Ionis Launches Phase 3 Trial of Donidalorsen for Preventing Attacks

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Ionis Pharmaceuticals has launched a registrational Phase 3 clinical trial to evaluate the safety and effectiveness of its investigational therapy donidalorsen, formerly known as IONIS-PKK-LRx, in people with hereditary angioedema (HAE) types 1 and 2.

While the trial, called OASIS-HAE, may already be recruiting, information on recruitment status and locations is not yet available. Should the trial’s findings be positive, Ionis plans to use them to support applications seeking the therapy’s approval.

“Initiating the Phase 3 program for donidalorsen moves us one step closer to bringing a potential best-in-class prophylactic [preventive] treatment to market for people with HAE globally experiencing recurrent painful and severe HAE attacks,” Kenneth Newman, MD, Ionis’ vice president of clinical development and leader of the immunology and pulmonology franchise, said in a press release.

“Advancing this program underscores our commitment to the HAE patient community to deliver transformative treatments,” he added.

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Donidalorsen, designed with Ionis’ Ligand-Conjugated Antisense, or LICA, technology, works by binding to and inactivating the intermediate molecule derived from DNA that guides the production of the prekallikrein (PKK) protein.

PKK is the inactive form of plasma kallikrein, an enzyme that generates an inflammatory molecule called bradykinin, which is overly produced in HAE patients. Excess bradykinin levels cause blood vessels to widen and become leaky, leading to sudden swelling and pain attacks.

By preventing such high bradykinin levels, donidalorsen is thought to reduce HAE attacks.

Administered through under-the-skin injections once-a-month, the therapy is likely to have benefits similar to plasma kallikrein-suppressors approved for HAE, such as Takeda’s Takhzyro (lanadelumab), given via under-the-skin injections twice-monthly, and BioCryst Pharmaceuticals’ Orladeyo (berotralstat), taken orally once a day.

Donidalorsen’ safety and effectiveness were evaluated in 20 adults with HAE type 1 or 2 in a Phase 2 trial (NCT04030598). Participants were randomly assigned to receive either 80 mg of donidalorsen (14 patients) or a placebo (six patients) for 17 weeks (four doses in about four months).

Top-line data showed the trial met its main and key secondary goals, with donidalorsen reducing the number of monthly HAE attacks by 90% over the course of four months and by 97% after the second dose, compared with a placebo.

The therapy, starting at the second dose, led to a 96% drop in the number of moderate or severe attacks, and allowed all but one patient (92.3%) to remain attack-free, compared with no patients on placebo, according to detailed data presented early this month at the American College of Asthma, Allergy & Immunology Annual Scientific Meeting.

After the second dose of donidalorsen, the number of attacks requiring acute treatment was significantly reduced, and for the final month of the study, all donidalorsen-treated patients were attack-free.

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The therapy was generally safe and well-tolerated, with no serious adverse events reported. Most adverse events were mild and had a similar frequency between the two groups. The most commonly reported adverse events during the study were headache and nausea, which were seen less frequently among donidalorsen-treated patients than among those given a placebo.

After completing the trial, all patients chose to enroll in an open-label extension study (NCT04307381), in which they are receiving the experimental therapy for one year.

The upcoming Phase 3 OASIS-HAE trial will test the therapy in up to 84 people with HAE types 1 and 2. Patients will be randomly assigned to receive  donidalorsen or a placebo, once or twice a month for about six months. Following the placebo-controlled portion of the trial, participants will be given the choice to enter a one-year open-label extension study.