel currently contain approximately 14,700 sq/ft of manufacturing space and 3,400 sq/ft for a pilot plant, 11,700 sq/ft for offsite warehouse space and approximately 43,100 sq/ft of laboratories, front warehouse and office space, and are leased at a rate of approximately $85,000 per month.
In addition, we are entitled to use an additional 14,500 sq/ft in the same facility, which we intend to utilize in connection with an anticipated expansion of our manufacturing facilities.
In addition, we are entitled to use an additional 14,500 sq/ft in the same facility, which we may utilize in connection with any future expansion of our manufacturing facilities. Our facilities are equipped with the requisite laboratory services required to conduct our business, and we believe that the existing facilities are adequate to meet our needs for the foreseeable future.
The lease is currently in effect until 2026 and we retain an additional option to extend the term for another five-year period thereafter. Upon the exercise of each option to extend the term of the lease includes a 10% increase to the then current base rent. Item 3. Legal Proceedings We are not involved in any material legal proceedings.
Upon the exercise of each option to extend the term of the lease includes a 10% increase to the then current base rent. Item 3. Legal Proceedings We are not involved in any material legal proceedings. Item 4. Mine Safety Disclosures Not applicable. 62 Table of Contents PART II
Removed
Item 4. Mine Safety Disclosures Not applicable. ​ ​ ​ 61 Table of Contents PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

3 edited+0 added−0 removed2 unchanged
Biggest changePurchases of Equity Securities by the Issuer and Affiliated Purchasers None. Item 6. [Reserved] ​ 62 Table of Contents
Biggest changePurchases of Equity Securities by the Issuer and Affiliated Purchasers None.
Holders As of March 1, 2024, there were approximately 61 holders of record of our common stock. A substantially greater number of holders of our common stock are “street name” or beneficial holders, whose shares are held of record by banks, brokers and other financial institutions.
Holders As of March 1, 2025, there were approximately 60 holders of record of our common stock. A substantially greater number of holders of our common stock are “street name” or beneficial holders, whose shares are held of record by banks, brokers and other financial institutions.
Securities Authorized for Issuance under Equity Compensation Plans The following table provides information as of December 31, 2023 with respect to the shares of our common stock that may be issued under our existing equity compensation plan. ​ ​ ​ ​ ​ ​ ​ ​ ​ A B C ​ ​ ​ ​ ​ ​ ​ Number of Securities Remaining ​ ​ Number of Securities ​ ​ ​ ​ Available for Future Issuance ​ ​ to be Issued ​ Weighted Average ​ Under Equity Compensation Plans ​ ​ Upon Exercise of ​ Exercise Price of ​ (Excluding Securities Reflected in Plan Category ​ Outstanding Options ​ Outstanding Options ​ Column A) Equity Compensation Plans Approved by Stockholders 6,965,601 ​ $ 2.13 633,409 Equity Compensation Plans Not Approved by Stockholders — ​ — — Total 6,965,601 ​ $ 2.13 633,409 ​ Recent Sales of Unregistered Securities None.
Securities Authorized for Issuance under Equity Compensation Plans The following table provides information as of December 31, 2024 with respect to the shares of our common stock that may be issued under our existing equity compensation plan. ​ ​ ​ ​ ​ ​ ​ ​ ​ A B C ​ ​ ​ ​ ​ ​ ​ Number of Securities Remaining ​ ​ Number of Securities ​ ​ ​ ​ Available for Future Issuance ​ ​ to be Issued ​ Weighted Average ​ Under Equity Compensation Plans ​ ​ Upon Exercise of ​ Exercise Price of ​ (Excluding Securities Reflected in Plan Category ​ Outstanding Options ​ Outstanding Options ​ Column A) Equity Compensation Plans Approved by Stockholders 7,402,295 ​ $ 1.98 4,139,412 Equity Compensation Plans Not Approved by Stockholders — ​ — — Total 7,402,295 ​ $ 1.98 4,139,412 ​ Recent Sales of Unregistered Securities None.

Item 7. Management's Discussion & Analysis

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

57 edited+23 added−67 removed45 unchanged
Biggest changeThe increase was primarily due to a decrease of $ 0.9 million in income related to exchange rates as well as an increase in our interest expenses of $0.7 million which was partially offset by a gain recognized due to conversions of a portion of the 2024 Notes of $0.4 million and a $0.6 million increase in interest income. 70 Table of Contents Income taxes For the year ended December 31, 2023, we recorded income taxes of approximately $0.3 million, a decrease of $0.2 million, or 40%, compared to tax expenses of $0.5 million for the year ended December 31, 2022.
Biggest changeThe difference resulted primarily from a decrease of approximately $1.4 million in lower interest and related expenses due to the note conversions executed in 2023 and the September 2024 repayment in full of all the outstanding principal and interest payable under the 2024 Notes, as well as an increase in interest income, net of $0.7 million.
Research and Development Expenses For the year ended December 31, 2023, our total research and development expenses were approximately $17.1 million comprised of approximately $6.3 million in subcontractor-related expenses, approximately $7.8 million of salary and related expenses, approximately $0.6 million of materials-related expenses and approximately $2.4 million of other expenses.
