Danicopan as add-on to Ultomiris or Soliris improved haemoglobin levels and maintained disease control in patients with PNH experiencing signs or symptoms of clinically significant extravascular haemolysis, AstraZeneca

The data were presented at the European Hematology Association (EHA) Annual Meeting in Frankfurt, Germany.

Professor Jong Wook Lee, MD, PhD, Department of Haematology at Seoul St. Mary’s Hospital of The Catholic University of Korea, and investigator in the ALPHA trial, said: “While EVH is not life-threatening, its manifestations can be burdensome for patients. The ALPHA trial demonstrated that adding danicopan to standard of care with eculizumab or ravulizumab significantly improved fatigue and anaemia and reduced transfusion dependence, while still allowing for sustained control of IVH with terminal complement inhibition addressing the thrombotic risks associated with PNH. These results suggest danicopan has the potential to be an important option for the small subset of patients with PNH who experience clinically significant EVH while being treated with eculizumab or ravulizumab.”

At the prespecified interim analysis for the ALPHA trial – occurring after 63 study participants either completed or discontinued from the primary treatment period of 12 weeks – danicopan met the primary efficacy endpoint. In patients managing PNH with Ultomiris or Soliris, add-on treatment with danicopan was superior to placebo plus Ultomiris or Soliris based on change in haemoglobin from baseline to week 12, reported as least squares mean change from baseline and standard error of the mean (2.94 [0.211] g/dL vs 0.50 [0.313] g/dL; p<0.0001). further, significant improvements in haemoglobin were observed with danicopan by week 2 and maintained through week 12.></0.0001).>

All key secondary endpoints also met statistical superiority in favour of danicopan plus Ultomiris or Soliris, compared to placebo plus C5 inhibition . Results showed significantly more patients treated with danicopan (59.5%) versus placebo (0%) experienced an improvement in haemoglobin of greater than 2 g/dL at week 12 in the absence of transfusion (difference in danicopan-placebo: 46.9, 95% CI: 29.2–64.7, p<0.0001). additionally, significantly more patients treated with danicopan avoided transfusion (remaining transfusion-free and not requiring a transfusion as per protocol) through week 12, versus the comparator arm. improvements in fatigue, as measured by functional assessment of chronic illness therapy – fatigue (facit-fatigue) score, and absolute reticulocyte count, another indicator of clinically significant evh, were also shown. further, change from baseline in lactate dehydrogenase (ldh) at week 12 was -23.49 [8.29] u l in the danicopan plus ultomiris or soliris arm and -2.92 [11.91] u l in the placebo arm (p="0.1569)," demonstrating effective control of ivh was maintained with c5 inhibition in both arms.></0.0001).>

Results from this Phase III trial showed danicopan is generally well tolerated, and no new safety concerns were identified. The safety analysis set included 49 and 24 participants in the danicopan and placebo arms, respectively. No treatment-emergent adverse events (TEAEs) were Grade 4 or 5. The most common TEAEs were headache (10.2%), nausea (8.2%), arthralgia (8.2%) and diarrhoea (8.2%) in the treatment arm. There were no reported deaths, meningococcal infections or discontinuations due to haemolysis.

Regulatory submissions for danicopan for adults with PNH experiencing clinically significant EVH are currently under review with multiple global health authorities.