Evaluation of teplizumab's efficacy and safety in treatment of type 1 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Islets of Langerhans beta cells diminish in autoimmune type 1 diabetes mellitus (T1DM). Teplizumab, a humanized anti-CD3 monoclonal antibody, may help T1DM. Its long-term implications on clinical T1DM development, safety, and efficacy are unknown. AIM: To assess the effectiveness and safety of teplizumab as a therapeutic intervention for individuals with T1DM. METHODS: A systematic search was conducted using four electronic databases (PubMed, Embase, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. The odds ratio (OR) and risk ratio (RR) were calculated, along with their 95%CI. We assessed heterogeneity using Cochrane Q and I 2 statistics and the appropriate P value. RESULTS: There were 8 randomized controlled trials (RCTs) in the current meta-analysis with a total of 1908 T1DM patients from diverse age cohorts, with 1361 patients receiving Teplizumab and 547 patients receiving a placebo. Teplizumab was found to have a substantial link with a decrease in insulin consumption, with an OR of 4.13 (95%CI: 1.72 to 9.90). Teplizumab is associated with an improved C-peptide response (OR 2.49; 95%CI: 1.62 to 3.81) and a significant change in Glycated haemoglobin A1c (HbA1c) levels in people with type 1 diabetes [OR 1.75 (95%CI: 1.03 to 2.98)], and it has a RR of 0.71 (95%CI: 0.53 to 0.95). CONCLUSION: In type 1 diabetics, teplizumab decreased insulin consumption, improved C-peptide response, and significantly changed HbA1c levels with negligible side effects. Teplizumab appears to improve glycaemic control and diabetes management with good safety and efficacy.

Teplizumab's immunomodulatory effects on pancreatic ß-cell function in type 1 diabetes mellitus.

This review explores the immunomodulatory potential of Teplizumab and its impact on pancreatic ß-cell function in T1D. Characterized by the autoimmune destruction of insulin-producing beta cells, T1D's management involves maintaining glycemic control through exogenous insulin. Teplizumab, a humanized monoclonal antibody targeting the CD3 antigen, has shown promise in delaying T1D onset and preserving residual ß-cell function. The review employs a narrative approach, synthesizing evidence from diverse clinical trials and studies gathered through a meticulous literature search. It scrutinizes Teplizumab's mechanisms of action, including its influence on autoreactive CD8 + T cells and regulatory T cells, offering insights into its immunological pathways. The synthesis of findings from various trials demonstrates Teplizumab's efficacy in preserving C-peptide levels and reducing exogenous insulin requirements, particularly in recent-onset T1D. Considering Teplizumab's real-world implications, the paper addresses potential obstacles, including side effects, patient selection criteria, and logistical challenges. It also emphasizes exploring combination therapies and personalized treatment strategies to maximize Teplizumab's benefits. The review contributes a nuanced perspective on Teplizumab's clinical implications and future directions in T1D management, bridging theoretical understanding with practical considerations.

Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects.

Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes.

From pre-clinical efficacy to promising clinical trials that delay Type 1 diabetes.

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials. We then discuss the pre-clinical studies using suitable mouse models that eventually led to contemporary clinical trials targeting immune cell functionality and cytokine signaling pathways. Collectively, these discoveries promote the exciting paradigm of immune system modulation to mitigate autoimmunity, which continues to broaden. Notably, the use of baricitinib, a potent JAK1/2 inhibitor, and teplizumab, an anti-CD3 monoclonal antibody, represent discrete methodologies converging upon a singular outcome: the preservation of islet beta-cell functionality. The latter interventional strategies build on the original idea that tempering specific facets of the immune system will generate therapeutic benefit. Enthusiasm from these discoveries stems from efficacy with reduced side effects when compared with past approaches. The success of therapeutic intervention(s) in pre-clinical studies, combined with knowledge about stages of progression to clinical T1D, have ultimately encouraged the design of more successful clinical trials targeting highly specific populations at risk. Collectively, these findings instill a profound sense of optimism, suggesting that the prevention and even reversal of T1D may soon be within reach.

Safety of teplizumab in patients with high-risk for diabetes mellitus type 1: A systematic review.