For the year ended December 31, 2023, our total research and development expenses were approximately $17.1 million comprised of approximately $7.8 million of salary and related expenses, approximately $6.3 million in subcontractor-related expenses, approximately $0.6 million of materials-related expenses and approximately $2.4 million of other expenses.
Currency fluctuations during the year ended December 31, 2022, resulted in $1.0 million being recognized as financial income. We do not believe currency fluctuations have had a material effect on our results of operations during the years ended December 31, 2022 or 2023.
Currency fluctuations during the year ended December 31, 2022, resulted in $1.0 million being recognized as financial income. We do not believe currency fluctuations have had a material effect on our results of operations during the years ended December 31, 2023 or 2024.
Under the Chiesi US Agreement, Protalix Ltd. is entitled to payments of up to a maximum of $20.0 million to cover development costs for pegunigalsidase alfa, and to receive additional payments of up to a maximum of $760.0 million, in the aggregate, in regulatory and commercial milestone payments.
Under the Chiesi US Agreement, Protalix Ltd. was entitled to payments of up to a maximum of $20.0 million to cover development costs for pegunigalsidase alfa, and is entitled to receive additional payments of up to a maximum of $760.0 million, in the aggregate, in regulatory and commercial milestone payments.
If all of the contingencies with respect to milestone payments under our research and license agreements are met, as of December 31, 2023, the aggregate milestone payments payable would be approximately $8.4 million, and would be payable, if at all, as our projects progress over the course of a number of years.
If all of the contingencies with respect to milestone payments under our research and license agreements are met, as of December 31, 2024, the aggregate milestone payments payable would be approximately $8.4 million, and would be payable, if at all, as our projects progress over the course of a number of years.
Cash Flows Net cash used in operations was $1.3 million for the year ended December 31, 2023.
Net cash used in operations was $1.3 million for the year ended December 31, 2023.
The net income for the year ended December 31, 2023 of $8.3 million was decreased by a $13.2 million decrease in contracts liability, a $3.1 million 71 Table of Contents increase in deferred tax assets, a $2.2 million increase in inventories, a $0.4 million increase in accounts receivable-trade and other assets and a $0.4 million financial income-net.
The net income for the year ended December 31, 2023 of $8.3 million was decreased by a $13.2 million decrease in contracts liability, a $3.1 million increase in deferred tax assets, a $2.2 million increase in inventories, a $0.4 million increase in accounts receivable-trade and other assets and a $0.4 million financial income-net.
We agreed to supply Chiesi with drug substance for Elfabrio and, following relevant technology and technical information transfer activities, Chiesi has agreed, among other things, to provide us with commercial fill/finish services for Elfabrio, including to support the anticipated global launch of Elfabrio.
We agreed to supply Chiesi with drug substance for Elfabrio and, following 65 Table of Contents relevant technology and technical information transfer activities, Chiesi has agreed, among other things, to provide us with commercial fill/finish services for Elfabrio, including to support the anticipated global launch of Elfabrio.
In addition, under the Chiesi Ex-US Agreement, Protalix Ltd. was entitled to additional payments of up to $25.0 million in pegunigalsidase alfa development costs, and to receive additional 64 Table of Contents payments of up to $320.0 million, in the aggregate, in regulatory and commercial milestone payments.
In addition, under the Chiesi Ex-US Agreement, Protalix Ltd. was entitled to additional payments of up to $25.0 million in pegunigalsidase alfa development costs, and to receive additional payments of up to $320.0 million, in the aggregate, in regulatory and commercial milestone payments.
You should read “Risk Factors” in Item 1A of this Annual Report on Form 10-K for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
You should read “ Risk Factors ” in Item 1A of this Annual Report on Form 10-K for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
Recently Issued Accounting Pronouncements Certain recently issued and recently adopted accounting pronouncements are discussed in Note 1(r) of the financial statements included in Item 8 of this Annual Report on Form 10-K. 73 Table of Contents
Recently Issued Accounting Pronouncements Certain recently issued and recently adopted accounting pronouncements are discussed in Note 1(r) of the financial statements included in Item 8 of this Annual Report on Form 10-K.
Our material cash needs for the next 24 months will include, among other expenses, (i) costs of preclinical and clinical trials, (ii) employee salaries, (iii) payments for rent and operation of our manufacturing facilities, (iv) fees to our consultants and legal advisors, patent advisors and fees for service providers in connection with our research and development efforts, (v) payments of principal and interest on our outstanding 2024 Notes and (vi) tax payments.
Our material cash needs for the next 24 months will include, among other expenses, (i) costs of preclinical and clinical trials, (ii) employee salaries, (iii) payments for rent and operation of our manufacturing facilities, (iv) fees to our consultants and legal advisors, patent advisors and fees for service providers in connection with our research and development efforts and (v) tax payments.
As of December 31, 2023, we have a contractual obligation of approximately $0.7 million for employee rights upon retirement. We are also party to certain research and license agreements.
As of December 31, 2024, we have a contractual obligation of approximately $0.6 million for employee rights upon retirement. We are also party to certain research and license agreements.
We believe that the funds currently available to us are sufficient to satisfy our capital needs for at least 12 months. As discussed above, we may be required to raise additional capital to develop our product candidates and continue research and development activities.
