Protalix BioTherapeutics, Inc., a development stage company, engages in developing and producing recombinant therapeutic proteins that are expressed through its plant cell system in the United States. Its principal product candidate, prGCD, is a proprietary plant cell expressed recombinant Glucocerebrosidase enzyme-based protein for the treatment of Gaucher Disease. The company is also developing PRX-102, a proprietary alpha Galactosidase enzyme for the treatment of Fabry disease, a genetic lysosomal storage disorder in humans, the symptoms of which involve the accumulation of lipids in the cells of the kidneys, heart, and other organs; and PRX-111, a human fertility hormone targeted at the infertility market. In addition, it is developing a proprietary plant-based acetylcholinestrase and its molecular variants for use in various therapeutic and prophylactic indications, including a Biodefense program; and an oral platform for delivering active recombinant proteins systematically through enteral administration through the oral administration of transgenic plant cells. Protalix BioTherapeutics has strategic collaboration with Teva Pharmaceutical Industries, Ltd. for the development and manufacturing of two proteins using the company's plant cell expression system; and Yeda Research and Development Company Limited to design Glucocerebrosidase for the treatment of Gaucher Disease, as well as a licensing agreement with Icon Genetics AG to license Icon's amplification technology for utilization in the expression of its products. The company was founded in 1993 and is based in Carmiel, Israel.
Proprietary Protein Therapeutics with Clinically Improved Profiles
Protalix is a biopharmaceutical company focused on the development, production and commercialization of recombinant therapeutic proteins produced by our proprietary ProCellEx® plant cell-based protein expression system. Our pipeline consists of proprietary, potentially clinically superior versions of recombinant therapeutic proteins that target established pharmaceutical markets.
Track record of success
Protalix was founded by Dr. Yoseph Shaaltiel and began as a greenhouse company in Israel’s northern town of Kiryat Shmona, in 1993. The first manufacturing facility was constructed in May 2004 in Carmiel in the Western Galilee, which was later expanded and upgraded at the end of 2009 in preparation for the commercial production of Elelyso® and production of pipeline candidates for clinical trials. We maintain the highest global quality of product and quality assurance standards. Our cGMP manufacturing facility has been successfully inspected and audited by multiple regulatory agencies including the US FDA, EMA, Australian TGA, Brazilian ANVISA, and the Israeli Ministry of Health.
Protalix is proud to be the first company to gain FDA approval for a plant cell culture expressed protein. Elelyso® (taliglucerase alfa for injection) is Protalix’s first drug product produced by its proprietary ProCellEx® protein expression system, and was approved for marketing by the FDA in May 2012, followed soon after by approval by ANVISA in Brazil, Israel’s Ministry of Health, and other regulatory authorities around the world. For more information about Elelyso®, please visit http://www.elelyso.com
Protalix’s ProCellEx® platform has the ability to manufacture complex proteins, antibodies, and vaccines and has the ability to orally deliver certain therapeutic proteins as demonstrated in animal models.
Elelyso® for Gaucher Disease
ABOUT GAUCHER DISEASE
Gaucher disease, also known as glucocerebrosidase deficiency, is an autosomal recessive disorder and the most prevalent Lysosomal Storage Disorder (LSD) in the world. It is one of a group of disorders that affect specific enzymes that normally break down materials for reuse in the cells. If the enzymes are missing or do not work properly, the materials can build up and become toxic. Gaucher disease occurs when a lipid called glucosylceramide accumulates in the bone marrow, lungs, spleen, liver, and sometimes the brain. It is present in approximately 1 in 20,000 live births. Gaucher disease symptoms can include fatigue, anemia, easy bruising and bleeding, severe bone pain and easily broken bones, and distended stomach due to an enlarged spleen and thrombocytopenia. The gold standard of care for Gaucher disease is enzyme replacement therapy (ERT). Enzyme replacement therapy is a medical treatment in which recombinant enzymes are injected into patients in whom the enzyme is lacking or dysfunctional. For Gaucher disease, recombinant glucocerebrosidase (GCD) is injected to replace the mutated or deficient natural GCD enzyme. ERT treatment may help people live normal lives.
