The first-in-class complement factor D inhibitor danicopan (Voydeya) has been approved by the European Commission as an add-on agent for certain patients with the rare disease paroxysmal nocturnal hemoglobinuria (PNH).
PNH is a rare, chronic, progressive, multisystemic disease caused by an acquired genetic mutation of the X-linked gene PIGA. The mutation results in the expansion of a clone of hematopoietic cells that are deficient in glycosylphosphatidylinositol-linked proteins. These abnormal red cells provoke complement activation that leads to lysis and paroxysmal flares of characteristic intravascular hemolysis, along with granulocyte and platelet activation, which can result in thrombotic events, serious infections, and bone marrow failure.
Intravascular hemolysis leads to release of free hemoglobin into the blood and toxic effects including hypercoagulability, changes in vascular tone from reduction of circulating nitric oxide, and renal damage. Extravascular hemolysis also occurs because complement component 3 accumulates on the surface of the affected erythrocytes, leading to opsonization with reticuloendothelial destruction in the liver and spleen.
Chronic hemolytic anemia is a common manifestation of PNH but nocturnal hemoglobinuria is rare.
Rare but Potentially Life-Threatening
Symptoms and signs of PND may include blood clots, back or abdominal pain, esophageal spasm and difficulty swallowing, erectile dysfunction or priapism, dyspnea, fatigue, anemia, and dark-colored urine. It can be diagnosed at any age but typically arises in the early to mid-30s and affects men and women equally.
The disorder may lead to renal insufficiency, thrombosis, or pulmonary hypertension and is potentially life-threatening. Despite best supportive care, 5- and 10-year mortality rates are approximately 35% and 50%, respectively.
Standard treatment is complement blockade by the anti-C5 monoclonal antibody inhibitors ravulizumab (Ultomiris) or eculizumab (Soliris), administered by infusion. These can lead to significant improvement in symptoms and quality of life, with a significant reduction in hemolysis and number of thrombotic events. However, 10%-20% of treated patients still have clinically significant extravascular hemolysis (EVH) with residual hemolytic anemia.
New Drug Inhibits Complement Activation
Danicopan is an oral selective inhibitor of factor D, a complement system protein that plays a key role in the amplification of the complement system response in PNH. It has been designated a breakthrough therapy by the US Food and Drug Administration; given Priority Medicines status by the European Medicines Agency; and granted orphan drug status for the treatment of PNH in the US, European Union, and Japan.
European Commission approval of danicopan as an addition to ravulizumab or eculizumab in adult patients with PNH and continuing clinically significant EVH follows a positive opinion of the Committee for Medicinal Products for Human Use in February and is based on the protocol-prespecified interim efficacy analysis of results published in December 2023 from the first 63 patients (42 receiving danicopan and 21 receiving placebo) in the ongoing phase 3 ALPHA trial.
ALPHA showed that addition of danicopan resulted in a statistically significant increase in mean hemoglobin level at 12 weeks (2.94 vs 0.50 g/dL with placebo). This was associated with reduced fatigue and anemia and a reduced need for transfusions. The drug was generally well tolerated, with no serious adverse events reported.