The New England Journal of Medicine Publishes Phase 1/2 Study of Denali Therapeutics’ Tividenofusp Alfa (DNL310) for Hunter Syndrome (MPS II)

Q: What is the FDA decision date for tividenofusp alfa (DNLI)?

The FDA set a PDUFA date of April 5, 2026 for the tividenofusp alfa BLA under Priority Review.

Q: What biomarker changes did tividenofusp alfa achieve at Week 24 in the DNLI study?

At Week 24, mean CSF heparan sulfate fell 91% and mean urine HS fell 88% from baseline.

Q: Did tividenofusp alfa show clinical improvements in the DNLI Phase 1/2 data?

Yes; the study reported liver volume normalization at 24 weeks , improved hearing thresholds, and skill gains in adaptive behavior and cognition.

Rhea-AI Impact

(Moderate)

Rhea-AI Sentiment

(Neutral)

Rhea-AI Summary

Denali Therapeutics (Nasdaq: DNLI) announced Phase 1/2 results for tividenofusp alfa (DNL310) in Hunter syndrome published in The New England Journal of Medicine and supporting a FDA Priority Review with a PDUFA date of April 5, 2026.

In an open-label study of 47 children (median age 5), tividenofusp alfa produced large reductions in disease biomarkers: CSF heparan sulfate −91% at Week 24 (maintained 92% at Week 153; N=16), urine HS −88% at Week 24 (91% at Week 153; N=10), and NfL −21% at Week 49 (76% at Week 153; N=13). Clinical signals included liver volume normalization at 24 weeks, improved hearing thresholds, and gains in adaptive behavior and cognition. Infusion-related reactions were the most common treatment-related adverse events and declined with continued dosing.

Positive

CSF HS −91% from baseline at Week 24
Urine HS −88% from baseline at Week 24
NfL −76% from baseline at Week 153
Liver volume normalized after 24 weeks
FDA Priority Review with PDUFA date April 5, 2026

Negative

Most common treatment-related events were infusion-related reactions
Long-term biomarker cohorts small: N=16 (CSF Week 153), N=10 (urine Week 153), N=13 (NfL Week 153)
Open-label Phase 1/2 design limits randomized efficacy conclusions

News Market Reaction – DNLI

-1.03%

1 alert

-1.03% News Effect

On the day this news was published, DNLI declined 1.03%, reflecting a mild negative market reaction.

Data tracked by StockTitan Argus on the day of publication.

Key Figures

Study participants: 47 participants CSF HS reduction: 91% reduction at Week 24 CSF HS long-term: 92% reduction at Week 153 +5 more

8 metrics

Study participants 47 participants Phase 1/2 Hunter syndrome trial population size

CSF HS reduction 91% reduction at Week 24 Mean cerebrospinal fluid heparan sulfate; 95% CI 90%–92%; N=44

CSF HS long-term 92% reduction at Week 153 Maintained mean CSF heparan sulfate lowering; 95% CI 90%–93%; N=16

Normalization CSF HS 93% participants Reached CSF heparan sulfate levels within range of unaffected children at Week 24

Urine HS reduction 88% reduction at Week 24 Mean urine heparan sulfate; 95% CI 85%–90%; N=40

NfL reduction long-term 76% reduction at Week 153 Serum neurofilament light; 95% CI 68%–82%; N=13

NfL normalization 85% participants Reached NfL levels within range of children without MPS II at Week 153

PDUFA date April 5, 2026 FDA Priority Review decision date for tividenofusp alfa BLA

Market Reality Check

Price: $19.68 Vol: Volume 1,165,677 is 0.67x...

low vol

$19.68 Last Close

Volume Volume 1,165,677 is 0.67x the 20-day average of 1,742,134 shares, suggesting muted pre-news activity. low

Technical Shares at $16.58 are trading above the 200-day MA of $15.07 but sit 31.9% below the 52-week high and 56.86% above the 52-week low.