On May 1, 2012, the U.S. Food and Drug Administration (FDA) approved taliglucerase alfa for injection, as an enzyme replacement therapy (ERT) for the long-term treatment of adult patients with a confirmed diagnosis of type 1 Gaucher disease. Taliglucerase alfa is a proprietary, recombinant form of glucocerebrosidase (GCD) is the company’s first approved drug product developed using ProCellEx®. Taliglucerase alfa was also approved by the Israeli Ministry of Health in September 2012, by the Brazilian Ministry of Health in March 2013, and by the applicable regulatory authorities of certain other countries. Taliglucerase alfa is the first plant cell-based recombinant therapeutic protein approved by the FDA or any other major regulatory authority. In 2009 Protalix entered into a collaboration agreement with Pfizer Inc. for the continued development and commercialization of Elelyso®. In October 2015, this agreement was amended providing Pfizer worldwide marketing rights for Elelyso® , marketed in Latin America under the name Uplyso™) with exception of Brazil. In Brazil, taliglucerase alfa is sold under the brand name Bio-Manguinhos alfataliglicerase under a special supply and technology transfer agreement with Fundação Oswaldo Cruz.
Moving forward: Leveraging the benefits of our platform technology
We will continue to leverage multiple unique advantages of the proprietary plant cell culture expression technology platform:
- We have internal capabilities to improve biologic dynamics (e.g., glycosylation, half-life extension) of a protein and have been successful in leveraging these capabilities in the current pipeline.
We can develop and commercialize recombinant proteins without infringing upon the method-based patents or other intellectual property rights of third parties
Our platform has the ability to express certain proteins that are difficult to express in other systems.
Our system enjoys a lower cost of scale-up (CapEx) and production.
Through our system we have the ability to more rapidly develop a protein for clinical testing versus other protein platforms.
Protalix’s vision is to become a fully integrated biopharmaceutical company leveraging the advantages of our
unique technology platform and internal research and development capabilities
MANAGEMENT: Moshe Manor
has served as our President and Chief Executive Officer and as a director of our company since November 2014. Prior to joining Protalix, Mr. Manor served in a number of senior executive positions at Teva, from 1984 through 2012. Most recently, he served as President, Teva Asia & Pacific where he led the strategy and development of a high growth region for Teva. Prior to that, he was Group Vice President, Global Branded Products, leading the Innovative Commercial and Research & Development franchises. From 2006 through 2008, Mr. Manor was Senior Vice President, Global Innovative Resources, and was responsible for generating over $3 billion in sales with Copaxone_ and Azilect. Previously, he served as director of Teva Israel. Most recently, Mr. Manor serves on the Board of Directors of Kamedis Ltd. and Coronis Partners, and as Chairman of the Board of Directors of a startup company, MEway Pharma. He holds a BA in Economics from the Hebrew University in Jerusalem, and an M.B.A. from the Tel-Aviv University. Yoseph Shaaltiel, Ph.D
. founded Protalix Ltd. in 1993 and has served as our Executive Vice President, Research and Development since December 31, 2006. Prior to establishing Protalix Ltd., from 1988 to 1993, Dr. Shaaltiel was a Research Associate at the MIGAL Technological Center. He also served as Deputy Head of the Biology Department of the Biological and Chemical Center of the Israeli Defense Forces and as a Biochemist at Makor Chemicals Ltd. Dr. Shaaltiel was a Postdoctoral Fellow at the University of California at Berkeley and at Rutgers University in New Jersey. He has co-authored over 40 articles and abstracts on plant biochemistry and holds several patents. Dr. Shaaltiel received his Ph.D. in Plant Biochemistry from the Weizmann Institute of Science, an M.Sc. in Biochemistry from the Hebrew University and a B.Sc. in Biology from the Ben Gurion University. Einat Brill Almon, Ph.D
