When Doug Melton, Ph.D., began his mission to develop an insulin-producing beta cell from a stem cell, he predicted it would only take four or five years. Fortunately, he didn’t give up — because that first critical step took nearly 20 years, and the research is still ongoing.

Today, his research led to the development of VX-880 and VX-264 from Vertex Pharmaceuticals, two investigational stem cell-derived therapies in clinical trials intended to completely change how type 1 diabetes (T1D) may be treated.

Ongoing Vertex T1D Clinical Trials

  • VX-880 (Phase 1/2): This clinical trial is investigating infusing manufactured insulin-producing beta cells used with immunosuppression therapy with the aim to protect the beta cells from the T1D autoimmune attack.
  • VX-264 (Phase 1/2): This clinical trial is investigating the surgical implantation of a small device that is designed to be immunoprotective containing manufactured insulin-producing beta cells into the body of a person with T1D. The device is being researched to see if it could protect the insulin-producing cells from a T1D autoimmune attack, with the aim of eliminating the need for immunosuppressive therapy.
  • Note: Both VX-880 and VX-264 are investigational products and are not approved by any health authority. Safety and effectiveness of both VX-880 and VX-264 have not been established.

A little more than 30 years ago, diabetes research had never crossed Dr. Melton’s mind. It wasn’t until his son Sam’s diagnosis at the age of 6 months old that he turned his focus to T1D. His daughter, Emma, was also diagnosed with T1D several years later at age 14.

Fast forward three decades: Dr. Melton is one of the world’s leading stem cell researchers, a former Harvard professor and researcher, Founder of Semma Therapeutics, and the Scientific Co-Founder of Gilead Sciences. Vertex Pharmaceuticals acquired Semma Therapeutics in 2019 for nearly $1 billion to continue Dr. Melton’s work in developing a potential treatment for T1D.

Dr. Melton joined Vertex full-time in 2022 as Distinguished Research Fellow to continue his goal: changing outcomes for people living with T1D.

Discovery science takes time

“My 6-month-old son was so ill that no one at our great hospital knew what was wrong with him,” Dr. Melton tells T1D Exchange. “They thought he had spinal meningitis, and he was about to expire. They asked us to leave the room at one point, and then he peed. A very smart nurse did a dipstick in his urine for sugar and said, ‘He has diabetes!’”

“My wife, Gail, said, ‘You better do something about this!’” recalls Melton. “So, I switched my lab from researching frog biology to focusing on type 1 diabetes. Every parent wants to do something after their child is diagnosed, but I was fortunate enough to be in a position to think about a potential scientific approach to the problem.”

“I would guess it cost us about $50 million dollars,” says Dr. Melton on achieving that first step of turning a basic stem cell into an insulin-producing cell — thanks to tremendous support from many colleagues and the dedication of his research students in the Melton Lab.

One colleague in particular — Felicia Pagliuca, Ph.D. — was part of the final step in the lab when the team figured out how to make the stem cell-derived islets cells they were creating secrete insulin. Dr. Pagliuca introduced herself to Dr. Melton when she was earning her Ph.D. as a student at Cambridge University in the UK.

“I went to Doug’s seminar about stem cell research,” recalls Dr. Pagliuca, who serves at Vertex today as the Type 1 Diabetes Disease Area Executive. “I remember sitting and listening to his idea that medicine has always been thought of as a way to kill cancer cells, but maybe we could use cells as a way to treat and cure diseases. It was a lightbulb moment and an opportunity in science that had never been pursued before with the potential to truly impact people’s lives.”

Dr. Melton was told over and over by other experts in stem cell research that his goal was impossible — that you can’t create functional cells in a petri dish, it has to happen in the body. Dr. Melton and his team of many scientists, involving tens of graduate students, research assistants, some undergraduates, and postdoctoral fellows, including Dr. Pagliuca, weren’t deterred, despite numerous snags and scientific setbacks.

The small-but-mighty team spent countless hours nurturing cells until the cells behaved the way they wanted them to behave — producing insulin.

A stem cell is just a blank slate

“You start with a stem cell that you can duplicate over and over,” explains Dr. Pagliuca. “It’s important because you need trillions of cells. But you need to grow and expand these cells while keeping them very high quality.”

The original stem cell is a blank slate; ambitious scientists work for years developing a recipe to essentially tell the cell what they want it to do and become.

