Denali Therapeutics Announces FDA Selection of DNL126 for START Program to Accelerate MPS IIIA Therapy Development

In a significant move for rare disease treatments, Denali Therapeutics, a biopharmaceutical company known for developing therapies that cross the blood-brain barrier (BBB), has announced its selection to participate in the U.S. Food and Drug Administration’s (FDA) START Pilot Program. This initiative, formally known as Support for Clinical Trials Advancing Rare Disease Therapeutics, aims to accelerate the development of novel drugs and biological products targeting rare diseases.

The START Pilot Program, launched on September 29, 2023, by the FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), is designed to fast-track the development of therapies for rare diseases. DNL126, Denali's investigational enzyme replacement therapy, has been chosen as one of three products regulated by CDER for participation in this program. This selection was based on several criteria, including the potential clinical benefit for a rare neurodegenerative disease and the sponsor’s ability to advance the development towards a marketing application.

DNL126 targets MPS IIIA, also known as Sanfilippo syndrome type A, a rare genetic lysosomal storage disease that leads to neurodegeneration due to the lack of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH). Currently, there are no approved treatments for MPS IIIA, which underscores the urgency and potential impact of Denali's work.

The START program provides selected participants with enhanced opportunities for frequent advice and rapid communication with FDA review staff, addressing product-specific development issues more efficiently. This collaborative effort aims to overcome the unique challenges in rare disease drug development. Denali's Chief Medical Officer, Carole Ho, M.D., expressed excitement about this opportunity and emphasized its importance in advancing treatments for individuals and families affected by rare diseases.

Denali is currently conducting a Phase 1/2 study of DNL126 in children with MPS IIIA. The study, which has garnered significant interest from the MPS IIIA community, aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory clinical efficacy of the therapy. The increased engagement with the FDA through the START program is expected to streamline the development pathway for DNL126, ultimately supporting a marketing application for the treatment.

In addition to DNL126, Denali is also progressing with tividenofusp alfa (DNL310), a potential treatment for MPS II (Hunter syndrome). This investigational therapy has received Fast Track designation from the FDA, facilitating increased communication and engagement with the agency. The Phase 2/3 COMPASS study for DNL310 is currently underway, with enrollment expected to be completed within the year.

Denali’s approach to drug development leverages its proprietary Transport Vehicle (TV) platform, which addresses the challenges posed by the BBB. This technology enables the delivery of large therapeutic molecules, such as enzymes and antibodies, across the BBB, achieving significant brain exposure and distribution. This advancement is crucial for treating central nervous system diseases, which have traditionally been difficult to address due to the protective nature of the BBB.

The participation of DNL126 in the START Pilot Program represents a promising step forward in the quest to develop effective treatments for rare diseases. As Denali continues its collaboration with the FDA, there is optimism that these efforts will lead to significant advancements and provide much-needed therapies for individuals suffering from MPS IIIA and other rare neurodegenerative conditions.

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