(M-001) Prediction of Percent Free Nerve Growth Factor Suppression following Administration of MEDI7352, a Bispecific Fusion Protein for Dual Targeting of NGF and TNFα, in Patients with Painful Diabetic Neuropathy and Osteoarthritis

Ahmed Salem – BioPharmaceuticals R&D, Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Gaithersburg, MD, USA – AsztraZeneca; Kirsten Scott – BioPharmaceuticals R&D, Neuroscience, AstraZeneca, Cambridge, UK – AsztraZeneca; Edward Emery – BioPharmaceuticals R&D, Neuroscience, AstraZeneca, Cambridge, UK – AsztraZeneca; Fraser Welsh – BioPharmaceuticals R&D, Neuroscience, AstraZeneca, Cambridge, UK – AsztraZeneca; Iain Chessell – BioPharmaceuticals R&D, Neuroscience, AstraZeneca, Cambridge, UK – AstraZeneca; Keith Tan – BioPharmaceuticals R&D, Neuroscience, AstraZeneca, Cambridge, UK – AsztraZeneca; Lindsay Clegg – BioPharmaceuticals R&D, Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Gaithersburg, MD, USA – AsztraZeneca; Weifeng Tang – BioPharmaceuticals R&D, Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Gaithersburg, MD, USA – AsztraZeneca; Daniel Kaschek – IntiQuan AG - A ProductLifeGroup Company, Basel, Switzerland. – IntiQuan AG; Isabelle Pouliquen – BioPharmaceuticals R&D, Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Cambridge, UK – AsztraZeneca; Meng Li – BioPharmaceuticals R&D, Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Gaithersburg, MD, USA – AsztraZeneca

Objectives: MEDI7352 is a bispecific fusion protein with selective, high-affinity binding to both nerve growth factor (NGF) and tumor necrosis factor (TNF)-α, which are key players of both neuropathic and inflammatory pain signaling [1,2]. MEDI7352 is under development for chronic pain treatment by modulation of local and systemic NGF and TNFα concentrations. In this analysis we aimed to i) develop a population pharmacokinetic/pharmacodynamic (PKPD) model relating MEDI7352 concentration with the time course of treatment effect on total NGF and identify covariates influencing pharmacodynamic parameters, ii) predict free NGF inhibition following MEDI7352 treatment.

Methods: Longitudinal total NGF concentrations were collected from three placebo-controlled studies: a Phase I study (NCT02508155) of single ascending doses (0.3–1000 μg/kg intravenously [IV] or 50 μg/kg subcutaneously [SC]) and multiple ascending doses (1–450 μg/kg IV biweekly ) in osteoarthritis patients, a Phase IIa study (5–450 μg/kg IV biweekly) in a Painful Diabetic Neuropathy (PDN) population (NCT03755934), and a Phase IIb study (7.5–150 mg SC biweekly) in the osteoarthritis population (NCT04675034). A full target-mediated drug disposition (TMDD) base model was selected to describe the relationship between MEDI7352 serum concentrations and total NGF concentrations through a non-linear mixed effect modeling approach. Baseline demographic characteristics (weight, age, sex, race), disease type, biomarker (total NGF), and anti-drug antibody (ADA) status/titer, were tested for potential covariate effect. Covariates were selected based on biological plausibility, graphical inspection of covariate–pharmacodynamic parameter relationships, and statistical significance (95% confidence interval not crossing the null value). Simulations were conducted to predict the time course and extent of free NGF inhibition at steady state (week 12 - 16) during MEDI7352 treatment.

Results: 5835 total NGF samples from 535 subjects were included in the PKPD analysis dataset. The TMDD model adequately fitted the observed total NGF concentrations. Statistically significant covariates included in the final model were ADA status, baseline total NGF concentration and disease type on baseline free NGF parameter and ADA status on the first-order elimination rate constant of the complex. The model predicted mean free NGF suppression (% inhibition from baseline) at steady state ranged between 15% to 21% following IV administration of 20 to 80 mg (Q4W), respectively and between 28% to 34% following SC administration of 75 to 150 mg Q4W, respectively. There was a large difference in the NGF inhibition between ADA positive and ADA negative participants (e.g. 13% vs 55% at IV 80 mg Q4W), primarily accounted for by the lower PK exposure associated with ADA formation. There was no clear impact of ADA identified on efficacy and safety.

Conclusions: The TMDD model adequately described the observed effect of MEDI7352 on the total NGF concentrations following IV and SC MEDI7352 treatment. The PKPD model was utilized to predict free NGF suppression and supported dose selection.

Citations: [1] Clarke, J. Going for gold to improve anti-NGF therapy in OA. Nat Rev Rheumatol 17, 508 (2021). https://doi.org/10.1038/s41584-021-00670-7
[2] Miller RE, Block JA, Malfait AM. What is new in pain modification in osteoarthritis? Rheumatology (Oxford). 2018 May 1;57(suppl_4):iv99-iv107. doi: 10.1093/rheumatology/kex522. PMID: 29361112; PMCID: PMC5905627.

Keywords: MEDI7352, NGF, Bispecific