GP2017, an adalimumab biosimilar: pharmacokinetic similarity to its reference medicine and pharmacokinetics comparison of different administration methods

ABSTRACT

Background: To compare the pharmacokinetics of Sandoz biosimilar adalimumab (GP2017) with reference adalimumab (Humira) in healthy volunteers (PK similarity study) and to compare the pharmacokinetics of GP2017 administered by autoinjector (AI) or prefilled syringe (PFS; delivery study).

Methods: Healthy male subjects were randomized to receive a single 40 mg subcutaneous injection of GP2017, US-licensed or EU-authorized reference adalimumab (US/EU-Humira; PK similarity study) or a single 40 mg subcutaneous injection of GP2017 via AI or PFS (delivery study). Pharmacokinetics, safety, and immunogenicity were assessed over 72 days post-injection.

Results: The geometric mean ratios (90% confidence intervals) for C_max and AUC_0–inf were 1.05 (0.99–1.11) and 1.04 (0.96–1.13) for GP2017/EU-Humira and 1.00 (0.94–1.06) and 1.08 (1.00–1.18) for GP2017/US-Humira, all within the prespecified margin of 0.80–1.25 (PK similarity study). Pharmacokinetic parameters of GP2017 matched between AI and PFS (delivery study). Safety and immunogenicity were similar across groups in both studies.

Conclusion: PK similarity between GP2017, EU- and US-Humira was demonstrated. The safety pro?le of GP2017 was consistent with previous reports for Humira. These results contribute to the ‘totality-of-the-evidence’ supporting biosimilarity of GP2017 to Humira. PK and tolerability were equivalent for GP2017 dosed by AI or PFS.

Trial registration: PK similarity study EudraCT no. 2015-000579-28; Delivery study: EudraCT no. 2014–002879-29     

Differences in immunogenicity associated with non-product related variability: insights from two pharmacokinetic studies using GP2017, an adalimumab biosimilar

ABSTRACT

Introduction: Antidrug antibody (ADA) development is known to occur with adalimumab treatment and impacts adalimumab exposure. Here, we compare the impact of immunogenicity on pharmacokinetics (PK) across two randomized PK studies of GP2017, an approved biosimilar adalimumab, in healthy subjects.

Methods: Healthy male subjects (N= 107 in study GP17-104; N= 90 in study GP17-103) received a single 40 mg subcutaneous injection of the same GP2017 drug product batch. Cross-study PK comparison was performed for log-transformed C_max, AUC_0–360h, AUC_0–last, and AUC_0–inf, using an ANCOVA model.

Results: The proportion of ADA-positive subjects was higher in GP17-103 (in total 71.1%) vs. GP17-104 (57.9%). Comparison of GP2017 PK between studies showed that the exposure was lower in GP17-103 vs GP17-104, with 90% confidence intervals (CIs) for geometric mean ratios of AUC_0–last and AUC_0–inf being outside the range of 0.80–1.25. A subgroup analysis showed that in ADA-negative subjects 90% CIs for all PK parameters were within range, with geometric mean ratios close to 1.00.

Conclusion: The differences in GP2017 PK between the two groups are not considered to be product-related, but may be due to currently unknown factors related to differences between the two study populations.     

Long-term safety,efficacy, and immunogenicity of adalimumab biosimilar BI 695501 and adalimumab reference product in patients with moderately-to-severely active rheumatoid arthritis: results from a phase 3b extension study (VOLTAIRE-RAext)

ABSTRACT

Objective: To evaluate long-term safety, efficacy, and immunogenicity of BI 695501 in patients with moderately-to-severely active rheumatoid arthritis (RA) who have completed VOLTAIRE-RA.

Methods: Eligible patients for this phase 3b open-label extension study (VOLTAIRE-RAext), who had completed 48 weeks’ treatment with BI 695501 (Group A), 24 weeks each of adalimumab RP then BI 695501 (Group B), or 48 weeks of adalimumab RP (Group C) in VOLTAIRE-RA, were enrolled.

