Interim results demonstrate statistically significant improvement compared to placebo in haemoglobin levels from baseline to week 12
A prespecified interim analysis of the ALPHA Phase III trial evaluating danicopan (ALXN2040), an investigational, oral factor D inhibitor, as an add-on to C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) showed positive high-level results in patients with paroxysmal nocturnal haemoglobinuria (PNH) who experience clinically significant extravascular haemolysis (EVH).
The trial met its primary endpoint of change in haemoglobin from baseline at 12 weeks and key secondary endpoints, including transfusion avoidance and change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score. Danicopan plus Ultomiris or Soliris demonstrated superiority compared to placebo plus Ultomiris or Soliris for this specific patient population, with statistically significant and clinically meaningful improvements in haemoglobin levels, transfusion avoidance and FACIT Fatigue scores from baseline.
PNH is a rare and severe blood disorder characterised by the destruction of red blood cells, 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.1-3
Professor
Danicopan was generally well tolerated and there were no clinically meaningful differences in safety results observed between the danicopan plus C5 inhibitor group and control group.
Alexion, AstraZeneca Rare Disease, will present these data at a forthcoming medical meeting and intends to proceed with regulatory submissions in the coming months.
Notes
PNH
PNH is a rare, chronic, progressive and potentially life-threatening blood disorder. It is characterised by red blood cell destruction within blood vessels (also known as intravascular haemolysis) and white blood cell and platelet activation, which can result in thrombosis (blood clots).1-3
PNH is caused by an acquired genetic mutation that may happen any time after birth and results in the production of abnormal blood cells that are missing important protective blood cell surface proteins. These missing proteins enable the complement system, which is part of the immune system and is essential to the body's defence against infection, to 'attack' and destroy or activate these abnormal blood cells.1 Living with PNH can be debilitating, and signs and symptoms may include blood clots, abdominal pain, difficulty swallowing, erectile dysfunction, shortness of breath, excessive fatigue, anaemia and dark-coloured urine.1, 4, 5
Clinically Significant EVH
EVH, the removal of red blood cells outside of the blood vessels, can sometimes occur in PNH patients who are treated with C5 inhibitors. Since C5 inhibition enables PNH red blood cells to survive and circulate, EVH may occur when these now surviving PNH red blood cells are marked by proteins in the complement system for removal by the spleen and liver.1,3, 6 PNH patients with EVH may continue to experience anaemia, which can have various causes, and may require blood transfusions.6 A small subset 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.
ALPHA
ALPHA is a pivotal, global Phase III trial designed to evaluate the efficacy of danicopanas an add-on to C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) in patients with PNH who experience clinically significant EVH. In the double-blind, placebo controlled, multiple-dose trial, patients were enrolled and randomised to receive danicopanor placebo (2:1) in addition to their ongoing C5 inhibitor therapy for 12 weeks. Prespecified interim analysis for efficacy was planned once 75 percent (N~63) of participants completed 12 weeks of treatment period 1. At 12 weeks, patients on placebo plus C5 inhibitor are switched to danicopanplus a C5 inhibitor and patients on danicopan plus a C5 inhibitor remain on treatment for an additional 12 weeks.
Patients who complete both treatment periods (24 weeks) have the option to participate in a long-term extension period and continue to receive danicopan in addition to C5 inhibitor therapy.
Danicopan (ALXN2040)
Danicopanis an investigational oral medicine in development as an add-on to C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) for patients with PNH who experience clinically significant EVH. It is designed to selectively inhibit factor D, a complement system protein that plays a key role in the amplification of the complement system response. Danicopanhas been granted Breakthrough Therapy designation by the
Alexion
Alexion, AstraZeneca Rare Disease, is the group within
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References
1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811.
2. Griffin M, Hillmen P, Munir T, et al. Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. Haematologica. 2019;104(3):e94-e96.
3. Hillmen P., et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2006;355(12):1233-43.
4. Hillmen, P., et al. Effect of the complement inhibitor eculizumab on thromboembolism on patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-4128.
5. Kulasekararaj,
6. Brodsky RA. A complementary new drug for PNH. Blood. 2020;135(12):884-885.
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