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What considerations should pharmacists make in relation to teplizumab use in patients with type 1 diabetes mellitus?

Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in childhood.1 Unlike type 2 diabetes mellitus (T2DM), the insulin deficiency in T1DM is caused by destruction of the insulin-producing pancreatic beta cells, requiring administration of exogenous insulin. Despite the availability of various medical therapies for T2DM, insulin remains the mainstay of T1DM management. Moreover, there are no curative therapies that prevent the autoimmune destruction of beta cells that lead to insulin deficiency in T1DM.

Teplizumab, a humanized anti-cluster of differentiation 3 (CD3) monoclonal antibody, is the first product approved by the US Food and Drug Administration to delay the time to onset of T1DM in at-risk patients.2 Teplizumab targets the antigen on the surface of T lymphocytes, thus attenuating the pathophysiologic response that leads to the autoimmune destruction of pancreatic beta cells.2-4 Given its novel mechanism and indication, questions may arise regarding considerations that pharmacists should make related to both T1DM and teplizumab therapy. These considerations may be unfamiliar to some pharmacists because they relate to the diagnosis and staging of T1DM. Therefore, this summary reviews these considerations, with an emphasis on disease stages and autoantibodies that are critical in determining appropriate use of teplizumab.

T1DM epidemiology, risk factors, and natural history
Type 1 diabetes mellitus is a serious, life-long autoimmune disease that is present in approximately 0.4% of the general population.1 The Centers for Disease Control and Prevention (CDC) estimate that 244,000 children and adolescents younger than 20 years had diagnosed T1DM in 2019.  However, many cases are diagnosed in adults, and the CDC estimates that 1.6 million US adults had T1DM and were using insulin in 2019.5 The prevalence of T1DM in individuals 19 years and younger has increased from approximately 1.48 to 2.15 per 1000 individuals between 2001 and 2017, and its incidence is expected to increase in the next decade.3

Family history
Family history is an important risk factor for the development of T1DM.6 Compared with the general population, the presence of a first-degree relative with T1DM is associated with an approximate 15-fold increased lifetime risk of T1DM. Lifetime risk ranges from approximately 1% to 4% in children of a mother with T1DM to over 70% in children with an identical twin with T1DM.1  Roughly 85% of individuals with a T1DM diagnosis do not have a family history of the disease, however, and different environmental exposures likely interact with genetic propensity in the development of autoimmunity.6

In the pivotal phase 3 clinical trial of teplizumab, participants were required to be nondiabetic relatives of patients with T1DM.7 Nonetheless, consistent with the natural epidemiology of T1DM, the approved indication of teplizumab is not restricted to those with a family history of disease.2

Autoantibodies and Human Leukocyte Antigen
In T1DM, autoantibodies cause the destruction of insulin-producing beta cells in the pancreas.6 Some autoantibodies associated with T1DM target glutamic acid decarboxylase 65, insulin, insulinoma-associated antigen 2, zinc transporter 8, and pancreatic islet cells. The presence of these autoantibodies is one consideration in staging of T1DM, which is now recognized in clinical, research, and regulatory settings and informs the risk of T1DM progression. Stage 1 involves the presence of multiple islet autoantibodies in the presence of normal blood glucose levels without clinical symptoms. Stage 2 involves the presence of multiple islet autoantibodies and abnormal glucose tolerance, usually without symptoms. Stage 3 is characterized by blood glucose levels above the American Diabetes Association (ADA) diagnostic thresholds, which may or may not be accompanied by symptoms. Finally, stage 4 is established T1DM.

Similarly, the presence of particular human leukocyte antigen (HLA) genes can indicate risk of T1DM.4 These genes are responsible for antigen presentation. Those that confer the highest risk of T1DM are haplotypes DR4-DQ8 and DR3-DQ2 (often abbreviated as DR4 and DR3, respectively). Current estimates are that either haplotype is present in up to 90% of patients with T1DM, and both are present in approximately 30% of patients.

The prescribing information of teplizumab indicates that patients should be confirmed to have stage 2 T1DM through documentation of at least 2 positive pancreatic islet cell autoantibodies and dysglycemia without overt hyperglycemia using an oral glucose tolerance test.2 In the pivotal clinical trial of teplizumab, patients were required to have at least 2 of the islet autoantibodies referenced above.7 Subgroup analyses were performed to assess the influence of HLA haplotypes on the effect of teplizumab, and results are described below.

Age of onset and residual beta cell function
Several characteristics have been associated with long-term morbidity and mortality in T1DM. For example, earlier age at onset of T1DM is an important determinant of survival.8 Compared with matched controls, mortality was higher for those diagnosed between 0 and 10 years (hazard ratio [HR], 4.11; 95% confidence interval [CI], 3.24 to 5.22), versus those diagnosed between 26 and 30 years (HR, 2.83; 95% CI, 2.38 to 3.37). Similarly, disease progression influences the production of C-peptide, a byproduct of the cleavage of proinsulin to insulin that serves as a marker for insulin production and beta cell function.3 Natural history cohorts of patients with new-onset T1DM indicate that many patients continue to produce insulin, as measured by detectable C-peptide.4 In the Diabetes Control and Complications Trial, individuals with residual C-peptide secretion experienced lower risk of retinopathy, nephropathy, and hypoglycemia.9

Taken together, these findings indicate the potential benefit of a disease-modifying therapy that may preserve residual C-peptide and insulin production and delay disease progression.4 Levels of C-peptide were assessed as an endpoint of trials of teplizumab, and were used as a stratification variable to assess outcomes in patients with high vs low C-peptide levels.7


