Positive results from the pivotal Phase III ALPHA trial showed that investigational, first-in-class oral Factor D inhibitor danicopan as add-on to standard of care C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) demonstrated a statistically significant and clinically meaningful increase in haemoglobin levels and maintained disease control in patients with paroxysmal nocturnal haemoglobinuria (PNH) who experience clinically significant extravascular haemolysis (EVH), compared to placebo plus established C5 inhibitor therapy.1
The data were presented today at the European Hematology Association (EHA) Annual Meeting in Frankfurt, Germany.
PNH is a rare and severe blood disorder characterised by the destruction of red blood cells within blood vessels, known as intravascular haemolysis (IVH), and white blood cell and platelet activation that can cause thrombosis (blood clots) and result in organ damage and potentially premature death.2-4 Approximately 10-20% of people living with PNH who are treated with a C5 inhibitor experience clinically significant EVH, which can result in continued symptoms of anaemia and require blood transfusions.1,5,6
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.”
Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: “As a leader in PNH for decades, Alexion has transformed the treatment landscape by developing the first approved medicine for this rare disease and establishing C5 complement inhibition as standard of care. These promising results presented at the EHA Annual Meeting underscore the potential for targeted Factor D inhibition with danicopan as an add-on to Ultomiris or Soliris to address clinically significant EVH while allowing patients to maintain disease control with established C5 complement inhibitors.”
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; p1
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 ≥2 g/dL at week 12 in the absence of transfusion (difference in danicopan-placebo: 46.9, 95% CI: 29.2-64.7, p1
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.1
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.
Summary of efficacy resultsi,ii
Danicopan add-on treatment to Soliris or Ultomiris resulted in a statistically significant increase in haemoglobin from baseline to week 12 versus placebo