We believe that the funds currently available to us are sufficient to satisfy our capital needs for at least 12 months from the date that these financial statements are issued . As discussed above, we may be required to raise additional capital to develop our product candidates and continue research and development activities.
The leases relate primarily to office, laboratory and manufacturing space and vehicles used by our employees. Our aggregate future minimum commitments under these facility and vehicles leases over the next five fiscal years is approximately $4.1 million as of December 31, 2023.
The leases relate primarily to office, laboratory and manufacturing space and vehicles used by our employees. Our aggregate future minimum commitments under these facility and vehicles leases over the next five fiscal years is approximately $2.8 million as of December 31, 2024.
The tax valuation allowance totaled approximately $56.0 million at December 31, 2023 (see Note 13 to our consolidated financial statements for additional information). Should our actual future taxable income by tax jurisdiction vary from estimates, additional allowances or reversals thereof may be necessary. Significant judgment is required in evaluating our uncertain tax positions.
The tax valuation allowance totaled approximately $50.7 million at December 31, 2024 (see Note 12 to our consolidated financial statements for additional information). Should our actual future taxable income by tax jurisdiction vary from estimates, additional allowances or reversals thereof may be necessary. Significant judgment is required in evaluating our uncertain tax positions.
To date, we have successfully developed two ERTs; Elfabrio (pegunigalsidase alfa) for the treatment of adult patients with a confirmed diagnosis of Fabry disease and Elelyso (taliglucerase alfa) for the treatment of adult patients with Gaucher disease.
To date, we have successfully developed two commercial products, both of which are ERTs; Elfabrio (pegunigalsidase alfa) for the treatment of adult patients with a confirmed diagnosis of Fabry disease and Elelyso (taliglucerase alfa) for the treatment of adult patients with Gaucher disease.
We expect research and development expenses to continue to be our primary expense as we enter into a more advanced stage of preclinical and clinical trials for certain of our product candidates.
We expect to continue to incur significant, increasing research and development expenses as we enter into a more advanced stage of preclinical and clinical trials for certain of our product candidates.
At the same time, clashes between Israel and Hezbollah in Lebanon have increased. In response, Israel’s security cabinet declared war against the Hamas and a military campaign against these terrorist organizations commenced in parallel to their continued rocket and terror attacks. Moreover, the attacks by Hamas and Hezbollah, and Israel’s defensive measures, may result in a greater regional conflict.
In response, Israel’s security cabinet declared war against the Hamas and a military campaign against these terrorist organizations commenced in parallel to their continued rocket and terror attacks. Moreover, the attacks by Hamas and Hezbollah, and Israel’s defensive measures, may result in a greater regional conflict.
Our liability for these unrecognized tax benefits totaled approximately $0.8 million at December 31, 2023 (see Note 13 to our consolidated financial statements for additional information). Research and Development Expense We expect our research and development expense to remain our primary expense in the near future as we continue to develop our product candidates.
Uncertain tax position totaled approximately $0.8 million at December 31, 2024 (see Note 12 to our consolidated financial statements for additional information). Research and Development Expense We expect our research and development expense to remain our primary expense in the near future as we continue to develop our product candidates.
We base our estimates on historical experience and on various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.
We base our estimates on historical experience and on various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the 66 Table of Contents carrying value of assets and liabilities that are not readily apparent from other sources.
Obtaining marketing approval with respect to any product candidate in any country is dependent on our ability to implement the necessary regulatory steps required to obtain such approvals, and demonstrate the safety and efficacy of its product candidates. We cannot reasonably predict the outcome of these activities.
Obtaining marketing approval with respect to any product candidate in any country is dependent on our ability to implement the necessary regulatory steps required to obtain such approvals, and demonstrate the safety and efficacy of its product candidates. We cannot reasonably predict the outcome of these activities. In March 2023, we initiated a phase I First-in-Human clinical trial of PRX-115.
Hamas also launched extensive rocket attacks on Israeli population and industrial centers located along Israel’s border with the Gaza Strip and in other areas within the State of Israel attacking a number of civilian and military targets while simultaneously launching extensive rocket attacks on the Israeli population and industrial centers.
Hamas also launched extensive rocket attacks on Israeli population and industrial centers located along Israel’s border with the Gaza Strip and in other areas within the State of Israel attacking a number of civilian and military targets. At the same time, clashes between Israel and Hezbollah in Lebanon increased.
These contracts do not contain minimum purchase commitments and are cancelable by us upon prior notice. Payments due upon cancellation consist only of payments for services provided or expenses incurred, including non-cancelable obligations of our service providers, up to the date of cancellation. In addition, we have a $0.1 million commitment payable to a business development consultant.
These contracts do not contain minimum purchase commitments and are cancelable by us upon prior notice. Payments due upon cancellation consist only of payments for services provided or expenses incurred, including non-cancelable obligations of our service providers, up to the date of cancellation.
For the year ended December 31, 2022, our total research and development expenses were approximately $29.3 million comprised of approximately $17.8 million in subcontractor-related expenses, approximately $7.3 million of salary and related expenses, approximately $1.4 million of materials-related expenses and approximately $2.8 million of other expenses.
