ASH 2022 – A tablet the future of paroxysmal nocturnal hemoglobinuria?

Knowledge

Oral monotherapy with iptacopan was shown to be superior to intravenous anti-C5 antibodies in patients with paroxysmal nocturnal haemoglobinuria nocturnal haemoglobinuria (PNH) and residual anaemia.
Iptacopan may represent a practice-changing outpatient treatment for suboptimal responses to standard treatment (SoC) and may be a preferred treatment option for all patients with hemolytic PNH.

Why this matters

Monoclonal anti-C5 antibodies (eculizumab, ravulizumab), the SoC therapy for PNH patients, control intravascular, but not extravascular hemolysis.
Up to two-thirds of patients remain anemic despite treatment, some of whom are transfusion-dependent.
Iptacopane, a selective factor B inhibitor, targets the proximal complement pathway and can thus control both intra- and extravascular hemolysis.

Study design

The Phase III APPLY-PNH study enrolled 97 adult PNH patients with clinically significant extravascular hemolysis despite SoC therapy.
Patients were randomized (8 : 5) and received 24 weeks of oral iptacopan (200-_mg, twice daily) or intravenous anti-C5 (as before randomization).
The primary endpoint was haematological response, defined as both an increase in baseline haemoglobin (Hb) levels to ≥ 2 g/dl and Hb levels of ≥ 12 g/dl without red blood cell transfusion.

Key results

Iptacopan was the __- SoC consider:

— haematological response (estimated proportion of patients with an increase in Hb level to ≥ 2 g/dl: 82,3 % vs. 2,0 %; Difference: 80.3 % [95 % CI: 71.3–87.6]; p <0.0001) and estimated proportion of patients with Hb levels of ≥ 12 g/dl: 68,8 % vs. 1,8 %; Difference: 67.0 % [95 % CI: 56.3–76.9]; p <0.0001)

— Transfusion independence (96,4 % vs. 26,1 %; Difference: 70.3 % [95 % CI: 52.6–84.9]; p <0.0001)

— annualized rate of clinical breakthrough hemolysis (rate ratio: 0.10 [95 % CI: 0.02–0.61]; p = 0.0118)

A clinically meaningful increase in Hb levels achieved with iptacopan was associated with a reduction in fatigue scores reported by patients.
Iptacopan monotherapy was well tolerated and safe.One patient had a serious transient ischemic attack, which was considered non-treatment-associated, and continued to receive the drug. One patient discontinued treatment due to pregnancy.

Funding