For tailored, single-person antisense oligonucleotides, FDA offers guidance on nonclinical testing
Over the last several years, a new wave of hyper-personalized therapies have quickly made their way into people, just one at a time, and often tailored to a specific genetic variant.
Success stories with these expensive to make, so-called “n-of-1” therapies – from 6-year-old Mila Makovec with Batten disease, a rare, inherited neurological condition to 3-year-old Ipek Kuzu with ataxia telangiectasia, a rare inherited disorder that affects the nervous and other systems – have caused the FDA to take notice, particularly as both are antisense oligonucleotide (ASO) treatments.
As part of efforts to help researchers developing these therapies, the FDA in January released its first guidance explaining how to submit INDs for the individualized ASOs. On Monday, the agency released additional draft guidance on nonclinical testing for these ASOs for severely debilitating or life-threatening diseases.
The two guidance documents are important because much of the development work for these individual therapies is done by academic investigators, many of whom will never seek to commercialize these therapies, but who also may not be familiar with the way that the FDA regulates them.
In the latest guidance, the agency explains how a single, 3-month toxicity study is considered adequate to assess the safety for initiating human dosing, dose escalation, and chronic treatment for ASOs.
But for a therapy for someone who is rapidly progressing to death or to substantial irreversible morbidity within one year, FDA said, “The IND submission should include at least 2 weeks of in-life data generated from an ongoing 3-month toxicity study.”
Because the timelines for developing these therapies can be much faster than typical drug development timelines, the FDA also warns that some problems may not be detected early on.
“The probability of identifying toxicity nonclinically may be reduced in comparison to standard nonclinical safety testing, and the potential for clinically significant adverse effects may therefore be increased,” FDA notes. But it also explains that as long as there are appropriate disclosures in the informed consent, “this increased risk is considered acceptable to FDA at this time in the context of an investigational antisense oligonucleotide covered by this guidance.”
Researchers also have to explain and justify to the FDA their methods for selecting the starting dose of any administered therapy, including the basis for calculating safety margins between doses tested in animals and the dose or doses selected for humans.
FDA also said it would consider, on a case-by-case basis, expanding this approach from the guidance “to other oligonucleotide chemistries or mechanisms of action (e.g., siRNA), or to other treatment modalities (e.g., individualized biologics) should be supported by a nonclinical approach that provides a similar understanding of the chemistry and mechanism of action sufficient to allow for safe FIH [first in human] dose selection, potential dose escalation, and an ability to predict the likely adverse effects that could occur, and how these can be clinically monitored.”