PB2054: EXPOSURE-RESPONSE ANALYSES OF PEGCETACOPLAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

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Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder associated with bone marrow failure and thrombosis. Pegcetacoplan, a targeted complement protein C3 therapy, is approved for the treatment of PNH in the European Union, the United Kingdom, and the United States. Aims: Exposure-response (E-R) relationships were investigated using hemoglobin (Hb) and lactate dehydrogenase (LDH) as clinical efficacy endpoints to inform the proposed clinical dose. Methods: A population E-R analysis was performed to describe responses of the biomarkers Hb and LDH to pegcetacoplan in patients with PNH using data from 5 clinical studies, including 2 phase 3 studies (PRINCE in patients naive to C5 inhibitors, PEGASUS in patients switched from eculizumab), both with pegcetacoplan 1080-mg subcutaneous (SC) twice-weekly dosing. Intrinsic (Asian race, age, body weight, baseline C3, creatinine clearance [CrCL], and sex) and extrinsic (pegcetacoplan exposure, eculizumab experience) factors were included in the model as prespecified covariates to quantify their impact on the E-R relationship. Simulations were performed to evaluate predicted Hb and LDH responses to pegcetacoplan 1080 mg SC dosed twice weekly or every 3 days. The E-R relationships for increased Hb and decreased LDH with increasing pegcetacoplan exposure were described with direct, sigmoidal maximal effect (Emax) models. Results: The maximum effect of pegcetacoplan was a 51.0% increase in Hb from a baseline of 8.74 g/dL. A pegcetacoplan concentration of 337 μg/mL achieved 50% of Emax (EC50) with a Hill coefficient of 4.66 describing the sigmoidicity of the relationship. The baseline LDH and LDH Emax were dependent on prior C5 inhibitor treatment while the LDH EC50 (187 μg/mL) and Hill coefficients (3.42) were consistent in both populations. The Emax was a 91.7% decrease from a baseline LDH of 1920 IU/L and a 20.0% decrease from a baseline LDH of 249 IU/L for C5 inhibitor-naive and experienced patients, respectively. The median (interquartile range [IQR]) steady-state pegcetacoplan serum concentration of 667 (551–782) μg/mL associated with 1080-mg twice-weekly dosing is expected to achieve at least 95% of Hb and LDH Emax in patients who are treatment-naive and in patients switching from C5 inhibitors. Baseline CrCL and sex affected Emax of Hb, but the magnitude of difference was not anticipated to be clinically relevant. Median (IQR) predicted Hb at steady-state for patients receiving pegcetacoplan 1080 mg twice weekly was 11.7 (10.5–13.3) g/dL. Median (IQR) predicted LDH at steady-state following pegcetacoplan 1080-mg twice-weekly dosing was 217 (170–292) U/L for complement inhibitor-naive patients and 192 (148–260) U/L for patients switching from eculizumab to pegcetacoplan, with 84.3% of naive patients and 96.7% of switch patients predicted to achieve LDH control (defined as <1.5 times the upper limit of normal). Asian race, age, body weight, and baseline C3 level were not found to have clinically or statistically meaningful effects on either Hb or LDH response to pegcetacoplan. Additionally, prior eculizumab treatment did not have an effect on Hb response. Sex and baseline CrCL did not have a meaningful effect on LDH response to pegcetacoplan. Summary/Conclusion: Relationships of Hb and LDH responses with pegcetacoplan exposure were well described by the models. Pegcetacoplan 1080 mg SC twice weekly dosing was supported by the models as effective in patients with PNH who are naive to complement inhibitors and in those switching from C5 inhibitors to pegcetacoplan. Keywords: Hemoglobin, Complement, Anemia, Paroxysmal nocturnal hemoglobinuria (PNH)

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