Berotralstat achieves long-term prophylaxis for hereditary angioedema attacks
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Key takeaways:
- Attack rates decreased as early as the first 4 weeks of treatment.
- Mean change in attack rate from baseline was –2.21 attacks per month.
- Patients reported quality of life improvements through 96 weeks.
Patients with hereditary angioedema who used berotralstat generally tolerated treatment and experienced reductions in attacks over 96 weeks, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
As an oral treatment, berotralstat (Orladeyo, BioCryst) also may be preferrable to parenteral therapies, William R. Lumry, MD, clinical professor of internal medicine, University of Texas Southwestern Medical School, and colleagues wrote.
“There are no head-to-head studies comparing berotralstat to other therapies,” Lumry told Healio.
Berotralstat is the only available oral, once-daily, highly selective inhibitor of plasma kallikrein, which is a serine protease that releases bradykinin, he continued. By decreasing the activity of plasma kallikrein, it prevents hereditary angioedema (HAE) attacks.
“While other plasma kallikrein inhibitors are available, they are injectables and therefore may carry an administration burden for patients, including those who are resistant to administering therapy with needles,” Lumry said.
“As the first and only oral therapy designed specifically to prevent attacks of HAE in adult and pediatric patients 12 years and older, berotralstat is a more convenient option for many patients,” he said.
Study design, results
Parts 1 and 2 of the APeX-2 study compared the use of berotralstat and placebo for 48 weeks. In part 3, 81 patients continued with the study and received at least one monthly dose of 150 mg of berotralstat with an option to continue for 4 more years.
“The primary objective of the open-label extension was to evaluate long-term safety and tolerability, while secondary objectives included effectiveness and impact of berotralstat on quality of life,” Lumry said.
Treatment in part 3 lasted for a median of 644 (range, 22-981) days, with 67 (82.7%) patients experiencing at least one treatment-emergent adverse event, most commonly nasopharyngitis (19.8%), urinary tract infection (9.9%), abdominal pain (6.2%), arthralgia (6.2%), coronavirus infection (6.2%) or diarrhea (6.2%).
Also, 12 (14.8%) patients had at least one drug-related treatment-emergent adverse event, mostly gastrointestinal disorders, but none of the patients experienced any drug-related rashes.
Overall, the researchers said that most treatment-emergent adverse events were mild or moderate, with 10 (12.3%) patients experiencing a grade 3 or 4 treatment-emergent adverse event, including one case of abdominal pain that was drug-related.
“Safety results in part 3 were consistent with those reported in the first two parts of the study, with no new safety signals observed,” Lumry said.
As early as 4 weeks after starting treatment, patients experienced decreases in attack rates that were maintained or that steadily decreased further through up to 96 weeks of continued treatment.
The 70 patients who completed 96 weeks of berotralstat treatment had a mean change in attack rate from baseline of –2.21 (standard error of the mean [SEM] = 0.2) attacks per month at month 24. Specifically, patients who completed 96 weeks of 150 mg berotralstat treatment experienced an average reduction of 90.8% in their attack rates at month 24.
Also at month 24, all treatment groups had a median attack rate of 0, and the patients who had received 150 mg of berotralstat through the full study had a median of 0 attacks for 11 of the 12 months of part 3.
Patients were attack-free for 93.1% of their days as well, with a mean number of attack-free days of 553.7 (SEM = 23.5). The average number of days between attacks was 81.4 (SEM = 14), with maximum durations of attack-free periods ranging from 15 to 1,022 days.
The patients in the 150 mg group had a mean average number of days between attacks of 80.9 (SEM = 15.6) and maximum durations of attack-free periods ranging from 32 to 946 days.
The use of on-demand medication for HAE declined as early as the first 4 weeks of berotralstat treatment as well, with prolonged treatment leading to further reductions before a mean adjusted number of doses per month falling under 1.25 in all treatment groups at month 24.
Again, the patients in the 150 mg group led the treatment groups with their adjusted number of doses per month falling from 3.8 (SEM = 0.76) at baseline to 0.4 (SEM = 0.18) at month 24. The 21 patients in this group who completed 96 weeks of treatment had a mean change of –2.4 (SEM = 0.51) doses per month from baseline to month 24, with an average reduction of 88.5%.
Patients began experiencing improvements in quality of life soon after beginning berotralstat, the researchers said, with improvements persisting through 96 weeks of treatment in all domains of the Angioedema Quality of Life (AE-QoL) questionnaire for all treatment groups, except for the fatigue/mood domain among patients who crossed over from 110 mg to 150 mg doses of berotralstat after starting with placebo.
Also, all the treatment groups experienced clinically meaningful improvements in mean AE-QoL at 96 weeks of treatment, with 70.6% of patients reporting clinically meaningful improvements.
The 150 mg group specifically had the largest improvements across every AE-QoL domain, with the 19 patients in this group who completed 96 weeks of treatment experiencing a mean change from baseline of –22.97 (SEM = 3.57) in total score (P < .0001).
Treatment satisfaction generally improved in all groups over all domains of the Treatment Satisfaction Questionnaire for Medication as well, the researchers said.
“Of note, patients who received 150 mg berotralstat from day 1 of the study and completed 96 weeks of treatment reported a mean change from baseline of +34.6 points in the convenience domain,” Lumry said.
Conclusions, next steps
Based on these findings, the researchers concluded that oral administration of berotralstat was well tolerated with no new safety signals and durable response that increased over time, considerable reductions in monthly HAE attacks and clinically relevant improvements in quality of life, indicating its potential as an effective and convenient treatment option.
“A key takeaway from these findings is that treatment with oral, once-daily berotralstat has the potential to minimize the treatment burden vs. that typically associated with injectable prophylactic and on-demand medicines while simultaneously reducing HAE attack frequency,” Lumry said.
Lumry also advised physicians who treat patients with HAE to take the time to listen to them and consider each patient’s individual circumstances to determine an optimal treatment regimen.
“There is an opportunity for appropriate patients to benefit from a more convenient therapy to help maintain or improve control of their HAE attacks, and an oral, once-daily prophylactic therapy could be a meaningful option for them,” Lumry said.
Berotralstat is now being evaluated in pediatric patients in the APeX-P study as well.
“As the standard of care in these patients are injectable therapies, an oral prophylactic therapy would be a welcome treatment option,” Lumry said.
Perspective
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Overall, these results are promising, as they show safety and efficacy for an oral medication to be used prophylactically in patients with HAE who have previously only had parenteral options available.
These results also are consistent with what I have experienced with my patients. Many of our HAE patients are “needle fatigued,” since only intravenous or subcutaneous medications have been available previously. In my experience, that can lead to a tendency for noncompliance. Patients have desired an oral option for years. I have seen that greater compliance with taking an oral medication daily without the fear or fatigue of needles has made a positive impact on our patients.
Also, the efficacy and safety data over an extended period in this study are impressive. However, one aspect that is of interest is that 18 patients (22.2%) in part 3 experienced abdominal-related gastrointestinal (GI) adverse effects as compared with placebo. GI symptoms can also be part of HAE attacks, and this may be confounding to patients.
Also, the small numbers in the trial and the selection bias of likely less severe patients must be considered in an individualized approach to patients when discussing treatment options. Depending on the patient’s experience and history, these factors may play a role in that shared decision-making process.
Lastly, the study reports quality of life improvements, but the placebo arm of the study also demonstrated that effect. It is important to always dive into the details and not just headlines when examining research studies.
Next, I think understanding the nature of the abdominal-related GI adverse effects and how those might be lessened would be of importance in this case since nearly a quarter of patients experienced them. Further, examining this medication in more severe patients would be of help as well.
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