. joined Protalix Ltd. in 2004, originally as a Senior Director and later as a Vice President and then Senior Vice President, Product Development, and became our Senior Vice President, Product Development on December 31, 2006. Dr. Almon has many years of experience in the management of life science projects and companies, including biotechnology and agrobiotech, with direct experience in clinical, device and scientific software development, as well as a strong background and work experience in intellectual property. Prior to joining Protalix Ltd., from 2001 to 2004, she served as Director of R&D and IP of Biogenics Ltd., a company that developed an autologous platform for tissue-based protein drug delivery. Biogenics, based in Israel, is a wholly-owned subsidiary of Medgenics Inc. Dr. Almon was trained as a biotechnology patent agent at leading IP firms in Israel. Dr. Almon holds a Ph.D. and an M.Sc. in molecular biology of cancer research from the Weizmann Institute of Science, a B.Sc. from the Hebrew University and has carried out Post-Doctoral research at the Hebrew University in the area of plant molecular biology. Yossi Maimon
, CPA, joined Protalix Ltd. in 2006 as its Chief Financial Officer and became our Vice President and Chief Financial Officer on December 31, 2006. Prior to joining Protalix, from 2002 to 2006, he served as the Chief Financial Officer of Colbar LifeScience Ltd., a biomaterial company focusing on aesthetics, where he led all of the corporate finance activities, fund raisings and legal aspects of Colbar including the sale of Colbar to Johnson and Johnson. Mr. Maimon has a B.A. in accounting from the City University of New York and an M.B.A. from Tel Aviv University, and he is a Certified Public Accountant in the United States (New York State) and Israel. Tzvi Palash
joined Protalix Ltd. in 2010 as its Chief Operating Officer, bringing with him over 25 years of expertise in commercial operations in the healthcare industry. This experience includes planning, construction, and scale-up of manufacturing facilities, product quality assurance (QA) and validation, regulatory compliance, and general production oversight for biotechnology and pharmaceutical plants. Prior to joining Protalix Ltd., from 2006 through 2010, Mr. Palash served as a General Manager of Colbar LifeScience Ltd., a biomaterial company focusing on aesthetics, that was sold to Johnson and Johnson. In that position, Mr. Palash served as a member of the Global Aesthetic Management Team at the Consumer Group of Johnson & Johnson. Prior to that, from 2001 through 2006, Mr. Palash served as the Vice President, Operations of ColBar, and he has served in different positions at Teva. Mr. Palash has an M.Sc. in Biochemistry from the Hebrew University and a B.Sc. in Biology from the Tel Aviv University. Yaron Naos
joined Protalix in 2004 as Vice President for Production. He has a wealth of hands-on experience and knowledge in the field of pharmaceutical development. Prior to joining Protalix, he served for a decade as R&D Product Manager at Dexxon Pharmaceutical Co., one of Israel's largest pharmaceutical companies, where he was responsible for technology transfer from R&D to production, and in charge of R&D activities that led to the commercialization of many products. Prior to Dexxon, Yaron was plant manager of Medibrands Pharmaceutical Company, as well as logistic manager of Mediline, responsible for all operational activities from procurement to distribution. Mr. Naos holds a BSc in Food Engineering and Biotechnology from the Technion-Israel technology Institute and an MBA from Haifa University. Moshe Chechik
joined Protalix in 2008 as Vice President for Engineering, bringing with him extensive experience in managing, engineering, manufacturing, and leading pharmaceutical projects. Prior to joining Protalix, Moshe served as Infrastructure Development Director at Teva Pharmaceuticals and as an Engineering Manager at the business unit with Teva in North America. Prior to that, he served in the Teva API division as Engineering Manager of a North American business unit. Prior to his career at Teva, Moshe served as Production Manager at Nitron Chemtech Ltd. and Engineering & Maintenance Manager at American Israeli Paper Mills Ltd. He holds a BSc in Chemical Engineering from the Technion-Israeli Institute of Technology and an MBA from Heriot-Watt University. Dr. Michal Kahana
joined Protalix in 2009 as Vice President for Quality Affairs with years of experience in QA management in the pharmaceutical industry and broad knowledge of GMP, GLP, and GCP requirements. Prior to joining Protalix, she managed the 85-employee quality department at Dexxon, one of Israel’s largest Pharmaceutical companies, where she guided the company through several FDA, European, and Israeli health authorities inspections. Michal holds a DVM degree from the University of Bologna, Italy. Ms. Dafna Shelly
joined Protalix in November 2010 as Vice President for Human Resources. Prior to joining Protalix, she held a number of executive management positions which combined her scientific and business skills, including over 18 years with Sigma-Aldrich. Her professional studies in the fields of Biology as well as Business Administration and Human Resources give her a wide and comprehensive understanding of both areas, which is important in managing human resources and other facets of a major biotechnology company. Dafna holds an MSc in Brain Research from the Weizmann Institute of Science and an MBA from the Hebrew University of Jerusalem. Dr. Raul Chertkoff
