For the Treatment of Diabetic Peripheral

Diabetes Care Volume 37, December 2014 3253

Aaron Vinik,1 Julio Rosenstock,2 Efficacy and Safety of Mirogabalin Uma Sharma,3 Karen Feins,4 Ching Hsu,4 and Domenico Merante,5 on behalf of the (DS-5565) for the Treatment of DS5565-A-U201 US Phase II Study Diabetic Peripheral Neuropathic Investigators Pain:ARandomized,Double-Blind, Placebo- and Active Comparator– Controlled, Adaptive Proof-of- Concept Phase 2 Study Diabetes Care 2014;37:3253–3261 | DOI: 10.2337/dc14-1044

OBJECTIVE We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efﬁcacy with manageable side effects for treatment of diabetic peripheral PATHOPHYSIOLOGY/COMPLICATIONS neuropathic pain (DPNP).

RESEARCH DESIGN AND METHODS

Adults (‡18 years) with type 1 or 2 diabetes, HbA1c £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. 1Eastern Virginia Medical School, Norfolk, VA Safety assessments included adverse events (AEs), clinical laboratory tests, and 2Dallas Diabetes and Endocrine Center at Medi- electrocardiograms. cal City, Dallas, TX 3MMS Holdings Inc., Canton, MI 4 RESULTS Daiichi Sankyo Pharma Development, Edison, NJ LS mean differences in change in ADPS from baseline to week 5 versus placebo 5Daiichi Sankyo Development, Gerrards Cross, were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and Buckinghamshire, U.K. 30-mg/day treatment groups, respectively, and –0.05 in the pregabalin group (P < Corresponding author: Aaron Vinik, vinikai@ 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs evms.edu. (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), Received 25 April 2014 and accepted 14 August and headache (6.1%); otherwise, mirogabalin was well tolerated. 2014. This article contains Supplementary Data online CONCLUSIONS at http://care.diabetesjournals.org/lookup/ Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS suppl/doi:10.2337/dc14-1044/-/DC1. versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally © 2014 by the American Diabetes Association. Readers may use this article as long as the work meaningful effect. Mirogabalin may be a promising new treatment option for is properly cited, the use is educational and not patients with DPNP. for profit, and the work is not altered. 3254 Efficacy and Safety of Mirogabalin Diabetes Care Volume 37, December 2014

