Ehab Mahgoub

Clinical and regulatory perspectives on biosimilar therapies and intended copies of biologics in rheumatology

Biologics are vital to the management of patients with rheumatic and musculoskeletal diseases such as rheumatoid arthritis and other inflammatory and autoimmune conditions. Nevertheless, access to these highly effective treatments remains an unmet medical need for many people around the world. As patents expire for existing licensed biologic (originator) products, biosimilar products can be approved by regulatory authorities and enter clinical use. Biosimilars are highly similar copies of originator biologics approved through defined and stringent regulatory processes after having undergone rigorous analytical, non-clinical, and clinical evaluations. The introduction of high-quality, safe, and effective biosimilars has the potential to expand access to these important medicines. Biosimilars are proven to be similar to the originator biologic in terms of safety and efficacy and to have no clinically meaningful differences. In contrast, “intended copies” are copies of originator biologics that have not undergone rigorous comparative evaluations according to the World Health Organization recommendations, but are being commercialized in some countries. There is a lack of information about the efficacy and safety of intended copies compared with the originator. Furthermore, they may have clinically significant differences in formulation, dosages, efficacy, or safety. In this review, we explore the differences between biosimilars and intended copies and describe key concepts related to biosimilars. Familiarity with these topics may facilitate decision making about the appropriate use of biosimilars for patients with rheumatic and musculoskeletal diseases.

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study

Objective To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. Methods This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6–24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Results Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. Conclusion ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. Trial registration This study was registered on www.ClinicalTrials.gov (NCT01981473).

Differentiating biosimilarity and comparability in biotherapeutics.

The manufacture of biologics is a complex process involving numerous steps. Over time, differences may arise as a result of planned changes to the manufacturing processes of a biologic from the same manufacturer. Comparability is the regulatory process that outlines the scope of an assessment required of an already licensed biologic after a manufacturing process change made by the same manufacturer. The aim of a comparability assessment is to demonstrate that any pre-manufacturing and post-manufacturing changes have no adverse impact on quality, safety, and efficacy of the biologic. A comparability assessment is distinct from a biosimilarity assessment, which involves extensive assessment of a biologic that is highly similar to the originator (reference product) in terms of quality, safety, and efficacy. The US Food and Drug Administration, European Medicines Agency, and World Health Organization have applied the fundamental comparability concepts into their respective biosimilarity guidance documents. In this review, we examine the rationale behind the distinct, highly regulated approval processes governing changes that may occur over time to an originator biologic due to planned manufacturing changes (as described by a comparability exercise) and those that outline the approval of a proposed biosimilar drug, based on its relationship with the reference product (biosimilarity evaluations).

Comparing the immunogenicity of the etanercept biosimilar SB4 with the innovator etanercept: another consideration

In their 2015 publication, Emery et al 1 reported findings of a phase III, randomised, double-blind study comparing the investigational etanercept biosimilar SB4 (Samsung Bioepis, Incheon, Korea) with the innovator etanercept in patients who have moderate-to-severe rheumatoid arthritis (RA) despite methotrexate treatment. Although the authors reported equivalent clinical efficacy between the SB4 and reference product, they found a significantly lower incidence of antidrug antibodies (ADAs) against SB4 than against etanercept, that is, 2 (0.7%) patients in the SB4 group and 39 (13.1%) patients in the etanercept group were ADA positive by week 24 (p<0.001). We acknowledge the two recently published Letters to the Editor of the Annals of the Rheumatic Diseases by Moots et al 2 and a response by Emery et al ,3 in which important aspects of these immunogenicity results were discussed, and would also like to offer an additional consideration. The etanercept immunogenicity findings reported in the original manuscript1 warrant closer inspection, as they are inconsistent with those reported in …

An epidemiological study to assess the prevalence of diabetic peripheral neuropathic pain among adults with diabetes attending private and institutional outpatient clinics in South Africa

Objective To determine the prevalence of diabetic peripheral neuropathic pain (DPNP) among South African adults with type 1 or type 2 diabetes. Methods This cross-sectional study recruited patients with diabetes from 50 institutional/private clinics. DPNP was diagnosed using Douleur Neuropathique 4 (DN4) questionnaire (score ≥4). Health-related quality-of-life (HRQoL) and sleep were assessed with EQ-5D and Daily Sleep Interference Scale (DSIS), respectively. Results Prevalence of DPNP was 30.3% (n = 1046). Risk of DPNP was significantly increased in people aged 50–64 years (odds ratio [OR] 1.71, 95% confidence intervals [CI] 1.21, 2.41), with diabetes for ≥10 years (OR 1.55, 95% CI 1.15, 2.08), female patients (OR 1.58, 95% CI 1.18, 2.12), and black patients (OR 1.71, 95% CI 1.19, 2.46). Mean ± SD EQ-5D and DSIS scores were 0.84 ± 0.16 and 0.83 ± 1.90, respectively, in participants without DPNP versus 0.64 ± 0.25 and 3.62 ± 2.96, respectively, in those with DPNP. Conclusions DPNP is widely prevalent in South Africa. Despite its negative impact on HRQoL and sleep, DPNP is inadequately treated. DN4 is an easy-to-use, validated questionnaire that can be used widely as a DPNP screening tool in clinical practice.