Peers on Argus

Peers showed mixed moves, with AGIO at -2.72%, TVTX at -1.47%, IDYA at -0.77%, F...

Peers showed mixed moves, with AGIO at -2.72%, TVTX at -1.47%, IDYA at -0.77%, FOLD roughly flat at +0.07%, and BLTE up 6.69%, indicating stock-specific rather than sector-wide drivers.

Historical Context

5 past events · Latest: Dec 10 (Negative)

Pattern 5 events

Date	Event	Sentiment	Move	Catalyst
Dec 10	Equity offering priced	Negative	-10.6%	Underwritten stock and pre-funded warrant offering priced, causing dilution concerns.
Dec 09	Equity offering proposed	Negative	-0.1%	Announced plan for $200M stock and pre-funded warrant sale plus upsizing option.
Dec 04	Royalty funding deal	Positive	+6.8%	$275M royalty funding with Royalty Pharma tied to tividenofusp alfa net sales.
Nov 06	Q3 earnings, pipeline	Neutral	+4.2%	Reported Q3 net loss and strong cash plus BLA progress and multiple clinical milestones.
Nov 06	Leadership, BLA update	Neutral	+4.2%	Board and CMO transition alongside mention of filed BLA for tividenofusp alfa.

Pattern Detected

Recent stock moves have generally aligned with news tone, including selloffs on offerings and gains on partnership and pipeline updates.

Recent Company History

Over the last few months, Denali combined capital raising with progress on tividenofusp alfa. A December public offering targeting about $200 million coincided with a sharp one-day decline, while a $275 million royalty funding deal tied to tividenofusp alfa saw a 6.84% gain. Earlier, Q3 2025 results highlighted a net loss of $126.9M but also priority review of the BLA and pipeline advances, with shares rising about 4.23%. Today’s NEJM Phase 1/2 publication and ongoing FDA Priority Review build directly on these prior clinical and regulatory milestones.

Market Pulse Summary

This announcement highlights detailed Phase 1/2 results for tividenofusp alfa, including large reduc...

Analysis

This announcement highlights detailed Phase 1/2 results for tividenofusp alfa, including large reductions in heparan sulfate and neurofilament light and normalization of liver volume and hearing measures for many participants. The data support the ongoing FDA Priority Review of the BLA, with a PDUFA date of April 5, 2026. Recent history includes a royalty funding deal and an equity offering, so investors may focus on future regulatory decisions and any confirmatory data as key milestones.

Key Terms

biologics license application, priority review, pdufa, blood-brain barrier, +4 more

8 terms

biologics license application regulatory

"The U.S. Food and Drug Administration (FDA) is conducting a Priority Review of the Biologics License Application (BLA)..."

A biologics license application is a formal request submitted to regulatory authorities seeking approval to market a new biological medicine, such as vaccines or treatments made from living organisms. It is a comprehensive review process that evaluates the safety, effectiveness, and manufacturing quality of the product. For investors, receiving approval signals that a biological therapy can be sold to the public, potentially leading to revenue growth and market success.

priority review regulatory

"Biologics License Application for tividenofusp alfa is under FDA Priority Review..."

Priority review is a regulatory fast-track that shortens the time an agency spends evaluating a drug, vaccine or medical device application so a decision comes sooner than normal. For investors, it matters because a faster review is like an express lane to market: it can speed revenue potential and reduce regulatory uncertainty, but it does not guarantee approval and still requires the product to meet safety and effectiveness standards.

pdufa regulatory

"with Prescription Drug User Fee Act (PDUFA) date of April 5, 2026"

PDUFA, short for the Prescription Drug User Fee Act, is a law that allows drug companies to pay fees to the government to speed up the review process for new medicines. This helps bring important drugs to market more quickly, which can impact their availability and pricing. For investors, PDUFA timelines can influence the timing of a drug’s approval and potential market success.

blood-brain barrier medical

"tividenofusp alfa is an investigational, next-generation enzyme replacement therapy engineered to cross the blood-brain barrier"

A protective barrier of tightly packed cells and supporting tissue that controls what substances in the blood can enter the brain, acting like a security checkpoint that keeps out most pathogens and many drugs while allowing essential nutrients through. For investors, the barrier matters because whether a therapy can cross or safely bypass it often determines clinical success, regulatory approval and commercial potential for treatments of brain disorders.

lysosomal storage disease medical

"MPS II is a life-limiting lysosomal storage disease caused by a deficiency in the iduronate 2-sulfatase..."