Research and Development Expenses For the year ended December 31, 2024, our total research and development expenses were approximately $13.0 million comprised of approximately $7.1 million of salary and related expenses, approximately $2.4 million in subcontractor-related expenses, approximately $0.9 million of materials-related expenses and approximately $2.6 million of other expenses.
Our product pipeline currently includes, among other candidates: (1) PRX-115, our plant cell-expressed recombinant PEGylated uricase (urate oxidase) – a chemically modified enzyme to treat severe gout; and (2) PRX-119, our plant cell-expressed PEGylated recombinant human DNase I product candidate being designed to elongate half-life in the circulation for NETs-related diseases.
Our product pipeline currently includes, among other candidates: (1) PRX-115, our plant cell-expressed recombinant PEGylated uricase (urate oxidase) – a chemically modified enzyme to treat uncontrolled gout; and 64 Table of Contents (2) PRX-119, our plant cell-expressed PEGylated recombinant human DNase I product candidate which we have designed for long and customized systemic circulation in the bloodstream for NETs-related diseases.
The F/F Agreement shall continue in force until December 31, 2025, unless terminated earlier in accordance with the terms of the F/F Agreement and the term may be extended by mutual agreement for an additional period of seven years upon mutual written agreement prior to expiration of the initial term.
Subsequently, we and Chiesi agreed that the F/F Agreement shall have an initial term of 10 years, unless terminated earlier in accordance with the terms of the F/F Agreement and the term may be extended by mutual agreement for an additional period of seven years upon mutual written agreement prior to expiration of the initial term.
Financial Expenses and Income, Net Financial expense, net was $1.9 million for the year ended December 31, 2023, an increase of $0.5 million, or 36%, compared to financial expenses of $1.4 million for the year ended December 31, 2022.
Financial Expenses and Income, Net Financial income, net was $0.2 million for the year ended December 31, 2024, compared to financial expenses, net of $1.9 million for the year ended December 31, 2023.
Although we expect the revenues generated from the sales of Elfabrio and Elelyso will increase, such revenues may not be sufficient to fund the expenditures. To the extent we need to obtain additional financing in excess of such anticipated revenues, it may be difficult for us to do so given the volatility of the price of our common stock.
To the extent we need to obtain additional financing in excess of such anticipated revenues, it may be difficult for us to do so given the volatility of the price of our common stock.
We have not generated significant revenues from sales of Elelyso, and commercial sales of Elfabrio only commenced in the middle of 2023. W e have generated operating losses from our continuing operations since our inception although the revenues generated in the year ended December 31, 2023 exceeded our expenditures for the same period.
W e have generated operating losses from our continuing operations since our inception although the revenues generated in the years ended December 31, 2023 and 2024 exceeded our expenditures for the same period.
Effective in 2022, Section 174 of the TCJA requires all U.S. companies, for tax purposes, to capitalize and subsequently amortize R&D expenses that fall within the scope of Section 174 over five years for research activities conducted in the United States and over 15 years for research activities conducted outside of the United States rather than deducting such costs in the current year.
Effective in 2022, Section 174 of the TCJA requires all U.S. companies, for tax purposes, to capitalize and subsequently amortize R&D expenses that fall within the scope of Section 174 over five years for research activities conducted in the United States and over 15 years for research activities conducted outside of the United States rather than deducting such costs in the current year. 69 Table of Contents Year ended December 31, 2023 Compared to the Year Ended December 31, 2022 For a discussion of the year ended December 31, 2023 compared to the year ended December 31, 2022, see Management’s Discussion and Analysis of Financial Condition and Results of Operations included in our Annual Report on Form 10-K for the year ended December 31, 2023.
Elfabrio, which we referred to as PRX-102 during its development stage, has been approved for marketing in the United States, the European Union, Great Britain, Switzerland and Israel. Chiesi is our commercialization partner for Elfabrio. We have licensed the rights to commercialize Elelyso worldwide (other than Brazil) to Pfizer, and in Brazil to Fiocruz, an arm of the Brazilian MoH.
Elfabrio, which we referred to as PRX-102 during its development stage, has been approved for marketing in the United States, the European Union, Great Britain, Switzerland, Peru, Israel, Russia and Singapore. Chiesi is our commercialization partner for Elfabrio.
We have a contractual obligation of approximately $0.4 million as of December 31, 2023 payable over the fiscal year ending December 31, 2024 in connection with contractual arrangements we enter into in the normal course of business with CROs, CMOs and other clinical providers and consultants for clinical trials, preclinical and other research studies and manufacturing services in connection with our primary product development process.
As of December 31, 2024, we are subject to open purchase orders issued to certain suppliers and other vendors mainly in connection with our research and development and manufacturing activities that were outstanding as of December 31, 2024 for approximately $9.2 million over the next five fiscal years. 71 Table of Contents We have a contractual obligation of approximately $1.5 million as of December 31, 2024 payable over the fiscal year ending December 31, 2025 in connection with contractual arrangements we enter into in the normal course of business with CROs, CMOs and other clinical providers and consultants for clinical trials, preclinical and other research studies and manufacturing services in connection with our primary product development process.
