Coversin, a Novel C5 Complement Inhibitor, Is Safe and Effective in the Treatment of PNH: Results of a Phase II Clinical Trial

Background:

GPI-anchored proteins play a critical role in protecting red cells from complement mediated lysis. An acquired deficiency in Paroxysmal Nocturnal Haemoglobinuria (PNH) leads to intravascular haemolysis. Until the advent of eculizumab, a monoclonal antibody which prevents the cleavage of C5 to C5a and C5b, PNH was associated with considerable morbidity and a poor long-term prognosis. However, eculizumab is administered by health care professionals by intravenous infusion which may interfere with the life-styles, occupations and personal privacy of patients. Interval dosing has led to concerns by some related to breakthrough haemolysis. Coversin is a protein suitable for small-volume subcutaneous (SC) injection and can be self-administered by patients.

Aims:

The aims of this study were to assess the safety and tolerability of Coversin, the efficacy of the dosing regime and whether self-injection by patients is well-accepted.

Methods:

Under the trial protocol of a Phase 2 single arm open label trial of Coversin patients, either newly diagnosed with PNH or who have not previously had access to complement inhibitors, were treated for 90 days. Coversin was supplied as a lyophilised powder, reconstituted with water for injection to give a buffered aqueous solution of Coversin 30mg/mL. The aim of the trial was to recruit 8 adult patients with a diagnosis of PNH confirmed by flow cytometry.

Treatment commenced with an ablating regime (AR) consisting of a fixed dose of 60mg followed by 1 - 3 doses of 30mg q12 hours delivered by SC injection. After being suitably instructed patients were encouraged to self-inject the drug. Following the AR, a dose of 15 or 22.5mg q12 hours was given. On day 28, they switched to 30 or 45mg q24 hours for the remainder of the trial. Those patients not satisfactorily controlled could be updosed or switched to the same dose divided into 2 doses administered q12 hours. All patients who completed the trial and wished to do so, continued to receive Coversin under a long-term safety and efficacy protocol.

A primary end point was LDH <1.8X ULN at the local laboratory at day 28. Secondary endpoints included LDH (xULN) at 60 and 90 days, terminal complement activity assessed by CH50 ELISA (Quidel®), haemoglobin stabilisation, reduction in requirement for blood transfusions, sheep erythrocyte haemolysis assay, PK (free and bound Coversin levels), anti-drug antibodies (ADA) and quality of life.

Results:

Results will be presented for all patients who were enrolled. The patients who completed the trial to date (07/31/17) experienced a reduction in serum LDH and PNH symptoms, stabilisation of haemoglobin levels, no transfusions during the trial (three of the four patients received transfusions in the 3 months prior to enrolment), no serious adverse events related to Coversin, tolerated the drug well, and for those experiencing them, the injection site reactions observed were mild to moderate, self-limiting and diminished with time. There has been no evidence of the formation of neutralising antibodies.

Summary/Conclusion:

Coversin may be an effective alternative for patients with PNH who prefer the independence of self-administration. The relatively short dose interval may also help to reduce breakthrough events.