Ionis Pharmaceuticals has committed to advancing its antisense therapy ION582 into Phase 3 clinical trials for Angelman syndrome, a rare genetic disorder with no approved treatments. This decision comes shortly after Biogen opted not to exercise its licensing option for the drug in May.
The company plans to initiate the pivotal Phase 3 program in the first half of 2025, following discussions with the FDA and other regulatory authorities about trial design. This announcement precedes the presentation of detailed data from the Phase 1/2 HALOS study at the 2024 Angelman Syndrome Foundation (ASF) family conference.
Promising Phase 1/2 Results
The HALOS study evaluated three doses of ION582 in 51 participants with Angelman syndrome. According to Ionis, the trial demonstrated "robust and consistent benefit" on communication, cognition, and motor function. Notably, 97% of participants receiving medium and high doses showed improvement in overall symptoms as measured by the Symptoms of Angelman Syndrome–Clinician Global Impression-Change (SAS-CGI-C) scale.
"The data from the HALOS study represents a significant step forward in addressing the underlying cause of Angelman syndrome," said Brett Monia, Chief Executive Officer at Ionis. Monia emphasized that ION582 will be "the cornerstone of Ionis' next wave of transformational, wholly-owned medicines for neurological conditions."
Patients who completed the initial phase of the HALOS study have transitioned to a long-term extension that will evaluate the two higher doses of ION582 for an additional 12 months, providing crucial data on sustained efficacy and safety.
Understanding Angelman Syndrome
Angelman syndrome affects approximately one in 21,000 births worldwide, with an estimated 500,000 to 1 million patients globally. The disorder is caused by several genetic mutations, with the most significant being loss of function in the maternally inherited UBE3A gene, leading to complications in the nervous system and severe issues with movement, balance, and learning.
Children with Angelman syndrome typically begin showing signs of delayed development between six and twelve months of age. The condition results in intellectual disability, seizures, and speech impairment, with no currently approved disease-modifying treatments.
In normal development, a child receives two copies of the UBE3A gene—one from each parent—but only the maternal copy is active in neurons. ION582 is designed to "unsilence" the normally inactive paternal UBE3A gene, potentially increasing production of the UBE3A protein in the brain.
Competitive Landscape in Angelman Syndrome Treatment
The race to develop effective treatments for Angelman syndrome has intensified in recent years. Ultragenyx Pharmaceutical is currently leading the field with its antisense oligonucleotide GTX-102, which has already entered Phase 3 trials in the ASPIRE study. In its Phase 1/2 trial, 22 of 28 patients achieved clinically meaningful improvement in at least one domain of the Multi-domain Responder Index.
Neuren Pharmaceuticals is pursuing a different approach with NNZ-2591, a twice-daily oral solution consisting of a synthetic peptide that modulates acetylcholine neurotransmission. The company reported positive Phase 2 results in August 2024, showing statistically significant and clinically meaningful improvements from baseline.
Other companies exploring treatments for Angelman syndrome include Roche/Genentech with an early-stage antisense candidate, and several organizations investigating gene therapies, including PTC Therapeutics, Bayer/AskBio, Bamboo/Pfizer, and Stride Bio/Sarepta.
Clinical Trial Considerations
Both Ionis and Ultragenyx are administering their therapies via intrathecal injection, with ongoing evaluation of optimal dosing frequencies ranging from monthly to once every three months. In contrast, Neuren's oral administration represents a less invasive approach.
The Phase 3 trials for both ION582 and GTX-102 will use improvement in the Bayley Scales for Infant and Toddler Development-4 as a primary endpoint, allowing for relatively direct comparisons between the two intrathecal products when final clinical trial results are released.
Looking Forward
With multiple promising candidates advancing through clinical development, the outlook for Angelman syndrome patients appears increasingly positive. The next 2-3 years will be critical as these therapies complete late-stage trials and potentially reach regulatory review.
For Ionis, the advancement of ION582 represents a strategic pivot following Biogen's decision to opt out of the program. The company now has the opportunity to retain full ownership of what could become a groundbreaking therapy for a condition with significant unmet medical need.
As Brett Monia noted, ION582 joins Ionis' growing portfolio of neurological treatments, which currently includes five clinical-stage programs. The company's commitment to advancing the drug independently underscores its confidence in the therapy's potential to transform the treatment landscape for Angelman syndrome.
