Denali Therapeutics Announces Primary Analysis and Long-Term Follow-Up of Phase 1/2 Study in Hunter Syndrome (MPS II) with Tividenofusp Alfa
Denali Therapeutics (NASDAQ: DNLI) announced primary analysis results from its Phase 1/2 study of tividenofusp alfa (DNL310) in 47 Hunter syndrome (MPS II) participants, along with long-term follow-up data. The study demonstrated sustained biomarker normalization and improvements in hearing, cognition, and adaptive behavior.
The treatment was generally well-tolerated over a median follow-up of two years, extending to more than four years. Most treatment-related adverse events were mild or moderate, with serious events occurring in 6.4% of participants. The company plans to submit a biologics license application (BLA) for accelerated approval in early 2025, targeting a potential launch in late 2025 or early 2026.
Key outcomes included normal liver volume after 24 weeks, hearing threshold improvements across all tested frequencies, and skill gains in most participants. The treatment led to significant reductions in central nervous system and peripheral biomarkers of disease, including CSF and urine heparan sulfate, and neurofilament light.
Denali Therapeutics (NASDAQ: DNLI) ha annunciato i risultati dell'analisi primaria del suo studio di Fase 1/2 su tividenofusp alfa (DNL310) in 47 partecipanti con sindrome di Hunter (MPS II), insieme a dati di follow-up a lungo termine. Lo studio ha dimostrato una normalizzazione sostenuta dei biomarker e miglioramenti nell'udito, nella cognizione e nel comportamento adattivo.
Il trattamento è stato generalmente ben tollerato con un follow-up mediano di due anni, estendendosi a più di quattro anni. La maggior parte degli eventi avversi correlati al trattamento è stata di entità lieve o moderata, con eventi gravi che si sono verificati nel 6,4% dei partecipanti. L'azienda prevede di presentare una domanda di licenza biologica (BLA) per approvazione accelerata all'inizio del 2025, puntando a un possibile lancio alla fine del 2025 o all'inizio del 2026.
I risultati principali hanno incluso un volume epatico normale dopo 24 settimane, miglioramenti della soglia uditiva in tutte le frequenze testate e aumenti di abilità nella maggior parte dei partecipanti. Il trattamento ha portato a significative riduzioni dei biomarker della malattia nel sistema nervoso centrale e periferico, inclusi il solfato di eparano nel liquido cerebrospinale e nelle urine, e la luce del neurofilamento.
Denali Therapeutics (NASDAQ: DNLI) anunció los resultados del análisis primario de su estudio de Fase 1/2 de tividenofusp alfa (DNL310) en 47 participantes con síndrome de Hunter (MPS II), junto con datos de seguimiento a largo plazo. El estudio demostró una normalización sostenida de los biomarcadores y mejoras en la audición, la cognición y el comportamiento adaptativo.
El tratamiento fue generalmente bien tolerado con un seguimiento mediano de dos años, que se extendió a más de cuatro años. La mayoría de los eventos adversos relacionados con el tratamiento fueron leves o moderados, con eventos graves que ocurrieron en el 6,4% de los participantes. La empresa planea presentar una solicitud de licencia biológica (BLA) para aprobación acelerada a principios de 2025, apuntando a un posible lanzamiento a finales de 2025 o principios de 2026.
Los resultados clave incluyeron un volumen hepático normal después de 24 semanas, mejoras en el umbral auditivo en todas las frecuencias probadas y ganancias de habilidades en la mayoría de los participantes. El tratamiento condujo a reducciones significativas en biomarcadores de la enfermedad del sistema nervioso central y periférico, incluidos el sulfato de heparán en el líquido cefalorraquídeo y la orina, y el neurofilamento ligero.
데날리 테라퓨틱스 (NASDAQ: DNLI)는 헌터 증후군 (MPS II) 참가자 47명을 대상으로 한 티비데노푸스 알파 (DNL310)의 1/2상 연구의 주요 분석 결과와 장기 추적 데이터를 발표했습니다. 이 연구는 바이오마커의 지속적인 정상화와 청력, 인지, 적응 행동의 개선을 보여주었습니다.
