Benefits of cell therapy for type 1 diabetes outweigh risks, FDA panel concludes
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An FDA advisory committee concluded that the investigational cell therapy donislecel demonstrated a favorable risk-benefit profile for certain patients with difficult-to-control type 1 diabetes.
“There is nothing patients [with diabetes] like more than freedom from dealing with the entire insulin issue,” Sandy Feng, MD, PhD, professor in residence with the department of surgery at University of California, San Francisco, and member of the Cellular, Tissue, and Gene Therapies Advisory Committee, told the panel. “I do think this therapy can help some patients and will be incredibly meaningful to those who receive it.”
Donislecel (Lantidra, CellTrans) — an allogeneic pancreatic islet cellular therapy — has been shown to increase insulin independence and decrease the number of severe hypoglycemic events among patients with difficult-to-control type 1 diabetes, based on pooled results of two open-label studies.
Despite the 12-4 vote recognizing the clinical value of donislecel, many committee members expressed concern about the potential risks associated with long-term immunosuppression and the size of the real-world population who may benefit from the therapy. Several suggested that, if donislecel is approved for commercial use, the FDA should require post-marketing studies to monitor safety.
“I very reluctantly voted yes ... because there are some patients who could benefit from this therapy,” Ellen W. Leschek, MD, program director for the division of diabetes, endocrinology and metabolic diseases at the National Institute of Digestive and Kidney Diseases, said during the meeting. “I am concerned that, if approved, too many people would opt for this treatment when, for many of them, the risks would outweigh the benefits.”
In 2017, the FDA granted donislecel orphan drug designation for the treatment of adults with brittle type 1 diabetes whose symptoms were not well-controlled by intensive insulin therapy.
The therapy comprises islet cells isolated from a single donor pancreas. The final cultured cell product is transplanted through infusion in the hepatic portal vein via percutaneous or transvenous transhepatic access or — if these are not feasible —via laparoscopic or open surgical access.
The FDA requested further clarification from the manufacturer regarding missing data and the inclusion of patients whose baseline values may have met or almost met the studies’ primary composite endpoint for efficacy of an HbA1c level of 6.5% or less and absence of severe hypoglycemic events at 1 year after the last transplant.
The FDA noted that only 16.7% of study patients had at least one documented severe hypoglycemic event in the year before their first donislecel transplant. Additionally, 37% subjects had an HbA1c level of 7% or less as their most recent value before their first transplant.
“Therefore, the FDA believes that the applicant has not demonstrated that allogeneic islet cell transplant with donislecel reduces the incidence of [severe hypoglycemic events] or restores hypoglycemia awareness in the subject population,” the agency wrote in its briefing document.
The efficacy analysis provided to the FDA included pooled results of separate phase 1/phase 2 and phase 3 trials of donislecel. The combined analysis included 30 adults (median age, 45.6 years; range, 21-67; 80% women; 100% white) with long-standing type 1 diabetes mellitus of at least 9 years since initial diagnosis.
Patients received up to three transplants of the targeted minimum total dose of 10,000 islet cell equivalents/kg to promote successful engraftment and insulin independence.
Results showed 63% of patients in the pooled analysis achieved treatment success as defined by the study’s primary endpoint. More granular analysis showed 16.7% of patients failed to meet the primary endpoint due to an HbA1c level greater than 6.5% at 1 year after their last transplant, whereas 23.3% experienced at least one serious hypoglycemic event during the same time frame.
Additionally, 25 patients (83.3%) in the pooled analysis achieved insulin independence after treatment. Among these patients, four were insulin independent for less than 1 year, 11 for 1 to 5 years and 10 for more than 5 years.
“The data on sustained insulin independence were compelling,” Sean J. Morrison, PhD, director of Children’s Medical Center Research Institute at The University of Texas Southwestern Medical Center, said during the meeting. The results met the minimum 4-year insulin-independence benchmark for providing clinically impactful benefit that the panel had agreed to earlier, he added.
“The evidence suggests that many patients have benefited from this type of transplantation so I voted yes, even if the market size for this therapy might decline over time,” Morrison said.
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FDA Briefing Document: Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. Available at: https://www.fda.gov/media/147525/download. Accessed April 16, 2021.
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