Iptacopan

Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway.

In PNH, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH.

Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers.

In PNH patients receiving concomitant anti-C5 treatment and iptacopan 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment naïve PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with iptacopan 200 mg twice daily.

In PNH patients on concomitant anti-C5 treatment and iptacopan 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment naïve PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH.

Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with iptacopan 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times upper limit of normal (ULN) at 13 weeks. In treatment naïve PNH patients, iptacopan 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years.

Cardiac Electrophysiology

In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval.

Absorption

Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold).

Effect of Food

Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree.

Distribution

Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein bound in vitro at the relevant clinical plasma concentrations. After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L.

Elimination

The half-life (t_1/2) of iptacopan at steady state is approximately 25 hours after administration of iptacopan 200 mg twice daily. The clearance of iptacopan at steady state is 7.96 L/h after administration of iptacopan 200 mg twice daily.

Metabolism

Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug related species. Iptacopan metabolites are not pharmacologically active.

Excretion

In a human study, following a single 100 mg oral dose of [ ¹⁴C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the feces and 24.8% in the urine, for a total mean excretion of >96% of the dose. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine, and 16.8% of the dose was excreted as parent iptacopan in feces.

Linearity / Non-linearity

At doses between 25 mg and 200 mg twice daily, iptacopan was overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional.

Specific Populations

A population pharmacokinetic (PK) analysis was conducted on iptacopan data from 234 patients. Age, body weight, race, and gender did not have a clinically significant effect on iptacopan PK.

Patients with Renal Impairment

The effect of renal impairment on the exposure of iptacopan was assessed using a population pharmacokinetic analysis. Renal function was estimated as eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. There were no clinically relevant differences in the exposure of iptacopan between patients with normal renal function compared to patients with mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment. The population pharmacokinetic analysis did not include a sufficient number of patients with severe renal impairment with or without hemodialysis.

Patients with Hepatic Impairment

In a study in subjects with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe hepatic impairment (Child-Pugh class C), there was a negligible effect of hepatic impairment on the total (bound+unbound) exposure of iptacopan. However, unbound iptacopan AUC_inf increased by 1.5, 1.6, and 3.7-fold in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function.

Drug Interaction Studies

Based on a clinical drug interaction study in healthy volunteers, iptacopan exposure did not change to a clinically relevant degree when coadministered with clopidogrel (a moderate CYP2C8 inhibitor) or cyclosporine (a P-gp, BCRP, and OATP 1B1/1B3 inhibitor). The exposure of digoxin (a P-gp substrate) and rosuvastatin (an OATP substrate) did not change to a clinically relevant degree when coadministered with iptacopan.