치료는 2년의 중앙 추적 관찰 기간 동안 전반적으로 잘 견뎌졌으며, 이는 4년 이상으로 연장되었습니다. 치료와 관련된 대부분의 부작용은 경미하거나 중간 정도였으며, 심각한 사건은 참가자의 6.4%에서 발생했습니다. 이 회사는 2025년 초에 가속 승인을 위한 생물 치료제 허가 신청(BLA)을 제출할 계획이며, 2025년 말 또는 2026년 초에 출시할 가능성을 목표로 하고 있습니다.
주요 결과에는 24주 후 정상 간 용적, 모든 시험 주파수에서의 청력 임계값 개선 및 대부분의 참가자에서의 기술 향상이 포함되었습니다. 이 치료는 중추 신경계 및 말초의 질병 바이오마커(예: CSF 및 소변 헤파란 황산, 신경 필라멘트 경량)의 유의미한 감소를 가져왔습니다.
Denali Therapeutics (NASDAQ: DNLI) a annoncé les résultats de l'analyse primaire de son étude de Phase 1/2 sur tividenofusp alfa (DNL310) chez 47 participants atteints du syndrome de Hunter (MPS II), ainsi que des données de suivi à long terme. L'étude a montré une normalisation durable des biomarqueurs et des améliorations dans l'audition, la cognition et le comportement adaptatif.
Le traitement a généralement été bien toléré avec un suivi médian de deux ans, s'étendant à plus de quatre ans. La plupart des événements indésirables liés au traitement étaient légers ou modérés, avec des événements graves survenant chez 6,4 % des participants. L'entreprise prévoit de soumettre une demande de licence biologique (BLA) pour une approbation accélérée au début de 2025, visant un lancement potentiel à la fin de 2025 ou au début de 2026.
Les résultats clés comprenaient un volume hépatique normal après 24 semaines, des améliorations des seuils auditifs à toutes les fréquences testées, et des gains de compétences chez la plupart des participants. Le traitement a entraîné des réductions significatives des biomarqueurs de la maladie dans le système nerveux central et périphérique, y compris le sulfate de héparane dans le liquide céphalorachidien et les urines, ainsi que la légèreté du neurofilament.
Denali Therapeutics (NASDAQ: DNLI) hat die Ergebnisse der Primäranalyse seiner Phase 1/2-Studie zu Tividenofusp alfa (DNL310) bei 47 Teilnehmern mit Hunter-Syndrom (MPS II) zusammen mit Langzeitfolgedaten bekannt gegeben. Die Studie zeigte eine nachhaltige Normalisierung der Biomarker und Verbesserungen in Hörvermögen, Kognition und adaptivem Verhalten.
Die Behandlung wurde über einen medianen Follow-up von zwei Jahren, der auf mehr als vier Jahre ausgedehnt wurde, insgesamt gut vertragen. Die meisten behandlungsbezogenen unerwünschten Ereignisse waren mild oder moderat, während schwerwiegende Ereignisse bei 6,4 % der Teilnehmer auftraten. Das Unternehmen plant, Anfang 2025 einen Antrag auf biologisches Lizenzverfahren (BLA) zur beschleunigten Genehmigung einzureichen, mit dem Ziel, Ende 2025 oder Anfang 2026 auf den Markt zu kommen.
Zu den wichtigsten Ergebnissen gehörten ein normales Lebervolumen nach 24 Wochen, Verbesserungen der Hörschwelle in allen getesteten Frequenzen und Fähigkeitsgewinne bei den meisten Teilnehmern. Die Behandlung führte zu signifikanten Reduzierungen der Biomarker für die Krankheit im zentralen und peripheren Nervensystem, einschließlich des Heparansulfats in der Rückenmarksflüssigkeit und im Urin sowie des Neurofilament-Leichtproteins.
