FDA Panel Decision On Eteplirsen: Disappointing But A Big Step Forward
By Ed Miseta, Chief Editor, Clinical Leader
There is an unmet medical need that exists for patients living with Duchenne muscular dystrophy (DMD), a disease that results in abnormality walking, muscle weakness, loss of muscle, or permanent shortening of muscles. The FDA acknowledged this necessity in a statement issued in 2014, noting the urgent need to make new treatments available. The agency also mentioned its commitment to working with companies to expedite the development and approval of safe and effective drugs to treat the disease, mentioning Sarepta Therapeutics by name.
In the years leading up to that statement, the FDA had worked extensively with Sarepta on the company’s development of eteplirsen, a treatment for DMD. The FDA provided guidance with respect to the data that would be necessary to determine if the treatment was effective and to support the filing of an NDA. In April 2014, Sarepta announced that with additional data to support efficacy and safety, an NDA “should be fileable.”
In its advice to Sarepta, the FDA has consistently maintained that it would be necessary to include data in its NDA demonstrating that eteplirsen increases production of the muscle protein dystrophin. Eteplirsen’s proposed mechanism of action is through increasing the production of this muscle protein.
Unfortunately, the hope for eteplirsen as a treatment for people with DMD hit a snag on April 25, 2016, when patients and family members learned an FDA panel voted against recommending approval of the drug. The advisory committee, voting 7 to 3 against with 3 abstentions, noted the study of just 12 patients did not provide sufficient evidence of the drug’s effectiveness.
Panel chairman G. Caleb Alexander, a professor at Johns Hopkins School of Public Health, noted the study was not well-controlled. Other FDA reviewers had previously concluded the study fell short of producing sufficient evidence. The panel members who abstained from the vote were undecided based on the evidence presented as well as the testimony of clinicians and parents who believed the children in the study were helped by the drug.
Initial Disappointment, But Hope Remains
Pat Furlong is no stranger to the disease. The former nurse raised two children, Christopher and Patrick, who lived with DMD. I personally became aware of DMD at last year’s Patients as Partners conference, where Furlong made an emotional presentation on the disease and how it took the lives of her two young sons. She now devotes her life to helping patients and caregivers through her advocacy group Parent Project Muscular Dystrophy (PPMD). For her personally, the decision by the panel was heartbreaking.
“It was a very difficult day for all of us who are involved with this disease and the search for a cure,” she says. “Hundreds of people in the Duchenne family, the largest gathering in history, came together to tell the FDA that eteplirsen is safe, effective, and should be approved for use. Being a part of that gathering was one of the highlights of my 30 years as a part of this community, but it also broke my heart. We went into the meeting very hopeful for this drug, and we came away disappointed.”
Although initially disappointed, Furlong and the other patients and advocates at the meeting did have reasons to be hopeful about both eteplirsen and the future of research on DMD. Certainly, this is not the end of the line for eteplirsen. The FDA panel only made a recommendation, and as yet no formal decision has been made. Furlong even believes the number of questions that were raised, as well as the mixed vote and comments of committee members, present opportunities. Patients and caregivers were given the opportunity to change minds and continue to influence the agency, a struggle that did not end on April 25th. The parents and groups she works with will also continue to advocate for a cure.
“We have a powerful and united community, especially when it comes to messaging,” says Furlong. “I think that meeting showed we are very good at coming together and having a consistent voice. Many of the attendees knew, from personal experience, that the drug helped boys walk up to the age of 15 or 16, and helped other young men to raise their arms over their heads, a task they had previously been unable to accomplish. We came away disappointed, but our fight will go on.”
A Good Place To Start
Furlong acknowledges that no one went into the meeting thinking the drug was magic, or that it would take a patient from a non-ambulatory condition to an ambulatory one. But she did feel that it was a good starting point to move the search for a cure forward. With many rare diseases, the population to be studied is highly variable in terms of its trajectory. Without biomarkers or sensitive outcome measures, Furlong believes we have to learn along the way. The best way to advance that learning is by finding a drug that seems to have potential and moving it forward.
