An ultra-rare disease drug missed on function but hit on survival and mortality. Is it enough for the FDA?
A California company developing a drug for an ultra-rare, universally fatal neurological disease manifesting in infancy reported Wednesday that its therapy missed the primary endpoint in a Phase II/III study, but showed good enough survival and mortality data to potentially persuade the FDA.
Retrotope revealed its candidate for infantile neuroaxonal dystrophy, or INAD, did not achieve statistical significance in a neurological assessment, showing no differences between patients who received treatment and those in a natural history study. Researchers did, however, see improvement in progression-free survival and a decrease in mortality, both of which mustered statistical significance in secondary endpoints.
The biopharma’s data come in the wake of Biogen’s controversial approval for its new Alzheimer’s drug, Aduhelm, and the potentially changing regulatory landscape in neurological diseases. Billy Dunn’s neuro crew showed a particular leniency in shepherding the drug across the finish line, according to STAT News reports, and pharma companies big and small are ostensibly taking advantage.
Notably, Eli Lilly is seeking an accelerated approval for its experimental Alzheimer’s drug donanemab using the same pathway afforded to Aduhelm. The Big Pharma also announced plans for a makeover, building a new neuroscience unit to allot more resources towards its Alzheimer’s efforts.
Roche is also engaging in discussions with the FDA about its own Alzheimer’s program in gantenerumab, an experimental therapy that failed to show efficacy in three clinical trials.
Given INAD’s classification as ultra-rare and the lack of any available treatment, the FDA asked Retrotope to request a feedback meeting so the pair can chart a path forward, Retrotope president Anil Kumar told Endpoints News.
“They asked us to request that when they saw the summary data,” Kumar said of the agency. “We’re going to say, ‘Here’s the data, it shows the best biomarker in this disease is survival.’”
Retrotope plans to include the neurological test as part of the data package, but the assessment, known as the Modified Ashworth Spasticity Scale, is like “trying to fit a square peg into a round hole,” Kumar added. The president said it shows a better correlation for patients later in their disease while Retrotope enrolled children at all INAD stages.
INAD results from the body’s inability to clear buildups of toxic byproducts of lipid peroxidation, a process that causes damage to cell membranes. The disease can emerge in infants as young as six months when muscle tone development falters, trial investigator Alex Fay told Endpoints, and from then on disease milestones that had been gained are soon lost.
“Kids lose the ability to sit up on their own, and social interactiveness also starts to be affected over time,” Fay said. “So while they may retain ability to smile, they lose expressive speech and language output.”
To conduct its study, Retrotope recruited 19 patients for active treatment and 36 for the natural history study, which ran concurrently. Children taking the drug, dubbed RT001, were treated for a minimum of one year and up to two years, while the natural history group has only been observed for a year, Kumar said.
On the primary endpoint, RT001 induced an improvement of 6.42 points on the scale compared to the control, missing statistical significance with a p-value of p=0.14. The scale measures spasticity, or a specific type of muscle stiffness that develops with injuries to the brain and spinal cord, Fay said.
Meanwhile, the progression-free survival mark of an 82.5% improvement clinched a p-value of p=0.021 and the decreased mortality risk came in at a 88.8% reduction, good for a p-value of p=0.014. Because of these figures, Kumar said the drug also proved remarkably safe, giving what Retrotope hopes is a benefit in discussions with the FDA.
It’s not yet clear what kind of approval Retrotope will seek, with more information expected to come during the FDA feedback meeting. Even though it would be “impossible” to do a placebo-controlled trial in INAD because it’s so rare, Kumar said the biopharma could utilize follow-up data from the natural history study in place of a confirmatory study.
Whereas the active trial has data for up to two years, the natural history group is only up to a year of observation. Kumar said he hopes the extra data could get the program to statistical significance and continue to show survival benefits.
Despite the FDA’s flexibility in Alzheimer’s disease, Retrotope’s pitch could end up closer to that of ALS advocates, who have argued patients are left with so few options for treatment they have nothing to lose from trying experimental therapies. In that field, a program from Amylyx Pharmaceuticals achieved statistical significance on function, and the biotech will be submitting for approval in the US after the FDA changed its mind on requiring another study.