RARE Daily

FDA Issues Guidance on Individualized ASOs for Ultra-Rare Conditions

April 27, 2021

FRare Daily Staff

The U.S. Food and Drug Administration issued guidance for sponsor-investigators about nonclinical information that the agency recommends to support an application for human testing for an individualized antisense oligonucleotide being developed to treat a severely debilitating or life-threatening genetic disease for an individual or just a few patients.

The agency said to offset a greater assumption of risk due to more limited data these therapies are likely to have, it is important that sponsors provide convincing in vitro and/or in vivo proof of concept data as part of any pre-investigational new drug meeting package or investigational new drug submission.

The agency also said sponsors should include nonclinical safety studies in their applications to assess possible off-target binding. They should also include evaluations of the safety of systemically administered experimental ASOs including to the cardiovascular, central nervous, and respiratory systems. If the therapy is delivered directly to the central nervous system, the safety pharmacology can be limited to the central nervous system.

For ASOs that do not create systemic or central nervous system exposure, such as those injected directly into the eye, safety pharmacology is generally not needed.

The agency recommends a standard battery of toxicological endpoints including clinical observations, body weight, food consumption, clinical pathology, toxicokinetic analysis, and histopathology of a comprehensive panel of tissues. It said a single three-month toxicity study should be adequate.

In determining the starting dose for testing, sponsors should describe and justify the method used.The agency said sponsors should include the basis for calculating safety margins between doses tested in animals and the dose selected for administration in a human. It noted that when an exposure-response for severe toxicity is seen, it should consider using smaller than usual dose increments for adjusting clinical dosing.

The agency said should a sponsor wish to expand the use of an ASO to a larger population or seek to commercialize it, it would typically warrant additional studies.


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