Results of Pegcetacoplan (APL-2) trial

A recently published study from Leeds, England, investigates the efficacy of the new drug pegcetacoplan for Paroxysmal Nocturnal Haemoglobinuria (PNH). Pegcetacoplan is not yet approved for PNH therapy in Europe, but approval is currently being considered by the European Medicines Agency (EMA). For this reason, we would like to briefly introduce the drug and the study to you and first take a brief look at the disorder of blood formation underlying PNH in order to understand how pegcetacoplan works:

Normally, certain proteins are found on the surface of the red blood cells (erythrocytes) that transport oxygen through our bodies. Among other things, these regulate the immune system and prevent the erythrocytes from being broken down prematurely as they circulate through the body. In PNH, these proteins are missing: both in the blood vessels (intravascular) and outside (extravascular), the red blood cells are increasingly destroyed in the spleen and liver by part of the body’s own immune system – by the complement system. This process is called haemolysis. The result can be, among other things, a lack of erythrocytes in the blood (with decreased haemoglobin levels) and a need for blood transfusions.

The active substances already approved for PNH treatment in Germany are eculizumab and ravulizumab: In the study described here, the efficacy of eculizumab was investigated in comparison with pegcetacoplan. Eculizumab, a so-called C5 complement inhibitor, primarily prevents the patient’s own immune system from destroying the red blood cells in the vessels, but has little effect on their premature estruction in the spleen and liver. This is where the C3 complement inhibitor pegcetacoplan comes in, which exerts its effect at both sites. In the study, a total of 80 PNH patients initially received four weeks of treatment with eculizumab and pegcetacoplan. After the first four weeks, about half of the participants continued the therapy with pegcetacoplan without eculizumab for another 16 weeks, while the other half were treated the other way round.

At the end of the study, it was found that the patients on pegcetacoplan therapy had significantly higher haemoglobin levels than the eculizumab group. They were also significantly less likely to need blood transfusions. In terms of side effects, pegcetacoplan treatment was associated with a higher incidence of injection site reactions (the drug is administered under the skin) and diarrhoea. Treatment with eculizumab resulted comparatively more often in haemolysis requiring treatment, as well as headaches and fatigue.

The study was conducted in a rather small group of patients and, due to the relatively short period of 16 weeks, cannot provide any certainty about possible long-term treatment effects, even though there does not seem to be any evidence for this at present. The EU Commission’s decision on approval is expected to be made later this year on the basis of the EMA recommendation and we will of course keep you informed.

Abstract in New England Journal of Medicine (NEJM)