Andrew Santulli1*, Cheryl Li2*, Sarah F. Cook1, Kaveri Suryanarayan3, Xavier Parot3, Scott Van Wart1, Donald E. Mager1,4, Neeraj Gupta2
1Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA 2Quantitative Clinical Pharmacology, Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA 3Clinical Science, Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA 4Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA
Introduction: Modakafusp alfa (TAK-573) is a novel, first-in-class Fc-fusion protein designed to deliver attenuated interferon alpha-2b (IFNα2b) to CD38-expressing cells. Targeted drug delivery and reduced affinity of attenuated IFNα2b for the IFN receptor were designed to minimize off-target systemic toxicity while maintaining efficacy. The results in this abstract have been previously presented at the American Conference on Pharmacometrics, National Harbor, MD, USA on November 5-8, 2023 and published in the conference proceedings as abstract PMX686.
Objectives: Conduct a population PK analysis and sequential population PK-PD analysis of serum myeloma protein (MP), the primary marker of tumor burden in multiple myeloma.
Methods: The PK analysis included 96 relapsed/refractory multiple myeloma (RRMM) patients who received intravenous infusions ranging from 0.001 to 6 mg/kg (QW to Q4W) as part of a Phase 1/2 study [1] (April 15 2022 sample cut). A quasi-equilibrium (QE) bispecific target-mediated drug disposition (TMDD) model using in vitro binding constants for CD38 and IFNR, a single receptor pool QE TMDD model, and a reduced linear plus Michaelis-Menten (MM) model were tested to account for nonlinear PK. Anti-drug antibody (ADA) impact was accounted for by enhancing linear clearance (CL) using a Hill-type function of observed individual ADA titers during each cycle. For the linear plus MM model, an alternative ADA binding model was also evaluated with the total ADA receptor pool concentration (Rtot,ADA) parameterized as a time-varying function of the observed individual ADA titers. Serum MP data from patients evaluable at baseline was fit using the Claret tumor growth inhibition (TGI) model [2] to characterize tumor growth, anti-tumor drug effect using an Emax model, and drug resistance. All population analyses were performed using NONMEM® Version 7.4.4 (ICON plc, Dublin, Ireland) and Monte Carlo importance sampling (IMP) expectation maximization with Laplacian was implemented for the PK analysis; and First-Order Conditional Estimation with Interaction (FOCEI) for the PD analysis.
Results: All structural PK models evaluated capably described the modakafusp alfa concentration-time data across cycles. Despite similar fittings, the linear plus MM structural model offered a substantial advantage over the bispecific TMDD model in terms of runtime/optimization. The linear plus MM model performed better when utilizing the ADA binding model rather than using ADA to enhance the linear CL and allowed prediction of both unbound and ADA-bound drug concentrations. Body weight was a statistically significant predictor of central volume of distribution (Vc-WTKG power of 0.509), but was not on elimination related parameters (α = 0.01). The TGI model using unbound drug as the PD driver performed best, and adequately described the MP data. Baseline serum albumin exhibited a strong inverse relationship with baseline serum MP (p < 0.00001).
Conclusion: A population PK model was developed for modakafusp alfa and accounted for impact of ADA across cycles. The PK model in conjunction with the TGI PK-PD model provided a simulation framework of efficacy to evaluate modakafusp alfa dosing regimens for treatment of RRMM.
References:
[1] A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (iinnovate-1). Identifier NCT03215030. U.S. National Library of Medicine. https://clinicaltrials.gov/study/NCT03215030 (accessed 2024-03-01).[2] Claret et al., Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics. J Clin Oncol. 2009;27(25):4103.
Reference: PAGE 32 (2024) Abstr 11068 [www.page-meeting.org/?abstract=11068]
Poster: Drug/Disease Modelling - Oncology