Diabetic peripheral neuropathic pain preparations from human and rat a2d stable concomitant medications during (DPNP), a common complication of di- subunit–expressed cells showed that the study period, and adequate contra- abetes, affects up to 50% of patients mirogabalin had a slower dissociation ception in women of child-bearing po- with diabetic neuropathy (1). DPNP con- rate from a2d-1 than a2d-2, in particu- tential during treatment and for 4 weeks tributes to depression, anxiety, and lar, a2d-1 compared with pregabalin after study completion. sleep disorders, which may profoundly (10). Additionally, mirogabalin showed Exclusion criteria included diagnosis of impact well-being and quality of life potent, sustained analgesic effects in mononeuropathy, major psychiatric dis- (2,3). Mechanisms underlying DPNP streptozotocin-induced diabetic rats orders, and known hypersensitivity to are multifactorial; however, voltage- with induced pain, and the superior pregabalin or gabapentin. Subjects with dependent Ca2+ channels appear to analgesic effects and wider CNS safety prior therapeutic failure of pregabalin or play a central role and represent a key margin relative to pregabalin were at- gabapentin (considered unresponsive or target for pharmacologic intervention tributed to its selectivity for and slow intolerant to treatment) were excluded; (4,5). Voltage-dependent calcium chan- dissociation from a2d-1 compared with therapeutic failure implied lack of efficacy nels are composed of a central pore- pregabalin (10). following full titration to effective doses forming a1 subunit, a disulfide-linked Mirogabalin is being developed world- (e.g., up to 300 mg/day for pregabalin). glycoprotein dimer of a2- and d-subunits wide as a preferentially selective a2d-1 Subjects who fulfilled eligibility crite- (a2d), an intracellular b-subunit, and a ligand intended for the treatment of neu- ria during the screening period (up to transmembrane glycoprotein g-subunit ropathic pain. We present efficacy and 3 weeks) discontinued analgesic and an- (in some Ca2+-channel types) (6). Ligands safety data for mirogabalin from a phase tidepressant medications (excepting for the a2d-subunit (a2d-1 and a2d-2) 2, randomized, double-blind, placebo- stable doses of selective serotonin- are thought to exert analgesic effects and active comparator–controlled study reuptake inhibitors). Duration of the by reducing Ca2+ influx into neurons with an adaptive trial design conducted in washout period varied according to throughout the central nervous system patients with DPNP. type of medication(s). Subjects re- (CNS) via a mechanism not yet fully elu- corded pain scores in a daily diary cidated (4). It is hypothesized that a re- RESEARCH DESIGN AND METHODS each morning to assess baseline pain duction in Ca2+ influx decreases release The study was conducted between 28 criteria. of excitatory neurotransmitters such as November 2011 and 7 September 2012 The study was designed to identify a glutamate, norepinephrine, and sub- at 80 U.S. sites (ClinicalTrials.gov identi- dose (or doses) of mirogabalin with stance P, which have been implicated fier NCT01496365) (Fig. 1) (for a list of meaningful clinical efficacy and manage- in animal models of induced neuropathic principal investigators, see Supplemen- able side effects for the treatment of pain (4,7–9). Recent studies suggest that tary Data). All participating clinical sites DPNP. The 5-week duration of this ligand selectivity for a2d-1 and a2d-2 received institutional review board ap- adaptive study was based on an anal- may result in different clinical outcomes. proval of the study protocol and study- ysis of seven randomized, placebo- Binding to a2d-1 appears to contribute related documents prior to enrollment, controlled DPNP trials, which showed to analgesic effects (10,11), whereas and all subjects provided written in- that 5 weeks was sufficient to detect a binding to a2d-2 appears to contribute formed consent. Details of the adaptive statistically meaningful difference in to CNS side effects (10,12). trial design are outlined in Supplemen- ADPS between pregabalin 300 mg/day Nonselective a2d ligands, gabapentin tary Data. and placebo (19). In the 5-week double- and pregabalin (13), are first-line treat- Adults ($18 years) with type 1 or 2 blind treatment phase, subjects who ments for DPNP (14,15); however, of diabetes and HbA1c #10% at screening met baseline pain criteria were ran- these, only pregabalin is approved by and on a stable antidiabetic medication domly assigned (2:1:1:1:1:1:1) to one the U.S. Food and Drug Administration regimen for $30 days were eligible for of seven treatment groups: placebo, for treatment of DPNP (14,16). For study participation. Subjects must have mirogabalin 5 mg/day (once daily at bed- many patients with DPNP, pain relief is had painful distal symmetric sensorimo- time), mirogabalin 10 mg/day (once daily inadequate and therapy is poorly toler- tor polyneuropathy (17) for $6months at bedtime), mirogabalin 15 mg/day ated (4). Response rates to analgesic based on neurologic history and/or (once daily at bedtime), mirogabalin monotherapy are only ;50%, and since medical examination. Diagnosis in- 20 mg/day (10 mg twice daily, in the efficacy wanes, dose escalation and cluded absent or reduced deep tendon morning and at bedtime), mirogabalin combination pharmacotherapy are reflexes at both ankles. A pain score 30 mg/day (15 mg twice daily, in the common (2,16). Consequently, there is $40 mm on the Short-Form McGill morning and at bedtime), or pregabalin still a clear unmet need for more effec- Pain Questionnaire (SF-MPQ) visual an- 300 mg/day (150 mg twice daily, in the tive and better-tolerated treatment op- alog scale (VAS) at screening and ran- morning and at bedtime). Titration de- tions for patients with DPNP. domization (18) and average daily pain tails are described in Fig. 1. No titration Mirogabalin (DS-5565; Daiichi Sankyo score (ADPS) $4 based on the 11-point was used in mirogabalin 5-, 10-, 15-, and Co., Ltd., Tokyo, Japan) is a novel, prefer- numeric rating scale (NRS; calculated 20-mg/day dosing arms to assess quicker entially selective a2d-1 ligand character- from a minimum of four pain ratings in pain relief (20). ized by high potency and selectivity to daily diary entries during the baseline The primary efficacy end point was to the a2d-1 subunit of voltage-sensitive period) at randomization were required. compare the change in ADPS from base- calcium-channel complexes in the CNS. Additional eligibility criteria included line to end point (week 5) for mirogabalin In vitro experiments using membrane creatinine clearance $60 mL/min, versus placebo. ADPS was based on the care.diabetesjournals.org Vinik and Associates 3255

Figure 1—Study design.

11-point NRS (0 [no pain] to 10 [worst as number of days from randomization Statistical Analyses possible pain]). Every morning, prior to until first pain score that represented a SAS (version 9.2 or higher) was used to taking study medication, each subject $30% decrease from baseline for sub- produce all summary tables, figures, and circled the number best describing jects with a $30% decrease in end point data listings. Unless otherwise specified, his/her pain over the past 24 h. Scores ADPS (exploratory analysis); and charac- analyses were two-sided and performed were averaged from the last seven on- terizing the safety and tolerability of at the 0.05 level. The full analysis set was treatment entries in subjects’ daily di- mirogabalin based on the overall inci- defined as all randomized subjects who aries. A minimally meaningful effect dence of adverse events (AEs), AEs of received $1 dose of study medication was defined as a decrease of at least special interest, discontinuations due and had $1 postrandomization pain rat- one point versus placebo on the NRS to AEs, and findings from physical ex- ing, in addition to a baseline value. The scale (21). aminations, electrocardiograms (ECGs), per-protocol analysis set, which was Secondary efficacy end points in- and other safety assessments. used for supportive analyses of the pri- cluded characterizing the dose response Safety assessments, performed at mary parameter, was defined as all sub- of mirogabalin on change from baseline each clinic visit and 1 week after end jects who received $1 dose of study in ADPS; assessing the incidence of re- of treatment, included analysis of AEs, medication and were sufficiently com- sponders, by treatment group, defined serious AEs (SAEs), and AEs of specific pliant with the protocol. The safety anal- as the proportion of subjects achieving interest among the treatment groups. ysis set included all subjects who $30 or $50% reduction from baseline Additionally, physical examinations, vi- received $1 dose of study medication. in ADPS; comparing the effects of miro- tal signs, neurologic assessments, clini- For the primary analysis, ANCOVA gabalin versus pregabalin 300 mg/day cal chemistry, hematology, urinalysis was conducted on the full analysis based on change from baseline in tests, and 12-lead ECGs were conducted set, with treatment arm as the factor ADPS and responder rate (22); assessing at prespecified time points throughout and baseline ADPS as covariate, to as- time to meaningful pain relief, defined the study. sess if there was an overall treatment 3256 Efficacy and Safety of Mirogabalin Diabetes Care Volume 37, December 2014

