Initial findings from a Phase 3 efficacy trial suggest Ionis Pharmaceuticals’ RNA-targeted treatment, given monthly or bimonthly, cut angioedema attacks more than placebo, the firm said Monday. 

The results set up a potential regulatory filing in the crowded hereditary angioedema (HAE) space for later this year. 

As shown in the topline data, donidalorsen met the primary endpoint in the drugmaker’s OASIS-HAE study, with a statistically significant reduction in the rate of HAE attacks in patients treated every four or eight weeks. 

The drug, injected subcutaneously, also demonstrated a favorable safety and tolerability profile, although detailed data have yet to be released.

It comes on the heels of findings shared last November from an ongoing Phase 2, open-label extension study demonstrating the med’s durability of efficacy and safety beyond the two-year mark. 

Based on the dual readouts, “We believe donidalorsen, if approved, could be an attractive new treatment option for patients with HAE,” stated Kenneth Newman, Ionis SVP and head of its clinical development program. 

Many patients continue to experience serious breakthrough attacks “despite currently available prophylactic treatments,” he added.

Donidalorsen, a ligand-conjugated antisense medicine, is an investigational RNA-targeted drug. When taken preventatively, it’s designed to silence the production of prekallikrein (PKK), interrupting the pathway that leads to HAE attacks.

While statistical significance was achieved on all secondary endpoints in the trial’s monthly arm, that wasn’t the case among the cohort dosed every eight weeks. There, statistical significance was met only on key secondary endpoints. 

The data leave “open questions” as far as the profile of a bimonthly regimen, cautioned Leerink Partners’ Mani Foroohar in an investor note Monday. The analyst estimated a rather modest $17.7 million in 2025 U.S. sales.

Nevertheless, preparations for an NDA filing have begun. 

Monday’s Phase 3 attack reduction rates, along with the Phase 2 extension data and soon-to-be-released Phase 3 OASIS-Plus OLE data — expected mid-year — “will clarify whether the commercial profile of donidalorsen supports broad switching, or will largely be driven by newly diagnosed patients,” Foroohar wrote.

The prophylactic HAE market is a crowded one, including BioCryst’s Orladeyo, Takeda’s Takhzyro and Cinryze, and CSL Behring’s Haegarda

Elsewhere in the HAE pipeline, as previously reported, the effects of Intellia Therapeutics’ CRISPR-based, one-time HAE treatment NTLA-2002 looked durable through Phase 1. The company said it’s planning to present results from a Phase 2 study of NTLA-2002 this year, and to initiate a Phase 3 study, as well.

Ionis is hoping to carve out a niche with its long-term dosing. In a subset analysis of the OLE trial, 62.5% of patients receiving donidalorsen every eight weeks remained attack-free over the two-year period and had a sustained mean reduction in HAE attack rates of 83% from baseline.

The company plans to present the Phase 3 OASIS-HAE results at an upcoming medical congress by mid-year. The results from OASIS-Plus will include data from both the open-label extension of the Phase 3 trial and a separate cohort of patients who have transitioned to donidalorsen from another prophylactic HAE medication — i.e., a “switch cohort.”

Last month, Ionis licensed donidalorsen’s European commercial rights to Otsuka. Terms call for Otsuka to handle European regulatory filings and commercialization, in exchange for $65 million in upfront payment, regulatory and sales milestones of an disclosed amount, and tiered royalties ranging from 20% to 30% of net sales. 

The firm is also launching the newly approved Wainua (eplontersen) in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN), along with partner AstraZeneca. 

For an April 2024 article about Ionis becoming set to launch an FCS agent, click here.