Efficacy and Safety Outcomes for Originator TNF Inhibitors and Biosimilars in Rheumatoid Arthritis and Psoriasis Trials: A Systematic Literature Review.

OBJECTIVE: Regulatory approval of biosimilar versions of originator biotherapeutics requires that new biological products be highly similar to originator products, with no clinically meaningful differences in safety, purity, and potency. In some trials of biosimilars of tumor necrosis factor inhibitors for the treatment of rheumatoid arthritis (RA) and plaque psoriasis (PsO), pre-specified margins for efficacy and safety have been met, but differences in treatment responses between pivotal originator trials and biosimilar trials have been noted. The objective of this systematic review was to examine these differences. METHODS: Searches were conducted to identify comparative randomized clinical trials of approved or proposed biosimilars of adalimumab, etanercept, and infliximab. RESULTS: Of 83 publications identified, 16 publications were included for analysis (RA: originators, n = 5; biosimilars, n = 6; PsO: originators, n = 2; biosimilars, n = 3). American College of Rheumatology 20% response rates were higher among patients with RA receiving originator biologics and biosimilars in biosimilar trials than among patients receiving the originator biologics in pivotal trials. In etanercept studies in PsO, a difference was observed in Psoriasis Area and Severity Index 75% response rates between biosimilar and pivotal trials. Insufficient efficacy data were available from adalimumab and infliximab biosimilar studies in PsO to determine any differences in treatment responses between pivotal and biosimilar studies. CONCLUSIONS: Observed differences in treatment response rates between pivotal originator trials and trials of originator biologics and their respective biosimilars may be attributable to fundamental differences in study design and/or baseline patient characteristics, which require further analysis.

Biosimilar Drugs for Psoriasis: Principles, Present, and Near Future.

Psoriasis is a chronic, inflammatory, lifelong disease with a high prevalence (afflicting approximately 1-5% of the population worldwide) and is associated with significant morbidity. The introduction of biologic therapies has improved the management of this disease. Multiple biologic medicines that block cytokine signaling, including tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, and infliximab) and inhibitors of interleukin (IL)-17 (brodalumab, ixekizumab, and secukinumab), IL-23 (guselkumab), or IL-12/23 (ustekinumab), are approved for the treatment of psoriasis. Despite the clinical benefits associated with use of biologics in psoriasis, many patients are not treated with biologic therapy, and access to treatment may be limited for various reasons, such as high treatment costs. Patents for many biologics have expired or will soon expire, and biosimilar versions of these agents are available or in development. A biosimilar is a biological product that is highly similar to an approved biologic (i.e., originator or reference) product, and has no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Biosimilars may offer less expensive treatment options for patients with psoriasis; they also may increase access to and address problems with underutilization of biologic therapy. Biosimilar development and approval follows a well-regulated process in many countries, with guidelines developed by the European Medicines Agency, US Food and Drug Administration, and World Health Organization. Currently, several anti-TNF biosimilars are available for use in patients with psoriasis, and other monoclonal antibodies are in development. This review provides dermatologists and those who treat and/or manage psoriasis with a working knowledge of the scientific principles of biosimilar development and approval. It also examines real-world experience with biosimilars available for or used in dermatology that will enable physicians to make informed treatment decisions for their patients with psoriasis. FUNDING: Pfizer Inc.

The Language of Biosimilars: Clarification, Definitions, and Regulatory Aspects.

Biologic therapies have revolutionized treatment of a number of diseases. Patents and exclusivity for a number of biologics are expiring. This has created the opportunity for the development and approval of biosimilars. Biosimilars are biologic products developed using a step-wise approach to result in a biologic that demonstrates no clinically meaningful differences in terms of quality attributes, efficacy, safety, and immunogenicity compared with an existing licensed, originator biologic. As more biosimilars receive regulatory approval and reach the market, it is increasingly important for healthcare providers to understand the terminology about biosimilars. To help support healthcare providers, the aim of this manuscript is to (i) support understanding of the language of biosimilars, (ii) review the regulatory and manufacturing processes employed in developing a biosimilar, and (iii) provide information for clinical decisions about the use of biosimilars. Because biologics are large, structurally complex proteins, biosimilars cannot be considered generic equivalents to the originator. Biosimilars are developed and evaluated using rigorous processes involving detailed analytical and functional studies, nonclinical assessments, and clinical trials. Clinical studies evaluating the potential biosimilar are designed differently than those for approval of a novel biologic since the aim is merely to confirm similar efficacy and safety and not to demonstrate clinical benefit per se. Extrapolation of data may be used to grant approval of biosimilars in indications not directly evaluated in clinical studies using the biosimilar.

