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Glaucoma Drug Eyed as Novel Diabetes Treatment 'Archetype'
August 22, 2014 (Medscape) - An old glaucoma drug could present a new avenue for treating type 2 diabetes and related conditions, a proof-of-concept study suggests.
Methazolamide, a carbonic-anhydrase (CA) inhibitor approved by the US Food and Drug Administration in 1959, significantly lowered HbA1c levels by 0.39 percentage points (P < .05) compared with placebo in the 24-week, randomized, double-blind, placebo-controlled study of 76 patients with type 2 diabetes, including 41 who were also taking metformin.
The results were published online August 14 in Diabetes Care by Richard W. Simpson, DM, FRCP, of Box Hill Hospital, Victoria, Australia, and colleagues. The study was funded by Verva Pharmaceuticals.
Other notable findings included a 19% (7/37) rate of metabolic acidosis, a known side effect of the drug that was not associated with clinically significant symptoms or study withdrawals, an "unexpected" 10units/L drop in alanine aminotransferase seen in the 22 patients who were taking metformin along with methazolamide, and a greater weight loss compared with placebo (2.2 vs. 0.3 kg), also seen only in the metformin/methazolamide group.
The investigators are calling the CA-inhibitor an "archetype" for a potential new class of type 2 diabetes therapy rather than pursing the drug in its current form, in part because the drug's CA inhibition is most likely not its glucose-lowering mechanism, Verva CEO Vincent J. Wacher, PhD, told Medscape Medical News.
"Our preclinical and mechanistic work has shown that methazolamide exerts its metabolic effect by a mitochondrial mode of action that is distinct from its antiglaucoma activity (CA inhibition) and hasn't previously been evaluated in diabetes. This is a proprietary program within Verva, so we aren't disclosing the target right now," he told Medscape Medical News in an email.
Since methazolamide is off patent, the idea would be to develop a next-generation analog molecule that would be optimized for the glucose-lowering mode of action and also could be "engineered to remove" the CA-inhibiting activity causing the metabolic acidosis, Dr. Wacher explained.
Asked to comment, Simeon I. Taylor, MD, PhD adjunct professor in the department of medicine at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News, "The authors propose that the glycemic efficacy is mediated by an undisclosed mitochondrial target. Once the identity of the proposed target is disclosed and selective compounds are identified, it will be possible to gain a better understanding of the clinical profile for what could be a novel class of antidiabetic drugs."
However, Dr. Taylor, who was formerly vice president, research and scientific affairs, at Bristol-Myers Squibb, said methazolamide's efficacy — a 0.4 percentage-point reduction in HbA1c — is "modest," less than that of many other oral antidiabetic drugs.
Dr. Wacher told Medscape Medical News that Verva is considering pursuing other diabetes-related indications for methazolamide itself, given that the metabolic acidosis wasn't problematic for patients in the study. "I definitely believe a lower-dose, extended-release methazolamide product would be beneficial, especially in a liver indication and possibly as a weight-loss adjuvant therapy. Further exploration of methazolamide in [nonalcoholic fatty-liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)] is definitely warranted."
Dr. Taylor said, "While fatty-liver disease in diabetes is a very significant unmet medical need, it would take a very substantial study to see whether this drug actually improves outcomes in those patients."
He also expressed concern about the idea of a low-dose or extended-release version of methazolamide itself due to the metabolic acidosis and its related long-term complications, including nephrolithiasis, nephrocalcinosis, and electrolyte disturbances.
"These side effects are potentially concerning in diabetic patients — especially those patients with concomitant kidney disease or cardiovascular disease. It would be important to conduct long-term safety studies in large numbers of patients to assess the magnitude of those potential safety concerns," Dr. Taylor told Medscape Medical News.
Indeed, Dr. Wacher acknowledged that methazolamide presents "an interesting conundrum."
"The data really warrant a larger study, but the cost of development in diabetes is so extraordinary now that companies are reluctant to spend the money on an off-patent/repurposed medicine when there are so many competing products. That's why the liver indication is so appealing," he said, pointing out that thus far there are no approved drugs for treating NAFLD/NASH.
"Considering the costs and resources required for drug development in metabolic diseases, Verva is now looking for partner(s) with the appropriate resources and infrastructure to advance the technology," Dr. Wacher told Medscape Medical News.