Long-term ALPHA phase III trial data showed danicopan as add-on to Ultomiris or Soliris sustained clinical improvements in subset of patients with PNH experiencing clinically significant extravascular haemolysis .- AstraZeneca

Results from the trial were presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

Danicopan is an investigational, first-in-class, oral, Factor D inhibitor. Data showed that improvements in mean haemoglobin levels and absolute reticulocyte count (ARC) levels, which were demonstrated at 12 weeks, were maintained through 48 weeks.

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. Immediate, complete and sustained terminal complement inhibition by blocking the C5 protein with Ultomiris or Soliris helps reduce symptoms and complications, resulting in improved survival for patients with PNH. Approximately 10-20% of people living with PNH who are treated with a C5 inhibitor experience clinically significant EVH (extravascular haemolysis), which can result in continued symptoms of anaemia and require blood transfusions.

Austin Kulasekararaj, MD, Consultant Haematologist at King's College Hospital, London and investigator in the ALPHA trial, said: “These new data further demonstrate the potential of danicopan as add-on to Ultomiris or Soliris to address the needs of the small subset of patients with PNH who experience clinically significant EVH. Expanding on positive 12-week results, the findings demonstrate sustained improvements in haemoglobin levels for up to 48 weeks, while also maintaining disease control, as measured by lactate dehydrogenase levels.”

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: “Unlike IVH, EVH is not life-threatening, but its manifestations can be burdensome for people living with this condition, which is why we continue to explore the potential of the complement system to advance patient care. The pivotal ALPHA results suggest that dual complement pathway inhibition at Factor D and C5 may be an optimal treatment approach for the 10-20% of patients with PNH who experience clinically significant EVH. Importantly, C5 inhibition maintains effective IVH control, which is critical for patients, and the addition of Factor D inhibition addresses signs and symptoms of EVH.”

The pivotal ALPHA Phase III trial is designed as a superiority study to evaluate the efficacy and safety of danicopan as an add-on to C5 inhibitor therapy Ultomiris or Soliris in patients with PNH who experience clinically significant EVH. A total of 86 patients were randomised. The prespecified interim analysis (primary analysis) occurred after 63 participants either completed or discontinued from the primary treatment period of 12 weeks. Following the 12-week randomised control period, patients were eligible to enrol in an open-label treatment period for an additional 12 weeks. During the open-label period, participants receiving placebo plus Ultomiris or Soliris switched to danicopan plus Ultomiris or Soliris (placebo-danicopan), and participants receiving add-on therapy with danicopan continued treatment with danicopan add-on therapy (danicopan-danicopan). The open-label treatment period was followed by the option to join a two-year LTE period during which all participants received danicopan add-on therapy. At the time of data cut-off on 20 September 2022, 60 of the 63 patients who were included in the primary analysis had reached 24 weeks and entered the LTE.

Data showed that the significant improvements in haemoglobin levels observed at 12 weeks [LSM (SEM) change 2.94 (0.21) g/dL] continued at 24 weeks [LSM (SEM) change 3.17 (0.30) g/dL] among patients treated with danicopan plus Ultomiris or Soliris and were sustained through 48 weeks.

Secondary endpoints measured at 24 weeks include change from baseline in haemoglobin, ARC, and lactate dehydrogenase (LDH) levels; the percentage of patients with haemoglobin increase of greater than 2 g/dL in the absence of transfusion; and the percentage of patients with transfusion avoidance. All key secondary endpoints met superiority in favour of danicopan plus Ultomiris or Soliris compared to placebo plus Ultomiris or Soliris at 12 weeks, and data showed benefits were maintained at 24 weeks in the danicopan-danicopan arm. Further, all key secondary endpoints showed meaningful improvement at 24 weeks in patients who switched from placebo to add-on treatment with danicopan at 12 weeks, including ARC levels and percentage of patients with transfusion avoidance, two indicators of potential EVH.

Additionally, mean (SD) LDH levels were maintained from baseline through 48 weeks in both treatment arms, demonstrating effective control of terminal complement activity and IVH with Ultomiris or Soliris.

Results from the ALPHA Phase III trial and LTE showed danicopan is generally well tolerated, and no new safety concerns were identified. The safety analysis was performed using data from all participants who took at least one dose of danicopan (n=80). The most common treatment-emergent adverse events (TEAEs) (greater than 10%) were COVID-19 (21.3%), diarrhoea (15%), headache (15%), pyrexia (13.8%), nausea (12.5%) and fatigue (10%). Additionally, an analysis of patient-reported outcomes from the ALPHA Phase III trial at 24 weeks was also presented at ASH, suggesting danicopan plus Ultomiris or Soliris has the potential to improve quality of life compared to C5 inhibitor therapy alone for the 10-20% of patients with PNH who experience clinically significant EVH. Findings showed clinically relevant patient-reported outcomes were observed in patients treated with danicopan as add-on to Ultomiris or Soliris during the first 12 weeks of treatment, compared to placebo plus C5 inhibition.

Additionally, data showed improvements in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30) scores were maintained during the open-label period to 24 weeks in the danicopan-danicopan arm and improved at 24 weeks in the placebo-danicopan arm.

ALPHA Phase III trial results from the primary prespecified interim analysis at 12 weeks were presented at the European Hematology Association (EHA) 2023 Hybrid Congress and published in The Lancet Haematology.

See- "Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase III trial".;Prof Jong Wook Lee, MD PhD ,Morag Griffin, MD, Jin Seok Kim, MD, et al. Published:December, 2023DOI:https://doi.org/10.1016/S2352-3026(23)00315-0. The Lancet Haematology.