A lysosomal storage disease is a class of inherited disorders where cells cannot break down certain waste materials because the cell’s recycling centers (lysosomes) lack a working cleanup enzyme, causing harmful buildup over time — like a house with a clogged garbage disposal. These conditions matter to investors because they create clear medical need and defined patient populations that drive drug development, regulatory incentives, pricing potential, and commercial risk for biotech and pharmaceutical efforts.

rare pediatric disease designation regulatory

"The FDA has granted Rare Pediatric Disease Designation and Breakthrough Therapy Designation to tividenofusp alfa."

A rare pediatric disease designation is an official regulatory status given to a drug or therapy that targets a serious or life‑threatening condition primarily affecting children and is uncommon in the population. It matters to investors because the status often brings financial and development perks — such as tax credits, reduced fees, faster review and periods of market protection — which can lower costs, speed approval and improve the commercial outlook; think of it as a VIP pass that makes bringing a scarce, child‑focused treatment to market easier and potentially more profitable.

breakthrough therapy designation regulatory

"The FDA has granted Rare Pediatric Disease Designation and Breakthrough Therapy Designation to tividenofusp alfa."

A breakthrough therapy designation is a regulatory fast-track given to a drug or treatment that shows early signs of providing a major improvement over existing options for a serious condition. Think of it as a VIP lane that can speed up development and more intensive guidance from regulators, which matters to investors because it can shorten time to market, reduce development risk and potentially increase a company’s value — though it does not guarantee approval.

neurofilament light medical

"Serum neurofilament light (NfL) chain levels, a well-established biomarker of neuronal injury..."

Neurofilament light is a protein found inside nerve cells that is released into blood and spinal fluid when those cells are injured or dying. Investors watch its levels because it acts like a smoke detector for brain and nerve damage—rising levels can signal disease progression or a drug’s effect, so changes can influence clinical trial outcomes, regulatory decisions and the perceived value of companies developing neurology diagnostics or treatments.

AI-generated analysis. Not financial advice.

12/30/2025 - 08:00 AM

Tividenofusp alfa treatment showed reduction and normalization in key disease biomarkers, stabilization or improvement in clinical endpoints including adaptive behavior, cognition and hearing, and normalization of liver volume
Most common treatment-related adverse events were infusion-related reactions, which decreased with continued use
Tividenofusp alfa is an investigational, next-generation enzyme replacement therapy engineered to cross the blood-brain barrier
Biologics License Application for tividenofusp alfa is under FDA Priority Review, with Prescription Drug User Fee Act (PDUFA) date of April 5, 2026

SOUTH SAN FRANCISCO, Calif., Dec. 30, 2025 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI) today announced the publication of results from the open-label Phase 1/2 clinical trial of its investigational, next-generation enzyme replacement therapy (ERT), tividenofusp alfa (DNL310), for the treatment of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) in the January 1, 2026 issue of The New England Journal of Medicine. The U.S. Food and Drug Administration (FDA) is conducting a Priority Review of the Biologics License Application (BLA) for tividenofusp alfa, which is supported by these data and for which Denali is seeking accelerated approval. A decision by the FDA on the tividenofusp alfa BLA is expected by April 5, 2026.