“This was certainly true with the HIV community when the first drug hit the market,” says Furlong. “The infected community told the drug manufacturers that it wasn’t good enough, which spurred even greater research. But you need that starting point in order to move forward. The degree to which it will work will depend on the young man and where he is in the trajectory of his illness. But if the drug appears safe and we all agree that it works, then advancing it forward has to be our common goal.”
Furlong also believes starting DMD-diagnosed boys on the drug earlier could have a significant impact on their lives. With new advances in screening, a child might be diagnosed with the disease at age two or three and immediately start treatments. That would result in a far different scenario than waiting until the patient is seven years old and has lost up to 50 percent of his muscle.
“By seven years, the loss of dystrophin and the physiological cascade that occurs after that loss of dystrophin is difficult to reverse,” notes Furlong. “Even if eteplirsen restores only small amounts of dystrophin, it would begin to impact that physiological cascade, and that is a good start.”
The FDA can certainly go against the recommendations of the committee, and Furlong is hopeful that Dr. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the FDA, will continue to work with all parties involved to bring a treatment to market. Woodcock did speak with patients and caregivers at a reception following the advisory committee meeting and expressed appreciation for their attendance and insights. Woodcock also voiced her conviction to continuing to work with Sarepta Therapeutics in bringing a cure to patients. Furlong believes Woodcock has played a vital role in working with patients and families, and will continue to work towards bringing all sides together.
Working Together To Move Forward
As the FDA continues its efforts to help bring a safe and effective drug to market, Furlong notes groups like PPMD will continue to work with both the FDA and Sarepta going forward. She notes they will also be speaking to the FDA about advisory committees in general.
“During the advisory committee meeting, I kept imagining myself up on the stage with the committee,” she states. “I kept asking myself if I was on the committee, how I would interpret the results and the presentations. At the end of the day I wanted them to vote yes, but also wondered how they were analyzing all of the information. There were 52 speakers at the meeting, including patients, caregivers, scientists, and clinical researchers. When I thought about that advisory committee, I couldn’t help but feel it would have been better if instead of presenting data and numbers, we could have actually had a story to present to them, recognizing that not all of these people live with DMD every day of their lives.”
In perfect world, Furlong would have liked to see the presentation start off with testimony from the patients in the study as well as family members. That would be followed by a presentation on changes in the abilities of patients in the study, as noted by clinicians working on the trial. Finally, scientists could present on dystrophin changes noted in patients, and how those changes may have affected them. Currently, FDA processes prohibit speakers from knowing their placement within the Open Public Hearing in advance of the day of the Advisory Committee meeting and the OPH speaker list is kept confidential, prohibiting the storytelling approach that Furlong proposes. Furlong and her team believe that revising this process is in keeping with ongoing patient engagement initiatives.
“I respect all of the committee members, and wanted them to be able to hear the whole story,” she says. “After that, anyone else could present on whatever they wanted. But that story about the patients and how their lives were affected needed to be told.”
For Furlong, it’s all about framing the patient story. Committee members come from all different walks of life. If they are told 10 of 12 trial participants were walking, what exactly does that mean? The walking being referenced is not the same walking that most people picture when they hear the word.
“When you look at some of these children, you can’t understand how they are even able to walk,” says Furlong. “It may have been better to start by defining what walking is for a DMD patient, and then show what it actually looks like. The advisory committee members have brilliant minds, but they are not around DMD 24/7. We have to be more aware of who we are convincing. Companies cannot go in there prepared to argue with the FDA. On that day, the real discussion has to revolve around telling the committee why the drug has value in the patient population. Some committee members had never seen a Duchenne patient, and we need to first give them a good understanding of what we are discussing.”
After discussing the ruling with Furlong, you certainly come away feeling hopeful for the future of eteplirsen and DMD patients. Research and analysis will continue, and she is convinced that Sarepta, the FDA, and the patient community will come together and bring a treatment to market. The discussions that took place at the meeting were unlike any that had taken place in the past, and even the committee members voting no seemed to have been affected by the stories of the patients and researchers.
“I am disappointed but more hopeful than I have ever been in my life,” says Furlong. “We made an impact and will continue to be heard. We have as much hope as we ever have, and will continue to help the voices of these young men be heard. With the help of Sarepta and the FDA, we will find a safe and effective treatment.”