By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first allogeneic pancreatic islet cellular therapy for treating “brittle” adult type 1 diabetes.1 Islet cells are sourced from deceased donors (cadaveric). Donislecel-jujn is distributed as Lantidra.
INDICATIONS
Donislecel-jujn can be prescribed to adults with type 1 diabetes who cannot approach target HbA1c levels because of current repeated episodes of severe hyperglycemia despite intensive diabetes management and education.2
DOSAGE
The recommended minimum dose is 5,000 equivalent islet number (EIN) per kg body weight for initial infusion. For subsequent infusions, the dose should be 4,500 EIN/kg administered through the portal vein.2 Preprocedural medications (30 minutes to 360 minutes before donislecel-jujn infusion) include nondepleting monoclonal anti-interleukin-2 receptor antibody (e.g., daclizumab), calcineurin inhibitor (e.g., tacrolimus), mTOR inhibitor (e.g., sirolimus), tumor necrosis factor (TNF) blocker (e.g., etanercept), and periprocedural antibiotic prophylaxis.2
There also is a post-infusion medication regimen that includes anti-infectives, a nondepleting anti-IL-2 receptor antibody, and a TNF-blocker. Administer Pneumocystis pneumonia and cytomegalovirus prophylaxis after donislecel-jujn. Insulin independence may take several weeks after infusion. Perform a second infusion if the patient does not achieve insulin independence within one year or within one year after losing independence after a previous infusion.2 Infuse a third dose based on the same criteria as for the second.
Donislecel-jujn is supplied as a purified allogeneic islets of Langerhans, from a single donor, suspended in a buffered medium, and containing not more than 1 × 106 EIN in 400 mL of transplant media.
POTENTIAL ADVANTAGES
In two nonrandomized, single-arm studies, participants received at least one infusion, up to a maximum of three. Eleven out of 30 achieved insulin independence for one to five years.2 Nine participants did not need insulin for more than five years.
POTENTIAL DISADVANTAGES
There is risk of bacterial, viral, fungal, and parasitic infections, as well as malignancies and severe anemia caused by the use of immunosuppressives.2 There also are potential procedural complications, such as liver laceration, hemorrhage, and intra-abdominal bleeding, associated with portal vein infusion. Patients with a positive T- and B-cell crossmatch between recipient and donor lymphocytes may be at higher risk of graft rejection.2
Severe adverse events were reported in 90% of study participants, and 27% experienced at least one life-threatening adverse reaction (with two deaths).2 Five of 30 participants in the single-arm study did not achieve insulin independence.1,2
COMMENTS
Donislecel-jujn is a suspension of cadaveric allogenic pancreatic islets, which contain endocrine hormone-secreting cells, including beta-, alpha-, pancreatic peptide-(PP-), delta- and epsilon-cells. After transplantation, these cells can restore endogenous insulin production, respond to fluctuations in blood glucose levels, and still aid in hyperglycemia response regulation.
The effectiveness of donislecel-jujn was demonstrated in two open-label, single-arm studies totaling 30 participants.2 Eleven received one infusion, 12 received two infusions, and seven received three infusions. With an average of 6.5 years of follow-up, of the 11 participants who received one infusion, four were insulin-independent. All seven who received a third infusion were insulin-independent. Twenty-five out of 30 participants achieved insulin independence (12 for one to five years and nine for longer than five years). Five participants did not achieve insulin independence. Insulin independence is defined as not requiring exogenous insulin to achieve adequate glycemic control (e.g., Hb1Ac 6.5% or less).
CLINICAL IMPLICATIONS
Type 1 diabetes is an autoimmune disease resulting in the destruction of the pancreatic islet beta-cells. A small proportion of patients experience wide variations in blood glucose (brittle diabetics).3 About 80,000 American adults are estimated to be living with brittle type 1 diabetes.4 Current therapies include the advanced hybrid closed-loop system (combined insulin delivery with continuous glucose monitoring), which help alleviate fluctuations in glucose levels.
Recently, the FDA approved a new automated insulin dosing system.5 This system does not require conventional carb counting but rather estimates the meal as small, medium, or large, and the system will adjust over time.
Pancreas transplant is an effective solution for selected patients. For those who are not candidates for a pancreas transplant, islet cell transplant is an alternative.
As the first cellular therapy for type 1 diabetes, donislecel-jujn represents an important breakthrough, but it carries a risk of significant adverse events — especially the procedural risk, risk of life-long immunosuppressives, and limited donor supply. Additionally, stem cell therapies offer another potentially promising approach by reconstitution of immunotolerance and preservation of islet beta-cell function.6
A group of investigators recently reported on their ongoing Phase I/II stem cell-derived, fully differentiated, insulin-producing beta-cell therapy trial.7,8 The researchers reported two of six subjects are insulin-independent beyond one year after infusion, and three others are on similar trajectories. The cost for donislecel-jujn was not available at the time of this review.
REFERENCES
1. U.S. Food & Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. June 28, 2023.
2. CellTrans. Lantidra prescribing information. June 2023.
3. National Organization for Rare Disorders. Brittle diabetes.
4. American Diabetes Association. Novel stem cell-derived islet cell therapy continues to show promise for achieving insulin independence for individuals with type 1 diabetes. June 23, 2023.
5. U.S. Food & Drug Administration. FDA clears new insulin pump and algorithm-based software to support enhanced automatic insulin delivery. May 19, 2023.
6. Wan XX, Zhang DY, Khan MA, et al. Stem cell transplantation in the treatment of type 1 diabetes mellitus: From insulin replacement to beta-cell replacement. Front Endocrinol (Lausanne) 2022; Mar 18: 13:859638. doi: 10.3389/fendo.2022.859638. eCollection 2022.
7. Vertex Pharmaceuticals. Vertex presents positive VX-880 results from ongoing phase 1/2 study in type 1 diabetes at the American Diabetes Association 83rd Scientific Sessions. June 23, 2023.
8. ClinicalTrials.gov. A safety, tolerability, and efficacy study of VX-880 in participants with type 1 diabetes. Last update posted July 7, 2023.
Lantidra can be prescribed to adults with type 1 diabetes who cannot approach target HbA1c levels because of current repeated episodes of severe hyperglycemia despite intensive diabetes management and education.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content