Biosimilars for the Treatment of Chronic Inflammatory Diseases: A Systematic Review of Published Evidence.

BACKGROUND: Clinicians are required to assimilate, critically evaluate, and extrapolate information to support appropriate use of biosimilars across indications. OBJECTIVES: The objective of this study was to systematically collate all published data in order to assess the weight (quantity and quality) of available evidence for each molecule and inform and support healthcare decision-making in chronic inflammatory diseases. METHODS: MEDLINE®, EMBASE®, and ISI Web of Science® were searched to September 2015. Selected conference proceedings were searched from 2012 to July 2015. Studies disclosing biosimilars with unique identifiers were categorized by originator, study type, and indication. Risk of bias assessments were performed. Intended copies were differentiated as commercially available agents without evidence of rigorous comparative biosimilarity evaluations. RESULTS: Proposed biosimilars for adalimumab, etanercept, infliximab, and rituximab are reported in the published literature. Across indications, approved biosimilars infliximab CT-P13, SB2, and etanercept SB4 have published studies involving the largest number of patients or healthy subjects (n = 1405, 743, and 734, respectively), mostly in rheumatoid arthritis. At data cut-off, only CT-P13 had published data in ankylosing spondylitis (n = 250; randomized control trial) and ulcerative colitis/Crohn's disease (n = 336; observational studies). Published data were not available for ongoing studies in psoriasis patients. Four intended copies were identified in published studies (total: n = 1430; n = 1372 in observational studies). Thematic analysis of non-empirical publications showed that indication extrapolation remains an issue, particularly for gastroenterologists. CONCLUSIONS: While most agents display a moderate to high degree of similarity to their originator in the published studies identified, large discrepancies persist in the overall amount and type of data available in the public domain. Significant gaps exist particularly for intended copies, reinforcing the need to maintain a clear differentiation between these molecules and true biosimilars.

Monoclonal Antibody and Fusion Protein Biosimilars Across Therapeutic Areas: A Systematic Review of Published Evidence.

BACKGROUND: Despite regulatory efforts to formalize guidance policies on biosimilars, there remains a need to educate healthcare stakeholders on the acknowledged definition of biosimilarity and the data that underpin it. OBJECTIVES: The objectives of the study were to systematically collate published data for monoclonal antibodies and fusion protein biosimilars indicated for cancer, chronic inflammatory diseases, and other indications, and to explore differences in the type and weight (quantity and quality) of available evidence. METHODS: MEDLINE, Embase, and ISI Web of Science were searched to September 2015. Conference proceedings (n = 17) were searched 2012 to July 2015. Included studies were categorized by originator, study type, and indication. To assess data strength and validity, risk of bias assessments were undertaken. RESULTS: Across therapeutic areas, 43 named (marketed or proposed) biosimilars were identified for adalimumab, abciximab, bevacizumab, etanercept, infliximab, omalizumab, ranibizumab, rituximab, and trastuzumab originators. Infliximab CT-P13, SB2, and etanercept SB4 biosimilars have the greatest amount of published evidence of similarity with their originators, based on results of clinical studies involving larger numbers of patients or healthy subjects (N = 1405, 743, and 734, respectively). Published data were also retrieved for marketed intended copies of etanercept and rituximab. CONCLUSIONS: This unbiased synthesis of the literature exposed significant differences in the extent of published evidence between molecules at preclinical, clinical, and post-marketing stages of development, providing clinicians and payers with a consolidated view of the available data and remaining gaps.

Venous thromboembolism prophylaxis and clinical consequences in medically ill patients.

