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An antisense oligonucleotide therapy showed efficacy as a prophylactic treatment for hereditary angioedema (HAE), the phase III OASIS-HAE trial showed.

The least-squares mean time-normalized HAE attack rate was 0.44 with donidalorsen given every 4 weeks and 1.02 with donidalorsen given every 8 weeks, both significantly lower than the 2.26 attack rate with placebo, reported Danny Cohn, MD, PhD, of Amsterdam University Medical Center in the Netherlands, and colleagues.

The mean attack rate from week 1 to week 25 was 81% lower in the 4-week donidalorsen group versus the placebo group (P<0.001) and 55% lower in the 8-week group versus the placebo group (P=0.004), they wrote in the .

The median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group.

"Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema," Cohn and team noted.

Clinicians may anticipate a changing landscape for HAE given the continued development of donidalorsen in step with sebetralstat, the latter poised to be the first on-demand treatment for HAE not requiring IV or subcutaneous administration. In the phase III KONFIDENT trial, that oral kallikrein inhibitor sped up symptom relief times during tissue swelling attacks of HAE.

"The designs and results of the two trials offer reassurance that both sebetralstat and donidalorsen can safely and effectively be administered as a patient-led treatment, reducing the burden on medical services for acute conditions," wrote Rohan Ameratunga, MBChB, PhD, and Hilary Longhurst, MBChB, PhD, both of Auckland Hospital and the University of Auckland in New Zealand, in an .

"The goals of management of hereditary angioedema have shifted from the preservation of life and the relief from unbearable pain to the complete control of the disease and the normalization of patients' lives. With a new highly effective prophylactic option with an acceptable side-effect profile and an orally administered on-demand option for breakthrough attacks, treatments for hereditary angioedema are closer to meeting these new goals," the duo wrote.

HAE is a rare disorder that is characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. HAE stems from either a deficiency (type 1 HAE) or dysfunction (type II HAE) of the C1 inhibitor protein. Both lead to excess bradykinin and bradykinin-induced vasodilation.

Donidalorsen is being developed as a prophylactic therapy, administered subcutaneously, with the promise of less frequent dosing and better prevention of breakthrough HAE attacks compared with existing options. Donidalorsen selectively blocks liver cells from expressing prekallikrein and therefore dampening downstream bradykinin activity that would cause swelling.

In , mean circulating prekallikrein concentrations at baseline were 128 μg/mL in the 4-week donidalorsen group and 144 μg/mL in the 8-week group, which then decreased by 46% and 52%, respectively, by week 5. The placebo group had a mean circulating prekallikrein concentration of 118 μg/mL and saw no reduction during the study.

During weeks 5 to 25, the mean HAE attack rate was 87% lower in the 4-week group than in the placebo group (P<0.001) and 60% lower in the 8-week group than in the placebo group.

Cohn's group reported that the most common adverse events in OASIS-HAE were erythema at the injection site, headache, and nasopharyngitis. Nearly all adverse events were mild or moderate in severity.

However, nearly one in 10 donidalorsen recipients reported urinary tract infections (vs none with placebo). Additionally, 9% of patients in the 8-week donidalorsen group had transient increases in alanine aminotransferase levels. There were generally fewer adverse events in the 8-week group compared with the 4-week group.

"This raises the possibility that patients could start receiving donidalorsen every 4 weeks to achieve an initial, rapid clinical response and then switch to every 8 weeks for maintenance, with the option of returning to every 4 weeks if they have an attack," Cohn and colleagues suggested.

Ameratunga and Longhurst cautioned that neither sebetralstat nor donidalorsen were directly compared with existing treatments in their respective studies. Even so, "the pharmacokinetics data and early clinical findings from the OASIS-HAE and KONFIDENT trials suggest that the efficacy of each agent will be at least similar to that of agents in current use."

The double-blind OASIS-HAE trial included patients ages 12 and older who had confirmed HAE type I or II and demonstrated at least two investigator-confirmed HAE attacks during the run-in period prior to randomization.

Out of 116 people screened, 91 made it to randomization to donidalorsen 80 mg or placebo once every 4 or 8 weeks. The mean age of this cohort was 37 years, including seven adolescents averaging 14 years of age. The vast majority had HAE type 1 (93%), and about half had a history of laryngeal attacks. An estimated 18% had received prophylactic therapy for HAE previously. Danazol was used concomitantly by a few patients.

"Patient-reported outcomes from this trial showed a significant and clinically meaningful improvement in quality of life," Cohn and colleagues wrote, noting that donidalorsen administered every 4 weeks and 8 weeks both resulted in more than 10-point improvements over placebo in the total score for the change at week 25 on the 100-point Angioedema Quality-of-Life Questionnaire.

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