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Over the past few years, a new wave of hyper-personalized therapies have quickly caught on among people, one at a time, and often tailored to a specific genetic variant.

Success stories with these expensive to manufacture, so-called “n-of-1” therapies – from Mila Makovec, 6, with Batten disease, a rare hereditary neurological disease, to Ipek Kuzu, 3, with ataxia telangiectasia, a rare inherited condition that affects the nervous system and other systems – have caused the FDA to take note, especially since both are antisense oligonucleotide (ASO) treatments.

As part of efforts to help researchers develop these therapies, the FDA released its first guide in January on how to submit INDs for individualized ASOs. On Monday, the agency released draft additional guidance on non-clinical testing of these ASOs for severely debilitating or life-threatening conditions.

Both guidance documents are important because much of the work in developing these individual therapies is done by academic researchers, many of whom will never seek to commercialize these therapies, but who may also be unfamiliar with how the therapy. FDA regulates them.

In the latest guidance, the agency explains how a single 3-month toxicity study is considered adequate to assess the safety of initiating a human dosage, dose escalation, and chronic treatment for ASOs.

But for therapy for someone who is progressing rapidly to death or to substantial irreversible morbidity within a year, the FDA said, “The IND submission must include at least 2 weeks of in-life data generated. from an ongoing 3 month toxicity study. “

Since the development times for these therapies can be much faster than typical drug development times, the FDA also cautions that some issues may go undetected at an early stage.

“The likelihood of identifying toxicity non-clinically may be reduced compared to standard non-clinical safety tests, and the potential for clinically significant adverse effects may therefore be increased,” notes the FDA. But he also explains that as long as there are appropriate disclosures in the informed consent, “this increased risk is currently considered acceptable by the FDA in the context of an investigational antisense oligonucleotide covered by this guide.”

Researchers should also explain and justify to the FDA their methods of selecting the starting dose of any therapy administered, including the basis for calculating the safety margins between the doses tested in animals and the dose (s) selected for the dose (s). ‘man.

The FDA has also said it would consider, on a case-by-case basis, extending this guideline approach “to other oligonucleotide chemistries or mechanisms of action (eg, siRNA), or other modalities of treatment (eg, individualized biologics) should be supported by a non-clinical approach that provides a similar understanding of the chemistry and mechanism of action sufficient to allow safe FIH [first in hu­man] dose selection, potential dose escalation, and ability to predict likely side effects that may occur and how these may be monitored clinically.

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