_Against type 1

Quick non-expert takes on research about insulin-dependent diabetes

Beta cells get clinical. The FDA has approved the first clinical trial with the insulin-producing beta cells pioneered by Douglas Melton’s lab at Harvard. Vertex Pharmaceuticals will test the cells among about 17 people with unusually difficult-to-manage type 1 diabetes (T1D), who will be given immunosuppressive drugs to protect the cells. Vertex sees an opportunity for these infusions among roughly 60,000 people in the U.S. and Europe.

Back in 2014, Melton and colleagues published a landmark Cell paper showing that highly functional beta cells developed with stem cell techniques could be produced in volume. Since then, there’s been a steady march of progress in many labs. Melton is among the experts who tell me that this challenge basically has been met.

Assuming the Vertex trial is successful, the next step will be to place the cells inside an implantable device that can ward off the immune system while still allowing the cells to work properly. Here the potential market is much larger, about 2.6 million people by company estimates. But the uncertainty is much greater, because implantable devices for cell therapies have never worked in people, despite decades of attempts.

Vertex bought implantable device research along with the Melton cell technology in its 2019 acquisition of Semma Therapeutics. “Semma has developed a very clever and effective encapsulation device,” Melton told me in an interview that July for a Knowable story. “I’ve never seen a device show such good results in rats and pigs and monkeys.”

Earlier that year when I talked with Semma president Bastiano Sanna for a story in The Scientist, he showed me a prototype of the core device component, which looked much like a silver-dollar-sized bandage. However, Sanna wouldn’t discuss how it worked.

In June 2019 at the International Society for Stem Cell Research annual meeting, Semma’s Felicia Pagliuca presented research showing that the device worked well in pigs. However, the company apparently never published these results.

Semma originally acquired its implantable device technology by purchasing CytoSolv, a Rhode Island startup aiming to commercialize research at Brown University. Those more gifted than I at interpreting patents may find hints at the device design in three Semma patents: WO2019178134A1, US20190201323A1 and US20200289407A1 (the latter two pending).

It’s great that Vertex is throwing its resources behind this work for a T1D “cure”. It’s also great that other firms are on similar paths, especially since Vertex products don’t come cheap (more than $300,000 a year for a cystic fibrosis drug package).

Among the rivals is Viacyte, the first company to launch clinical trials of device implants with stem-cell-derived beta cells, where new executives were appointed this week.* Sigilon Therapeutics creates therapies in which cells are protected by alginate microspheres and has launched a clinical study in hemophilia. The company is working towards a T1D trial led by partner Lilly (speaking of astonishingly high drug prices!). There also are numerous smaller entries such as Sernova, now running an apparently successful early trial for T1D with its Cell Pouch and immunosuppressive drugs. Good luck all! 1/30/21

* Viactye is launching another clinical trial without immunosuppressive drugs, using encapsulation membrane technology developed by W. L. Gore. 2/5/21

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Not throwing away our shots. Thirty years ago as Sufyan Hussain grew up in Pakistan, the daily standard of care for type 1 diabetes (T1D) was two shots of insulin, with only blunt color-coded urine tests of glucose levels. Today, hundreds of the patients he sees in a London clinic get much better care with insulin pumps and frequent blood tests.

But unfortunately, the worldwide standard of care for T1D is very much like what he received as a boy, Hussain said during an International Diabetes Foundation Europe meeting on Friday. Even today, only a tiny percentage of his patients have continuous glucose monitors, for instance.

This point was hammered over and over by patients and experts at the IDF forum: Access to best diabetes care typically is way too expensive, if it’s available at all.

“Even access to insulin is still difficult,” Hussain said, as the forum celebrated the centennial of the hormone’s discovery.

That’s true even in the U.S., where more than 8 million people use insulin but list prices are an order of magnitude higher those in many other countries.

Despite a lot of sound and fury, the federal government has done nothing to fix the pricing problem, which adds billions of dollars to its own annual budget. “A cost analysis found that Medicare Part D spent an estimated $7.8 billion on insulin products in 2017,” as Medpage reported. “If the agency had used [Veterans Administration]-negotiated prices, it would have spent only $5 billion, saving nearly $3 billion.”

