Empaveli injection-site reactions decline over time: Trial data

Most reactions in PEGASUS, OLE 307 were mild; few were moderate

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term treatment with Empaveli (pegcetacoplan) was generally well tolerated among adults with paroxysmal nocturnal hemoglobinuria (PNH), with the rate of injection-site reactions declining over time.

That’s according to data from the Phase 3 PEGASUS clinical trial (NCT03500549) and the open-label extension (OLE) Study 307 (NCT03531255) that spanned more than 1.5 years of treatment and included nearly 12,000 injections.

While Empaveli is self-administered using a commercially available infusion pump, a wearable, single-use automatic injector device has been developed to administer it into the abdomen. This device “may improve the patient experience with [Empaveli] self-injection by helping patients more conveniently manage PNH,” the researchers wrote in “Injection Site Reactions with Long-Term Pegcetacoplan Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Brief Report,” which was published in Advances in TherapyIt was supported by Apellis Pharmaceuticals and Sobi, which co-develop Empaveli.

In PNH, the overactivity of the immune complement system causes the destruction of red blood cells. A deficiency of these cells, or anemia, leads to symptoms such as fatigue, shortness of breath, and abdominal pain that often occur in sudden attacks.

Injected subcutaneously (under the skin) twice weekly, Empaveli suppresses complement activation by blocking C3, an important complement protein. It’s approved in the U.S. and Europe (where it’s sold as Aspaveli) for adults with PNH plus anemia despite receiving C5-targeted therapy for at least three months.

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Treatment with Empaveli

Empaveli demonstrated a favorable safety profile and superior efficacy to Soliris (eculizumab) — a C5-targeted therapy approved for PNH —  in the Phase 3 PEGASUS study. The trial enrolled 80 adults who’d been on a stable Soliris dose for at least three months before the trial, but were still anemic.

A subcutaneous route of administration offers advantages over intravenous infusions, including a lower cost and the ability to be self-administered. Injection-site reactions, including reddening, itching, discomfort, or pain, are common, however.

Such reactions were common in PEGASUS with up to a year of treatment, but were usually mild. To learn more about the long-term burden of Empaveli-associated injection-site reactions, the scientists examined safety data from patients who completed PEGASUS and then chose to enter the ongoing 307 OLE study, where those who finished previous Empaveli trials are being treated for two more years.

In PEGASUS’ main part, participants received both Soliris and Empaveli for four weeks, after which they were randomly assigned to either one for four months in the open-label period.

They then entered the extension, wherein all received Empaveli for 6-8 months, totaling about a year of Empaveli for those originally assigned to it.

Empaveli was self-administered twice weekly or every three days as a subcutaneous injection usually into the abdomen or an alternate site, such as the thigh or upper arm. Doses could be given as two separate injections (10 mL each over 30 minutes) or one injection (20 mL over an hour).

After enrolling in 307 OLE, patients continued on Empaveli twice weekly or every three days, which could be increased to three times weekly if needed.

Overall, 64 PEGASUS participants (32 in the Empaveli group, 32 in the Soliris-to-Empaveli group) entered 307 OLE. Their mean age was 48.5, 60.9% were women, and 62.5% were white. A total of 58 of them completed 48 weeks, or nearly a year, of treatment in the 307 OLE at the time of the data cutoff in August 2021.

The median duration of Empaveli treatment in PEGASUS was about seven months, with 5,960 completed injections. In the PEGASUS group of the 307 OLE study, the median treatment duration was an additional 337 days (nearly a year), with 5,972 more injections.

Injection-site reactions with long-term Empaveli treatment

The rate of injection-site reactions dropped with longer term treatment, the results showed.

During PEGASUS, 36.6% of Empaveli-treated patients had events in the main part of the trial, while only 26% of all patients reported them in the open-label-period. After nearly a year in the 307 OLE, injection-site reactions were reported in nine patients.

Most injection-site reactions in PEGASUS and the 307 OLE study were mild. Only a few were moderate. None were classified as severe or serious or led to discontinuing treatment.

In PEGASUS, the most common injection-site reaction was skin redness. Similarly, skin redness or hardening were the most common recation in the 307 OLE study, each occurring in four patients.

Exposure-adjusted rates of injection-site redness was 56.8 per 100 patient-years in the Empaveli group of PEGASUS’ main part, which declined to 20.1 for all participants in the open-label period. Patient-years is a measure of the number of people in the study and the time they were followed.

After a year in 307 OLE, exposure-adjusted rates of skin reddening or hardening were just 6.5 per 100 patient-years each.

“The percentage of patients reporting ISRs [injection-site reactions] declined from PEGASUS to the 307 OLE, which we postulate may be attributed to increased patient experience with [subcutaneous] injections and mitigation strategies,” the researchers wrote, adding these findings, along with the high treatment compliance rates (more than 95% in both trials), indicate injection-site reactions “are not a barrier to continued [Empaveli] treatment in patients with PNH.”

“Pre-treatments to mitigate ISRs [injection-site reactions], such as the use of skin-cooling interventions or topical numbing or analgesic agents, were not included in PEGASUS or the 307 OLE,” they added, meaning “the impact of these ISR mitigation strategies commonly used in the real-world setting” remains to be assessed.

The researchers said that the new wearable injector device for Empaveli was found to be safe and effective among adults with anemia after training in a feasibility study. “The new device, when coupled with patient education, is expected to improve the patient experience with self-injections,” they wrote.