Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II)

Q: What did Denali (DNLI) announce about FDA approval of AVLAYAH on March 25, 2026?

Denali announced FDA accelerated approval of AVLAYAH to treat neurologic manifestations of Hunter syndrome in pediatric patients ≥5 kg. According to the company, approval relied on a surrogate biomarker showing a 91% reduction in CSF heparan sulfate by week 24.

Q: How effective was AVLAYAH in reducing the biomarker CSF heparan sulfate in DNLI's trial?

AVLAYAH demonstrated a 91% reduction in CSF heparan sulfate from baseline by week 24. According to the company, 93% (41 of 44) of treated patients reached CSF HS levels within the non‑disease range at week 24.

Q: What are the dosing and administration details for AVLAYAH as described by Denali (DNLI)?

AVLAYAH is administered once weekly as an enzyme replacement therapy designed to cross the blood‑brain barrier. According to the company, it uses the TransportVehicle platform targeting the transferrin receptor to reach brain and peripheral tissues.

Q: What safety signals were reported for AVLAYAH in Denali's (DNLI) Phase 1/2 study?

The most common adverse reaction observed was infusion‑related reactions . According to the company, safety findings are being further evaluated in ongoing studies and monitoring programs as the therapy reaches patients.

Rhea-AI Impact

(High)

Rhea-AI Sentiment

(Positive)

Rhea-AI Summary

Denali Therapeutics (Nasdaq: DNLI) announced U.S. FDA accelerated approval of AVLAYAH (tividenofusp alfa-eknm) to treat neurologic manifestations of Hunter syndrome (MPS II) in pediatric patients ≥5 kg before advanced neurologic impairment. Approval is based on a biomarker surrogate: a 91% reduction in cerebrospinal fluid heparan sulfate (CSF HS) by week 24.

AVLAYAH is the first transferrin-receptor (TfR) enabled, brain-penetrant enzyme replacement therapy; dosing is once weekly. Continued approval may be contingent on confirmatory Phase 2/3 COMPASS trial results. A Rare Pediatric Disease Priority Review Voucher was awarded.

Positive

CSF heparan sulfate reduced by 91% from baseline by week 24
93% (41 of 44) of treated patients achieved CSF HS within non‑disease range at week 24
FDA accelerated approval granted for neurologic manifestations of MPS II
Rare Pediatric Disease PRV awarded with the approval
First TfR-enabled, brain-penetrant ERT—novel TransportVehicle platform validation

Negative

Continued approval may depend on confirmatory Phase 2/3 COMPASS trial results
Most common adverse reaction reported: infusion-related reactions
Approval based on a surrogate biomarker rather than direct clinical outcomes to date

News Market Reaction – DNLI

+7.15% 1.8x vol

61 alerts

+7.15% News Effect

+9.7% Peak Tracked

-10.2% Trough Tracked

+$227M Valuation Impact

$3.41B Market Cap

1.8x Rel. Volume

On the day this news was published, DNLI gained 7.15%, reflecting a notable positive market reaction. Argus tracked a peak move of +9.7% during that session. Argus tracked a trough of -10.2% from its starting point during tracking. Our momentum scanner triggered 61 alerts that day, indicating high trading interest and price volatility. This price movement added approximately $227M to the company's valuation, bringing the market cap to $3.41B at that time. Trading volume was above average at 1.8x the daily average, suggesting increased trading activity.

Data tracked by StockTitan Argus on the day of publication.

Key Figures

CSF HS reduction: 91% CSF HS 95% CI: 89%–92% Patients normalized CSF HS: 93% (41 of 44) +5 more

8 metrics

CSF HS reduction 91% Phase 1/2 trial, change from baseline at Week 24

CSF HS 95% CI 89%–92% Confidence interval around 91% reduction at Week 24

Patients normalized CSF HS 93% (41 of 44) AVLAYAH-treated patients within normal CSF HS range at Week 24

Minimum patient weight 5 kg Indication limited to pediatric patients ≥5 kg

Dosing frequency Once weekly AVLAYAH administration schedule

2025 net loss $512.5 million Full-year 2025 net loss from 8-K

2025 R&D expense $418.8 million Full-year 2025 R&D focused on TV-platform programs

Year-end cash $966.2 million Cash, cash equivalents and marketable securities at Dec 31, 2025

Market Reality Check

Price: $19.68 Vol: Volume 1,530,457 is near ...

normal vol

$19.68 Last Close

Volume Volume 1,530,457 is near the 20-day average of 1,609,715, showing no pre-approval accumulation spike. normal

Technical Price $20.97 is trading above the 200-day MA $16.73 and about 11.78% below the 52-week high.

