IPTACOPAN

Uncontrolled activation of usually tightly regulated alternative complement pathway is the underlying pathogenesis in most cases of aHUS. This leads to excessive formation of C3 and C5 convertases and consequent formation of the membrane attack complex (MAC) on the vascular cells mainly in the kidneys leading to TMA. Iptacopan (LNP023) is a potent oral highly selective inhibitor of factor B of alternative complement pathway. Iptacopan binds to Factor B to prevent activity of alternative complement pathway C3 convertases, inhibiting signaling from the alternative complement pathway and activation of the amplification loop to prevent downstream generation of the alternative complement pathway C5 convertase complex, alternative complement pathway-dependent opsonization, and alternative complement pathway-mediated formation of C3a and C5a anaphylatoxins and membrane attack complex. 

How is Iptacopan being studied in aHUS?

APPELHUS is a multicenter, phase 3, single arm, open label  study, which aims to evaluate the efficacy and safety of iptacopan in adult patients with aHUS. 50 patients naïve to complement inhibitors (including anti-C5 antibody therapy) will be enrolled. After an initial screening period of 7 days, patients will receive  iptacopan 200 mg twice daily for 26 weeks. Patients will thereafter continue receiving iptacopan at 200 mg twice daily for an additional 26 weeks as part of the extension period. The primary objective is to assess the proportion of patients treated with iptacopan achieving complete TMA response (i.e. hematological normalization in platelet count and LDH and  ≥25% serum creatinine reduction from baseline, maintained for 2 measurements obtained at least 4 weeks apart, and any measurement in between)  during 26 weeks of study treatment.

Image from Kavanagh at al, KI reports, April 2023

What are the eligibility criteria?

1. Adult patients with evidence of active  TMA, including thrombocytopenia, evidence of hemolysis, and acute kidney injury

2. Vaccinations against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections are required prior to the start of study treatment. 

Patient website: https://www.novartis.com/clinicaltrials/study/nct04889430