Sutimlimab

Sutimlimab is an IgG, subclass 4 (IgG4) monoclonal antibody (mAb) that inhibits the classical pathway (CP) and specifically binds to complement protein component 1, s subcomponent (C1s), a serine protease that cleaves C4. The activities of the lectin and alternative complement pathways are not inhibited by sutimlimab. Inhibition of the classical complement pathway at the level of C1s prevents deposition of complement opsonins on the surface of red blood cells, resulting in inhibition of haemolysis in patients with CAD, prevents generation of proinflammatory anaphylatoxins C3a and C5a and the downstream terminal complement complex C5b-9.

The pharmacokinetics (PK) of sutimlimab were characterized in 24 patients (CARDINAL) and 42 patients (CADENZA), which included 51 patients treated with 6500 mg and 15 patients with 7500 mg as per recommended posology. The total exposures at steady-state of proposed dosing regimen are presented in Table 6.

Table 6. Mean (SD) steady state exposure parameters:

^* Abbreviations: AUC_ss = area under the curve between 2 consecutive doses after steady state is achieved; C_min = trough concentration at steady state defined as 1 hour prior to next dose administration

Steady state was achieved by week 7 after starting sutimlimab treatment, with accumulation ratio of less than 2.

Distribution

The volume of distribution at steady state in central and peripheral compartments was approximately 5.8 L in patients with CAD.

Biotransformation

Sutimlimab is a protein. It is generally recognized that antibodies are metabolized by degradation into small peptides and individual amino acids.

Elimination

The half-life of sutimlimab is dependent on the plasma concentration. The terminal elimination halflife of sutimlimab at steady-state based on the total clearance (linear and non-linear clearance) is 16 days.

Linearity/non-linearity

Following single doses, sutimlimab clearance showed a steep initial decrease at doses less than 30 mg/kg (~2 g), becoming independent of dose between 60 and 100 mg/kg of sutimlimab.

Special populations

No clinically significant differences were observed in the pharmacokinetics of sutimlimab based on sex, age, hepatic impairment, or renal impairment. Exposure levels (C_max, C_min and AUC) at steady state were estimated based on 6500 mg (<75 kg) and 7500 mg (>= 75 kg) given Days 0, 7 and every 14 days thereafter. The population pharmacokinetic analysis showed similar exposure parameters between sexes with 101 male and 95 female participants.

The population pharmacokinetic analysis showed similar exposure parameters with participant’s race (94 White, 10 Black, 42 Asian).

Population pharmacokinetic analysis showed that body weight and ethnicity (Japanese versus nonJapanese) influenced the pharmacokinetics of sutimlimab. Lower exposure was observed in participants with higher body weight. Based on cross-study comparison, sutimlimab AUC_0-168 after 30 to 100 mg/kg was up to 38% higher in Japanese subjects than in non-Japanese participants.

Pharmacokinetic/pharmacodynamic relationship(s)

Sutimlimab concentration above 100 µg/mL resulted in maximal CP inhibition. The proposed dosing regimen resulted in adequate sutimlimab exposure at steady state to provide clinically relevant effects on Hgb, bilirubin, and total C4 levels.

An enhanced pre- and post-natal development (ePPND) study in cynomolgus monkeys revealed no evidence of adverse developmental outcomes with intravenous administration of sutimlimab during organogenesis through delivery, at exposures approximately 2-3 times the AUC in humans at the maximum recommended dose. In repeat-dose studies with sutimlimab with exposures at up to approximately 4 times the recommended human dose, no effects on reproductive organs were observed in cynomolgus monkeys.

No animal studies have been conducted to evaluate the carcinogenic potential of sutimlimab.

Non-clinical data revealed no special hazard for humans based on nonclinical studies in cynomolgus monkeys.