BioMarin Pharmaceutical said today it has withdrawn its Marketing Authorization Application (MAA) for Kyndrisa™ (drisapersen), the company’s drug candidate for Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.
BioMarin said it will also stop clinical development of three first-generation follow-on products to Kyndrisa, the exon-skipping oligonucleotides BMN 044, BMN 045, and BMN 053. All are now in Phase II studies for distinct forms of DMD.
The decision followed discussions at the May 2016 Committee for Medicinal Products for Human Use (CHMP) meeting that according to BioMarin clearly indicated that the CHMP intended to issue a negative opinion.
“The withdrawal of the MAA and discontinuation of our current experimental drugs for Duchenne is a difficult but necessary decision at this time,” BioMarin Chairman and CEO Jean-Jacques Bienaimé said in a statement.
BioMarin said it plans to work with physicians, patient groups, and regulators to develop a transition plan for patients now being treated with Kyndrisa, BMN 044, BMN 045, and BMN 053. The company also said it will continue to explore development of next-generation oligonucleotides for DMD.
BioMarin’s decision comes nearly 6 months after the FDA issued a Complete Response letter to the company's NDA for Kyndrisa, with the agency “concluding that the standard of substantial evidence of effectiveness has not been met,” the company disclosed in a January 14 announcement.
Kyndrisa is an antisense oligonucleotide designed to induce exon skipping to provide a molecular patch for dystrophin transcripts produced by certain mutated dystrophin genes.
BioMarin said the European withdrawal of Kyndrisa had no effect on its previous forecast that it expects to achieve non-GAAP break-even or better results in 2017.
BioMarin is one of several drug developers to run into regulatory roadblocks in the development of DMD treatments in recent months.
On May 25, Sarepta Therapeutics said it was notified by the FDA that it would not be able to act on its NDA for eteplirsen, indicated for DMD amenable to exon 51 skipping, by May 26 as planned, but would instead continue its review and internal discussions and make a decision “in as timely a manner as possible.” Sarepta’s statement came a month after an FDA advisory committee recommended against approval of the drug, with the company and the agency clashing on the adequacy of the company’s clinical program for eteplirsen.
Sarepta has based its NDA on a Phase IIb clinical program (Studies 201 and 202) assessing the effect of eteplirsen on 12 patients, on long-term outcomes (through 168 weeks) from the Study 202 open-label extension study, and on 4-year clinical effectiveness data based on a comparison of patients in Study 201/202 to a historical control group—a major amendment to the NDA in January.
According to Sarepta, after 4 years of treatment with eteplirsen, only two of the 12 boys treated with eteplirsen lost the ability to walk compared to 10 of 13 untreated boys, as measured by a 6-minute walk test. However, the untreated boys were not part of the clinical program but derived from historical data—among concerns raised by the agency.
Also, PTC Therapeutics said February 29 it received a Refuse to File (RTF) letter from the FDA in response to its NDA for Translarna™ (ataluren), the company’s candidate for nonsense mutation DMD. In a letter received by the company on February 22, the FDA stated that the NDA for ataluren was not sufficiently complete to permit a substantive review.
PTC said the letter conveyed the FDA’s view that both the Phase 2b and ACT DMD trials were negative and did not provide substantial evidence of effectiveness. The FDA also characterized adjustments to the ACT DMD study as post hoc and therefore not effective. PTC added that the FDA noted that the NDA did not contain adequate information regarding the abuse potential of ataluren, a requirement for new molecules that cross the blood–brain barrier.
