Donislecel for Brittle Type 1 Diabetes: Do Not Use

Type 1 diabetes is a chronic autoimmune disease that affects the body’s ability to produce insulin.[1] Patients rely on intensive insulin therapy for which they must carefully monitor their blood glucose (blood sugar) levels. Insulin is administered through multiple daily injections or a small computerized device known as an insulin pump (the pump delivers insulin through a thin tube underneath the skin).[2] Using the correct amount of insulin is important to prevent both hyperglycemia (high blood sugar) and hypoglycemia (low blood sugar). In severe instances, both hyperglycemia and hypoglycemia can be life-threatening conditions. Hyperglycemia can cause nausea, weakness, confusion and coma, as well as diabetic ketoacidosis and other serious health problems. Hypoglycemia can cause many health problems, including rapid heartbeat, feeling weak, difficulty walking or seeing clearly, strange behavior, confusion and seizures.

Some patients with type 1 diabetes have symptoms that are not well-controlled despite intensive insulin therapy. This rare condition is known as brittle or unstable type 1 diabetes.[3] Patients with brittle diabetes have unexplained, severe and frequent changes in blood glucose levels that make it very difficult for them to determine the correct amount of insulin to administer.[4] At times, these patients also develop hypoglycemia unawareness, which makes it difficult for them to recognize when they require treatment. Patients with brittle type 1 diabetes are at high risk of severe hypoglycemia.

In June 2023, the Food and Drug Administration (FDA) approved donislecel (LANTIDRA), a pancreatic islet cellular therapy, for the treatment of adults with type 1 diabetes who are unable to adequately control their diabetes because of repeated episodes of severe hypoglycemia despite intensive diabetes management and education.[5] Donislecel is the first FDA-approved diabetes therapy of its type.

Because the serious risks associated with donislecel treatment do not outweigh its benefits, Public Citizen’s Health Research Group urged the FDA not to approve donislecel.[6] We have designated donislecel as a Do Not Use drug.

What is donislecel and how does it work?

Pancreatic islets contain the cells in the body that secrete insulin. Donislecel consists of islet cells that are derived from a donor pancreas.[7] Patients receive between one and three doses of donislecel. The cells are infused through the hepatic (liver) portal vein.[8] The goal of this treatment is for the infused cells to produce enough insulin so that the patient is no longer dependent on administering insulin to control their diabetes.[9] If a patient does not achieve independence from insulin treatment within one year of the infusion or loses this independence, a second or third infusion may be necessary. There are no data on the safety and effectiveness of more than three infusions.

Pancreatic islet cellular therapy is a form of organ transplantation, but is regulated in the United States, instead, as a drug. A whole pancreas transplant, which is also used to treat patients with brittle type 1 diabetes, is a solid organ transplant. Patients treated with donislecel need to take concomitant immunosuppressive therapy, with its attendant risks of infections, malignancies and severe anemia, to decrease the risk that their body will reject the donor islet cells. Patients also need to continue monitoring their blood glucose levels and may continue to require supplemental insulin.

Evidence of donislecel’s effectiveness and safety

The FDA’s approval of donislecel was based on two small, single-arm trials that included a total of only 30 subjects; one trial (10 patients) was initiated in 2004; the other trial (20 patients) was initiated in 2007. The subjects were between the ages of 21 and 67 and had type 1 diabetes and hypoglycemic unawareness.[10] All subjects were white and the majority (80%) were women.[11]

The subjects in the trials were followed for an average of 6.5 years. Across both trials, subjects had a total of 56 infusions, with 11 receiving a single infusion and 19 requiring a second or third infusion.

Of the 30 subjects, 25 became at least temporarily independent of supplemental insulin; four were insulin independent for less than a year. Ten subjects were insulin independent for more than five years.[12] Five subjects never achieved insulin independence at all.

The most common adverse reactions included nausea, fatigue, anemia, diarrhea and abdominal pain.[13] Of the 30 subjects, 27 also had at least one serious adverse event.[14] In the year after the first infusion, subjects across both trials had 75 severe adverse events, including eight that were life-threatening. In the following years, more serious adverse events were reported.[15]

For example, six of the 30 subjects had complications with the infusion procedure, such as liver lacerations or internal bleeding from damaged blood vessels. In some cases, the complications were severe enough to require emergency surgery and prolonged hospitalizations.[16],[17] Of most concern, however, were the adverse events associated with immunosuppression. Across both trials, 26 subjects had infections, 24 became anemic, and 11 developed cancers, such as skin, breast and thyroid cancer. Moreover, eight subjects discontinued immunosuppressants because of health concerns, resulting in the loss of the infused islet cells. Two patients died after the transplant, one within two years and the other within 10 years.

Immunosuppressive therapy has serious risks. It is uncertain, however, how the adverse event rates in subjects treated with donislecel compare to those for patients receiving a pancreas transplant; the donislecel trials did not include such a comparison arm.

At present, there are no studies comparing the outcomes of patients with type 1 diabetes receiving a pancreas transplant to those receiving pancreatic islet cellular therapy. Because islet cell infusions are less invasive than a solid organ transplant, it is possible that a whole pancreas transplant has a higher overall risk. It is known, however, that the success rate for insulin independence is higher for recipients of pancreas transplants than for those receiving islet cellular therapy.[18]

Additional considerations

Prior to the approval of donislecel, a pancreas transplant was the only treatment option for patients with brittle type 1 diabetes, in addition to intensive diabetes management.[19] However, because of the severe adverse effects associated with a pancreas transplant and the need for immunosuppression, the surgery is usually only performed in patients with end-stage kidney disease who also require a kidney transplant. Similar limitations have not been suggested for donislecel transplants.

