But the decision by the U.S. Food and Drug Administration (FDA) to approve a treatment without clear data supporting its clinical benefits has clearly unsettled some researchers and regulators, who believe the FDA has sidestepped its own scientific standards.
To help give context to the controversy, and clarify the status of an FDA-required confirmatory trial for Exondys 51’s continued approval, Muscular Dystrophy News spoke to Ian Estepan, Sarepta’s executive director of corporate affairs.
“We’re very committed to looking at technologies that can create more dystrophin, or combination approaches,” Estepan said. “[We’re] looking at multiple ways of tackling this disease.”
Exondys 51 and clinical benefit
Unlike most of the FDA’s approvals, the agency based its September 2016 accelerated approval of Exondys 51 on data showing that the drug increased levels of the dystrophin muscle protein — which is lacking in DMD — to about 0.4 percent of what is found in a healthy person.
It’s a tiny change, but research indicates it can translate to clinical benefits. Patients with mutations in exon 44 are known to have only minute amounts of spontaneous exon skipping in their muscle and are known to lose their ability to walk about two years later than those with an exon 51 mutation do.
To verify that this small dystrophin increase makes a difference in disease progression or severity, the FDA requires Sarepta to conduct a confirmatory study — a common practice for therapies approved through the accelerated regulatory pathway.
The Phase 3 PROMOVI trial (NCT02255552) seemed a likely candidate, and is marked as a confirmatory study in the clinical trials registry. But Estepan says this is not the case. “The FDA has not asked for this to be a post-marketing commitment,” he said.
One reason appeared to be that the FDA “didn’t want an open-label study [a treatment-group only] to be the confirmatory study,” Estepan said. Instead, the agency suggested higher doses be tested, including the possibility of daily infusions, but that’s “quite burdensome” in children, he said.
For now, the two are still in talks. “We’re trying to do everything in lockstep with the FDA, listening to their recommendations” of what a future confirmatory trial will look like, Estepan said.
Sarepta, which is based in Cambridge, Massachusetts, is clearly making use of the agency’s new draft guidance for exon skipping in DMD.
That guidance has already had an impact on Exondys 51’s development program, with safety studies launched in patients with early (NCT02420379) and advanced (NCT02286947) stages of the disease. These groups were excluded from earlier trials because of the difficulty in measuring clinical impact in them.
The six-minute walk test, for instance, is a standard way of evaluating walking ability — and, therefore, treatment effectiveness — in DMD trials. But it’s a poor measure with younger children, whose stride is changing, and with patients who have lost the ability to walk, Estepan said. So these two trials are a chance for researchers to evaluate alternative outcome measures.
In young patients, this might mean measuring muscle function using magnetic resonance imaging (MRI) — an outcome included in the early-stage DMD trial, Estepan said.
Earlier data also indicated that Exondys 51 appears to slow respiratory decline. As such, preserving breathing ability in non-ambulatory patients might be a treatment goal.
The disease also affects heart muscle, but so far, nothing suggeests that Exondys 51 — or any other investigative exon-skipping therapies, for that matter — penetrate the heart muscle.
But, Estepan points out, delaying the loss of one function, such as walking, is “well-known and documented” to delay the loss of others, thereby prolonging survival.
“Even if you’re not directly working on the heart, the fact that you are potentially keeping patients walking longer, potentially helping with the respiratory function, all this does play into some secondary effects on cardiac function,” he said. Steroids that help with ambulation, he said as an example, help patients surve an extra three to seven years.
Exon skipping’s impact on the heart muscle might also be about to change.
Sarepta’s new-generation technology, called the PPMO platform, may allow the drug to better penetrate tissue. Preclinical data indicate that exon skipping occurs in the heart with this approach, which Sarepta is working to move “forward aggressively,” Estepan said. He hopes to have the FDA approve it for use in clinical trials by year’s end.
