Race for the first drug approval by FDA for treating Duchenne Muscular Dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is an inherited disorder that involves muscle weakness, which quickly gets worse. Duchenne muscular dystrophy is caused by a defective gene for dystrophin (a protein in the muscles). However, it often occurs in people without a known family history of the condition. Because of the way the disease is inherited, it usually affects boys. Duchenne muscular dystrophy occurs in about 1 out of every 3,600 male infants. DMD is a rare disease and is an orphan disease indication for the drug development.

In June 2015, FDA issued its draft guidance for industry “Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment” which delineated the details about FDA’s thinking about the drug development for treating Duchenne Muscular Dystrophy.

FDA recognized that Duchenne Muscular Dystrophy is life-threatening and severely debilitating disease with unmet medical need (no FDA-approved drug up to this date). The statutory standards for effectiveness apply to drugs for dystrophinopathies just as they do for all other drugs. FDA has long stressed, however, that it is appropriate to exercise flexibility in applying the statutory standards to drugs for serious diseases with important unmet needs, while preserving appropriate guarantees for safety and effectiveness.

Several companies are racing to developing and getting FDA approval for the first drug for treating DMD. Here are some updates on the progression of DMD drug development by these companies: 2014 updates and 2015 updates. Three companies are in the front: BioMarin Pharmaceutical, PTC Therapeutics, and Sarepta Therapeutics. So far, there are more disappointing news for these companies.

• Jan 14, 2016 FDA rejects BioMarin's muscle wasting drug; Sarepta drug in focus
• On Feb 23, 2016, FDA rejected PTC’s application for Duchenne drug, rattling investors and parents
• PTC shares sink as FDA says application does not merit review 
• 01/15/16 Sarepta Plunges on Harsh FDA Eteplirsen Review Ahead of Next Week's Advisory Panel Meeting
• 02/23/2016 Hope for Sarepta Drug Approval Found in Obscure FDA Document
• 04/22/2016 Sarepta shares plunges as FDA questions muscular dystrophy drug
• 04/26/2016 FDA advisory committee vote against the Serepta DMD drug

FDA usually organizes advisory committee meetings when they face the challenges in deciding whether or not approve a drug. While FDA does not need to follow the advisory committee's suggestion, the voting results from the advisory committee usually put a great weight on FDA's decision. In DMD situation, the designated FDA advisory committee is Peripheral and Central Nervous System Drugs Advisory Committee (PCNS in short). FDA organized an PCNS meeting
before rejecting Biomarin’s NDA for NDA 206031 Drisapersen. FDA’s briefing documents indicated FDA’s concerns about approving Drisapersen. The meeting minutes indicated that the majority of the advisory committee members were not convinced by the efficacy of the Drisapersen and were concerned about the risk of safety issues outweighing the benefits.

FDA is now planning to have an advisory committee for Sarepta‘s Eteplirsen. FDA’s briefing document did not sound encouraging. FDA officials said they “concluded that the standard of substantial evidence of effectiveness has not been met” and that the drug “is not ready for approval in its present form.” The meeting was originally scheduled for Jan 22, 2016, but was delayed/rescheduled for a late date (TBD) due to the winter storm in DC area.

FDA did not hold the advisory committee meeting for PTC therapeutics’ rolling NDA submission. PTC’s Translarna was approved by EMA for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older. See Translarna’s EMA approval information and Translarna’s Summary of Product Characteristics. Luckily, the PTC's translarna also got the endorsement from UK's NICE. NICE is usually not nice in terms of the drug's cost-benefit assessment. 

Now that FDA has rejected PTC’s Translarna and Biomarin’s Drisapersen, Sarepta’s Eteplirsen becomes the only choice to be approved by FDA as the first drug for treating DMD. FDA’s assessment as delineated in their briefing book do not look promising. The patient communities and medical experts in the field are starting to put the pressures on FDA to approve the drug.

• CUREDUCHENNE urges regulators to approve Eteplirsen, stresses the importance of multiple drugs in the pipeline
• 36 Duchenne experts sign UCLA letter in support of approval of Sarepta’s drug
• FDA urged to approve Sarepta’s DMD drug by dozens of medical experts
• Duchenne pioneer says FDA rejection of Sarepta’s drug ‘would be a travesty’
• FDA Faces Sensitive Challenge With Review of DMD Drug
• Muscular dystrophy drug advocates plan to pack crucial meeting
• Sarepta shares sink as FDA staff stay sour on muscle drug

Sometimes the medical experts can have biases toward the drug approval. If you are working on something for so long, you will be more likely to see the benefit of the treatment and tend to make judgment in favor of the drug approval even though the evidence and the clinical trial results are not strong. In the interview, one DMD expert Dr Kunkel said he believes the Sarepta’s drug's promises far outweigh the risk – completely different from FDA’s assessment.

“My feeling is, it can’t hurt to be approved, in the sense that it’s got such a safety profile, it looks like its efficacious, and it’s making protein,” said Kunkel, who agreed to serve on a new scientific advisory board for Sarepta last year. “That, to me, would predict it to have an effect. And it would be a travesty not to let patients have it.”

It is always interesting to see how flexible FDA will be willing to lower the requirements for approving a drug for treating life-threatening and severely debilitating orphan disease. It is also interesting to see how FDA will withstand the pressures from the patient advocate group and the medical experts.

Last August, we saw that FDA approved the Addyi as the first female Viagra for treating acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women under the pressure of being accused of sexist. The Addyi's approval process demonstrated that while not often, FDA could be influenced by outside groups to approve a drug even though they felt the risks outweighed the benefits.