By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a first-in-class agent to delay the onset of type 1 diabetes (T1D). Teplizumab-mzwv is a Fc receptor, nonbinding anti-CD3-directed, humanized monoclonal antibody, which delays the onset of clinical T1D by slowing the immune process that attacks insulin-producing cells in the pancreas.
The FDA granted the agent priority review, accelerated approval, and a breakthrough therapy designation.1 It is distributed as Tzield.
INDICATIONS
Teplizumab can be prescribed to delay the onset of stage 3 T1D in adults and pediatric patients age 8 years and older with stage 2 T1D.2
DOSAGE
Administer daily intravenous infusion (over a minimum of 30 minutes) once daily for 14 consecutive days.2 The regimen is as follows: day 1, 65 mcg/m2; day 2, 125 mcg/m2; day 3, 250 mcg/m2; day 4, 500 mcg/m2; and days 5 through 14, 1,030 mcg/m2. The following premedications are recommended: a nonsteroidal anti-inflammatory drug or acetaminophen, an antihistamine, and/or an antiemetic before each dose for at least the first five days of treatment. Teplizumab is available as 1 mg/mL in 2 mL single-dose vials.
POTENTIAL ADVANTAGES
Teplizumab is the first FDA-approved drug to delay the progression to clinical T1D in high-risk patients with stage 2 diabetes. The drug requires one 14-day course of treatment.
POTENTIAL DISADVANTAGES
Lymphopenia developed in 78% of teplizumab-treated subjects and 11% of control-treated subjects.2 Assess complete blood count before initiation and monitor during treatment. Discontinue treatment for severe lymphopenia (< 500 cells per mcL) lasting one week or longer.2 Cytokine release syndrome occurred in 5% of teplizumab-treated subjects vs. 0.8% of control-treated subjects. Bacterial and viral infections also occurred at a higher rate (3.5% vs. 2%).
Teplizumab may interfere with the immune response to vaccination and affect vaccine efficacy. Administer all age-appropriate vaccinations before initiating teplizumab treatment. Live-attenuated vaccinations are not recommended within eight weeks before and/or up to 52 weeks after treatment. For inactivated or mRNA vaccine, the time intervals are two weeks before and six weeks after treatment. Other common reported adverse reactions (vs. placebo) were rash (36% vs. 0%), anemia (27% vs. 21%), liver enzyme elevation (25% vs. 11%), leukopenia (21% vs. 0%), lower calcium levels (19% vs. 13%), lower bicarbonate levels (15% vs. 7%), and headache (11% vs. 6%).
COMMENTS
T-cell-mediated destruction of beta cells in the pancreas causes T1D. Teplizumab reduces T-cell activation and immunogenicity. Its effectiveness was evaluated in a randomized, double-blind, placebo-controlled study in patients with stage 2 T1D and at high risk for developing clinical disease.2,3 Subjects were 97% white, 55% were men, and 72% were younger than age 18 years. Subjects were positive for two or more pancreatic islet autoantibodies (glutamic acid decarboxylase 65, insulin, insulinoma-associated antigen 2, zinc transporter 8 [ZnT8A], or islet cell) and dysglycemia on oral glucose tolerance testing. For genetic markers HLA-DR3 and DR4, 40% exhibited DR4 only. Subjects were randomized to teplizumab (n = 44) or placebo (n = 32). The primary endpoint was the elapsed time from randomization to clinical diagnosis of diabetes based on oral glucose tolerance tests (stage 3). The median times to stage 3 T1D were 50 months for teplizumab and 25 months for placebo (HR, 0.41; 95% CI, 0.22-0.78). In a subgroup analysis, the absence of HLA-DR3 (but the presence of HLA-DR4 and the absence of anti-ZnT8 antibodies) was associated with good response to teplizumab.3 Eighteen percent of teplizumab-treated subjects vs. 6% of placebo-treated subjects were followed for more than five years and were not diagnosed with stage 3 T1D.4
CLINICAL IMPLICATIONS
Approximately 1 million to 1.5 million Americans are living with T1D. Stage 2 T1D carries nearly 100% lifetime risk of progression to clinical T1D, and a 75% risk of developing clinical disease within five years.5 Teplizumab delays the disease by about two years (and possibly longer) in some patients after a single treatment course. The cost of teplizumab is $13,850 per vial, which translates to $193,900 for a 14-day course of treatment (14 vials) for a patient with body surface area of 1.2 m2. The results of an analysis published in 2020 suggested teplizumab would be cost effective only for those who were negative for ZnT8 antibodies if the price was less than $193,700.6 That group represents 26% of at-risk individuals.1,2,6
REFERENCES
1. U.S. Food & Drug Administration. FDA approves first drug that can delay onset of type 1 diabetes. Nov. 17, 2022.
2. Provention Bio. Tzield prescribing information. November 2022.
3. Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 2019;381:603-613.
4. Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Tranl Med 2021;13:eabc8980.
5. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: A scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015;38:1964-1974.
6. Mital S, Nguyen HV. Cost effectiveness of teplizumab for prevention of type 1 diabetes among different target patient groups. Pharmacoeconomics 2020;38:1359-1372.
Teplizumab can be prescribed to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients age 8 years and older with stage 2 type 1 diabetes.
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