Retrotope misses main endpoint but plans to take improved survival late-stage trial data in ultrarare disorder to FDA

Retrotope misses main endpoint but plans to take improved survival late-stage trial data in ultrarare disorder to FDA

Retrotope’s oral treatment for an ultrarare infant disease improved muscle tone in a late-stage trial but wasn’t statistically significant enough to meet that primary endpoint.

Despite missing the main goal, Retrotope plans to ask the FDA about a path forward with the drug in its lead indication of infantile neuroaxonal dystrophy, or INAD, given the treatment’s statistically significant improvements in survival and slowing of progression. The treatment, dubbed RT001, is also in a late-stage trial in patients with Friedreich’s ataxia (FA) and midstage studies in other neurodegenerative disorders.

The biotech said the primary endpoint, based on the modified Ashworth Spasticity Scale, was difficult to reach because of the small study size. Nineteen patients received treatment, while the disease impacts about 100 children in the U.S. and 400 to 500 worldwide, executives said in an interview.

Retrotope switched the primary endpoint to the Ashworth scale this summer after the FDA sent an advice letter saying its original main goal—elements of activities of daily living and vital functions— needed “further validation and standardization,” said Anil Kumar, president of Retrotope. The biotech adjusted the protocol to comply with the agency’s recommendation that Retrotope “identify an existing assessment tool or develop a standardized assessment tool.”

The median age of the treated patients was four years, Kumar explained. “Spasticity tends to be most exacerbated toward the later stage of the average of 10 years of life.”

“So unless you have patients that you brought in specifically at an almost-too-late stage and then measure the spasticity, you don’t see many changes in the first couple of years, so this is the challenge with a disease like this where there’s no perfect scale,” he added. “There just doesn’t exist a known neurology scale that will show marked difference.”

The data comes from 12 months of treatment, and endpoints were measured at baseline and then every six months, Kumar said. Many of the patients still received treatment beyond the 12-month mark, with the longest regimen going to 32 months.

The drug demonstrated a statistically significant reduction of 82.5% in morbidity risk and an 88.8% drop in mortality risk in the 19 patients treated when compared to the natural history of 36 patients who did not receive any treatment at all.

Out of the 19 patients treated, two died, with one passing away 10 months into the trial. In the control group, 11 of the 36 patients died. The trial also looked at physician and parental observations of certain measures of quality of life. Physicians noted improvement in patients being able to repeat simple sounds, put words together and bite strength. Parents observed improvements in their kids being able to put words together, sit with support and swallow saliva.

Although the treatment didn’t statistically improve muscle tone, Retrotope will ask to meet with the FDA about a regulatory pathway given the improved survival and progression-slowing data. The regulator has already given the treatment rare pediatric disease designation for INAD.

Within a span of less than 10 years, patients with INAD usually die after losing vital functions, such as being able to walk, crawl, speak, bite and swallow.

“We thought if our drug is going to have an impact on mortality, it would be in this rapidly progressive disease in which children die very quickly,” said Peter Milner, M.D., chief medical officer, in the joint interview.

Retrotope is also studying RT001 in other neurodegenerative disorders.

Data should be available soon for a recently completed phase 3 trial of RT001 in FA. “If it’s good, it should be adequate to be a registrational trial,” Kumar said.

A phase 2 trial in amyotrophic lateral sclerosis is a few weeks from completion, and patients are slated to complete a midstage study in progressive supranuclear palsy (PSP) next summer, Kumar said.

Other biotechs investigating treatments for FA, a recessive genetic disorder that affects nerves, include Lexeo Therapeutics, Stealth BioTherapeutics and Larimar Therapeutics, which was told by the FDA to halt its trial in May. PSP has also proven to be a tough disease to treat, with failures from Biogen and AbbVie, both in 2019.

Further down the pipeline, Retrotope expects to begin a clinical trial of its second compound, RT011, in the first few months of 2022, Kumar said. The biotech will investigate the treatment in intermediate age-related macular degeneration and geographic atrophy.

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