Ionis Announces Pivotal Phase 3 Trial Design for ION582 in Angelman Syndrome
Ionis Pharmaceuticals announced the design of its pivotal Phase 3 REVEAL trial for ION582, following successful alignment with the FDA. The trial, targeting Angelman syndrome (AS), will enroll approximately 200 children and adults with maternal UBE3A gene deletion or mutation. The study will use Bayley-4 expressive communication as the primary endpoint, with patients randomized 2:1 to active therapy or placebo. The Phase 2 HALOS study showed promising results, with 97% of participants in medium and high dose groups showing improvement in overall AS symptoms. The Phase 3 trial is planned to begin in H1 2025.
Ionis Pharmaceuticals ha annunciato la progettazione del suo trial REVEAL di Fase 3 per ION582, a seguito di un allineamento positivo con la FDA. Lo studio, che si concentra sulla sindrome di Angelman (AS), prevede l'arruolamento di circa 200 bambini e adulti con delezione o mutazione del gene materno UBE3A. La ricerca utilizzerà la comunicazione espressiva Bayley-4 come obiettivo principale, con i pazienti randomizzati 2:1 a terapia attiva o placebo. Lo studio di Fase 2 HALOS ha mostrato risultati promettenti, con il 97% dei partecipanti nei gruppi a dosi media e alta che ha mostrato un miglioramento nei sintomi complessivi dell'AS. La fase 3 del trial è prevista per iniziare nel primo semestre del 2025.
Ionis Pharmaceuticals anunció el diseño de su ensayo REVEAL de Fase 3 para ION582, tras una alineación exitosa con la FDA. El ensayo, que se enfoca en el sindrome de Angelman (AS), inscribirá aproximadamente a 200 niños y adultos con deleción o mutación del gen UBE3A materno. El estudio utilizará la comunicación expresiva Bayley-4 como el objetivo principal, con pacientes aleatorizados 2:1 para terapia activa o placebo. El estudio de Fase 2 HALOS mostró resultados prometedores, con el 97% de los participantes en los grupos de dosis media y alta mostrando una mejora en los síntomas generales del AS. El ensayo de Fase 3 está programado para comenzar en el primer semestre de 2025.
아이오니스 제약은 FDA와의 성공적인 협의를 통해 ION582에 대한 3상 REVEAL 임상시험 디자인을 발표했습니다. 안젤만 증후군(AS)을 타겟으로 하는 이 임상시험은 모체 UBE3A 유전자 결실 또는 변이를 가진 약 200명의 아동 및 성인을 등록할 예정입니다. 본 연구는 베일리-4 표현 의사소통을 주요 평가 지표로 사용하며, 환자는 2:1 비율로 활성 치료 또는 위약에 무작위 배정됩니다. 2상 HALOS 연구는 중간 및 고용량 그룹의 97% 참여자가 AS 증상 전반에 개선을 보이는 promising results를 나타냈습니다. 3상 시험은 2025년 상반기 시작 예정입니다.
Ionis Pharmaceuticals a annoncé la conception de son essai phare de Phase 3 REVEAL pour ION582, suite à un alignement réussi avec la FDA. L'essai, ciblant le syndrome d'Angelman (AS), recrutera environ 200 enfants et adultes présentant une délétion ou mutation du gène UBE3A maternel. L'étude utilisera la communication expressive Bayley-4 comme principal critère d'évaluation, les patients étant randomisés dans un rapport de 2:1 pour recevoir une thérapie active ou un placebo. L'étude de Phase 2 HALOS a montré des résultats prometteurs, avec 97% des participants des groupes de dose moyenne et élevée montrant une amélioration des symptômes globaux de l'AS. L'essai de Phase 3 est prévu pour commencer au premier semestre 2025.
Ionis Pharmaceuticals gab das Design ihrer Phase 3 REVEAL-Studie für ION582 bekannt, nachdem ein erfolgreicher Austausch mit der FDA stattgefunden hat. Die Studie, die sich auf Angelman-Syndrom (AS) konzentriert, wird voraussichtlich etwa 200 Kinder und Erwachsene mit maternaler UBE3A-Genmutation oder -deletion einschließen. Die Studie wird Bayley-4 expressive Kommunikation als primären Endpunkt verwenden, wobei die Patienten im Verhältnis 2:1 entweder zu aktiver Therapie oder Placebo randomisiert werden. Die Phase 2 HALOS-Studie zeigte vielversprechende Ergebnisse, da 97% der Teilnehmer in den mittleren und hohen Dosisgruppen eine Verbesserung der AS-Symptome zeigten. Die Phase-3-Studie ist für das erste Halbjahr 2025 geplant.