The objective of this study was to examine venous thromboembolism (VTE) prophylaxis use, risk reduction, and readmission in medically ill patients during hospitalization and after discharge. This 5-year retrospective study linked outpatient files from MarketScan Commercial and Medicare Supplemental databases. Patients were categorized into prophylaxis and non-prophylaxis groups based on guideline-recommended anticoagulant use from the index date to 180 days posthospital discharge and before the first VTE event date. Outcome variables were VTE events and rehospitalization. Risk adjustment was conducted within the prophylaxis group and between the prophylaxis and non-prophylaxis groups using propensity score matching. Among 4467 patients, 28.99% of the patients (n = 1295) were admitted with cancer, 18.03% (n = 805) with pneumonia, 14.06% (n = 628) with heart failure, 11.06% (n = 494) with stroke, 11.11% (n = 496) with sepsis, 8.08% (n = 361) with infectious diseases, 5.6% (n = 250) with severe respiratory disorders, 1.81% (n = 81) with inflammatory bowel disease, 1.05% (n = 47) with obesity, 0.20% (n = 9) with neurologic disorders, and 0.02% (n = 1) with acute rheumatic fever. Among those with 180-day continuous enrollment after the index date (n = 3511), 51.81% (n = 1819) received anticoagulant therapy only, 2.48% (n = 87) received mechanical compression treatment only (stocking or pneumatic compression), and 4.41% (n = 155) received both during hospitalization. Anticoagulant therapy rates ranged from 88.64% (obesity) to 32.39% (inflammatory bowel disease). Among anticoagulant therapy patients, 740 patients (40.68%) received low-molecular weight heparin only and 806 patients (44.31%) received unfractionated heparin. After risk adjustment, compared with patients without VTE prophylaxis, anticoagulant prophylaxis patients had lower VTE (3.62% vs. 4.27%, P < 0.04) and readmission rates (24.22% vs. 27.95%, P < 0.02) during the 6 months post-index hospital admission. In conclusion anticoagulant prophylaxis is underutilized and is associated with reduced VTE risk and a decrease in rehospitalizations for medically ill patients.

Survey of physician experiences and perceptions about the diagnosis and treatment of fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a condition characterized by widespread pain and is estimated to affect 0.5-5% of the general population. Historically, it has been classified as a rheumatologic disorder, but patients consult physicians from a variety of specialties in seeking diagnosis and ultimately treatment. Patients report considerable delay in receiving a diagnosis after initial presentation, suggesting diagnosis and management of FM might be a challenge to physicians. METHODS: A questionnaire survey of 1622 physicians in six European countries, Mexico and South Korea was conducted. Specialties surveyed included primary care physicians (PCPs; n=809) and equal numbers of rheumatologists, neurologists, psychiatrists and pain specialists. RESULTS: The sample included experienced doctors, with an expected clinical caseload for their specialty. Most (>80%) had seen a patient with FM in the last 2 years. Overall, 53% of physicians reported difficulty with diagnosing FM, 54% reported their training in FM was inadequate, and 32% considered themselves not knowledgeable about FM. Awareness of American College of Rheumatology classification criteria ranged from 32% for psychiatrists to 83% for rheumatologists. Sixty-four percent agreed patients found it difficult to communicate FM symptoms, and 79% said they needed to spend more time to identify FM. Thirty-eight percent were not confident in recognizing the symptoms of FM, and 48% were not confident in differentiating FM from conditions with similar symptoms. Thirty-seven percent were not confident developing an FM treatment plan, and 37% were not confident managing FM patients long-term. In general, rheumatologists reported least difficulties/greatest confidence, and PCPs and psychiatrists reported greatest difficulties/least confidence. CONCLUSIONS: Diagnosis and managing FM is challenging for physicians, especially PCPs and psychiatrists, but other specialties, including rheumatologists, also express difficulties. Improved training in FM and initiatives to improve patient-doctor communication are needed and may help the management of this condition.

Long-term maintenance of response across multiple fibromyalgia symptom domains in a randomized withdrawal study of pregabalin.

OBJECTIVE: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). METHODS: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. RESULTS: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. DISCUSSION: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT00151489).

Safety profile and tolerability of up to 1 year of pregabalin treatment in 3 open-label extension studies in patients with fibromyalgia.

