Vincent Chow

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment

AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug-drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15-25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC(12) ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC(12) ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX.

A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab

Objective To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. Methods Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax). Secondary end points included safety and immunogenicity. Results AUCinf and Cmax were similar across the three groups. Geometrical mean ratio (GMR) of AUCinf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of Cmax was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUCinf and Cmax were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. Conclusions Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. Trial registration number EudraCT number 2012-000785-37; Results.

SAT0167 Relationship Between Pharmacokinetics and Anti-Drug Antibody Status of ABP 501, A Biosimilar Candidate to Adalimumab

Background ABP 501 is being developed as a biosimilar candidate to adalimumab (Humira®), a fully human recombinant monoclonal antibody (mAb). ABP 501 has the same amino acid sequence and similar post-translational modifications as adalimumab. It is well known that serum antibodies to adalimumab are associated with lower serum adalimumab concentration.1 Objectives To evaluate the pharmacokinetics (PK) and anti-drug antibody (ADA) relationship of ABP 501 and adalimumab sourced from the US and EU. Methods This was a single-blind, single-dose, three-arm, parallel-group study. Healthy men and women were randomized to receive 40-mg subcutaneous (SC) injection of ABP 501, adalimumab (US), or adalimumab (EU); PK, safety, and immunogenicity were evaluated. For PK evaluation, serum samples were collected predose; 1, 4, 8, 12, and 24 hours postdose; at each return visit (days 3, 4, 5, 6, 7, 8, 9, 11, 14, 16, 22, 29, 36, 43, 50, and 57); and at the end of study (day 63). Serum concentrations of each mAb were determined using a validated electrochemiluminescent (ECL) assay. Individual concentration-time data for all three molecules were analyzed by noncompartmental PK analysis methods. For ADA analysis, serum samples were collected on days 1 (predose), 16, 29, and 63. A screening immunoassay was used to detect and a confirmatory immunoassay was used to confirm the specificity of binding antibodies. All samples were tested against all three test molecules. The assay sensitivity for ADAs in presence of 25 μg/mL drug was approximately 0.02 μg/mL. Results Results demonstrating the equivalence of PK, safety, and immunogenicity of ABP 501 compared with adalimumab (US) and adalimumab (EU) have been previously presented.2,3 No preexisting ADAs were detected at baseline. Subjects who developed binding antibodies in each group were as follows: ABP 501, 36 (54%); adalimumab (US), 38 (55%); and adalimumab (EU), 45 (67%). Median time to maximum concentration (tmax) and geometric means of maximum observed serum concentration (Cmax) were similar following the single-dose SC injection of all three molecules independent of ADA status. Overall exposure (area under serum concentration-time curve, AUC) was approximately 20%–30% lower in ADA-positive compared with ADA-negative subjects for all three molecules. Consistent with lower exposure were the shorter elimination half-lives (t1/2) in ADA-positive subjects. On average, t1/2 was 6–7 days in ADA-positive subjects compared with 12–15 days in ADA-negative subjects. Conclusions Results of this analysis demonstrated that ADA status influences the pharmacokinetics of ABP 501, adalimumab (US), and adalimumab (EU). This is in line with the previously published literature. It is important to continue to monitor this relationship in subsequent pivotal studies when comparing the biosimilar candidate to the reference product to understand if there is an associated change in efficacy. References Bartelds GM, et al. Ann Rheum Dis. 2007;66(7):921-926. Kaur P, et al. Presented at: European League Against Rheumatism Annual Meeting; June 2014; Paris, France. Abstract FRI0264. Kaur P, et al. Presented at: American College of Rheumatology Annual Meeting; November 2014; Boston, MA. Abstract 1504. Acknowledgements Michael Moxness, PhD for clinical immunology work, Amy Rasmussen for study management and Monica Ramchandani, PhD for medical writing. Disclosure of Interest P. Kaur Shareholder of: Amgen stock, Employee of: Amgen, V. Chow Shareholder of: Amgen stock, Employee of: Amgen, N. Zhang Shareholder of: Amgen stock, Employee of: Amgen, R. Markus Shareholder of: Amgen stock, Employee of: Amgen

Correction to: A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men

The article [A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men]

A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small‐molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every‐2‐week dose‐escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty‐five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment‐related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway‐related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway‐specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

