FABHALTA

Paroxysmal Nocturnal Hemoglobinuria (PNH)

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 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 109/L. About 13% of patients had a history of MAVEs. No patients discontinued from the core treatment period of the study.

Immunoglobulin A Nephropathy (IgAN)

The effect of FABHALTA was evaluated in a multicenter, randomized, placebo-controlled, double-blind study (APPLAUSE-IgAN, NCT04578834) in adults with biopsy-proven IgAN, eGFR ≥ 20 mL/min/1.73 m2, and urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g on a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy with or without a stable dose of an SGLT2 inhibitor. Patients with other glomerulopathies or those who had been recently treated with systemic immunosuppressants were excluded. Patients were included in either the Main Study Population (eGFR ≥ 30 mL/min/1.73 m2) or the Severe Renal Impairment population (eGFR ≥ 20 and < 30 mL/min/1.73 m2). Within each group, patients were randomized (1:1) to either FABHALTA 200 mg or placebo twice daily. Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial.

Patients were required to be vaccinated againstNeisseria meningitidisandStreptococcus pneumoniaeand were recommended to be vaccinated againstHaemophilus influenzaetype b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered.

The efficacy analysis was based on the first 250 patients with an eGFR ≥ 30 mL/min/1.73 m2(Main Study Population), who had completed or discontinued the study prior to the Month 9 visit. At baseline, the mean age of these patients was 39 years (range 18 to 74 years); 52% were male, 44% White, 54% Asian, and < 1% Black or African American; the mean eGFR was 64 mL/min/1.73 m2; the geometric mean UPCR (sampled from a 24-hr urine collection) was 2.0 g/g, and 12% had a UPCR ≥ 3.5 g/g. At baseline, 99% of patients were treated with an ACEi or ARB and 13% were on an SGLT2i. Approximately 59% had a history of hypertension, 6% had a history of type 2 diabetes, and 75% had hematuria based on urine dipstick.

Figure 1: Geometric Mean Percent Change from Baseline in UPCR by Visit in APPLAUSE-IgAN

Abbreviations: CI, confidence interval; FAB, FABHALTA; MMRM, mixed model repeated measures; N, number of subjects in each group; PBO, placebo; UPCR, urine protein-to-creatinine ratio.

The treatment effect on UPCR at Month 9 was consistent across all subgroups including age, sex, race, baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i.

Complement 3 Glomerulopathy (C3G)

The efficacy of FABHALTA in reducing proteinuria in adult patients with native kidney C3G was demonstrated in the APPEAR-C3G trial. Safety and effectiveness of FABHALTA in patients with recurrent C3G following kidney transplant have not been established.

APPEAR-C3G was a randomized, double-blind, placebo-controlled study in 74 adult patients with biopsy confirmed native kidney C3G who had a urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g and eGFR ≥ 30 mL/min/1.73 m2(NCT04817618). Patients were randomized (1:1) to receive either FABHALTA 200 mg orally twice daily (N = 38) or placebo (N = 36) for 6 months, followed by a 6-month open-label treatment period in which all patients received FABHALTA 200 mg orally twice daily.

Patients were required to be on a maximally tolerated renin-angiotensin system (RAS) inhibitor and could be on a corticosteroid and/or mycophenolate mofetil/sodium (MMF/MPS) at baseline. All background therapies (i.e., RAS inhibitors, corticosteroids and MMF/MPS) were required to be at stable doses for 90 days prior to randomization and throughout the study. Randomization was stratified according to whether patients were receiving concomitant immunosuppressive therapy.

Patients were required to be vaccinated againstNeisseria meningitidisandStreptococcus pneumoniaeand were recommended to be vaccinated againstHaemophilus influenzaetype b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered.

At baseline, the mean age of patients was 28 years (range 18 to 60 years), 64% were male, 69% were White, 24% were Asian, and 9% were Hispanic or Latino. The mean baseline eGFR (mL/min/1.73 m2) was 89 and 99 in the FABHALTA and placebo groups, respectively, and the geometric mean 24-hour UPCR (g/g) at baseline was 3.3 and 2.6 in the FABHALTA and placebo groups, respectively.

Twenty four percent of patients in the FABHALTA group and 3% in the placebo group had dense deposit disease. Baseline use of corticosteroids and/or MMF/MPS, and RAS inhibitor was balanced among the FABHALTA and placebo groups. Overall, 45% of patients were on corticosteroids and/or MMF/MPS, and 99% of patients were on a RAS inhibitor at baseline.

Following the initial 6-month treatment period, all patients were treated with FABHALTA for an additional 6 months. In patients initially randomized to FABHALTA, the reduction in 24-hour UPCR seen at 6 months was maintained at Month 12. In patients who switched from placebo to FABHALTA, the magnitude of the reduction in 24-hour UPCR from Month 6 to 12 was similar to the reduction seen in patients initially randomized to FABHALTA. The geometric mean percent change from baseline in UPCR (measured as first morning void [FMV]) over time is shown in Figure 2.

Figure 2: Geometric Mean Percent Change from Baseline in UPCR FMV (g/g) up to Month 12 (APPEAR-C3G)

The treatment effect of FABHALTA on UPCR at Month 6 was generally consistent across subgroups including age, sex, race, baseline disease characteristics (such as baseline proteinuria and eGFR levels) and use of immunosuppressive therapies.