difference in end point ADPS (week 5 with last observation carried forward [LOCF]). This was followed by ANCOVA

contrasts of mean change from baseline = 452) N

in end point ADPS for each mirogabalin (

treatment arm with placebo and, for the All dose groups pregabalin arm with placebo, with P values, corresponding 95% CIs, and treat- d ment effect least squares (LS) means

provided for each contrast. Numeric = 57) n mean changes from baseline in ADPS ( 30 mg/day for each mirogabalin arm were also compared with the numeric mean change

from baseline for the pregabalin arm. A c baseline observation carried forward

(BOCF) method was used for imputation = 56) n (

in a sensitivity analysis using ANCOVA. 20 mg/day Assuming a common SD of 2.1 ADPS units and a type 1 error of 0.05, a sample size of 400 subjects would provide 77% b statistical power to detect a treatment = 57) n

difference of 1.0 ADPS unit (using ( 15 mg/day change from baseline to week 5 with Mirogabalin LOCF) for a mirogabalin treatment arm versus placebo. b Pearson correlation coefﬁcients were

computed by treatment group to assess = 57) n the relationship between VAS and ADPS. ( 10 mg/day

RESULTS

Disposition b A total of 913 subjects were screened, = 57)

and 452 were randomly assigned to n ( double-blind treatment (Supplementary 5 mg/day Fig. 3). Eighty-ﬁve percent (383 of 452) of subjects completed the study. Rates of discontinuation were 13.4% in the a

placebo group; 10.5, 7, 22.8, 17.9, and = 56) n 10.5% in the mirogabalin 5-, 10-, 15-, 20-, ( Pregabalin and 30-mg/day treatment groups, re- 300 mg/day spectively; and 26.8% in the pregabalin 15 mg twice daily.

group. Reasons for discontinuation in- d cluded AEs (n = 25), withdrawal by sub-

ject (n = 19), protocol violation (n = 5), = 112) n Placebo loss to follow-up (n = 3), lack of efﬁcacy ( (n = 2), and other reasons (n = 15). 10 mg twice daily. Subject Demographics and Baseline c Characteristics

Subjects were mostly white (75%), with c Islander 0 (0.0) 2 (3.6) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 1 (1.8) 4 (0.9) ﬁ slightly more men (53.5%) than women (46.5%), and a mean (6SD) age of 60.1 (69.26) years (Table 1). Most (91.8%) Once-daily dosing. b

subjects had type 2 diabetes, with a (%) n mean HbA1c of 7.4% at baseline and

BMI typical of an adult population with (%) , mean (SD) 33.4 (6.94) 33.5 (7.62) 33.9 (7.68) 34.9 (6.85) 35.8 (7.67) 35.5 (6.87) 34.7 (6.82) 34.4 (7.19) Demographics and disease characteristics at baseline (all randomized population) 2

2 n

diabetes (;34 kg/m ). — (%) (%) n Mean duration of DPNP was 5.8 years , %, mean (SD) 7.3 (1.25) 7.5 (1.46) 7.1 (1.23) 7.4 (1.20) 7.5 (1.07) 7.4 (1.19) 7.6 (1.21) 7.4 (1.24) n 1c Hispanic or LatinoNot Hispanic or LatinoAmerican Indian or Alaska NativeBlack or African AmericanNative Hawaiian or Other Paci 1 (0.9) 94 18 (83.9) (16.1) 27 (24.1) 52 0 (92.9) (0.0) 4 (7.1) 17 (30.4) 45 (78.9) 0 12 (0.0) (21.1) 11 (19.3) 45 (78.9) 12 (21.1) 1 (1.8) 9 (15.8) 51 (89.5) 6 (10.5) 12 0 (21.1) (0.0) 46 (82.1) 10 (17.9) 10 (17.9) 0 (0.0) 47 (82.5) 10 (17.5) 8 (14.0) 380 0 (84.1) (0.0) 72 (15.9) 94 (20.8) 2 (0.4) AsianWhiteOther 3 (2.7) 81 (72.3) 0 (0.0) 36 (64.3) 1 (1.8) 0 (0.0) 45 (78.9) 0 (0.0) 1 (1.8) 43 (75.4) 4 (7.0) 44 0 (77.2) (0.0) 1 (1.8) 44 (78.6) 0 (0.0) 1 (1.8) 46 (80.7) 0 (0.0) 339 (75.0) 1 (1.8) 1 (1.8) 11 (2.4) 2 (0.4) Type 1Type 2 13 (11.6) 99 (88.4) 1 (1.8) 55 (98.2) 53 4 (93.0) (7.0) 51 (89.5) 6 (10.5) 51 (89.5) 6 (10.5) 54 (96.4) 2 (3.6) 52 (91.2) 5 (8.8) 415 (91.8) 37 (8.2) across all treatment arms (range, 4.8 to MaleFemale 56 (50.0) 56 (50.0) 32 (57.1) 24 (42.9) 27 (47.4) 30 (52.6) 29 (50.9) 28 (49.1) 34 (59.6) 23 (40.4) 32 (57.1) 24 (42.9) 32 (56.1) 25 (43.9) 242 (53.5) 210 (46.5) 150 mg twice daily. Table 1 Parameter a Ethnicity, Race, HbA Duration of DPNP, years, mean (SD) 5.9 (4.61) 5.7 (5.00) 4.8 (4.05) 4.9 (4.40) 7.7 (6.40) 5.3 (4.39) 6.1 (5.26) 5.8 (4.93) Type of diabetes, 7.7 years). Gabapentin was previously Age, years, mean (SD)Sex, Height, cm, mean (SD)Weight, kg, mean (SD)BMI, kg/m 60.2 (9.57) 59.5 (9.40) 169.7 (9.89) 96.2 (19.87) 58.9 171.6 (9.85) (10.01) 98.9 (24.87) 169.3 (10.79) 60.9 (9.92) 97.3 (23.85) 170.7 (10.25) 61.4 (8.70) 101.9 (22.46) 173.0 (9.47) 106.6 60.4 (21.70) (8.59) 170.5 (10.03) 103.4 (21.27) 59.3 171.2 (8.54) (9.60) 101.5 (20.13) 170.7 (10.00) 60.1 (9.26) 100.2 (21.96) care.diabetesjournals.org Vinik and Associates 3257