Peers on Argus

Peers in biotechnology showed mixed moves (e.g., AGIO +2.24%, IDYA -1.86%, TVTX ...

1 Up

Peers in biotechnology showed mixed moves (e.g., AGIO +2.24%, IDYA -1.86%, TVTX -1.29%), suggesting no clear sector-wide reaction aligned to this FDA approval.

Previous Fda approval Reports

4 past events · Latest: Apr 02 (Positive)

Same Type Pattern 4 events

Date	Event	Sentiment	Move	Catalyst
Apr 02	BLA submission start	Positive	+11.8%	Initiation of rolling BLA for accelerated approval of tividenofusp alfa.
Jan 08	Breakthrough designation	Positive	+0.3%	FDA Breakthrough Therapy Designation for tividenofusp alfa in Hunter syndrome.
Sep 03	FDA meeting outcome	Positive	+2.8%	Successful FDA meeting enabling accelerated approval plan using CSF HS surrogate.
Jun 03	START program selection	Positive	+9.8%	FDA START selection for DNL126 and continued progress of tividenofusp program.

Pattern Detected

Past FDA-pathway announcements for Denali, including designations and accelerated-approval steps, have generally coincided with positive share moves, averaging about 6.18% gains over four tagged events.

Recent Company History

Over the past two years, Denali has steadily advanced tividenofusp alfa for Hunter syndrome through the FDA pathway, from START program selection and positive Phase 1/2 data to Breakthrough Therapy Designation and BLA filing for accelerated approval. These fda approval-tagged milestones typically produced positive single- to low-double-digit price moves. Today’s accelerated approval and PRV award build directly on that trajectory, converting prior regulatory momentum and biomarker data into the first commercial approval for this TransportVehicle-enabled therapy.

Historical Comparison

+6.2% avg move · In the past 4 FDA-pathway announcements, DNLI averaged a 6.18% move with consistently positive react...

fda approval

+6.2%

Average Historical Move fda approval

In the past 4 FDA-pathway announcements, DNLI averaged a 6.18% move with consistently positive reactions. Today’s full accelerated approval and PRV build on that same regulatory narrative and extend it into commercialization.

Regulatory milestones progressed from FDA engagement and START selection to Breakthrough designation, then rolling BLA for accelerated approval, culminating in today’s accelerated approval for tividenofusp alfa in Hunter syndrome.

Market Pulse Summary

The stock moved +7.2% in the session following this news. A strong positive reaction aligns with Den...

Analysis

The stock moved +7.2% in the session following this news. A strong positive reaction aligns with Denali’s history of favorable responses to FDA-pathway milestones, where prior fda approval-tagged events averaged about a 6.18% move. The approval converts extensive biomarker data into an approved product and adds a Priority Review Voucher. However, investors must weigh this against substantial $512.5 million annual net losses and high R&D spend, as well as prior insider sales, when considering how durable enthusiasm might be after initial commercialization optimism fades.

Key Terms

lysosomal storage disease, blood-brain barrier, enzyme replacement therapy, cerebrospinal fluid, +4 more

8 terms

lysosomal storage disease medical

"First new FDA-approved treatment option in nearly 20 years for families living with this rare lysosomal storage disease"

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.

blood-brain barrier medical

"first FDA-approved biologic specifically designed to cross the blood-brain barrier and reach the whole body"

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.

enzyme replacement therapy medical

"AVLAYAH is an enzyme replacement therapy indicated for the treatment of neurologic manifestations"

Enzyme replacement therapy is a medical treatment that involves providing patients with artificial versions of natural enzymes their bodies are missing or not producing enough of. This approach can help manage certain health conditions by restoring essential functions, similar to replacing a faulty part in a machine to keep it running smoothly. For investors, advancements or approvals in this therapy can signal progress in biotech innovation and potential market growth.

cerebrospinal fluid medical

"based on the reduction of a key disease biomarker, cerebrospinal fluid heparan sulfate (CSF HS)"

A clear fluid that surrounds and cushions the brain and spinal cord, acting like a protective bath and cleanup system that removes waste and helps circulate nutrients. For investors, cerebrospinal fluid matters because it is a common source of diagnostic markers and a route for delivering or testing neurological drugs; changes in its composition can signal disease or affect a therapy’s development, approval prospects, and market value.

