Long-term Orladeyo safe, effective in HAE patients: Trial data

Results reflect two years of data from completed APeX-2 study

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by Andrea Lobo |

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Long-term prophylaxis, or preventive treatment, with Orladeyo (berotralstat) is well tolerated, and results in sustained reductions in swelling attacks and gains in quality of life in adolescents and adults with hereditary angioedema (HAE).

That’s according to nearly two years of data from the completed Phase 3 APeX-2 clinical trial (NCT03485911), whose previous one-year data supported the regulatory approvals of BioCryst Pharmaceuticals’ oral therapy.

“We continue to see long-term safety and effectiveness data that reinforce Orladeyo as an important treatment option for patients with HAE, and we look forward to sharing additional real-world evidence at upcoming medical congresses,” Ryan Arnold, BioCryst’s chief medical officer, said in a company press release.

“Long-term prophylaxis with Orladeyo has enabled patients with HAE to better manage their condition, including reducing the number of HAE attacks they experience and demonstrating clinically meaningful improvement in their quality of life,” said William R. Lumry, MD, clinical professor of internal medicine at the University of Texas Southwestern Medical School. “I have seen firsthand in my practice evidence that the longer patients remain on Orladeyo, the better their outcomes are.”

The final trial findings were described in “Once-daily oral berotralstat for long-term prophylaxis of hereditary angioedema: The open-label extension of the APeX-2 randomized trial,” in the Journal of Allergy and Clinical Immunology: In Practice.

HAE is a genetic condition marked by sudden, but temporary swelling attacks in the deeper layers of the skin. It’s mainly caused by mutations that lead to high levels of bradykinin, a molecule that promotes blood vessel widening, allowing fluid to flow into nearby tissues.

Orladeyo is approved to prevent swelling in people with HAE, age 12 and older. It works by blocking the activity of kallikrein, a protein that triggers bradykinin’s production.

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Breakdown of three-part APeX-2 study

The three-part APeX-2 trial enrolled 121 HAE patients at sites in the U.S. and Europe. All had had at least two swelling attacks in the two months prior. In the first part, participants were randomly assigned to receive a daily oral capsule of Orladeyo (110 or 150 mg) or a placebo for 24 weeks (about six months).

All 108 participants who completed the first part entered Part 2, an extension phase, wherein those assigned to Orladeyo continued the same treatment dosage while those who had a placebo received Orladeyo at either 110 or 150 mg for another 24 weeks.

Both doses were well tolerated and significantly reduced the frequency of monthly HAE attacks after six months relative to a placebo. The higher dose showed the greatest benefits, lowering attack rates by 44% and significantly improving quality of life.

Subsequent data from the extension phase showed Orladeyo’s benefits were sustained for nearly a year.

Finally, 81 participants entered Part 3, a long-term open-label extension phase where all received the 150 mg dose for up to four years. This part evaluated Orladeyo’s long-term safety, tolerability, and effectiveness.

Longer-term treatment of Orladeyo supported

The newly published results concern 81 patients who received at least one Orladeyo dose in Part 3. They were treated for a median of 21 months (nearly two years), ranging from less than a month to more than 2.5 years.

The therapy continued to be well tolerated with longer-term treatment. Most side effects were mild or moderate in severity and there were no new safety concerns. The most frequent side effect was the common cold (19.8%), followed by urinary tract infections (9.9%), abdominal pain, joint pain, coronavirus infection, and diarrhea (6.2% each). The rate of treatment-related abdominal and gastrointestinal side effects was reduced over time (40.7% in Parts 1 and 2 vs. 4.9% in Part 3).

In all treatments groups, HAE attack rates dropped as early as the first month and were maintained or continued to decrease for up to two years of treatment.

The 70 patients who completed the two-year follow-up saw a mean reduction of 2.21 attacks a month. Those completing two years of treatment with 150 mg showed a 90.8% attack rate reduction, on average.

During the last month of the two-year treatment, “all treatment groups had a median attack rate of zero,” and “in the 150 mg group, the median attack rate was zero for 11 of the 12 months of Part 3,” the researchers wrote.

During Part 3, participants were attack-free for 93.1% of the days. The maximum time patients in the high-dose group went without an attack ranged from about one month to 2.5 years.

For all treatment groups, monthly doses of on-demand medication for swelling attacks were reduced over time, reaching a mean of 1.25 at two years. Patients on the 150 mg dose saw a significant drop from 3.8 monthly doses at the start of the study to 0.4 after two years.

All the patients reported clinically meaningful improvements in nearly all quality of life domains, with major effects in functioning. Treatment satisfaction was also generally improved in all treatment groups.

“The results from this open-label extension of APeX-2 are consistent with the safety and efficacy results observed in Parts 1 and 2 and support the long-term benefits of prophylactic treatment with oral [Orladeyo], including improvements in [quality of life],” the researchers wrote.