BACKGROUND: Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. OBJECTIVE: To evaluate the safety profile and tolerability of pregabalin (75-300 mg BID) treatment for up to 1 year in patients with FM. METHODS: Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. RESULTS: Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0-100) from the open-label baseline to the end of treatment was -21 (30.5) in study 1 (1 year), -26.7 (28.8) in study 2 (12 weeks), and -20.1 (26.8) in study 3 (12 weeks). CONCLUSIONS: The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75-300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]).

Central amplification and fibromyalgia: disorder of pain processing.

Fibromyalgia (FM), a complex chronic pain disorder affecting a heterogeneous patient population, is an area of active basic and clinical research. Although diagnostic criteria for FM have been available for 2 decades, there remains no definitive diagnostic and no consensus regarding its etiology. Accumulating evidence suggests the underlying cause of FM pain results from abnormal pain processing particularly in the central nervous system rather than from dysfunction in peripheral tissues where pain is perceived. In this review, we examine recent studies investigating abnormalities in central pain processing as a component of FM in both preclinical models of generalized muscle hypersensitivity and clinical research in patients with FM. We focus our discussion on two areas where strong evidence exists for abnormalities in sensory signaling: the reduction of descending control, including suppression of descending inhibitory pathways and/or enhancement of descending facilitatory pathways, and changes in key neurotransmitters associated with central sensitization. Finally, we discuss currently available pharmacological treatments indicated for the management of pain in FM patients, based on their proposed mechanism of action and efficacy.

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials.

OBJECTIVE: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials. METHODS: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change. RESULTS: A large proportion of patients exhibited concomitant headache, immunological (allergy), gastroesophageal, and/or psychiatric disorders. The efficacy analyses performed on these subgroups of patients, amongst others, showed - with few exceptions - consistent pain reductions of similar magnitude with pregabalin. CONCLUSION: Comorbid conditions are common among patients with fibromyalgia and their presence is not associated with altered pregabalin efficacy.

Treatment response to pregabalin in fibromyalgia pain: effect of patient baseline characteristics.

OBJECTIVE: The objective of this study was to evaluate the effect of patients' characteristics at baseline on the magnitude of pain response to pregabalin in patients with fibromyalgia. METHODS: Data from four randomized, multicenter, placebo-controlled clinical studies of pregabalin in patients with fibromyalgia were used for the analysis. Approved doses (300 and 450 mg/day) were pooled to enhance the sensitivity of the interaction tests. A centered covariate interaction model was used to assess the treatment effects; a noncentered model was used for estimated mean pain changes and least square means across different levels of baseline covariates. The interaction was considered significant if p < 0.10. RESULTS: In total, 2061 patients (median age, 49 years; median pain score, 7.0; median duration of fibromyalgia, 83 months) were included in this analysis. No significant interaction was observed between treatment and anxiety, depression, or duration of fibromyalgia. Significant treatment by baseline mean pain (p = 0.037), treatment by baseline sleep score (p = 0.071), and treatment by age (p = 0.051) interactions were observed. CONCLUSION: The magnitude of response to pregabalin in terms of changes in pain may depend on age, pain, and sleep levels at baseline in patients with fibromyalgia.

A patient survey of the impact of fibromyalgia and the journey to diagnosis.

BACKGROUND: Fibromyalgia is a painful, debilitating illness with a prevalence of 0.5-5.0% that affects women more than men. It has been shown that the diagnosis of fibromyalgia is associated with improved patient satisfaction and reduced healthcare utilization. This survey examined the patient journey to having their condition diagnosed and studied the impact of the condition on their life. METHODS: A questionnaire survey of 800 patients with fibromyalgia and 1622 physicians in 6 European countries, Mexico and South Korea. Patients were recruited via their physician. RESULTS: Over half the patients (61%) were aged 36-59 years, 84% were women, and the mean time since experiencing fibromyalgia symptoms was 6.5 years. Patients had experienced multiple fibromyalgia symptoms (mean of 7.3 out of 14), with pain, fatigue, sleeping problems and concentration difficulties being the most commonly reported. Most patients rated their chronic widespread pain as moderate or severe and fibromyalgia symptoms were on average "fairly" to "very" disruptive, and had a "moderate" to "strong" impact on patients' lives. 22% were unable to work and 25% were not able to work all the time because of their fibromyalgia. Patients waited on average almost a year after experiencing symptoms before presenting to a physician, and it took an average of 2.3 years and presenting to 3.7 different physicians before receiving a diagnosis of fibromyalgia. Patients rated receiving a diagnosis as somewhat difficult on average and had difficulties communicating their symptoms to the physician. Over one third (35%) felt their chronic widespread pain was not well managed by their current treatment. CONCLUSIONS: This survey provides further evidence that fibromyalgia is characterized by multiple symptoms and has a notable impact on quality of life and function. The diagnosis of fibromyalgia is delayed. Patients wait a significant period of time before presenting to a physician, adding to the prolonged time to diagnosis. Patients typically present with a multitude of symptoms, all resulting in a delay in diagnosis and eventual management. Helping clinicians to diagnose and manage patients with fibromyalgia should benefit both patients and funders of healthcare.