worked for over a decade in executive medical management in Klalit Health Services, one of the largest global Health Care Service Organizations. He has served for 10 years as Chairman of the Israeli Gaucher Association and was a co-founder and executive member of the European Gaucher Alliance. Additionally, Raul has vast experience in the Public Health and Clinical Sectors, interacting with doctors and patients in clinical research studies, especially in the field of Gaucher disease. Raul received his MD from the Faculty of Medicine at the Technion-Israel Institute of Technology, and an MBA from the Hebrew University of Jerusalem. William Taylor
joined Protalix in 2015 as Vice President, Business Development. He has thirty-plus years of experience in the Life Sciences/Biopharmaceutical industry, in which he has performed both R&D and Business Development roles. Prior to joining Protalix, he served as Director, Business Development & Commercial Operations with Pfenex, Inc. and as Manager, Strategic Alliances at Pfizer Inc., during which he worked across the global biotech community in roles involving scouting/identification, contract/license negotiation, and alliance management. He holds a M.Sc. in Organic Chemistry from Ohio State University and a B.Sc. in Chemistry from Rochester Institute of Technology. Ronen Rosenberg
joined Protalix in March 2015 as Vice President of Commercial and Product Planning. He brings close to 20 years of experience in the pharmaceutical industry in marketing, sales, commercial and strategic planning, and business development. He held a number of senior managerial positions at Teva Pharmaceutical Industries, including global marketing of Copaxone®
, innovative pipeline management and business development, and as Commercial Head of the Global Women’s Health franchise. Prior to his career at Teva, he served as product and marketing manager for leading pharma companies in the local market. Ronen currently lectures on Pharma Marketing at the College of Management Academic Studies’ MBA Biomed track program. Ronen holds a BSc, in Biology from Bar Ilan University and an MBA from Tel Aviv University Recanati Business School. **************************************************************
Orally Delivered Proteins
The first company to gain FDA approval of a protein produced through plant cell-based expression
Protalix’s first commercially available plant cell culture produced protein product, taliglucerase alpha (Elelyso®), was approved by the FDA in May 2012 for long-term enzyme replacement therapy (ERT) for patients with a confirmed diagnosis of type 1 Gaucher disease.
Protalix is dedicated to researching, developing, and marketing recombinant therapeutic proteins with clinically improved profiles produced by our ProCellEx® plant cell-based protein expression platform.
Our multidisciplinary scientific teams are focused on modifying biological properties of biotherapeutics aimed at improving clinical outcomes of therapies in areas of unmet need. These capabilities are well demonstrated in Protalix’s current pipeline.
A Proven Alternative to Mammalian Cell-Based Production Technology
Our platform is a proven alternative to the mammalian cell-based production technology (the most common form of recombinant protein production), overcoming many of its weaknesses while offering significant production, regulatory, and cost benefits.
- As opposed to mammalian cells, plant cells tolerate a relatively wide range of culturing conditions and naturally do not carry the risk of infection by human or animal pathogens. This translates into lower capital investment in the set up as well as in ongoing maintenance of the production plant.
Plant cells provide a natural barrier to human and animal pathogens and are able to utilize a simple culture medium with no requirement to any animal originated supplements. This may prove to be important advantage from a regulatory perspective.
Protalix’s ProCellEx® platform uses flexible polyethylene disposable bioreactors designed and optimized for plant cell cultures. As opposed to the large stainless steel reactors commonly used for recombinant protein production, the ProCellEx® bioreactors are easy to use, entail low initial capital investment, and can be scalable cost-effectively. Additionally, they require relatively low hands-on maintenance between cycles.
ProCellEx® can potentially express certain proteins that are difficult to express in other systems.