- Received Breakthrough Therapy designation
- Plans for BLA submission in early 2025 with potential launch by early 2026
- Demonstrated sustained biomarker normalization and clinical improvements
- Treatment showed positive results in hearing, cognition, and behavior
- Generally well-tolerated safety profile with mostly mild/moderate adverse events
- Serious treatment-related adverse events occurred in 6.4% of participants
- One participant discontinued treatment due to adverse events
Insights
The Phase 1/2 study results for tividenofusp alfa represent a significant milestone in treating Hunter syndrome (MPS II), with multiple compelling aspects that strengthen its potential market position. The data demonstrates sustained biomarker normalization across both central nervous system and peripheral markers, particularly noteworthy for CSF heparan sulfate and neurofilament light (NfL) levels.
Several key factors make these results particularly impactful:
- The study's robust sample size of 47 participants and extended follow-up period of up to 4+ years provide substantial evidence for both efficacy and safety
- The demonstrated improvements in hearing, cognition and adaptive behavior address critical unmet needs in the current treatment landscape
- The safety profile appears manageable, with mostly mild to moderate adverse events and low discontinuation rate (only one participant)
- The recent Breakthrough Therapy designation coupled with these results significantly enhances the probability of regulatory success
The commercial implications are substantial. Hunter syndrome affects approximately 1 in 100,000 to 170,000 males, representing a specialized but important market. The planned BLA submission in early 2025 positions Denali for potential market entry by late 2025 or early 2026, addressing an area with effective treatment options, particularly for neurological manifestations.
The research presented on unmet needs and biomarker levels further strengthens the market positioning, highlighting the limitations of existing treatments and establishing clear diagnostic and monitoring parameters. This comprehensive approach suggests strong potential for market adoption, particularly given the drug's ability to address both peripheral and neurological manifestations of the disease.
The Phase 1/2 results represent a pivotal value-driving catalyst for Denali, substantially de-risking their lead program and strengthening their position in the rare disease space. Several key financial implications emerge:
- The robust efficacy and safety data significantly increase the probability of regulatory success, potentially leading to commercialization by late 2025
- The comprehensive treatment effect, addressing both peripheral and neurological manifestations, suggests potential premium pricing power in line with other rare disease treatments
- The Breakthrough Therapy designation could accelerate time-to-market and reduce development costs
- Success in Hunter syndrome validates Denali's broader platform technology, particularly relevant for their Sanfilippo syndrome program
From a market perspective, while Hunter syndrome represents a rare condition, orphan drug pricing typically supports substantial revenue generation. The demonstrated multi-system benefits and long-term efficacy data could support favorable reimbursement discussions. Furthermore, the validation of Denali's transport vehicle technology platform could have significant implications for their broader pipeline, particularly in other lysosomal storage diseases.
The comprehensive data package, including both clinical efficacy and real-world burden of illness research, suggests a well-planned commercial strategy. This positions Denali strongly for both regulatory approval and market access negotiations, potentially leading to meaningful revenue generation starting in late 2025 or early 2026.
- Long-term data demonstrate that robust reductions and normalization in key biomarkers from baseline were maintained over time with continued improvement in hearing, cognition and adaptive behavior
- Long-term safety data with median follow-up of two years, and out to more than four years, demonstrate that tividenofusp alfa was generally well tolerated
- 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
SOUTH SAN FRANCISCO, Calif., Feb. 06, 2025 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ: DNLI), today announced the primary analysis of the Phase 1/2 study in 47 participants with Hunter syndrome (MPS II) in the 24-week treatment period and additional long-term follow-up of its investigational therapeutic tividenofusp alfa (DNL310). These data, along with recent Breakthrough Therapy designation, further support the company’s plan to submit a biologics license application (BLA) in early 2025 for accelerated approval and deliver this potential treatment to the Hunter syndrome community in late 2025 or early 2026. The Phase 1/2 results are being presented this week at the 21st Annual WORLDSymposium™ conference in San Diego, California.
“Longer-term clinical data add to confidence that normalization of key biomarkers endures over time and that treatment with tividenofusp alfa is associated with continued improvement in hearing, cognition and behavior, which is meaningful to affected individuals and their families,” said Joseph Muenzer, M.D., Ph.D., Director of the Muenzer MPS Center and Professor in Pediatric Genetics at the University of North Carolina at Chapel Hill School of Medicine as well as an investigator in the Phase 1/2 study. “I look forward to new treatment options urgently needed by the Hunter syndrome community that effectively address the full spectrum of the disease.”
