Abstract

Patients with an ultra-rare disease are often in critical need but without an approved drug and only limited options for care. A robust nonclinical program is essential, but like all aspects of drug development can be of relatively long duration, even when considering N=Few or N=1 personalized therapies. To meet the challenge of high/immediate need when safety remains essential, the nonclinical program must adapt. Antisense oligonucleotides (ASO) and AAV gene therapy have made significant progress in ultra-rare disease. This has been accomplished with consideration of each patients unique condition, for instance, how an ASO can address a specific mutation, and identifying critical safety parameters to be evaluated in nonclinical studies. Recent regulatory guidelines from the FDA have bolstered an adaptive and highly focused approach for Severely Debilitating or Life-Threatening Disease. While clearly encouraging, continued progress is dependent upon collaboration among researchers, drug development teams, medical professionals, industry and regulatory bodies. Ultimately a goal is to provide a fast, efficient, and safe pathway for patients with a rare/ultra-rare disease.