RARE Daily

FDA Selects Dinali, Grace, and Neurogene Candidates for START Program

June 3, 2024

Rare Daily Staff

The U.S. Food and Drug Administration has selected three additional candidates for its Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program, an effort by the agency to accelerate the development of drugs to treat rare diseases.

The agency selected Neurogene’s NGN-401 gene therapy for Rett Syndrome, Grace Science’s GS-100 gene therapy for NGLY1 Deficiency, and Denali Therapeutics’ enzyme replacement therapy DNL126 for the potential treatment of MPS IIIA (Sanfilippo syndrome type A). The selections are in addition to Larimar Therapeutics’ experimental therapy nomlabofusp for Friedreich’s ataxia announced last week.

The START pilot program was launched by the FDA in September 2023 with an initial selection of up to six novel drugs, three by the Center for Drug Evaluation and Research and three by the Center for Biologics Evaluation and Research, intended to treat a rare disease or other serious condition with high unmet medical need through an enhanced mechanism for communication with the FDA.

Rett syndrome is a complex condition caused by a genetic mutation on the MECP2 gene. It is characterized by a period of normal development until six to 18 months of age, followed by significant developmental regression with loss of acquired communication skills and purposeful hand use. Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities.

NGN-401 is an investigational AAV9 gene therapy being developed as a one-time treatment for Rett syndrome. It is the first clinical candidate to deliver the full-length human MECP2 gene under the control of Neurogene’s EXACT technology. The EXACT technology utilized in NGN-401 is an important advancement in gene therapy for Rett syndrome, specifically because the disorder requires a treatment approach that enables targeted levels of MECP2 transgene expression without causing overexpression-related toxic effects associated with conventional gene therapy.

NGLY1 Deficiency is a serious, life-threatening disease with no approved therapy. Patients with this disease suffer from debilitating symptoms that present early in life, including global developmental delay, cognitive impairment, (hypo)alacrima, movement disorders, and other neurological symptoms.

GS-100 is a gene therapy being developed to treat NGLY1 Deficiency, a rare autosomal recessive disease that devastates the central nervous system. GS-100 is an AAV9 single-stranded viral vector that encodes the full length human NGLY1 protein.

MPS III, also called Sanfilippo syndrome, is a rare, genetic lysosomal storage disease that causes neurodegeneration. There are four main types of MPS III, depending on the enzyme affected. Type A is caused by genetic defects that result in reduction in the activity of N-sulfoglucosamine sulfohydrolase (SGSH), an enzyme responsible for degrading heparan sulfate in the lysosome. There are no approved treatments for MPS IIIA. A natural history study of biomarkers and adaptive behavior in MPS IIIA is ongoing.

DNL126 is an experimental, intravenously administered, enzyme transport vehicle (ETV)-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy designed to cross the blood-brain barrier via receptor-mediated transcytosis into the brain and to enable broad delivery of SGSH into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS IIIA.

Sponsors selected can benefit from more frequent and rapid ad-hoc interactions with the FDA to help facilitate the development of programs to the pivotal clinical study or pre-BLA meeting stage, and to generate high-quality and reliable data intended to support a BLA or New Drug Application.

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