MPS II is a life-limiting lysosomal storage disease caused by a deficiency in the iduronate 2-sulfatase (IDS) enzyme, which is needed to break down complex sugars called glycosaminoglycans (GAGs). In individuals with MPS II, GAGs build up in cells throughout the body, including the brain, resulting in progressive damage to organs and tissues starting at a young age. MPS II occurs along a spectrum of disease severity, with approximately two-thirds of individuals developing progressive neurocognitive decline (neuronopathic MPS II). Current therapies do not cross the blood-brain barrier and therefore lack the potential to address the impact of the disease on cognitive abilities and behavior.

“There is an urgent need for new treatment options to address the full spectrum of Hunter syndrome, which can include severe cognitive and motor deficits such as losing the ability to hear, speak and walk,” said Joseph Muenzer, M.D., Ph.D., lead investigator of the Phase 1/2 study, Director of the Muenzer MPS Research and Treatment Center and the Bryson Distinguished Professor in Pediatric Genetics at the University of North Carolina at Chapel Hill. “The Phase 1/2 data demonstrate that treatment with the brain-penetrant enzyme replacement therapy tividenofusp alfa substantially reduced central nervous system and peripheral biomarkers of substrate accumulation and neuronal injury, with the potential for improving clinical outcomes in MPS II. This novel treatment could have a profound impact for individuals and families living with this devastating disease.”

Tividenofusp alfa is composed of IDS fused to Denali’s TransportVehicle™ platform and is engineered to cross the blood-brain barrier, aiming to treat neurological manifestations of MPS II in addition to physical symptoms. The FDA has granted Rare Pediatric Disease Designation and Breakthrough Therapy Designation to tividenofusp alfa.

“Our investigational treatment, tividenofusp alfa, has the potential to become the first FDA-approved enzyme replacement therapy designed to treat the whole body, including the brain. We are excited by the clinical trial data showing that after treatment with tividenofusp alfa, the majority of participants had normalization of heparan sulfate levels in both cerebrospinal fluid and urine to levels in the range observed in children unaffected by this disease,” said Peter Chin, M.D., Acting Chief Medical Officer and Head of Development of Denali Therapeutics. “We are deeply thankful to the individuals and families, clinical investigators and their teams contributing to the efforts to improve treatment options for the MPS community. We are committed to advancing and preparing for potential availability of tividenofusp alfa for individuals with Hunter syndrome.”

“These data further validate our TransportVehicle as a platform with the potential to establish a new class of medicines that leverage natural transport mechanisms, such as the transferrin receptor (TfR), to enable and enhance delivery of biotherapeutics throughout the body, including the brain,” said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics. “Tividenofusp alfa would be the first FDA-approved TfR-enabled medicine specifically designed to cross the blood-brain barrier. In addition to evaluating our TransportVehicle to enable enzyme replacement across lysosomal storage disorders and neurodegenerative diseases, we are pursuing the potential of the platform to deliver antibodies and oligonucleotides for diseases that impact the brain.”

Tividenofusp Alfa Phase 1/2 Trial Results

The primary objective of the Phase 1/2 study was safety and tolerability, and secondary objectives evaluated central nervous system and peripheral effects of tividenofusp alfa by measuring the GAG heparan sulfate (HS) in cerebrospinal fluid (CSF) and urine, adaptive behavior and liver volume. The study evaluated treatment in 47 ERT-naïve (n=15) and previously treated (n=32) study participants (aged 0.3–13 [median, 5] years), ranging from less severe to severe disease variants. Safety and tolerability data were consistent with previously reported results from this Phase 1/2 trial. The most common treatment-related adverse events were infusion-related reactions, which decreased in incidence with continued use. Results from key secondary endpoints are:

