Marlene Busko

June 26, 2017

SAN DIEGO — The tyrosine kinase inhibitor imatinib that suppresses the immune system and is approved to treat chronic myelogenous leukemia and a few other cancers may help to preserve some beta-cell function in people newly diagnosed with type 1 diabetes, an early study suggests.

Stephen Gitelman, MD, from the University of California, San Francisco, presented initial 1-year findings from this 2-year randomized phase 2 clinical trial of 67 adults, at the recent American Diabetes Association (ADA) 2017 Scientific Sessions.

"We feel that imatinib is a novel, promising therapy based on the findings that adults with new-onset type 1 diabetes treated for 6 months had improved beta-cell function...and reduced exogenous insulin needs out to 12 months," he reported, adding that overall, imatinib was well tolerated.

"This is the first time this class of drug has been evaluated in a randomized clinical trial in type 1 diabetes, [and] the results are preliminary but encouraging," Dr Gitelman told Medscape Medical News in an email.

However, this is still initial research, he stressed. "This could one day be a treatment for type 1 diabetes, but this remains very early days, and we need to work through [certain issues] and conduct larger studies before the US Food and Drug Administration [FDA] will consider this further."

Early Promise in Mouse Studies

Type 1 diabetes results from the autoimmune destruction of insulin-producing beta cells in the pancreas, and the question this type of research tries to answer is "What can we do to make beta cells great again?" Dr Gitelman explained in his presentation.

Imatinib is one of the "rare agents" that can not only prevent diabetes but can also reverse diabetes in nonobese diabetic mice (Proc Natl Acad Sci. 2008;105:18895-18900), he noted. "Furthermore, if you treat for 10 weeks and then withdraw treatment, at least half the mice remain in remission."

Thus, the current study aimed to evaluate the safety and efficacy of imatinib as a novel therapy for type 1 diabetes.

The researchers had hoped to enroll children, but the FDA required that they show benefit in adults first, in a prospective trial.

They enrolled 67 subjects who were 18 to 45 years old (with a mean age of 27) who were newly diagnosed with type 1 diabetes at multiple sites in the United States.

The participants were randomized 2:1 to receive 400 mg/day of the study drug or placebo for 6 months, with a planned follow-up of another 18 months after the end of therapy.

"Our last subject reached the 12-month end point about 2 weeks ago," Dr Gitelman said, so the results are very fresh.

The study participants had an initial HbA1c of around 7.2%, with modest use of exogenous insulin.

The primary outcome was the C-peptide area under the curve (AUC) over the first 2 hours of a 4-hour mixed meal glucose tolerance test, a measure of endogenous insulin production. This was measured at regular monthly visits and assessed at the 1-year visit.

In the placebo group, the endogenous insulin production determined by this test declined steadily over the year, but in the treated group, "the curve looks very different, particularly from 3 months onward," and there was a significant between-group difference at 1 year (= .05).

Moreover, those in the treated group used less supplemental insulin, most notably in the first 6 months (while on treatment), but there was still a between-group difference at 12 months.

"This indicates that the treatment may have enhanced the function of beta cells, with more insulin [being] produced, and/or it improved the body's response to insulin (insulin sensitivity)," said Dr Gitelman.

"There is evidence that it can do both," he added.

HbA1c levels were well controlled in both groups throughout the study.

The patients who received the study drug had a greater number of mild to moderate adverse events related to therapy, consisting of cell-count shifts and liver-function changes, which required dose adjustments and resolved uneventfully.

Some patients also had gastrointestinal side effects (nausea and occasional diarrhea and vomiting) that are known to occur with this drug and usually resolve spontaneously.

Next Steps...

Dr Gitelman and colleagues plan to continue this study out to 2 years and look at the impact of age and dose on response to therapy.

They plan to investigate "what happens over the next 12 months; will the positive effects be sustained or wane?" he said.

"We anticipate moving this approach down to children, since they have a more aggressive loss of beta-cell function following diagnosis, and there are now many examples of therapies that do not seem to have an impact on adults but have a significant impact on children."

This type of approach is novel compared with past trials that often target T cells.

"If we pair [imatinib] with one of the T-cell therapies, we may have a synergistic effect that is significantly greater than the results seen to date with single drugs," said Dr Gitelman.

There may be other barriers to progressing this approach, however. Currently, as reported by Medscape Medical News, imatinib is very costly.

"In Canada, generic imatinib is available for $3000 to $8800/year and Gleevec [Novartis] is available for $38,000/year," Hagop Kantarjian, MD, chair of the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston, told Medscape Medical News.

But in the United States, Gleevec is priced at about $146,000/year, with a generic version available at about $45,000 a year, Yogin Patel, PharmD, from the University of Texas MD Anderson Cancer Center, confirmed in an email.

The study was funded by JDRF, and Novartis supplied the study drug and placebo. Dr Gitelman is on the advisory panel and is a speaker for Roche Pharma, Genentech, and Caladrius Biosciences; a board member and speaker for Novo Nordisk; and receives research support from and is a speaker for Caladrius Biosciences.

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American Diabetes Association 2017 Scientific Sessions; June 12, 2016; San Diego, California. Session 5-IT-SY07

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