Paroxysmal nocturnal haemoglobinuria: targeting C3 delivers better outcomes

Pegcetacoplan offered better haemtologic and clinical outcomes than eculizumab in a UK trial of patients with paroxysmal nocturnal haemoglobinuria (PNH). The therapy, which targets complement C3  could offer an option to patients who experience persistent anaemia despite long-term therapy with C5 inhibitors.

PNH is a rare acquired disease, characterised by complement-mediated haemolysis. Patients often suffer from fatigue, increased susceptibility to thrombosis, and some degree of bone marrow dysfunction.

The development of complement C5 inhibitors transformed outcomes for PNH patients through control of intravascular haemolysis. However, extravascular haemolysis remains an issue, manifesting as persistent anaemia and contributing to the need for continued blood transfusions in spite of C5 inhibitor treatment.

Pegcetacoplan is a pegylated pentadecapeptide that can control both intra- and extravascular hemolysis. The PEGASUS trial tested the agent against the C5 inhibitor eculizumab in patients with PNH and persistent anaemia in spite of at least three months of previous eculizumab treatment. The results were published in the NEJM.

The trial included a total of 80 patients, all of whom were first treated with their current eculizumab dose along with twice-weekly pegcetacoplan. This was followed by randomisation to either eculizumab or pegcetacoplan monotherapy for 16 weeks, and then a 32-week period in which all patients received pegcetacoplan.

The study met its primary endpoint, with a better mean change in haemoglobin level from baseline to week 16 in the patients receiving pegcetacoplan. The mean change was 2.37 g/dL with the study drug, and -1.47 g/dL with eculizumab, for a mean difference between the treatments of 3.84 g/dL (p < .001).

The improvement in haemoglobin levels occurs relatively quickly, with increases seen as early as two weeks into the 16-week trial period, and they were maintained throughout. Most of the patients receiving pegcetacoplan were transfusion-free during the 16-week trial period (85%), compared with only 15% of the eculizumab group (p < .001).

Other clinical outcomes were also better with pegcetacoplan. Functional Assessment of Chronic Illness Therapy–Fatigue scores increased by 9.2 points, while they decreased with eculizumab by 2.7 points, a difference deemed by the authors to be clinically significant. Most of the patients receiving pegcetacoplan (73%) had at least a three-point increase (which is considered clinically significant) at week 16, while none of those in the eculizumab group did.

“Fatigue is the most commonly reported symptom in patients with PNH and can have a tremendous adverse effect on quality of life,” wrote study authors led by Prof Peter Hillmen, of St James University Hospital, Leeds, UK.

“The effect of improvements in haemoglobin levels and control of underlying hemolysis translates not only to clinical variables such as freedom from transfusion but also to improvements in patient-reported outcomes.”

The most common adverse events with pegcetacoplan included injection site reactions (37%) and diarrhea (22%), though in both cases they were generally mild. Breakthrough hemolysis occurred in 10% of pegcetacoplan and 23% of eculizumab patients.

“In this population, treating intravascular haemolysis as well as preventing extravascular haemolysis by proximal complement inhibition with pegcetacoplan may result in better control of disease than treatment with eculizumab,” the authors concluded.

The TGA has granted pegcetacoplan orphan drug designation for the treatment of patients with PNH in Australia, and manufacturer Apellis has submitted a marketing application in Australia.

The trial was supported by Apellis Pharmaceuticals, which markets pegcetacoplan.

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