Iptacopan for paroxysmal nocturnal haemoglobinuria

Background:
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare blood disorder caused by mutations in the phosphatidylinositol glycan A (PIGA) gene. These mutations result in red blood cells that are vulnerable to attack by the complement (immune) system. This results in complement-mediated haemolysis with associated thrombosis, organ dysfunction and bone marrow failure.¹ Prior to the advent of complement inhibitors, PNH had a high mortality rate, most commonly due to thrombosis.² Complement inhibitors, which act on the alternative complement pathway (as distinct from classical and leptin complement pathways), have transformed management and patient outcomes.² They first became available in Australia in 2009 when eculizumab, a complement-5 (C5) inhibitor, was approved.³ Since then, other C5 inhibitors (e.g. ravulizumab) and, more recently, complement-3 (C3) inhibitors (e.g. pegcetacoplan, iptacopan) have become available.

Many patients with PNH experience persistent haemolytic anaemia, despite intravenous anti-C5 therapy, due to C3-mediated extravascular haemolysis.

Mechanism of action:
Iptacopan is an orally administered C3 inhibitor.¹ Iptacopan acts by inhibiting factor B, thereby preventing the activation of C3 convertase and the subsequent generation of C5 convertase, thereby stopping C3- and C5-mediated intravascular (in the circulation) and extravascular (in the spleen, bone marrow or liver) haemolysis.

Clinical trials:
The efficacy and safety of iptacopan for PNH in adults were assessed in 2 open-label, multi-centre, phase 3 trials: APPLY-PNH and APPOINT-PNH.¹ Participants in both trials were similar at baseline: PNH confirmed as per standardised diagnostic criteria, anaemia (haemoglobin less than 100 g/L) and no evidence of marrow failure.¹ Exclusion criteria for both studies included bone marrow failure, active systemic infection, major or unstable comorbidities, malignancy within the past 5 years, and pregnancy or breastfeeding.¹

The APPLY-PNH study recruited 97 patients who had been on anti-C5 therapy (eculizumab or ravulizumab) for at least 6 months. Patients were randomised to receive iptacopan 200 mg twice daily (62 patients) or to continue anti-C5 therapy (35 patients) for 24 weeks. Iptacopan was superior to anti-C5 therapy in increasing haemoglobin, avoiding transfusion, decreasing fatigue and improving a range of other secondary outcomes.¹

The APPOINT-PNH study comprised a single group of 40 adults who had not been treated with complement inhibitors in the preceding 3 months and who had levels of lactate dehydrogenase more than 1.5 times the upper limit of normal (indicating high levels of haemolysis). All patients received iptacopan 200 mg twice daily for 24 weeks.

Both studies had primary endpoints relating to haemoglobin level without red-cell transfusion. APPLY-PNH had 2 primary endpoints: increase in haemoglobin of at least 20g/L from baseline and sustained haemoglobin level of at least 120 g/L. APPOINT-PNH had one primary endpoint: increase in haemoglobin of at least 20g/L from baseline (and sustained haemoglobin level of at least 120 g/L was a secondary endpoint). Secondary endpoints in both studies included avoidance of transfusions, level of fatigue, reticulocyte count, change in lactate dehydrogenase level, haemolysis, major adverse vascular events and safety.

There was significant improvement reported across all primary and secondary outcomes (Table 1).¹

Table 1 Selected outcome data from APPLY-PNH and APPOINT-PNH trials¹

Outcomes	APPLY-PNH response rate iptacopan (n=60 [NB1]) versus anti-C5 therapy (n=35)	APPOINT-PNH response rate iptacopan (n=33 [NB2]) observational data
Increase in haemoglobin greater than or equal to 20 g/L without transfusion [NB3]	85% versus 0% patients	94% patients
Sustained haemoglobin greater than or equal to 120 g/L without transfusion	70% versus 0% patients	58% patients
Transfusion avoidance rate	95% versus 40% patients	98% patients
Haemoglobin mean increase	+36 g/L versus −0.6 g/L	+43 g/L
Decrease in lactate dehydrogenase	No difference between groups	−83.6%
NB1: 60/62 patients included in evaluation, 2 excluded for missing data NB2: 33/40 patients included in evaluation, 7 excluded for missing data NB3: haemoglobin reported in Australian units of g/L; reported in original studies as g/dL

