Ionis on Monday revealed new six-month data from its Angelman syndrome program, presenting Phase 1/2a results from a pooled group of patients taking three different doses of ION582 and saying it’s preparing for a Phase 3 study.
Researchers’ main goal for the open-label trial was to measure 51 patients’ progress on a range of cognitive and functional endpoints after three months, and then follow up at six months. On a scale known as the Bayley-4, which is considered the gold standard for measuring Angelman syndrome progress, 67% of patients in the pooled medium- and high-dose groups saw their cognition scores improve, Ionis said.
CEO Brett Monia told Endpoints News the company chose to pool the results of the two higher doses because each cohort’s demographics ended up being very different age-wise. The medium dose group only had children, whereas all adults in the trial received the high dose. (Angelman syndrome patients have near-normal life expectancy, but are typically diagnosed before they turn 1 year old.)
“Different aspects of the disease affect different age groups, and the ability to show improvement in different age groups is going to be different,” Monia said. “So it’s comparing apples to oranges.”
Monia added that Ionis opted to “homogenize” the results to increase the data sample and to not give the impression that there was no dose-response between the different dose cohorts.
“The natural thing will be to make comparisons,” Monia said. “It’s not really going to tell you whether you have a dose-response because you’re looking at different patient populations.”
The company did not report how many patients in each cohort improved or unveil the exact figures of improvement in each of the scales they measured. In addition to cognition, Ionis also reported improvements in other aspects of Bayley-4, including communication and motor skills.
Though the study was not powered against a placebo, Ionis did note that the improvements were numerically higher than natural history studies.
Stepping back
Angelman syndrome is a rare neurodevelopmental disease that affects about one out of every 12,000 to 20,000 people in the US. It’s caused when the patients’ maternal allele of the UBE3A gene is deleted or mutated, causing the paternal allele to be silenced. ION582 is an antisense oligonucleotide designed to unsilence the paternal allele and restore UBE3A protein levels.
A handful of companies have sought to develop a drug for Angelman syndrome in recent years. Ultragenyx announced last week that the FDA has agreed on its Phase 3 trial design, which will track improvement in cognition using the Bayley-4 measurement, after reporting mid-stage data in April.
Roche, meanwhile, halted development in June 2023 on its own drug and came close to out-licensing the program to a partner. A spokesperson told Endpoints there were no updates on a new partner as of last week. Regenxbio also discontinued its Angelman drug last November.
Ionis had been partnered with Biogen on ION582, but Biogen did not exercise its option to move forward when Ionis reported a brief sampling of topline data in May. At the time, some analysts viewed Biogen’s decision as a surprise. Monia said Ionis is confident it can run a Phase 3 Angelman study on its own.
On Monday, the company also committed to launching a Phase 3 study next year. Monia said Ionis will push for it to happen “as early as possible in 2025,” pending discussions with the FDA. He wouldn’t say what Ionis is considering for a primary endpoint, however.
“It’s probably not wise to comment on a Phase 3 trial design until we actually get agreement with the FDA,” Monia said. “With that said, we’re thinking of up to a couple hundred patients, treatment for maybe — about a year or so in the study.”
— Kyle LaHucik contributed reporting.