Vertex Pharmaceuticals, a global biotech company and forerunner in stem cell-derived therapies for people living with type 1 diabetes (T1D), announced promising 90-day data for their first human subject in a phase 1/2 clinical trial of VX-880 — an investigational, allogeneic human stem cell-derived islet cell therapy. The results are truly remarkable, with Vertex reporting a 91% decrease in daily exogenous insulin requirements, with the individual receiving only half of the targeted VX-880 dose.

Following receipt of Fast Track designation for VX-880 therapy from the FDA in March of this year, Vertex began this single-arm, open-label study for individuals living with T1D and severe hypoglycemia or impaired hypoglycemia awareness, in addition to other designated criteria. Vertex will enroll 17 patients in this multi-part clinical trial to evaluate the efficacy of VX-880, which is set to be administered in a variable dosing regimen. Efficacy of this novel therapy is being measured through c-peptide levels, glucose and HbA1c values, and exogenous insulin needs of human subjects.

VX-880 is an allogeneic cell therapy. As a result of this, immunosuppressive drugs are required to protect stem cells from the subject’s immune system during this phase of the clinical trial. In 2022, Vertex plans to file for investigational new drug (IND) status for their encapsulated islet cell program.

Phase 1/2 of VX-880 clinical trial continues in the U.S.; more information about the study and enrollment can be found here.

T1D Exchange Q&A with Felicia Pagliuca, PhD, Disease Area Executive, Type 1 Diabetes, Vertex Pharmaceuticals

Felicia Pagliuca, PhD, is the Disease Area Executive for T1D at Vertex, responsible for the overall program strategy and execution of T1D therapies. Previously, she co-founded Semma Therapeutics with a mission to develop transformative cell therapies for T1D; Vertex acquired Semma in 2019. Prior to Semma, Pagliuca completed her postdoctoral fellowship with Douglas Melton, PhD at the Harvard Stem Cell Institute, where she discovered how to generate stem cell-derived pancreatic beta cells. Pagliuca is a scientist, entrepreneur, and drug developer.

What is Vertex’s mission and timeline with T1D therapies?

As exciting as the last decade has been in this space, the next decade is going to be even more so, especially now that we know these cells work — It’s just incredibly exciting. Vertex has developed transformative medicines for cystic fibrosis, and our mission with T1D is no less ambitious.

We’re starting with VX-880, which is the trial that we reported on just this week. For the very first time, this trial brings fully differentiated insulin-producing stem cell-derived islets into the clinic. It’s a core cell therapy that we think has the potential to address the underlying cause of the biology of T1D — the absence or destruction of native pancreatic islets.

This study is in phase 1/2, and we’re very excited to move the program forward as quickly as we can. It is admittedly early in development, and as a result we’re still working through processes for it to become an approved medicine — but we’re very optimistic. There’s so much unmet need in T1D; your community knows that inside and out, and we echo those voices. Second, we know the product has a potential to have a profound clinical impact. With these two pillars, we think we can move with great urgency towards developing and launching this as a medicine.

What is cell therapy?

Cell therapy in essence is a living medicine. In some diseases, the ability to reverse or cure the disease requires a more sophisticated solution than we can provide with a pill or an injection. It really relies on a complex cellular function. In these cases, we’re designing cell therapies to replace the missing or destroyed function of those cells in the body. With T1D, of course that’s the insulin-producing cells in the islet — the beta cells.

What’s so unique about these cells is that they have an intrinsic circuitry of being able to turn insulin off and on when blood sugar levels change. We just can’t replicate that with injected insulin, mechanical pumps, and CGMs. While these tools are helpful, the only way to replicate natural biology is by putting the missing cells back.

Using a patient’s own cells (autologous cells) isn’t an option in T1D. The cells are destroyed, so there’s no autologous source. Cells must be sourced from a donor or be manufactured. What’s exciting about allogeneic cell therapies is that we can start with a single cell line — or bank of these cells — and use that to produce as many doses needed. Developing scalable, off-the-shelf therapies has been a real focus area for us at Semma and Vertex.

Please describe the role immunosuppression therapy plays in this study.

This first therapy is the cells on their own, not cells in a device or gene-edited cells, which are to come. Immunosuppression is necessary to protect the cells from the immune system (similar to an organ transplant). Patients will continue to take immunosuppressant medications for as long as the cells are providing them benefit.

The calculus for any medicine is a benefit/risk ratio, and that is one of the reasons our focus for the first therapy is for those who have severe hypoglycemia or recurrent severe events. This is a group of people who have been eligible for cadaveric islet transplants in the past, and we know that can provide tremendous benefit to these patients, but they have limitations. Not least of which, is donor availability, but also consistency, quality, and the ability to give an effective dose for clinical benefit. We can solve all of these things with a manufactured cell.

