Denali Therapeutics Announces New Interim Data from Phase 1/2 Study of DNL310 (ETV:IDS) in MPS II (Hunter Syndrome) at SSIEM 2023

• Additional biomarker data up to two years of treatment continue to demonstrate rapid and sustained normalization of CSF heparan sulfate to normal healthy levels and improvement in lysosomal function biomarkers
• Additional safety data up to two years of treatment continue to demonstrate that DNL310 is generally well tolerated
• Previously reported data showed robust and statistically significant reduction of NfL, a marker of neuronal damage, and positive clinical outcome changes in adaptive behavior, cognition, and auditory function
• Recruitment in the global Phase 2/3 COMPASS study is ongoing

SOUTH SAN FRANCISCO, Calif., Aug. 30, 2023 (GLOBE NEWSWIRE) — Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for the treatment of neurodegenerative diseases and lysosomal storage diseases, today announced new interim data from the ongoing open-label, single-arm Phase 1/2 study of DNL310 (ETV:IDS) in children with MPS II (Hunter syndrome). DNL310 is an investigational enzyme replacement therapy designed to cross the BBB and address the behavioral, cognitive, and physical manifestations of MPS II. The interim data from the Phase 1/2 study of DNL310 were highlighted in an oral presentation at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2023 in Jerusalem, Israel. A PDF of the Phase 1/2 presentation is available on Denali’s website on the Events page of the Investor section.

“It is encouraging to see normalization of heparan sulfate in CSF as well as reductions in lysosomal lipid biomarkers and neurofilament light over two years, even in patients with high pre-existing anti-drug antibodies,” said Barbara Burton, MD, Attending Physician, Genetics, Genomics and Metabolism at the Ann & Robert H. Lurie Children’s Hospital of Chicago, who presented the Phase 1/2 data at SSIEM. “The treatment effect seen on these biomarkers of neurocognitive decline, along with one-year data demonstrating positive changes in adaptive behavior, cognition, and auditory function, continue to support the potential of DNL310 to offer meaningful benefit for people living with MPS II. I look forward to learning more as recruitment continues in the global Phase 2/3 COMPASS study.”

The interim Phase 1/2 data presented at SSIEM included new biomarker and safety data from additional participants receiving up to two years of treatment with DNL310 as well as previously presented clinical outcomes data for participants receiving one year of treatment. A summary of key results includes:

• Achievement of normal levels of CSF heparan sulfate, sustained over time, including in participants with high pre-existing anti-drug antibodies
• Sustained normal levels of CSF lysosomal lipids in most participants consistent with improved lysosomal function
• Robust reduction in serum neurofilament light (NfL), a marker of neuronal damage, reached statistical significance after 61 weeks and a 64% reduction after two years of treatment with DNL310
• Improvements in mean cognitive Bayley Scales of Infant and Toddler Development III (BSID-III) and Vineland Adaptive Behavior Scales II (VABS-II) raw scores, and auditory brainstem response (ABR) thresholds at week 49 of DNL310 treatment, suggest positive effects on cognition, adaptive behavior, and hearing
• DNL310 continues to be generally well tolerated
• The interim safety profile, clinical outcomes data, and biomarker effects, including normalization of CSF heparan sulfate and reduction in NfL, continue to support development of DNL310 in MPS II

“We are excited to share sustained effects on key disease biomarkers in MPS II with DNL310 treatment, now out to two years,” said Carole Ho, MD, Chief Medical Officer of Denali. “Importantly, the robust reduction in serum levels of NfL suggests improvement in neuronal health, which is not addressed by current enzyme replacement therapies. We are encouraged to see positive changes across multiple clinical outcomes measures in the ongoing Phase 1/2 study. We look forward to continued partnership with the MPS community as we enroll the global Phase 2/3 COMPASS study in MPS II and plan for expanding the enzyme transport vehicle, including initiating clinical studies in other lysosomal storage diseases.”

About MPS II (Hunter syndrome)

MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, world-wide, and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan. MPS II is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of glycosaminoglycans (GAGs) in lysosomes — the part of the cell that breaks down materials including GAGs. The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed. Therapies that address behavioral, cognitive, and physical manifestations of the disease are one of the greatest unmet needs for this community.

About DNL310

DNL310 is an investigational fusion protein composed of IDS fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the blood-brain barrier via receptor-mediated transcytosis into the brain. Preclinical studies demonstrate that DNL310 delivers IDS to lysosomes, where it is needed to break down GAGs. DNL310 is engineered for broad delivery of IDS into cells and tissues throughout the body, including the brain, with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II. In March 2021, the U.S. Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II. In May 2022, the European Medicines Agency granted DNL310 Priority Medicines designation. DNL310 is an investigational product candidate and has not been approved by any Health Authority.

About the Phase 2/3 COMPASS study

Based on supportive clinical and preclinical data to date, Denali is conducting the Phase 2/3 COMPASS study, which is expected to enroll 54 participants with MPS II with and without neuronopathic disease. The participants will be randomized 2:1 to receive either DNL310 or idursulfase, respectively. Cohort A will include children ages 2 to 6 with neuronopathic disease; cohort B will include children ages 6 to 17 without neuronopathic disease.

The Phase 2/3 COMPASS study is being conducted globally in North America, South America, and Europe. Upon completion of the ongoing Phase 1/2 study, and together with data from the global COMPASS study, this combined data package is intended to support registration. More information about the COMPASS study can be found here.

About Denali’s Transport Vehicle Platform

The blood-brain barrier is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the blood-brain barrier has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the blood-brain barrier after intravenous administration. The Transport Vehicle technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptors, which are expressed at the blood-brain barrier and deliver the Transport Vehicle and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the Transport Vehicle technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates.

About Denali Therapeutics

Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding Denali’s plans, timelines, and expectations related to DNL310, the ongoing Phase 2/3 COMPASS study, and the open-label, single-arm Phase 1/2 study, including the continued recruitment of participants for the Phase 2/3 COMPASS study and the timing and availability of data for both studies; the potential for data from the ongoing DNL310 studies to support registration; expectations regarding the therapeutic potential of Denali’s Transport Vehicle platform and DNL310; and statements made by Drs. Barbara Burton and Carole Ho. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: Denali’s early stages of clinical drug development; Denali’s dependence on successful development of its BBB platform technology and TV-enabled product candidates; Denali’s ability to initiate and enroll patients in its current and future clinical trials; Denali’s ability to conduct or complete clinical trials on expected timelines; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; the potential for clinical trial results to differ from preclinical, early clinical, preliminary, or expected results; the risk of significant adverse events, toxicities, or other undesirable side effects; the possibility that results from early clinical biomarker studies will not translate to clinical benefit in late clinical studies; the likelihood of regulatory approval of DNL310 necessary for commercialization; developments relating to Denali’s competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights; and other risks and uncertainties. In light of these risks, uncertainties, and assumptions, the forward-looking statements in this press release are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s Annual and Quarterly Reports filed on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 27, 2023, and August 8, 2023, respectively, and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results, or to make changes in Denali’s expectations, except as required by law.

Investor and Media Contact: 

Laura Hansen, Ph.D.
Vice President, Investor Relations 
(650) 452-2747 
hansen@dnli.com