The Use of Pharmacometrics to Optimize Biosimilar Development

Pharmacometric approaches can assist in biosimilar development by leveraging quantitative knowledge of the originator product characteristics such as dose-exposure and exposure-response information to support a targeted approach to clinical studies. The degree to which these approaches can be applied relies on the level of information known about the originator and information that supports application of the originator model to the biosimilar. A model-based approach testing the hypothesis that the biosimilar PK and/or PK/PD profile is similar to the originator in the target patient population is aligned with the central comparability exercise required for the biosimilar approval. This Commentary details the key opportunities in study design and study analysis where pharmacometrics approaches can aid biosimilar development.

Abstract CT045: Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors

Purpose: Aurora kinases are associated with high proliferation, poor prognosis, and therapeutic resistance in several human tumor types. AMG 900 is an investigational, oral, highly potent, selective, pan-aurora kinase inhibitor. We evaluated the safety, tolerability, pharmacokinetics, and clinical activity of AMG 900 in pts with advanced solid tumors (NCT00858377). Methods: In the dose escalation phase, eligible pts were ? 18 years old, with advanced solid tumors that were refractory to standard treatment, measurable disease per RECIST, ECOG ? 2, and life expectancy > 3 months. In the dose expansion phase, eligible pts had taxane- and platinum-resistant epithelial ovarian cancer (OC), taxane-resistant triple-negative breast cancer (TNBC), or castration-resistant and taxane- or cisplatin-etoposide-resistant stage IV prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at doses of 1 to 50 mg/day (dose escalation), and at the maximum tolerated dose of 40 mg/day with G-CSF support (dose-expansion). The primary objective was safety. Tumor response was determined per RECIST for all pts and additionally by GCIG CA-125 for pts with OC. Results: Treatment-related AEs were reported by 98 of 105 pts (93.3%). Myelotoxicities were the most common grade ? 3 treatment-related AEs. In the dose escalation (N = 50), 1 pt with OC (30-mg cohort) had a partial response (PR) by RECIST and GCIG. In the dose expansion (N = 55), 3 of 29 pts (10.3%) with OC had a PR by RECIST, and 7 of 29 pts (24.1%) had a PR by GCIG; 72.4% of pts with OC had stable disease (SD), and the disease control rate (PR + SD) was 82.8%. Median (95% CI) duration of response in pts with OC per RECIST was 24.1 (16.1, 34.1) weeks, and median (80% CI) PFS was 31.1 (23.6, 34.1) weeks. See table for additional results. Conclusions: AMG 900 had manageable toxicity with G-CSF support and promising single-agent activity in pts with heavily pretreated taxane- and platinum-resistant OC. Citation Format: Montasser Shaheen, Ben Markman, Michael Carducci, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar Goodman, Erick Gamelin, Vincent Chow, Gloria Juan, Erik Rasmussen, Gregory R. Friberg, Florian D. Vogl, Jayesh Desai. Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT045.

Abstract P6-13-12: Comparative similarity of ABP 980 and trastuzumab: Results of functional similarity and human pharmacokinetic assessment

