Targeting Complement C3 Improves Outcomes in Paroxysmal Nocturnal Hemoglobinuria

Peter Hillmen, MD, PhD

Pegcetacoplan, an inhibitor of complement C3 investigated for paroxysmal nocturnal hemoglobinuria (PNH), was superior to conventional treatment with a C5 inhibitor, eculizumab, in a recently published trial that was pivotal in the US Food and Drug Administration (FDA) granting priority review of the New Drug Application (NDA).

"For more than a decade, the only treatment options available for PNH have been C5 inhibitors, and many patients still suffer from persistently low hemoglobin, often resulting in debilitating fatigue and frequent transfusions," said Federico Grossi, MD, PhD, Chief Medical Officer of the sponsoring manufacturer, Apellis Pharmaceuticals, in an announcement of the FDA action.

"The NDA priority review takes us one step closer to bringing pegcetacoplan, a targeted C3 therapy with the potential to redefine PNH treatment, to patients in need," he said.

The study lead author Peter Hillmen, MD, PhD, St. James University Hospital, Leeds, UK, and colleagues point out that while C5 inhibitors are useful in controlling intravascular hemolysis in PNH, they do not address extravascular hemolysis. The persistence of anemia despite C5 inhibition may contribute to the need for continued blood transfusions.

"Pegcetacoplan is a pegylated pentadecapeptide that targets complement C3 to control both intravascular and extravascular hemolysis," Hillmen and colleagues assert.

The 48-week, multi-site PEGASUS phase 3 clinical trialcompares efficacy and safety of pegcetacoplan to that of eculizumab, one of two C5 inhibitors approved to treat PNH. The current report by Hillman and colleagues describes outcomes after the initial 16-week randomized, controlled period.

The investigators enrolled 80 adult patients with PNH diagnosed by high-sensitivity flow cytometry, and with hemoglobin levels less than 10.5 gm/dL despite at least 3 months of eculizumab treatment. Pegcetacoplan 1080mg subcutaneously twice weekly was added to the pre-existing bi-weekly intravenous eculizumab regimen for a 4-week run-in period, before randomization 1:1 to monotherapy with either agent. Three of 41 patients in the pegcetacoplan discontinued therapy before week 16 due to breakthrough hemolysis.

Hillmen and colleagues reported that pegcetacoplan was superior to eculizumab in increasing hemoglobin level from baseline to week 16, with mean difference of 3.84 gm/dL. The investigators noted that hemoglobin levels with pegcetacoplan began to increase as early as week 2, and were maintained throughout the 16-week study period.In addition, 35 (85%) of those receiving pegcetacoplan did not require transfusion during the study period, compared to 6 (15%) of those on eculizumab.

Pegcetacoplan was found noninferior to eculizumab in the change in absolute reticulocyte count, although not in change in lactate dehydrogenase LDH) level.Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores improved (increased) with pegcetacoplan by mean 9.2 points, which was determined clinically significant in comparison to a decrease of mean 2.7 points with eculizumab.

The most common adverse events in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs 3%), diarrhea (22% vs 3%), breakthrough hemolysis (10% vs 23%), headache (7% vs 23%) and fatigue (5% vs 15%). Although broad complement inhibition possibly increases risk of encapsulated bacterial infection, there were no incidents of meningococcal infection in either study group, and no difference in the incidence of infections between groups (29% vs 26%).

Hillmen discussed these findings with HCPLive, and considered whether they suggest that a C3 inhibitor could replace C5 inhibitors as agent of choice for PNH.

"We need more data...on the safety and efficacy in a larger group of patients over a longer period of time," Hillmen said. "If this continues then pegcetacoplan will replace C5 inhibitors for some patients.However, some patients will continue to benefit from C5 inhibitors and remain on these."

Hillmen elaborated on the distinct mechanisms and relative efficacy of the two approaches. "Some patients are severely affected by extravascular hemolysis on C5 inhibitors and therefore benefit from pegcetacoplan. Whereas some patients are well controlled and don't require an altertative. Also, a small proportion of patients have breakthrough hemolysis on pegcetacoplan and need C5 inhibitors," he explained.

The 3 cases of breakthrough hemolysis on pegcetacoplan that occurred in this trial illustrate the challenge of determining the preferable treatment for particular patients, Hillmen indicated.

"We need to optimize the dosing in these patients but it may be that even if the dose of pegcetacoplan is increased, that these patients are still not controlled adequately," Hillmen said. "We need to study such breakthroughs in a larger number of patients."

In announcing publication of safety and efficacy results from the 16-week study period, Grossi commented, "The PEGASUS study results demonstrate that, if approved, pegcetacoplan has the potential to elevate the standard of care for PNH by providing more complete disease control."

The study, "Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria," was published online in The New England Journal of Medicine.