Revenues Our primary sources of revenues include our sales of BioManguinhos alfataliglicerase in Brazil, of drug substance to Pfizer under our Amended Pfizer Agreement and of drug product to Chiesi under the Chiesi Agreements.
Actual results may differ from these estimates under different assumptions or conditions. Revenue Recognition Our primary sources of revenues include our sales of drug product to Chiesi under the Chiesi Agreements, of BioManguinhos alfataliglicerase to Brazil and of drug substance to Pfizer under our Amended Pfizer Agreement.
Research and development expense consists of: ● internal costs associated with research and development activities; ● payments made to third party contract research organizations, investigative/clinical sites and consultants; ● manufacturing development costs; ● personnel-related expenses, including salaries, benefits, travel and related costs for the personnel involved in research and development; ● activities relating to the advancement of product candidates through preclinical studies and clinical trials; and 67 Table of Contents ● facilities and other allocated expenses, which include direct and allocated expenses for rent and maintenance of facilities, as well as laboratory and other supplies.
Research and development expense consists of: ● internal costs associated with research and development activities; ● payments made to third party contract research organizations, investigative/clinical sites and consultants; ● manufacturing development costs; ● personnel-related expenses, including salaries, benefits, travel and related costs for the personnel involved in research and development; ● activities relating to the advancement of product candidates through preclinical studies and clinical trials; and ● facilities and other allocated expenses, which include direct and allocated expenses for rent and maintenance of facilities, as well as laboratory and other supplies. 67 Table of Contents The following table identifies our current major research and development projects: Project Status Expected Near Term Milestones PRX-115 – PEGylated Uricase Phase I (completed) Phase II clinical trial expected to launch in the second half of 2025. ​ PRX-119 – Long Acting DNase I Preclinical ​ ​ We anticipate incurring increasing costs in connection with the continued development of PRX-115 and PRX-119 and in the expansion of our pipeline.
During the year ended December 31, 2023, we raised gross proceeds equal to approximately $24.9 million from the sale of 12,560,150 shares of our common stock under our ATM program. All such sales were completed during the quarters ended March 31, 2023 and June 30, 2023.
During the year ended December 31, 2024, we raised gross proceeds equal to approximately $3.8 million from the sale, in the aggregate, of 2,216,692 shares of our common stock under our ATM program. All such sales were completed during the quarter ended December 31, 2024.
Revenues from License and R&D services We recorded revenues from license and R&D services of $25.1 million for the year ended December 31, 2023, an increase of $2.8 million, or 13%, compared to revenues of $22.3 million for the year ended December 31, 2022.
Revenues from License and R&D services We recorded revenues from license and R&D services of $0.4 million for the year ended December 31, 2024, a decrease of $24.7 million, or 98%, compared to revenues of $25.1 million for the year ended December 31, 2023.
Liquidity and Capital Resources Our sources of liquidity include our cash balances and bank deposits. At December 31, 2023, we had $44.6 million in cash and cash equivalents and short term bank deposits. We have primarily financed our operations through equity and debt financings, business collaborations, and grants funding.
Liquidity and Capital Resources Our sources of liquidity include our cash balances and bank deposits. At December 31, 2024, we had $34.8 million in cash and cash equivalents and short term bank deposits.
As of December 31, 2023, shares of Common Stock for total gross proceeds of approximately $6.4 million remain available to be sold under the 2023 Sales Agreement. Under each of the Chiesi Agreements, Chiesi made an upfront payment to Protalix Ltd. of $25.0 million in connection with the execution of each agreement.
Under each of the Chiesi Agreements, Chiesi made an upfront payment to Protalix Ltd. of $25.0 million in connection with the execution of each agreement.
As of December 31, 2023, shares of our common 72 Table of Contents stock for total gross proceeds of approximately $6.4 million remain available to be sold under the 2023 Sales Agreement.
As of December 31, 2024, shares of common stock for total gross proceeds of approximately $2.5 million were available to be sold under the 2023 Sales Agreement. Since December 31, 2024, we sold the remaining shares of common stock available for sale under the 2023 Sales Agreement thereby completing the ATM program thereunder.
Revenues from license and R&D services represent mainly the revenues we recognized in connection with the Chiesi Agreements. Cost of Goods Sold Cost of goods sold was $23.0 million for the year ended December 31, 2023, an increase of $3.4 million, or 17%, compared to cost of goods sold of $19.6 million for the year ended December 31, 2022.
Cost of Goods Sold Cost of goods sold was $24.3 million for the year ended December 31, 2024, an increase of $1.3 million, or 6%, compared to cost of goods sold of $23.0 million for the year ended December 31, 2023. The increase in cost of goods sold was primarily the result of the increase in sales to Chiesi.
As of the issuance of these financial statements, the impact of the war has not had a material adverse effect on our operations. 65 Table of Contents We believe that our cash and cash equivalents and short-term bank deposits as of December 31, 2023 are sufficient to satisfy our capital needs for at least 12 months from the date that these financial statements are issued.
See “ Risk Factors—Significant parts of our operations are located in Israel and, therefore, our results may be adversely affected by political, economic and military conditions in Israel. ” We believe that our cash and cash equivalents and short-term bank deposits as of December 31, 2024 are sufficient to satisfy our capital needs for at least 12 months from the date that these financial statements are issued.
