Provention Bio’s teplizumab FDA advisory committee (AdCom) meeting for an approval in delaying type 1 diabetes (T1D) will likely focus on safety concerns, experts said. While this may invite additional caution for an approval, strong efficacy data supporting a multiyear, clinically meaningful delay in T1D onset nevertheless bolsters the potential for a regulatory nod, they added.

Because teplizumab is an immunotherapy given to a population both without active disease and predominantly under 18 years old, there is a higher bar for safety, said experts. The 76-patient Phase II data may be too small and short to gather comprehensive data, which would ideally give a good estimate on long-term safety and confidence in its use, many experts said. While this will warrant additional scrutiny in the AdCom, it may not be enough to stave off an approval.

The safety concerns related to an increased risk of infections or potential secondary malignancies may be allayed by additional teplizumab data from other trials or settings, and may depend on details in Provention’s full BLA package, a few experts noted.

Still, delaying the onset of T1D, particularly in adolescents, could provide a substantial clinical benefit as managing T1D costs an average of $2,500 per year with insurance, according to public information. Adherence to strict dosing schedules and glucose monitoring is much tougher at a younger age, most experts added. Even though the Phase II trial included only 76 participants, ages 8.5–49.5 years, it showed two weeks of teplizumab delays the onset of clinical T1D by approximately three years compared to placebo, which experts deemed clinically relevant. This benefit may be especially significant for parents of children with T1D who would be highly motivated to delay the onset of T1D in their other children.

Teplizumab has an AdCom tentatively scheduled on 27 May and a PDUFA date of 2 July. The treatment received FDA priority review designation, according to a 4 January press release.

T1D affects about 1.6 million patients in the US, but the large majority do not have relatives with T1D. Teplizumab has estimated peak global sales of 691m in 2027, according to a GlobalData consensus, while Provention Bio has a market cap of $725.94m. Provention Bio declined to comment for this story.

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Long-term safety poses concerns despite strong efficacy 

Although the existing teplizumab efficacy data are strong, the AdCom could raise concerns over the overall risk/reward profile of giving a biologic to patients who do not have active disease, said Dr Emily Sims, pediatric endocrinologist, Riley Hospital for Children, Indianapolis, Indiana. The questions on its safety will likely focus on hematologic adverse events (AEs) and rash seen in the Phase II, including how these risks stack up against the lifetime morbidity associated with T1D, added Dr Hertzel Gerstein, professor, Department of Medicine, McMaster University, Hamilton, Canada.

In the treatment group (n=44), 33 patients had blood/bone marrow AEs, 16 had dermatologic AEs, eight had infections, and 16 had a spontaneously resolving rash. In the placebo group (n=32), two patients had blood/bone marrow AEs, one had a dermatological AE, and five had infections (Herold, K, et al. New England Journal of Medicine, 2019; 381:603–613).

Because the trial primarily enrolled adolescents, the FDA will likely focus on the safety concerns, Gerstein and Sims agreed. Of the 76 patients enrolled, 55 were under age 18 years, according to published results.

While there were no serious AEs, the trial size was very small and it is unknown if the observed transient reduction in white blood cells could lead to any acute complications, said Dr Edoardo Mannucci, associate professor of Endocrinology, University of Florence, Italy. Lymphocytes were at a nadir at day 5 of treatment, with 20 cases of Grade 3 lymphopenia occurring in the teplizumab group. Of these, 19 cases resolved by day 45 and the final case resolved at day 105. Although Sims said the quick improvement in the transient drop in lymphocytes alleviates most concerns, Mannucci noted it is still important to understand the complete risk profile. For example, antithyroid drugs can cause low white blood cell counts and are known to occasionally cause agranulocytosis, which can be lethal, he said.

The need for additional studies of both this subgroup of high-risk individuals and of a broader range of those at high risk of developing T1D could be a subject of discussion at the AdCom, said Phase II Principal Investigator Dr Carla Greenbaum, director, Diabetes Research Program, Benaroya Research Institute, Seattle Washington.

To adequately establish safety, a larger study is necessary, particularly since teplizumab affects lymphocytes and is administered to adolescents, said Dr Milos Miraz, endocrinologist, Institute of Clinical and Experimental Medicine, Prague, Czech Republic. Subsets of lymphocytes can play various roles in the immune system, which can be associated with increased risk of infections. Longer term studies are needed to understand the risk of infections and malignancies, said Dr Zan Fleming, ex-FDAer and president, healthcare consultancy Kinexum, Harpers Ferry, West Virginia.

Nevertheless, the exact regulatory response may be hard to predict since the drug’s BLA will likely include additional safety data from other teplizumab trials, which could provide better insight into the severity of the rash and hematological AEs, Gerstein noted.

Efficacy benefit still attractive despite safety hedge

Overall, experts agreed any safety concerns would be weighed against what most saw as a substantial clinical benefit. After a median follow-up of 2.5 years, 22% of teplizumab patients compared to 50% of placebo patients had developed T1D, with a median delay to the onset of clinical diabetes and insulin dependence of 32.5 months, according to a 3 March company press release.

For children under age 18 years, delaying the onset of insulin dependence can substantially improve quality of life, explained Sims, who authored the follow-up study. Adherence to strict glucose monitoring and insulin dosing, particularly as diets change drastically with age, can be particularly tough for adolescents, she said. However, teplizumab does not outright prevent T1D, which has become less difficult to manage over time, so it is unknown if the limited efficacy sample outweighs the potential long-term safety consequences, said Fleming.

While preventative therapies with any side effects have traditionally given clinicians pause when patients have no active disease, this trial enrolls only patients who are almost guaranteed to develop T1D, explained Sims. The fact enrolled patients are nearly certain to develop T1D during their lifetimes could alleviate this concern, she said. Inclusion criteria for the trial required patients to have a relative with T1D, have at least two diabetes antibodies, and have impaired glucose intolerance, according to

William Newton is a Reporter and Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.