Donidalorsen may reduce hereditary angioedema attack rates

Key takeaways:

• Donidalorsen was effective in improving disease control and quality of life measures in patients with hereditary angioedema.
• Over 2-month dosing, the drug showed a continued attack rate reduction.

Donidalorsen trials showed positive results in treating patients with hereditary angioedema, exhibiting significant reductions in attack rates, according to a study published in The New England Journal of Medicine.

The study findings support the potential prophylactic use of the drug for HAE, with patients reporting significant and clinically meaningful improvements in their quality of life and disease control, Marc A. Riedl, MD, clinical director, U.S. HAEA Angioedema Center, University of California at San Diego, and colleagues wrote.

“People living with HAE can experience significant anxiety around the anticipation of their next attack, making it difficult to carry out daily tasks like going to work or school — or even simply leaving the house,” a spokesperson from Ionis Pharmaceuticals, which manufactures donidalorsen, told Healio. “Despite currently available prophylactic treatments, many patients continue to experience painful and potentially fatal breakthrough attacks, and new treatment options are needed.”

The study consisted of a clinical development program that included the OASIS-HAE and OASISplus trials. Both trials intended to evaluate the safety and efficacy of donidalorsen, an antisense oligonucleotide that lessens prekallikrein expression, as a prophylactic medicine for HAE.

Methods

The multinational, double-blind, randomized and placebo-controlled phase 3 trial aimed to evaluate the safety and efficacy of donidalorsen in an 80 mg subcutaneous dose in patients with HAE with an end point of establishing a time-normalized number of investigator-confirmed HAE attacks per 4 weeks from the study time of week 1 to week 25.

Patients were aged 12 years or older and had a confirmed diagnosis of HAE type I or II as well as at least two investigator-confirmed HAE attacks between a run-in period of 56 days to 1 day before trial randomization.

Patients were randomly assigned 2:1 to a 4-week dosing interval or 8-week dosing interval, followed by a second randomization in a 3:1 ratio to receive 80 mg donidalorsen or placebo.

Patients completed trial-site visits at weeks 1, 5, 9, 13, 17, 21 and 25 during the treatment period and then after the treatment period at weeks 4, 8 and 13.

Researchers also evaluated patients in Angioedema Quality-of-Life (AE-QoL) and Angioedema Control Test (AECT) scores from baseline to week 25 and at week 25, respectively.

Safety was assessed by incidence and severity of adverse events related to the trial regimen and the number of ED visits. Changes in the Patient Global Impression of Change (PGI-C) scale were tracked as well.

Results

Among 116 screened patients, 90 patients were randomly assigned to one of the two donidalorsen doses or placebo. The mean age of the patients was 37 years, with seven patients aged younger than 18 years (mean age, 14 years).

Eighty-four patients (93%) had HAE type I and six patients (7%) had HAE type II. Forty-five patients received donidalorsen in the 4-week group and 23 received it in the 8-week group, whereas 22 received placebo.

One patient in each study drug group and three in the placebo group withdrew due to a lack of efficacy. One patient in the placebo group withdrew due to pregnancy, and another from the 8-week group withdrew due to an adverse event.

The mean HAE attack rates per 4 weeks during the run-in period included 3.61 in the 4-week group, 3.18 in the 8-week group and 2.9 in the placebo group.

From weeks 1 to 25, the 4-week group had a least-squares mean time-normalized attack rate of 0.44 (95% CI, 0.27 to 0.73), the 8-week group had a 1.02 rate (95% CI, 0.65 to 1.59) and the placebo group had a 2.26 rate (95% CI, 1.66 to 3.09). This equated to mean attack rates being 81% lower (95% CI, 65%-89%; P < .001) in the 4-week group and 55% lower (95% CI, 22%-74%; P = .004) in the 8-week group vs. placebo.

There also was a 90% median reduction from baseline in the attack rate for the 4-week group, an 83% reduction in the 8-week group and a 16% reduction in the placebo group.

From weeks 5 to 25, least-squares mean time-normalized attack rates included 0.3 (95% CI, 0.15 to 0.58) in the 4-week group vs. 2.25 (95% CI, 1.59 to 3.18) in the placebo group, which was an 87% (95% CI, 72%-95%; P < .001) lower rate with donidalorsen.