Background: ABP 980 is being developed as a biosimilar to trastuzumab, a monoclonal antibody (mAb) that binds human epidermal growth factor receptor 2 (HER2), resulting in proliferation inhibition (PI) and induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Biosimilar mAbs are likely to have minor differences with the reference product due to variances in expression systems, bioprocess, and purification; demonstration of analytical, pharmacologic, and pharmacokinetic (PK) similarity is the foundation for biosimilarity. Functional (PI, ADCC, and tumor xenograft models) and PK similarity between ABP 980 and EU-authorized trastuzumab reference product has been previously evaluated. Objective: To demonstrate functional and PK similarity between ABP 980 and FDA-licensed trastuzumab reference product. Methods: Potency of ABP 980 and FDA-licensed trastuzumab was compared by measuring PI and recombinant HER2 (rHER2) binding affinity. PI activity was evaluated using BT-474 cells. Surface plasmon resonance analysis was used to determine the equilibrium binding affinity (Kd) to rHER2. PK similarity was evaluated in a randomized, single-blind, single-dose, parallel-group study in healthy adult men. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUC inf ) and maximum observed serum concentration (C max ). Secondary endpoints were safety, tolerability, and immunogenicity. Results: ABP 980 displayed PI and rHER2 binding activities comparable to trastuzumab. The range of relative potency by PI was 82%–114% for ABP 980 and 91%–116% for trastuzumab. The Kd ranged from 75–79 pM for ABP 980 and 67–80 pM for trastuzumab. PK similarity was demonstrated for the comparison of ABP 980 with trastuzumab. The geometric mean (GM) ratios for C max and AUC inf were 1.04 (90% CI, 0.995–1.079) and 1.06 (90% CI, 0.997–1.117). Both CIs fell within the standard prespecified bioequivalence criteria of 0.80–1.25. After 6 mg/kg intravenous infusion, the GM of C max and AUC inf were 135.90 µg/mL and 34061.43µg·h/mL for ABP 980 and 131.19µg/mL and 32271.67µg·h/mL for trastuzumab. The incidence of treatment-emergent adverse events (TEAEs) was comparable between treatment groups. TEAEs occurred in 84% subjects receiving ABP 980 and 75% of subjects receiving trastuzumab; no anti-drug antibodies were detected. Conclusions: ABP 980 has been shown to be similar to FDA-licensed trastuzumab in functional tests and binding affinity to antigen, as well as in a phase 1 human PK study. Citation Format: Hanes V, Born T, Chow V, Zhang N, Howard M, Schulz A, Markus R. Comparative similarity of ABP 980 and trastuzumab: Results of functional similarity and human pharmacokinetic assessment. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-12.

Abstract 3359: Translating preclinical PK/PD tumor volume modeling data to predict AMG172 PK and dose-escalation scheme in FIH.

Background: AMG 172 is an antibody drug conjugate (ADC) comprised of a human IgG1 monoclonal antibody (mAb), a non-cleavable linker (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) conjugated to lysine residues in the antibody and DM1, a semi-synthetic derivative of maytansine. AMG 172 binding and internalization into target-expressing tumor cells, induces metaphase arrest and subsequent cellular apoptosis, leading to tumor cell death. AMG 172 is being developed as a treatment for clear cell renal cell carcinoma (ccRCC), and other indications, as a single agent or in combination with chemotherapy. The primary goals of this study were, 1) to predict human AMG 172 PK disposition from non-clinical data, 2) to determine AMG 172 exposure anti-tumor activity relationships in mouse xenograft models, and develop an AMG 172 anti-tumor PK/PD model, and 3) to integrate non-clinical toxicology, pharmacology and pharmacokinetic data to support selection of doses for the first in human (FIH) clinical study Materials and Methods: A PK model in cynomolgus monkey was developed from single and multiple-dose pharmacokinetics and toxicokinetics, and used to predict the human PK of AMG 172. In vivo anti-tumor activity was demonstrated by AMG 172 in human ccRCC subcutaneous tumor xenografts in mice. Tumor growth inhibition in mouse xenografts was modeled using a tumor inhibition PK/PD model. Primary model assumptions for extrapolation of non-clinical PK/PD to human were: a) AMG 172 PK can be scaled directly from cynomolgus monkey, and b) anti-tumor efficacy in mouse xenografts is drug dependent and species independent. Results: A two compartment open linear model best described AMG 172 pharmacokinetics in cynomolgus monkey. AMG 172 CL was estimated to be 9.45 mL/hr in a typical human (70 kg) based on species-invariant time scaling methods. At the STD10 in rats and the HNSTD in cynomolgus monkey, anticipated AUC margins are approximately 17.9/11.9 and 15.7/10.5 times for Q3wk/Q2wk dosing regimens, respectively, at the projected clinical starting dose of 0.15 mg/kg. Using the mouse xenograft PK and PD data, clinical dose projections were generated that attained model-based, putative target trough concentrations. Collectively, these results support potential AMG 172 dosing every 2–3 weeks, thereby providing flexibility in the clinic. Conclusions: This work demonstrates efficient integration of non-clinical toxicology, preclinical pharmacology and pharmacokinetic data in order to support rational selection of AMG 172 doses for FIH clinical studies. Citation Format: Nelson L. Jumbe, William Fanslow, Sonal Patel, Benny Amore, Marc Retter, Vincent Chow. Translating preclinical PK/PD tumor volume modeling data to predict AMG172 PK and dose-escalation scheme in FIH. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2013-3359 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.