Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181)

John Powderly, Alexander Spira, Shunsuke Kondo, Toshihiko Doi, Jason J Luke, Drew Rasco, Bo Gao, Minna Tanner, Philippe A Cassier, Anas Gazzah, Antoine Italiano, Diego Tosi, Daniel E Afar, Apurvasena Parikh, Benjamin Engelhardt, Stefan Englert, Stacie L Lambert, Sreeneeranj Kasichayanula, Sven Mensing, Rajeev Menon, Gregory Vosganian, Anthony Tolcher, John Powderly, Alexander Spira, Shunsuke Kondo, Toshihiko Doi, Jason J Luke, Drew Rasco, Bo Gao, Minna Tanner, Philippe A Cassier, Anas Gazzah, Antoine Italiano, Diego Tosi, Daniel E Afar, Apurvasena Parikh, Benjamin Engelhardt, Stefan Englert, Stacie L Lambert, Sreeneeranj Kasichayanula, Sven Mensing, Rajeev Menon, Gregory Vosganian, Anthony Tolcher

Abstract

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD-1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body-weight-based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune-related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD-1 targeting agents. No treatment-related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD-1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure-safety analyses did not indicate any trends. Observed PK and PD-1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

Trial registration: ClinicalTrials.gov NCT03000257.

Conflict of interest statement

AbbVie provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the abstract. J.P.: Honoraria: BMS, Genentech, Merck; Financial Compensation: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Stock: Iovance, BlueBird, Juno, Kite Pharma, BioCytics. Ownership: Carolina BioOncology Institute (principal owner). Research Funding: BMS, Genentech, EMD Serono, AstraZeneca, InCyte, Arcus, FLX BioSciences, Alkermes, Tempest, Curis, Corvus, AbbVie, and Sequenom. Institutional Funding Support: Nucleus. Non‐Financial: BioCytics Inc. is developing immune cellular therapies and is collaborating with multiple biotech and biopharma companies, including Arcus, Nucleus, Terumo, and Miltenyi. Submitted investigator‐initiated trial proposals for developing future cellular therapies with BMS, EMD Serono, Genentech, and AstraZeneca. Other: Developing intellectual property for autologous immune cellular therapies, and actively discussing potential collaboration projects with multiple biotech and biopharma companies. A.S.: Research Funding AbbVie, Consulting Amgen, AstraZeneca/Medimmune, Novartis. S.K.: Research funding, Pfizer (Inst), Merck Serono (Inst), AstraZeneca (Inst), Bayer (Inst), and Eli Lilly (Inst). T.D.: Consulting or Advisory Role: MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer, Boehringer Ingelheim, and Rakuten Medical. Research Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Merck Serono (Inst), MSD (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Eli Lilly (Inst), Sumitomo Group (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Bristol‐Myers Squibb (Inst), AbbVie (Inst), Quintiles (Inst), and Eisai (Inst). Honoraria: BMS, Ono Pharmaceutical, AbbVie, Astellas Pharma, Oncolys BioPharma, and Taiho Pharmaceutical. J.J.L.: Data and Safety Monitoring Board: TTC Oncology; Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Mavu (now part of AbbVie), Pyxis, Springbank, and Tempest. Consultancy: AbbVie, Akrevia, Algios, Array, Astellas, AstraZeneca, Bayer, Bristol‐Myers Squibb, Compugen, Eisai, EMD Serono, Ideaya, Immunocore, Incyte, Janssen, Leap, Merck, Mersana, Novartis, RefleXion, Silicon, Tesaro, and Vividion. Research Support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Boston Biomedical, Bristol‐Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, and Xencor. Travel: Akrevia, AstraZeneca, Bayer, Bristol‐Myers Squibb, EMD Serono, Immunocore, Incyte, Janssen, Merck, Mersana, Novartis, and RefleXion. Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti‐PD‐1/PD‐L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). D.R.: Research funding from AbbVie. B.G.: Advisory Board MSD. M.T.: Consulting or Advisory role: Roche Finland, Pfizer, Novartis, Lilly, and AstraZeneca. Data and Safety Monitoring Board: Orion Corporation Orion Pharma. Honoraria: Novartis, Roche Finland, AstraZeneca, Teva, Novartis, Pfizer, Lilly, and MSD. Research support (institution) from Novartis, Roche, Genentech, MacroGenics, and AbbVie. P.A.C.: Received honorarium from Amgen, AstraZeneca, Blueprint Medicines, Novartis, Roche/Genentech, and Merck KGaA/Serono. Research support (institution) from Amgen, AstraZeneca, AbbVie, Blueprint Medicines, BMS, Celgene, GSK, Janssen, Lilly, MSD, Merck Serono, Novartis, and Roche/Genentech. A.G.: no conflicts of interest to declare. A.I.: Research grant: BMS, MSD, Bayer, Roche, PharmaMar, and AstraZeneca. Advisory board: Bayer, Roche, Epizyme, Springworks, and IPSEN. D.T.: Consultant: BioMarin, and Actelion. Preclinical research support (to institution): Astellas, Janssen, and Ipsen. Patent: “Association of actives for treating prostate cancer,” #EP17306576.4 (pending). Travel, Accommodations, Expenses: Nutricia, Amicus Therapeutics, BioMarin, Astellas Pharma, MSD, and AstraZeneca. D.E.A., A.P., B.E., S.E., S.L.L., S.K., S.M., R.M., and G.V. are AbbVie employees and may own stock. A.T.: Consultant AbbVie, Adagene, Agenus, Aro Biotherapeutics, Ascentage, Aximmune, Bayer, Boston Bio, Cello Health, EMD Serono, Elucida Oncology, Forbius (formerly Formation Biologics), Genentech/Roche IDMC, Gilde Healthcare Partners, HBM, Immunomet, Ignyta, Mekanistic Therapeutics, Menarini Researche, Mirati IDMC, Nanobiotix, Nuvalent, Inc., OSI Pharmaceuticals, Partner Therapeutics, Pfizer, Pieris Pharmaceuticals, Pierre Fabre, Seattle Genetics, and Symphogen. Advisory Board ADC Therapeutics, Abgenomics, Aro Biotherapeutics, BioInvent International, Immunome, Jazz, Mirati, Sesen (formerly Eleven Bio), NBE Therapeutics, Pelican, PSI Pharma Support America, Inc. (Innate Pharma), TFS Trial Form Support International, and Zymeworks. Research Support: (all to institution for clinical trials) AbbVie, ADC Therapeutics, Adagene, Aminex, Ascentage, Asana, Birdie, CStone, Arrys, Deciphera GlaxoSmithKline, Inhibrx, Innate, Kiromic, Mersana, NatureWise, NextCure, Nitto BioPharma, Pfizer, Pieris, Syndax, Symphogen, Tizona, and Zymeworks.

