In late June, the U.S. Food and Drug Administration (FDA) approved a new cell therapy that can restore insulin production in people with type 1 diabetes. Donislecel (Lantidra) is a transplant of insulin-producing pancreatic islet cells from deceased organ donors, the first such therapy to be approved in the United States.
The therapy can restore insulin secretion, reducing or even eliminating the need for exogenous insulin injections. Its side effects, however, can be extremely burdensome, limiting its applicability.
Lantidra, developed by the biotech startup CellTrans, is only indicated for adults with type 1 diabetes with extreme management challenges: those who experience recurring severe hypoglycemic episodes and who also cannot meet A1C targets. Severe hypoglycemia — low blood sugar events in which patients are so affected that they cannot treat themselves — can cause seizures, comas, and death. The danger is especially high for people with hypoglycemia unawareness, because they do not reliably feel the symptoms (such as tingling, hunger, and dizziness) that serve as the body’s warning system for low blood sugar levels.
The FDA’s decision to validate a single business’ approach, however, has appeared to cause some consternation among a community of experts hoping to increase access to islet cell transplant therapy.
A Controversial Decision
Until now, islet cell transplants have been unavailable in the United States (except under the auspices of a medical experiment) because of a regulatory quirk: According to the National Organ Transplant Act of 1983, subparts of organs don’t count as organs and are not covered by the network of rules and programs governing organ transplantation. Instead, transplantable islet cells are regulated as if they were drugs, subjecting them to high standards for precision and consistency that they cannot easily meet. Many of the nation’s prominent diabetes and transplantation experts have decried the situation (PDF).
Only one week before Lantidra’s approval, Senator Mike Lee (R-Utah) authored a bill to intended to improve the “outdated regulation of islet transplantation.” Instead, by approving Lantidra, the FDA has rapidly gone in a very different direction.
Advocates with the Islets for US Collaborative described the decision as “purely political,” alleging that it would compromise patient safety and stifle innovation by granting a monopoly on the practice of islet cell transplantation to a single for-profit company.
Reducing or Eliminating Insulin Needs
The pivotal studies that led to Lantidra’s approval tested the procedure in 30 patients. Of those 30:
9 (30 percent) achieved insulin independence for greater than five years.
12 (40 percent) achieved insulin independence for one to five years.
4 (13 percent) achieved insulin independence for less than one year.
5 (17 percent) did not achieve insulin independence.
Though the experiment supporting Lantidra’s approval was small, we also have good data on related types of islet cell transplants. Some transplant recipients have remained free of insulin therapy for many years following the procedure, with only minor side effects, although most patients require some insulin therapy five years after their transplant.
Studies of islet cell transplantation also show that patients improve their blood sugar control and can reduce their usage of exogenous insulin, even if they cannot wholly eliminate it.
Lantidra Will Be Used Only Rarely
Lantidra will not be used widely: There simply aren’t enough donor cells available. Islet cells for Lantidra are harvested from the pancreas of a deceased organ donor, putting a hard cap on the number of procedures that could possibly be performed. According to the Health Resources & Services Administration, there were 9,528 liver transplants conducted in the United States in 2022, 4,111 heart transplants, and only 108 pancreas transplants. Over 1 million Americans have type 1 diabetes.
While we know that islet cell transplantation is effective, the complications involved with both sourcing the cells and treating patients with immunosuppressive drugs will limit Lantidra’s reach. But for patients with a profound need — those with extreme glucose management challenges and hypoglycemia unawareness — islet transplantation could be a lifesaver.
The Dangers of Immunotherapy
Lantidra will also be limited to the patients in greatest need of help because it is itself a high-risk treatment. The side effects are considerable, and recipients will need immunosuppressive drugs to protect the donated islet cells from the body’s immune system, weakening the body’s defense against infection.
When Diabetes Daily spoke to James Shapiro, MD, the surgeon who performed the world’s first islet cell transplants, he explained that “immunosuppressive drugs are the big barrier for why we don’t do large numbers of cell transplants today. The dangers include increased risk of cancers, increased risk of life-threatening infections, side effects on the kidney, and they can also be toxic to the functioning of the transplanted cells and their ability to make insulin.”
In the trials that led to Lantidra’s approval, a whopping 87 percent of participants experienced at least one “severe” reaction, and 27 percent experienced at least one life-threatening adverse reaction. The 26 participants to experience infections attributed to immunosuppression totaled 211 separate incidents of infection. One subject died when an infection caused sepsis, leading to multi-organ failure.
Immunosuppression also greatly increases the risk of “malignancy,” leading to high rates of cancer. Lantidra recipients saw their risk of skin cancer skyrocket, in particular.
Twenty-seven percent of trial participants needed to discontinue their immunotherapy, which leads inescapably to the destruction of their transplanted islet cells. (The holy grail of type 1 diabetes research is a therapy that employs an abundant source of islet cells that can somehow escape the immune system, obviating the need for immunotherapy.)
The procedure itself (participants undergo either one or two surgeries) was also associated with complications. About 10 percent of transplant recipients experienced anemia due to surgery and required blood transfusions. The surgeries caused one life-threatening liver laceration and several cases of hemorrhaging and hematoma on or near the liver. A majority of participants reported symptoms such as vomiting, diarrhea, and abdominal pain.
In short, Lantidra entails very significant risks.
Takeaways
A new islet cell transplant procedure, the first approved in the United States, has the potential to help some people with type 1 diabetes achieve insulin independence. The therapy, named donislecel (Lantidra), will be available only to adults with a history of recurrent severe hypoglycemia and is not expected to become a mainstream treatment in the foreseeable future. Most people with type 1 diabetes will not be candidates for Lantidra, but the procedure could be a lifesaver for others, despite a very burdensome side effect profile.
While it seems natural to applaud the approval of any new treatment, some islet cell transplantation experts are very skeptical of the FDA’s decision to grant exclusive rights to a single business, fearing that it will ultimately serve to make cell transplant therapies less accessible to Americans.