Avlayah (tividenofusp alfa-eknm) / Denali Therap, Royalty - LARVOL DELTA

COMPASS: A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (clinicaltrials.gov) - P2/3 | N=65 | Active, not recruiting | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hunter Syndrome • Pediatrics

Phase 1/2 study of intravenous tividenofusp alfa for MPS II: an analysis by ERT status (SSIEM 2026) - P1/2 | "Treatment reduced biomarkers and improved/maintained clinical outcomes, regardless of previous ERT exposure. Funder: Denali Therapeutics"

P1/2 data • NEFL

Phase 1/2 study of intravenous tividenofusp alfa for mucopolysaccharidosis type II: an analysis by genotype (SSIEM 2026) - P1/2 | "Tividenofusp alfa has potential to address CNS and somatic MPS II manifestations regardless of genotype. Funder: Denali Therapeutics."

P1/2 data • Hunter Syndrome • NEFL

Treatment of MPS II with Intravenous Tividenofusp Alfa (SSIEM 2026) - "Sponsored by Denali Therapeutics"

Rare Diseases

Tividenofusp Alfa: First Approval. (PubMed, Mol Diagn Ther) - "Tividenofusp alfa has also been granted Priority Medicine designation by the European Medicines Agency. This article summarises the milestones in the development of tividenofusp alfa leading to this first approval for MPS II."

Journal • Hunter Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases

Denali Therapeutics…announced it has entered into a definitive agreement to sell its Rare Pediatric Disease Priority Review Voucher (PRV) for gross proceeds of $195 million (GlobeNewswire) - "The U.S. Food and Drug Administration (FDA) awarded the PRV to Denali following accelerated approval of the enzyme replacement therapy AVLAYAH (tividenofusp alfa-eknm) for the treatment of Hunter syndrome (mucopolysaccharidosis type II; MPS II) in March 2026....The PRV transaction is subject to customary closing conditions, including expiration of the applicable waiting period under the Hart-Scott Rodino Antitrust Improvements Act."

Commercial • Hunter Syndrome

Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II) (GlobeNewswire) - "Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial....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."

FDA approval • Hunter Syndrome

Phase 1/2 Study of Intravenous Tividenofusp Alfa for Mucopolysaccharidosis Type II (ACMG 2026) - P1/2 | "Tividenofusp alfa treatment was associated with IRRs, a known risk of enzyme replacement therapies. Treatment with tividenofusp alfa reduced CNS and peripheral biomarkers of substrate accumulation and neuronal injury to levels within the range of unaffected children in most patients. Clinical end points also improved."

P1/2 data • Hunter Syndrome • NEFL

Tividenofusp alfa treatment in a male sibling pair with non-neuronopathic mucopolysaccharidosis type II (ACMG 2026) - P1/2, P2/3 | "Study funder: Denali Therapeutics. Abstract previously submitted to WORLD Symposium 2026."

Hepatology • Hunter Syndrome • Infectious Disease • Otorhinolaryngology • Rare Diseases

An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II. (PubMed, N Engl J Med) - P1/2 | "In participants with MPS II, tividenofusp alfa treatment was commonly associated with adverse events. Heparan sulfate, the primary substrate that accumulates in the CSF and urine in persons with MPS II, appeared to decrease to levels within the range of unaffected children. A randomized trial is ongoing to further evaluate these effects. (Funded by Denali Therapeutics; ClinicalTrials.gov number, NCT04251026; EudraCT number, 2019-004909-27.)."

Journal • Dermatology • Hunter Syndrome • Immunology • Urticaria

Royalty Pharma plc...and Denali Therapeutics, Inc. (Nasdaq: DNLI) today announced a $275 million synthetic royalty funding agreement based on future net sales of tividenofusp alfa. (GlobeNewswire) - "A Biologics License Application (BLA) for accelerated approval of tividenofusp alfa is under review by the U.S. Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target date of April 5, 2026....At the closing, Royalty Pharma will make an initial payment of $200 million and Royalty Pharma will be obligated to make an additional payment of $75 million upon achieving European Medicines Agency (EMA) approval of tividenofusp alfa by December 31, 2029."

EMA approval • Financing • PDUFA • Hunter Syndrome

Interim, 24-month results of a phase 1/2 study of weekly intravenous DNL310 ( brain-penetrant enzyme replacement therapy) in MPS II (SSIEM 2023) - P2/3 | "Interim data from this Ph1/2 study supports the potential of DNL310 therapy to slow the decline of neurodevelopmental function in MPS II. Based on these encouraging results, this once-weekly IV therapy for treatment of MPS II is being evaluated in the COMPASS Ph2/3 study (NCT05371613)."

P1/2 data

Denali Therapeutics Announces FDA Review Extension of BLA for Tividenofusp Alfa for the Treatment of MPS II (Hunter Syndrome) (GlobeNewswire) - "The Prescription Drug User Fee Act (PDUFA) target date has been extended from January 5, 2026, to April 5, 2026. The extension follows Denali’s submission of updated clinical pharmacology information in response to an information request from the FDA....The FDA classified the submission as a Major Amendment (MA) to the BLA..."