Manufacturing history of etanercept (Enbrel®): Consistency of product quality through major process revisions

ABSTRACT Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production. Multiple orthogonal biochemical analyses, which included evaluation of attributes indicative of product purity, potency, and quality, were assessed on >2,000 batches of ETN from three sites of DS manufacture, during the period 1998–2015. Based on the key quality attributes of product purity (assessed by hydrophobic interaction chromatography HPLC), binding activity (to TNF by ELISA), potency (inhibition of TNF-induced apoptosis by cell-based bioassay) and quality (N-linked oligosaccharide map), we show that the integrity of ETN DS has remained consistent over time. This consistency was maintained through three major enhancements to the initial process of manufacturing that were supported by detailed comparability assessments, and approved by the European Medicines Agency. Examination of results for all major quality attributes for ETN DS indicates a highly consistent process for over 18 years and throughout changes to the manufacturing process, without affecting safety and efficacy, as demonstrated across a wide range of clinical trials of ETN in multiple inflammatory diseases.

Variability of intended copies for etanercept (Enbrel®): Data on multiple batches of seven products

ABSTRACT Fusion protein and monoclonal antibody-based tumor necrosis factor (TNF) inhibitors represent established treatment options for a range of inflammatory diseases. Regulatory authorities have outlined the structural characterization and clinical assessments necessary to establish biosimilarity of a new biotherapeutic product with the innovator biologic drug. Biologic products that would not meet the minimum World Health Organizations standard for evaluation of similar biotherapeutic products are available in some countries; in some cases relevant data to assess biosimilarity and appropriate regulatory approval pathways are lacking. Batches of seven intended copy (IC) products for etanercept (Enbrel®) were subjected to a subset of test methods used in the routine release and heightened characterization of Enbrel®, to determine key attributes of identity, quality, purity, strength, and activity. While a number of quality attributes of the IC lots tested met the release specifications for Enbrel®, none fell within these limits across all methods performed, and there were no IC lots that satisfied the criteria typically applied by the innovator to support comparability with Enbrel®. Although the consequences of these differences are largely unknown, the potential for unanticipated clinical outcomes should not be overlooked.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies

OBJECTIVES Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. METHODS Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. RESULTS 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. CONCLUSIONS In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population.

SAT0164 Association between flare and radiographic progression in patients with rheumatoid arthritis

Background Biologic therapy has improved RA management, enabling some patients to achieve remission. Many clinicians decrease the biologic dose for patients in low disease activity (LDA) or remission. However, it is unclear which patients may flare and if flare contributes to radiographic progression. Objectives To assess whether patients who flared had a higher incidence of radiographic progression, and to compare patients with and without flares. Methods PRESERVE (ClinicalTrials.gov: NCT00565409) was a 2-period trial in patients with moderate RA despite MTX. Period 1 was open-label, single treatment induction with etanercept (ETN) 50mg+MTX weekly (QW) for 36 wks. Patients in LDA or remission (disease activity score for 28 joints [DAS28] ≤3.2) during wks 12 to 36 continued to Period 2, the randomized, double-blind phase to evaluate maintenance of LDA/remission. Patients were randomized to ETN 50mg+MTX QW, ETN 25mg+MTX QW, or placebo+MTX QW to wk 88. This post hoc analysis evaluated flare and radiographic progression at wk 88. Flare was defined 2 ways: 1) loss of LDA with/without DAS28 change of 0.6; and 2) relapse (DAS28>5.1 or DAS28>3.2 at ≥2 time points). Radiographic progression was evaluated according to 4 levels of stringency: 1) minimally clinically important difference (modified total Sharp score [mTSS] change ≥5); 2) smallest detectable difference (mTSS change ≥2.3); 3) mTSS change ≥0.5; and 4) mTSS change >0. Baseline (BL) characteristics were compared for patients with vs without flare, defined as loss of LDA and DAS28 change of 0.6. Analysis of covariance and chi-square test compared continuous and categorical outcomes, respectively. Results Age, race, BMI, and disease duration did not differ significantly for flare vs non-flare, total N=531. BL DAS28 was higher for flare vs non-flare: mean (SD) 4.37 (0.45) vs 4.27 (0.45), p=0.046. Other BL disease characteristics were similar between groups. With flare defined as relapse, significantly more flare than non-flare patients showed all 4 degrees of radiographic progression (table). With flare defined as LDA loss with/without DAS28 change of 0.6, radiographic progression did not differ significantly between groups, but numerically more patients with flare progressed. This was the trend for all treatments; the numbers were too small to analyze. Numerically more placebo patients progressed, regardless of flare status or progression category (data not shown). Table. Radiographic progression at week 88 Outcome Flare Patients Non-flare Patients P-value* Flare defined as loss of LDA and DAS28 change of 0.6  mTSS >0 43/271 (15.9) 31/260 (11.9) 0.2109  mTSS ≥0.5 38/271 (14.0) 24/260 (9.2) 0.1045  mTSS ≥2.3 20/271 (7.4) 10/260 (3.8) 0.0914  mTSS ≥5.0 9/271 (3.3) 2/260 (0.8) 0.0633 Flare defined as loss of LDA  mTSS >0 44/280 (15.7) 30/251 (12.0) 0.2586  mTSS ≥0.5 39/280 (13.9) 23/251 (9.2) 0.1043  mTSS ≥2.3 20/280 (7.1) 10/251 (4.0) 0.1338  mTSS ≥5.0 9/280 (3.2) 2/251 (0.8) 0.0670 Flare defined as relapse  mTSS >0 35/181 (19.3) 39/350 (11.1) 0.0119  mTSS ≥0.5 31/181 (17.1) 31/350 (8.9) 0.0065  mTSS ≥2.3 19/181 (10.5) 11/350 (3.1) 0.0011  mTSS ≥5.0 9/181 (5.0) 2/350 (0.6) 0.0015 *Fishers exact test. Overall treatment group. Values are n/N (%). Conclusions Using relapse as a rigorous definition of flare, radiographic progression occurs in significantly more flare than non-flare patients, demonstrating that it is a consequence of flare following biologic withdrawal. Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, Lilly, MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Speakers bureau: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, H. Jones Shareholder of: Pfizer, Employee of: Pfizer, E. Mahgoub Shareholder of: Pfizer, Employee of: Pfizer, R. Pedersen Shareholder of: Pfizer, Employee of: Pfizer, L. Marshall Shareholder of: Pfizer, Employee of: Pfizer