Through the ProCellEx® system, it is possible in certain cases to develop and commercialize recombinant proteins without infringing upon the method-based patents or other intellectual property rights of third parties.
Additionally, the ProCellEx® platform has the ability to more rapidly develop clinical material for testing versus other protein platforms.
Development of transgenic cell lines for production of target protein
A solution for oral delivery of proteins has been a long sought-after aspiration of the biopharmaceutical industry.
Orally delivered proteins provide more convenient drug administration than some of the current delivery options for proteins, which include intravenous infusions and intra-muscular and subcutaneous injections. An oral delivery solution is expected to result in better patient compliance along with increased quality of life.
To date, efforts have been met with very limited success due to the inability of proteins to survive the gastric environment of the digestive tract and to act only in the intestine. There is a need for a safe, non-invasive method for continuous delivery of protein therapeutics.
Oral delivery of protein therapies produced through the ProCellEx® platform can be made possible due to the unique cellulose wall of plant cells that makes them resistant to degradation when passing through the digestive tract. The plant cell can serve as a natural vehicle for oral administration.
OPRX-106 is an oral anti-Tumor Necrosis Factor (anti-TNF) candidate, currently in a phase II clinical trial for inflammatory bowel diseases.
From Concept to Market Pipeline Overview
Our pipeline consists of proprietary, potentially clinically superior versions of recombinant therapeutic proteins that target established pharmaceutical markets. All of our pipeline candidates are proteins expressed via our proprietary ProCellEx® system.
We are advancing clinical programs addressing Fabry disease, cystic fibrosis, and immune and inflammatory diseases. In addition, Protalix is conducting initial research to evaluate additional programs for developing proprietary proteins with improved clinical profiles exploiting the unique nature of plant cell expression.
Pegunigalsidase alfa (PRX-102) for the treatment of Fabry Disease
About Fabry Disease
Fabry disease is an X-linked inherited disease that results from abnormal deposits of a fatty substance called globotriaosylceramide in blood vessel walls throughout the body. It occurs in one person per 40,000. Patients with Fabry disease inherit a deficiency of the enzyme alpha-galactosidase-A, which is normally responsible for the breakdown of globotriaosylceramide. The abnormal storage of globotriaosylceramide increases with time and so it accumulates, primarily in the blood and in the blood vessel walls. The channels of blood vessels narrow, leading to decreased blood flow and decreased tissue nourishment. The ultimate consequences of globotriaosylceramide deposition range from episodes of pain and impaired peripheral sensation to end-organ failure—particularly of the kidneys, but also of the heart and cerebrovascular system.
Fabry Disease is generally treated by enzyme replacement therapy (ERT), meaning replacing the missing alpha-Galactosidase-A enzyme with a recombinant protein via intravenous infusion once every two weeks.
About Pegunigalsidase alfa
Pegunigalsidase alfa is a plant cell culture expressed and a chemically modified version of the recombinant alpha-Galactosidase-A protein. Protein sub-units are covalently bound via chemical cross-linking using PEG chains, resulting in a more active and stable molecule than the current available versions. PRX 102 demonstrated enhanced circulatory half-life, with higher enzyme activity in target organs affected by Fabry disease.
Protalix believes that this may potentially lead to a better clinical efficacy and an improved safety profile compared to currently available treatments.
See the latest presentation
Clinical data from Phase I/II Study
14 days of active enzyme
In clinical trials, pegunigalsidase alfa has been shown to be active in the plasma for the entire two weeks between infusions
This level of enzyme activity in the blood is substantially higher than that of currently available enzyme replacement therapies.
Pegunigalsidase alfa has demonstrated a half-life of approximately 80 hours. It is a more stable molecule with a significantly longer circulatory half-life than the currently marketed enzyme replacement therapies.
Positive Impact on Kidney Function
Results of the Phase I/II study with pegunigalsidase alfa showed a stability in eGFR levels of the patients from baseline (BL) through 6 months and 12 months of treatment with the drug. eGFR (estimated glomerular filtration rate) measures level of kidney function and determines stage of kidney disease and function. Consistent eGFR levels means that the kidney function does not deteriorate.