No sales were completed during the quarters ended September 30, 2023 and December 31, 2023. During the year ended December 31, 2021, we raised gross proceeds equal to approximately $8.8 million from sales of common stock under our ATM program through the sale of 1,867,552 shares of our common stock.
During the year ended December 31, 2023, we raised gross proceeds equal to approximately $24.9 million from the sale of 12,560,150 shares of our common stock under our ATM program. Cash Flows Net cash provided by operations was $8.7 million for the year ended December 31, 2024 .
Results of Operations Year ended December 31, 2023 Compared to the Year Ended December 31, 2022 Revenues from Selling Goods We recorded revenues from selling goods of $40.4 million for the year ended December 31, 2023, an increase of $15.1 million, or 60%, compared to revenues of $25.3 million for the year ended December 31, 2022.
Income taxes For the year ended December 31, 2024, we recorded income taxes of approximately $1.2 million, an increase of $0.9 million, or 300%, compared to income taxes of $0.3 million for the year ended December 31, 2023.
The increase 69 Table of Contents resulted primarily from an increase of $14.1 million in sales of Elfabrio drug product to Chiesi, following the approvals by the FDA and the EMA of Elfabrio , an increase of $0.1 million in sales to Pfizer and of $0.9 million in sales to Brazil, resulting from timing differences.
The increase resulted primarily from an increase of $11.8 million in sales to Chiesi, an increase of $0.6 million in sales to Brazil and an increase of $0.1 million in sales to Pfizer.
See “Risk Factors— Clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs, which may have a material adverse effect on our business, results of operations and financial condition .” Share-Based Compensation We measure share-based compensation cost for all share-based awards at the fair value on the grant date and recognition of share-based compensation over the related service period.
See “ Risk Factors—Preclinical and clinical trials are very expensive, time-consuming and difficult to design and implement and may result in unforeseen costs, which may have a material adverse effect on our business, results of operations and financial condition. ” Results of Operations Year ended December 31, 2024 Compared to the Year Ended December 31, 2023 Revenues from Selling Goods We recorded revenues from selling goods of $53.0 million for the year ended December 31, 2024, an increase of $12.6 million, or 31%, compared to revenues of $40.4 million for the year ended December 31, 2023.
As we increase our research and developments efforts with respect to our current and future product candidates, we expect to continue to incur significant expenditures. We cannot anticipate the costs or the timing of the occurrence of such costs.
As the 2024 Notes were paid in full during the year ended December 31, 2024, we are no longer subject to the financial limitations related to such notes. As we increase our research and developments efforts with respect to our current and future product candidates, we expect to continue to incur significant expenditures.
Selling, General and Administrative Expenses Selling, general and administrative expenses were $15.0 million for the year ended December 31, 2023, an increase of $3.3 million, or 28%, from $11.7 million for the year ended December 31, 2022.
Selling, General and Administrative Expenses Selling, general and administrative expenses were $12.2 million for the year ended December 31, 2024, a decrease of $2.8 million, or 19%, from $15.0 million for the year ended December 31, 2023. The decrease resulted primarily from a decrease of $1.8 million in professional fees and of $1.0 million in salaries and related expenses .
On May 5, 2023, the EC announced that it had approved the MAA for Elfabrio and on May 9, 2023, the FDA announced that it had approved the BLA for Elfabrio, each for adult patients with a confirmed diagnosis of Fabry disease. Both approvals cover the 1 mg/kg every two weeks dosage.
Elfabrio, our second commercial product, an ERT for the treatment of Fabry disease, was approved by the EC for marketing in the EU and by the FDA for marketing in the United States in May 2023 for adult patients. Both approvals cover the 1 mg/kg every two weeks dosage.
It is currently not possible to predict the duration or severity of the ongoing conflict or its effects on our business, operations and financial conditions. The ongoing conflict is rapidly evolving and developing, and could disrupt certain of our business and operations, among others.
We have elected to store manufactured drug substance in multiple locations, both within and outside of Israel, to mitigate the risk of loss due to the military operations. It is currently not possible to predict the duration or severity of the ongoing conflict or its effects on our business, operations and financial conditions.
Net cash provided by financing activities was $24.7 million resulting primarily from the sale of common stock under our ATM program. Future Funding Requirements Since our inception, we have incurred significant research and development expenditures which have not been offset by revenues.
Future Funding Requirements Since our inception, we have incurred significant research and development expenditures which have not been offset by revenues. We have not generated significant revenues from sales of Elelyso, and commercial sales of Elfabrio only 70 Table of Contents commenced in the middle of 2023.
The increase in cost of goods sold was primarily the result of the increase in sales of goods to Chiesi, Brazil and to Pfizer. Sales to Chiesi included certain drug substance costs which had already been recognized as research and development expenses as it was produced as part of research and development activities.
In addition, during the year ended December 31, 2023, a portion of the costs for certain drug substance sold were recognized as research and development expenses, not cost of goods sold, as such drug substance was produced as part of our research and development activities.