used by 31.3% of placebo recipients, 24.6% of mirogabalin recipients (all treatment arms combined), and 17.9% of pregabalin recipients. Previous pregabalin use was 4.5, 5.6, and 12.5%, respectively.

Efficacy A total of 433 subjects were included in the full analysis set, providing at least 80% of statistical power. At baseline, mean ADPS was 7.0 in the placebo arm, 6.7 across all five mirogabalin treatment arms, and 6.6 in the pregabalin arm. This indicates that pain was classified in all treatment groups similarly as moderate/ severe (i.e., ADPS $4) according to the NRS or Likert scale (22). Mean changes in ADPS from baseline to week 5 were –1.9 in the placebo group; –2.0, –2.3, –2.7, –2.6, and –2.8 inthemirogabalin5-,10-,15-,20-,and 30-mg/day treatment groups, respectively; and –1.8 in the pregabalin group (Supplementary Table 4). In subjects receiving mirogabalin, LS mean differ- encesinchangeinADPSfrombaseline 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 for pregabalin 300 mg/day. These differences were statistically significant (P , 0.05) versus placebo at the mirogabalin 15-, 20-, and 30-mg/day dose levels (Fig. 2A). These changes be- gan at week 1 and continued through week 5 (P , 0.05). The LS mean differences for pregabalin 300 mg/day were statistically significant versus placebo — group at weeks 1 and 2 (P , 0.05) but Figure 2 Mean change from baseline in ADPS by week and treatment group (full analysis set) (A) and proportion of patients with $30 and $50% reductions in ADPS at week 5 compared with notatweeks3,4,or5(P =NS). baseline (LOCF) (B). LS mean differences in change in ADPS from baseline to week 5 versus LS mean differences in change in placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and ADPS from baseline to week 5 versus 30-mg/day treatment groups, respectively. These differences were statistically significant (P , pregabalin 300 mg/day were –0.17, 0.05) versus placebo at the mirogabalin 15-, 20-, and 30-mg/day dose levels, beginning at week 1 , –0.47, –0.89, –0.83, and –0.96 for the and continuing through week 5 (P 0.05). The LS mean differences for pregabalin 300 mg/day were statistically significant versus placebo group at weeks 1 and 2 (P , 0.05) but not at weeks 3, mirogabalin 5-, 10-, 15-, 20-, and 30- 4, or 5 (P =NS). mg/day treatment groups, respectively. These differences were statistically significant (P , 0.05) versus the pregabalin –0.58, and –1.18 for the mirogabalin 5-, in the top four mirogabalin treatment 300-mg/day group at the 15- and 30- 10-, 15-, 20-, and 30-mg/day treatment arms (i.e., 10, 15, 20, and 30 mg/day); mg/day dose levels. groups, respectively. These differences 39–44% of subjects achieved $50% re- Results of the sensitivity analysis were statistically significant (P , 0.05) duction in ADPS in the top three miro- (BOCF) were generally similar to that of versus placebo at the 10-, 15-, and gabalin treatment arms (i.e., 15, 20, and the primary analysis (LOCF) except that 30-mg/day dose levels. 30 mg/day); and 23% of subjects the mirogabalin 10-mg/day group was The proportion of responders, de- achieved $75% reduction in ADPS in significantly different versus placebo fined as subjects who achieved $30 or the mirogabalin 30-mg/day group whereas the mirogabalin 20-mg/day $50% reduction in ADPS from baseline (data not shown). There was a positive group was not. LS mean differences in to week 5, are shown by treatment correlation between VAS and ADPS from change in ADPS from baseline to week 5 group in Fig. 2B. Fifty-six to 67% of sub- randomization (Supplementary Fig. 5) to versus placebo were –0.53, –0.93, –0.98, jects achieved $30% reduction in ADPS week 5 (LOCF), with r values ranging 3258 Efficacy and Safety of Mirogabalin Diabetes Care Volume 37, December 2014