heparan sulfate medical

"a key disease biomarker, cerebrospinal fluid heparan sulfate (CSF HS), as a surrogate endpoint"

Heparan sulfate is a long, chain-like sugar molecule found on the surface of most cells and in the spaces between them, acting like tiny antennae and Velcro that help cells communicate, stick together, and interact with proteins, including some viruses and drugs. Investors should care because it is a common biological entry point and regulator for therapies and diagnostics; drugs that target or use heparan sulfate pathways can affect efficacy, safety, and market potential in biotech and pharmaceutical development.

transferrin receptor medical

"platform, which binds to the transferrin receptor (TfR) and delivers IDS to peripheral tissues"

A transferrin receptor is a protein on the surface of many cells that acts like a doorway for iron-carrying transferrin to enter the cell; iron is essential for cell growth and metabolism. Investors watch it because changes in its level or function can indicate disease activity, serve as a biomarker, or be used as a delivery target for drugs and diagnostic agents — think of it as a lock drug makers can exploit to get therapies into specific cells.

receptor-mediated transcytosis medical

"central nervous system through receptor-mediated transcytosis across the blood-brain barrier"

A natural cell process where a molecule binds to a specific surface receptor and is carried across a cell barrier inside the cell, like a courier picking up a package at one door and delivering it out the other. It matters to investors because companies use this route to deliver medicines or imaging agents into hard-to-reach places (for example, across the blood–brain barrier), which can determine a product’s technical feasibility, market potential, regulatory hurdles, and valuation.

Rare Pediatric Disease Priority Review Voucher regulatory

"In connection with the approval of AVLAYAH, the FDA granted Denali Therapeutics a Rare Pediatric Disease Priority Review Voucher (PRV)."

A rare pediatric disease priority review voucher is a transferable regulatory benefit awarded to a company that wins approval for a drug treating a serious but uncommon childhood illness. It works like a “fast-pass” with regulators: the holder can use it to get an accelerated review of a future drug application or sell the voucher to another company, often for a large sum. Investors care because it can speed time to market or generate immediate cash, boosting potential returns and lowering risk on other programs.

AI-generated analysis. Not financial advice.

03/25/2026 - 11:50 AM

First new FDA-approved treatment option in nearly 20 years for families living with this rare lysosomal storage disease
First FDA-approved medicine in emerging new class of biotherapeutics that leverage transferrin receptor to cross blood-brain barrier
Denali’s first medicine enabled by its TransportVehicle™ platform designed to deliver biotherapeutics to whole body, including brain
Rare Pediatric Disease Priority Review Voucher (PRV) awarded in connection with FDA approval
Denali to host conference call and webcast today at 12:30 p.m. Eastern time

SOUTH SAN FRANCISCO, Calif., March 25, 2026 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI) today announced the U.S. Food and Drug Administration (FDA) has granted accelerated approval for AVLAYAH™ (tividenofusp alfa-eknm), the first FDA-approved biologic specifically designed to cross the blood-brain barrier and reach the whole body, including the brain. AVLAYAH is an enzyme replacement therapy indicated for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

“The approval of AVLAYAH is a new era for the Hunter syndrome community as we deliver the first FDA-approved therapy designed to cross the brain’s protective barrier for individuals and families living with this debilitating disease. This approval reflects the determination and partnership of the MPS community, as well as the FDA’s collaborative engagement to incorporate biomarker evidence to help accelerate the development of urgently needed treatments,” said Ryan Watts, Ph.D., co-founder and Chief Executive Officer of Denali Therapeutics. “This milestone validates our TransportVehicle platform and its potential to overcome the long-standing challenge of delivering biologic medicines across the blood-brain barrier, with the aim to transform the treatment of a wide range of neurodegenerative diseases, lysosomal storage disorders and other serious diseases that impact millions worldwide."

Hunter syndrome is a rare genetic 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 Hunter syndrome, GAGs build up in cells throughout the body, including the brain, resulting in progressive damage to organs and tissues beginning at a young age. Individuals living with the disease can develop cognitive, behavioral, hearing and motor decline that may include losing the ability to speak and walk.