Results: Altogether, 430 patients received BI 695501 fortnightly for 48 weeks: Group A, n = 225; Group B, n = 103; Group C, n = 102. The proportion of patients with drug-related adverse events (AEs; overall 20.2%) was similar across Groups A, B, and C: 21.3%, 20.4%, and 17.6%, respectively. The majority of treatment-emergent AEs were non-serious and of mild/moderate intensity. Consistent with adalimumab RP’s safety profile, most drug-related AEs were in the system organ class infections and infestations. BI 695501 and adalimumab RP responses at the end of VOLTAIRE-RA were sustained during VOLTAIRE-RAext and all efficacy and immunogenicity endpoints were similar across groups.

Conclusion: Over 2 years, BI 695501 showed similar safety, efficacy, and immunogenicity to adalimumab RP, independent of initial treatment in VOLTAIRE-RA. No previously unknown adalimumab side effects were identified.

Clinical trial registration: NCT02640612.     

Biosimilars of adalimumab: the upcoming challenge in IBD

ABSTRACT

Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are successfully used in all indications for whom the reference product (RP) was approved.

Areas covered: In late 2018, adalimumab biosimilars will also be available in patients with inflammatory bowel disease (IBD).

ABP501, BI 695501, GP2017, and SB5 have been approved by the EMA for the same indications of the reference product (RP, Humira®). Preclinical data show high similarity between all biosimilars and the RP. Clinical data in patients with rheumatoid arthritis and psoriasis also show no differences in terms of efficacy, safety, and immunogenicity. Data in IBD patients are still lacking.

Expert opinion: Biosimilars of adalimumab appear to be clinically equivalent to the RP. Decisions based on choosing the ideal patient to receive or to be switched to a biosimilar of adalimumab, or choosing one biosimilar vs. another, or cross-switching among biosimilars remain the next challenge in the field of IBD.     

Preoperative Management of Gastrointestinal and Pulmonary Medications: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement

Perioperative medication management is integral to preoperative optimization but remains challenging because of a paucity of literature guidance. Published recommendations are based on the expert opinion of a small number of authors without collaboration from multiple specialties. The Society for Perioperative Assessment and Quality Improvement (SPAQI) recognized the need for consensus recommendations in this area as well as the unique opportunity for its multidisciplinary membership to fill this void. In a series of articles within this journal, SPAQI provides preoperative medication management guidance based on available literature and expert multidisciplinary consensus. The aim of this consensus statement is to provide practical guidance on the preoperative management of gastrointestinal and pulmonary medications. A panel of experts with anesthesiology, perioperative medicine, hospital medicine, general internal medicine, and medical specialty experience was drawn together and identified the common medications in each of these categories. The authors then used a modified Delphi approach to review the literature and to generate consensus recommendations.     

Preoperative Management of Medications for Rheumatologic and HIV Diseases: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement

Perioperative medical management is challenging because of the rising complexity of patients presenting for surgical procedures. A key part of preoperative optimization is appropriate management of long-term medications, yet guidelines and consensus statements for perioperative medication management are lacking. Available resources use recommendations derived from individual studies and do not include a multidisciplinary focus on formal consensus. The Society for Perioperative Assessment and Quality Improvement identified a lack of authoritative clinical guidance as an opportunity to use its multidisciplinary membership to improve evidence-based perioperative care. The Society for Perioperative Assessment and Quality Improvement seeks to provide guidance on perioperative medication management that synthesizes available literature with expert consensus. The aim of this consensus statement is to provide practical guidance on the preoperative management of immunosuppressive, biologic, antiretroviral, and anti-inflammatory medications. A panel of experts including hospitalists, anesthesiologists, internal medicine physicians, infectious disease specialists, and rheumatologists was appointed to identify the common medications in each of these categories. The authors then used a modified Delphi process to critically review the literature and to generate consensus recommendations.     

Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease

Several selective antagonists for adenosine A_2A receptors (A_2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D₂ and adenosine A_2A receptors in the basal ganglia. At present it is believed that A_2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A_2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D₂ receptors (D₂Rs) expressed in the striatum are known to form heteromers with A_2A adenosine receptors. Thus, the development of heteromer-specific A_2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.     

Assessment of anti-inflammatory efficacy of acupuncture in patients with inflammatory bowel disease: A systematic review and meta-analysis

BackgroundInflammation has a significant role in the onset and progression of inflammatory bowel disease (IBD). Increasing attention has been paid to the use of acupuncture in IBD patients; however, its regulatory effects on inflammatory factors in IBD still require validation. Here, we systematically evaluated the effects of acupuncture on inflammatory factors in IBD patients.MethodsEight electronic databases were searched for studies that met the inclusion criteria. After evaluating the quality of the studies selected by two reviewers, the meta-analysis was performed to assess the efficacy of acupuncture in IBD patients and the impact on inflammatory factors (TNF-α, IL-1, IL-8 and IL-10).ResultsFour randomized controlled trials with a total of 228 patients satisfied the inclusion criteria. Acupuncture has a positive therapeutic impact on IBD (MD = 1.22, 95% CI [1.07, 1.39], P = 0.003). Moreover, it regulates the levels of TNF-α (MD =−60.58, 95% CI [−100.30, −20.89], P = 0.003), IL-8 (MD =−56.40, 95% CI [−60.02, −52.14], P < 0.00001) and IL-10 (MD =35.96, 95% CI [11.02, 60.91], P = 0.005) in IBD patients. However, the P value of meta-analysis in IL-1 great than 0.05.(MD =−27.90, 95% CI [−97.82, 42.02], P = 0.11).ConclusionAcupuncture has a positive therapeutic impact on IBD and can effectively regulate inflammatory factors in IBD patients. TNF-α, IL-8 and IL-10 are more appropriate inflammatory indicators for clinically evaluating the anti-inflammatory response in the blood of IBD patients by acupuncture.     

Risk of Hematologic Malignancies in Elderly Patients With Ankylosing Spondylitis: A Cohort Study and Systematic Review

ObjectiveTo examine the risk of hematologic malignancies in older adults with ankylosing spondylitis (AS).Patients and MethodsWe used US Medicare data from January 1, 1999, to December 31, 2010, to identify a population-based cohort of beneficiaries with AS. We also included beneficiaries with inflammatory bowel disease (IBD) as disease controls and beneficiaries without AS or IBD as unaffected controls. We excluded those treated with tumor necrosis factor inhibitors in this period. We followed up each group for new diagnosis claims for hematologic malignancies until September 30, 2015.ResultsWe included 12,451 beneficiaries with AS, 234,905 with IBD, and 10,975,340 unaffected controls, with a mean follow-up of 9.9, 9.3, and 8.0 years, respectively. We identified 297 hematologic malignancies in the AS group, 4538 malignancies in the IBD group, and 128,239 malignancies in unaffected controls. The standardized incidence ratio in AS vs unaffected controls was 1.39 (95% CI, 1.05 to 1.61) for non-Hodgkin lymphoma, 1.50 (95% CI, 1.17 to 1.92) for chronic lymphocytic leukemia, and 1.52 (95% CI, 1.12 to 2.06) for multiple myeloma. Risks of acute myeloid leukemia and chronic myeloid leukemia were not elevated in AS, and there were too few cases of Hodgkin lymphoma to compute risks. Risks were comparable to those of beneficiaries with IBD. We also performed a systematic literature review of the risk of hematologic malignancy in AS, focusing on age associations, which have not been previously examined. We identified 21 studies in the systematic literature review, which included mainly young or middle-aged patients. Results suggested that AS was largely not associated with an increased risk of hematologic malignancies. Two cohort studies reported an increased risk of multiple myeloma in AS.ConclusionThe risks of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma are increased among elderly patients with AS.