Ionis and Ultragenyx are competing to develop oligonucleotide treatments for Angelman syndrome, but will Neuren’s peptide catch up?
Several companies are working on new investigational treatments for Angelman syndrome, a rare genetic disorder that affects the nervous system and causes developmental delays, intellectual disability, seizures and speech impairment. Ionis and Ultragenyx are competing to bring investigational antisense oligonucleotide treatments to the market, while Neuren is betting on a synthetic peptide that can be delivered orally. It’s a tight race in a disease space with a high unmet need.
Affecting 500,000 to 1 million patients worldwide, Angelman syndrome has no approved disease-modifying treatments. Although antiseizure medication is available, these drugs do not address the root cause, a genetic mutation in the UBE3A gene on chromosome 15. In Angelman syndrome, only the copy of the UBE3A gene inherited from the mother is functional, while the father’s allele is mutated.
Both Ionis and Ultragenyx are currently in Phase III trials with their oligonucleotides, called ION582 and GTX-102, respectively. Meanwhile, Neuren is conducting a mid-stage trial on NNZ-2591, a twice-daily oral solution consisting of a synthetic peptide that modulates acetylcholine neurotransmission.
Ionis’ ION582 is an investigational intrathecal injection that targets a long noncoding RNA to increase expression of the UBE3A protein in neurons. In November 2024, Ionis announced positive Phase II results from its Phase I/IIa HALOS trial. According to Ionis, 97% of participants given the medium or high dose saw an improvement on the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. The HALOS trial had three parts. The first consisted of five multiple ascending dose cohorts, while the second and third part each used two groups to assess the long-term effects of ION582. Ionis has said it plans to start Phase III trials for ION582 in the first half of 2025.
Ultragenyx’s GTX-102 is an intrathecally administered antisense oligonucleotide that inhibits expression of UBE3A by using a human-mouse hybrid protein to reactivate expression of the deficient protein. In November 2024, Ultragenyx announced positive data from its Phase I/II trial of the investigational drug. According to Ultragenyx, 22 of 28 patients achieved clinically meaningful improvement in at least one domain within the Multi-domain Responder Index, a tool for assessing clinical benefit in rare diseases such as Angelman. As of December 2024, Ultragenyx had dosed the first patient in its Phase III ASPIRE trial for Angelman syndrome.
For its part, Neuren is focusing on a different mechanism. Excessive acetylcholine has been found to lead to neural hyperexcitability and seizures in Angelman syndrome patients. In August 2024, the company released positive Phase II results from an open-label trial of NNZ-2591. According to Neuren, participants showed statistically significant and clinically meaningful improvement from baseline. (In addition to Angelman syndrome, NNZ-2591 is undergoing clinical trials for other diseases, including Phelan-McDermid Syndrome, Pitt Hopkins Syndrome and Prader-Willi Syndrome.)
Overall, while Ionis and Ultragenyx are currently ahead in the Angelman syndrome race for approval, Neuren’s NNZ-2591 has potential in multiple indications that could allow for flexibility in the market. All three investigational products so far appear to be safe and efficacious, and the ultimate deciding factor in their success may boil down to whichever reaches the market first. But there are other factors to consider.
Ionis and Ultragenyx are still determining optimal dosing strategies, testing injection frequencies ranging from approximately once per month to once every three months, while Neuren’s oral administration route is the least invasive of the three products.
The race may seem to be too close to call, but given that both Ionis and Ultragenyx are relying on improvement in the Bayley Scales for Infant and Toddler Development-4 as a primary endpoint for their Phase III trials, relatively direct comparisons can be made between the two intrathecal products when the final clinical trial results are released.
Keep an eye on the Angelman syndrome race as more data come out in the next 2–3 years.