Medicare is prohibited from doing so, and despite the uproar about drug costs, the pharmaceutical lobby still dominates Congress, which is still easily puzzled about health as a human right.

At the state level, a California bill passed last fall will create an agency designed to procure affordable insulin and other difficult-to-access drugs. It’s not clear, though, what the FDA will require to approve those drugs or whether the state’s effort will be stomped by legal assaults. (The feds, of course, are immune from legal challenge on the patents that they grant.)

Maybe the National Institutes of Health should take a small fraction of those billions thrown away each year and create a MoonShots initiative to create genuinely next-generation insulins.

Maybe those drugs could be smart insulins, which automatically adjust to blood glucose levels, a longstanding dream that never seems to make it through early clinical trials. Or, much closer to home, maybe they could be oral insulins. This week Oramed Pharmaceuticals launched a phase 3 study of its ORMD-0801 capsule for people with T2D. This seems to be the only oral insulin headed for approval, but surely other promising approaches are lurking in the labs.

MoonShots could generate open-source insulins made inexpensively by manufacturers anywhere, for people with diabetes anywhere, who now number almost half a billion. 1/24/21

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Mixing up a cure. Last week Prevention Bio asked the Food & Drug Administration to approve teplizumab for people at high risk of type 1 diabetes (T1D). Teplizumab will be the first drug to delay the onset of the disease among people at high risk, as shown in a phase 2 clinical trial.

The drug is a monoclonal antibody that targets CD-3, a receptor protein that can activate T cells expressing the CD-8 receptor. Those cells are thought to be the main players attacking insulin-producing beta cells in pancreatic islets and triggering T1D. Exactly how teplizumab works, and on whom, is very much under study.

To date, more than 2100 clinical trials have tried to stop T1D, notes a Biomolecules review published in December by Gabriel Brawerman and Peter Thompson of the University of Manitoba in Winnipeg. Almost all of the trials, understandably enough, aimed to fiddle with the immune system.

However, “a growing body of evidence supports the idea that beta cell dysfunction is just as critical as the autoimmune process, and that T1D is also a disease of the beta cells/islets,” Brawerman and Thompson write. “Thus, a new emphasis on beta cell drug therapies could be an exciting avenue to reduce beta cell death, restore beta cell function and avert T1D onset.”

“The classic view is that autoreactive T cells mistakenly destroy healthy (‘innocent’) beta cells,” say Bart Roep of the City of Hope in Los Angeles and colleagues in a December Nature Reviews Endocrinology paper. “We propose an alternative view in which the beta cell is the key contributor to the disease.”

Researchers led by Decio Eizirik of the Indiana Biosciences Research and Université Libre de Bruxelles continued the theme last week in a Science Advances paper. “There is increasing evidence that the target tissues of these diseases are not innocent bystanders of the autoimmune attack but participate in a deleterious dialog with the immune system that contributes to their own demise, as shown by our group and others in the case of T1D,” the scientists declare.

Eizirik’s team examined gene expression in the tissues under autoimmune attack in T1D, lupus, multiple sclerosis, and rheumatoid arthritis. Among their findings, the scientists pinpointed a number of genes that are highly expressed in the tissues for some or all of these conditions, many of these genes related to local inflammation. Moreover, more than 80% of the top risk genes show changes in expression among the tissues at risk rather than among immune cells. “These observations suggest that future research on autoimmune diseases should focus on both the immune system and the target tissues, and on their dialog,” they conclude.

So, combining beta cell therapies with immunotherapies indeed will be a promising avenue of research. “However, the use of combination therapies would not be without its challenges in the clinic,” Brawerman and Thompson write. “Each of the therapies alone present a distinct set of risks for adverse side-effects… A further limitation to implementing combination therapy in T1D could stem from the unpredictability of the effects of the one therapy on the other cell type.”

“Our understanding of T1D will continue to evolve and be refined due to advancements in experimental tools and approaches,” the Manitoba biologists conclude. “But progress will also depend on the willingness to challenge dogma and long-held assumptions about T1D.” 1/9/21