Unlike in the U.S., in many countries, pancreatic islet cellular therapy is regulated as a donor organ and not a drug.[20] Treatment with pancreatic islets has similar risks to those for organ transplants. In addition to immunosuppression, these include the risk of transmission of communicable diseases from the donor and decreased chances of finding a matching donor organ in the future because of the immunologic effects of the cellular therapy.

The FDA also noted “significant issues” regarding the data that was the basis of the donislecel approval. For example, before their donislecel infusions, 17 of 30 subjects had already achieved reasonable control of their diabetes and only five had experienced a severe hypoglycemic event in the year prior the trial. Thus, it was impossible to determine whether donislecel helped to restore hypoglycemia awareness or reduced the incidence of severe hypoglycemic events. Further, because each dose of donislecel is made from one donor pancreas, there are substantial potency and purity differences between doses.[21]

What You Can Do

Public Citizen’s Health Research Group has classified donislecel as a Do Not Use drug and recommends that that it not be used for the treatment of brittle type 1 diabetes. Although donislecel treatment can restore insulin independence in some patients, there are no data that identify patient characteristics that are associated with a greater likelihood of success.[22]

If you have type 1 diabetes, develop hypoglycemia unawareness and suffer from severe hypoglycemic events, discuss with your clinician the best way to manage your diabetes. Newer automated technologies, including continuous glucose monitors, insulin pumps and so-called hybrid closed-loop systems that can function as an artificial pancreas, can help reduce the risk of hypoglycemia.[23]
 

References

[1] Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. June 28, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes. Accessed November 1, 2023.

[2] Food and Drug Administration. FDA briefing document. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. BLA 125734. April 15. 2021. https://www.fda.gov/media/147525/download. Accessed November 1, 2023.

[3] Cleveland Clinic. Britte diabetes. March 26, 2021. https://my.clevelandclinic.org/health/diseases/21499-brittle-diabetes. Accessed November 1, 2023.

[4] Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. June 28, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes. Accessed November 1, 2023.

[5] CellTrans. Label: donislecel solution (LANTIDRA). June 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24610d9f-0c5a-4f55-93b3-d456300bfd5d&type=display. Accessed November 1, 2023.

[6] Public Citizen. Letter to the FDA urging the agency not to approve the biologics license application for donislecel for the treatment of “brittle” type 1 diabetes. April 30, 2021. https://www.citizen.org/article/letter-to-the-fda-urging-the-agency-not-to-approve-the-biologics-license-application-for-donislecel-for-the-treatment-of-brittle-type-1-diabetes/. Accessed November 1, 2023.

[7] Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. June 28, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes. Accessed November 2, 2023.

[8] CellTrans. Label: donislecel solution (LANTIDRA). June 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24610d9f-0c5a-4f55-93b3-d456300bfd5d&type=display. Accessed November 2, 2023.

[9] Robertson RP, Rickels MR. Pancreas and islet transplantation in diabetes mellitus. UpToDate. Updated August 2, 2023.

[10] CellTrans. Label: donislecel solution (LANTIDRA). June 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24610d9f-0c5a-4f55-93b3-d456300bfd5d&type=display. Accessed November 3, 2023.

[11] Food and Drug Administration. FDA briefing document. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. BLA 125734. April 15. 2021. https://www.fda.gov/media/147525/download. Accessed November 3, 2023.

[12] Ibid.

[13] Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. June 28, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes. Accessed November 3, 2023.

[14] CellTrans. Label: donislecel solution (LANTIDRA). June 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24610d9f-0c5a-4f55-93b3-d456300bfd5d&type=display. Accessed November 3, 2023.

[15] Food and Drug Administration. FDA briefing document. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. BLA 125734. April 15. 2021. https://www.fda.gov/media/147525/download. Accessed November 3, 2023.

[16] Ibid./em>

[17] CellTrans. Label: donislecel solution (LANTIDRA). June 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=24610d9f-0c5a-4f55-93b3-d456300bfd5d&type=display. Accessed November 3, 2023.

[18] Robertson RP, Rickels MR. Pancreas and islet transplantation in diabetes mellitus. UpToDate. Updated August 2, 2023.

[19] Food and Drug Administration. FDA briefing document. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. BLA 125734. April 15. 2021. https://www.fda.gov/media/147525/download. Accessed November 3, 2023.

[20] Witkowski P, Philipson LH, Kaufman DB, et al. The demise of islet allotransplantation in the United States: A call for an urgent regulatory update. Am J Transplant. 2021;21(4):1365-1375.

[21] Food and Drug Administration. FDA Briefing Document Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. Session on Product Characterization (AM Session). April 15, 2021. https://www.fda.gov/media/147524/download. Accessed November 3, 2023.

[22] Food and Drug Administration. FDA briefing document. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. BLA 125734. April 15. 2021. https://www.fda.gov/media/147525/download. Accessed November 13, 2023.

[23] Mayo Clinic. Type 1 Diabetes. https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/diagnosis-treatment/drc-20353017. Accessed November 3, 2023.