FABHALTA Hard capsule Ref.[107283] Active ingredients: Iptacopan

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 FABHALTA 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 FABHALTA 200 mg twice daily.

In PNH patients on concomitant anti-C5 treatment and FABHALTA 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 FABHALTA 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, FABHALTA 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 FABHALTA 200 mg twice daily. The clearance of iptacopan at steady state is 7.96 L/h after administration of FABHALTA 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.

Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.

Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9-times the MRHD based on AUC.

In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeat-dose toxicity studies with oral administration in dogs at doses ≥ 2-times the MRHD based on AUC, with no clear effects on sperm numbers, morphology or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre- and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to ~11-times the MRHD based on AUC.

14.1 Paroxysmal Nocturnal Hemoglobinuria

APPLY-PNH: Anti-C5 treatment Experienced Patients With PNH

The efficacy of FABHALTA administered orally in adults with PNH was evaluated in a multi-center, open-label, 24-week, active comparator-controlled trial (APPLY-PNH; NCT04558918).

The study enrolled adults with PNH and residual anemia (hemoglobin <10 g/dL) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization.

Ninety-seven patients were randomized in an 8:5 ratio to switch to FABHALTA 200 mg orally twice daily (n=62) or to continue anti-C5 treatment (US-approved and non-US-approved eculizumab product n=23 or US-approved and non-US-approved ravulizumab product n=12) throughout the duration of the 24-week randomized controlled period. Randomization was stratified based on prior anti-C5 treatment and transfusion history within the last 6 months. Following completion of the 24-week randomized controlled period, all patients were eligible to enroll in a 24-week treatment extension period and receive FABHALTA monotherapy. Subsequently, patients were eligible to enter a separate long-term extension study.

Patients were required to be vaccinated against Neisseria meningitidis and recommended to be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type B. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to the first dose of study medication. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered.

Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 2). The mean time on prior anti-C5 treatment was 3.8 and 4.2 years for the FABHALTA and anti-C5 groups, respectively. The baseline mean PNH RBC clone size (Type II + III) was 64.6% for FABHALTA and 57.4% for the anti-C5 group.

Table 2. Patient Baseline Demographics and Characteristics in APPLY-PNH:

Abbreviations: LDH, lactate dehydrogenase; MAVEs, major adverse vascular events (includes thrombosis, stroke and myocardial infarction); SD, standard deviation.

Efficacy was established based on demonstration of superiority of switching to FABHALTA compared to continuing on anti-C5 therapy in achieving hematological response after 24 weeks of treatment, without a need for transfusion, by assessing the proportion of patients demonstrating: 1) sustained increase of ≥ 2 g/dL in hemoglobin levels from baseline (hemoglobin improvement) and 2) sustained hemoglobin levels ≥ 12 g/dL. Additional efficacy endpoints included transfusion avoidance, change from baseline in hemoglobin levels and change from baseline in absolute reticulocyte counts.

The efficacy results from the APPLY-PNH trial are provided in Table 3.

Table 3. Efficacy Results for the 24-week Randomized Treatment Period for APPLY-PNH:

Abbreviations: RR, rate ratio
^a Assessed between Day 126 and 168.
^b Adjusted difference in proportion.
^c Assessed between Day 14 and 168.
^d Transfusion avoidance is defined as absence of administration of packed-red blood cell transfusions between Day 14 and 168.
^e Adjusted mean assessed between Day 126 and 168.
^f Excludes values within 30 days post-transfusion.

APPOINT-PNH: Complement Inhibitor Naïve Patients with PNH

Study APPOINT-PNH (NCT04820530) is a single arm study in adults with PNH who were not previously treated with a complement inhibitor. This study enrolled a total of 40 adults with PNH (RBC clone size ≥10%), hemoglobin <10 g/dL, and LDH >1.5 times upper limit of normal (ULN). All 40 patients received FABHALTA 200 mg orally twice daily during the 24-week open-label core treatment period. Subsequently, patients were eligible to enroll in a 24-week treatment extension period and continue to receive FABHALTA, followed by a separate long-term extension study.

The mean age of the patients was 42.1 years and 42.5% were female. The mean disease duration was 4.7 years. The baseline mean PNH RBC clone size (Type II + III) was 42.7%, mean baseline hemoglobin was 8.2 g/dL, and approximately 70% of patients required a transfusion in the 6 months prior to treatment. The baseline mean LDH level was 1,699 U/L and the mean absolute reticulocyte count was 154 X 10 ⁹/L. About 13% of patients had a history of MAVEs. No patients discontinued from the core treatment period of the study.

In total, 77.5% (95% CI: 61.5%, 89.2%) of patients (31/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, based on central laboratory hemoglobin values. In a sensitivity analysis, 87.5% (95% CI: 73.2%, 95.8%) of patients (35/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, including local laboratory hemoglobin values when central laboratory hemoglobin values were not available.