Mean CSF levels of HS, the primary substrate found in high levels in the brain of individuals with MPS II, were reduced from baseline by 91% (95% CI, 90% to 92%; N=44) at Week 24 and maintained through Week 153 (92%; 95% CI, 90% to 93%; N=16). At Week 24, 93% of study participants reached levels within the range of children without MPS II.
Mean urine HS levels were reduced by 88% (95% CI, 85% to 90%; N=40) from baseline at Week 24 and maintained through Week 153 (91%; 95% CI, 87% to 94%; N=10). At Week 24, 58% of participants reached levels in the range of children without MPS II.
Serum neurofilament light (NfL) chain levels, a well-established biomarker of neuronal injury and an exploratory endpoint of the study, were reduced by 21% (95% CI, 5% to 35%; N=34) from baseline at Week 49. At Week 153, NfL was reduced by 76% (95% CI, 68% to 82%; N=13), and 85% of participants reached levels within the range of children without MPS II.
Clinical results included normalization in liver volume after 24 weeks, improvement in hearing thresholds across tested frequencies, and skill gains in most participants on measures of adaptive behavior and cognition.

About Tividenofusp Alfa

Tividenofusp alfa (DNL310) is composed of the iduronate 2-sulfatase (IDS) enzyme fused to Denali’s proprietary TransportVehicle™ (TV) platform, designed to deliver IDS into the brain and the body, with the goal of addressing behavioral, cognitive and physical symptoms of Hunter syndrome (MPS II). In addition to Rare Pediatric Disease Designation and Breakthrough Therapy Designation, the U.S. Food and Drug Administration has granted Fast Track and Orphan Drug designations to tividenofusp alfa for development in the treatment of MPS II. The European Medicines Agency has granted Priority Medicines designation to tividenofusp alfa.

Denali is conducting the Phase 2/3 COMPASS study in participants with MPS II in North America, South America and Europe to support global approval. Participants are randomized 2:1 to receive either tividenofusp alfa or idursulfase, respectively. More information about the COMPASS study can be found here.

Tividenofusp alfa is an investigational therapeutic and has not been approved for use by any Health Authority.

About Hunter Syndrome (MPS II)

Hunter syndrome, also known as MPS II, is a rare genetic lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. This results in a deficiency of the IDS enzyme, which is responsible for breaking down glycosaminoglycans (GAGs) such as heparan sulfate and dermatan sulfate. The accumulation of GAGs leads to progressive damage in multiple organs and tissues, including the brain. Symptoms of Hunter syndrome include developmental delays, cognitive decline, behavioral abnormalities and physical complications such as joint stiffness, hearing loss and organ dysfunction. Current standard-of-care enzyme replacement therapies do not cross the blood-brain barrier and therefore do not address the neurological symptoms of the disease. There is a significant unmet need for therapies that address both the central nervous system (CNS) and peripheral manifestations of Hunter syndrome.

About the Denali TransportVehicle^™ Platform

The blood-brain barrier (BBB) is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB 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 TransportVehicle^™ (TV) platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes and oligonucleotides throughout the whole body, including the brain, by crossing the BBB after intravenous administration. The TV platform is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor and CD98 heavy chain amino acid transporter, which are expressed at the BBB and deliver the TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV platform demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Oligonucleotides engineered with the TV platform demonstrate more than a 1,000-fold greater brain exposure in primates than systemically delivered oligonucleotides 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. The TV platform has been clinically validated and three TV-enabled programs are currently in clinical development.

About Denali Therapeutics

Denali Therapeutics is a biotechnology company pioneering a new class of biotherapeutics designed to cross the blood-brain barrier using its proprietary TransportVehicle™ platform. With a clinically validated delivery platform and a growing portfolio of therapeutic candidates across all stages of development, Denali Therapeutics is advancing toward its goal of delivering effective medicines to transform the lives of people living with neurodegenerative, lysosomal storage and other serious diseases.

