Stem Cell Transplants Could Be 'Transformational' in Type 1 Diabetes

Miriam E. Tucker

June 06, 2022

NEW ORLEANS ­— Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical's investigational allogeneic stem-cell derived islets (VX-880), with the first person now completely insulin-independent at 9 months post-transplant.

Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem-cell derived islet transplants as they are 'foreign' to the recipient).

The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post-transplant. Both patients were given just half the targeted VX-880 dose.

Data for those two patients — the first in Vertex's phase 1/2 multicenter, single-arm, open label clinical trial of VX-880 — were reported today at the annual Scientific Sessions of the American Diabetes Association (ADA), by James F. Markmann, MD, PhD.

He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.

Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they're limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.

"This is a new area…We hope this will be the same or potentially better. With stem-cell derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets," he commented during a press briefing here.  

A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the US Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Markmann said.

In answer to a question about how Patient 1 is doing now, Markmann replied, "He's doing great. He's probably the most appreciative patient I've ever met. His life was being destroyed by diabetes. He couldn't work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate."

When Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied, "I want to participate. If I die from this and I help somebody else I'd be happy, but I can't go on living the way I'm living."

"These people really suffer and this, I think, brings hope to them," Markmann said.    

"Beautiful Data" Seen in Two Patients, With "Transformational" Potential

Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told Medscape Medical News, "It's beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells…it was impossible to get sufficient beta cells from cadaveric transplants. It's just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like Patient 1, this will be transformational."

Markmann presented data for the most recent study visit for each of the two patients, 270 days for Patient 1 and 150 days for Patient 2. Prior to the transplants, Patient 1 had experienced five severe hypoglycemic events and Patient 2 had experienced three.

Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, Patient 1 showed a "robust" C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, "possibly due to improved insulin sensitivity," Markmann said.

Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.  

Hemoglobin A1c dropped in Patient 1 from 8.6% at baseline to 6.9% at day 180, to a "remarkable" 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.  

Both patients also had significant reductions in insulin dose. For Patient 1, the dose reduction was more than 90% — from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.

Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.

Asked why Patient 2's results weren't quite as impressive as Patient 1's, Markmann replied "I think what's important is that both patients did great and since this was a half-dose we might have expected that the outcome was going to be more like Patient 2 rather than Patient 1. So, I think we're just going to have to do more patients to understand where it falls." 

Although Patient 1 experienced a cluster of six severe hypoglycemic events early in the post-transplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.

Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a "mild and self-limited" rise in liver function test and also experienced two severe adverse events: a rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2's adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.

Immunosuppression: Work is Ongoing

The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well-tolerated, Markmann said.

Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.

"This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn't require immunosuppression...But if we had a way of transplanting the cells without the need for immunosuppression then it could be really widely available. That's an opportunity for the future since these cells can be made in unlimited quantities," Markmann commented during the press briefing.

Asked for his thoughts about the immunosuppression aspect, Pragnell told Medscape Medical News, "Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They're going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it's amazing."

He added: "The 'artificial pancreas' is a huge step forward, but it's just a bridge to a cure, whereas if they're able to show safety and efficacy, this is potentially a cure…I'm very excited about it."

Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Pragnell is an American Diabetes Association employee and has no further disclosures.

American Diabetes Association 82nd Scientific Sessions: Abstract 259-OR. Presented June 6, 2022. 

Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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