THU0209 Responder vs Non-Responder Baseline Characteristics and Early Response in Patients with Non-Radiographic Axial Spondyloarthritis

Background Tumor necrosis factor (TNF) inhibitors, including etanercept (ETN), have demonstrated efficacy in patients with non-radiographic axial spondyloarthritis (nr-axSpA) and an inadequate response to NSAIDs. However, not all patients respond to TNF-inhibitors. Thus, it is of interest to determine whether responders and non-responders have different baseline (BL) characteristics and/or early response patterns. This information could aid clinicians in deciding which patients to treat with a TNF-inhibitor. Objectives To compare demographics, BL characteristics, and response to ETN treatment for the wk 24 ASAS40 responders and non-responders in the EMBARK study. Methods Patients had axSpA per ASAS classification criteria without meeting modified NY radiographic criteria, symptoms for >3 months and <5 yrs, BASDAI score ≥4, and failed ≥2 NSAIDs. Patients were randomized to ETN 50 mg/wk or placebo (PBO) for 12 wks; then all patients received open-label ETN 50 mg/wk. This analysis includes the open-label modified intent-to-treat (mITT) population randomized to ETN. Patients were grouped according to ASAS40 response at wk 24. Clinical efficacy endpoints were assessed at 2, 4, 8, 12, 16 and 24 wks. Comparison of BL characteristics used one-way analysis of variance for continuous variables and Fishers exact test or chi-square for all yes/no or categorical variables. Comparison of clinical responses used analysis of covariance with BL as covariate or Fishers exact test. Results 205 patients were in the open-label mITT population (ETN/ETN, n=100; PBO/ETN, n=105). For the 100 ETN/ETN patients in this analysis, mean (SD) age was 31.8 (7.8) yrs, 64.0% were male, symptom duration was 2.4 (2.0) yrs; 66% were HLA-B27+, and 84% were MRI sacroiliitis+. Significantly more males than females were 24-wk ASAS40 responders (77.3% vs 22.7%, table); there were no statistically significant differences in age, race, height/weight, or symptom duration. There were positive associations between 24-wk ASAS40 response and several BL disease characteristics related to back pain and also the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score; there was a negative association with enthesitis (table). According to 24-wk ASAS40 response, there were no significant differences in BL BASDAI, BASFI, ASDAS, physician global assessment, SPARCC MRI spinal score, swollen joint count, MRI sacroiliitis(+/-), HLA-B27(+/-), or several health-related patient-reported outcomes. Although higher BL CRP was significantly associated with ASAS40 response at 12 wks,1 it was not at 24 wks (BL mean CRP 7.3 for 24-wk ASAS40 responders, 7.0 for non-responders; p=ns). Notably, for endpoints with a significant difference according to 24-wk ASAS40, the distinction was apparent at wk 2 for all but ASDAS inactive disease, which differentiated by wk 8 (table). There were no significant differences in change in BASMI, CRP or ESR per 24-wk ASAS40 result. Conclusions Categorizing patients according to 24-wk ASAS40 result demonstrated significant differences in several BL characteristics and clinical results; many clinical endpoints differentiated after only 2 wks of treatment. This information may aid clinicians in choosing which patients to treat with a TNF-inhibitor. References Dougados M, et al. Arthritis Rheumatol. 2014;66:2091-102 Disclosure of Interest J. Sieper Consultant for: Böhringer-Ingelheim, Janssen, Novartis, AbbVie, Merck, Pfizer, UCB, H. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bukowski Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Pedersen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Mahgoub Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Marshall Shareholder of: Pfizer Inc, Employee of: Pfizer Inc