- 97% of participants in Phase 2 HALOS trial medium and high dose groups showed improvement in AS symptoms
- Successful FDA alignment on Phase 3 trial design
- ION582 demonstrated favorable safety and tolerability at all dose levels in Phase 2
- Strong evidence of clinically meaningful improvement across all functional domains in Phase 2
- Phase 3 trial won't begin until H1 2025, indicating a lengthy timeline to potential approval
- No approved medicines currently exist for Angelman syndrome
Insights
The Phase 3 trial design for ION582 represents a significant milestone in Angelman syndrome treatment development. The 200-patient study features several compelling design elements:
- A 2:1 randomization ratio favoring active treatment
- Quarterly dosing without loading regimen
- Two dose levels based on positive Phase 2 data
- One-year primary analysis timeline
The Phase 2 HALOS results are particularly encouraging, with
This development positions Ionis favorably in the untapped Angelman syndrome market, which currently has no approved treatments. The FDA alignment on trial design significantly de-risks the regulatory pathway. With trial initiation planned for H1 2025, positive Phase 3 results could lead to market entry by 2027-2028. The robust Phase 2 efficacy data, particularly the
- Positive End of Phase 2 discussion with FDA, including alignment on Phase 3 design
- Bayley-4 expressive communication selected as Phase 3 study primary endpoint
- Initiation of ION582 Phase 3 study planned for H1 2025
- Ionis to share ION582 program update at the FAST Global Science Summit in November
"Following positive results for ION582 in the Phase 2 HALOS trial, we are pleased to have alignment with the FDA on the design of our Phase 3 REVEAL trial, which will address clinical endpoints that reflect the most pressing and meaningful outcomes for people living with AS and their caregivers," said Brett Monia, Ph.D., chief executive officer of Ionis. "We will enroll a broad group of individuals living with AS in the global pivotal Phase 3 trial, planned to begin in the first half of 2025. We look forward to working with the community to advance a potential new treatment targeting the underlying cause of disease in this debilitating neurological condition that has no approved medicines."
The planned global, randomized, placebo-controlled Phase 3 study will enroll approximately 200 children and adults with AS that have a maternal UBE3A gene deletion or mutation. The primary analysis will occur after approximately one year of treatment, followed by all patients transitioning into an open-label long-term extension (LTE) phase of the study. Patients will be randomized 2:1 to active therapy or placebo, and ION582 will be evaluated at two dose levels which will be dosed quarterly without a loading regimen. The primary endpoint will be improvement in expressive communication as assessed by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4), an objective and direct clinician-administered assessment of clinical functioning. Deficits in expressive communication are reported to be the symptoms most challenging to caregivers of people with AS. The study will evaluate several secondary endpoints including overall disease severity, cognition, communication, sleep, motor functioning and daily living skills, in addition to other exploratory endpoints.
The End of Phase 2 meeting was supported by data from the Phase 2 open-label HALOS study. In the recently completed multiple ascending dose (MAD) portion of the study, ION582 treatment provided strong evidence of clinically meaningful improvement on all functional domains including communication, cognition and motor function. Overall,
At the FAST Global Science Summit this weekend (November 8-9), Ionis will provide an update to the community on the Phase 3 program and review data from the MAD portion of the HALOS trial.
About ION582
ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) and increase production of UBE3A protein, for the potential treatment of Angelman syndrome (AS). In 2022, the
About Angelman Syndrome (AS)
AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by profound intellectual disability, balance issues, motor impairment and debilitating seizures. Most patients are unable to speak. Individuals with AS have a normal lifespan but require complete care from a caregiver. Some symptoms can be managed with existing medicines; however, there are no approved disease modifying therapies.
About Ionis' Neurology Franchise
Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUA™ (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS. The clinical-stage portfolio includes 11 therapies, of which five are wholly owned by Ionis. Ionis' investigational portfolio includes medicines for which there are few or no disease modifying treatments, such as rare diseases including Prion disease and Alexander disease and more common conditions such as Alzheimer's and Parkinson's disease.
About Ionis Pharmaceuticals, Inc.
For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients.
To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram.
Ionis Forward-looking Statements
This press release includes forward-looking statements regarding Ionis' business, and the therapeutic and commercial potential of Ionis' commercial medicines, ION582 and Ionis' additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions, or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at www.Ionis.com.
In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries.
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ION582 is an investigational medicine that has not been approved for the treatment of any disease by regulatory authorities.
Ionis Pharmaceuticals Investor Contact: D. Wade Walke, Ph D. - IR@ionis.com - 760-603-2331
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FAQ
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