tividenofusp alfa (DNL310) / Denali Therap, Royalty - LARVOL DELTA

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

COMPASS: A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (clinicaltrials.gov) - P2/3 | N=54 | Recruiting | Sponsor: Denali Therapeutics Inc.

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

An Extension Study of the Long-Term Safety, Tolerability, and Efficacy of DNL310 in Participants With Mucopolysaccharidosis Type II (MPS II) From Study DNLI-E-0002 or Study DNLI-E-0007 (clinicaltrials.gov) - P2/3 | N=99 | Enrolling by invitation | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Enrolling by invitation

Enrollment status • Hunter Syndrome

An Extension Study of the Long-Term Safety, Tolerability, and Efficacy of DNL310 in Participants With Mucopolysaccharidosis Type II (MPS II) From Study DNLI-E-0002 or Study DNLI-E-0007 (clinicaltrials.gov) - P2/3 | N=99 | Recruiting | Sponsor: Denali Therapeutics Inc.

New P2/3 trial • Hunter Syndrome

A Study to the Efficacy and Safety of DNL310 vs Idursulfase in Pediatric Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (clinicaltrials.gov) - P2/3 | N=54 | Recruiting | Sponsor: Denali Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hunter Syndrome • Pediatrics

A Study to the Efficacy and Safety of DNL310 vs Idursulfase in Pediatric Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (clinicaltrials.gov) - P2/3 | N=54 | Not yet recruiting | Sponsor: Denali Therapeutics Inc.

New P2/3 trial • Hunter Syndrome • Pediatrics

Study to determine effectiveness and safety of DNL310 vs Idursulfase in Pediatric Participants With Neuronopathic or Non-Neuronopathic Hunter Syndrome (clinicaltrialsregister.eu) - P2/3 | N=54 | Sponsor: Denali Therapeutics Inc.

New P2/3 trial • Hunter Syndrome • Pediatrics

A Study of DNL310 in Pediatric Participants With Hunter Syndrome (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: Denali Therapeutics Inc. | N=30 ➔ 45 | Trial completion date: Mar 2024 ➔ Jul 2027 | Trial primary completion date: Mar 2024 ➔ Jul 2027

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

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome. (PubMed, JCI Insight) - "Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II."

Journal • Preclinical • CNS Disorders • Hunter Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

A Study of DNL310 in Pediatric Participants With Hunter Syndrome (clinicaltrials.gov) - P1/2; N=30; Recruiting; Sponsor: Denali Therapeutics Inc.; N=16 ➔ 30; Trial completion date: Jan 2023 ➔ Mar 2024; Trial primary completion date: Jan 2023 ➔ Mar 2024

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Hunter Syndrome • Pediatrics

A Study of DNL310 in Pediatric Subjects With Hunter Syndrome (clinicaltrials.gov) - P1/2; N=16; Recruiting; Sponsor: Denali Therapeutics Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Gene Therapies • Hunter Syndrome • Pediatrics