An advisory panel to the US Food and Drug Administration (FDA) has approved pancreatic islet cell transplant therapy for people with type 1 diabetes that current therapies cannot treat.
On April 15, the FDA’s Advisory Committee on Cell, Tissue and Gene Therapies voted 12-4 in favor of Donislecel (Lantidra). There was one abstention. The panel viewed the drug as “an overall favorable benefit-risk profile for some patients with type 1 diabetes”. The product consists of purified Langerhans allogeneic pancreatic islets obtained from cadaver donors and is infused into the portal vein of the liver.
Treatment benefits include the potential for insulin independence and the elimination of severe hypoglycemia. Risks are those associated with surgery and long-term immunosuppression.
The therapy is manufactured by CellTrans. According to Dr. Jose Oberholzer, Founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association (ADA) criteria for pancreatic all-organ transplantation (ie, pancreas transplant) not kidney).
The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and / or ketoacidosis that requires medical attention; clinical or emotional problems with the use of exogenous insulin; and consequent failure of insulin-based management to prevent acute diabetes complications.
Success in two thirds of patients in small studies
Oberholzer presented data from two single-arm open label studies: a phase 1/2 study with 10 patients that began in 2004 and a phase 3 study with 20 patients that began in 2007. However, the inclusion criteria differed somewhat between the two studies. All 30 patients had hypoglycemic ignorance. The mean follow-up was 7.8 years for the phase 1/2 study and 4.7 years for the phase 3 study.
All patients had positive post-transplant C-peptide levels. The composite endpoint for success – an A1c value of ≤ 6.5% and an absence of severe hypoglycemic episodes for 1 year – was met in 19 patients (63.3%). Five patients (16.7%) did not meet the A1c target and seven patients (23.3%) experienced a severe episode of hypoglycaemia.
Twenty of the 30 patients achieved insulin independence for at least 1 year.
Improvements were also seen after 1 year in the results of the mixed meal tests, fasting blood sugar levels, and overall blood sugar control. Survival of the graft 10 years after the transplant was achieved by 60% of the patients, Oberholzer said.
Adverse Events Not unexpected, but still worrying
Two patients died, one from fulminant sepsis 20 months after the transplant and the other from severe dementia 9 years after the transplant. Three patients had four serious procedural events including one liver injury and two liver hematomas. Increases in portal pressure occurred in two patients.
Most of the adverse events were related to immunosuppression. This included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were serious. Renal function decreased persistently in two patients (20%), and six (20%) developed new proteinuria after one year.
The procedure-related adverse events and immunosuppression-related problems were not unexpected and were in line with those described for patients who received a full pancreas transplant, FDA assessor Patricia Beaston, MD, said in her review of the CellTrans data.
The panel members support the treatment of a small group of patients
During the discussion, several panelists suggested that the target patient population for this treatment is likely to be smaller today than it was when the two studies began, as advances in diabetes care have been made. These advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically stops insulin delivery to prevent hypoglycemia.
Panel chairwoman Lisa Butterfield, PhD, surgeon and immunologist at the University of California at San Francisco, voted for approval. But she added, “I support collecting post-approval data to learn more about the product. I don’t know how many patients will really benefit from it, but I think it needs to be determined.”
Christopher K. Breuer, MD, a general and pediatric surgeon at the Regenerative Medicine Center at Nationwide Children’s Hospital in Columbus, Ohio, said he supported the approval of “two very small subpopulations where this would be the only viable therapy”: however, those who are eligible for a pancreas transplant cannot tolerate major surgery; and those who are already using the latest automated insulin delivery systems and still cannot achieve acceptable glycemic control.
Temporary Voting Member David Harlan, MD, Director of the University of Massachusetts Diabetes Competence Center, Worcester, Massachusetts, voted no.
He noted that there are only about 100 pancreatic-only transplants in the United States annually and that such transplants are “very effective, so we’re talking about patients who are not pancreatic transplant candidates who may get it”.
Additionally, Harlan said, “I’ve seen the terrible things that can happen to recipients after the transplant. It’s really difficult to get that informed consent from someone when you ask them to think about a future they don’t know. When it works, it’s great. If it doesn’t work, it can be disastrous. I’m just worried about having to open Pandora’s box. “
The only other diabetes specialist on the panel, Temporary Voting Member Ellen Leschek, MD, said she “reluctantly voted yes because some people might benefit, but I think it’s a much smaller number than the company thinks could.”
Leschek of the National Institute for Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, said she was concerned that “if approved, too many people will be treated this way when, in fact, many of those people are at risk.” outweigh the benefits. “
Sandy Feng, MD, PhD, of the Department of Surgery at the University of California, San Francisco, pointed out that regarding immunosuppressive therapy, “We are concerned about the toxicity of what we are currently using, but there is developed additional therapies that could mitigate those toxicities that would be beneficial for this population. “
Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing like that [patients with type 1 diabetes] like more than the freedom to deal with the whole insulin problem. This has made a great impression on me over the past twenty years of clinical practice. I think this can help some people and will be incredibly meaningful to those people. “
Members of the FDA advisory panel are screened for conflicts of interest and special exemptions are granted if necessary. No such exemptions were granted for this meeting.
Miriam E. Tucker is a freelance journalist based out of Washington, DC. She is a regular contributor to Medscape. Her work has appeared in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.
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