Mirogabalin (DS5565)

Mirogabalin: could it be the next generation gabapentin or pregabalin?

Except for carbamazepine for trigeminal neuralgia, gabapentinoid anticonvulsants have been the standard for the treatment of neuropathic pain. Pregabalin, which followed gabapentin, was developed with the benefit of rapid peak blood concentration and better bioavailability. Mirogabalin besylate (DS-5565, Tarlige?) shows greater sustained analgesia due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion (DRG). Additionally, it produces a lower level of central nervous system-specific adverse drug reactions (ADRs), due to a low affinity to, and rapid dissociation from, the α2δ-2 subunits in the cerebellum. Maximum plasma concentration is achieved in less than 1 hour, compared to 1 hour for pregabalin and 3 hours for gabapentin. The plasma protein binding is relatively low, at less than 25%. As with all gabapentinoids, it is also largely excreted via the kidneys in an unchanged form, and so the administration dose should also be adjusted according to renal function. The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin and over 1,200 mg of gabapentin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel, safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain in the DRG and lower ADRs in the cerebellum.

Efficacy of Mirogabalin (DS-5565) on Patient-Reported Pain and Sleep Interference in Patients with Diabetic Neuropathic Pain: Secondary Outcomes of a Phase II Proof-of-Concept Study

Objective: To evaluate the effects of mirogabalin on patient-reported pain and sleep interference in diabetic peripheral neuropathic pain (DPNP).
Subjects: Adults (≥18 years) with type 1 or 2 diabetes, glycosylated hemoglobin of 10% or less at screening, and DPNP for six months or more were eligible for participation.
Methods: Subjects (N = 452) were randomly assigned (2:1:1:1:1:1:1) to receive placebo, dose-ranging mirogabalin (5, 10, 15, 20, 30 mg/day), or pregabalin (300 mg/day) for five weeks. Secondary efficacy end points studied here included patient global impression of change (PGIC), modified brief pain inventory (BPI), and average daily sleep interference score (ADSIS). Correlation plots were generated to examine the relationship between ADSIS and average daily pain score (ADPS).
Results: At week 5, significant reductions in ADSIS were observed in the mirogabalin 15, 20, and 30 mg/day groups, compared with placebo (P < 0.05). Baseline ADSIS and ADPS were strongly correlated (R2 = 0.4407), as were mean changes from baseline in ADSIS and ADPS at week 5 (R2 = 0.6694). The mirogabalin 30 mg/day group showed significant improvement compared with placebo in four of six BPI subscales at end point; the mirogabalin 15 mg/day group showed significant improvement in three of six BPI subscales (P < 0.05). At end of treatment, the percentage of subject with PGIC status of "much improved or better" was greater in all mirogabalin dose groups than in the placebo group (P < 0.05). A low incidence of treatment-related adverse events was reported for mirogabalin.
Conclusions: Results support the effectiveness of mirogabalin in improving patient-reported pain and sleep interference in DPNP.

Efficacy and safety of mirogabalin (DS-5565) for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo- and active comparator-controlled, adaptive proof-of-concept phase 2 study

Objective: We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP).
Research design and methods: Adults (≥18 years) with type 1 or 2 diabetes, HbA?c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms.
Results: LS mean differences in change in ADPS from baseline to week 5 versus placebo were -0.22, -0.53, -0.94, -0.88, and -1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and -0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated.
Conclusions: Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Mirogabalin (DS-5565) is a novel preferentially selective α₂ δ-1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open-label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]) were enrolled and completed the study. The AUC_last increased with severity of renal impairment; the geometric least-squares mean ratios of AUC_last compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUC_last increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment-related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

Exposure-response modeling of average daily pain score, and dizziness and somnolence, for mirogabalin (DS-5565) in patients with diabetic peripheral neuropathic pain

Mirogabalin (DS-5565) is an α2δ-1 ligand being developed for pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. Nonlinear mixed-effects analyses were performed on average daily pain and on the incidence of the adverse events dizziness and somnolence. These models were used to predict the dose of mirogabalin equivalent to pregabalin and the probability of meaningful reduction in pain compared with placebo and pregabalin. In addition, regimen effects were evaluated for reductions of adverse events. Mirogabalin was estimated to be 17-fold more potent than pregabalin. The effectiveness of 150 mg pregabalin, dosed twice daily, attenuated by week 5. Therefore, the estimated mechanism-based equivalent dose (ED) of 17.7 mg mirogabalin was higher than that predicted to achieve comparable pain reduction. If attenuation of the pregabalin effect is real, mirogabalin doses lower than the ED could yield comparable pain reduction, albeit with less differentiation in pain from placebo. The incidence rate of dizziness and somnolence decreased over time. Twice-daily dosing of mirogabalin was predicted to yield a lower incidence rate of dizziness than once-daily dosing; thus, titration of dosages should reduce adverse event rates. These model results were used to influence phase 3 dosing selection.