Date: 2011-12-20
Type of information: Granting of a Market Authorisation in the US
Product name: Elelyso®/Uplyso®
Compound: alfataliglicerase (plant-cell expressed form of glucocerebrosidase)
Therapeutic area: Rare diseases
Action mechanism: enzyme replacement therapy. Elelyso® is the first plant cell-expressed enzyme replacement therapy (ERT) for the treatment of Gaucher disease. It is also the first approved plant cell-expressed drug that is derived from ProCellEx®, the Company's proprietary plant cell-based protein manufacturing system, using genetically engineered carrot cells. Elelyso® is a form of the human lysosomal enzyme, glucocerebrosidase, used to treat Gaucher disease
Company: Protalix (Israel) Pfizer (USA - NY)
Disease: type 1 Gaucher disease
Latest news: * On November 22, 2016, Protalix BioTherapeutics announced that the Brazilian National Health Surveillance Agency (ANVISA, Agencia Nacional de Vigilancia Sanitaria) has granted regulatory approval for alfataliglicerase as a long-term enzyme replacement therapy for children four years old and above with a confirmed diagnosis of Type I Gaucher disease. Gaucher disease is a rare lysosomal storage disorder, with approximately 700 patients treated in Brazil. Brazil has the third largest number of identified Gaucher patients worldwide, after the United States and Israel. Alfataliglicerase was approved by ANVISA in March 2013 for long-term enzyme replacement therapy (ERT) for adults with a confirmed diagnosis of Type I Gaucher disease. * On August 28, 2014, Pfizer and Protalix BioTherapeutics announced that the FDA approved Elelyso™ (taliglucerase alfa) for injection for pediatric patients. Elelyso™ is therefore now indicated for long-term enzyme replacement therapy (ERT) for adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease. * On May 30, 2014, Protalix BioTherapeutics announced that Health Canada has granted regulatory approval to Elelyso™ (taliglucerase alfa for injection) for the long-term enzyme replacement therapy for both adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso™may also be used for the hematological manifestations in pediatric patients with a confirmed diagnosis of Type 3 Gaucher disease. Elelyso™ will be marketed in Canada by Pfizer Inc., the Company's commercialization partner. * On May 22, 2014, Protalix BioTherapeutics announced that the Australian Therapeutic Goods Administration (TGA) has granted regulatory approval to Elelyso™ (taliglucerase alfa) for long-term enzyme replacement therapy for both adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease associated with at least one of the following: splenomegaly, hepatomegaly, anemia, thrombocytopenia. Elelyso™ will be marketed in Australia by Pfizer, the Company's commercialization partner. * On April 29, 2013, Protalix BioTherapeutics has announced that the Mexican Federal Commission for the Protection against Sanitary Risk (COFEPRIS) and the Public Health Institute of Chile have both granted regulatory approval to Uplyso® (alfataliglicerase) for the long-term enzyme replacement therapy for adults with a confirmed diagnosis of Type I Gaucher disease. Uplyso® will be marketed in Mexico and Chile by Pfizer Inc., the Company's commercialization partner. Uplyso® is known as Elelyso® (taliglucerase alfa) outside of Latin America. * On November 1, 2012, Pfizer and Protalix BioTherapeutics have announced that the European Commission has endorsed the European Medicines Agency (EMA)'s CHMP recommendation not to issue a Marketing Authorization for taliglucerase alfa (Elelyso®) in the European Union. The CHMP recommendation was not related to the safety, quality or efficacy of taliglucerase alfa, but solely to the specific requirements of the European Union (EU) Orphan Drug Regulation. As first disclosed on June 22, 2012, the CHMP issued its opinion on taliglucerase alfa and gave a positive risk-benefit assessment concluding that the benefits of the medicine outweighed its risks in the treatment of Type 1 Gaucher disease. Despite the positive risk-benefit assessment, the CHMP could not recommend Marketing Authorization due to the fact that Shire's velaglucerase alfa had received prior Marketing Authorization with orphan drug designation for the same condition. Therefore, Shire's treatment has orphan market exclusivity in the EU for a ten-year period commencing on its authorization in August 2010. Pfizer pursued a request for derogation from Shire's orphan market exclusivity based on a number of factors but the request was denied. * On September 27, 2012, Protalix BioTherapeutics has announced that is has received marketing authorization from the Israeli Ministry of Health for Elelyso® (taliglucerase alfa) for injection, for the long-term treatment of adults with Type 1 Gaucher