from 0.792 to 0.859 in all treatment was reported in .1 subject (one in the 30-mg/day group experienced mild groups at week 5. mirogabalin 5-mg/day group and one in bradycardia (n = 1) and mild syncope Median time to meaningful pain relief the mirogabalin 20-mg/day group). (n =1).Onesubjectinthemirogabalin was 30, 16, 20, and 16 days in the miro- Overall rates of AEs of special inter- 15-mg/day group had a mild increase in gabalin 10-, 15-, 20-, and 30-mg/day est, including CNS effects, cardiac con- heart rate, and one subject in the groups,comparedwith36daysinthe duction abnormalities, arrhythmias, pregabalin group experienced moder- placebo group (P , 0.05 for all compar- edema, visual disorders, and potential ate bradycardia. Overall incidence of isons). Median values could not be cal- for abuse, were low. CNS effects were edema was 1.0% in the placebo group, culated for the mirogabalin 5-mg/day or observed in 2.8% of subjects in the pla- 5.1% in the mirogabalin groups (all arms pregabalin 300-mg/day groups because cebo group, 14.1% of subjects in the combined), and 10% in the pregabalin .50% of the subjects in each group did mirogabalin groups (all arms com- group. Peripheral edema was most not achieve $30% pain reduction from bined), and 12.0% of subjects in the common in all groups and most cases baseline. When meaningful pain relief pregabalin group. Dizziness and som- of edema resolved by study end. Mildly was deﬁned in terms of a $50% re- nolence were the most commonly ob- blurred vision was the most commonly sponder rate, the mirogabalin 15-, 20-, served CNS effects; most were mild in reported visual disorder, occurring in and 30-mg/day groups continued to severity and resolved before study end. 1.9% of subjects in the placebo group, demonstrate a shorter time to pain re- The incidence of somnolence increased 1.8% of subjects in the mirogabalin lief than the placebo group (P , 0.05 for with increasing doses of mirogabalin. groups, and 4.0% of subjects in the all comparisons). Cardiac conduction abnormalities oc- pregabalin 300-mg/day group. With re- curred in two subjects. One subject in gard to abuse potential, one subject in Safety and Tolerability the mirogabalin 15-mg/day group ex- the mirogabalin 30-mg/day group ex- A total of 435 subjects were included in perienced mild bundle branch block, perienced moderate euphoria that re- the safety analysis. AEs occurring in $5% and one subject in the placebo group solved after 9 days. The event was of subjects in any treatment group are experienced mild QT prolongation. Ar- considered related to study drug, and shown in Table 2. Most AEs were mild. rhythmias were observed in four sub- the patient was discontinued from the Headache was the only severe AE that jects. Two subjects in the mirogabalin study.

Table 2—Most frequent AEs (>5%) by system organ class and preferred term Mirogabalin Pregabalin Placebo 300 mg/daya 5 mg/dayb 10 mg/dayb 15 mg/dayb 20 mg/dayc 30 mg/dayd All System organ class, preferred term, n (%) (n =108) (n =50) (n =55) (n =56) (n =53) (n =56) (n = 57) (n =277) Number of AEs 117 69 64 80 110 89 88 431 Nervous system disorders 8 (7.4) 11 (22.0) 9 (16.4) 11 (19.6) 12 (22.6) 19 (33.9) 21 (36.8) 72 (26.0) Dizziness 2 (1.9) 3 (6.0) 0 (0.0) 7 (12.5) 6 (11.3) 4 (7.1) 9 (15.8) 26 (9.4) Headache 4 (3.7) 2 (4.0) 6 (10.9) 4 (7.1) 1 (1.9) 5 (8.9) 1 (1.8) 17 (6.1) Somnolence 1 (0.9) 4 (8.0) 1 (1.8) 1 (1.8) 3 (5.7) 5 (8.9) 7 (12.3) 17 (6.1) Balance disorder 0 (0.0) 2 (4.0) 0 (0.0) 0 (0.0) 1 (1.9) 3 (5.4) 3 (5.3) 7 (2.5) Gastrointestinal disorders 10 (9.3) 5 (10.0) 7 (12.7) 11 (19.6) 9 (17.0) 6 (10.7) 5 (8.8) 38 (13.7) Constipation 2 (1.9) 1 (2.0) 1 (1.8) 5 (8.9) 2 (3.8) 1 (1.8) 3 (5.3) 12 (4.3) Nausea 2 (1.9) 1 (2.0) 2 (3.6) 4 (7.1) 2 (3.8) 2 (3.6) 1 (1.8) 11 (4.0) Diarrhea 3 (2.8) 0 (0.0) 3 (5.5) 3 (5.4) 1 (1.9) 1 (1.8) 0 (0.0) 8 (2.9) Vomiting 4 (3.7) 0 (0.0) 1 (1.8) 3 (5.4) 2 (3.8) 1 (1.8) 1 (1.8) 8 (2.9) General disorders and administration site conditions 12 (11.1) 8 (16.0) 3 (5.5) 5 (8.9) 12 (22.6) 6 (10.7) 10 (17.5) 36 (13.0) Edema peripheral 1 (0.9) 4 (8.0) 2 (3.6) 4 (7.1) 2 (3.8) 3 (5.4) 2 (3.5) 13 (4.7) Fatigue 2 (1.9) 2 (4.0) 0 (0.0) 2 (3.6) 4 (7.5) 2 (3.6) 2 (3.5) 10 (3.6) Investigations 10 (9.3) 5 (10.0) 4 (7.3) 6 (10.7) 5 (9.4) 8 (14.3) 5 (8.8) 28 (10.1) Weight increased 1 (0.9) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 3 (5.4) 1 (1.8) 5 (1.8) Infections and infestations 8 (7.4) 6 (12.0) 2 (3.6) 7 (12.5) 5 (9.4) 8 (14.3) 5 (8.8) 27 (9.7) Urinary tract infection 5 (4.6) 4 (8.0) 2 (3.6) 2 (3.6) 0 (0.0) 4 (7.1) 0 (0.0) 8 (2.9) Metabolism and nutrition disorders 6 (5.6) 3 (6.0) 3 (5.5) 3 (5.4) 4 (7.5) 3 (5.4) 2 (3.5) 15 (5.4) Hyperglycemia 1 (0.9) 0 (0.0) 0 (0.0) 3 (5.4) 2 (3.8) 0 (0.0) 1 (1.8) 6 (2.2) Injury, poisoning, and procedural complicationse 8 (7.4) 3 (6.0) 2 (3.6) 5 (8.9) 1 (1.9) 2 (3.6) 2 (3.5) 12 (4.3) Fall 1 (0.9) 1 (2.0) 1 (1.8) 3 (5.4) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.4) a150 mg twice daily. bOnce-daily dosing. c10 mg twice daily. d15 mg twice daily. eAEs were grouped by Medical Dictionary for Regulatory Activity terms. care.diabetesjournals.org Vinik and Associates 3259

