Overcoming Obstacles in Pursuit of a Vaccine for Type 1 Diabetes

-Sony Salzman

Nobody said developing a vaccine for type 1 diabetes would be easy, but that hasn’t stopped the Swedish biotech company Diamyd Medical from doggedly pursuing its antigen-specific immunotherapy for the past 25 years.

This quest began with the company’s founder and first CEO, Anders Essen-Möller, whose daughter was diagnosed with type 1 diabetes in 1991. Already an accomplished biotech entrepreneur, Essen-Möller staked his next venture on the promise of immunotherapy and formed Diamyd Medical.

Type 1 diabetes is an autoimmune disorder with limited treatment options — it is generally managed, rather than treated. Meanwhile, other autoimmune disorders, such as rheumatoid arthritis and psoriasis, are treated with a range of medications that target a patient’s immune system. These medicaments (a technical term for a wide range of substances used for medical treatments) are also associated with substantial risks for side effects, as the immune systems become generally suppressed.

In pursuit of a type 1 diabetes therapy that harnesses the immune system, Essen-Möller landed on a protein called GAD65, a molecule that is abundant in the nerve system as well as in pancreatic beta cells, a self-structure, that can be targeted by the immune system, thus becoming an autoantigen. The rights to the then newly sequenced autoantigen was licensed from UCLA, as researcher Professor Dan Kaufman there had been able to show that GAD could prevent diabetes from developing in an animal model. It was believed the GAD protein could one day form a treatment or vaccine for type 1 diabetes.

With the help of pharma giant Johnson & Johnson, Diamyd Medical brought its candidate (also called Diamyd) through to Phase III trials, where it faced a setback. It failed to demonstrate a clinically meaningful effect on the preservation of beta cell function more than a year after administration of the drug.

Back to the drawing board

After those disappointing results were announced in 2011, Diamyd Medical’s executives went back to the drawing board.

First, they realized that the drug worked better in trial participants in non-Nordic countries, and they also recorded a greater effect among people who did not receive the flu vaccine against influenza A (H1N1), also known as the Swine flu, at the same time as the Diamyd injection. This suggested that the flu vaccine may have interfered with its effectiveness.

Backed up by a world-wide continued interest in the GAD65 protein and its role as biomarker of type 1 diabetes from some of the world’s top scientific experts in the field — among them Professors Mark Atkinson (University of Florida, US), (Johnny Ludvigsson (Linkoping University, Sweden) and Åke Lernmark (Lund’s University, Sweden) — Diamyd Medical decided to reexamine its data and chart a path for the future. Pulling data together from all conducted studies (a meta-analysis), it was found with a 98 percent probability that the Diamyd therapeutic has a positive biological effect on the preservation of the insulin producing beta cells.

Diamyd Medical CEO Ulf Hannelius

In particular a pilot trial named DIAGNODE-1 used the novel approach to inject the compound directly into the lymph node. By the end of 2016 interim reports from the DIAGNODE-1 had shown quite positive and clinically meaningful results. The company, led by CEO Ulf Hannelius, PhD, MBA, now decided to relaunch efforts and raised new capital for a larger placebo-controlled European Phase II trial, DIAGNODE-2.

According to Hannelius, patients feel confident enrolling in the DIAGNODE-2 study because of the drug’s well-established safety profile, as already demonstrated in studies with more than 1,000 patients.

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In general, autoantigen-specific therapy (one that uses GABA molecules derived from the patient themselves) is considered “very safe,” says Hannelius. As the development program continues, the company is “getting more and more contacts from patients from around the world who want to get access to the therapeutic.”

By November 2018, 11 out of the 12 patients enrolled and treated with Diamyd in the pilot trial DIAGNODE-1 were in partial remission of type 1 diabetes approximately 18 months after diagnosis of the disease — a major victory for the embattled company!

Accepting the Diabetes Innovation Challenge

In 2016, Diamyd Medical was chosen as a semi-finalist in that year’s Diabetes Innovation Challenge presented by T1D Exchange and M2D2, and supported by the American Diabetes Association and JDRF. The company participated in the “Preclinical and Translational Projects” category with its project proposal based on the therapeutic use of GABA in long-term type 1 diabetes patients.

The Diabetes Innovation Challenge was part of the decision to develop Remygen, a second candidate drug. While Diamyd is turning off the autoimmune inflammation, Remygen is thought to stimulate growth of the now-surviving insulin producing cells. In October 2018, an investigator-initiated trial was launched in Sweden to evaluate the safety of Remygen and its effect on the ability to regenerate insulin-producing beta cells.

 A promising path toward a cure

If Diamyd is eventually approved, type 1 diabetes patients may want to use it for halting the autoimmune destruction of any remaining or regenerated beta cells. This in turn will allow for beta cell regeneration medicaments such as Remygen to hopefully fully eliminate the need for insulin injections. For pre-diabetic patients or those with a genetic predisposition for the disease, there is a potential to halt the destruction of beta cell function before the onset of clinically open (insulin-requiring) type 1 diabetes.

According to Hannelius, the long history of Diamyd Medical’s clinical research program has been a double-edged sword. On the one hand, the candidate’s safety profile is well-established, and new data certainly seems to be encouraging.

On the other, the failed Phase III trial means “we sort of have had to prove our case probably a bit more,” he says. Though the company has pivoted over the years, Hannelius says Diamyd Medical’s mission hasn’t changed since 1994.

“Our mission is to cure type 1 diabetes,” Hannelius says, “and we are closer than ever to reach that goal.”

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