Does Novel Biologic Do Enough to Stave Off Type 1 Diabetes?

Whether teplizumab safely delays clinical type 1 diabetes mellitus (T1D) in at-risk individuals is the issue at hand for the FDA Endocrinologic and Metabolic Drugs Advisory Committee when it meets on Thursday.

Developer Provention Bio has asked for an indication of the IV drug, given as a single 14-day course of infusions with the proposed trade name Tzield, to delay clinical type T1D in at-risk individuals. The humanized monoclonal antibody against CD3 is thought to expand regulatory T cells and re-establish immune tolerance.

Approval largely hangs on evidence from the TN-10 trial (TrialNet Natural History/Pathway to Prevention), which showed a relative 59% reduction in risk for developing T1D with teplizumab versus placebo, with a median time to diagnosis of 48.4 and 24.4 months, respectively.

Pre-meeting FDA briefing documents homed in on just how clinically meaningful that 2-year delay in diagnosis was.

Pushing back the onset of T1D may help patients avoid diabetic ketoacidosis, delay the need for insulin therapy and its accompanying risks, reduce the significant disease burden associated with T1D, and allow for better glycemic control due to older age at diagnosis, the documents noted.

Confirmatory evidence came from a meta-analysis showing slower decline in beta-cell function marker C-peptide with teplizumab in new- or recent-onset clinical T1D. However, the effect wasn’t significant beyond 1 year.

While the FDA review acknowledged that the single small trial with the meta-analysis could be enough to meet the standard for approval, it pointed out that the meta-analysis was a post hoc analysis in clinical T1D patients rather than at-risk people. Additionally, the C-peptide endpoint used in the meta-analysis isn’t validated as a surrogate for clinical benefit.

Another question the panel will be asked to review is whether the 44 patients exposed to teplizumab in the trial (and 750 patients exposed to the drug in other controlled clinical studies) could be sufficiently reassuring on safety.

The clinical development program showed risks including cytokine release syndrome, transient hepatic enzyme elevations, occasional bilirubin increases, transient lymphopenia, and generally non-serious rash.

“It is important to note, however, that slightly more than 10% of patients were not able to receive the full course of teplizumab secondary to meeting protocol-specified withdrawal criteria, usually related to laboratory abnormalities,” the FDA reviewers noted.

They also pointed out potential for immunosuppression because teplizumab affects T-cell signaling. There was a higher frequency of serious infection in the TN-10 trial, although the overall safety database of patients exposed to the drug didn’t suggest infection is an important risk of the drug.

The panel will be asked about the potential for longer-term safety issues, like malignancy, that weren’t observed, but might be expected from the mechanism of action of teplizumab, and whether such safety concerns could be adequately addressed by labeling or postmarketing studies.

Proposed labeling originally suggested this would be a drug for patients in stage 2 of T1D, who have progressed to having two or more autoantibodies and the beginnings of the resulting progressive beta-cell loss, but not yet the symptoms.

The TN-10 trial enrolled patients, ages 8 years and older, who had a relative (typically a sibling) with T1D. Participants already had two or more positive autoantibodies and an abnormal oral glucose tolerance test result.

Provention Bio revised the proposed indication from “the delay or prevention of clinical type 1 diabetes mellitus in at-risk (Stage 2) individuals” to “the delay of clinical type 1 diabetes mellitus in at-risk individuals.” However, the advisory committee will delve into how exactly to describe candidates for whom the biologic would stand to give more benefit than risk.

One additional issue the FDA will weigh in on is a teplizumab manufacturing issue related to faster pharmacokinetic clearance of the planned commercial agent than that used in the trial, which is made in a different facility.