The most common AEs related to CONCLUSIONS from baseline to end point were 27, 39, study drug were increased blood creat- This phase 2, randomized, double-blind, and 47% versus placebo (22%), respec- inine phosphokinase levels (1.9%) in the placebo- and active comparator– tively (P , 0.0001 for pregabalin 300 placebo group; dizziness (7.6%) and controlled adaptive study demonstrated and 600 mg/day). somnolence (5.1%) in the mirogabalin that mirogabalin was effective in reduc- It is noteworthy that no statistically groups (all arms combined); and somno- ing pain and was generally well tolerated significant differences were observed lence (8.0%), balance disorder (4.0%), in subjects with DPNP at doses ranging between pregabalin 300 mg/day and fatigue (4.0%), and peripheral edema from 5 to 30 mg/day. Beginning at week placebo in ADPS or proportion of re- (4.0%) in the pregabalin 300-mg/day 1, the highest three mirogabalin dosing sponders at end point in the current study. group. groups (15, 20, and 30 mg/day) had sig- Numeric improvements were observed in No deaths occurred during the study. nificantly greater mean reductions from ADPS and the proportion of responders in SAEs occurred in 1% of subjects in the baseline to week 5 in ADPS compared the pregabalin 300-mg/day group at end placebo group, 2.9% of subjects in the point, but differences were not statistically with placebo, and one dosing group mirogabalin groups, and no subjects in significant versus placebo. Of note, statis- (30 mg/day) met the criteria for mini- the pregabalin group. Only one SAE was tically significant differences in ADPS were mally clinically meaningful effect (i.e., a considered related to study medication. observed between pregabalin 300 mg/day decrease $1.0 point versus placebo). A 73-year-old white man with a medical and placebo at weeks 1 and 2, but not at These data are compelling given the history of obesity, uric acid elevation, weeks3,4,and5. study population had DPNP for a mean and hypertension experienced acute el- This was not an unexpected finding, as of 5.8 years, which is longer than those evations of aspartate aminotransferase pregabalin has shown inconsistent effi- (AST), alanine aminotransferase (ALT), who participated in pregabalin trials, cacy results previously, similar to what and total bilirubin after receiving miro- where subjects were excluded if the was observed in the current study. For . – gabalin 15 mg/day. Hepatic ultrasound, duration of DPNP was 5 years (20,23 example, in the pregabalin (Lyrica) regis- fi performed 6 days after abnormal labo- 25). Analysis of responders, de ned as tration program, pregabalin 300 mg/day $ $ ratory findings were observed, showed subjects who attained 30 or 50% showed approximately comparable effi- fatty infiltration and a 1.5-cm gallstone. reduction from baseline in ADPS, were cacy to placebo in two of five DPNP trials, No signs of bile stasis or dilation of the generally supportive of a mirogabalin and of the three studies that evaluated biliary tract were noted. The subject treatment effect compared with placebo, pregabalin 600 mg/day, results were took the last dose of study drug on day as improvements relative to placebo positive in two and negative in the other 35; total bilirubin returned to normal were statistically significant at 15-, 20-, (26). Additionally, recent evidence sug- (0.6 mg/dL) 6 days after the last dose, and 30-mg/day dose levels using one or gests that baseline comorbidities may and all elevated liver function test re- both responder definitions. Further- predict response to pregabalin. A post sults resolved 14 days after the last more, median time to clinically meaning- hoc analysis of data pooled from 16 dose. The patient was asymptomatic ful pain relief, calculated as time to reach placebo-controlled trials of pregabalin in throughout the course of events. $30% reduction from baseline ADPS, patients with DPNP or postherpatic neu- Twenty-four subjects discontinued was significantly shorter (44–56%) than ralgia (N = 4,527) demonstrated that the the study because of $1AEs:2(1.9%) placebo in the mirogabalin 15-, 20-, and presence of comorbid sleep disturbance subjects in the placebo group (hypergly- 30-mg/day groups. at baseline may, in part, predict substan- cemia, feeling hot), 20 (7.2%) subjects in The efficacy and safety of pregabalin tial pain relief in response to pregabalin the mirogabalin groups (dizziness, som- for the treatment of DPNP have been treatment (27). It is not known what role, nolence, and nausea were most com- evaluated extensively. Freeman et al. if any, baseline comorbidities had on re- mon), and 2 (4.0%) subjects in the (19) pooled and analyzed efficacy and sponse to pregabalin treatment in the pregabalin group (disturbance in atten- safety data from seven randomized, current study. The high placebo effect ob- tion, peripheral edema, fluid retention). placebo-controlled pregabalin trials. Tri- served in the current study may have also There was no notable difference in als ranged in duration from 5 to 13 weeks; contributed to the lack of statistically ECGs, physical examination, or neuro- included pregabalin 150-, 300-, and 600- significant differences between the pre- logic examinations and no clinically mg/day treatment arms (administered gabalin 300 mg/day and placebo arms. significant trends in hematology, bio- either twice daily or three times daily); Placeboeffectiscommoninclinicaltrials chemistry, or clinical laboratory test val- and excluded those who had DPNP longer of DPNP (28). In the analysis of pregabalin ues over time. One subject in the than 5 years. Overall, pregabalin showed DPNP trials conducted by Freeman et al. pregabalin 300-mg/day group and two variable and inconsistent reductions in (19), the average placebo response was subjects in the mirogabalin 15-mg/day ADPS and statistically significant in- –1.47. In our study, the placebo response group experienced ALT level $33 the creases in the proportion of responders. was somewhat higher at –1.86, which upper limit of normal (ULN) and AST In pregabalin 150-, 300-, and 600-mg/day may have made it harder for pregabalin level $33 ULN, one of whom also groups, LS mean differences in change to separate from placebo. However, and had a concomitant total bilirubin level from baseline to week 5 in ADPS were most notably, despite the magnitude of $23 ULN (case described above). No –1.98, –2.44, and –2.75 versus placebo the placebo response, mirogabalin sepa- trends for ALT/AST elevations $33 (–1.47; P # 0.01 for all comparisons, rated from placebo in a dose-dependent ULN were observed across treatment LOCF). The proportion of subjects who manner, reaching statistical significance groups. achieved $50% reductions in ADPS at the highest three dose levels. 3260 Efficacy and Safety of Mirogabalin Diabetes Care Volume 37, December 2014

