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Diamyd® in Type 1 Diabetes

The dominating hypothesis among diabetes researchers today is that the key to curing type 1 diabetes is to simultaneously tackle the disease on several fronts by combining various therapeutics or by providing treatment before onset of the disease. Combination therapies have, for example, played a decisive role in the advances made in cancer treatment in recent years. Many leading scientists also believe that future treatment of type 1 diabetes must involve a so called autoantigen, such as GAD, which is the active substance in the diabetes vaccine, Diamyd®. Diamyd’s vaccine has the advantage of being ready for clinical studies in children due to its favourable safety profile in earlier clinical trials and an established manufacturing process.

Two researcher initiated clinical studies with Diamyd® are in progress: A Swedish Phase II study, DiAPREV-IT, aiming to evaluate whether Diamyd® can prevent or delay type 1 diabetes in children who are at high risk of developing the disease and; a Swedish Phase II study, DIABGAD-1, where Diamyd® is tested in a unique combination with relatively high doses of vitamin D and the anti-inflammatory drug ibuprofen in newly diagnosed type 1 diabetes children and adolescents, aiming to potentiate the effect of the Diamyd® diabetes vaccine to preserve the body´s own ability to control the blood sugar level.

DiAPREV-IT
The DiAPREV-IT study started in 2009, and is a double-blind, placebo-controlled Phase II study including a total of 50 children aged four and older who through analysis of diabetes markers, so-called auto-antibodies, in the blood are demonstrated to be at high risk of developing type 1 diabetes. Half of the children receive two injections of Diamyd®, and the remaining half receive placebo (inactive substance). The children will be monitored for a total of five years by means of sampling and glucose tolerance tests to evaluate the beta cell function, a measure of the body's own ability to regulate blood sugar. The study was fully enrolled in January 2012 and the first results are planned to be available during 2015, i.e. 3 years after the last subject was enrolled.

Preventive treatment with the diabetes vaccine Diamyd® is intended to intervene in the autoimmune process at an early stage, and thus prevent the disease from developing. Today there is no treatment that can halt the progress of disease in type 1 diabetes.

The study is being conducted by a research group at Lund University and is led by Dr. Helena Elding Larsson, a pediatrician in Malmö and researcher at Lund University. The study is funded by research grants. Diamyd Medical has participated in the design of the study, is responsible for providing study drug, and can utilize the study results.


DIABGAD-1
The DIABGAD-1 study started early 2013, and is a double-blind, randomized and placebo-controlled Phase II study including a total of 60 participants between 10 and 18 years old, newly diagnosed with type 1 diabetes. The study will comprise a total of 30 months, with a first analysis focusing on immunological markers already after 6 months.

The study, which is the first study of its kind, combines the diabetes vaccine Diamyd® with relatively high doses of vitamin D and the anti-inflammatory drug ibuprofen. The purpose of the treatment is to preserve the body's own ability to control the blood sugar level in children and adolescents newly diagnosed with type 1 diabetes.

Four different treatment groups, each including 15 participants, will be evaluated: the first group will receive one prime injection of Diamyd® and a booster injection 4 weeks later, combined with ibuprofen for 90 days and vitamin D for 450 days; the second group will receive one prime injection of Diamyd® and a booster injection 4 weeks later, and vitamin D for 450 days; the third group will receive two prime injections of Diamyd® and two booster injections 4 weeks later, and vitamin D for 450 days; and the fourth group will receive placebo only.

The study will also evaluate the effect of a double dose of Diamyd® and the protein GAD.

The study is being conducted at several pediatric diabetes clinics in Sweden and is led by Professor Johnny Ludvigsson, at Linkoping University. The study is funded by research grants. Diamyd Medical has participated in the design of the study, is responsible for providing study drug and to cover certain other costs, and can utilize the study results.


PREVIOUS CLINCIAL STUDIES
In May 2011 Diamyd reported results from a European Phase III study with Diamyd® including more than 320 young patients with recent-onset type 1 diabetes. The study did not show a statistically significant preservation of beta cell function after 15 months of follow-up compared to placebo, although a small positive effect was seen. Furthermore, Diamyd® was well tolerated as demonstrated by a similar number of adverse events across treatment groups. In June 2011, the Company decided not to complete the follow-up period of the European Phase III study of Diamyd® and to also initiate the closure of a parallel US Phase III study. In June 2011, results of a Phase II study with similar design conducted by the research consortium Type 1 Diabetes TrialNet were presented. The study did not show a statistically significant effect of the study drug. The European Phase III study was published in February 2012 in The New England Journal of Medicine and the TrialNet Phase II study was published in July 2011 in The Lancet.

In 2008, Diamyd Medical reported positive results from a 30-month, randomized, double-blind, placebo controlled, Phase II study of 70 children and adolescents with type 1 diabetes. Significant long-term efficacy was demonstrated in preserving beta cell function, i.e. endogenous insulin producing capacity. The treatment was well received by patients, their doctors and family members. No serious side effects related to the treatment were reported in the study. The study was published in the fall of 2008 in The New England Journal of Medicine.

In the years 2010 to 2012, several competing firms have reported limited efficacy in other Phase III studies using other compounds than GAD to try to preserve beta cell function in type 1 diabetes patients. This has led the diabetes scientific field to lean towards trying combinations of drugs to attack this complex disease from several angles to try to intervene in the autoimmune disease process underlying type 1 diabetes, or, to try to intervene earlier in the disease process in order to prevent type 1 diabetes in persons at high risk of developing the disease.

Lessons learned are guiding the future development of Diamyd® and GAD. Ways forward being explored include combining GAD with other drugs, administering GAD earlier in the disease process to prevent type 1 diabetes, and different treatment regimens or new formulations of GAD.

The dominating hypothesis among diabetes researchers today is that the key to curing type 1 diabetes is to simultaneously tackle the disease on several fronts by combining various therapeutics or by providing treatment before onset of the disease. Combination therapies have, for example, played a decisive role in the advances made in cancer treatment in recent years. Many leading scientists also believe that future treatment of type 1 diabetes must involve a so called autoantigen, such as GAD, which is the active substance in the diabetes vaccine, Diamyd®. Diamyd’s vaccine has the advantage of being ready for clinical studies in children due to its favourable safety profile in earlier clinical trials and an established manufacturing process.

Accordingly, the continued development of the Diamyd® diabetes vaccine is primarily taking place via researcher-initiated, externally funded studies in which Diamyd provides the vaccine. Two researcher-initiated Phase II trials of Diamyd® are currently in progress. One study evaluates whether the diabetes vaccine can prevent type 1 diabetes in children who are at high risk of developing the disease and one study evaluates whether Diamyd® in combination with relatively high doses of vitamin D and ibuprofen, can preserve the body’s own ability to regulate the blood sugar level in children and adolescents newly diagnosed with type 1 diabetes.