PDUFA • Hunter Syndrome

A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome (clinicaltrials.gov) - P1/2 | N=47 | Active, not recruiting | Sponsor: Denali Therapeutics Inc. | Trial completion date: Jul 2027 ➔ Feb 2031 | Trial primary completion date: Jul 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hunter Syndrome • Pediatrics

COMPASS: A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (clinicaltrials.gov) - P2/3 | N=63 | Recruiting | Sponsor: Denali Therapeutics Inc. | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Hunter Syndrome • Pediatrics

Denali Therapeutics Announces FDA Acceptance and Priority Review of Biologics License Application (BLA) for Tividenofusp Alfa for Hunter Syndrome (MPS II) (GlobeNewswire) - "Denali Therapeutics Inc...announced that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) seeking accelerated approval for tividenofusp alfa for the treatment of Hunter syndrome (mucopolysaccharidoses type II, or MPS II), a rare and progressive genetic disorder. The FDA granted the BLA Priority Review with a Prescription Drug User Fee Act (PDUFA) target action date of January 5, 2026...The BLA submission is supported by data from the open-label, single-arm Phase 1/2 study of tividenofusp alfa in 47 participants with Hunter syndrome. Denali continues to prepare for a potential commercial launch in the U.S. and is conducting the ongoing Phase 2/3 COMPASS study to support global regulatory approvals."

FDA filing • PDUFA • Priority review • Hunter Syndrome

Tividenofusp alfa (DNL310, ETV:IDS) for Hunter syndrome (MPS II) (GlobeNewswire) - "Today, Denali announced completion of submission of a Biologics License Application (BLA) for tividenofusp alfa under the U.S. Food and Drug Administration’s (FDA’s) accelerated approval pathway based on data from the Phase 1/2 study in participants with Hunter syndrome. The submission of the final BLA modules initiates the FDA’s 60-day filing review process and, upon acceptance of the application, the FDA will communicate the Prescription Drug User Fee Act (PDUFA) target action date."

FDA filing • Hunter Syndrome

Denali Therapeutics Announces Primary Analysis and Long-Term Follow-Up of Phase 1/2 Study in Hunter Syndrome (MPS II) with Tividenofusp Alfa (GlobeNewswire) - P1/2 | N=47 | NCT04251026 | Sponsor: Denali Therapeutics Inc. | "Regulatory submission for accelerated approval is planned for early 2025; U.S. launch preparation is ongoing to deliver tividenofusp alfa to families with MPS II in late 2025 or early 2026...The Phase 1/2 results are being presented this week at the 21st Annual WORLDSymposium....The additional Phase 1/2 long-term data demonstrated that treatment with tividenofusp alfa led to substantial and significant reductions to normal and near-normal levels in central nervous system and peripheral biomarkers of disease, including cerebrospinal fluid (CSF) and urine heparan sulfate, and neurofilament light (NfL), a well-established marker of neurodegeneration. Clinical outcomes included normal liver volume after 24 weeks, hearing threshold improvement in all tested frequencies, and skill gains in most participants on measures of adaptive behavior and cognition."

FDA filing • Launch US • P1/2 data • Hunter Syndrome

Denali Therapeutics Announces Upcoming Presentations on Hunter Syndrome (MPS II) and TransportVehicle Enabled Investigational Therapeutic Tividenofusp Alfa at the 2025 WORLDSymposium (GlobeNewswire) - "Denali Therapeutics Inc...today announced upcoming oral (platform) and poster presentations at the 21st Annual WORLDSymposium, which will be held February 3-7, 2025, in San Diego, California. The oral presentation includes clinical results related to its Hunter syndrome (MPS II) investigational therapeutic, tividenofusp alfa (DNL310)."

Clinical data • Hunter Syndrome

Denali Therapeutics Announces U.S. FDA Breakthrough Therapy Designation Granted to Tividenofusp Alfa for the Treatment of Hunter Syndrome (MPS II) (GlobeNewswire) - "Denali Therapeutics Inc..today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310) for the treatment of individuals with Hunter syndrome (MPS II)...Denali expects to submit a Biologics License Application (BLA) for tividenofusp alfa in early 2025 for regulatory review under the accelerated approval pathway...'Data from the open-label Phase 1/2 study have shown promising results, with positive effects on evidence-based surrogate endpoints and early signs of improved clinical outcomes in participants with Hunter syndrome.'"

Breakthrough therapy • FDA filing • Hunter Syndrome

INTERIM ANALYSIS OF A PHASE 1/2 STUDY OF WEEKLY INTRAVENOUS TIVIDENOFUSP ALFA IN MUCOPOLYSACCHARIDOSIS TYPE II (SSIEM 2024) - P1/2 | "These data suggest that treatment of tividenofusp alfa results in CNS and somatic benefits."

P1/2 data • Hunter Syndrome • NEFL

NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS ARE ASSOCIATED WITH GENOTYPE AND DISEASE SEVERITY IN MUCOPOLYSACCHARIDOSIS (MPS) TYPE II (SSIEM 2024) - P1/2, P2/3 | "These data suggest that NfL levels can be used as a marker of neurodegeneration, provides valuable insight into disease severity, and suggests that early treatment may provide greater impact on neurodegeneration in MPS II. These data support tividenofusp alfa's potential for CNS disease modification in MPS II and for it's continued development in this trial (NCT04251026), and the ongoing COMPASS Phase 2/3 study (NCT05371613)."

CNS Disorders • Hunter Syndrome • NEFL

INTERIM ANALYSIS OF A PHASE 1/2 STUDY OF WEEKLY INTRAVENOUS TIVIDENOFUSP ALFA IN MUCOPOLYSACCHARIDOSIS TYPE II (SSIEM 2024) - P1/2 | "These data suggest that treatment of tividenofusp alfa results in CNS and somatic benefits."

P1/2 data • Hunter Syndrome • NEFL

A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome (clinicaltrials.gov) - P1/2 | N=47 | Active, not recruiting | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hunter Syndrome • Pediatrics

A Study of Tividenofusp Alfa (DNL310) in Pediatric Participants With Hunter Syndrome (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: Denali Therapeutics Inc.

Trial completion date • Trial primary completion date • Hunter Syndrome • Pediatrics