Rare Daily Staff

Apellis Pharmaceuticals reported positive results from the phase 3 PEGASUS study evaluating its targeted experimental therapy pegcetacoplan in adults with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, life-threatening blood disorder associated with abnormally low hemoglobin levels due to the destruction of oxygen-carrying red blood cells, or hemolysis. Persistently low hemoglobin can result in frequent transfusions and debilitating symptoms such as severe fatigue and difficulty breathing.

Pegcetacoplan is an experimental, targeted C3 inhibitor designed to regulate excessive complement activation, which can lead to the onset and progression of many serious diseases. Pegcetacoplan is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b. Apellis is evaluating pegcetacoplan in several clinical studies including PNH, geographic atrophy (GA), and C3 glomerulopathy. Pegcetacoplan was granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of PNH and the treatment of GA.

Apellis noted that retrospective studies show that, even on the currently approved therapy eculizumab (Soliris), approximately 70 percent of people with PNH have low hemoglobin levels, and 36 percent require one or more transfusions a year.

“Pegcetacoplan is the first and only investigational therapy to demonstrate superiority compared to eculizumab on hemoglobin levels. We are also excited to see that 85 percent of patients treated with pegcetacoplan were transfusion free,” said Federico Grossi, chief medical officer of Apellis. “These results show that pegcetacoplan has the potential to transform the lives of people with PNH. We look forward to meeting with regulators in the first half of the year to discuss next steps.”

The PEGASUS study is a multi-center, randomized, open-label, active-comparator controlled phase 3 study in 80 adults with PNH. The primary objective of the study was to establish the efficacy and safety of pegcetacoplan compared to eculizumab. Participants must have been on eculizumab (stable for at least 3 months) with a hemoglobin level of <10.5 g/dL at the screening visit. During the four-week run-in, patients were dosed with 1080 mg of pegcetacoplan twice weekly in addition to their current dose of eculizumab. During the 16-week randomized, controlled period, patients were randomized to receive either 1080 mg of pegcetacoplan twice weekly or their current dose of eculizumab. All participants completing the randomized controlled period entered the open-label pegcetacoplan treatment period where they received pegcetacoplan, regardless of the prior treatment received in the randomized, controlled period.

Top-line data from the late-stage study show that pegcetacoplan met the study’s primary efficacy endpoint, demonstrating superiority to eculizumab with a statistically significant improvement in adjusted means of 3.8 g/dL of hemoglobin at week 16. At week 16, pegcetacoplan-treated patients had an adjusted mean hemoglobin increase of 2.4 g/dL from a baseline of 8.7 g/dL, compared to eculizumab-treated patients who had a change of -1.5 g/dL from a baseline of 8.7 g/dL.

Additionally, pegcetacoplan showed promising results in key secondary endpoints, including non-inferiority on transfusion avoidance and absolute reticulocyte count. Pegcetacoplan also showed positive trends on lactate dehydrogenase and fatigue as measured by the Functional Assessment of Chronic Illness Therapy fatigue score.

“The majority of patients with PNH currently receiving treatment with eculizumab have continuing anemia,” said Peter Hillmen, professor of experimental hematology at the University of Leeds and an investigator in the PEGASUS study. “The PEGASUS results show that pegcetacoplanhas the potential to become a new standard of care for patients with PNH.”

In this study, the safety profile of pegcetacoplan was comparable to eculizumab. Seven of 41 patients in the pegcetacoplan group experienced a serious adverse event (SAE), and 6 of 39 patients in the eculizumab group experienced SAEs. The most common adverse events reported during the 16-week, randomized, controlled treatment period in the pegcetacoplan and eculizumab groups, respectively, were injection site reactions, diarrhea, headache, and fatigue. Another common adverse event was hemolysis, which was reported in four patients in the pegcetacoplan group and nine patients in the eculizumab group. This led to the three discontinuations in pegcetacoplan group.

All patients who completed the randomization period in both groups entered the 32-week open-label pegcetacoplan treatment period.

“Going into the study, our most optimistic expectation was to see a 2 g/dL or more change in hemoglobin and a trend on the key secondary endpoints. Needless to say, we are thrilled with these results,” said Cedric Francois, co-founder and CEO of Apellis. “These data give us strong confidence in the further development of pegcetacoplan as a targeted C3 inhibitor in geographic atrophy and other serious complement-driven diseases.”

Photo:  Cedric Francois, co-founder and CEO of Apellis

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