Also within the 4-week group, 37 patients (82%) had a 70% or more reduction in attacks vs. four patients (18%) in the placebo group (P < .001), with 53% of patients in the 4-week group being attack-free vs. 9% in the placebo group (P = .003).

The 4-week group vs. placebo also saw an 89% (95% CI, 66%-97%; P < .001) lower rate of moderate to severe attacks per 4 weeks and a 92% lower (95% CI, 77%-97%; P < .001) use of on-demand therapy.

From baseline to 25 weeks, the 4-week group saw a significant reduction of at least 6 points and improvement of 24.8 points in the least-squares mean AE-QoL total score (least-squares mean difference vs. placebo, 18.6 points; 95% CI, 9.5-27.7; P <0.001).

The 8-week group also showed a significant reduction in HAE attack rates from weeks 5 to 25. The donidalorsen group had a least-squares mean decrease of 0.9 (95% CI, 0.53-1.52), which showed a 60% (95% CI, 25%-79%; P = .004) lower rate vs. placebo. Among the treatment group, 15 patients (65%) had a 70% reduction in attacks from baseline vs. four (18%) in the placebo group (P = .004).

“We see that with longer-term treatment, patients got even better on all measures: upwards of 90% reduction in attack rates, high levels of disease control and improvements in quality of life,” the Ionis spokesperson told Healio.

AECT scores showed that 41 (91%) patients in the 4-week group reported well-controlled disease corresponding with a score of at least 10 at week 25 vs. nine (41%) in the control group (OR = 14.8; 95% CI, 3.9-56.1). The 8-week group had a least-squares mean AE-QoL total score decrease of 19.9 points from baseline to 25 weeks (least-squares mean difference, 13.7; 95% CI, 3.3-24).

The 4-week group had 93% (95% CI, 63%-99%) fewer ED visits from weeks 1 to 25 for any cause vs. the placebo group (least-squares mean rate, 0.02 vs. 0.26) and 95% (95% CI, 48%-100%) fewer HAE-attributable emergency visits.

Within the 8-week group, 92% (95% CI, 33%-99%) patients had fewer ED visits from any cause vs. patients in the placebo group (least-squares mean rate, 0.02 vs. 0.26) and 93% (95% CI, 11% to 100%) fewer HAE-attributable emergency visits.

PGI-C responses showed that 39 (95%) of patients in the 4-week group and 20 (91%) of patients in the 8-week group reported improvements at week 25 compared with 10 (56%) of patients in the placebo group (4-week vs. placebo, OR = 15.6; 95% CI, 2.9-85.2; 8-week vs. placebo, OR = 8; 95% CI, 1.4-44.9).

Adverse events were reported by 65 (72%) patients, including 33 (73%) in the 4-week group, 14 (61%) in the 8-week group and 18 (82%) in the placebo group. The most common adverse events were erythema at the injection site, headache and nasopharyngitis, with 98% of events ranking mild or moderate in severity.

Conclusions

“The totality of our phase 3 data demonstrates donidalorsen treatment significantly reduced HAE attacks, translating to high levels of disease control and significant and clinically meaningful improvements in quality of life across multiple measures in a vast majority of patients,” the Ionis spokesperson said.

The spokesperson further told Healio that results from this study support the company’s belief that donidalorsen can satisfy all of the attributes that people with HAE are looking for in prophylactic treatment, such as durable efficacy, unique switch data, tolerability and safety with the convenience of monthly or every 2 months self-administration via an autoinjector.

“HAE is a lifelong disease, so the durable efficacy we’ve seen across these studies is paramount in maintaining long-term disease control,” the spokesperson said.

While there has been significant activity in developing new treatments for HAE, there is still an urgent need for a medicine that can effectively reduce HAE attacks, according to Ionis.

“Our first-of-its-kind prospective study included a specific protocol that patients followed when switching from their prior prophylactic HAE medication to donidalorsen,” the spokesperson said. “We believe that, if approved, donidalorsen could advance the treatment paradigm for people living with HAE.”