Denali’s DNL126 selected by FDA for START pilot program
ERT candidate for Sanfilippo type A chosen for rare disease program
The U.S. Food and Drug Administration (FDA) has selected DNL126, an enzyme replacement therapy being developed by Denali Therapeutics for Sanfilippo syndrome type A, to join its START pilot program — fully, Support for Clinical Trials Advancing Rare Disease Therapeutics.
As part of this pilot program, launched last fall, the company can expect to engage in more frequent and rapid interactions with the FDA, which should help streamline clinical development toward a future marketing application for DNL126.
“We are thrilled to be selected by the FDA for participation in START and see this as another important opportunity to work together to solve challenges unique to rare disease drug development,” Carole Ho, MD, Denali’s chief medical officer, said in a company press release.
Denali is sponsoring a Phase 1/2 clinical study (NCT06181136) that’s enrolling children and adolescents, ages 2 to 18, with a confirmed diagnosis of Sanfilippo syndrome type A. Recruitment is underway at four sites, one each in California, Iowa, North Carolina, and Texas.
START program will allow Denali more interactions with FDA on DNL126
Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a genetic disease in which the body lacks certain enzymes needed to break down the sugar molecule heparan sulfate, leading to its toxic buildup in body tissues, especially in the brain.
DNL126 is an enzyme replacement therapy or ERT specifically developed to address the deficiency of SGSH, the enzyme lacking in Sanfilippo syndrome type A (MPS IIIA). To cross into the brain and overcome the blood-brain barrier, a protective layer that prevents harmful substances from entering the brain, DNL126 takes advantage of the transferrin receptor. This receptor naturally transports iron across the barrier, allowing DNL126 to essentially piggyback on this mechanism for effective delivery into the brain.
Given as an injection directly into the bloodstream, DNL126 is expected to travel to the brain and other tissues, where it can break down heparan sulfate. In doing so, DNL126 is expected to ease symptoms of Sanfilippo syndrome, which may include behavioral challenges and developmental delay.
In preclinical studies with mice producing the human version of the transferrin receptor and very low levels of the SGSH enzyme, weekly injections of DNL126 reduced levels of heparan sulfate in the animal’s brain and cerebrospinal fluid, the liquid that flows around the brain and spinal cord.
The main objective of the clinical trial is to evaluate the safety profile of the experimental ENT and assess its efficacy in reducing heparan sulfate levels. The initial phase of the study spans six months, during which time patients will receive the treatment and undergo assessments. Following this period, participants have the option to enroll in an open-label extension study lasting up to 18 months — providing further insights into the long-term safety and effectiveness of DNL126.
It is an exciting time to be part of the collective effort of making new treatments available to individuals and families living with rare diseases. … We look forward to continued collaboration with [the FDA center] CDER to determine the most efficient development path for DNL126 in [Sanfilippo type A].
The START pilot program was launched as a joint effort between two FDA centers: CDER, or the Center for Drug Evaluation and Research, and CBER, or the Center for Biologics Evaluation and Research. It’s milestone-driven, with specific goals agreed upon by both the FDA and the sponsor.
“It is an exciting time to be part of the collective effort of making new treatments available to individuals and families living with rare diseases,” Ho said. “We look forward to continued collaboration with CDER to determine the most efficient development path for DNL126 in MPS IIIA, a devastating and progressive disease for which treatments are urgently needed.”
Denali also is developing DNL310 (tividenofusp alfa) for another rare disease called Hunter syndrome, or MPS II, and expects to complete enrollment for its Phase 2/3 COMPASS study (NCT05371613) later this year.
DNL310 is not part of the START pilot program, but the FDA has granted it fast track designation, which also allows the company to engage in more frequent communication with the agency throughout the treatment candidate’s clinical development.
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