alipogene tiparvovec - Glybera; AMT-011; AAV1-LPL(S447X)
Status - MAA approved by the EU in July 2012, becoming the first US/EU marketed gene therapy
Organizations involved:
uniQure BV – Manuf.; R&D; Tech.; World mark.
Amsterdam Molecular Therapeutics (AMT) – Former
University of Pennsylvania – Tech.
Description: Alipogene tiparvovec (AMT-011, Glybera) is an adeno-associated viral vector (AAV1) based gene therapy administered intramuscularly (IM) at multiple-sites in a single session for delivery and intramuscular (intracellular) expression of a Ser(447)X variant of the human lipoprotein lipase (LPL) gene, (LPLSer(447)X). AAV1 carrying the human variant LPLS447X gene is delivered to skeletal muscle, where it becomes active. The LPL protein is expressed and transported to the capillary endothelium where it binds to chylomicrons and VLDL.
Glybera becomes the first gene therapy approved by regulatory authorities in the Western world. Alipogene tiparvovec is intended as a curative measure for patients with LPLD and, as well as enhancing chylomicron metabolism, may prevent episodes of pancreatitis.
Nomenclature: Glybera [TR]; alipogene tiparvovec [INN]; recombinant adeno-associated virus serotype 1 (AAV1) vector expressing the S447X variant of the human lipoprotein lipase (LPL) gene [CAS]; AAV1-LPL(S447X) [SY]; AMT-011 [SY]; LPLSer(447)X gene therapy [SY]; adenoassociated virus vector for delivery of human lipoprotein lipase (LPL) Ser(447)X [SY]
Biological.: Lipoprotein lipase deficiency (LPLD) is an inherited metabolic disorder, characterized by abnormally elevated plasma concentrations of chylomicrons and triglycerides. LPLD includes patients classified as having hyperlipoproteinaemia type 1 (also known as familial chylomicronaemia) due to a deficiency of lipoprotein lipase (LPL) and those with a deficiency of apolipoprotein C-II, a lipase activating protein. LPL hydrolyses the triglyceride component of circulating chylomicrons and very low density lipoproteins (VLDL). When LPL activity is reduced, chylomicrons accumulate within the bloodstream and cause symptoms such as: abdominal pain, an enlarged spleen and liver, eruptive xanthomas and potentially lethal pancreatitis. The gene encoding for LPL is located on chromosome 8 and is expressed mainly in skeletal muscle, adipose tissue, and heart muscle.
Progenika Biopharma (Spain) obtained a CE mark for its LPLchip DNA chip for detecting mutations in the lipoprotein lipase (LPL) gene. LPLchip is designed to diagnose patients with complete and partial lipoprotein lipase deficiency (LPLD), and it detects more than 120 mutations in the LPL gene. The EU approval is the first for a DNA chip for LPL mutations, the firm claims. The product was developed as part of a 2009 agreement between Progenika and Amsterdam Molecular Therapeutics (AMT) to develop a companion diagnostic for use alongside Glybera gene therapy for LPLD.
Companies.: Developed and manufactured by Amsterdam Molecular Therapeutics (AMT), now uniQure BV. Note, after receiving its 2nd EU refusal to approval Glybera in Nov. 2011, "Amsterdam Molecular Therapeutics was de-listed, with the gene therapy assets being signed over to privately held uniQure."
In July 2013, Chiesi Famaceutici (Italy) licensed exclusive rights to commercialize Glybera as well as uniQure's pipeline products for hemophilia B, in Europe and selected other countries (Brazil, Mexico, Pakistan, Turkey, Russia, CIS countries, plus China for Glybera only)
FDA class: Biologic BLA
Indications: (EU indications upon approval]:
The need for just a single treatment differentiates between Glybera and enzyme replacement therapies for similar inherited enzyme deficiency disorders, which must be administered on a chronic basis.
Status: An MAA was filed in Jan. 2010 for lipoprotein lipase deficiency (LPLD). In April 2010, the MAA was rejected. EMA told AMT that it has not provided enough evidence of the long-term efficacy of the product. LPLD is an extremely rare condition, and the clinical trial data submitted to EMA for approval included only 27 patients. The EMA said there were too few patients for whom sufficiently long-term data were available, and as a result, there was insufficient evidence of a reduction in the rate of pancreatitis. The EMA did not have any concerns about the safety of Glybera, which supports that the safety of gene therapy is no longer the roadblock to regulatory approval. [Note,, the first gene therapy product ever to be filed for approval with EMA was Cerepro, a gene therapy for treating brain cancer, which also presented no concerns about the safety of the product. The EMA refused approval of Cerepro, because there was not enough evidence that Cerepro was effective].
