Add-on danicopan improves outcomes in patients with PNH, cs-EVH

In the ongoing pivotal phase III ALPHA trial, add-on danicopan, an investigational first-in-class oral inhibitor of Factor D, appears better than placebo in increasing haemoglobin levels and maintaining disease control in individuals with paroxysmal nocturnal haemoglobinuria (PNH) and clinically significant extravascular haemolysis (cs-EVH) who were already on C5 inhibitors (ravulizumab or eculizumab).

“The primary endpoint and all key secondary endpoints were achieved,” said the investigators, led by Dr Jong Wook Lee from The Catholic University of Korea, Seoul St Mary’s Hospital, Republic of Korea.

At week 12, there was a clinically meaningful and statistically significant increase in haemoglobin from baseline in the danicopan vs the placebo arm (least squares mean [LSM] change from baseline, 2.94 vs 0.496 g/dL; p<0.0001). The improvement was seen as early as week 2 (LSM change from baseline, 2.854 vs 0.699) and remained stable up until week 12.

There were also substantial improvements with add-on danicopan vs placebo across all key secondary endpoints, namely the fractions of patients with haemoglobin increase ≥2 g/dL in the absence of transfusion (60 percent vs 0 percent; p<0.0001) and of those with transfusion avoidance (83 percent vs 38 percent; p=0.0004), as well as changes from baseline in FACIT-Fatigue* score (LSM change from baseline, 7.97 vs 1.85; p=0.0021) and in ARC** (LSM change from baseline, –83.8 vs 3.5; p<0.0001). [EHA 2023, abstract P771]

The overall incidence of any treatment-emergent adverse event was higher in the danicopan vs the placebo arm (71 percent vs 62 percent), but none were grade 4/5 in severity. Despite the slightly higher incidence of liver enzyme elevations with danicopan vs placebo (12 percent vs 8 percent), none were deemed serious. There were only two serious AEs reported with danicopan.

There were no reports of deaths, meningococcal infections, discontinuations owing to haemolysis, or any new safety signals.

Favourable risk-benefit profile

Despite treatment with C5 inhibitors, individuals with PNH may continue to experience anaemia owing to EVH, bone marrow failure, or breakthrough intravascular haemolysis (IVH). [Am J Hematol 2021;96:E232-E235; Front Immunol 2019;10:1157; Ther Adv Hematol 2019;10:2040620719873321] Moreover, about a fifth of patients with PNH who have received a C5 inhibitor therapy experience signs and symptoms of cs-EVH. [EHA 2023, abstract PB2056]

The team thus sought to evaluate the efficacy and safety of add-on danicopan in 63 PNH patients who were still experiencing cs-EVH (haemoglobin ≤9.5 g/dL; ARC ≥120 x 10⁹/L) while on ravulizumab or eculizumab for ≥6 months.

Participants were randomized 2:1 to receive add-on danicopan or placebo for 12 weeks. Following which, those on placebo switched to danicopan, while those on danicopan carried on with their regimen for another 12 weeks. Initial danicopan dose of 150 mg TID may be increased to 200 mg TID based upon clinical response at the investigator’s discretion.

“In summary, the findings showed that danicopan as an add-on to ravulizumab or eculizumab significantly improved haemoglobin and reduced the need for transfusion by addressing cs-EVH while maintaining essential control of terminal complement activity and IVH,” the investigators concluded.

The current results align with evidence reflecting the favourable risk-benefit profile of danicopan in this patient subgroup. [Blood 2021;138:1928-1938; Haematologica 2021;106:3188-3197]