Hereditary angioedema attack rates fall with berotralstat

Key takeaways:

• Attack rates fell for patients with and without C1 inhibitor deficiencies.
• Monthly attack rates fell from 2.35-2.64 at baseline to 0.62-0.79 during follow-up for patients with C1-inhibitor deficiency.

BOSTON — Patients with hereditary angioedema saw significant reductions in attacks for 18 months after beginning berotralstat, according to two posters at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

Attacks fell for patients who had and who did not have C1 inhibitor deficiencies alike, Raffi Tachdjian, MD, MPH, associate clinical professor of medicine and pediatrics, division of allergy and clinical immunology, David Geffen School of Medicine, University of California Los Angeles, and colleagues wrote.

The drug’s mechanics

Patients with a C1-inhibitor deficiency experience excess bradykinin production, making them vulnerable to type I/II hereditary angioedema (HAE) attacks. However, some patients with normal plasma C1-inhibitor levels and function also develop HAE, or HAE-nl-C1-INH, in these cases.

Berotralstat (Orladeyo; BioCryst Pharmaceuticals) was designed to prevent HAE attacks among patients aged 12 years and older via an oral medication taken once a day.

“Prior to berotralstat, most patients with HAE were treated with prophylactic therapies administered through subcutaneous injections. This can be challenging for some patients, especially those who dislike needles and the overall treatment burden of injectable therapy,” Donald S. Fong, MD, MPH, chief medical officer at BioCryst Pharmaceuticals, told Healio. Fong was not one of the authors of the study.

Donald S. Fong

“Berotralstat is the first and only oral, once-daily prophylactic therapy for HAE, which works to prevent HAE attacks by decreasing the activity of plasma kallikrein,” Fong continued. “Clinical studies and real-world evidence have shown berotralstat to offer both outstanding effectiveness and convenience for the majority of patients who remain on treatment long term.”

Fong noted that most patients with HAE have type I or II HAE, leading to repeated painful and unpredictable swelling attacks. Meanwhile, patients with HAE-nl-C1-INH and normal C1-INH levels and function often experience delays in diagnosis.

“Based on our recent findings, the baseline attack frequency prior to starting berotralstat was also observed to be higher, potentially indicating greater disease burden in this patient population,” Fong said. “Our results show that there is potential for long-term prophylaxis treatment with berotralstat to help reduce HAE attack rates regardless of HAE type.”

Study results

The retrospective, real-world study included data from the only dispenser of berotralstat in the United States, Optime Specialty Pharmacy, from Dec. 15, 2020, to Jan. 8, 2024. Data included self-assessments of baseline HAE attacks from the 90 days prior to the first administration of the drug and mean and monthly attack rates taken at the first administration and every 90 days afterward.

“Berotralstat was shown to be associated with statistically significant and sustained reductions in attack rates over an 18-month period in both patients with HAE with C1-INH deficiency and those with normal levels and function of C1-INH,” Fong said.

The cohort included 466 patients (mean age, 40.3 years; mean weight, 81 kg; 63.9% female) with type I/II HAE, indicating a C1-inhibitor deficiency, who reported one attack or more at baseline and during the follow-up and who received two or more doses of berotralstat.

Also, 95.1% of these patients had visited an allergist/immunologist. Regionally, 47% were from the South, 23.2% were from the Midwest, 15.9% were from the West, 13.5% were from the Northeast and 0.4% were unknown.

Attack rates fell from 2.35 to 2.64 per month at baseline to 0.62 to 0.79 per month during each 90-day interval, which the researchers called a significant decrease. Specific mean reductions included 1.65 at 3 months, 1.59 at 6 months, 1.62 at 9 months, 1.71 at 12 months, 2 at 15 months, and 1.96 at 18 months.

The cohort also included 353 patients (mean age, 48.1 years; mean weight, 84 kg; 78.5% female) with HAE-n1-C1-INH, indicating no C1 inhibitor deficiency, who also had one attack or more at baseline and during the follow-up and who received two or more doses of berotralstat.

Similarly, 88.4% had visited an allergist/immunologist. Regionally, 47.6% were from the South, 23.5% were from the Midwest, 15.3% were from the West, 11.9% were from the Northeast, and 1.7% were unknown.

Monthly attack rates in this group fell from 4.3 to 4.66 at baseline to 1.63 to 2.04 during each 90-day follow-up interval. Specific mean reductions included 2.59 at 3 months, 2.95 at 6 months, 2.7 at 9 months, 2.91 at 12 months, 2.71 at 15 months and 2.53 at 18 months.

Conclusions, next steps

“What makes this particularly noteworthy is these retrospective real-world results include patients who self-reported zero attacks at baseline, which makes the reductions that much more impressive when compared to results from clinical studies that do not include patients with less than two attacks per month at baseline,” Fong said.

For example, Fong said, patients in the pivotal APeX-2 study were required to report a minimum of two attacks at baseline as part of its inclusion criteria.

“So, you are seeing real-world data showing that many HAE patients who are well controlled on other prophylaxis therapies maintain, or even improve, attack control when they start oral, once daily berotralstat,” Fong said.

Further, Fong said the statistical significance of the reductions in attack rate is noteworthy since patients whose HAE was well controlled experienced continued or improved attack control over the long term with berotralstat.

“This aligns with findings from previously reported clinical and real-world evidence that have shown that the longer patients remain on berotralstat, the better it works for them,” Fong said.

The researchers cautioned that patients may have defined their attacks differently as part of their self-assessments of the 90 days before treatment. Also, reports that berotralstat was dispensed does not necessarily mean the drug was taken, the researchers added.

However, the researchers still believe these findings indicate statistically significant and sustained associations between berotralstat and reduced attacks among patients with HAE who have and who do not have C1 inhibitor deficiency.

Fong also advised physicians to keep the dialogue with the patients ongoing for a better understanding of their individualized experiences and to provide tailored treatment recommendations for each one of them.

“By analyzing insights from the real world, we have additional evidence that suggests berotralstat is a meaningful treatment for patients who are seeking better control of their HAE regardless of their C1-INH status,” Fong said.

Additionally, Fong said that researchers have seen impressive reductions in attack rates each time that they have extended the duration of the follow-up period in retrospective real-world studies of berotralstat.

“Now that we have conducted this analysis in patients both with and without C1-INH deficiency, we plan to continue to conduct similar analyses to understand if these results are sustained beyond 18 months,” Fong said.

“There are also plans to link these data to U.S. claims data to generate additional evidence on berotralstat to help inform the shared decision-making approach with patients and quantify the value of berotralstat to payers,” he said.

Reference:

• Davis-Lorton M, et al. Sustained real-world attack reductions following berotralstat initiation among patients with hereditary angioedema without C1-inhibotor deficiency. Presented at: ACAAI Annual Scientific Meeting; Oct. 25-28, 2024; Boston.