PopPK Modeling of NGM438 in Advanced/Metastatic Solid Tumor Patients

Abstract

BACKGROUND: Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is a collagen-binding inhibitory receptor expressed on immune cells. NGM438 is a humanized IgG1 monoclonal antibody that specifically binds to LAIR1 and blocks LAIR1/collagen engagement. Population analysis was conducted to characterize the pharmacokinetic (PK) properties of NGM438 in patients with advanced or metastatic solid tumors.

METHODS: PK data from 25 subjects in a Phase 1/1b study of NGM438 as a monotherapy or in combination with pembrolizumab were simultaneously modeled using a population approach. Since 9.5% of post first dose PK data were recorded as below the limit of quantitation (BLQ), model development was performed using both M1 (excluding BLQ observations) and M3 (likelihood of BLQ observations) methods. The predictive performances of both models were assessed by goodness-of-fit diagnostics and visual predictive check (VPC).

RESULTS: Following intravenous infusions, NGM438 PK were adequately described by a two-compartment model with parallel first-order and nonlinear elimination pathways. Posterior VPC assessments demonstrated that M3 method substantially outperformed M1 for the overall fitting to NGM438 PK data. With the M3 method, estimated systemic clearance of the first-order elimination pathway (CL), central (Vc) and peripheral volume of distribution (Vp) were 0.285 L/d, 3.43 L and 1.94 L, respectively. Both CL and Vc increased with body weight, typical for therapeutic monoclonal antibodies. Baseline albumin was identified as a significant covariate, where lower albumin level was associated with faster CL of NGM438.

CONCLUSION: PK of NGM438 was typical for therapeutic monoclonal antibodies. Besides body weight, only baseline albumin level was identified as a relevant PK covariate. Age, sex, race and baseline peripheral blood mononuclear cell counts had no impact on NGM438 PK.

Background

NGM438 is a potent, first-in-class antibody targeting the myeloid-enriched inhibitory receptor LAIR1, with potential to reprogram LAIR1-expressing suppressive myeloid cells within the tumor via disruption of Collagen-LAIR1 mediated immune cell signaling

Methods

Study Design: A Phase 1/1b Dose Escalation/Expansion Study of NGM438 as Monotherapy and in Combination with Pembrolizumab in Advanced or Metastatic Solid Tumors (NCT05311618)

Primary Objectives: Safety and tolerability

Conclusions

• The pharmacokinetics of NGM438 is linear in a dose range of 800 to 2400 mg and adequately described by a two-compartment model with parallel first-order and nonlinear elimination pathways.
• Body weight and baseline albumin were identified as significant covariates
• Other common covariates had no clinically relevant impact on the pharmacokinetics of NGM438

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