*Germaine et al; 2015
Favorable safety and tolerability
Throughout the Phase I/II trial 417 infusions of pegunigalsidase alfa were administered. This amounts to approximately 16 patient years.
Pegunigalsidase alfa was found to be well tolerated, with 98% of events being mild and moderate
Pegunigalsidase alfa demonstrated lower immunogenicity: Only three patients (19%) tested positive for treatment-induced anti-drug antibodies.
Lower immunogenicity means that the drug provokes a lower immune response. As such, patients may potentially experience less side effects
*Fabrazyme prescribing information
POSITIVE IMPACT ON Cardiac FUNCTION
Results of the Phase I/II study with pegunigalsidase alfa showed stability in key parameters relating to cardiac function.
MEANINGFUL REDUCTION IN Pain
Results of the Phase I/II study showed that patients experienced less pain while being treated with pegunigalsidase alfa.
In 2016, we have commenced two pivotal trials to support registration of pegunigalsidase alfa.
The BALANCE Study is a randomized, double blind, active control study of pegunigalsidase alfa (PRX-102) compared to Fabrazyme® in Fabry patients previously treated with Fabrazyme®. The objective of the study is to demonstrate superiority of pegunigalsidase alfa (PRX-102) in renal function by comparison of the eGFR slope (mean annualized change) between treatment groups.
The BRIDGE study is an open label, single arm switch-over study to assess the efficacy and safety of pegunigalsidase alfa (PRX-102) in Fabry patients currently treated with Replagal®.
Alidornase alfa (PRX-110) for the Treatment of Cystic Fibrosis
About Cystic Fibrosis
Cystic fibrosis (CF) is a life-threatening genetic disease affecting the lungs and digestive system. An estimated 70,000 children and adults worldwide have CF. In patients with CF, a defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs. This may lead to lung damage, high exposure to lung infections and loss of respiratory function. Additionally the thickened mucus obstructs the pancreas and stops natural enzymes from helping the body break down food and absorb vital nutrients. Current therapies include multiple daily physiotherapy sessions to improve breathing, various drug therapies, as well as acute and preventive antibiotic therapy. Despite progress in understanding and treating CF, it remains a challenge to significantly improve quality of life and prolong life.
PRX-110 (alidornase alfa)
Alidornase alfa (PRX-110) is a proprietary plant cell-expressed recombinant form of human deoxyribonuclease I (DNase I), that Protalix has designed, through chemical modification, to be resistant to inhibition by actin. DNase I is part of current CF therapy, intended to reduce sputum viscosity that accumulates in the lungs of CF patients, which exposes patients to recurrent infections and compromises lung function. The current therapy is known as Pulmozyme® (dornase alfa). Given actin is a potent inhibitor of DNase I activity, Protalix’s alidornase alfa (PRX-110)
has the potential to enhance the enzyme’s efficacy significantly in CF patients when compared to the currently approved DNase treatment (Pulmozyme®).
However, DNase I activity is compromised by actin, a globular multi-functional protein, found in high concentration in CF patients’ sputum, which is a potent inhibitor of DNase I. Actin may decrease the enzyme’s DNA degradation activity and potentially interfere with the effectiveness of inhaled DNase I in the lungs of CF patients.
In order to reduce the actin-DNase I interaction and the subsequent inhibition of DNase I activity by actin, Protalix developed alidornase alfa by chemically modifying the enzyme forming an Actin Inhibition Resistant DNase I. This novel treatment may result in an improved lung function and decreased incidence of recurrent infections in patients. Inhaled alidornase alfa (PRX-110) was found safe in healthy volunteers. Protalix has begun a phase IIa trial of alidornase alfa (PRX-110) in CF patients, following which Protalix intends to actively seek collaboration with strategic partners for further development.
PRX-110 Clinical Data
We have completed a phase I trial with 18 healthy volunteers. alidornase alfa (PRX-110) was found to be safe and tolerable.
