Primal Kaur

Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study

Objectives ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. Methods In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. Results A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. Conclusions Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. Trial registration number NCT01970475; Results.

Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study

Background ABP 501 is a biosimilar of adalimumab. Objective We sought to compare the efficacy and safety of ABP 501 with adalimumab. Methods This 52‐week, double‐blind study randomized patients with moderate to severe psoriasis to ABP 501 or adalimumab. At week 16, those with 50% or more improvement in Psoriasis Area and Severity Index score from baseline on ABP 501 continued the same treatment, whereas adalimumab‐treated patients were rerandomized to adalimumab or ABP 501. Clinical similarity in Psoriasis Area and Severity Index percent improvement from baseline to week 16 (primary end point) was established if the point estimate of treatment difference and its 2‐sided 95% confidence interval between groups was within equivalence margin of ±15. Patients, including those undergoing a single transition at week 16, were evaluated for safety and immunogenicity. Results Psoriasis Area and Severity Index percent improvement at week 16 was 80.9 for ABP 501 and 83.1 for adalimumab (least‐square mean difference −2.18 [95% confidence interval −7.39 to 3.02]). Adverse events (67.2% [117/174] vs 63.6% [110/173]) and antidrug antibody incidence (55.2% [96/174] vs 63.6% [110/173]) for ABP 501 vs adalimumab were similar. Safety, including immunogenicity, was similar among groups after single transition (week 20). Limitations The 52‐week data are not reported here. Conclusions ABP 501 was shown to be clinically similar to adalimumab. Safety and immunogenicity were not impacted immediately after single transition (adalimumab to ABP 501).

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.

AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo‐controlled phase IIa study evaluated the dose–effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33–35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose–effect trend was observed with the twice‐daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once‐daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

Clinical Similarity of the Biosimilar ABP 501 Compared With Adalimumab After Single Transition: Long-Term Results From a Randomised, Double-Blind, 52-Week, Phase 3 Study in Moderate-to-Severe Plaque Psoriasis Patients

ABP 501, a U.S.A. Food and Drug Administration‐ and European Medicines Agency‐approved biosimilar, is highly similar to adalimumab in structure, function and pharmacokinetics.

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

Cost-effectiveness of sequenced treatment of rheumatoid arthritis with targeted immune modulators

Abstract Aims: To determine the cost-effectiveness of treatment sequences of biologic disease-modifying anti-rheumatic drugs or Janus kinase/STAT pathway inhibitors (collectively referred to as bDMARDs) vs conventional DMARDs (cDMARDs) from the US societal perspective for treatment of patients with moderately to severely active rheumatoid arthritis (RA) with inadequate responses to cDMARDs. Materials and methods: An individual patient simulation model was developed that assesses the impact of treatments on disease based on clinical trial data and real-world evidence. Treatment strategies included sequences starting with etanercept, adalimumab, certolizumab, or abatacept. Each of these treatment strategies was compared with cDMARDs. Incremental cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment sequence relative to cDMARDs. The cost-effectiveness of each strategy was determined using a US willingness-to-pay (WTP) threshold of

FRI0191 Biosimilar Candidate ABP 501: Additional Efficacy Analyses from The Phase 3 Study

150,000/QALY. Results: For the base-case scenario, bDMARD treatment sequences were associated with greater treatment benefit (i.e. more QALYs), lower lost productivity costs, and greater treatment-related costs than cDMARDs. The expected ICERs for bDMARD sequences ranged from ∼

Manufacturing of Biologics

126,000 to