Mirogabalin is a novel, preferentially previously, and ;25% had received pre- fees from Sanofi, Novo Nordisk, Eli Lilly, selective a2d-1 ligand with a unique bind- gabalin previously. It is difficult to specu- GlaxoSmithKline, Takeda, Merck, Daiichi Sankyo, ing profile that may translate to clinically late if this, combined with the high placebo Janssen, Novartis, Boehringer Ingelheim, MannKind, Halozyme, Intarcia, and Lexicon and received meaningful differences in both efficacy response, may have contributed to the grants/research support from Merck, Pfizer, and safety. A slower dissociation rate low efficacy observed with pregabalin in Sanofi, Novo Nordisk, Roche, Bristol-Myers from a2d-1 than a2d-2 may provide a the current study. However, a post hoc Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, wider therapeutic index with fewer CNS analysis of subjects with and without pre- AstraZeneca, Amylin, Janssen, Daiichi Sankyo, MannKind, Boehringer Ingelheim, Intarcia, and AEs (10). In support of this premise, miro- vious exposure to gabapentinoids did not Lexicon. K.F. and C.H. are employees of Daiichi gabalin demonstrated a balanced safety show differences in efficacy results (data Sankyo Pharma Development, and D.M. is an profile across all study treatments; no not shown). Last, durability of pain relief employee of Daiichi Sankyo Development Ltd. No deaths occurred during the study, and was not assessed, and long-term studies other potential conflicts of interest relevant to this there was a low overall rate of both AEs are needed to determine whether reduc- article were reported. Author Contributions. A.V., J.R., U.S., K.F., and AEs of special interest, including tions in ADPS observed with mirogabalin and D.M. interpreted the data and critically weight gain, edema, and balance disor- persist over time. reviewed and edited the paper. C.H. inter- der. The most common AEs of dizziness In summary, results of the first clini- preted the data, critically reviewed and edited and somnolence are expected based on cal trial using an adaptive design in pa- the paper, and provided the analyses. All the mechanism of action of mirogabalin. tients with DPNP show that mirogabalin authors had access to the data. A.V. is the guarantor of this work and, as such, had full Dizziness and somnolence are also ob- was effective and well tolerated in this access to all the data in the study and takes served with pregabalin, with dizziness ap- patient population at doses ranging responsibility for the integrity of the data and pearing to be dose related (19). Of note, from5to30mg/day.Overallefficacy the accuracy of the data analysis. the incidence of these AEs were some- and safety data suggest that miro- Prior Presentation. Parts of this study were what lower in the current study com- gabalin, given either once or twice daily presented at the Annual Meeting of the Amer- ican Academy of Neurology, Philadelphia, PA, pared with analysis of pregabalin DPNP with or without titration, provides anal- 26 April–3 May 2014 and at the 74th Scientific trials conducted by Freeman et al. (19), gesic effects with a potentially wider Sessions of the American Diabetes Association, where the incidences were 23.3 and safety margin compared with current San Francisco, CA, 13–17 June 2014. 14.3%, respectively. In addition to safety first-line treatments for DPNP. Three and tolerability, mirogabalin also has sev- of the mirogabalin arms (15, 20, and References eral appealing convenience characteristics 30 mg/day) had statistically significant 1. Veves A, Backonja M, Malik RA. Painful di- compared with current treatment options, reductions in ADPS versus placebo at abetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. including a potential for once-daily dosing week 5 and one (30 mg/day) met the Pain Med 2008;9:660–674 without titration and bedtime admin- criteria of “minimally meaningful ef- 2. Vinik AI, Nevoret ML, Casellini C, Parson H. istration. Bedtime administration is ben- fect,” defined as a $1.0-point decrease Diabetic neuropathy. Endocrinol Metab Clin eficial because pain tends to worsen at versus placebo. In addition, statistically North Am 2013;42:747–787 night, and nighttime dosing may limit significant reductions in ADPS versus 3. Doth AH, Hansson PT, Jensen MP, Taylor RS. The burden of neuropathic pain: a systematic the frequency and severity of dizziness placebo were observed as early as review and meta-analysis of health utilities. and somnolence during the day. week 1 in the mirogabalin 15-, 20-, Pain 2010;149:338–344 The current study has a few limitations and 30-mg/day groups and continued 4. Tesfaye S, Boulton AJ, Dickenson AH. Mech- that should be considered. First, the throughweek5despiteahighplacebo anisms and management of diabetic painful dis- – tal symmetrical polyneuropathy. Diabetes Care uniqueness of the study design precludes response rate. Finally, 56 67% of sub- 2013;36:2456–2465 direct comparisons to other studies. Dif- jects achieved $30% reduction in ADPS 5. Tesfaye S, Selvarajah D. Advances in the ep- ferences in study duration, patient popu- in the top four mirogabalin treatment idemiology, pathogenesis and management of lations, and other variables can greatly arms (i.e., 10, 15, 20, and 30 mg/day). diabetic peripheral neuropathy. Diabetes – impact efficacy; therefore, comparisons Although phase 3 studies are needed to Metab Res Rev 2012;28(Suppl. 1):8 14 fi 6. Catterall WA. Voltage-gated calcium chan- must be made with caution. Second, the con rm and further these results, these nels. Cold Spring Harb Perspect Biol 2011;3: 5-week duration of the study may have multiple lines of evidence, when taken a003947 been too short to observe the full magni- together, suggest that mirogabalin may 7. Li CY, Zhang XL, Matthews EA, et al. Calcium tude of pain reduction or the placebo re- be a promising new treatment option channel alpha2delta1 subunit mediates spinal sponse. Third, the proportion of subjects for patients with DPNP. hyperexcitability in pain modulation. Pain 2006;125:20–34 with type 1 diabetes was relatively low in 8. Taylor CP. Mechanisms of analgesia by the mirogabalin 30 mg/day group (1.8%), gabapentin and pregabalindcalcium channel and it is unknown whether this impacted Acknowledgments. The authors acknowledge alpha2-delta [Cavalpha2-delta] ligands. Pain the results. Low incidences of subjects editorial assistance provided by Drs. W. Lesley 2009;142:13–16 with type 1 diabetes is consistent with R. Castro and Lynn Brown, both at ApotheCom, 9. Field MJ, Li Z, Schwarz JB. Ca2+ channel which was funded by Daiichi Sankyo, Inc. The alpha2-delta ligands for the treatment of neu- other clinical development programs authors also acknowledge Julie Pitcher, RN, ropathic pain. J Med Chem 2007;50:2569–2575 (26). Fourth, pregabalin 300 mg/day was BSN, Biostatistics and Data Operations Depart- 10. Yokoyama T, Arakawa N, Domon Y, et al. administered as 150 mg twice daily, and it ment at Daiichi Sankyo Pharma Development, Pharmacological, pharmacokinetics and safety fi is unknown whether other pregabalin Edison, NJ. pro les of DS-5565 a novel a2a ligand. Poster Duality of Interest. A.V. has received research presented at the World Congress of Neurology, dosing regimens would have resulted funding from Daiichi Sankyo for the conduct of Vienna, Austria, 21–26 September 2013 in a similar response (29). Overall, ;6% the study. J.R. has served on scientific advisory 11. Field MJ, Cox PJ, Stott E, et al. Identification of of subjects had received gabapentin boards and received honorarium or consulting the alpha2-delta-1 subunit of voltage-dependent care.diabetesjournals.org Vinik and Associates 3261

