In late 2020, the US Food and Drug Administration (FDA) approved plasma kallikrein inhibitor berotralstat, making it the first oral, once-a-day treatment available for the prevention of hereditary angioedema (HAE) attacks in patients aged 12 years and older.
Now, new results from an ongoing phase 3 trial, published in the Journal of Allergy and Clinical Immunology, show berotralstat at 110 mg and 150 mg per day significantly reduced the rate of attacks among patients with HAE compared with placebo, with the most favorable benefit-to-risk profile seen in the 150 mg dose group.
Berotralstat is easier to use than other standard-of-care infusion and injectable treatment options, such as lanadelumab, as it doesn’t require preparation or refrigeration. In addition to its easier storage, berotralstat is taken orally, thereby simplifying the administration of the therapy for those who need it.
“We now have a new option and first once-a-day pill that is safe, effective, and…accepted by patients for the prevention of HAE attacks,” said study author Aleena Banerji, MD, an associate professor at Harvard Medical School and the clinical director of the Allergy and Clinical Immunology Unit at Massachusetts General Hospital, in an interview with Medscape Medical News .
In the most recent double-blind, parallel-group study, Banerji and colleagues compared two doses of berotralstat with placebo over 24 weeks to identify the efficacy of the agent in reducing HAE attacks. The study cohort included patients with HAE caused by C1 inhibitor deficiency who were aged 12 years or older.
Only patients who had two or more confirmed HAE attacks in the first 56 days of the study’s prospective run-in period were included in the efficacy analysis. Overall, the mean attack rate during this period was three attacks per month.
Participants were randomly assigned to either placebo (n = 40) or once-daily berotralstat at doses of 110 mg (n = 41) or 150 mg (n = 40).
Over the 24-week follow-up period, the HAE attack rate was significantly reduced in the berotralstat dose groups of 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) compared with the placebo group (2.35 attacks per month).
Compared with the placebo group, patients treated with the 150 mg dose of berotralstat had sixfold higher odds of achieving a 70% reduction in HAE attacks relative to baseline (50% vs 15%; odds ratio, 5.63).
Abdominal pain, back pain, diarrhea, and vomiting were the most frequent treatment-emergent adverse events associated with berotralstat. The researchers observed no serious adverse events related to the drug.
This represents the first randomized, placebo-controlled trial to prove berotralstat is effective at reducing HAE attacks, at least over 24 weeks, said Ted Kelbel, MD, section chief of allergy and immunology at Spectrum Health Medical Group. Kelbel was not involved in the study.
“As it is a different delivery option than current therapies, it creates a new option for patients to consider,” he said. “The oral formulation might be especially helpful for patients who are afraid of needles, enabling greater treatment utilization in this patient community.”
Limitations and Further Questions
While the findings show promise for berotralstat in the prevention of HAE, Banerji emphasized the once-daily drug is primarily used for long-term prophylaxis of HAE. But berotralstat shouldn’t be considered an acute therapy. “In the future, it would be ideal to understand which patients with HAE would benefit most of a treatment like this,” Banerji explained.
Additionally, the short 24-week treatment period represents a potential limitation of the study, considering HAE is a lifelong condition.
Kelbel noted that further longitudinal efficacy assessments are likely needed to determine whether the attack rate reduction continues to decrease over time or if it plateaus at a certain point. He added that he also hopes to see future research asses an oral berotralstat solution in the pediatric population.
Study co-author Jonathan Bernstein, MD, of the University of Cincinnati College of Medicine, said in an email that clinicians also need to gain further experience on how to transition from one agent to another for the prevention of HAE attacks. “However, if they can reformulate berotralstat so it not only prevents HAE attacks but is also capable to treat an acute attack, this would be ideal,” he said.
The study was funded by BioCryst Pharmaceuticals. Banerji disclosed research funding, advisory/consulting fees, or other support from BioCryst Pharmaceuticals, CSL Behring, KalVista, Pharming, Pharvaris, and Takeda. Bernstein, an employee of BioCryst Pharmaceuticals, disclosed research funding, advisory/consulting fees, and other support from the company. Kelbel is on advisory boards for Takeda, Biocryst, and Pharming.
J Allergy Clin Immunol. 2021;148:164-72.e9. Full text
Brandon May is a freelance medical journalist who has written more than 1800 articles for medical publications in the US and the UK. He resides in New York City. Twitter: @brandonmilesmay.
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