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, plans, timelines and expectations related to tividenofusp alfa and Denali’s TransportVehicle platform; expectations regarding the treatment impact, efficacy and safety of tividenofusp alfa; the timing of the PDUFA action date and expectations regarding the adequacy of the Phase 1/2 or the Phase 2/3 COMPASS trial results to support regulatory review and achieving approvals from the FDA, EMA or other global regulatory agencies; plans to conduct development and commercialization activities, including the size of the potential market, the number of patients likely to be treated with tividenofusp alfa and the timing and likelihood of commercial launch; expectations for ongoing communications with the FDA; and statements made by Denali’s Acting Chief Medical Officer and Head of Development and Chief Executive Officer. Actual results may differ materially from those expressed or implied by these forward-looking statements due to a variety of risks and uncertainties. These include, but are not limited to, uncertainties related to the FDA’s policies and accelerated approval program, including risks that the PDUFA action date may be extended, the FDA may ultimately determine not to approve tividenofusp alfa or the BLA in its present form or at all, and the FDA may not grant Denali a Priority Review Voucher upon approval of the BLA; risks arising from adverse economic conditions and their impact on Denali’s business and operations; the possibility of events or changes that could lead to the termination of Denali’s collaboration agreements; challenges associated with Denali’s transition to a late-stage clinical drug development and commercial company; the ability of Denali and its collaborators to complete the development and, if approved, the commercialization of product candidates; difficulties in patient enrollment for ongoing and future clinical trials; whether the current ongoing trials have been powered sufficiently to demonstrate approvability to regulatory agencies; reliance on third-party manufacturers and suppliers for clinical trial materials; dependence on the successful development of Denali’s blood-brain barrier platform technology and related programs; potential delays or failures in meeting expected clinical trial timelines; the risk that promising preclinical profiles may not be replicated in clinical settings; discrepancies between preclinical, early-stage or preliminary clinical results and outcomes from later-stage trials; the occurrence of significant adverse events or other undesirable side effects; and the uncertainty surrounding regulatory approvals required for commercialization in the U.S., Europe or other international jurisdictions; Denali’s ability to advance a pipeline of product candidates or develop commercially successful products; 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 related to its product candidates; implementation of Denali’s strategic plans for its business, product candidates and blood-brain barrier platform technology; Denali's ability to obtain additional capital to finance its operations, as needed; Denali's ability to accurately forecast future financial results in the current environment; and other risks and uncertainties, including those described in Denali's most recent Annual and Quarterly Reports on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 27, 2025 and November 6, 2025, respectively, and Denali’s future reports to be filed with the SEC. Denali's product candidates are investigational, and their safety and efficacy profiles have not yet been established. No Denali product candidates have been approved by any Health Authority for any use. 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 Contact:
Laura Hansen, Ph.D.
hansen@dnli.com

Media Contact:
Erin Patton
epatton@dnli.com

FAQ

What did Denali announce about tividenofusp alfa (DNLI) on December 30, 2025?

Denali announced Phase 1/2 results published in NEJM showing large biomarker reductions and clinical improvements for tividenofusp alfa in Hunter syndrome and that the BLA is under FDA Priority Review.

What is the FDA decision date for tividenofusp alfa (DNLI)?

The FDA set a PDUFA date of April 5, 2026 for the tividenofusp alfa BLA under Priority Review.

How many patients were in the tividenofusp alfa Phase 1/2 trial reported by Denali (DNLI)?

The open-label study enrolled 47 participants aged 0.3–13 years (median age 5).

What biomarker changes did tividenofusp alfa achieve at Week 24 in the DNLI study?

At Week 24, mean CSF heparan sulfate fell 91% and mean urine HS fell 88% from baseline.

Did tividenofusp alfa show clinical improvements in the DNLI Phase 1/2 data?

Yes; the study reported liver volume normalization at 24 weeks, improved hearing thresholds, and skill gains in adaptive behavior and cognition.

What safety issues were reported for tividenofusp alfa in Denali's (DNLI) trial?

The most common treatment-related adverse events were infusion-related reactions, which decreased in incidence with continued dosing.

The New England Journal of Medicine Publishes Phase 1/2 Study of Denali Therapeutics’ Tividenofusp Alfa (DNL310) for Hunter Syndrome (MPS II)