© 2020 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Percentage programmed cell death 1 (%PD‐1) receptor saturation on CD4 T central memory (CD4 TCM) by cycle (C) and day (D). Mean ± SEM values are shown for each cohort. All patients included in the analysis had baseline and at least one post‐baseline assessment, with the baseline normalized to 100%. The number of patients included in each cohort is given in parentheses. mAb, monoclonal antibody.
Figure 2
Figure 2
Preliminary pharmacokinetic profiles for flat and body‐weight‐based dosing of budigalimab. (a) Mean serum concentration‐time profiles of budigalimab in cycle 1 following first intravenous administration of 1 mg/kg, 3 mg/kg, 10 mg/kg (Q2W), 250 mg (Q2W) and 500 mg (Q4W) budigalimab. Plots are shown on log‐linear scale. (b) Comparison of budigalimab cycle 1 maximum plasma concentration (Cmax) and area under the curve (AUC) for Japanese and Western patients.
Figure 3
Figure 3
Violin‐plots of model‐predicted (a) minimum plasma concentration (Cmin) and (b) maximum plasma concentration (Cmax) for budigalimab following multiple dosing (week 12) of 3 mg/kg and 250 mg Q2W, 375 mg Q3W, and 500 mg Q4W regimens. Dashed lines represent 3 mg/kg Q2W median values.
Figure 4
Figure 4
Model‐predicted pharmacokinetic (PK) profiles overlaid with observed data. The solid lines represent population median PK predictions and dashed lines with shaded region represent the 95% prediction intervals. The observed serum concentration data points for budigalimab are shown as scatter (filled symbols) for the (a) 250 mg Q2W dose during cycle 1, (b) 250 mg Q2W dose during cycle 3, (c) 500 mg Q4W dose during cycle 1, and (d) 500 mg Q4W dose during cycle 3.
Figure 5
Figure 5
Exposure‐safety analysis. Incidence of the maximum grade of adverse events (AEs) recorded (immune related and other, shown in blue and green filled symbols, respectively) with respect to budigalimab average concentrations in cycle 1. AEs across the 3 mg/kq Q2W, 250 mg Q2W, and 500 mg Q4W dose groups are represented with different symbols, respectively.

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