Adverse effects:
The most common adverse effects reported in the APPLY-PNH and APPOINT-PNH studies were upper respiratory tract infections (19.4% and 17.5% respectively), headache (17.7% and 27.5%), diarrhoea (14.5% and 7.5%) and abdominal pain (14.5% and 7.5%). Adverse effects were not a reason for discontinuing treatment in either trial.^1,4

Dosage and administration:
The recommended dose of iptacopan is 200 mg orally twice daily.^1,4

To reduce the risk of haemolysis, patients switching from anti-C5 therapies (e.g. eculizumab, ravulizumab) to iptacopan need to be advised to start iptacopan no later than 1 week after the last dose of eculizumab and no later than 6 weeks after the last dose of ravulizumab. Switching from other therapies has not been studied.⁴

Dose adjustment is not required in patients with mild to moderate renal (eGFR greater than or equal to 30 mL/min/1.73m²) or hepatic impairment. There are no data on the use of iptacopan in patients with severe renal impairment, including those on dialysis. Iptacopan is not recommended for patients with severe hepatic impairment.⁴

Precautions and practice points:
Complement inhibitors increase the risk of serious infection, particularly with encapsulated bacteria. All patients need to be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B at least 2 weeks prior to starting iptacopan. Clinicians should be alert to the risk of serious infection,⁵ and patients should be monitored for early signs and symptoms of serious infection during therapy and advised when to seek review.⁴

Iptacopan is a substrate of cytochrome P450 (CYP) 2C8 and for the transporters P-glycoprotein, BCRP, MRP2, OATP1B1 and OATP1B3. Concomitant use with strong inducers should be avoided as this has not been studied.⁴

Iptacopan has the potential to induce CYP3A4 and inhibit CYP2C8, affecting sensitive substrates, and caution should be exercised when co-administering with substrates that have a narrow therapeutic index.⁴

Iptacopan is not generally combined with other complement inhibitors and the timing of switching from one complement inhibitor to another should be carefully planned to avoid haemolysis from rapid treatment discontinuation.⁴

Use in pregnancy and breastfeeding:
There are limited data on the safety of iptacopan in pregnancy. It is classified as TGA pregnancy category B1.⁴ Untreated PNH in pregnancy is associated with adverse maternal and fetal outcomes; the use of iptacopan in pregnancy requires assessment of risks and benefits. It is unknown whether iptacopan is excreted in human milk.⁴

Place in therapy:
In the APPLY-PNH and APPOINT-PNH studies, iptacopan significantly increased haemoglobin levels, reduced fatigue, and achieved normal or near-normal haemoglobin levels in patients with PNH who had persistent anaemia despite anti-C5 therapy and in patients who were treatment-naive.¹ Iptacopan is the first oral complement inhibitor and can potentially inhibit both intra- and extra-vascular complement-mediated haemolysis.

This new drug comment was finalised on 1 September 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Peffault de Latour R, Roth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med 2024;390:994-1008.
2. Gerber GF, Broome CM, Weitz IC. Navigating the paroxysmal nocturnal hemoglobinuria (PNH) landscape. Clin Adv Hematol Oncol 2025;23 Suppl 8:1-19.
3. Therapeutic Goods Administration. Australian Public Assessment Report for Eculizumab. Department of Health, Disability and Ageing; 2020. [cited 2025 Sep 1]
4. Therapeutic Goods Administration. Australian Product Information - FABHALTA iptacopan 200 mg hard capsules blister pack. Department of Health, Disability and Ageing; 2024. [cited 2025 Sep 1]
5. Therapeutic Goods Administration. Australian Public Assessment Report for Fabhalta. Department of Health, Disability and Ageing; 2025. [cited 2025 Sep 1]

 

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