Cell therapies in clinical trials: Moving the needle forward

Late last year, Vertex announced the expansion of their manufactured islet therapy, VX-880 (Zimislecel), to a phase 1/2/3 clinical trial, the final step before seeking FDA approval. This decision stemmed from groundbreaking data in the initial phases of the trial in which 11 of 12 participants reduced or eliminated the need for external insulin therapy. Currently, zimislecel is limited to people with severe hypoglycemia and requires chronic immunosuppression.

The results of the VX-880 trial are highly anticipated since this is the first time a scalable treatment for T1D has entered a final clinical testing stage, and regulatory submission is expected in 2026. Vertex is working closely with regulators to expand its manufacturing capabilities and ensure they are prepared for the therapy to hit the market.

Zimislecel would not have been possible without years of support from Breakthrough T1D and The T1D Fund: A Breakthrough T1D Venture. This includes research grants, an investment by the Fund in Semma Therapeutics (which was later acquired by Vertex), and much more.

It doesn’t stop there: Vertex is expanding their pipeline and investigating different ways to keep manufactured islets safe without standard anti-rejection immunosuppressants, including alternative immunosuppressive regimens, gene-edited immune-protected cells, and novel encapsulation devices.

Although Vertex’s T1D portfolio is progressing, the clinical development of VX-264, an encapsulated islet therapy that does not require immunosuppression, has been discontinued. While it was safe and well-tolerated in clinical trials, it did not meet efficacy and safety endpoints as measured by C-peptide, a biomarker for insulin production.

UP421 consists of islets derived from deceased donors that have been engineered to be hypoimmune, meaning they can avoid detection by the immune system without the need for immunosuppressants. Incredibly, the first person who received a partial dose of UP421, implanted in to forearm muscles, in a phase 1 clinical trial is making their own insulin, as demonstrated by increased C-peptide, without any side effects.

This is the first proof-of-concept evidence showing that this cell engineering approach can enable implanted islets to avoid immune destruction. The next step is applying this method to manufactured islets.

Breakthrough T1D is supporting research exploring similar cell engineering approaches to allow implanted islets to evade the immune system. The T1D Fund has also invested in Sana due to their distinctive hypoimmune manufactured islet replacement program, and Breakthrough T1D continues to work closely with them.

Tegoprubart is an immunotherapy that interferes with immune cell communication and dampens the immune response. This therapy is being tested in a Breakthrough T1D-funded phase 1/2 clinical trial as a novel anti-rejection immunosuppressant for people with severe hypoglycemia who have received deceased donor islets. Building on ongoing kidney transplant studies, this study will determine if tegoprubart can protect transplanted islets from rejection with fewer side effects compared to standard immunosuppressants, which is harsh on people and the implanted cells.

So far, of the first three participants, two have achieved insulin therapy independence. According to the study, tegoprubart is safer for both people and transplanted cells in comparison to standard immunosuppression, with milder side effects and greater islet survival. This study holds promise for preventing rejection of manufactured islets as well.

The T1D Fund has made several investments in Eledon to support this effort as it sees the potential to address the key unmet need of safe and effective immunosuppression for people who receive islet replacement therapies.

Cell Pouch™ is an implantable bio-hybrid organ that provides a specialized environment for transplanted islet cells by allowing them to access oxygen and nutrients provided by blood vessels, called vascularization.

The first cohort of a phase 1/2 clinical trial enrolled participants with severe hypoglycemia who received deceased donor islets within Cell Pouch in addition to standard immunosuppressants. Of the six enrollees, five remain insulin therapy independent from one year to more than five years. Cohort B is currently evaluating a higher-capacity Cell Pouch that can accommodate 50% more islet volume, and the trial will soon advance to Cohort C to further test safety and efficacy of the system.

Most excitingly, Sernova recently announced that following the conclusion of the ongoing clinical trial, they will initiate a new trial to test Cell Pouch implanted with manufactured islets—paving the way towards a scalable solution to T1D.

Breakthrough T1D has supported the development of Cell Pouch™ and continues to work with Sernova.

SR-02 is a manufactured islet cell therapy implanted onto the omentum, a fatty, protective layer around organs. This therapy is in a phase 1/2 clinical trial for people with severe hypoglycemia and requires immunosuppression. The trial is evaluating safety and insulin production as measured by C-peptide.

Seraxis is also working on another manufactured islet therapy (SR-03) that has been gene-edited so that anti-rejection immunosuppressants are not needed. They are hoping to initiate a new clinical trial for SR-03 in 2026.

The T1D Fund has invested in Seraxis to aid in the development of these therapies based on their distinctive and promising islet replacement approach.

CTX211 is another manufactured islet therapy that has been gene-edited to evade the immune system so that recipients do not have to take immunosuppressants. In an ongoing phase 1/2 clinical trial, these cells are implanted within a specialized device to help keep the cells alive in the body, and investigators are evaluating safety as well as insulin production measured by C-peptide. Results are expected this year.

Breakthrough T1D was a long-time supporter of ViaCyte, which initially developed the manufactured islets and partnered with CRISPR Therapeutics to genetically modify them. ViaCyte was acquired by Vertex in July 2022, and now CRISPR Therapeutics is the sole owner of this therapeutic platform.

• OPF-310 (Otsuka Pharmaceutical): encapsulated islets derived from pigs in phase 1/2 clinical trials
• ENC-201-CED (Encellin): donor-derived islets in a proprietary encapsulation device implanted subcutaneously in a phase 1 clinical trial
• Gastrin: a phase 1/2 trial testing if gastrin, a naturally occurring hormone involved in pancreatic development, is safe and helps retain or grow islets following donor-derived islet transplantation