A little-used asthma drug called amlexanox may potentially be repurposed to treat type 2 diabetes, according to findings from a small proof-of-concept study published in the July issue of Cell Metabolism.
Results showed that using the drug for 12 weeks was linked to significantly reduced HbA1c in some patients with obesity, type 2 diabetes, and nonalcoholic fatty-liver disease (NAFLD).
"The overall significant reduction in HbA1c over this relatively short trial indicates that amlexanox can benefit some patients with type 2 diabetes. The reduction in HbA1c is on the order of a [dipeptidyl peptidase-4] DPP-4 inhibitor when given alone over the same time period," commented first author Elif Oral, MD, director of the MEND Obesity and Metabolic Disorder Program at the University of Michigan, Ann Arbor.
Researchers also looked at baseline inflammation, which revealed an interesting finding: people with higher levels of inflammation responded better.
"Among drug-treated patients, there seemed to be a greater degree of inflammation in responders compared with nonresponders. This is interesting, since we know that inflammatory pathways drive up expression of the targets of amlexanox," Dr Oral said.
Amlexanox inhibits two enzymes: IKKƐ and TBK1. Studies in mice have shown that inhibiting these enzymes improves weight, insulin resistance, fatty liver, and inflammation.
Another intriguing result: responders showed over 1100 gene changes, and these changes were found only in this group.
"The drug response was characterized by a unique and dramatic molecular signature of gene-expression changes, consistent with what was seen in mouse models, in which expression of energy-expenditure genes were increased. We're still investigating the importance and significance of these gene-expression changes," Dr Oral added.
Amlexanox Developed in Japan to Treat Allergies and Asthma
Amlexanox was developed in Japan in the 1980s to treat asthma and allergic rhinitis. However, it requires thrice-daily dosing and was never introduced to the United States, because of heavy competition from more popular medications like montelukast, which can be taken once a day. Even in Japan, the prescription rate was very low, and therefore amlexanox was discontinued this year for commercial reasons.
However, its exact mechanism of action has never been fully investigated. It was not until Dr Oral and colleagues screened 150,000 chemicals, looking for inhibitors of IKKƐ and TBK1, that they hit upon amlexanox as a potential antidiabetes drug.
They first tested amlexanox in mice and did an open-label safety study in humans. Both the animal and human trials pointed to fat tissue as an important target for amlexanox.
So researchers next tested amlexanox in a randomized double-blind placebo controlled study that included 42 obese individuals with type 2 diabetes and NAFLD. Participants were randomized to 12 weeks of 50-mg amlexanox three times daily or placebo.
About one-third of participants showed a robust response to amlexanox, with reductions in HbA1c of ≥ 0.5% percentage points or more, which was significantly different from placebo (P = .05). Responders also showed significant decreases in fructosamine, a marker for shorter-term glucose control (P = .024).
Similar to results in mice, at 2 to 4 weeks responders showed a transient increase in IL-6, followed by decreased fasting glucose and improved insulin sensitivity. A subgroup of responders with NAFLD showed improvement in fatty liver.
Responders also had higher levels of baseline inflammation than nonresponders or placebo patients, including higher levels of CRP, which correlated with the amount of reduction in HbA1c. And analyses of fat biopsies showed they also had higher baseline activation of genes involved in inflammation.
Fat biopsies also replicated findings from the open-label study in humans, showing responders treated with amlexanox had higher expression of genes involved in energy expenditure and "browning" of fat.
Seven patients in the amlexanox group developed a rash at 4 weeks, which resolved within 2 weeks using local treatment. No other adverse events attributable to amlexanox occurred. This is consistent with the long-term safety profile in Japan, in which about 5% of patients developed rash, Dr Oral pointed out.
"We don't understand the mechanism for why participants with more underlying inflammation responded better. However, previous work has shown that TBKI and IKKƐ are upregulated in the setting of more inflammation. So it is possible that inflammation oversensitizes the pathway that the drug targets," she explained.
More Studies Planned
The team is now planning a longer 6-month prospective, randomized study in humans that will test whether individuals with elevated CRP and higher levels of fat inflammation at baseline have better responses to amlexanox.
They also plan another trial in humans that will test amlexanox in combination with mirabegron (Myrbetriq, Astellas Pharma), a pure beta agonist used to treat overactive bladder. The idea is to see whether amlexanox can restore catecholamine sensitivity.
Future studies will also determine the optimal safe dose and dosing regimen for amlexanox.
"If we can really prove that those patients with higher inflammation will respond better with this drug, it will be the first time that such an observation will be made, which is exciting. It's another way of customizing therapy for patients," Dr Oral stressed.
The group is currently looking for ways to partner with companies and investors, but currently none are involved.
Dr Saltiel has several patent applications that include amlexanox. The coauthors report no relevant financial relationships.
Cell Metab. 2017;26:103-122. Abstract
For more diabetes and endocrinology news, follow us on Twitter and on Facebook.
Medscape Medical News © 2017
Cite this: Obscure Asthma Drug Shows Promise for Treating Diabetes - Medscape - Jul 13, 2017.
Comments