Race Heats Up for Angelman Syndrome Treatments as Ionis, Ultragenyx, and Neuren Advance Clinical Trials

In a significant development for patients with Angelman syndrome, a rare genetic disorder affecting the nervous system, three pharmaceutical companies are making substantial progress in their efforts to bring novel treatments to market. Ionis Pharmaceuticals, Ultragenyx Pharmaceutical, and Neuren Pharmaceuticals are each advancing unique approaches to address this condition, which currently lacks approved disease-modifying therapies.

Oligonucleotide Treatments Lead the Pack

Ionis and Ultragenyx are at the forefront of this race, both developing antisense oligonucleotide treatments that target the root cause of Angelman syndrome: a genetic mutation in the UBE3A gene on chromosome 15.

Ionis' candidate, ION582, is an intrathecal injection designed to increase expression of the UBE3A protein in neurons. The company recently announced positive Phase II results from its HALOS trial, with 97% of participants receiving medium or high doses showing improvement on the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. Ionis plans to initiate Phase III trials for ION582 in the first half of 2025.

Ultragenyx's GTX-102, also administered intrathecally, takes a slightly different approach by inhibiting UBE3A expression using a human-mouse hybrid protein to reactivate the deficient protein. In its Phase I/II trial, Ultragenyx reported that 22 out of 28 patients achieved clinically meaningful improvement in at least one domain of the Multi-domain Responder Index. The company has already begun its Phase III ASPIRE trial, with the first patient dosed in December 2024.

Neuren's Novel Peptide Approach

While Ionis and Ultragenyx focus on oligonucleotide treatments, Neuren Pharmaceuticals is pursuing a different strategy with NNZ-2591, a synthetic peptide that modulates acetylcholine neurotransmission. This approach targets the excessive acetylcholine levels found to cause neural hyperexcitability and seizures in Angelman syndrome patients.

Neuren's Phase II open-label trial results, released in August 2024, showed statistically significant and clinically meaningful improvements from baseline. Notably, NNZ-2591 is administered orally twice daily, potentially offering a less invasive treatment option compared to the intrathecal injections required for the oligonucleotide therapies.

Comparing Approaches and Future Outlook

As these companies progress through late-stage clinical trials, several factors may influence the ultimate success of their respective treatments. While Ionis and Ultragenyx are currently leading in terms of development stage, Neuren's oral administration route could provide a significant advantage in patient convenience and compliance.

The race to market approval remains close, with all three investigational products demonstrating promising safety and efficacy profiles thus far. The pharmaceutical industry and the Angelman syndrome community will be closely watching the outcomes of these trials over the next 2-3 years, as they have the potential to dramatically improve the lives of the estimated 500,000 to 1 million patients worldwide affected by this rare disorder.