AstraZeneca Announces Positive Phase III ALPHA Trial Results for First-in-Class Oral Factor D Inhibitor Danicopan in PNH Patients with Clinically Significant Extravascular Hemolysis

On June 9, AstraZeneca announced positive results from the pivotal Phase III ALPHA trial. In patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing clinically significant extravascular hemolysis (EVH), the investigational first-in-class oral Factor D inhibitor danicopan, as an add-on therapy to the standard treatment C5 inhibitors Ultomiris (ravulizumab) or Soliris (eculizumab), demonstrated a statistically significant and clinically meaningful increase in hemoglobin levels compared to placebo plus standard therapy, with sustained disease control.

PNH is a rare, chronic, and serious complement-mediated blood disorder. Due to acquired mutations in certain hematopoietic stem cells (located in the bone marrow, which can grow and develop into red blood cells, white blood cells, and platelets) in PNH patients, red blood cells that are prone to premature destruction by the complement system are produced, leading to intravascular hemolysis (IVH, destruction of red blood cells within blood vessels) and extravascular hemolysis (EVH, destruction of red blood cells primarily in the spleen and liver). This results in anemia (low levels of circulating red blood cells), thrombosis (formation of blood clots), fatigue, and other debilitating symptoms that may affect quality of life. Among PNH patients treated with C5 inhibitors, approximately 10% to 20% experience clinically significant EVH, which may lead to persistent anemia symptoms requiring blood transfusion therapy.

In the pre-specified interim analysis of the ALPHA trial (conducted after 63 subjects completed or discontinued the 12-week primary treatment period), danicopan achieved the primary efficacy endpoint. In patients with PNH receiving Ultomiris or Soliris, danicopan in combination with Ultomiris or Soliris demonstrated superior efficacy compared to placebo plus Ultomiris or Soliris based on changes in hemoglobin levels from baseline to Week 12 (2.94 [0.211] g/dL vs. 0.50 [0.313] g/dL; p<0.0001). Additionally, significant improvement in hemoglobin levels was observed in the danicopan group as early as Week 2 and was sustained through Week 12.

Compared with the placebo group, the danicopan group also showed statistically significant advantages in all key secondary endpoints. The results showed that the proportion of patients in the danicopan group with an improvement in hemoglobin of ≥2 g/dL at week 12 without transfusion was significantly higher (59.5% vs. 0%; difference between groups: 46.9, 95% CI: 29.2-64.7, p<0.0001).

Primary Endpoint Data (Source: AstraZeneca Official Website)

In addition, compared with the placebo group, the number of patients in the danicopan group who avoided transfusions (no transfusions and no need for transfusions) significantly increased within 12 weeks, and patient fatigue symptoms also improved.

Compared with baseline, at week 12, the change in lactate dehydrogenase (LDH) was -23.49 [8.29] U/L in the danicopan group and -2.92 [11.91] U/L in the placebo group (p=0.1569), indicating that the use of C5 inhibitors effectively controlled IVH in both groups.

The results of this Phase III clinical trial showed that danicopan was generally well-tolerated, with no new safety issues identified. No Grade 4 or 5 treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs in the treatment group were headache (10.2%), nausea (8.2%), arthralgia (8.2%), and diarrhea (8.2%). Currently, regulatory agencies in multiple countries worldwide are reviewing the marketing application for danicopan for use in adult PNH patients with clinically significant EVH.

Competition in the PNH field continues to heat up, with three PNH treatment drugs currently approved globally: Alexion's (acquired by AstraZeneca) two C5 antibodies, Ultomiris and Soliris, as well as Apellis' complement C3 antibody pegcetacoplan. Soliris was the first therapy approved for PNH, with an injection frequency of once every two weeks. Ultomiris is a second-generation C5 inhibitor, first approved for marketing in December 2018. It has a longer half-life than eculizumab and requires injections every eight weeks. Pegcetacoplan was approved for marketing in May 2021 under the brand name Empaveli, becoming the first FDA-approved targeted complement C3 therapy for PNH.

Novartis' oral monotherapy iptacopan has achieved great success in the head-to-head Phase III study against C5 monoclonal antibodies (eculizumab or ravulizumab), and its marketing application has been included in the priority review by the CDE. The success of AstraZeneca's danicopan add-on to C5 monoclonal antibody therapy in the Phase III study for clinically significant EVH in adult PNH patients will provide it with another important competitive edge in this disease area.

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