With cell or gene therapy, manufacturing is at the core of the entire program. At Vertex, we’re invested in hiring the best people in cell therapy manufacturing, and we’re building a 270,000 square-foot facility in Boston for research and manufacturing of T1D cell therapies. That’s a signal of how committed Vertex is and how excited we are about the potential for this medicine.

What is cell engraftment?

VX-880 is infused into a patient’s body through the portal vein (a blood vessel that goes into the liver). They engraft, or stay, in the liver and become surrounded by blood vessels enabling them to do what they’re designed to do. The vessels provide all the nutrients they need to survive, and they’re able to sense changes in blood glucose levels and secrete insulin on demand.

We’re so excited that the cells are surviving in patient 1, and that they’re doing exactly what we hoped they would do in terms of replacing lost islet functioning. With our first patient needing 91% less exogenous insulin, it tells us unambiguously that these cells are working in a manner that can change the clinical course for this individual. We’ll follow this patient for a long time to track the performance of the cells; their diabetes management will continue in conjunction with their endocrinologist.

We’ve seen from cadaveric islet transplant that once you infuse these cells and they settle into the liver, that they can last for a very long time. We also know that beta cells (in a person without diabetes) are some of the longest living cells in the body, so when we put replacement cells back in the body, we’re optimistic that they’ll have a long durability. Of course we have to test this in our clinical trials, but it’s interesting to look at the data that’s already out there.

Measuring study successes

There are three things that we want to understand in the initial phase of the clinical trial: If the therapy is safe, if the cells actually work, and if the therapy matters to an individual’s clinical experience.

As you saw in the press release, it’s been very well tolerated so far, and that’s important for such a novel therapy. It’s the first time that anyone’s ever put a fully differentiated, insulin-producing islet manufactured in a lab — into a person. Although our preclinical data suggests that they’re bonafide cells, we needed to know if they’ll work like a real islet when they’re inside a patient.

We used mixed-meal tolerance testing to measure this. With overnight fasting, we can measure c-peptide levels to see if the cells are producing basal insulin, which is so important to glycemic control. This is followed by a meal to see if the cells produce more insulin in response — which is what you’d expect from a bonafide islet. What we saw from clinical data is that these cells are making basal insulin as expected, and they can be stimulated to produce even more insulin with a meal.

Finally, we needed to know if the cells were working well enough to have meaningful health impacts for an individual patient. This is why we’re looking at efficacy measures such as how much exogenous insulin is needed, glucose control and A1c, and of course other measures that we’ll report on at future medical and scientific conferences.

The clear answer is that every measure we’ve looked at for efficacy, shows that these cells work in a clinical setting; the clinical outcomes we’re seeing in patient 1 are profound. Because this individual was taking 91% less insulin and the glycemic control was getting better and better, it tells us that we are absolutely on the right track with the medicine itself — the cells, the dosing, and the administration.

The initial patient received 1/2 of the dosing schedule for VX-880— will the remainder of participants receive full doses?

Our clinical protocol was designed in a thoughtful and methodical way, engaging with FDA and other regulators. In this design, the first and second patients will receive 1/2 doses to ensure safety and tolerability, then we’ll move into full target dosing.

What are the next steps for the encapsulated islet cell program?

Encapsulation is the next program in our pipeline. As much as we have advanced the science of cell biology and stem cell biology over the last decade, we’ve done exactly the same thing in encapsulation — in developing novel devices that can protect these cells from immune destruction, allowing us to deliver them to people living with T1D without immunosuppression.

This program is headed to an investigational new drug application (IND) with the FDA next year, which would allow us to do the same thing that we’ve done with VX-880. We can start this clinical trial and test these same cells that we’ve shown have hallmarks of being bonafide, glucose responsive insulin secreting cells — inside an encapsulation device and bring those cells back to people with T1D.

We’re so close on the second program in our pipeline, and because the cells are a common link, the early data we’re seeing in the VX-880 gives us enormous confidence about our encapsulated islet program.

What’s the takeaway message in terms of hope for the T1D community?

We are right there with the T1D community in wanting to move as quickly as we possibly can and get these therapies to patients — it’s been the driving force for all of us. The hopeful message here is that we’re in a clinical trial with our first therapy today — and it’s working — it’s early, but it’s working. We’re getting as close as we’ve ever been.

Finally, I want to thank the T1D community. As a scientist, research is so exciting, but it doesn’t mean anything unless we have clinical research participants. I’m so grateful for people living with T1D that are participating in clinical studies. They are the bridge between exciting science and a medicine that can help many people.