Paroxysmal nocturnal haemoglobinuria treatment with pegcetacoplan

The novel complement C3 inhibitor pegcetacoplan is significantly better at improving haemoglobin as well as other key clinical outcomes at week 16 versus the current standard of care, eculizumab, in patients with paroxysmal nocturnal haemoglobinuria (PNH).

Prof. Peter Hillmen (St James's University Hospital, UK) presented the findings from the phase 3 PEGASUS trial [1]. Preliminary data from the phase 1b PHAROAH and PADDOCK trials provided proof-of-principle that pegcetacoplan could improve lactate dehydrogenase and haemoglobin levels in patients who had experienced a suboptimal response to eculizumab, and in eculizumab-naïve patients, respectively.

In PEGASUS, 80 adult PNH patients completed a 4-week run-in period with pegcetacoplan plus eculizumab before being randomised to 1,080 mg of subcutaneous pegcetacoplan twice weekly (n=41) or continued eculizumab (n=39). The primary endpoint of PEGASUS was the change in haemoglobin level from baseline to week 16. Key secondary endpoints included transfusion avoidance, reticulocyte counts, lactate dehydrogenase levels, Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-f) score, and safety.

PEGASUS’ primary efficacy endpoint was met. At week 16, patients in the pegcetacoplan arm had improved their adjusted mean haemoglobin levels from a baseline level of 8.7 g/dL by 3.84 g/dL, 53% higher than the eculizumab arm (95% CI 2.33-5.34; P<0.0001). In patients with low or no transfusion requirements, pegcetacoplan-treated patients (n=20) had an adjusted mean haemoglobin increase of 2.97 g/dL versus eculizumab-treated patients (n=16) who had a mean change of -0.01 g/dL from the 8.9 g/dL baseline. However, the difference between the treatment arms was more evident in patients with high transfusion requirements, where pegcetacoplan-treated patients (n=21) had an adjusted mean haemoglobin increase of 2.11 g/dL versus eculizumab-treated patients (n=23) who had a mean change of -4.02 g/dL from the 8.5 g/dL baseline.

The secondary endpoint of transfusion avoidance was achieved in 85% of patients (n=35) with pegcetacoplan versus 15% of patients (n=6) with eculizumab, with an adjusted risk difference of 63% (95% CI 48-77). Reticulocyte counts decreased with pegcetacoplan and increased with eculizumab, translating to an adjusted risk difference of -164 (95% CI -189.9 to -137.3). Lactate dehydrogenase levels were not significantly different between the arms, changing by -15 (42.7) in the pegcetacoplan arm and -10 (71.0) U/L in the eculizumab arm (95% CI -181.3 to 172.0). The FACIT-f assessment score increased with pegcetacoplan (9.2 [1.61]) and decreased with eculizumab (-2.7 [2.82]), although noninferiority was not evaluated due to the prespecified hierarchical testing.

The safety profile of pegcetacoplan was comparable with eculizumab, with adverse events being reported in 87.8% in the pegcetacoplan arm versus 87.2% in the eculizumab arm. The rate of serious adverse events was 17.1% and 15.4%, respectively. Treatment discontinuation due to haemolysis occurred in 9.8% of patients in the pegcetacoplan arm and 23.1% of patients in the eculizumab arm.

“PEGASUS is the first randomised phase 3 trial of a proximal C3 inhibitor and shows a rapid and sustained improvement in haemoglobin, a reduction in ongoing breakdown of blood cells, a marked reduction in blood transfusions, and a marked improvement in fatigue,” concluded Prof. Hillmen.

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   1. Hillmen P, et al. Results of the PEGASUS phase III randomized trial demonstrating superiority of the c3 inhibitor, pegcetacoplan, compared to eculizumab in patients with paroxysmal nocturnal haemoglobinuria. EHA25 Virtual, 11-21 June 2020, Abstract S192.

 



Posted on 28 August, 20206 January, 2021