“The FDA approval of AVLAYAH represents a breakthrough advance as the first therapeutic innovation for the Hunter syndrome community in nearly 20 years,” said Joseph Muenzer, M.D., Ph.D., lead investigator of the AVLAYAH Phase 1/2 clinical trial, 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 neurologic manifestations of Hunter syndrome, which affect nearly all patients, have been one of the most challenging and persistent medical needs for the community and a central focus of many years of scientific research. As the first FDA-approved, brain-penetrant medicine for Hunter syndrome, AVLAYAH will substantially change how we treat patients and has the potential to become a new standard of care.”

The approval of AVLAYAH is based on the reduction of a key disease biomarker, cerebrospinal fluid heparan sulfate (CSF HS), as a surrogate endpoint reasonably likely to predict clinical benefit in the treatment of neurologic manifestations of Hunter syndrome. In a Phase 1/2 clinical trial, AVLAYAH demonstrated a 91% (95% CI: 89%, 92%) reduction in CSF HS levels from baseline by week 24 of treatment. At week 24, 93% (41 of 44) of AVLAYAH-treated patients had CSF HS levels within the range of individuals without Hunter syndrome. The most common adverse reaction in the study was infusion-related reactions. Results from the Phase 1/2 study were published in the January 1, 2026, issue of The New England Journal of Medicine. The ongoing global Phase 2/3 COMPASS study is designed to generate confirmatory evidence and support global regulatory submissions for AVLAYAH. This study includes young adults living with Hunter syndrome.

“Today’s accelerated approval of AVLAYAH is an important advancement for the Hunter syndrome community as the first and only enzyme replacement therapy designed to reach the central nervous system and periphery that is now FDA-approved to treat neurologic manifestations for individuals living with this disease. We extend our sincere gratitude to the study participants and families, investigators, clinicians and advocates whose courage and commitment made the approval of AVLAYAH possible,” said Peter Chin, M.D., Chief Medical Officer and Head of Development of Denali Therapeutics. “We continue to study AVLAYAH in our Phase 2/3 COMPASS study with the goal of confirming the clinical evidence across the MPS II patient spectrum.”

“This accelerated approval for MPS II based on a biomarker as a surrogate endpoint is an extraordinary day for the MPS and rare disease community. It represents both recognition that time matters profoundly for families affected by these devastating disorders and the potential to accelerate drug development more broadly across MPS and other rare diseases,” said Terri Klein, President and Chief Executive Officer of the National MPS Society. “This approval affirms that when strong science and advocacy come together, meaningful change, continued progress and hope are possible for individuals living with MPS and other rare diseases who are waiting for treatments.”

“For families living with Hunter syndrome, progress has often felt incremental while the disease itself continues to move relentlessly forward. For many, disease progression includes cognitive impacts that can add emotional weight to an already challenging diagnosis,” said Kristin McKay, President and Executive Director of Project Alive and parent of a child with Hunter syndrome. “Families have been waiting for new options that reach the brain, so the availability of this new therapeutic approach brings renewed optimism and hope for our community.”

AVLAYAH is composed of the IDS enzyme fused to Denali’s proprietary TransportVehicle™ (TV) platform, which binds to the transferrin receptor (TfR) and delivers IDS to peripheral tissues and to the central nervous system through receptor-mediated transcytosis across the blood-brain barrier. AVLAYAH is the first FDA-approved TfR-enabled medicine engineered to specifically cross the blood-brain barrier.

AVLAYAH is administered once weekly and will be available in the U.S. shortly after approval. Denali Therapeutics will offer personalized support services to patients, caregivers and healthcare providers through Denali Patient Services, a dedicated program offering individualized assistance with treatment access and support resources. For more information about Denali Patient Services, call 844-DNLI365 (844-365-4365).

In connection with the approval of AVLAYAH, the FDA granted Denali Therapeutics a Rare Pediatric Disease Priority Review Voucher (PRV). This voucher may be used to obtain priority review for a future marketing application or transferred to another sponsor. The PRV program is intended to incentivize the development of therapies for serious and life-threatening rare pediatric diseases by providing a mechanism to potentially accelerate regulatory review timelines for subsequent applications.

Conference Call and Webcast Information

Denali Therapeutics will host a live conference call and webcast to discuss the FDA approval of AVLAYAH beginning at 12:30 p.m. Eastern Time today. The webcast can be accessed on the Events page of the Investor section on Denali’s corporate website at https://investors.denalitherapeutics.com/events or click here. The archived webcast and slides will be available on Denali’s website following the event.