Total decrease in research and developments expenses was $12.2 million, or 42%, for the year ended December 31, 2023 compared to the year ended December 31, 2022. The decrease in research and development expenses resulted primarily from a $11.5 million decrease in subcontractor-related expenses in connection with our PRX-102 clinical trials, and a $0.8 million decrease in materials-related expenses .
Total decrease in research and developments expenses was $4.1 million, or 24%, for the year ended December 31, 2024 compared to the year ended December 31, 2023.
Except with respect to Elfabrio and Elelyso, we hold the worldwide commercialization rights to our other proprietary development candidates.
In 2024, we generated $29.3 million from sales of Elfabrio to Chiesi. We continuously evaluate potential strategic marketing partnerships as well as collaboration programs with biotechnology and pharmaceutical companies and academic research institutions. Except with respect to Elfabrio and Elelyso, we hold the worldwide commercialization rights to our other proprietary development candidates.
During the quarters ended March 31, 2023 and June 30, 2023, we sold, in the aggregate, 12,560,150 shares of Common Stock under the 2021 Sales Agreement and the 2023 Sales Agreement, generating aggregate gross proceeds equal to approximately $24.9 million.
Subsequent to December 31, 2024, we sold, in the aggregate, an additional 1,223,935 shares of common stock under program generating gross proceeds equal to approximately $2.5 million. Such sales completed the ATM program.
Contractual obligations Our contractual obligations include obligations under our convertible notes, operating lease obligations, purchase obligations, certain clinical contracts and the liability for employee rights upon retirement. Our convertible senior notes had an aggregate outstanding principal balance of $20.42 million at December 31, 2023.
Contractual obligations Our contractual obligations include operating lease obligations, purchase obligations, certain clinical contracts and the liability for employee rights upon retirement. We lease certain assets under operating leases, which expire through 2026, with an option to extend the lease on our main facility to 2031.
The increase resulted from the $20.0 million regulatory milestone payment from Chiesi in connection with the FDA approval of Elfabrio which was partially offset by a decrease of $17.2 million in revenues recognized in connection with the R&D performance obligation under the Chiesi Agreements as we have completed the phase III clinical program thereunder.
Revenues from license and R&D services are comprised primarily of revenues we recognized in connection with the Chiesi Agreements. The revenues from license and R&D services for the year ended December 31, 2023 included the $20.0 million regulatory milestone payment from Chiesi in connection with the FDA approval of Elfabrio granted during that period.
Removed
Elelyso is marketed as BioManguinhos alfataliglicerase in Brazil. Our strategy is to develop proprietary recombinant proteins designed to address high, unmet needs in the rare disease space that are therapeutically superior to existing recombinant proteins currently marketed for the same indications. Consistent with this strategy, we have a number of product candidates in varying stages of the clinical development process.
Added
We are committed to leveraging our track record of success as we progress with the development of treatments for rare and orphan diseases. In addition, we continuously work on the further development and enhancement of our ProCellEx technology.
Removed
The EMA approval followed the February 2023 adoption of a positive opinion and recommendation of marketing authorization for Elfabrio by the CHMP.
Added
Accordingly, we are turning our focus to new, early-stage product candidates that treat indications for which there are high unmet needs in terms of efficacy and safety, including renal diseases. Treatments of interest will address both genetic and non-genetic diseases.
Removed
Elfabrio was approved by the FDA with a boxed warning for hypersensitivity reactions/anaphylaxis, consistent with Enzyme Replacement Therapy (ERT) class labeling, and Warnings/Precautions providing guidance on the signs and symptoms of hypersensitivity and infusion-associated reactions seen in the clinical studies as well as treatments to manage such events should they occur.
Added
We intend to use our ProCellEx platform and PEGylation capabilities, as well as other modalities such as small molecules and antibodies, to take advantage of highly innovative opportunities. We are also exploring novel platform technologies.
Removed
The Warnings/Precautions for membranoproliferative glomerulonephritis (MPGN) alert prescribers to the possibility of MPGN and provide guidance for appropriate patient management.
Added
Our first product, Elelyso, an ERT for the treatment of patients with Gaucher disease, was first approved by the FDA in May 2012 and is now approved for marketing in 23 markets including Brazil, Israel and others.
Removed
Overall, the FDA review team concluded that in the context of Fabry disease as a rare, serious disease with limited therapeutic options that may not be suitable to all individual patients, the benefit-risk of Elfabrio is favorable for the treatment of adults with confirmed Fabry disease.
Added
In June 2012, the CHMP issued a positive opinion regarding the benefit of Elelyso but did not immediately grant marketing authorization because of the ten-year market exclusivity granted to Vpriv in August 2010 for the same condition, which was extended for an additional two years, and expired in August 2022.
Removed
Elfabrio was the subject of a phase III clinical program studying the drug as a treatment of patients with Fabry disease, a rare, genetic lysosomal disorder. The phase III clinical program included three separate studies, the BALANCE study, the BRIDGE study and the BRIGHT study.
Added
We have granted the marketing rights to Elelyso globally, excluding Brazil, to Pfizer through an exclusive licensing agreement. We maintain the distribution rights to Elelyso in Brazil, where it is currently marketed as BioManguinhos alfataliglicerase, through the Brazil Agreement.
