Novartis' Fabhalta (iptacopan) has received FDA approval as the first oral monotherapy for adults with paroxysmal nocturnal hemoglobinuria (PNH). This Factor B inhibitor offers a novel approach by acting proximally in the alternative complement pathway, providing comprehensive control of red blood cell destruction both within and outside blood vessels.
Clinical Trial Success
The FDA approval was primarily based on the Phase III APPLY-PNH trial, which included patients with residual anemia (hemoglobin < 10 g/dL) despite prior anti-C5 treatment. Patients who switched to Fabhalta experienced significant improvements in hemoglobin levels compared to those who remained on anti-C5 treatments. Key results from the 24-week core treatment periods in the APPLY-PNH trial include:
- 82.3% of anti-C5-experienced Fabhalta patients achieved a sustained increase in hemoglobin levels ≥ 2 g/dL from baseline without transfusions, compared to 0% for anti-C5 (P<0.0001).
- 67.7% of anti-C5-experienced Fabhalta patients achieved a sustained hemoglobin level ≥ 12 g/dL without transfusions, compared to 0% for anti-C5 (P<0.0001).
- The transfusion avoidance rate was 95.2% for anti-C5-experienced Fabhalta patients versus 45.7% for anti-C5 (P<0.0001).
These results were supported by the Phase III APPOINT-PNH study in complement inhibitor-naïve patients, where 77.5% achieved a similar outcome. According to Vinod Pullarkat, MD, MRCP, Clinical Professor at City of Hope, "In clinical studies, iptacopan was superior to anti-C5s in hemoglobin improvement in the absence of RBC transfusion and transfusion avoidance rate, and also effective in complement inhibitor-naïve individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions."
Addressing Unmet Needs in PNH
PNH is a rare, chronic blood disorder characterized by the premature destruction of red blood cells due to an acquired genetic mutation. Current anti-C5 therapies, administered as infusions, may leave PNH symptoms uncontrolled. Studies show that up to 88% of patients on anti-C5 treatment may still experience persistent anemia, with over one-third requiring blood transfusions annually.
Fabhalta offers a significant advancement by targeting Factor B, a key protein in the complement system's alternative pathway. By inhibiting Factor B, Fabhalta prevents both intravascular and extravascular hemolysis, addressing a critical unmet need in PNH management.
Safety and Tolerability
In the APPLY-PNH trial, common adverse reactions (≥10%) with Fabhalta included headache (19%), nasopharyngitis (16%), diarrhea (15%), abdominal pain (15%), bacterial infection (11%), nausea (10%), and viral infection (10%). Fabhalta carries a boxed warning for serious infections caused by encapsulated bacteria and is available only through a Risk Evaluation and Mitigation Strategy (REMS) program that requires vaccinations for encapsulated bacteria.
Ongoing Development
Novartis is also exploring the potential of Fabhalta in other complement-mediated diseases, including immunoglobulin A nephropathy (IgA nephropathy), C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS).
