The Science of Biosimilars-Updating Interchangeability.

This Viewpoint from the US Food and Drug Administration (FDA) summarizes a recent update to an FDA draft interchangeability guidance regarding the need for clinical switching studies to illustrate the FDA's ongoing efforts to streamline the development of biosimilar medications that are in line with the latest science.

Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis.

Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S. Food and Drug Administration (FDA). These findings were augmented with data from peer reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized following PRISMA guidelines. Meta-analysis was conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biologic were identified. Safety data including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00) across STPs, respectively. Immunogenicity data showed similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biologic and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients. This first systematic review using statistical methods to address the risk of switching patients between reference biologics and biosimilars finds no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or a biosimilar.

Prescriber Perspectives on Biosimilar Adoption and Potential Role of Clinical Pharmacology: A Workshop Summary.

The approval and adoption of biosimilar products are essential to contain increasing healthcare costs and provide more affordable choices for patients. Despite steady progress in the number of the US Food and Drug Administration (FDA) biosimilar approvals over the years, biosimilar adoption in the United States has been slow and gradual, largely driven by payers rather than clinicians. In order to better understand the barriers to biosimilar adoption in the clinic, the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) and the FDA jointly hosted a virtual workshop on April 13, 2022, titled "Biosimilars: A Decade of Experience and Future Directions - Strategies for Improving Biosimilar Adoption and the Potential Role of Clinical Pharmacology." This summary documents the experiences of four leading academic clinicians with specialties in oncology, rheumatology, gastroenterology, and endocrinology and their perspectives on how to increase biosimilar adoption, including the role of clinical pharmacology. Besides systemic changes in pricing and reimbursement, there is a need for additional education of a broad range of providers, including advanced care practitioners, and patients themselves. Educational efforts highlighting the rigor of the studies that support the approval of biosimilars-including the clinical pharmacology studies-and the benefits of biosimilars, can play a major role in improving biosimilar acceptance.

Impact of Sex on Clinical Response in Rheumatoid Arthritis Patients Treated With Biologics at Approved Dosing Regimens.

The prevalence of rheumatoid arthritis (RA) is higher in females than in males. With the development of new treatment options and strategies such as biologics, we found it worthwhile to identify whether males and females warrant different treatment regimens to ensure the best clinical response. Our meta-analysis included 11 clinical trials of RA patients in support of the Food and Drug Administration's approval of 6 biological products. We evaluated the data of American College of Rheumatology 20 (ACR20) 24 or 26 weeks after treatment. Logistic regression models were applied to compute the odds ratio (OR) of treatment responses between sexes. The ORs of ACR20 response rates in males and females were similar across all studies and not significantly different in overall studies (OR, 1.05; 95% confidence interval, 0.96-1.16) analyzed with a fixed-effects model. Further analyses on the 7 ACR20 subcomponents showed high heterogeneity among studies (Q statistic P < .00007, I2 > 95%), with no observed clinically meaningful sex-related difference. Thus, our meta-analysis did not find significant difference in ACR20 response rates between male and female RA patients treated with biologics at approved dosing regimens. This result supports the current clinical practice of not requiring sex-dependent treatment regimens for RA patients.

Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: Identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI.

Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis.

Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 2: Continuous Model).

Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation-based power analysis. The developed population PK/PD models adequately described the relationship between serum concentrations and changes in ACR subcomponents. The trial simulation and subsequent power analysis showed that SJC and TJC appeared to be more sensitive than the other 5 ACR subcomponents to detect treatment effect over placebo/methotrexate. These 7 ACR subcomponents had similar power in detecting the treatment difference between different doses. In addition, the continuous measures of ACR subcomponents did not appear to be more sensitive than binary measures.

Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 1: Binary Model).

American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria. The models were then used to simulate the clinical outcomes at various time points following different treatment regimens. The relative sensitivity of these criteria components was assessed using power analysis. As compared to the composite endpoints (ACR20/ACR50/ACR70), the individual ACR criteria components had adequate power and higher sensitivity in distinguishing treatment effects over placebo/methotrexate control. The 3 individual ACR criteria components appeared to have similar powers at different dose levels after long-term treatment. This research provides a unique approach to assess the relative sensitivity of the 3 binary components of ACR response criteria which would be useful to support future dose selection and trial design in the treatment of rheumatoid arthritis.

Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation.

The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure-response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. The trial simulation and subsequent power analysis showed that both ACR20 and DAS28 exhibit much lower power in distinguishing between two doses investigated compared with distinguishing treatment effect over placebo/Methotrexate (MTX) control. ACR20 response rate is generally more powerful in detecting treatment effect over placebo/MTX control as compared to DAS28. The findings of current study provide useful information which will help future clinical trial design for the treatment of patients with RA.

Dosing regimen determination for juvenile idiopathic arthritis: a review of studies during drug development.

Juvenile idiopathic arthritis (JIA) is the most common childhood arthritis. In the past 10-15 years, the medical treatment options of JIA have greatly evolved and expanded due to a better understanding of the disease and the application of biologic agents. Regulations pertinent to pediatric clinical research have also helped provide a legal basis for investigating the effects of drugs and biologics in pediatrics and facilitate the pediatric drug development. The evaluation of clinical pharmacology, efficacy, and safety has provided valuable labeling information for pediatric use, including comparing exposure between adult and pediatric patients, bridging different formulations and regimens, providing appropriate dose selection recommendation with the modeling and simulation approach, and assessing the risks and benefits. This review summarizes the drugs and biologics with JIA labeling implications and discusses the application of clinical pharmacology, safety, and efficacy assessment in determining pediatric dosing regimens.

Injection of human bone marrow and mononuclear cell extract into infarcted mouse hearts results in functional improvement.

BACKGROUND: We have previously shown that mouse whole bone marrow cell (BMC) extract results in improvement of cardiac function and decreases scar size in a mouse model of myocardial infarction (MI), in the absence of intact cells. It is not clear if these results are translatable to extracts from human BMC (hBMC) or mononuclear cells (hMNC), which would have significant clinical implications. METHODS: Male C57BL/6J (10-12 weeks old) mice were included in this study. MI was created by permanent ligation of the left anterior descending artery. Animals were randomized into three groups to receive ultrasound-guided myocardial injections with either hBMCs extract (n=6), hMNCs extract (n=8) or control with 0.5% bovine serum albumin (BSA) (n=7). Cardiac function was assessed by echocardiography at baseline, 2 and 28 days post-MI. Infarct size and vascularity was assessed at 28 days post-MI. RESULTS: hBMC and hMNC extract preserve cardiac function and result in smaller scar size post-MI when compared with the control group. CONCLUSIONS: The current study for the first time reports that hBMC and hMNC extracts improve cardiac function post-MI in a mouse MI model. Further studies are necessary to fully address the potential clinical benefits of these therapies.

Treatment of pulmonary arterial hypertension with circulating angiogenic cells.

Despite advances in the treatment of pulmonary arterial hypertension, a truly restorative therapy has not been achieved. Attention has been given to circulating angiogenic cells (CACs, also termed early endothelial progenitor cells) because of their ability to home to sites of vascular injury and regenerate blood vessels. We studied the efficacy of human CAC therapy in the treatment of pulmonary arterial hypertension at two different stages of disease severity. Cells were isolated from peripheral blood and administered to nude rats on day 14 ("early") or day 21 ("late") after monocrotaline injection. The control group received monocrotaline but no cell treatment. Disease progression was assessed using right heart catheterization and echocardiography at multiple time points. Survival differences, right ventricular hypertrophy (RVH), and vascular hypertrophy were analyzed at the study endpoint. Quantitative PCR was performed to evaluate cell engraftment. Treatment with human CACs either at the early or late time points did not result in increased survival, and therapy did not prevent or reduce the severity of disease compared with control. Histological analysis of RVH and vascular muscularization showed no benefit with therapy compared with control. No detectable signal was seen of human transcript in transplanted lungs at 14 or 21 days after cell transplant. In conclusion, CAC therapy was not associated with increased survival and did not result in either clinical or histological benefits. Future studies should be geared toward either earlier therapeutic time points with varying doses of unmodified CACs or genetically modified cells as a means of delivery of factors to the pulmonary arterial circulation.