Beyond exon 51: New trials and challenges
Exondys 51 treats DMD patients with mutations in the 51st exon of the dystrophin gene. Though these boys comprise the largest group of patients, they still make up only about 13 percent of the entire Duchenne population.
Both therapies are now being examined in a Phase 3, placebo-controlled study called ESSENCE (NCT02500381), with earlier studies running in parallel. (Enrollment and other information for ESSENCE, which is underway across the United States, Canada and Europe, is available through the trial’s ID number.)
The news triggered speculation that Sarepta might seek accelerated approval for golodirsen, as it did with Exondys 51. Estepan said no such plans exist until trial data is available and shared with the FDA.
Doug Ingram, Sarepta’s CEO, was optimistic and willing to look ahead. “We are certainly going to discuss that issue with the FDA and solicit … their views on an accelerated pathway to get golodirsen to physicians and ultimately the patients,” he said in a separate interview last week.
But as Sarepta works to broaden its exon-skipping reach, it increasingly faces a problem common to all rare disease research — gathering enough patients for a trial.
PROMOVI, as mentioned, planned to use patients not amenable to exon 51 skipping as a control group. To make the comparison valid, it included people with a disease course similar to those with exon 51 mutations — which happened to be mutations in exons 45 and 53.
But with the launch of the ESSENCE trial — exploring exon skipping of these two mutations — patients rightfully moved over to the newer study.
This makes the PROMOVI study’s future uncertain, and is forcing Sarepta — and possibly the FDA to consider other approaches to support Exondys 51’s effectiveness.
“Over time, it’s going to be very challenging to enroll trials, so there has got to be innovative ways of collecting information in an extremely small patient population,” Estepan said. “And when it’s mutation-specific, we’re no longer talking just about a rare disease, we’re talking about an ultra-rare disease.”
Sarepta is not certain if the FDA would consider a trial that includes historical controls to be confirmatory. But the Phase 3 ESSENCE study could also provide valuable data supporting Exondys 51’s continuing approval. A historically controlled study uses data on patients who participated in earlier studies documenting DMD’s natural progression.
In its guidance for confirmatory trials of exon skipping in Duchenne, the FDA specifically mentions the possibility of using data from a trial that explores the same approach in patients with other mutations.
What a confirmatory trial for Exondys 51 might eventually look like is yet to be decided, as is the role PROMOVI might play in it.
For now, Sarepta’s goal is pushing ahead with potentially viable treatments, exon skipping or otherwise.
The company is working on a platform approach to exon skipping that could potentially involve patients with rare DMD mutations, and new technologies, like PPMO, that could improve the therapies’ potency. It is also engaging in partnerships with Nationwide Children’s Hospital of Columbus, Ohio, and French pharmaceutical company Généthon to bring DMD gene therapies to clinical trials.
“We are committed to looking at every viable approach,” Estepan explained. “People say, ‘oh, we’re a leader in this or that space.’ I think being a leader, being committed, means you are going to look at every viable option to treating this disease.”
“We are agnostic in our approach,” he added, with a nod to the company’s partnerships. “We are 100 percent committed to being involved in anything that we think is a viable approach.”
Patient input definitely contributed to the early approval of Exondys 51, and to criticisms that the FDA allowed patient advocates to influence the outcome of a drug approval process. But while some find it radical, Sarepta’s CEO sees it as “perfectly appropriate and completely consistent with a science-based approach to considering and approving new treatments.”
According to Ingram, it is crucial to consider the severity of a disease, as well as the therapy’s impact on daily life and disease progression. Patient advocates and caregivers likely possess some of the best knowledge about these impacts, he said, adding that the agency’s actions in the case of Exondys 51 hopefully signal an “increasing willingness of the FDA to consider the impact of the disease as it considers new therapies.”
“I think that is only positive,” Ingram concluded. He added that once a confirmatory trial for Exondys 51 is rolled out, the Duchenne community can rest assured that its interests will be considered.