About the AVLAYAH Clinical Trial Program

The accelerated approval of AVLAYAH is based on a Phase 1/2 international, multi-center, open-label trial in 47 enzyme replacement therapy (ERT)-naïve (n=15) and previously treated (n=32) study participants (aged 0.3–13 [median, 5] years) with Hunter syndrome (MPS II). The primary objective of the Phase 1/2 study was to evaluate the safety and tolerability of AVLAYAH, and secondary objectives evaluated central nervous system and peripheral effects of AVLAYAH by measuring the glycosaminoglycan (GAG) heparan sulfate (HS) in cerebrospinal fluid (CSF) and urine, adaptive behavior and liver volume. Continued approval for AVLAYAH may be contingent upon verification of clinical benefit in the Phase 2/3 COMPASS confirmatory trial, in which participants are randomized 2:1 to receive either AVLAYAH or idursulfase, respectively. Denali is conducting the Phase 2/3 COMPASS study in participants with Hunter syndrome in North America, South America and Europe to support global regulatory approval. As previously announced, Cohort A of the COMPASS study has completed enrollment, and Cohort B is currently enrolling. More information about the COMPASS study can be found here.

About Hunter Syndrome (MPS II)

Hunter syndrome, also known as MPS II, is a rare genetic lysosomal storage disorder that primarily affects boys and impacts approximately 500 individuals in the United States and 2,000 individuals worldwide. The disease is caused by mutations in the iduronate 2-sulfatase (IDS) gene that 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.

About AVLAYAH™ (tividenofusp alfa-eknm)

AVLAYAH (tividenofusp alfa-eknm) is an intravenous enzyme replacement therapy composed of the iduronate 2-sulfatase (IDS) enzyme fused to Denali’s proprietary TransportVehicle™ (TV) platform. The Fc component of AVLAYAH binds to the apical domain of the transferrin receptor (TfR) and delivers IDS to peripheral tissues and to the central nervous system through receptor-mediated transcytosis across the blood-brain barrier. AVLAYAH is internalized via binding to the mannose-6-phosphate receptor on the cell surface and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated glycosaminoglycans (GAGs). In addition, since TfR is ubiquitously expressed, it is expected that the interaction of AVLAYAH and TfR will contribute to its uptake into cells in the brain and peripheral tissues. In addition to Rare Pediatric Disease Designation and Breakthrough Therapy Designation, the U.S. Food and Drug Administration granted Fast Track and Orphan Drug designations to AVLAYAH for the treatment of MPS II.

The European Medicines Agency has granted Priority Medicines designation to tividenofusp alfa. AVLAYAH is not approved by health authorities outside of the U.S.

AVLAYAH U.S. Indication

AVLAYAH is approved for the treatment of neurologic symptoms in pediatric patients weighing at least 5 kg with Hunter syndrome prior to advanced neurologic disease. This approval is based on a reduction of heparan sulfate (HS) in the cerebrospinal fluid (CSF) surrounding the brain and spinal cord. Studies are ongoing to confirm how well it works in improving clinical symptoms.

Limitations of Use

AVLAYAH is not recommended for use in combination with other enzyme replacement therapies.

Important Safety Information

AVLAYAH may cause serious side effects, including:

Hypersensitivity Reactions including Anaphylaxis. Life-threatening allergic reactions occurred both early in treatment and after many doses over time, including:

Fast heartbeat
Dizziness or fainting
Wheezing
Vomiting
Hives
Swelling of the lips and tongue

Notify your healthcare provider immediately if these symptoms occur. If a serious allergic reaction happens, your treatment will be stopped and emergency treatment will be given, including use of epinephrine.

Infusion-Associated Reactions (IARs). IARs occurred during or within 24 hours after receiving AVLAYAH, including:

Chills
Swelling
Low blood pressure (dizziness or fainting)
Fast heartbeat
Hives
Wheezing
Fever
Flushing or reddening of the skin
Rash
Cough
Diarrhea
Abdominal pain
Vomiting
Headache
Irritability
Small bumps on the skin

If you have an IAR, your doctor may slow down, pause, adjust your dose, or stop the infusion depending on how serious the reaction is. You may also be given medicine before infusions to help prevent these reactions. Patients with heart or lung problems may be at higher risk of serious complications from these reactions and will be monitored closely.

Anemia (Low Red Blood Cell Count) occurred during AVLAYAH treatment and may require periodic laboratory tests for hemoglobin. Contact your healthcare provider if you experience any symptoms (e.g., fatigue, pale skin) suggestive of anemia.