“We figured out how to turn off or on certain genes, certain functions,” explains Dr. Pagliuca. “Then we need it to become something very specific that replicates something from the pancreas. We do this by carefully adding certain molecules while it’s living in a liquid that provides the nutrients and oxygen it needs to thrive. There are many, many steps to turn it into exactly what you want.”

Dr. Melton’s team succeeded. They were able to produce insulin-producing cells without the need for organ donation in the lab, making it a possibility to be reproduced for research in human clinical trials. But this was just the first step. Next is battling the immune system of a person with T1D, which will surely attack and destroy the cell upon its first encounter.

To pursue the next step, Dr. Melton founded Semma Therapeutics in 2014.  A key component of Semma was building a strong scientific team, and Melton was delighted that Dr. Pagliuca agreed to join and help lead the science at the biotech company. Over the course of five years, their work at Semma (a portmanteau of Dr. Melton’s children, Sam and Emma) focused on developing their stem-cell work to the point of readiness for human trials.

“We needed to move beyond the lab and academic space,” explains Pagliuca. “We needed to assemble a team with a variety of expertise, including manufacturing and clinical trials. We really focused on the translational work of reaching clinical development.”

Trusting a pharmaceutical company with their work

Dr. Melton recalls sitting next to David Altshuler, M.D., Ph.D., Executive Vice President of Global Research and Chief Scientific Officer at Vertex Pharmaceuticals, during a Massachusetts General Hospital board meeting. Dr. Altshuler was one of his former students at Harvard.

“I showed him a vial of beta cells I was carrying in my pocket that we had manufactured in the lab,” says Dr. Melton. Within just a few months, Vertex Pharmaceuticals acquired Semma Therapeutics.

“I’m convinced Vertex is the place to hopefully solve this problem,” explains Dr. Melton. “Vertex has an unusual commitment to do research to fix a disease, and they stick with it.”

Vertex has developed treatments for cystic fibrosis and hopes to do the same in sickle cell disease and beta-thalassemia, pain, and T1D, among others. This commitment to T1D convinced Dr. Melton to leave his work at Harvard. He also trusted that the company’s driving motivations were science-backed and patient-focused.

“Vertex is also run by physician-scientists,” adds Dr. Melton. “The Chief Executive Officer, Reshma Kewalramani, M.D., FASN, is a physician-scientist, the Chairman of the Board of Directors, Jeffrey Leiden, M.D., Ph.D., is a physician-scientist, and of course, the Chief Scientific Officer is a physician-scientist, on and on.” Most executive and board member positions at Vertex are held by people with backgrounds in medicine and research.

“Everyone,” adds Dr. Pagliuca, “is aligned on what really matters. And we’ve continued to optimize every single piece of the process.”

What keeps Drs. Melton and Pagliuca busy today?

Today, Drs. Melton and Pagliuca are leading different endeavors within Vertex — but both are still focused deeply on changing lives for people with T1D.

“I oversee all of our programs in diabetes, from research to commercialization,” explains Dr. Pagliuca, who is essentially preparing for the day when a potentially life-changing product is hopefully available to be administered to people with T1D once the study is complete.

“It’s my job to make sure we are investing in each of these puzzle pieces now. We don’t just stop with research or clinical trials. We need to work all the way through the development process for this science to eventually reach patients.”

Dr. Melton, on the other hand, is busy pursuing the next Herculean task: creating an insulin-producing cell that’s invisible to the T1D immune system.

“We need to make universal cells,” explains Dr. Melton, universal in the sense that they can survive in any patient. “I feel that we are on our way with continued research ongoing for the first problem— we can make beta cells in the lab. Next is to prevent rejection.”

They won’t stop until they’re done

Dr. Melton believes in setting truly ambitious long-term goals and seeing just how close he can get to them.

The reality is that living with T1D is a precarious, all-consuming, hour-by-hour game of survival. In the long term, it threatens every organ in your body. Short-term, it can kill you at a moment’s notice. For Dr. Melton and Dr. Pagliuca, this is an area long overdue for therapeutic innovation.

“My children have long been my motivation and guiding light for my T1D research journey; they’ve instilled in me an unwavering commitment to bringing potentially transformative therapies to people living with T1D,” said Dr. Melton.

“What we’ve seen so far in our research and ongoing clinical study is nothing short of remarkable, and we are endlessly optimistic about what lies ahead for this community.”