The EU granted Glybera orphan designation in
March 2004, granting this to Mr. Aart Brouwer, the Netherlands, and transferring it to AMT in Dec. 2006. This provides 10 years of EU exclusivity (for diseases affecting fewer than five people in every 10,000).
On July 20, 2012, the CHMP, EMA/EU, recommended full approval to Glybera "as a treatment for LPL "under exceptional circumstances for Glybera, 3 x 10.sup.12 gc/ml, solution for injection, for treatment of patients diagnosed with lipoprotein lipase deficiency and suffering of severe or multiple pancreatitis attacks," meaning it will be administered at just a few specialist centers, e.g., with the company citing ". "We might need three clinics in Germany, two in Holland, for example." uniQure will be required to set up a registry to monitor outcomes in patients treated with Glybera, which the EMA will review.
Note, neither the CHMP nor its expert advisory group, the Committee for Advanced Therapies (CAT), had any safety concerns about Glybera’s use of an adeno-associated virus vector to deliver working copies of the LPL gene into muscle cells.
On Nov. 2, 2012, Glybera received full EU MAA approval.
At the time of approval, uniQure report spending "50 million euros (US$60.8 million) in developing Glybera, of which it was forced to lavish 15 million euros on the protracted regulatory process." This is an incredibly low cost for development of a highly-innovative product (the type that mainstream Big Pharma companies typically costs them well over $1 billion to bring to market).
Tech. transfer: Dr. James M. Wilson and co-workers, University of Pennsylvania, is reported to be the source for the adenovirus vector, with him receiving a number of adenovirus vector and gene therapy-related patents.
Trials: AMT has conducted two clinical studies for lipoprotein lipase deficiency (LPLD) in Europe and Canada and long term follow-up from these, along with a further study in Canada. The MAA included clinical trials data from a total of 27 patients, significant number for this very orphan indication. In these three studies Glybera showed a sizeable decrease in the incidence of pancreatitis, or acute inflammation of the pancreas, the most debilitating complication of LPLD. These studies also indicate that Glybera has an excellent safety profile.
Medical: The need for just a single treatment differentiates between Glybera and enzyme replacement therapies for similar inherited enzyme deficiency disorders, which must be administered on a chronic basis.
Disease: Lipoprotein lipase deficiency (LPLD; also known as familial chylomicronaemia or hyperlipoproteinaemia type I) is a seriously debilitating, and potentially lethal, orphan disease, for which no approved therapy exists today. The disease is caused by mutations in the LPL gene, resulting in highly decreased or absent activity of LPL protein in patients. This protein is needed in order to break down large fat-carrying particles that circulate in the blood after each meal. When such particles, called chylomicrons, accumulate in the blood, they may obstruct small blood vessels, which in turn can lead to pancreatitis. Recurrent pancreatitis in LPLD patients can result in difficult-to-treat diabetes. LPLD is associated with significant morbidity and mortality.
Patients with LPL are unable to digest fat particles in the bloodstream, which accumulate to cause severe attacks of pancreatitis. Patients with LPL are often afraid of eating a normal meal, because it can lead to acute and extremely painful inflammation of the pancreas, often resulting in a visit to intensive care. As noted by uniQure, "Now, for the first time, a treatment exists for these patients that not only reduces this risk of getting severely sick, but also has a multiyear beneficial effect after just a single injection."
Upon EU approval, uniQure reported its "estimate there are between 1 ,000 to 5,000 [LPLD patients] worldwide.'
Market: Upon approval, uniQure noted that marketed enzyme replacement therapies cost between 150,000 euros and 450,000 euros per patient, per annum, and that pricing for Glybera should be a multiple of some price in that range to reflect the fact that a one off-treatment with Glybera has an effect that lasts over years.
Glybera may cost close to $1 million/patient/year when it launches in the Summer of 2013 in Europe.
Index Terms:
Companies involvement:
Full monograph
227.2 LPL gene therapy
Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein (see section 4.4).
Nomenclature:
Glybera [TR]
alipogene tiparvovec [INN]
recombinant adeno-associated virus serotype 1 (AAV1) vector expressing the S447X variant of the human lipoprotein lipase (LPL) gene [CAS]
AAV1-LPL(S447X) [SY]
AMT-011 [SY]
human lipoprotein lipase (LPL) [SY]
LPLSer(447)X gene therapy [SY]
FDA Class: Biologic BLA
biopharmaceutical products
Gene Activation
recombinant DNA
adenine triphosphate (ATP)
cells, human
octoxynol (Triton X-100)
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM001 Marketed Product in EU
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