Richard Markus

Denosumab Treatment of Prostate Cancer With Bone Metastases and Increased Urine N-Telopeptide Levels After Therapy With Intravenous Bisphosphonates: Results of a Randomized Phase II Trial

PURPOSE Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. MATERIALS AND METHODS Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. RESULTS Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. CONCLUSIONS In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates.

Recent Time Trends in the Epidemiology of Stage IV Prostate Cancer in the United States: Analysis of Data From the Surveillance, Epidemiology, and End Results Program*

OBJECTIVES To describe recent epidemiologic trends in stage IV prostate cancer. Although advances in screening and diagnostic techniques have led to earlier detection of prostate cancer, a portion of patients still present with late-stage disease. METHODS Population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program (cases from 1988 to 2003, follow-up through 2005) were used to calculate annual age-adjusted incidence rates of stage IV prostate cancer (overall and for the subset presenting with distant metastases) and to assess time trends in patient, tumor, and treatment characteristics and survival. RESULTS From 1988 to 2003, the age-adjusted incidence of stage IV prostate cancer significantly declined by 6.4% each year. The proportion of men diagnosed at younger ages, with poorly differentiated tumors, or who underwent a radical prostatectomy significantly increased over time. Five-year relative survival improved across the study period (from 41.6% to 62.3%), particularly in those diagnosed at younger ages or with moderately to well-differentiated tumors. Later years of diagnosis were independently associated with a decreased risk of death (from all causes and from prostate cancer specifically) after controlling for important patient, tumor, and treatment characteristics. Tumor grade and receipt of radical prostatectomy appeared to be the strongest independent prognostic indicators. Temporal trends were similar in the subset presenting with distant metastases, except that no significant improvement in survival was observed. CONCLUSIONS As younger men may expect to live longer with advanced prostate cancer, there remains a need to widen the range of therapeutic and supportive care options.

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.

Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community

Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between biosimilars and reference products in some aspects are expected; likewise, biosimilar products will differ from each other. The objective of this review is to discuss the challenges associated with the development and approval of biosimilar products that are unique because of their complex structure and specialized manufacturing processes, which can impact not only efficacy but also immunogenicity and safety. Regulatory guidelines recommend a totality-of-evidence approach focused on stepwise development that involves demonstration of structural similarity and functional equivalence. Structural and functional characteristics of the proposed biosimilar are compared with the reference product; similarity of these functions forms the foundation of the biosimilar development program, including potential animal studies, a human pharmacokinetics/pharmacodynamics equivalence study, and a clinical study to confirm similar efficacy, safety, and immunogenicity. The clinical study should be performed in a sensitive population using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product if such differences exist. In conclusion, development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product and the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar product.

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

489PFUNCTIONAL SIMILARITY ASSESSMENT RESULTS COMPARING BEVACIZUMAB TO BIOSIMILAR CANDIDATE ABP 215

ABSTRACT Aim: ABP 215 is being developed as a biosimilar to bevacizumab, a recombinant monoclonal antibody that binds vascular endothelial growth factor (VEGF) and inhibits binding to receptors. Although bevacizumab and intended biosimilars share the same amino acid sequence, differences will likely exist in product quality attributes due to differences in expression systems, bioprocess and purification. Equivalence of product quality attributes, especially functional equivalence, is of primary importance during stepwise development of a biosimilar in order to provide confidence for similar clinical safety and efficacy in patients. Functional equivalence to bevacizumab is also a critical consideration when considering extrapolation of indications for the candidate biosimilar product. The aim of these studies is to examine functional simiarlity of ABP 215 to bevacizumab. Methods: Comparative assessment of biological activity included testing binding of ABP 215 and bevacizumab to VEGF and VEGF isoforms by surface plasmon resonance and to cell-surface expressed FcRn and to FcgRIIIa by AlphaLISA. The inhibition of proliferation and VEGFR2 autophosphorylation was compared in human umbilical vein endothelial cells. Anti-tumor activity was compared in A431 and Colo205 tumor xenograft models. Results: Equilibrium binding affinity (Kd) to VEGF was similar between ABP 215 (117 pM) and bevacizumab (112 pM). Binding to VEGF165 and VEGF121 was also similar. Binding (3 lots each) to FcRn was similar between ABP 215 (95-102%) and bevacizumab (114-127%) as was binding to FcgRIIIa comparing ABP 215 (100-115%) to bevacizumab (100-105%). Potency in proliferation inhibition was similar across three lots each of bevacizumab (87-98%) compared to ABP 215 (92-101%). Inhibition of autophosphorylation (IC50) was similar for a single lot each of ABP 215 (0.0871 µg/ml) compared to bevacizumab (0.0858 µg/ml). The effects of ABP 215 and bevacizumab were also similar in vivo, in terms of inhibition of both tumor growth and tumor-associated vasculature in A431 and Colo205 models. Conclusions: ABP 215 appears to be highly similar to bevacizumab in multiple sensitive preclinical pharmacologic assessments. Disclosure: T.L. Born: author is a stockholder and emplyoee of of Amgen; Q. H uynh, A. Mathur, J. Velayudhan, J. Canon, K. Reynhardt, T.J. Goletz and R.A. Markus: Amgen employee and stockholder

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]

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.