BACKGROUND: The incidence of diabetes mellitus type 1 (DM1) has been rising worldwide because of improvements in diagnostic techniques and improved access to care in countries with lower socioeconomic status. A new anti-CD4 antibody, Tep-lizumab, has been shown to delay the progression of DM1 and is the only medication approved for this indication. However, more information is needed about the safety profile of this drug. AIM: To identify the odds ratios (OR) of systems-based adverse effects for Teplizumab when compared to Placebo. METHODS: An extensive systematic review was conducted from the inception of the medication until December 31, 2023. All clinical trials and studies that evaluated Teplizumab vs placebo were included in the initial review. The study protocol was designed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines guidelines and was registered in PROSPERO (ID: CRD42024496169). Crude OR were generated using RevMan Software version 5.4. RESULTS: After screening and review, 5 studies were selected to determine the risk of adverse effects of teplizumab compared to placebo. A total of 561 patients were included in the study population. Total adverse effects and system-based adverse effects were studied and reported. We determined that patients receiving Teplizumab had a higher risk of developing gastrointestinal (GI) (OR = 1.60, 95%CI: 1.01-2.52, P = 0.04), dermatological (OR = 6.33, 95%CI: 4.05-9.88, P < 0.00001) and hematological adverse effects (OR = 19.03, 95%CI: 11.09-32.66, P < 0.00001). These patients were also significantly likely to have active Epstein-Barr Virus infection (OR = 3.16, 95%CI: 1.51-6.64, P < 0.002). While our data showed that patients receiving Teplizumab did have a higher incidence of total adverse effects vs placebo, this finding did not reach statistical significance (OR = 2.25, 95%CI: 0.80-6.29, P = 0.12). CONCLUSION: Our systematic review suggests that Teplizumab patients are at risk for significant adverse effects, primarily related to GI, dermatological, and hematological systems. The total adverse effect data is limited as study populations are small. More studies should be conducted on this medication to better inform the target population of potential adverse effects.

Efficacy of teplizumab for treatment of type 1 diabetes: A meta-analysis of randomized controlled trials.

BACKGROUND: The management of Type 1 Diabetes Mellitus (T1DM) is a significant clinical challenge. This study evaluated the efficacy of teplizumab, an immunomodulatory drug, in patients with T1DM, using a systematic review and meta-analysis approach. METHODS: We systematically searched multiple databases including Medline, Scopus, and others up to 10 January 2024, without language or regional restrictions. We included randomized controlled trials (RCTs) comparing teplizumab with placebo in T1DM patients. RESULTS: Our analysis incorporated 8 RCTs, predominantly involving participants aged 7-35 years, diagnosed with T1DM and treated with 14-day courses of teplizumab. The primary outcomes included insulin use, C-peptide levels, and HbA1c levels. We observed a significant reduction in insulin use in the teplizumab group standardised mean difference of -0.50 (95% Confidence Interval [CI]: -0.76 to -0.23, p < 0.001; I2 = 49%). C-peptide levels were consistently higher in the teplizumab group, indicating improved endogenous insulin production. However, no significant change was noted in HbA1c levels between the groups. Quality assessment indicated a low risk of bias in most studies. CONCLUSIONS: Teplizumab has a significant impact on reducing insulin dependence and enhancing endogenous insulin production in T1DM patients. However, its effect on long-term glycaemic control, as indicated by HbA1c levels, remains inconclusive.

Effect of Immunotherapy on C-peptide Levels in Patients With Type I Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials.