Pregabalin in treatment-refractory fibromyalgia.

CONTEXT: Fibromyalgia is a chronic musculoskeletal pain disorder. The pain can be intractable and may not respond to commonly-used treatments, such as tricyclic antidepressants and opioids. OBJECTIVES: To evaluate pregabalin response in the subset of patients with fibromyalgia whose pain had been judged refractory to other treatments. METHODS: Patients had previously participated in a controlled trial of pregabalin and had moderate to severe pain despite treatment with gabapentin, a tricyclic antidepressant, and a third medication (e.g., other anticonvulsants, opioid, selective serotonin reuptake inhibitors, tramadol). Flexible-dose pregabalin 150-600 mg/day was added for 3-month treatment cycles, each followed by 3- to 28-day pregabalin "drug holiday" that lasted until a relapse occurred. Pain intensity was measured using the visual analogue scale of the Short-Form McGill Pain Questionnaire completed at baseline, the end of each 3-month treatment period and at the relapse visit. Analysis was at 15 months (after 5 cycles). RESULTS: In total, 25 patients were included and 19 completed the 15-month analysis period. At baseline, 88% were receiving ≥1 pain medication. Pregabalin 150-600 mg/day was associated with statistically significant, clinically meaningful pain reduction during each treatment cycle. Pain quickly returned to baseline levels during the "drug holidays" in a median time of 2-4 days. Somnolence (n=5) and dizziness (n=4) were the most common adverse events. CONCLUSIONS: These results suggest that pregabalin may be beneficial in patients with fibromyalgia who have had an unsatisfactory response to treatment with other medications.

Treatment of acute gout in hospitalized patients.

OBJECTIVE: To record practice patterns of treatment of acute gout in hospitalized patients. METHODS: We performed a retrospective chart review of hospitalized patients diagnosed with gout. RESULTS: Seventy-nine (43%) patients were diagnosed with acute gout during their hospitalization. Fifty-eight (73%) patients with acute gout were found to have a reduction in their glomerular filtration rate. Twenty patients (25%) underwent arthrocentesis. The most widely used drugs for acute gout were colchicine, n = 42 (53%), and nonsteroidal antiinflammatory drugs (NSAID), n = 40 (51%). Combination therapy was used in 52% of patients with acute gout. Thiry-six (86%) patients treated with colchicine and 32 (80%) patients treated with NSAID had renal failure. DISCUSSION: Crystal analysis, the gold standard for diagnosing gout, was performed in only 25% of patients suspected of acute gout. Combination antiinflammatory agents are used in over 50% of patients despite the absence of evidence to support use of such combinations. Renal failure was present in 73% of patients with acute gout. Colchicine and NSAID should therefore be used with caution in these patients. Practice patterns vary widely and often appear to be in conflict with recommended diagnostic and treatment measures for acute gout.

Reactive arthritis.

ReA consists of sterile axial or peripheral articular inflammation,enthesitis, and extra-articular manifestations. Most patients are HLA-B27 positive, although determining the B27 status of an individual patient is irrelevant. Exposure to specific bacterial antigens is usually the inciting factor. Diagnosis usually can be made by clinical examination and history. The current standard therapy is NSAIDs and physiotherapy, but molecular biologic treatment may ultimately become the mainstay in recalcitrant and severe ReA.