Purpose: Alpha-1 antitrypsin deficiency (AATD) can result in the unchecked or excessive enzymatic activity of neutrophil elastase (NE) leading to progressive lung tissue destruction. AATD affects approximately 200,000 individuals in the USA and Europe combined and accounts for approximately 3% of the chronic obstructive pulmonary disease (COPD) population. Current augmentation therapies with various preparations of plasma derived AAT (pAAT) have insufficient PK and require weekly IV dosing due to short serum half-life of 5-6 days. In addition, serum levels of AAT in augmented individuals are below the lower level of normal (20 μM) for several days using the approved and standard pdAAT dosing of 60 mg/kg IV weekly. Inhibrx developed INBRX-101, a novel, recombinant human Fc fusion protein (rhAAT-Fc) comprised of two recombinant human alpha-1 antitrypsin molecules covalently linked to the Fc domain of human IgG4 to improve the PK profile by extending half-life. The purpose of this study is to evaluate the preclinical PK of INBRX-101 and translate the animal data to guide dose and dosing interval selection of the first-in-human (FIH) clinical program.
Methods: INBRX-101 serum concentration-time data from toxicokinetics studies on 26 cynomolgus monkeys (cyno) and 54 rats with 1688 observations were used to perform a non-compartmental analysis (NCA) in WinNonlin 6.4 and population PK (pop-PK) analysis using nonlinear mixed-effects modeling (NLME) in Phoenix, NLME 1.3. The dose and demographics for cyno and rat studies were as follows: (1) male to female ratio of 1:1; (2) dose levels at 50, 150 and 450 mg/kg; (3) mean cyno body weight (BW) of 2.98 kg (range 2.6-3.4 kg); mean rat BW of 0.228 kg (range 0.175-0.281 kg). The serum concentration-time curves were plotted and examined. Dose proportionality was graphically explored. Various compartmental models with different residual errors were tested for the structural pop-PK model with verification using standard goodness-of-fit and diagnostic plots. Covariate factors including BW, sex and species were also explored.
Results: NCA results on preclinical data indicated a significantly longer half-life for INBRX-101, as compared to pdAAT. The INBRX-101 PK was dose proportional for both cyno and rats, suggesting a linear PK profile. A preclinical structural pop-PK model was built using diagnostics and visual predictive check (VPC) simulations. Covariates describing population characteristics were explored and identified covariates were tested in the pop-PK model.
Conclusion: The preclinical PK data of INBRX-101 confirmed the strategy of using an Fc fusion protein to successfully increase the elimination half-life and exposure of AAT with linear PK. A preclinical pop-PK model was developed to explore the population covariates to translate the animal data to human patients. The findings from the preclinical pop-PK model and their implications to guide dose and dosing selection for the FIH clinical trial will be discussed.
Hiren Mehta– Sr. Pharmacokineticist, Syneos Health, Ontario
Galina Bernstein– Director, Pharmacometrics, Syneos Health, Ontario
Pierre-Olivier Tremblay– Vice-President, Clinical Pharmacology, Syneos Health, Quebec
Analeah Heidt– Director, Translational Research, Inhibrx, Inc., California
Klaus Wagner– Chief Medical Officer, Inhibrx, Inc., California