Dyax's HAE drug Kalbitor delayed in US by REMS
This article was originally published in Scrip
The US FDA is requesting a formal risk evaluation and mitigation strategy (REMS), but no additional clinical trials, before it will approve Dyax's Kalbitor (ecallantide; DX88) for treating acute attacks of hereditary angioedema (HAE).
Dyax announced receipt of an FDA complete response letter requesting submission of a REMS and additional information on the BLA's chemistry, manufacturing and controls section. Specifically, the FDA seeks clarification around analytical methodologies and specifications, and additional information on validation activities associated with drug product filling and packaging, Dyax said.
Although ecallantide has not yet secured approval, the lack of a request for additional clinical data should be viewed as a positive for Dyax given the safety concerns expressed by an FDA advisory panel last month.
The pulmonary-allergy drugs advisory committee voted six to five, with two abstentions, that safety and efficacy data provided substantial and convincing evidence to support approval for Dyax's proposed indication for ecallantide to treat HAE attacks in patients aged 10 years and older.
The narrowly favourable recommendation came despite the majority of panellists concluding that safety, particularly the risk of anaphylaxis, had not been adequately assessed in adults or children. Most advisors also said evidence of a clinically meaningful benefit had not been demonstrated in patients aged 10-17 years. However, the panel was strongly swayed by the orphan nature of the disease, its potentially life-threatening complications and the lack of other available treatments (scripnews.com, February 5th, 2009).
HAE affects between 6,000 and 30,000 patients in the US. It is caused by genetic mutations affecting the C1 esterase inhibitor (C1-INH) gene. During an HAE attack, mutated C1-INH fails to appropriately regulate kallikrein, resulting in endogenous release of bradykinin that causes vasodilation and progressive swelling of various parts of the body. Ecallantide is a recombinant human plasma kallikrein inhibitor that works to suppress bradykinin and is administered subcutaneously.
restrictions
At the panel meeting Dyax outlined plans for a "safe use" programme intended to mitigate the risks of anaphylaxis, which occurred in about 3.7% of patients in the ecallantide safety database. Dyax said it is in the process of converting the safe use programme into a REMS as part of its response to the FDA.
As outlined, the programme included a restricted distribution system with a centralised speciality pharmacy and mandatory patient registry. Patients experiencing an attack would have to go to a predetermined location for treatment, and data would be collected on hypersensitivity reactions. Patients experiencing a reaction would be subject to rechallenge, and if this failed future use of ecallantide would be restricted.
Panellists recommended that ecallantide should only be used in healthcare settings capable of treating anaphylactic reactions.
There are no medicines specifically indicated for treating HAE acute attacks in the US. Prophylactic therapies include attenuated androgens, antifibrinolytic agents and Lev Pharmaceuticals' (now ViroPharma) Cinryze, a plasma-derived C1 inhibitor that was approved in October. Cinryze is undergoing FDA review for a treatment indication. With a user fee date of June 3rd, it could be in a position to secure approval ahead of ecallantide.
Last year CSL Behring received an FDA complete response for its human plasma-derived C1-INH product, Berinert, for acute treatment. Pharming is also pursuing FDA approval of its recombinant C1 inhibitor Rhucin, which is produced in the milk of transgenic rabbits. Last year the agency deemed Jerini's (now Shire) bradykinin B2 antagonist Firazyr (icatibant) not approvable for treating HAE attacks.