Two-Drug Combo Aims to Restore Insulin Production in Diabetes

Miriam E Tucker

July 02, 2015

Enrollment is set to begin for the largest-ever study to test a two-drug therapy aimed at restoring insulin production in people with type 1 diabetes.

The protocol combines two already-available generic oral drugs, the immunosuppressant cyclosporine and the proton-pump inhibitor omeprazole, to try to overcome the immune system attack on the pancreatic islets and promote beta-cell regeneration, respectively.

"We're not talking about replacing insulin. We're here to regenerate new islets with new pools of beta cells so the pancreas will manage blood sugars as it should. We're regenerating healthy functional pancreases," Claresa Levetan, MD, founder and chief scientific officer of Perle Bioscience, Charleston, South Carolina, told Medscape Medical News.

The initial proof-of-concept, open-label study will enroll 81 newly diagnosed type 1 patients at seven centers in Italy and, pending approval, two other countries. Subjects will be randomized to omeprazole alone or omeprazole plus low-dose cyclosporine, with the latter at a starting dose of 5 mg/kg, far lower than the doses used in organ-transplant patients in the 1980s and 1990s.

Subjects will take the two pills twice a day for 6 months. Glucose levels will be carefully monitored and insulin doses adjusted accordingly. Subjects who meet the primary end point of insulin independence will continue for another year, while the cyclosporine dose is titrated downward. Kidney function will be closely watched as well.

Asked to comment, long-time type 1 diabetes researcher Mark A Atkinson, PhD, director of the University of Florida Diabetes Institute, Gainesville, Florida, said there are myriad reasons why this approach is unlikely to work. However, he applauds Dr Levetan for thinking outside the box and said he would be happy to be proven wrong.

Mouse vs Human

Previous studies that have "cured" type 1 diabetes in rodent models using various immune-tolerance agents have failed when moved to human trials. Recently, scientists have recognized that mouse islets are far more tightly packed with insulin-producing beta cells than are human islets and far less vascular, thereby explaining the lack of success when trying to translate these findings.

Human islets are also more complex, secreting six different hormones that all play a role in glucose regulation, Dr Levetan explained.

In humans, she says, "our hypothesis is that you can't just suppress the immune response. You have to upregulate the beta cells....This will be the first large trial using an agent that has the potential to stabilize if not increase new islets by increasing gastrin, which is what the proton-pump inhibitors do. We're creating new islets from ductal progenitor [cells]."

"The concept is an interesting one," Dr Atkinson told Medscape Medical News. "If you go back to attempts dating back to the 1970s and 1980s to prevent or reverse diabetes, the vast majority have used monotherapy. And almost every one of those have used an immune-based agent....This is innovative in using a combination-based approach."

And, he added, "there's growing evidence that type 1 diabetes isn't just the result of an autoimmune disease, but there's likely a contribution of the beta cell as well as the pancreas itself to the disorder that has been underappreciated in the past....Those facets could...be very important."

But he cautioned that there is little proof in human adolescents and adults that the beta cells are capable of regenerating. "I'm not saying it's impossible, but the evidence to suggest that the human pancreas can regenerate in the setting of human type 1 diabetes is minimal at best."

Is Islet Regeneration Possible?

But Dr Levetan points out that there is one strong example of beta-cell regeneration in type 1 diabetes: during pregnancy, when the mother's immune system is downregulated so as not to reject the fetus as foreign.

Insulin requirements typically decline during the first trimester, and one study found that C-peptide levels had risen to the normal range by 10 weeks' gestation in 10 women who had type 1 diabetes for a mean duration of 21 years (Diabetologia 2000;43:1329-1330).

"Pregnancy is one of the rare times when you actually have islet neogenesis," she explained.

But Dr Atkinson isn't convinced, noting that the C-peptide production disappears almost immediately after birth. "What does that mean? It deregenerates? I would not, personally, view the data on pregnancy in those with type 1 diabetes as being unequivocally supportive. Indeed, studies of pancreatic pathology do not support that concept."

Beyond this, he said there is the problem of immune memory. "So even if you were to temporarily deplete the self-destructive cells with cyclosporine, it doesn't kill memory cells. Hence, over the long term, that forms a problem. I would predict that if a short-term benefit was observed, it would not last....I don't believe there's sufficient scientific evidence to be optimistic that this trial as proposed will work."

However, he said, "I give Dr Levetan kudos for her attempts to be innovative and challenge conventional ideas. We need more people who are unconventional, as they serve an important role. I would love nothing better than to be proven wrong."

Dr Levetan, on the other hand, is so confident of the approach that her company has already planned ahead. They're collaborating with researchers from Yale University on subsequent trials in patients with longstanding type 1 diabetes, using new patented peptides that are expected to be much more potent than proton-pump inhibitors in regenerating islets from ductal tissue. The plan is to test those in combination with even lower doses of cyclosporine.

She concludes: "I believe this is a new model for the future...not only to render patients insulin independent but to make pancreases function again."

Dr Levetan is founder and CEO of the company conducting the trial, Perle Bioscience. Dr Atkinson has no relevant financial relationships.

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