Type 1 diabetes mellitus is an autoimmune condition characterized by insulin deficiency resulting from loss of function of beta cells in the pancreas, leading to hyperglycemia and associated long-term systemic complications and even death. Immunotherapy demonstrates beta cell function-preserving potential; however, its impact on C-peptide levels, a definitive biomarker of beta cell function, and endogenous insulin secretion remain unclear. A systematic review of various immunotherapeutic interventions is hence needed for a comprehensive assessment of their effectiveness as well as identifying research gaps and influencing future research and clinical decisions. An extensive literature search was done in PubMed, Scopus, and Cochrane Library databases using precise keywords and filters to identify relevant studies. Three independent reviewers assessed eligibility according to predetermined eligibility criteria, and data was extracted. The Cochrane risk of bias assessment tool (RoB 2.0) was used to evaluate the quality and validity of the included studies. A senior reviewer resolved discrepancies and differences of opinion between independent reviewers. A total of 11 studies were included, with 1464 study participants. Both Phase II and III trials were included. Within the included studies, four studies assessed the anti-CD3 monoclonal antibody otelixizumab as an intervention. Another anti-CD3 monoclonal antibody, teplizumab, was assessed as an intervention in four studies, whereas two studies assessed the anti-CD20 antibody rituximab and one study assessed abatacept as its interventional drug. Otelixizumab demonstrated benefits at higher doses but was associated with adverse effects like Ebstein-Barr virus reactivation and cytomegalovirus infection, while at lower doses it failed to show a significant difference in C-peptide levels or glycosylated hemoglobin (HbA1c). Teplizumab, on the other hand, showed promise in reducing C-peptide loss and exogenous insulin requirements and was associated with adverse events such as rash, lymphopenia, urinary tract infection, and cytokine release syndrome. However, these reactions were only associated with therapy initiation, and they subsided on their own. Rituximab improved C-peptide responses, and abatacept therapy demonstrated reduced loss of C-peptide, improved C-peptide levels, and lowered HbA1c. Teplizumab, rituximab, otelixizumab, and abatacept show potential for preserving beta cell function by reducing C-peptide loss in patients with type I diabetes mellitus. However, careful monitoring of adverse reactions, particularly viral infections and cytokine release syndrome, is necessary for the safe implementation of these therapies.

Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at T-cell marker CD3, is the first medication approved by the FDA to delay progression from stage 2 to stage 3 type 1 diabetes. To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance on the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration, and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Safety and efficacy of teplizumab in the treatment of type 1 diabetes mellitus: An updated systematic review and meta-analysis of randomized controlled trials.

AIM: To provide updated efficacy and safety information for teplizumab in the treatment of Stage 3 type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: The PubMed, Embase and Cochrane databases were searched for randomized controlled trials (RCTs) comparing teplizumab to placebo for T1DM that reported any of the following outcomes: (1) C-peptide area under the curve (AUC); (2) glycated haemoglobin (HbA1c) levels; (3) insulin requirements; and (4) adverse events. Heterogeneity was examined with I2 statistics. p values <0.05 were taken to indicate statistical significance. The continuous endpoints were compared through the pooled mean difference (MD) and binary endpoints were assessed using risk ratios, both with 95% confidence intervals (CIs). Statistical analyses were performed using Review Manager Web software. RESULTS: Eight RCTs with 1052 patients (754 receiving teplizumab) were included. Teplizumab significantly increased the AUC of C-peptide levels at 6 (MD 0.10 nmol/L, 95% CI 0.05, 0.16), 12 (MD 0.13 nmol/L, 95% CI 0.06, 0.20), 18 (MD 0.18 nmol/L, 95% CI 0.09, 0.27) and 24 months (MD 0.16 nmol/L, 95% CI 0.02, 0.31), significantly reduced HbA1c levels at 6 (MD -0.57%, 95% CI -1.07, -0.08) and 12 months (MD -0.31%, 95% CI -0.59, -0.02), and significantly reduced insulin requirements at 6 (MD -0.12 U/kg, 95% CI -0.16, -0.08), 12 (MD -0.11 U/kg, 95% CI -0.15, -0.07), 18 (MD -0.17 U/kg, 95% CI -0.26, -0.09) and 24 months (MD -0.11 U/kg, 95% CI -0.22, -0.01). CONCLUSION: Teplizumab increases AUC of C-peptide levels and decreases HbA1c levels and insulin use, without raising serious adverse event risk.

Role of Teplizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Managing Newly Diagnosed Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D. METHODS: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline. RESULTS: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia. CONCLUSION: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes: A new horizon.