“Our primary analysis in 47 participants with MPS II and the additional long-term data in up to more than four years, support the potential of tividenofusp alfa to address neurocognitive, behavioral, and physical effects for all individuals living with MPS II. We are working as fast as possible to enable tividenofusp alfa as a treatment option for individuals living with MPS II and enable access for them and their families,” said Carole Ho, M.D., Chief Medical Officer of Denali. “We expect the progress achieved in our Hunter syndrome program to inform and accelerate additional therapeutics programs in our lysosomal storage disease portfolio, including Sanfilippo syndrome Type A (MPS IIIA).”
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. Administration of tividenofusp alfa was generally well tolerated in study participants. Most treatment-related adverse events (TEAEs) were mild or moderate, including infusion-related reactions (IRRs), anemia, vomiting, pyrexia, respiratory infections, and rash. Serious TEAEs in three participants (
Denali also supported additional research relating to Hunter syndrome (MPS II) at the WORLDSymposium™ conference. Research presented by Barbara Burton, M.D., Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago identified unmet needs including limitations of existing treatments across disease manifestations and the challenges in care associated with diagnosis and continuation of care. Denali researchers also presented research at the conference demonstrating that age-based levels of CSF and urine biomarkers in Hunter syndrome (MPS II) were elevated above biomarker levels at pediatric age-based reference intervals.
About Hunter Syndrome (MPS II)
Hunter syndrome (MPS II) is a rare genetic disease that affects over 2,000 individuals in commercially accessible geographies, primarily males, and leads to physical, cognitive, and behavioral symptoms. Hunter syndrome 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 physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of individuals with Hunter syndrome are not addressed. Therapies that address the range of behavioral, cognitive, and physical manifestations of the disease are recognized as an unmet need for the Hunter syndrome community.1
About Tividenofusp Alfa and the Phase 2/3 COMPASS Study
Tividenofusp alfa (or DNL310) is composed of the iduronate 2-sulfatase (IDS) enzyme fused to Denali’s proprietary Enzyme TransportVehicle™ (ETV), uniquely 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). The U.S. Food and Drug Administration has granted Fast Track and Breakthrough Therapy designations to tividenofusp alfa for development in the treatment of Hunter syndrome (MPS II). The European Medicines Agency has granted Priority Medicines designation to tividenofusp alfa.
The Phase 2/3 COMPASS study is enrolling 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. Enrollment of the planned 33 participants with neuronopathic MPS II in Cohort A has been completed; Denali has increased the sample size of Cohort A by nine participants, bringing the total to 42 participants. Cohort B continues to enroll participants with non-neuronopathic MPS II. More information about the COMPASS study can be found here.
Tividenofusp alfa is an investigational therapeutic candidate and has not been approved for use by any Health Authority.
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 plans, timelines, and expectations related to Denali's TransportVehicle™ (TV) platform and its therapeutic and commercial potential; plans, timelines, and expectations relating to DNL310, including enrollment in the ongoing global Phase 2/3 COMPASS study, the likelihood of global approvals, the timing of planned regulatory filings, and the timing, likelihood, and scope of regulatory approvals and commercial launch; plans, timelines, and expectations related to DNL126; and statements made by Dr. Muenzer and Denali’s Chief Medical Officer. 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: 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 risk that results from early clinical biomarker studies will not translate to clinical benefit in late clinical studies; the risk that product candidates may not receive regulatory approval necessary to be commercialized; 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. 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. 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 28, 2024, and November 6, 2024, 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.
References
- Muenzer, J., et al. Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses. Mol Genet Metab. 2024 Aug;142(4):108535
Investor Contact
Laura Hansen, Ph.D.
Vice President, Investor Relations
(650) 452-2747
hansen@dnli.com
Media Contact
Rich Allan
FGS Global
(503) 851-0807
rich.allan@fgsglobal.com
FAQ
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