May 2022 Update

Vertex Pharmaceuticals Incorporated today provided updates on its Phase 1/2 clinical trial of VX-880, an investigational stem cell-derived, fully differentiated pancreatic islet cell replacement therapy for people with type 1 diabetes (T1D) with impaired hypoglycemic awareness and severe hypoglycemia. According to the results released on May 2, data from the first two patients in Part A established proof-of-concept for VX-880, with one patient achieving insulin independence at day 270 and the other patient showing reductions in insulin requirements through Day 150.

Additionally, the Independent Data Monitoring Committee recommended advancement to Part B, where patients receive the full target dose of VX-880, which has been generally well-tolerated to date. Vertex also announced that VX-880 Phase 1/2 study has been placed on clinical hold in the U.S. by the Food and Drug Administration (FDA) due to a determination that there is insufficient information to support dose escalation with the product.

Click HERE to read the full article about this update.

Commentary

Authors:

Vincenzo Cirulli, M.D., Ph.D.

Scientific Director, Diabetes Research Connection

Department of Medicine, UW Diabetes Institute

University of Washington

Institute for Stem Cells and Regenerative Medicine

Alberto Hayek, M.D.

Medical Director, Scripps/Whittier Diabetes Institute

Co-Founder, Diabetes Research Connection

David Winkler

Co-founder, past Chair and current CFO, Diabetes Research Connection

Past Chair, Scripps Whittier Diabetes Institute

Past Chair, American Diabetes Association, San Diego Chapter

Type 1 Diabetes Patient for 62 years  

A Cure for Type 1 Diabetes? For One Man, It Seems to Have Worked.

This article, which appeared in the New York Times (NYT) on Saturday, November 27, 2021, provides a promise for achieving a cure for type 1 diabetes (T1D). Dr. Melton, a brilliant scientist at Harvard, and an inspired father of two T1D patients is credited with overseeing this important effort which built on many past and present researchers’ discoveries.

While we applaud Dr. Melton and his team’s efforts for taking the necessary steps to bring this research to the bed-side, there are some questions that will need to be addressed. It remains to be determined if any issue or side effects will arise over time in some of the 17 patients participating to this initial clinical trial. Patient immunosuppression may be problematic, as it has been the case for some recipients of cadaveric human islet transplants. The long-term survival and function of these stem cell-derived beta cells will also need to be assessed, and design plans to replace them with additional transplants should they fail. Ultimately, the cost of the procedure and required FDA approval will also need to be addressed.

In the year 2000, the New England Journal of Medicine published an article that caused many to believe a cure for T1D had been discovered. The principal investigator, Dr. James Shapiro, initiated what became known as the Edmonton Protocol. This multicenter trial involved transplanting human cadaveric islets. Some issues soon arose: 1) an insufficient supply of islets; 2) failure of the islet transplants to function long-term; 3) complications associated with the site of transplantation into the portal vein of the liver, and 4) side effects caused by the immunosuppression of the recipients.

Undoubtedly, the most significant development since 2000 has been the conversion of pluripotent stem cells into insulin-producing cells to provide an unlimited supply of islet tissue for transplantation in T1D patients.

The need for immunosuppressive drugs to prevent rejection of the islet transplants remains an ongoing concern, although these types of drugs, and their regimen protocols have improved considerably since 2000. Notwithstanding, immunosuppression continues to have issues. Better drugs will be needed to ensure that the transplanted islet tissue is not rejected, retains its insulin-producing function over time, and that the recipients’ immune systems is not negatively impacted for its important primary function of fighting off other diseases.

Another approach to avoid rejection of pluripotent stem cell-derived beta cells is to encapsulate them. However, to date, these cells have not prospered in such enclosed environments, because current cell encapsulation technologies do not allow for these beta cells to intimately interact with blood vessels of the host to receive nutrients and oxygen to survive long term while performing their insulin secretory function in response to circulating glucose levels.

In two recent studies just published in peer-reviewed journals (https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00415-X), Canadian investigators led by Dr. Timothy Kieffer in collaboration with ViaCyte, and by ViaCyte scientists in collaboration with Dr. James Shapiro (https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00338-4) reported that transplantation of immature stem cell-derived pancreatic islet progenitors in 15 and 17 patients, respectively, produced negligeable, yet detectable levels of human C-peptide production in response to a meal after a year from the day of transplantation. These studies were conducted using devices that allow some level of interaction of the transplanted cells with the patient’s blood vessels, thus requiring immune suppression. The bottom line is that after ~1 year, none of the patients became independent from insulin injections and all required exogenous insulin during the trial.

A possible solution to the problem of allorejection (i.e., immune rejection of “non-self” cells, coming from a different genetic background) may involve the use of a T1D patient’s own cells to generate induced pluripotent stem cells (or iPS), produced through a technique of reprogramming, and then convert these iPS cells into pancreatic beta cells. These “self-cells” may evade rejection by mechanisms of allo-immunity; however, auto-reactive immune cells that caused T1D in the first place in these patients may still target and destroy these newly transplanted beta cells.

San Diego’s ViaCyte is pursuing another potential cure. This company recently announced a collaboration with Crisper, a biotech leader in DNA editing to genetically modify the stem cells to avoid the need for immune therapy post-transplantation.

Ultimately, in order to ensure that all of the above treatments are safe for transplantation in the general population of T1D patients the FDA will require: 1) a careful peer-reviewed analysis of the results on all patients; 2) a long-term assessment of the survival and function of the transplanted cells; 3) evaluation of the long-term effects of immunosuppression; and 4) determination of the acceptability of all side effects.

Collectively, what all of these recent advancements show is that there is much more to be learned before stem cell derived islet tissue can be routinely and safely used for cell replacement therapy in T1D.

Hence, notwithstanding these open questions, substantial progress is being made towards a functional cure for T1D. We must proceed with hope and caution while pursuing additional innovative research.

The DRC is committed to continue supporting innovative basic and translational research by early-career scientists who strive to prevent, find better treatments for, and cure T1D.