Type 1 diabetes (T1D) is a chronic autoimmune condition that destroys insulin-producing beta cells in the pancreas, leading to insulin deficiency and hyper-glycemia. The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels. However, this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells. Recent research has explored the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a novel intervention to modify the disease course and delay the onset of T1D. GLP-1RAs are medications initially developed for treating type 2 diabetes. They exert their effects by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D. This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D, possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells. This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification, which should open new avenues for preventing and treating T1D, improving the quality of life and long-term outcomes for individuals at risk of T1D.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes.

CONTEXT: Type 1 diabetes (T1D) results from the autoimmune T-cell mediated destruction of pancreatic beta cells leading to insufficient insulin secretion. At the time of diagnosis of T1D, there is residual beta cell function that declines over the subsequent months to years. Recent interventions have been approved to preserve beta cell function in evolving T1D. OBJECTIVE: The aim of this review is to summarise the approaches used to assess residual beta cell function in evolving T1D, and to highlight potential future directions. METHODS: Studies including subjects aged 0 to 18 years were included in this review. The following search terms were used; "(type 1 diabetes) and (partial remission)" and "(type 1 diabetes) and (honeymoon)". References of included studies were reviewed to determine if additional relevant studies were eligible. RESULTS: There are numerous approaches to quantifying beta cell reserve in evolving T1D. These include c-peptide measurement after a mixed meal or glucagon stimuli, fasting c-peptide, the urinary c-peptide/creatinine ratio, insulin dose-adjusted haemoglobin A1c, and other clinical models to estimate beta cell function. Other biomarkers may have a role, including the proinsulin/c-peptide ratio, cytokines, and microRNA. Studies using thresholds to determine if residual beta cell function is present often differ in values used to define remission. CONCLUSIONS: As interventions are approved to preserve beta cell function, it will become increasingly necessary to quantify residual beta cell function in research and clinical contexts. In this report, we have highlighted the strengths and limitations of the current approaches.

Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.

Diabetes is a chronic illness that can become debilitating owing to its microvascular and macrovascular complications. Its prevalence is increasing and so is its cost. Diabetes, particularly type 2, appears to have a very close relationship with obesity. While lifestyle modifications, exercises, and current therapeutics have substantially improved clinical outcomes, the need for new therapeutics and regimens continue to exist. Several new medications and regimens for diabetes, obesity, and diabesity are showing promising results in advanced clinical trials. For type 1 diabetes mellitus (T1DM), they include teplizumab, ustekinumab, jakinibs, and cell therapies, whereas for type 2 diabetes mellitus (T2DM), they include once-weakly insulin, tirzepatide, high oral dose of semaglutide, orforglipron, retatrutide, CagriSema, and survodutide. Given their structural and mechanistic diversity as well as their substantial efficacy and safety profiles, these medications and regimens are paradigm shifting and promise a brighter future. They will likely enable better disease prevention and management. This review will provide details about each of the above strategies to keep the scientific community up to date about progress in the fields of diabetes and obesity.

Journey of Teplizumab: A Promising Drug in the Treatment of Type 1 Diabetes Mellitus.

Type 1 diabetes (T1D) is a chronic autoimmune disease caused by CD4+ and CD8+ that are activated via CD3+ cells and finally lead to the macrophages destroying the beta cells in the pancreas thereby causing diabetes. The anti-CD3 humanized monoclonal antibody was approved on 17th November 2022 by the United States Food Drug Administration (USFDA) with the name teplizumab and the brand name TZIELD. This is the only approved drug that treats type 1 diabetes (T1D) by delaying the onset of stage 3 in type 1 diabetes (T1D). This review outlines essential features of teplizumab including its brief introduction to its mechanism and other therapies for the treatment and various risks as well as the pharmacokinetics and pharmacodynamics of this disease and the clinical trial reports for the completed and ongoing therapies.

Anti-CD3 monoclonal antibodies in treatment of type 1 diabetes: a systematic review and meta-analysis.

