Fabhalta Drug Information

• 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 < 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 3). 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 the FABHALTA group and 57.4% for the anti-C5 group.
• Table 3: Patient Baseline Demographics and Characteristics in APPLY-PNH 11.9 13.5 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 4.
• Table 4: Efficacy Results for the 24-week Randomized Treatment Period for APPLY-PNH 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. All 40 patients received FABHALTA 200 mg orally twice daily during the 24-week open-label core treatment period. 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. About 13% of patients had a history of MAVEs. No patients discontinued from the core treatment period of the study. In total, 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, 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.

Immunoglobulin A Nephropathy (IgAN)

The effect of FABHALTA on proteinuria and kidney function (estimated glomerular filtration rate, eGFR) was evaluated in a randomized, placebo-controlled, double-blind, multicenter, global study (APPLAUSE-IgAN, NCT04578834) in adults with biopsy-proven primary IgAN, eGFR ≥ 20 mL/min/1.73 m 2, 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 a sodium-glucose co-transporter 2 inhibitor (SGLT2i). Patients with other glomerulopathies or those who had been recently treated with systemic immunosuppressants were excluded. 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. The primary efficacy endpoint for the interim analysis was the relative change from baseline in UPCR (sampled from a 24-hour urine collection) at Month 9 based on the first 250 randomized patients (Main Study Population). The primary efficacy endpoint for the final analysis was the annualized total eGFR slope over 24 months (Main Study Population).

At baseline, 99% of patients were treated with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and 19% were on a SGLT2i. In the final analysis of 477 randomized patients, the treatment effects on UPCR observed at Month 9 and Month 24 were consistent with the results obtained at the interim analysis. The geometric mean percent change from baseline in UPCR over the course of the double-blind period is shown in Figure 1.

Figure 1: Geometric Mean Percent Change from Baseline in UPCR and 24-hour UPCR by Visit in APPLAUSE-IgAN Log transformed ratio to baseline in UPCR was analyzed using an MMRM with stratification factors: geographic region, baseline eGFR and baseline UPCR. MMRM analysis included UPCR data during the double-blind period up to Month 24 based on all patients. UPCR data after the intercurrent events and missing data were handled by the pre-defined strategies and imputation approaches. 24-hour UPCR and UPCR were analyzed separately using the same analysis method. *Represents the number of patients with values non-missing and not imputed as per the intercurrent event handling strategy by visit and treatment group.

Abbreviations: bid, twice daily; CI, confidence interval; eGFR, estimated glomerular filtration rate; MMRM, mixed model repeated measures; N, number of patients in each group with non-missing baseline and covariates; UPCR, urine protein-to-creatinine ratio; 24-hour UPCR, urine protein-to-creatinine ratio sampled from a 24-hour urine collection; UPCR, urine protein-to-creatinine ratio sampled from first morning void. Estimated Glomerular Filtration Rate (eGFR) The study met the prespecified primary endpoint for final analysis, the annualized total eGFR slope over 24 months in the Main Study Population. The mean change from baseline in eGFR during the double-blind period is shown in Figure 2.

The treatment effect on the change from baseline in eGFR estimated at 24 months was generally consistent across key subgroups including age, sex, race, baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i. Figure 2: Mean Change from Baseline in eGFR (mL/min/1.73 m 2 ) by Visit in APPLAUSE-IgAN The mean change from baseline in eGFR was estimated from an MMRM with stratification factors: geographic region, baseline eGFR and baseline UPCR. MMRM analysis included all eGFR data during the double-blind period up to Month 24 regardless of treatment discontinuation for any reason with exception of the initiation of kidney replacement therapy which were handled by a worst-case imputation method. Represents the number of patients with values non-missing and not imputed as per the intercurrent event handling strategy by visit and treatment group.

Table 5 shows the treatment effect of FABHALTA compared to placebo on the key secondary endpoint of time to first occurrence of a kidney composite event, consisting of a sustained ≥30% decline in eGFR from baseline, sustained eGFR <15 mL/min/1.73 m², maintenance dialysis, receipt of kidney transplant, and death from kidney failure. The treatment effect was driven by an effect on a sustained decline in eGFR ≥30% from baseline. 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 m 2 (NCT04817618). 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. 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. The primary efficacy endpoint was the log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 6 months. At 6 months, the geometric mean UPCR ratio relative to baseline was in the FABHALTA and placebo groups, respectively, resulting in a 35% reduction in 24-hour UPCR from baseline in the FABHALTA group compared to placebo (p = 0.0028).

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 ) over time is shown in Figure 3. Compared to patients treated with placebo, patients treated with FABHALTA had a 7-fold higher odds (p = 0.0166) of achieving a composite renal endpoint defined as a ≥ 50% reduction in 24-hour UPCR compared to baseline and stable or improved eGFR compared to baseline at 6 months. Although a greater proportion of patients in the FABHALTA arm (30%) as compared to placebo (6%) achieved a ≥ 50% reduction in 24-hour UPCR compared to baseline, there was no difference between arms in the proportion of patients with stable or improved eGFR compared to baseline at 6 months (90% in FABHALTA vs 89% in placebo).

Figure 3: 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. Figure 1: Geometric Mean Percent Change from Baseline in UPCR and 24-hour UPCR by Visit in APPLAUSE-IgAN Figure 2: Mean Change from Baseline in eGFR (mL/min/1.73 m²) by Visit in APPLAUSE-IgAN Figure 3: Geometric Mean Percent Change from Baseline in UPCR FMV (g/g) up to Month 12 (APPEAR-C3G)