In July 2016, the first patient was dosed in Protalix’s phase IIa clinical trial of alidornase alfa (PRX-110). In January 2017, Protalix announced positive interim results from the phase II clinical trial for the first 13 CF patients enrolled in the study. At that time, 15 patients had been enrolled in, and were expected to complete, the study. The initial primary efficacy result shows that alidornase alfa (PRX-110) improves lung function as demonstrated by a mean absolute increase in the percent predicted forced expiratory volume in one second (ppFEV1) of 4.1 points from baseline. A commercially available small molecule CFTR modulator for the treatment of CF has reported a mean absolute increase in ppFEV1 of 2.5 from baseline in its registration clinical study. This score was achieved while 74% of the patients participating in the trial of the CFTR modulator were also treated with Pulmozyme® on top of the modulator. While this marketed CFTR addresses a certain mutation applicable to less than 50% of CF patients, alidornase alfa (PRX-110) is being developed to treat all CF patients.
Sputa available DNA samples were analyzed for approximately half of the patients. A mean reduction of approximately 60% in DNA content from baseline was observed, and a mean reduction of approximately 90% from baseline was observed for sputa visco-elasticity. This data provides further supportive evidence of improved lung function after treatment with alidornase alfa (PRX-110), as demonstrated by the increase in ppFEV1.
No serious adverse events were reported, and all adverse events that occurred during the study were mild and transient in nature.
The phase II trial is a 28-day switch-over study of 15 CF patients previously treated with Pulmozyme® to evaluate the efficacy and safety of alidornase alfa (PRX-110) in CF patients. Participation in the trial is preceded by a two-week washout period from Pulmozyme® before treatment with PRX-110 via inhalation. The main efficacy endpoint is the change of forced expiratory volume (FEV1) and forced vital capacity (FVC). Additional endpoints include safety and tolerability, immunogenicity and pharmacokinetic data. In the trial, alidornase alfa (PRX-110) is administered through Philips Respironics’ I-neb AAD Inhaler System, for which Protalix has a supply agreement for the exclusive use of the device for the development of an inhaled product based on dornase alfa for the treatment of CF. The I-neb AAD is a small, lightweight, virtually silent device that is fully portable and has a unique vibrating mesh technology that allows for faster administration than conventional jet or ultrasonic nebulizers.
AIR DNase™ (PRX-110) remains active
In vitro assays have shown that that alidornase alfa (PRX-110) remains active in the relevant concentrations of actin and alidornase alfa (PRX-110), as opposed to Pulmozyme® which loses activity.
Reduction in mucus viscosity
Through rheological measurements in human sputa samples, alidornase alfa (PRX-110)
demonstrated a greater reduction in mucus viscosity compared to Pulmozyme®.
for the Treatment of Inflammatory Diseases
About auto-immune-mediated disorders
Auto-immune-mediated inflammatory disorders are conditions that are characterized by common pathways that lead to inflammation and are caused or triggered by a compromised or dysregulation of the normal immune response. Immune-mediated inflammatory disorders can cause organ damage, and are associated with increased morbidity. Common auto-immune diseases include Rheumatoid Arthritis, Inflammatory Bowel Disease such as Ulcerative Colitis and Crohn’s Disease, psoriasis, and others. Some of the major treatments are anti-Tumor necrosis factor (anti-TNF) drugs, administered as subcutaneous injections or as intravenous infusions. Sales of anti-TNF drugs exceeded $30 billion annually.
OPRX-106 is a plant cell-expressed recombinant human tumor necrosis factor receptor II fused to an IgG1 Fc domain (TNFRII-Fc), in development for oral administration. When administered orally and while passing through the digestive tract, the plant cells function as a natural delivery vehicle, having the unique attribute of a cellulose cell wall which makes them resistant to degradation compared to proteins produced via mammalian cell expression.
Pre-Clinical Data and Clinical Studies
In November 2016, the first patient was enrolled in Protalix’s phase II clinical trial of OPRX-106 for the treatment of ulcerative colitis. OPRX-106 is a plant cell-expressed recombinant human tumor necrosis factor receptor II fused to an IgG1 Fc domain (TNFRII-Fc). The phase II clinical trial is a randomized, open label, 2-arm study of OPRX-106 in 20 patients with active mild to moderate ulcerative colitis. Patients will be randomized to receive 2 mg or 8 mg of OPRX-106 administered orally, once daily, for 8 weeks. The primary endpoint of the study is safety, including monitoring for adverse events following daily administration of the drug. Key efficacy endpoints include relevant disease parameters of the drug, including Mayo score and rectal bleeding. If successful, OPRX-106 will be the first ever oral enzyme treatment as currently there are no other oral enzyme treatments available.
