112 Chapter 6 Table 3. Summary of parameter estimates from published population PK models. Study Population Parameter estimates Inter-individual variability Yoneyama et al. (2018)a Japanese volunteers (n = 24) Caucasian volunteers (n = 18) Dose finding study in PwHA - 0.3mg/kg QW (n = 6) - 1 mg/kg QW (n = 6) - 3 mg/kg QW (n = 6) PK parameters: Cl/F 0.222 L/day Vd/F 10.2 L t1/2, abs 1.56 days t1/2,eli 31.8 days for volunteer t1/2,eli 30.1 days for PwHA Response parameters: λ 21.9 events/year EC50 1.19 µg/mL Variance: Cl/F 0.0737 Vd/F 0.0455 t1/2, abs 0.502 Retout et al. (2020)b Dose finding study in PwHA (n = 16) Phase III trials in PwHA with approved dosing regimens - HAVEN 1 (n = 112) - HAVEN 2 (n = 63) - HAVEN 3 (n = 148) - HAVEN 4 (n = 48) PK parameters: Cl/F 0.272 L/dayb Vd/F 10.4 Lb KA 0.536 1/dayb t1/2, abs 1.61 days t1/2,eli 26.8 days Variability (%): Cl/F 28.7 Vd/F 25.9 KA 72.5 aStandardized for a volunteer of 70 kg, without anti-drug antibodies. bStandardized for a subject of 70 kg, albumin 45 g/L, age <30 years. Abbreviations: PK: pharmacokinetic, PwHA: people with haemophilia A; QW: weekly dose interval; CL/F: apparent clearance; Vd/F: apparent volume of distribution; EC50: half maximal effective concentration; Ka: absorption rate constant; t½,abs: terminal half-life of absorption; and t½,abs: terminal half-life of elimination. Eleven PwHA study subgroups within five studies [18-20,31,32], provided the modelbased mean ABRs of treated bleeds. The Ctrough,ss was the only exposure metric that could be extracted in combination with these ABRs. The ABRs were fitted with corresponding Ctrough,ss values in an Emax model (Figure 3). The EC50 (i.e., 50% of maximum drug effect) was estimated at 1.47 µg/mL (standard error [SE] 0.90) assuming ABR baseline of 28.0 and Emax of 0.96. The effectiveness plateau of the concentration−response relationship was clearly established, and all ABR observations resided herein. Based on this model, a Ctrough,ss of 30 and 50 µg/mL would result in ABRs of treated bleeds of 2.4 and 1.9, respectively, and with an RRR of 91% and 93%, respectively. A second Emax model was fitted with the ABRs of treated joint bleeds, instead of treated bleeds, with corresponding Ctrough,ss values (Supplemental Figure SF3). The EC50 was estimated at 1.09 µg/mL (SE 0.36, assuming baseline ABR 21.6 and Emax 0.98, and Ctrough,ss values of 30 and 50 µg/mL would result in ABRs of treated joint bleeds of 1.1 and 1.0, respectively, and with an RRR of 94.9% and 95.4%, respectively.

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