Mirogabalin (Daiichi Sankyo) has shown promise as a potential treatment for diabetic peripheral neuropathic pain in a dose-ranging, proof-of-concept study that pitted it against both placebo and pregabalin (Lyrica, Pfizer).
Results from a phase 2, randomized, double-blind study were presented September 12 at Neurodiab, the annual meeting of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes by Domenico Merante, MD, of Daiichi Sankyo, Buckinghamshire, United Kingdom, and were also published online September 17 in Diabetes Care by Aaron Vinik, MD, of Eastern Virginia Medical School, Norfolk, and colleagues.
In the study of 452 subjects with type 1 or type 2 diabetes who also had painful distal symmetric sensorimotor polyneuropathy for 6 months or longer, mirogabalin doses of 5, 10, 15, 20, and 30 mg produced greater reductions in average daily pain scores at 5 weeks than did either placebo or 300-mg pregabalin, both of which performed similarly.
Both gabapentin and pregabalin are first-line treatments for diabetic peripheral neuropathic pain, but only pregabalin is approved specifically for this indication by the US Food and Drug Administration, Dr. Vinik and colleagues explain. Mirogabalin is being developed worldwide by Daiichi Sankyo for the treatment of neuropathic pain.
Conference session comoderator James W. Russell, MBChB, professor of neurology, anatomy, and neurobiology at the University of Maryland, Baltimore, told Medscape Medical News, "This is a phase 2 study, so it's really the first serious look at this compound. Obviously, one needs more data to be able to say that mirogabalin is superior to pregabalin or is itself efficacious."
He also cited some concerns, including the lack of effect for the established treatment pregabalin compared with placebo, the short duration of the trial, and combining data from patients with type 1 and type 2 diabetes. Nonetheless, he noted that the study was well-conducted and that the investigators are "top-notch."
"I think mirogabalin is definitely a promising medication. It is a potential therapy to be added to our armamentarium for a very serious and disabling complication, painful diabetic sensory polyneuropathy," he told Medscape Medical News.
Mirogabalin More Selective for Pain than Pregabalin?
In the paper, Dr. Vinik and colleagues explain that mirogabalin binds to the same neuropathic pain-associated alpha-2-delta calcium-channel ligand subunits as pregabalin but is preferentially selective for alpha-2-delta-1, which is believed to be associated with analgesic effects, whereas pregabalin nonselectively targets both alpha-2-delta-1 and alpha-2-delta-2, which appears to contribute to central nervous system (CNS) side effects.
Thus, mirogabalin may provide a wider therapeutic index with fewer CNS complications, they suggest.
Of the 452 patients randomized to 1 of the 7 treatment groups in the trial, 383 completed the study, but 433 were included in the analysis using a last-observation-carried-forward design. Discontinuation rates were 13% for placebo, 18% for mirogabalin 30 mg, and 27% for pregabalin.
The subjects were 75% white and 54% male. Most (92%) had type 2 diabetes, with a mean HbA1c of 7.4% at baseline and an average 5.8 years of diabetic peripheral neuropathic pain. About a third had used either pregabalin or gabapentin in the past.
The primary end point was mean change from baseline in the 11-point average daily pain score (with 0 being no pain and 10 being worst possible pain).
At baseline, that score was 7.0 in the placebo arm, 6.7 across mirogabalin groups, and 6.6 for the pregabalin subjects.
Mean Reductions in the Pain Score at Week 5
|Treatment||Reduction in Pain Score|
|Pregabalin, 1.8 mg||1.8|
The drops for the highest 3 mirogabalin doses were statistically significant compared with placebo (P < 0.05), beginning at week 1 and continuing through week 5.
The mean differences for pregabalin vs placebo were significant at weeks 1 and 2 but not weeks 3 through 5. The difference between mirogabalin 15 mg and 30 mg and pregabalin 300 mg were statistically significant, the investigators report.
The proportion of subjects achieving pain-score improvements of 30% or greater were 56% through 67% in the top 3 mirogabalin dose groups, compared with 38% with pregabalin and 42% with placebo.
Improvement of 50% or more points was achieved in 39% to 44% of the 15-, 20- and 30-mg mirogabalin groups, vs 28% with pregabalin and 24% for placebo.
But Lack of Effect of Pregabalin Is Concerning, and Side Effects Seem Similar
Dr. Russell urged caution in interpreting these findings. "The study actually showed a minimal effect on neuropathic pain scores with pregabalin compared with mirogabalin. This to me is a little concerning, since there are at least 3 class I studies showing efficacy of pregabalin and over longer periods of time. When you're doing a comparison of a new drug vs the established approved medication, it raises a little bit of concern when the established proved medication doesn't perform as expected."
He added, "I think most physicians who use pregabalin extensively would agree it clearly has a benefit in the treatment of painful diabetic sensory polyneuropathy."
With regard to safety, adverse events were mostly mild, and included central nervous system events in 2.8% with placebo, 14% in all mirogabalin groups combined, and 12% with pregabalin. Dizziness and somnolence were the most common, and most had resolved by study end.
Edema occurred in 1% of those taking placebo, 5% of the mirogabalin subjects, and in 10% of those on pregabalin. Mildly blurred vision was reported in 2% of both placebo and mirogabalin groups and 4% with pregabalin. No deaths occurred during the study, and only 1 serious medication-related adverse event — a gallstone in a man with comorbidities taking 15 mg mirogabalin — was reported.
Study discontinuations due to adverse events were 2% of the placebo group, 7% of mirogabalin subjects, and 4% with pregabalin.
Dr. Russell told Medscape Medical News that he didn't see much difference between the side-effect profiles of mirogabalin and pregabalin, but that future studies would need to compare whatever the most effective dose of mirogabalin turns out to be with the standard 300-mg dose of pregabalin.
"You compare the optimal dose of each drug, so it's apples to apples."
More Data Needed, and Longer Duration
Dr. Russell added — and the authors acknowledge as well — that 5 weeks is probably not long enough for a study to evaluate the full effects of a neuropathy medication.
"Until we start to see data to at least 12 weeks or even longer showing mirogabalin is efficacious over that period of time, we have to remain open as to its overall efficacy," he commented.
He also said that although mirogabalin's half-life is longer than pregabalin's and therefore could perhaps be dosed less often — once or twice daily vs 2 or 3 times a day — most of the pain effect would likely be related to peak drug levels.
"With a longer study, you'd get more info about when peaks and troughs occur and whether peak levels correspond to changes in average daily pain scores."
Also related to the longer half-life is a potential concern about renal excretion in patients with impaired renal function. The study excluded such patients, but the issue is important because painful diabetic neuropathy and impaired renal function often coexist in patients with long-term diabetes, Dr. Russell noted.
He also said that because neuropathy in type 1 and type 2 diabetes differs, studies shouldn't lump the 2 patient groups together.
"Type 1 diabetes is far more dependent on glycemic control than type 2, whereas other factors are more important in type 2, like lipid metabolism and inflammatory markers. They really are different. I'd like studies to move away from the idea that all diabetic neuropathy is the same."
Dr. Vinik received research funding from Daiichi Sankyo for this study, and Dr. Merante is an employee of the company. Disclosures for the coauthors are listed in the article. Dr. Russell's institution received a grant from Impeto Medical to study a device to measure neuropathy, but he personally received no direct funding.
Diabetes Care. Published online September 17, 2014. Abstract
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Cite this: Diabetic Neuropathy Pain: Mirogabalin Promising in Pilot Study - Medscape - Oct 10, 2014.