In August 2015, we announced positive clinical study results from our Phase I clinical trial of OPRX-106. PRX-106 demonstrated a favorable safety and tolerability profile and biological activity in the gut. The phase I Clinical trial was a randomized, parallel-design, open-label study designed to evaluate the safety and pharmacokinetics of PRX-106 in healthy volunteers. The trial enrolled 14 subjects that were randomized to one of three dosing cohorts receiving PRX-106 doses equivalent to 2mg, 8mg or 16mg Tumor Necrosis Factor receptor-Fc fusion protein. Subjects received once daily oral administrations for five consecutive days. The results demonstrated that oral administration of PRX-106 is safe and well tolerated. No major side effects were noted, and no suppression of the immune system was observed. Regulatory T cell activation showing biological activity in the gut was observed. Fluorescence-activated cell sorting analysis (FACS) was performed using various antibodies for surface markers, and it was observed that all three dosages of PRX-106 promoted the induction of various subsets of T cells, some of which are correlated with anti-inflammatory response.
The efficacy of OPRX-106 was shown in preclinical studies using mouse models of immune-mediated diseases such as IBD (inflammatory bowel diseases) and immune-mediated hepatitis. Results showed that PRX-106 has the potential to positively affect these diseases, displaying changes in symptoms and in serum levels of anti-inflammatory markers.
Inflamatory Disease Animal Model
Oral Anti-tumor Necrosis Factor Alpha (anti TNF α) OPRX-106 for Inflammatory Diseases.
Potential to locally deliver higher doses with fewer side effects in an oral formulation
Protalix is leveraging internally developed capabilities to improve biologic dynamics (e.g., glycosylation, half-life extension) of a protein combined with the multiple unique advantages of its proprietary ProCellEx® protein expression system, including advanced genetic engineering technology and plant cell-based protein expression methods, to develop a pipeline of novel, next-generation or clinically superior versions of recombinant therapeutic proteins. Significant advantages of ProCellEx® over existing expression systems of mammalian, bacterial, yeast and transgenic cell-based expression technologies, include biologic optimization, the ability to penetrate certain patent-protected markets, a broad range of expression capabilities, significantly lower capital and production costs, elimination of the risk of viral transmission or infection by mammalian components, and the potential ability to administer active therapeutic proteins and vaccines orally.
We believe that all these elements along with our success in bringing Elelyso® (taliglucerase alfa for injection) through clinical trials, regulatory agency approval, and into the market demonstrates a full set of capabilities which make Protalix a partner of choice for other complex therapeutic proteins.
Protalix is interested in considering partnership opportunities on biobetter and novel therapeutic proteins and vaccines as well as exploring oral delivery of biotherapeutics and vaccines by utilizing ProCellEx® technology, in addition to collaborations relating to Protalix’s current pipeline of proprietary therapeutic proteins.
For partnership inquiries, please contact:
Vice President Business Development
In October 2015, we entered into an amended agreement with our commercialization partner for taliglucerase alfa, Pfizer Inc., pursuant to which we licensed to Pfizer the worldwide development and commercialization rights for taliglucerase alfa, excluding Brazil, where we retain full rights. Our original agreement with Pfizer, which was entered into in November 2009, provided that we share with Pfizer revenues and expenses for the development and commercialization of Elelyso on a 60%/40% basis globally, excluding Israel and Brazil. The amended agreement effectively represents the sale of our share in the collaboration agreement to Pfizer. As part of the sale, we agreed to transfer our rights to Elelyso in Israel to Pfizer, and retained such rights in Brazil.
Fundação Oswaldo Cruz
In June 2013, Protalix entered into a supply and technology transfer agreement with Fundação Oswaldo Cruz, an arm of the Brazilian Ministry of Health. The technology transfer is intended to transfer to Fiocruz the capacity and skills required for the Brazilian government to construct its own manufacturing facility, at its sole expense, and to produce a sustainable, high quality and cost effective supply of alfataliglicerase (taliglucerase alfa).