A Denali Therapeutics drug for the rare enzyme deficiency Hunter syndrome is still in pivotal testing, but the company has guidance from the FDA on a pathway to get this therapy to the market sooner. Denali now has additional data from an earlier study that will be the main component of an application seeking accelerated approval.

The updated Phase 1/2 data, presented Thursday during the WORLDSymposium conference in San Diego, continue to show benefit for patients, some of whom have received the experimental therapy, tividenofusp alfa, for nearly four years. South San Francisco-based Denali reiterated that it plans to file a biologics license application with the FDA early this year.

In Hunter syndrome, genetic mutations lead to deficiency of iduronate-2-sulfatase (IDS), an enzyme key to the function of lysosomes, a component of cells that breaks down material. Lacking IDS leads to a buildup of glycosaminoglycans (GAGs), a type of sugar. GAG buildup in lysosomes leads to organ dysfunction, joint stiffness, hearing loss, neurocognitive symptoms and impaired development. In severe cases, Hunter syndrome patients can die in their teens.

Standard treatment for Hunter syndrome is weekly infusions of IDS enzymes. While these engineered enzymes help, they don’t cross the blood-brain barrier so they can’t address the cognitive and behavioral symptoms of the disease. Denali’s solution is to get IDS enzymes into the brain.

Tividenofusp alfa is a fusion protein made with Denali’s Enzyme TransportVehicle technology, or ETV. The drug, administered as a once-weekly infusion, uses ETV to target transferrin, a receptor on the blood-brain barrier whose role is to transport iron from the blood into cells. The Denali drug binds to transferrin, which then transports the IDS enzyme cargo across the blood brain-barrier. Denali is part of a group of biotechs targeting transferrin as a way to deliver drugs into the brain.

The open-label Phase 1/2 clinical trial for tividenofusp alfa enrolled 47 pediatric participants, both those who had previously received enzyme replacement therapy and those who had not. The study’s main goal is assessing safety; results so far show the therapy continues to be safe and well tolerated. Secondary goals include measuring for heparan sulfate (HS) in cerebrospinal fluid and urine. HS, a component of GAGs, accumulates in the tissues of Hunter syndrome patients.

Trial results show that by week 24, 93% of study participants achieved HS levels in their cerebrospinal fluid that were within normal ranges. That percentage continued to increase with longer duration of treatment. All three patients who have reached 201 weeks have HS levels within normal ranges. In addition, the results show lowering of neurofilament light (NfL), a protein that indicates neuronal damage. Improvement on these biological indicators appears to translating to improvement on the symptoms of the disease. The latest results show improvement on measures of hearing and cognition.

Last September, Denali announced the FDA agreed that measuring for HS in cerebrospinal fluid may be used as a surrogate endpoint supporting accelerated approval of tividenofusp alfa in Hunter syndrome. Denali said its application will include both preclinical and clinical measures of this biomarker. The submission will also include measures for NfL.

In a note sent to investors, William Blair analyst Sarah Schram noted that the data are early and in a limited number of patients, but the results so far appear to be translating to clinical benefit. She added that normalization on multiple markers of Hunter’s syndrome reinforce the Denali therapy’s potential to become a best-in-class treatment option for the disease.

“While additional patient data at extended follow-ups will be needed to continue building this profile, the data is important as it illustrates potential for significant broad symptom benefit and potential for a single weekly treatment option for patients across the Hunter syndrome spectrum,” Schram said.

A brain-penetrating fusion protein is already available to Hunter syndrome patients in Japan. This JCR Pharmaceuticals drug, marketed as Izcargo, also leverages the transferrin receptor to transport an engineered version of IDS into the brain. Japanese authorities approved this once-weekly infused therapy in 2021. Ashiya, Japan-based JCR is conducting a global Phase 3 test that could support an FDA submission.

Takeda Pharmaceutical holds an exclusive option to commercialize the JCR therapy in the U.S. following completion of the pivotal test. Under a separate agreement, the pharmaceutical giant secured rights to commercialize JCR’s Hunter syndrome treatment in the rest of the world, excluding Japan and certain Asian countries. Takeda already has a presence in the Hunter syndrome market with Elaprase, an enzyme replacement therapy that came from its acquisition of Shire.

At the WORLDSymposium, JCR presented a retrospective case study in nine patients after four years. Two died due to the progression of their disease. In the remaining seven, 71% showed increased muscle strength and 42% showed improved motor skills. Furthermore, 57% of participants showed cognitive and gait improvement.

Meanwhile, Regenxbio is gearing up to bring Hunter syndrome patients the option of a one-time treatment. The company’s gene therapy, RGX-121, delivers to cells of the central nervous system a functioning version of the gene that codes for IDS. In RGX-121’s pivotal test, Regenxbio reported a statistically significant 86% reduction of HS levels in cerebrospinal fluid. In the third quarter of 2024, Regenxbio began a rolling biologics license application seeking accelerated approval. The company expects this application will be complete in the first quarter of this year.

Regenxbio has a commercialization partner for its Hunter syndrome gene therapy as well as RGX-111, a gene therapy for the enzyme deficiency known as Hurler syndrome. Per deal terms announced in January, Nippon Shinyaku will commercialize both therapies in the U.S. and certain Asian countries. The Kyoto, Japan-based company agreed to pay Regenxbio $110 million up front; another $700 million is tied to the achievement of milestones.

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