Iptacopan delivers durable responses in anti-C5-treated PNH patients with anaemia

The final results of the pivotal phase III APPLY-PNH trial show sustained efficacy and safety of the oral factor B inhibitor iptacopan in anti-C5-treated patients with paroxysmal nocturnal haemoglobinuria (PNH) and persistent anaemia.

“Patients on iptacopan for 48 weeks had sustained improvements in multiple haematological and clinical outcomes, including maintenance of increased haemoglobin (Hb), mean normal/near-normal Hb levels, transfusion avoidance, and decreased patient-reported fatigue,” said principal co-investigator Dr Antonio Risitano from the Azienda Ospedaliera di Rilievo Nazionale San Guiseppe Moscati, Avellino, Italy, at ASH 2023.

“These benefits quickly emerged [among those who switched from anti-C5 to iptacopan,] supporting the benefit of switching from C5 inhibitors to iptacopan monotherapy,” he continued.

The study included 97 PNH patients with residual anaemia (mean age 51 years, 69 percent female, mean baseline Hb 8.9 g/dL) despite stable anti-C5 therapy* for ≥6 months. They were randomized 8:5 to iptacopan 200 mg BID or IV anti-C5 therapy for 24 weeks. A 24-week extension period ensued thereafter, wherein iptacopan recipients went on with their regimen (iptacopan arm) while those on anti-C5 switched to iptacopan (switch arm). [ASH 2023, abstract 571]

In the iptacopan arm, the week-24 Hb increase was sustained at week 48 (mean Hb level, 12.2 g/dL; adjusted mean difference, -0.41 g/dL). In the switch arm, the week-24 mean Hb level (9.1 g/dL) increased within a week after the switch and by week 28, it was already around the 12-g/dL mark. This was sustained until week 48 (mean Hb level, 12.1 g/dL).

More than 90 percent of iptacopan recipients were transfusion-free between weeks 2 and 48. Among switchers, only 40 percent were able to avoid transfusions pre-switch. However, this jumped to 94 percent post-switch.

In the iptacopan arm, mean FACIT-F** score was sustained from week 24 to week 48 (43.6). In the switch arm, the week-24 score jumped from about 30.0 to 44.6 by week 48.

Other outcomes

Regarding absolute reticulocyte count, the week-24 reduction seen in the iptacopan arm was sustained at week 48 (80.84 x 10⁹/L). In the switch arm, a rapid drop occurred a week following the switch and stabilized to 78.48 x 10⁹/L by week 48.

Clinical breakthrough haemolysis (BTH) events were infrequent with iptacopan between weeks 24 and 48 (8 percent and 3 percent in the respective iptacopan and switch arms). “All clinical BTH events reported during iptacopan monotherapy were mild or moderate in severity and resolved without iptacopan discontinuation,” Risitano said.

All major adverse vascular events reported (transient ischaemic attack, portal vein thrombosis) were deemed unrelated to iptacopan and resolved without the need to stop iptacopan.

The safety profile of iptacopan at week 48 aligned with that observed at week 24. There were no serious treatment-emergent adverse events (TEAEs) of haemolysis nor were there any serious infections***, TEAE-related treatment discontinuations, or deaths.

Potentially practice-changing

More than 80 percent of PNH patients remain anaemic despite anti-C5 therapies largely due to emerging extravascular haemolysis. Subsequently, some become transfusion-dependent. Hence, there remains a significant unmet need in PNH treatment. [Blood 2009;113:4094-4100; Front Immunol 2019;10:1157; Hematol Rep 2023;15:266-282]

“[These new] data are an expansion of the robust outcomes we saw in the randomized phase and demonstrate that PNH patients who took iptacopan experienced Hb improvement over the longer term – nearly a year,” Risitano noted in a press release.

“[Taken together,] these long-term data show durable responses with iptacopan, with good comprehensive control of intravascular and extravascular haemolysis,” Risitano said.

“Our findings continue to support oral iptacopan monotherapy as a promising therapeutic option and potentially practice-changing outpatient treatment for haemolytic PNH patients with persistent anaemia despite anti-C5 therapy,” he concluded.

Readout of the 48-week findings from the phase III APPOINT-PNH trial is anticipated in 2024 to shed light on iptacopan’s role in treatment-naïve PNH patients.