Switching from androgens to Orladeyo reduces HAE swelling attacks

Patients reviewed who stopped androgens in under 60 days before APeX-S

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with hereditary angioedema (HAE) who switched from long-term androgen treatment to BioCryst Pharmaceuticals’ Orladeyo (berotralstat) saw a reduction in the number of swelling attacks.

That’s according to a new analysis of data from patients who discontinued androgens less than 60 days (two months) before entering APeX-S (NCT03472040), a Phase 2/3 clinical study that tested the safety and effectiveness of Orladeyo in people with HAE types 1 and 2.

While most had a smooth switch with no or few side effects, a small group experienced liver-related side effects when transitioning quickly in under 14 days (two weeks), indicating the optimal transition period requires more investigation.

Findings from the analysis, funded by BioCryst, were detailed in “Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial,” which was published in the World Allergy Organization Journal.

In HAE, the protein kallikrein becomes overactive and triggers a signaling molecule called bradykinin to be produced. Too much bradykinin causes blood vessels to widen and become leaky, resulting in swelling attacks that can arise rapidly in any part of the body.

Orladeyo is an oral medication approved to prevent swelling attacks in adults and children with HAE, ages 12 and older. It works by blocking kallikrein, thereby preventing bradykinin levels from rising too high and triggering an attack.

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Switching to Orladeyo

In clinical practice, some patients are switching to Orladeyo from androgens, which are often used as a second-line treatment for HAE. While the abrupt discontinuation of androgens isn’t recommended, “the optimal approach for discontinuing androgens … has not been identified.”

“Factors to consider include the timing of transition, dosing schedules, patient-specific preferences and characteristics that may affect transition, and androgen withdrawal,” the researchers wrote.

APeX-S was an open-label extension study where patients were given one capsule of either 110 mg or 150 mg of Orladeyo by mouth once daily for up to 96 weeks (almost two years) in the U.S. and 240 weeks (about 4.5 years) elsewhere.

Once it was found that the 150 mg dose worked better than the 110 mg one, everyone was given the higher dose. Of the 387 patients who took part in the study, 287 received the 150 mg dose for the entire study, while 100 initially received the lower dose.

Of those 287 patients on only the 150 mg dose, 145 had a history of androgen use. Of these, 39 stopped taking androgens less than 60 days before enrolling in the study. For 18 patients, discontinuation occurred in under 14 days before switching to Orladeyo.

All the patients who switched to Orladeyo in under 60 days saw a reduction in the number of monthly swelling attacks. Monthly attacks dropped from an average of 1.3 on the first month to 0.7 on month 12 of treatment with Orladeyo in the entire patient subset. This was observed regardless on how long patients had been on androgens or when they started transitioning.

Quality of life, side effects with Orladeyo

Quality of life was evaluated using the patient-reported Angioedema Quality of Life Questionnaire (AE-QoL), where lower scores indicate better quality of life. The minimal clinically important difference was defined as a 6-point reduction in the total score.

Average AE-QoL scores dropped from 33.7 at the start to 15.4 at month 12 of treatment with Orladeyo. The more than 18-point decrease indicated improvements in quality of life greatly exceeded the minimal clinically important difference.

“[Orladeyo] treatment led to sustained HAE symptom control irrespective of duration of prior androgen therapy or timing of transition,” the researchers wrote. This translated into better quality of life, which was consistent with previous data.

Orladeyo was mostly well tolerated. The most common side effects were cold-like symptoms (20.5%), upper respiratory tract infection (15.4%), nausea (15.4%), diarrhea (15.4%), and abdominal pain (10.3%). Side effects related to Orladeyo occurred in 21 (53.8%) patients.

Androgens may cause liver damage. Seven of the 145 patients with a history of androgen use had high blood levels of alanine aminotransferase, a liver enzyme that can signal liver damage, when elevated. All seven patients had transitioned to Orladeyo in under 14 days. In six, the side effects were serious, but all recovered without any long-lasting issues.

“Most patients safely transitioned from long-term androgens to [Orladeyo]. Although occurring in a small group of patients, liver-related adverse events following “[Orladeyo] treatment may be associated with a shorter androgen washout period,” the researchers wrote. “Reducing time without prophylaxis (“washout” period) during androgen discontinuation by avoiding abrupt discontinuation of androgen therapy may need to be considered to ensure a positive initial experience with [Orladeyo].” More research is needed to confirm this, they said.