disease. Elelyso® will be marketed in Israel by Protalix Ltd., the holder of all marketing rights to Elelyso in the Israeli market. This is the second marketing approval of Elelyso®, which was approved by the FDA on May 1, 2012. Marketing applications have been filed in additional territories. Elelyso® is marketed in the United States by Pfizer. Protalix has announced that it intends to sell Elelyso® in Israel at a competitive price compared to other products already available to Gaucher patients. Over the past five years, the Company has treated over 60 Gaucher patients in Israel with Elelyso® through clinical trials and compassionate use programs and expects that a substantial proportion of these patients will soon be treated through commercial programs. * On June 22, 2012, Pfizer and Protalix BioTherapeutics have announced that the EMA has adopted an opinion recommending against the marketing authorization of their enzyme replacement therapy, taliglucerase alfa, for the treatment of Gaucher disease. As part of its Opinion, the CHMP gave a positive risk-benefit assessment for taliglucerase alfa concluding that the benefits of the medicine outweighed its risks in the treatment of Type 1 Gaucher disease. The partners have indicated that Pfizer pursued a request for derogation from Shire's orphan market exclusivity based on a number of factors. This request, however, was denied. * On June 21, 2012, the EMA has announced that the Committee for Medicinal Products for Human Use (CHMP) has recommended the refusal of a marketing authorisation for the medicinal product Elelyso®, intended for the treatment of type 1 Gaucher disease. The CHMP noted that the main study showed that Elelyso® led to clinically relevant reductions in the size of the spleen as well as the liver. There were also improvements in haemoglobin levels and blood platelet counts. The side effects seen with Elelyso® appear to be similar to those of other enzyme replacement therapies. The CHMP therefore concluded that the benefits of the medicine outweighed its risk in the treatment of type 1 Gaucher disease. However, the CHMP also concluded that the medicine cannot be granted marketing authorisation in the EU because of the ten-year market exclusivity that had been granted for Vpriv® (Shire's velaglucerase alfa), which was authorised in August 2010 for the same condition. Market exclusivity for orphan medicines is given as an incentive for companies to develop medicines for rare diseases, which may otherwise not be developed due to the high costs and small patient populations. The exclusivity means that another medicine cannot be authorised for the same condition if it is similar to the medicine already authorised. In this case, the CHMP concluded that Elelyso® is similar to Vpriv®, as they are both enzyme replacement therapies that work in the same way. The CHMP also considered the legal exemptions that could have allowed Elelyso® to be authorised in spite of the Vpriv®’s market exclusivity. The possible exemptions related to whether Elelyso® was clinically superior to Vpriv® and whether there were supply problems with Vpriv®. However, the CHMP concluded that there is no good evidence that Elelyso® would offer patients any important advantages over Vpriv® or that Vpriv® is in short supply. The Committee therefore recommended the refusal of the marketing authorisation. * On May 1, 2012, Pfizer and Protalix BioTherapeutics have announced that the FDA approved Elelyso® (taliglucerase alfa) for injection, for the long-term treatment of adults with a confirmed diagnosis of type 1 Gaucher disease. Elelyso® is the first FDA-approved plant cell-based ERT for Gaucher disease. It is also the first approved plant cell-expressed drug that is derived from ProCellEx® Protalix's proprietary manufacturing system, using genetically engineered carrot cells. The approval is based on the review of Protalix's clinical development program: In a study of 31 adult patients with Type 1 Gaucher disease naïve to enzyme replacement therapy, the safety and efficacy of Elelyso® was assessed. The trial was a nine-month, multi-center, double blind, randomized study in patients with Gaucher disease-related enlarged spleens and thrombocytopenia. Patients were randomized to receive Elelyso® at a dose of either 30 Units/kg (n=15) or 60 Units/kg (n=16). Data showed the pivotal phase III clinical trial achieved its primary endpoint as Elelyso® significantly reduced spleen volume after nine months compared to baseline in both treatment groups. Secondary endpoints of liver volume, hemoglobin and platelet counts also showed improvement. Twenty-six patients continued to be treated with Elelyso® in an extension of this study in a blinded manner for a total treatment duration of 24 months. The data