Clinical evidence
The FDA approval of teplizumab was based on a phase 2 randomized controlled trial in 76 patients with stage 2 T1DM.7 Overall, 74% of patients were <18 years old, 71% were positive for 3 or more autoantibodies, and the presence of HLA-DR4, HLA-DR3, or both was documented in 34%, 48%, and 25% of patients, respectively.2,7 All patients were required to have a first-degree relative with T1DM; most patients (58%) had a sibling with T1DM. Patients were randomized to double-blind teplizumab or placebo once daily for 14 days.7 After a median follow-up of 51 months, the primary endpoint of time to clinical diagnosis of T1DM occurred at a median 48.4 months in patients treated with teplizumab vs 24.4 months in those treated with placebo (hazard ratio [HR], 0.41; 95% confidence interval [CI] 0.22 to 0.78). Overall, stage 3 T1DM was diagnosed in 43% and 72% of patients treated with teplizumab and placebo, respectively. Teplizumab had a pronounced effect during the first year of treatment; T1DM was diagnosed in 7% vs 44% of patients treated with teplizumab and placebo, respectively (HR, 0.13; 95% CI, 0.05 to 0.34).

Notably, patients who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative experienced greater benefit from teplizumab.7 Other assessed autoantibodies were not associated with response. Patients with levels of C-peptide that were below the sample median were also more likely to benefit. This observation is consistent with the hypothesis that an active autoimmune response must first be present for the mechanism of teplizumab to exert benefit, suggesting that earlier intervention may be less efficacious. Important limitations of the trial include its small size, lack of assessment of anti-drug antibody effects, and limited generalizability to non-white individuals and those who do not have first-degree relatives with T1DM. In an extension of the trial, the median time to diagnosis of T1DM was 59.6 vs 27.1 months in patients treated with teplizumab and placebo, respectively.10 This extension also reported that, compared with placebo, teplizumab was associated with significantly greater C-peptide area under the curve (AUC) and a more favorable slope measuring rate of decline in C-peptide AUC.10

Safety profile
In the phase 2 clinical trial, the most common adverse effects of teplizumab during treatment and through 26 days after the last dose were lymphopenia (73%), rash (36%), leukopenia (21%), headache (11%), neutropenia (5%), increased alanine aminotransferase levels (5%), nausea (5%), diarrhea (5%), and nasopharyngitis (5%).2 Notable warnings are present in the prescribing information of teplizumab for cytokine release syndrome (CRS), serious infection, and lymphopenia. Cytokine release syndrome occurred in 5% of patients who received teplizumab in all clinical trials (including studies in unapproved populations), which generally occurred within the first 5 days of treatment. Premedication and monitoring of liver enzymes are recommended to mitigate the risk of CRS. Teplizumab is not recommended in patients with active serious or chronic infection because of the risk of serious infection, which occurred in 3.5% of treated patients. Lymphopenia developed in 78% of teplizumab-treated vs 11% of control-treated patients in clinical trials, which generally improved after the fifth day of treatment and returned to baseline values within 2 weeks of treatment completion. White blood cells should be monitored throughout teplizumab treatment.

Clinical uptake
Currently, there are no conclusive recommendations from professional societies such as the ADA on the place in therapy of teplizumab, although they recognize the potential benefit of disease-modifying therapies in T1DM.11 The association commented that given the requirement for life-long insulin replacement therapy, providing a 2-year delay from the burden of T1DM is a “tremendous accomplishment” that will likely be associated with long-term benefits in acute and long-term complications, as well as quality of life of both individuals with T1DM and their families. Similarly, the International Society for Pediatric and Adolescent Diabetes (ISPAD) does not overtly recommend for or against therapies such as teplizumab, but does recognize the potential benefit of autoantibody screening.6 The ISPAD states that when immunotherapies that can delay T1DM progression are available and economic issues related to screening are optimized, general pediatric screening is expected to expand.

The ultimate clinical uptake of teplizumab remains to be seen. Logistical challenges include the requirement for intravenous administration once daily over 14 days.2 This may introduce challenges related to administration and adherence, and the effects of missed or delayed doses are not fully elucidated. A recent analysis modeled the cost-effectiveness of teplizumab when used in different candidate populations.12 If only individuals with at least 1 of the 2 favorable HLA markers received treatment (those without the HLA-DR3 allele, with the HLA-DR4 allele, or both of these conditions; 76% of patients in the phase 2 trial), teplizumab was estimated to be cost-effective at a maximum cost of $58,200 over a lifetime time horizon at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year. When restricted to only those with highest response to teplizumab (individuals both without HLA-DR3 and with HLA-DR4), this value was estimated at $88,300, and when modeled with administration to all individuals, $48,900. Currently, a 14-day supply of teplizumab costs $193,900.13

The approval of teplizumab to delay the onset of diagnosis of T1DM introduces new considerations given the novelty of its use in this population. Pharmacists should be aware of the use of islet autoantibodies in staging and diagnosing T1DM, the importance of family history on risk of T1DM, and the impact and measurement of preserved beta cell function with markers such as C-peptide. In the prescribing information and the pivotal phase 2 trial supporting the current indication of teplizumab, these considerations played important roles in the eligible trial participants and evaluation of efficacy overall and in relevant subgroups. The generalizability of teplizumab effects in patients poorly represented in the phase 2 clinical trial remain unknown, as does the optimal time of initiation in relation to C-peptide production. Teplizumab has not yet been addressed in major clinical guidelines, but major professional societies predict a likely expansion of T1DM screening programs that may identify eligible candidates for teplizumab therapy.

Prepared by:
Ryan Rodriguez, PharmD, MS, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2023

The information presented is current as March 3, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.


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