AMO Pharma scored a unique victory last month when global regulators, including the FDA, said that hospitalization can be a primary endpoint in its registration trial for a rare disease candidate.
In terms of late-stage studies for orphan drugs, this “might be the first time” regulators have allowed such an endpoint, according to CEO Mike Snape.
It’s a simple yet “elegant” measure for success in treating congenital myotonic dystrophy, a rare, inherited neuromuscular disorder that not only has a small patient population but an incredibly varied presentation, Snape said.
“One individual might be a wheelchair user. The individual that you see next might walk or run faster than I do,” he said.
Having no single outcome to measure a disease that can also cause problems with the heart, breathing, eyesight or swallowing made clinical trial design a challenge for the company.
“We were a bit stuck, to be frank, and we were going around and around, talking to the FDA, and collectively trying to find a way through this,” Snape said. “There was an acknowledgment that for these ultra-rare genetic diseases of childhood that have such a variable presentation, there is an issue. There is no precedent, no gold standard way of dealing with that problem.”
Then Snape remembered a conversation he’d had with a patient parent at the beginning of the program for its candidate, AMO-02. He asked her what success of a new therapeutic would look like, and she said keeping her child out of the hospital for 12 months “would mean so much.”
But Snape wasn’t convinced the drug’s efficacy could be proven with that measuring stick.
“Hospitalization will never be an outcome measure,” he said then. “You'd never get the regulators to agree to it.”
He was wrong. The company announced last month that the FDA, the U.K. Medicines and Healthcare products Regulatory Agency and Health Canada all agreed to the study design. In addition to using hospitalization as the primary efficacy endpoint, the study will also include several functional assessments as secondary outcome measures. And its impact could ripple through the rare disease R&D space.
Why it matters
Using hospitalization as a primary outcome measure is another demonstration of regulators granting flexibility in clinical trial design for rare diseases.
That flexibility came to fruition when Stealth BioTherapeutics nabbed an accelerated FDA approval in Barth syndrome, an ultra-rare and often fatal pediatric mitochondrial disease with no previously approved treatments. At the time, industry watchers believed it showcased that regulators understood the challenges in rare disease drug development. One of Stealth’s studies included only 12 patients, a tiny amount compared to typical clinical trials.
Despite that win — and the FDA’s stated flexibility in rare disease drug development — the road to approval was still tough.
Stealth’s drug was originally rejected, and its eventual FDA nod came with post-market study requirements and a narrower population of approved patients than Stealth wanted.
The FDA also recently raised eyebrows when it rejected Regenxbio’s gene therapy for the ultra-rare neurodegenerative condition Hunter syndrome, citing a lack of a placebo-controlled arm, despite previously agreeing to the study protocol “in principle,” according to the company.
Although the FDA later backtracked on that decision and agreed that Regenxbio’s existing clinical data was sufficient to seek approval, the back and forth left lingering questions over the agency’s approach to rare disease drug development.
Still, Snape doesn’t anticipate the company will run into the same issues with AMO’s study.
“We're running a very conventional design. It’s placebo controlled,” he said. “The reliance on regulatory flexibility is around the endpoint. It's not about the rest of the trial design and the whole of the program in general.”
Success could also mean more companies using hospitalization as a primary endpoint.
“There must be many, many conditions where this is potentially applicable,” Snape said.
In addition, the study design drives home the importance of engaging with patients throughout the entire clinical process and using their feedback to steer drug development.
“We never wanted to show a statistically significant 3% change in the strength of your middle finger or something,” Snape said. “We wanted to look at something meaningful. We’re not in the business of just trying to get something approved on something that nobody cares about. So if we could show a change on [the hospitalization] measure, I think we’d feel very satisfied.”
AMO Pharma, which has two other candidates in the clinic for rare conditions, intends to provide updates on the planned study initiation during the third quarter, according to a company spokesperson.
