Iptacopan offers solution for patients with PNH and residual anaemia after standard-of-care 

Iptacopan outperformed standard-of-care in patients with paroxysmal nocturnal haemoglobinuria (PNH) who had residual anaemia after anti-C5 standard-of-care treatment, results from the phase 3 Apply-PNH trial demonstrated. Together with the favourable safety profile of iptacopan, this agent presents itself as a potential practice-changing treatment for this patient group.

In patients with PNH, targeting the terminal complement pathway at C5 with ravulizumab or eculizumab helps to control intravascular haemolysis [1,2]. However, residual anaemia, mostly due to extravascular haemolysis, occurs in up to two-thirds of patients [3]. Iptacopan, a first-in-class, oral, selective factor B inhibitor, targets the complement system proximally, via the alternative pathway [4]. A recently published phase 2 study showed that iptacopan controlled haemolysis in a group of 10 patients with PNH and active haemolysis who did not respond well to eculizumab [5].

To further investigate iptacopan, the Apply-PNH trial (NCT04558918) randomised 97 patients with PNH and residual anaemia despite treatment with standard-of-care 8:5 to iptacopan 200 mg oral, twice daily or to the intravenous anti-C5 standard-of-care they received before randomisation [6]. The primary endpoints were:

• Achieving an increase from baseline in haemoglobin of ≥2 g/dL in the absence of red-blood cell transfusions
• Achieving an increase from baseline in haemoglobin of ≥12 g/dL in the absence of red-blood cell transfusions.

Prof. Régis de Latour (Saint-Louis Hospital, France) presented the primary results after 24 weeks of treatment.

In total, 51 out of 60 patients in the iptacopan arm achieved the first primary endpoint compared with 0 out of 35 in the standard-of-care arm, with a population estimate difference of 80.3% (95% CI 71.3–87.6; P<0.0001). The second primary endpoint was reached by 42 patients in the iptacopan arm and by 0 patients in the standard-of-care arm. The corresponding population estimate difference was 67.0% (95% CI 56.3–76.9; P<0.0001). Furthermore, transfusion could be avoided in 60 out of 62 patients in the iptacopan arm and in 14 out of 35 patients in the standard-of-care arm (population estimate difference 70.3%; 95% CI 52.6–84.9; P<0.0001).

The safety analysis showed an apparent higher incidence of headache (16.1% vs 2.9%) and diarrhoea (14.5% vs 5.7%) in the iptacopan arm, but breakthrough haemolysis was more common in the standard-of-care arm than in the iptacopan arm (17.1% vs 3.2%). Finally, the rate of serious treatment-emergent adverse events seemed to be higher in the standard-of-care arm (14.3% vs 9.7%).

“Iptacopan may represent a practice-changing, oral, outpatient therapy for patients with PNH who do not respond well to ravulizumab or eculizumab,” suggested Prof. de Latour.

1. Hillmen P, et al. N Engl J Med. 2006;355:1233–1243.
2. Kulesakararaj AG, et al. Blood. 2019;133(6):540–549.
3. Risitano AM, et al. Front Immunol. 2019;10:1157.
4. Schubart A, et al. Proc Natl Acad Sci USA. 2019;116:7926–7931.
5. Risitano AM, et al. Lancet Haematol. 2021;8(5):e344–e354.
6. de Latour RP, et al. Oral Monotherapy with Iptacopan, a Proximal Complement Inhibitor of Factor B, Has Superior Efficacy to Intravenous Terminal Complement Inhibition with Standard of Care Eculizumab or Ravulizumab and Favorable Safety in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Randomized, Active-Comparator-Controlled, Open-Label, Multicenter, Phase III Apply-PNH Study. Late-Breaking Abstract 2, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 202327 March 2024