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An agreed that cadaveric allogeneic pancreatic islet cells (donislecel) for treating brittle type 1 diabetes is worth the risks for certain patients.

In a 12-4 vote Thursday with one abstention, members of the Cellular, Tissue, and Gene Therapies Advisory Committee felt that, although this procedure will likely benefit only a select few patients, the benefits of possible insulin independence for them outweigh the risks that come with long-term immunosuppressive treatment.

The therapy's sponsor, CellTrans, explained that existing options are limited for the some 80,000 American adults estimated to have "brittle" type 1 diabetes -- a subset of type 1 characterized by a particularly refractory form of complete insulin deficiency where patients often have vast swings in blood glucose levels.

Those existing therapies include whole-pancreas transplantation (with or without concurrent kidney transplant) or tried-and-true insulin therapy, which can come in the form of multiple daily injections or a closed-loop insulin pump and continuous glucose monitoring system.

"There are two very small sub-populations that it would provide the only viable therapy," said Christopher Breuer, MD, of Nationwide Children's Hospital in Columbus, Ohio, on why he voted in favor. "Those would be the ones who are eligible for transplantation but couldn't tolerate a big operation... and those that were on the best standard-of-care -- the feedback responsive pumps -- but were not tolerating those."

Also voting "yes," Randy Hawkins, MD, of a private practice in Inglewood, California, said: "I do have concerns about the adverse effects of immunosuppressants. I think we should keep this in a toolbox, but I believe the patients need to be given strict informed consent about the risks."

Speaking as one of the four opposing voices, David Harlan, MD, of the University of Massachusetts Medical School in Worcester, said there may be some patients that could benefit from this option, but there are very few out there.

"There's only a hundred pancreas transplants done in this country every year and that's very effective," he said, adding "so were talking about patients who are not candidates for pancreas transplants that might get this."

"I voted no because I too take care of patients with diabetes and I have transplanted islets before -- I've done both and I've seen them both pre- and post-transplant. And I've seen the awful things that can happen in post-transplant recipients. It's really hard to get that informed consent from someone when you're asking them to consider a future that they don't know."

"When it works, it's great. When it doesn't work, it can be catastrophic," Harlan said.

These risks in question ultimately boil down to two factors: the short-term risks incurred during the actual islet transplantation procedure, as well as the long-term term risks tied to immunosuppression.

As detailed in , the transplantation process works by manufacturing each lot of donislecel from a deceased human donor pancreas. Each patient may receive up to three lots during the course of their treatment. Islets of Langerhans from the deceased donor are then transplanted into the hepatic portal vein. For each transplantation, there was a target minimum islet dose of approximately 10,000 IE/kg recipient body weight.

The mechanism behind this process include the β-cells that are able to restore endogenous insulin production, and the glucagon-producing α-cells that aid in hypoglycemia response regulation.

Efficacy of this procedure was determined in two open-label studies: the phase I/II UIH-001 study and the phase III UIH-002 study. Pooled results from both showed 70% (21 of 30) of the participants were able to achieve at least one full year of insulin independence while maintaining glycemic control following islet transplantation. Insulin independence was defined as not using insulin while keeping HbA1c at 6.5% or lower two weeks after transplant.

Five patients (16.7%) in the phase III trial never became insulin dependent at any time during the average 6.5-year follow-up, one of whom received two transplants.

In total, there were 1,319 adverse events reported during the first year after transplantation, eight of which were life-threatening and 75 severe. One patient in the phase III trial died due to multiorgan failure from an infection 592 days after initial transplant, which the sponsor deemed "probably related to immunosuppression/study drug."

As for the serious adverse events considered "life-threatening," these included reports of neutropenia, anemia, breast cancer, hyperlipidemia, pancytopenia, papillary thyroid cancer, post-transplant lymphoproliferative disease, and urosepsis.

While islet cell transplantation is less invasive than a whole pancreas transplant, procedure risks include possible damage to the liver, gall bladder, and intra-abdominal blood vessels. Paired with those risks, the required immunosuppressive regimen can increase their risk for a slew of adverse events -- besides infection, these include cancers, neurological disorders, anemia, gastrointestinal events, and more.

"I look forward to further developments in immunosuppression that would mitigate the current toxicity that we're facing," Sandy Feng, MD, PhD, of the University of California San Francisco, said after casting her vote in favor of the therapy. "There are definitely additional therapies that are being developed that might mitigate those toxicities that would be beneficial to this population."

"I have taken care of patients -- I do pancreas transplants -- and I can tell you that there is nothing that a person likes more than their pancreas transplant and their freedom from dealing with the entire insulin issue," she added. "I think that this can help some people and I think that it would be incredibly meaningful to those people."

Although the FDA is not required to follow its advisory committees' recommendations, it typically does.

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