PURPOSE: This meta-analysis aimed to assess the efficacy and safety of anti-CD3 monoclonal antibodies (mAbs) for type 1 diabetes. METHODS: We searched PubMed, Embase and Cochrane until 23 February 2023 for randomized controlled trials that compared anti-CD3 mAbs with placebo in type 1 diabetes. The primary outcome was the area under the curve (AUC) of C-peptide, daily insulin dose or HbA1c. RESULTS: Totally 12 trials that included 1870 participants were eligible for inclusion in the review. Compared with the control group, anti-CD3 mAbs increased AUC of C-peptide at 1 year (P = 0.0005, MD 0.14, 95% CI [0.06, 0.22], I2 = 94%), and 2 years (P = 0.0003, MD 0.20, 95% CI [0.09, 0.30], I2 = 88%). The use of anti-CD3 mAbs decreased insulin use at 1 year (P = 0.001, MD -0.09, 95% CI [-0.15, -0.04], I2 = 90%), and 2 years (P < 0.00001, MD -0.18, 95% CI [-0.25, -0.12], I2 = 86%). But there was no statistically significant effect on HbA1c levels. Vomiting, nausea, rash, pyrexia and headache were reported more frequently with anti-CD3 mAbs than with placebo. However, incidence of total adverse events and serious adverse events was similar when comparing anti-CD3 mAbs with placebo. CONCLUSIONS: Our results suggest that anti-CD3 mAbs were a potential therapy for improving AUC of C-peptide and insulin use in type 1 diabetes.

Teplizumab: promises and challenges of a recently approved monoclonal antibody for the prevention of type 1 diabetes or preservation of residual beta cell function.

INTRODUCTION: Type 1 diabetes (T1D) is a chronic autoimmune endocrinopathy with increasing incidence that results in the depletion of pancreatic beta cells and exogenous insulin dependence. Despite technological advances in insulin delivery, disease control remains suboptimal, while previous immunotherapy options have failed to prevent T1D. Recently, teplizumab, an immunomodulating monoclonal antibody, was approved to delay or prevent T1D. AREAS COVERED: Five randomized controlled trials have tested different regimens of administration, mostly 14-day schemes with dose escalation. In participants with new-onset T1D, teplizumab delayed C-peptide decline, improved glycemic control, and reduced insulin demand for a median of 1 or 2 years. Studies in at-risk relatives of patients showed a decrease in T1D incidence during 2 years of follow-up. Subgroups of responders with unique metabolic and immunological characteristics were identified. Mild to moderate adverse effects were reported, including transient rash, cytopenia, nausea, vomiting, and infections. EXPERT OPINION: Teplizumab marks a turning point in T1D therapy. Areas of future research include the ideal population for screening, cost-effectiveness, and challenges in treatment accessibility. More studies are essential to evaluate the ideal duration of the regimen, the potential benefit of combinations with other drugs, and to identify endophenotypes with a high probability of response.

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab.

AIMS/HYPOTHESIS: We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab. METHODS: Adults (18-42 years) and adolescents (12-17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12-42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively. RESULTS: Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy. CONCLUSIONS/INTERPRETATION: Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 FUNDING: This study was funded by Precigen ActoBio.

Sex-oriented perspectives in immunopharmacology.

Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and undesirable effects of these drugs represent major issues, and overall efficacy remains unpredictable. Males and females show a distinct difference in immune system responses, with females generally mounting stronger responses to a variety of stimuli. Therefore, exploring sex differences in the efficacy and safety of immunopharmacological agents would strengthen the practice of precision medicine. As a pharmacological target highlight, programmed cell death 1 ligand 1 (PD-L1) is the first functionally characterized ligand of the coinhibitory programmed death receptor 1 (PD-1). The PD-L1/PD-1 crosstalk plays an important role in the immune response and is relevant in cancer, infectious and autoimmune disease. Sex differences in the response to immune checkpoint inhibitors are well documented, with male patients responding better than female patients. Similarly, higher efficacy of and adherence to tumor necrosis factor inhibitors in chronic inflammatory conditions including rheumatoid arthritis and Crohn's disease have been reported in male patients. The pharmacological basis of sex-specific responses to immune system modulating drugs is actively investigated in other settings such as stroke and type 1 diabetes. Advances in therapeutics targeting the endothelium could soon be wielded against autoimmunity and metabolic disorders. Based on the established sexual dimorphism in immune-related pathophysiology and disease presentation, sex-specific immunopharmacological protocols should be integrated into clinical guidelines.