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FDA issues a complete response letter for teplizumab BLA

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Provention Bio, Inc. has announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter relating to the company’s biologics license application (BLA) for teplizumab for the delay of clinical type 1 diabetes (T1D) in at-risk individuals. In the letter, the FDA stated that a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers to compare planned commercial product with drug product originating from drug substance manufactured for historic clinical trials had failed to show PK comparability. This deficiency, and others noted in the letter, will need to be suitably addressed before approval.

Teplizumab (PRV-031) is a humanized IgG1k that binds to an epitope of the CD3-epsilon chain expressed on mature T lymphocytes, and thereby modulates the pathological immunologic responses underlying T1D and other autoimmune diseases. Teplizumab was granted FDA’s Breakthrough Therapy designation for the prevention or delay of clinical T1D, and EMA granted teplizumab PRIME designation for the prevention or delay of clinical T1D in individuals at risk of developing the disease. Provention Bio acquired worldwide development and commercialization rights to teplizumab from MacroGenics, Inc. in 2018.

A rolling BLA for teplizumab for the delay or prevention of clinical Type 1 Diabetes (T1D) in at-risk individuals, as indicated by the presence of two or more T1D-related autoantibodies, was started in April 2020 and completed by November 2020. The BLA includes data from the Phase 2 “At-Risk” study (NCT01030861), which evaluated whether administration of teplizumab can prevent or delay the development of T1D in high-risk autoantibody-positive non-diabetic relatives of patients with T1D.  Participants received IV infusions of teplizumab given for 14 consecutive days (n=44) or placebo (n=32). Extended follow-up data showed that, compared to placebo, one course of teplizumab delayed insulin-dependence in presymptomatic T1D patients by a median of approximately three years. Participants in the “At-Risk” study who develop clinical type 1 diabetes after the conclusion of that trial can enroll in an extension study (NCT04270942) and receive teplizumab treatment within one year of diagnosis of clinical type 1 diabetes.

Teplizumab is also being evaluated in the Phase 3 PROTECT study (NCT03875729), which will determine whether teplizumab slows the loss of β cells and preserves β cell function in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks. Estimated enrollment for the PROTECT study is 300 patients, and the estimated primary completion date is May 2022.

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Defying the “inevitable” development of type 1 diabetes

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Post written by Raquel Barroso Ferro, University of Aberdeen

Regular exogenous insulin injections, monitoring food and activity levels, increased risk of developing heart and kidney disease. These are some of the many challenges faced by people with type 1 diabetes (T1D), an autoimmune disease where the body’s own immune cells destroy its insulin-producing beta cells. This chronic condition affects over 540,000 children worldwide according to a leading UK charity, and is the second most common childhood disease in the US after asthma (1). Current estimates place a global increase in incidence of 2-5% every year (2), highlighting the increasing number of individuals having to physically, emotionally, and financially bear this burden and the need to develop therapeutics that can prevent, cure or improve the management of this condition.

Development of drugs that can delay the onset of T1D is ongoing. One such drug is teplizumab (hOKT3 γ1(Ala-Ala)), a humanized anti-CD3 monoclonal antibody that has been engineered to have reduced Fc receptor binding. Teplizumab works by modulating T cells, which are immune cells believed to be key players in the destruction of beta cells (3). Maintaining the remaining activity of the beta cells and enabling self-blood glucose control without the need for exogenous influence is critical to controlling the disease.

Results of a Phase 2 study (TrialNet TN10, NCT01030861) of teplizumab reported in 2019 were very promising (4). This randomized, blinded trial investigated if a single two-week course of treatment with teplizumab could delay or prevent the onset of T1D in high-risk individuals that were without a clinical diagnosis of T1D. The researchers observed that over the course of approximately 7 years (July 2011 to November 2018) teplizumab was able to delay the onset of T1D. Furthermore, this trial provided additional evidence of the importance of the T-cell mediated response for the onset of T1D, suggesting the value of using immunomodulation to affect disease development.

Sims et al. (5) extended the follow-up of participants in the original study, and have now reported that the effects persisted in the initial participants who received teplizumab. The median time to onset of T1D was more than double in participants who received teplizumab compared to those who received the placebo (~5 vs 2 years, respectively). Moreover, they observed improvements in beta cell function and, in some, a partial reversal in the decline of insulin secretion. Despite using a small cohort (total study enrolment = 76 participants) and a single 14-day course of drug, the results of this study form the foundation for exciting work in the future to actively prevent the onset of this lifelong condition whose prevalence only seems to be increasing.

A biologics license application for teplizumab for the delay or prevention of clinical T1D in at-risk individuals is undergoing priority review by the U.S. Food and Drug Administration, and their first action on the application is expected by July 2, 2021. The European Medicines Agency is evaluating a marketing authorization application for teplizumab.

References
1.       Menke et al. (2013). The prevalence of type 1 diabetes in the United States. Epidemiology 2013;24:773-774.
2.       Moobaseri et al. (2020).  Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020; 10(2): 98–115. DOI: 10.34172/hpp.2020.18.
3.       Gaglia J, Kissler S. Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707.
4.       Herold et al. (2019). An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019; 381:603-613. DOI:  10.1056/NEJMoa1902226.
5.       Sims et al. (2021).  Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science Translational Medicine. 13 (583); eabc8980. DOI: 10.1126/scitranslmed.abc8980.