demonstrated continued improvement in the clinical parameters. In a study of 25 patients with Type 1 Gaucher disease who were switched from imiglucerase to Elelyso®, the safety and efficacy of Elelyso® was assessed. The trial was a nine-month, multi-center, open-label, single arm study in patients who had been receiving treatment with imiglucerase at doses ranging from 11 Units/kg to 60 Units/kg for a minimum of 2 years. Imiglucerase therapy was stopped, and treatment with Elelyso® was administered every other week at the same number of units as each patient's previous imiglucerase dose. Organ volumes and hematologic values remained stable on average through nine months of Elelyso® treatment. The most common adverse reactions during clinical studies were infusion reactions. Other commonly observed adverse reactions in less than ten percent of patients were URTI/nasopharyngitis, pharyngitis/throat infection, headache, arthralgia, influenza/flu, UTI/pyelonephritis, back pain and extremity pain. There are currently two other ERTs approved for Gaucher disease in the U.S., imiglucerase (Cerezyme® - Genzyme) and velaglucerase (VPRIV® - Shire). Pfizer has announced that Elelyso® will be available to U.S. patients at a cost that will be priced at 25 percent below the cost of imiglucerase. With the approval of Elelyso®, Pfizer is also introducing Gaucher Personal Support (GPS), a specialized support program for people living with Gaucher disease. Through the GPS program, Pfizer will provide an assistance program covering 100 percent of prescription co-pay expenses for eligible patients on Elelyso® who have commercial health insurance. Additionally, Pfizer will provide financial assistance for eligible patients who are uninsured or under-insured where allowed by law. * On February 25,2011, Protalix announced that the FDA issued a Complete Response Letter regarding its New Drug Application (NDA) for taliglucerase alfa for the treatment of Gaucher disease. The main questions raised by the FDA regarding the NDA relate to clinical and chemistry, manufacturing and controls (CMC). In the clinical section, the FDA requested additional data from the Company’s switchover trial and long-term extension trial. At the time the NDA was submitted, full data from these trials was not available. In the CMC section, the FDA requested information regarding testing specifications and assay validation. Protalix and its partner Pfizer will work with the FDA to address its requests.
The safety and efficacy of Elelyso™ were assessed in fourteen pediatric patients with type 1 Gaucher disease in two clinical trials. The first trial consisted of nine patients in a 12-month, multi-center, double-blind, randomized study in treatment-naïve patients aged two to 13 years. At the end of the 12-month study, therapeutic efficacy of Elelyso™ was demonstrated, as measured by a decrease in spleen and liver volume and an increase in platelet count. A second trial consisted of 5 pediatric patients aged 6 to 16 years who were switched from imiglucerase to Elelyso™. The trial was a 9-month, multi-center, open-label, single-arm study in patients who had been receiving treatment with imiglucerase at dosages ranging from 9.5 units/kg to 60 units/kg every other week for a minimum of 2 years. Elelyso™ was administered for 9 months at the same dose as each patient’s previous imiglucerase dose. If needed, adjustment of dosage was allowed during the study in order to maintain stability of clinical parameters. Mean spleen and liver volume, platelet count and hemoglobin value remained stable through 9 months of Elelyso™ treatment.
The recommended dosage of Elelyso™ for treatment-naïve adult and pediatric patients four years of age and older is 60 units per kg of body weight administered every other week as a 60 to 120 minute intravenous infusion.
Patients previously treated on a stable dosage of imiglucerase are recommended to begin treatment with Elelyso™ at that same dosage when they switch from imiglucerase to Elelyso™. Dosage adjustments can be made based on achievement and maintenance of each patient’s therapeutic goals.
Patents:
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2012-05-01
UE authorization:
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2009-09-03
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news: * On November 30, 2009, Pfizer and Protalix BioTherapeutics entered into an agreement to develop and commercialize taliglucerase alfa. Protalix has retained exclusive commercialization rights in Israel, while Pfizer received exclusive licensing rights for the commercialization of Elelyso® in all other markets. As part of this agreement, and at the conclusion of the FDA approval process, Protalix will transfer the Elelyso® NDA and IND to Pfizer.
