Date: 2012-04-02
Type of information: Refusal of a Market Authorisation in the EU
Product name: Kynamro®
Compound: mipomersen
Therapeutic area: Genetic diseases - Rare diseases - Cardiovascular diseases
Action mechanism: Mipomersen is a first-in-class apo-B synthesis inhibitor and acts by blocking the production of apolipoprotein B (apoB), the protein that provides the structural core for these atherogenic particles, including LDL and lipoprotein-a (Lp(a)). This antisense drug is metabolized without affecting the CYP450 pathways used in commonly prescribed drugs. No clinically relevant pharmacokinetic interactions were reported between Kynamro® and warfarin, or between Kynamro® and simvastatin or ezetimibe.
Company: Genzyme (USA - MA), a Sanofi company (France)/Isis Pharmaceuticals (USA - CA), now Ionis Pharmaceuticals (USA - CA)
Disease: homozygous (HoHF) and severe heterozygous familial hypercholesterolemia (HeFH)
Latest news: * On March 21, 2013, the Committee for Medicinal Products for Human Use (CHMP) has confirmed the refusal of marketing authorisation for Kynamro®, intended for the treatment of patients with certain forms of familial hypercholesterolaemia. In December 2012, the CHMP was concerned that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolaemia, mainly due to side effects. This was considered an important limitation because Kynamro® is intended for long-term treatment. The CHMP was also concerned by the potential long-term consequences of liver test results showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that more cardiovascular events (problems with the heart and blood vessels) were reported in patients taking Kynamro than in patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its potential cardiovascular risk. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Kynamro® did not outweigh its risks and recommended that it be refused marketing authorisation. During the re-examination in March 2013, the CHMP’s concerns remained unresolved and were not fully addressed by measures proposed by the company.
* On January 29, 2013, the FDA has approved Kynamro® (mipomersen sodium) injection as an addition to lipid-lowering medications and diet to treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemia (HoFH). The addition of Kynamro® helps to reduce low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B, total cholesterol, and non-high density lipoprotein-cholesterol (non HDL-C). The drug is given as a 200 mg weekly subcutaneous injection.
Kynamro® is the first systemic antisense drug to reach the market. Its approval is supported by a randomized, double-blind, placebo-controlled, multi-center trial that enrolled 51 patients age 12 to 53 years, including 7 patients age 12 to 16 years, who were maintaining a regimen of maximally-tolerated lipid lowering medications. Treatment with Kynamro® further reduced LDL-C levels by an average of 113 mg/dL, or 25%, from a treated baseline of 439 mg/dL, and further reduced all measured endpoints for atherogenic particles. In March 2010, these data were published in The Lancet by Professor Raal, University of the Witwatersrand in South Africa.
Safety data are based on pooled results from four Phase 3, randomized, double-blind, placebo-controlled trials with a total of 390 patients of which 261 patients received weekly subcutaneous injections of 200 mg of Kynamro® and 129 patients received placebo for a median treatment duration of 25 weeks. Eighteen percent of patients on Kynamro® and 2% of patients on placebo discontinued treatment due to adverse reactions. The most common adverse reactions in patients treated withKynamro® that led to treatment discontinuation and occurred at a rate greater than placebo were: injection site reactions (5.0%), alanine aminotransferase (ALT) increased (3.4%), flu-like symptoms (2.7%), aspartate aminotransferase (AST) increased (2.3%), and liver function test abnormal (1.5%).
Kynamro® contains a Boxed Warning citing the risk of hepatic toxicity. Patients taking Kynamro® should have liver enzyme testing before starting the drug and periodically thereafter. The drug is available only through a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS.
* On December 14, 2012, Genzyme has announced that the company plans to request a re-examination of the CHMP Opinion. An application is currently under review by the FDA.
* On 13 December 2012, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Kynamro®, intended for the treatment of patients with certain forms of familial hypercholesterolaemia. Genzyme may request a re-examination of the opinion within 15 days of receipt of notification of this negative opinion.
The CHMP noted that Kynamro® was effective at reducing LDL cholesterol levels in patients with homozygous and severe heterozygous familial hypercholesterolaemia. After 26 weeks, the approximate average reduction seen in patients taking Kynamro® was between 25% and 36%, while it was between 3% and 13% in patients taking placebo. However, the CHMP was concerned about the medicine’s safety. The Committee noted that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolaemia, mainly due to side effects such as flu-like symptoms, injections site reactions and liver toxicity. This was considered important because Kynamro® is intended for long-term treatment in order to maintain the cholesterol-lowering effect. The CHMP was also concerned by liver test results in patients taking Kynamro® showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that a greater proportion of patients taking Kynamro® experienced serious cardiovascular events (problems with the heart and blood vessels) than patients taking placebo. This prevented the CHMP from concluding that Kynamro®’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its cardiovascular risk.
Therefore, at that point in time, the CHMP was of the opinion that the benefits of Kynamro® did not outweigh its risks and recommended that it be refused marketing authorisation.
* On October 18, 2012, Sanofi, its subsidiary Genzyme, and Isis Pharmaceuticals have announced that the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 9 to 6 that Genzyme had provided sufficient efficacy and safety data to support the marketing of Kynamro® (mipomersen sodium) for the treatment of patients with Homozygous Familial Hypercholesterolemia (HoFH).
* On May 29, 2012, Genzyme and Isis Pharmaceuticals have announced that the FDA has accepted for filing the NDA for Kynamro® (mipomersen sodium) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH). The NDA filing with the FDA triggers a $25 million milestone payment to Isis from Genzyme. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (PDUFA) date of January 29, 2013.
* On March 29, 2012, Genzyme, a Sanofi company, and Isis Pharmaceuticals have announced that Genzyme has submitted a New Drug Application (NDA) to the FDA seeking approval for Kynamro® (mipomersen sodium) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH).
* On July, 26, 2011, Genzyme, a Sanofi company and Isis Pharmaceuticals have announced that Genzyme has submitted a marketing authorization application to the European Medicines Agency seeking approval for the 200 mg weekly dose of mipomersen for the treatment of homozygous and severe heterozygous familial hypercholesterolemia.
Patents:
Submission of marketing authorization application USA : 2012-03-29
Submission of marketing authorization application UE: 2011-07-26
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2013-01-29
UE authorization:
Favourable opinion UE:
Favourable opinion USA: 2012-10-18
Orphan status USA: 2006-05-23
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