Membranous Nephropathy (Kidney disorder that affects the filters that help remove wastes and fluids from the kidney) occurred in an AVLAYAH-treated patient. Your doctor will monitor your kidney function during treatment.

The most common side effects (in 20% or more of patients):

Infusion-associated reactions
Upper respiratory infections
Ear infection
Fever
Anemia (low red blood cell count)
Cough
Vomiting
Diarrhea
Rash
COVID-19
Runny or congested nose
Falls
Headache
Skin injuries
Hives

Contact your healthcare provider right away if you experience any side effects. These are not all the possible side effects of AVLAYAH. You may report side effects to FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Denali Therapeutics at 1-833-ONE-DNLI (1-833-663-3654).

Please see the full Prescribing Information, including Boxed Warning, at https://www.denalitherapeutics.com/wp-content/uploads/2026/03/USPI-AVLAYAH-Mar2026.pdf for additional Important Safety Information.

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 five TV-enabled programs are currently in clinical development.

About Denali Therapeutics

Denali Therapeutics Inc. 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 is advancing toward its goal of delivering effective medicines to transform life for people with neurodegenerative diseases, lysosomal storage disorders and other serious diseases. For more information, please visit www.denalitherapeutics.com.

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 Denali’s TransportVehicle™ platform, including its potential application across current and future product candidates and its ability to deliver therapeutics to the whole body, including the brain; plans and expectations related to AVLAYAH™, including its therapeutic potential, efficacy, safety profile, availability, launch timing, patient access, support services and potential side effects; expectations regarding the adequacy of the Phase 1/2 trial and the Phase 2/3 COMPASS trial results to support regulatory submissions, confirm clinical benefit and achieve approvals from the European Medicines Agency (EMA) or other global regulatory agencies; plans to conduct development and commercialization activities for AVLAYAH and other product candidates; expectations regarding Denali’s Rare Pediatric Disease Priority Review Voucher (PRV), including its potential value and any strategic benefits; and statements made by Dr. Watts, Dr. Muenzer, Dr. Chin, Ms. McKay and Ms. Klein regarding the potential benefits, future clinical impact and treatment paradigm of AVLAYAH and related technologies. 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; 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 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; 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; the implementation and success 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 Form 10-K filed with the Securities and Exchange Commission (SEC) on February 26, 2026, and Denali’s future reports to be filed with the SEC. Except for AVLAYAH, Denali's product candidates are investigational, and their safety and efficacy profiles have not yet been established. 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

A video accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/9bb19496-6824-41c1-a066-d8b4339712b8

FAQ

What did Denali (DNLI) announce about FDA approval of AVLAYAH on March 25, 2026?

Denali announced FDA accelerated approval of AVLAYAH to treat neurologic manifestations of Hunter syndrome in pediatric patients ≥5 kg. According to the company, approval relied on a surrogate biomarker showing a 91% reduction in CSF heparan sulfate by week 24.

How effective was AVLAYAH in reducing the biomarker CSF heparan sulfate in DNLI's trial?

AVLAYAH demonstrated a 91% reduction in CSF heparan sulfate from baseline by week 24. According to the company, 93% (41 of 44) of treated patients reached CSF HS levels within the non‑disease range at week 24.

What are the dosing and administration details for AVLAYAH as described by Denali (DNLI)?

AVLAYAH is administered once weekly as an enzyme replacement therapy designed to cross the blood‑brain barrier. According to the company, it uses the TransportVehicle platform targeting the transferrin receptor to reach brain and peripheral tissues.

Does Denali (DNLI) need additional trials after AVLAYAH's accelerated approval?

Yes. Continued approval may be contingent on confirmatory evidence from Denali's ongoing Phase 2/3 COMPASS study. According to the company, COMPASS is designed to generate confirmatory clinical data across the MPS II patient spectrum.

What safety signals were reported for AVLAYAH in Denali's (DNLI) Phase 1/2 study?

The most common adverse reaction observed was infusion‑related reactions. According to the company, safety findings are being further evaluated in ongoing studies and monitoring programs as the therapy reaches patients.

What is the significance of the Rare Pediatric Disease PRV awarded to Denali (DNLI)?

The PRV may be used to secure priority review for a future marketing application or transferred to another sponsor. According to the company, the voucher recognizes the therapy's status as a treatment for a rare pediatric disease and has potential regulatory value.

Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II)