Ionis outlined full Phase 3 results for its rare disease drug donidalorsen on Friday, prepping for a potential FDA submission by the end of the year.
The study is Ionis’ third Phase 3 win in the last two years, following positive readouts for the ATTR drug Wainua (eplontersen) and the familial chylomicronemia syndrome program olezarsen. Most famous for developing the spinal muscular atrophy drug Spinraza with Biogen, Ionis has since worked toward independent drug launches, with olezarsen expected to be the first.
Now, the company could launch two drugs by itself in the span of 12 months. CEO Brett Monia told Endpoints News that Ionis’ pace building up to wholly-owned products has been intentional. It’s also representative of how far the antisense technology on which Ionis is built has come, he said.
“This is not your father’s or grandfather’s antisense,” Monia said. “This is a highly advanced medicinal chemistry that’s utilizing all the pioneering work we’ve done over the decades to take advantage of the very, very best, newest-generation chemistries available.”
The donidalorsen data come from a randomized Phase 3 study that Ionis toplined in January, as well as an open-label extension and what Ionis is calling a “switch cohort,” examining how patients fare when moving from an approved therapy onto its experimental drug. About 70% of patients with the rare disease hereditary angioedema, or HAE, are currently on treatment, Monia said.
The randomized trial looked at two dosing schedules of donidalorsen, once every four weeks and once every eight weeks, compared to placebo. Ionis enrolled 91 patients and randomized them at a 2:1:1 ratio to the study arms.
After 24 weeks, the every-four-week cohort saw an 81% reduction in monthly HAE attacks compared to placebo, good enough to hit the primary endpoint for a p-value of p<0.001. The every-eight-week arm also achieved the primary, inducing a 55% reduction in monthly attacks, for a p-value of p=0.004.
Ionis will file for approval for both dosing schedules. Monia noted that one of the currently approved treatments, Takeda’s Takhzyro, also has two approved schedules — once every two weeks and once every four weeks — allowing patients the flexibility to shift between them depending on their frequency of HAE attacks.
“What we’re doing in this case is now extending that duration from every four- to every eight-week option,” Monia said.
Most side effects were mild or moderate, Ionis said, with injection site reactions being the most common. One patient in the eight-week arm discontinued due to noncompliance and a side effect that was deemed unrelated to the drug.
The open-label extension study followed 69 eligible patients for up to one year at both schedules, showing 93% and 92% improvement from baseline, respectively, compared to the start of the randomized study.
And in the “switch cohort,” Ionis enrolled another 64 patients who had been taking one of three kinds of approved prophylactic HAE drugs (Takhzyro, Orladeyo or a C1 esterase inhibitor) for at least 12 weeks, switched them over to donidalorsen and followed up after 17 weeks. After that period, patients saw an average 62% improvement in monthly HAE attacks over baseline.
One patient in the switch cohort also discontinued due to a side effect deemed unrelated to the drug. Monia said the FDA filing for donidalorsen will come in the second half of this year, and Otsuka, which has EU rights, will also file by the end of 2024.