Denali Therapeutics (NASDAQ:DNLI) is targeting all eligible U.S. patients for its Hunter disease treatment AVLAYAH, while preparing data updates across a pipeline that includes treatments for Sanfilippo syndrome, Pompe disease and Alzheimer’s disease.
Chief Scientific Officer Joe Lewcock said AVLAYAH generated $7.8 million in commercial revenue in its second quarter after launch. About 70% of commercial lives were covered, and 20 states had Medicaid coverage for the treatment, he said.
Lewcock estimated that roughly 375 of the approximately 500 U.S. patients with Hunter disease are eligible for AVLAYAH under its label. “Our goal is to really switch 100% of eligible patients,” he said.
Denali has guided for fourth-quarter commercial revenue of $30 million to $32 million. Lewcock said the company expects continued growth, although at a more measured pace, after faster-than-anticipated payer coverage expansion and clinical trial patients switching to commercial treatment contributed to an earlier rapid increase.
Confirmatory Trial and Sanfilippo Plans
Lewcock expressed confidence in COMPASS, AVLAYAH’s placebo-controlled confirmatory study, citing data from 47 patients in earlier-phase programs. Those studies provided biomarker results as well as behavioral and cognitive data that helped Denali design the trial, he said.
After initially giving different timelines during the discussion, Lewcock clarified that COMPASS is expected to complete in 2027, with data reading out in 2028. He said the company hopes the study will support treatment of the broader Hunter disease population, including adults.
For its Sanfilippo syndrome program, Lewcock said Denali has worked with the Food and Drug Administration to align on reduction of heparan sulfate as the basis for an accelerated approval filing. In an early dose-finding cohort, the company observed reductions of more than 80%, with levels normalizing in many patients, he said.
A cohort of 20 patients has completed the study, and Denali plans to present detailed data at the WORLDSymposium in early 2027, followed by a planned filing during 2027. The company also intends to examine neurofilament as a biomarker, Lewcock said.
Pompe and Alzheimer’s Programs
Denali’s ongoing Phase 1 study of DNL952 in Pompe disease is enrolling patients already receiving enzyme treatment. The company plans to assess biomarkers after patients switch therapies, including urine Glc4, a measure related to glycogen, and serum creatine kinase, a measure of muscle health.
Lewcock said some patients on existing treatment have normalized Glc4 levels while others do not, which could complicate interpretation. He cited preclinical results suggesting DNL952 could improve delivery to muscle tissue compared with earlier enzyme therapies.
For Alzheimer’s disease, Denali is starting a Phase 1 study of its anti-amyloid beta candidate DNL921 in healthy volunteers. Lewcock said the initial study could provide information on exposure and potential risks such as immunogenicity and anemia. A subsequent patient study would assess plaque clearance and monitor for amyloid-related imaging abnormalities, though larger studies would be needed to determine their incidence more precisely.
Denali is also exploring subcutaneous administration of DNL921 but has not provided an exact dosing plan. Lewcock said the company could consider partnering its Alzheimer’s programs after generating initial data, or continue developing them independently. Denali ended the last quarter with $1.01 billion in cash, he said.
For a separate tau program, the first meaningful clinical readout will be whether the treatment reduces tau levels in cerebrospinal fluid, Lewcock said. He described tau PET imaging as a subsequent, longer-term measure of its effect on pathology.
Progranulin Study Extended
Denali extended its progranulin study from six months to 12 months after regaining full rights to the program from Takeda. Lewcock said the additional time could improve the company’s ability to detect a meaningful change in neurofilament, or NfL, a biomarker on which Denali is placing particular emphasis because of a lack of strong clinical lysosomal biomarkers for the patient population.
Lewcock cautioned that the behavior of NfL in the disease remains poorly understood and that Denali has not set a specific target for the biomarker. The readout is expected in 2027. If the data are promising, the company would explore the possibility of accelerated approval, although it has not yet discussed that pathway with regulators, he said.
About Denali Therapeutics (NASDAQ:DNLI)
Denali Therapeutics is a biotechnology company focused on developing medicines for neurodegenerative diseases and other disorders involving the nervous system. Founded in 2015, the company is headquartered in South San Francisco, California. Its research and development programs target conditions including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and lysosomal storage disorders. Denali’s portfolio includes investigational drug candidates that aim to address underlying disease processes, as well as its TransportVehicle platform, designed to help therapeutic molecules cross the blood-brain barrier.