Removed
The phase III clinical program analyzed two potential dosing regimens: 1 mg/kg every two weeks and 2 mg/kg every four weeks. In addition, the phase III clinical program included two extension studies in which subjects that participated in our phase I/II clinical trials and phase III clinical trials had the opportunity to enroll and continue to be treated with PRX-102.
Added
In 2024, we generated $12.6 million from sales of Elelyso to Pfizer and $11.0 million from sales of BioManguinhos alfataliglicerase to the Brazilian MoH.
Removed
As of March 1, 2023, sponsorship of the two open label extension studies was transferred to Chiesi, which is now administering the extension studies. From time to time, and as Elfabrio is approved for marketing in different jurisdictions, participants withdraw from the open label extension studies.
Added
This study included 64 adult male and female subjects in a dose escalation design with eight sequential dosing cohorts, each composed of eight subjects (six active and two placebo) which is now complete.
Removed
Some of the withdrawals transfer to a commercial setting, others withdraw for other reasons. 63 Table of Contents The BLA for Elfabrio for the treatment of adult patients with Fabry disease was resubmitted to the FDA on November 9, 2022.
Added
The results were announced in a poster presentation at the American College of Rheumatology (ACR) Convergence 2024, held November 14-19, 2024 and are summarized in Item 1 of this annual report on Form 10-K. We are currently preparing for a phase II clinical trial of PRX-115 which we expect will commence in the second half of 2025.
Removed
An initial BLA for Elfabrio was submitted to the FDA on May 27, 2020 under the FDA’s Accelerated Approval pathway, but resulted in a CRL. The MAA was submitted to the EMA on February 7, 2022, after the October 8, 2021 meeting we held, together with Chiesi, with the Rapporteur and Co-Rapporteur of the EMA regarding PRX-102.
Added
Since the outbreak of the war, other regional actors, including Iran, have taken military action against Israel. During January 2025, a ceasefire with Hamas was declared. As of the date of this Annual Report on Form 10-K, the war is ongoing and continues to evolve.
Removed
The FDA publicly released the internal review documents for Elfabrio (pegunigalsidase alfa-iwxj) injection BLA 761161. These documents provide previously unavailable additional information regarding the basis for the FDA’s May 2023 approval decision.
Added
The attacks by Hamas and Hezbollah, and Israel’s defensive measures, as well as actions that could be taken in the future by NATO, the United States, the United Kingdom the European Union or Israel’s neighboring states and other countries have created global security concerns that may result in a greater or lasting regional conflict.
Removed
In particular, the FDA determined that substantial evidence of effectiveness for Elfabrio in Fabry patients was established with one adequate and well-controlled study with confirmatory evidence provided by the BALANCE study.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

5 edited+0 added−1 removed5 unchanged
Biggest changeInterest Rate Risk Our exposure to market risk is confined to our cash and cash equivalents.
Biggest changeThese measures, however, may not adequately protect us from material adverse effects due to the impact of inflation in Israel. 72 Table of Contents Interest Rate Risk Our exposure to market risk is confined to our cash and cash equivalents.
Foreign currency translation gains or losses are recognized in the statement of operations. Approximately 4 4 % of our costs, including salaries, expenses and office expenses, are incurred in NIS. Inflation in Israel may have the effect of increasing the U.S. dollar cost of our operations in Israel.
Foreign currency translation gains or losses are recognized in the statement of operations. Approximately 37% of our costs, including salaries, expenses and office expenses, are incurred in NIS. Inflation in Israel may have the effect of increasing the U.S. dollar cost of our operations in Israel.
The exchange rate of the U.S. dollar to the NIS, based on exchange rates published by the Bank of Israel, was as follows: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2021 ​ 2022 ​ 2023 ​ Average rate for period ​ ​ 3.230 ​ 3.360 ​ 3.687 ​ Rate at period-end ​ ​ 3.110 ​ 3.519 ​ 3.627 ​ ​ To date, we have not engaged in hedging transactions.
The exchange rate of the U.S. dollar to the NIS, based on exchange rates published by the Bank of Israel, was as follows: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ 2022 ​ 2023 ​ 2024 ​ Average rate for period 3.360 ​ 3.687 ​ 3.700 ​ Rate at period-end 3.519 ​ 3.627 ​ 3.647 ​ ​ To date, we have not engaged in hedging transactions.
In the future, we may enter into currency hedging transactions to decrease the risk of financial exposure from fluctuations in the exchange rate of the U.S. dollar against the NIS. These measures, however, may not adequately protect us from material adverse effects due to the impact of inflation in Israel.
In the future, we may enter into currency hedging transactions to decrease the risk of financial exposure from fluctuations in the exchange rate of the U.S. dollar against the NIS.
We do not use derivative financial instruments to limit exposure to interest rate risk. Our interest gains may decline in the future as a result of changes in the financial markets. Item 8. Financial Statements and Supplementary Data See the Index to Consolidated Financial Statements on Page F-1 attached hereto. Item 9.
We do not use derivative financial instruments to limit exposure to interest rate risk. Our interest gains may decline in the future as a result of changes in the financial markets.
Removed
Changes in and Disagreements with Accountants on Accounting and Financial Disclosure None.

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