calcium channels as a molecular target for pain 16. Vinik AI, Casellini CM. Guidelines in the of neuropathic pain associated with diabetic mediating the analgesic actions of pregabalin. management of diabetic nerve pain: clinical util- neuropathy: a randomized, double-blind Proc Natl Acad Sci U S A 2006;103:17537– ity of pregabalin. Diabetes Metab Syndr Obes study. Eur J Pain 2008;12:203–213 17542 2013;6:57–78 24. Richter RW, Portenoy R, Sharma U, 12. Barclay J, Balaguero N, Mione M, et al. 17. Argoff CE, Cole BE, Fishbain DA, Irving GA. Lamoreaux L, Bockbrader H, Knapp LE. Relief Ducky mouse phenotype of epilepsy and ataxia Diabetic peripheral neuropathic pain: clinical of painful diabetic peripheral neuropathy with is associated with mutations in the Cacna2d2 and quality-of-life issues. Mayo Clin Proc 2006; pregabalin: a randomized, placebo-controlled gene and decreased calcium channel current 81(Suppl.):S3–S11 trial. J Pain 2005;6:253–260 in cerebellar Purkinje cells. J Neurosci 2001;21: 18. Dworkin RH, Turk DC, Revicki DA, et al. De- 25.LesserH,SharmaU,LaMoreauxL,Poole 6095–6104 velopment and initial validation of an expanded RM. Pregabalin relieves symptoms of painful di- 13. Li Z, Taylor CP, Weber M, et al. Pregabalin and revised version of the Short-form McGill Pain abetic neuropathy: a randomized controlled tri- is a potent and selective ligand for a(2)d-1 and Questionnaire (SF-MPQ-2). Pain 2009;144:35–42 al. Neurology 2004;63:2104–2110 a(2)d-2 calcium channel subunits. Eur J Pharma- 19. Freeman R, Durso-Decruz E, Emir B. Effi- 26. European Medicines Agency. Lyrica scien- col 2011;667:80–90 cacy, safety, and tolerability of pregabalin treat- tific discussion [article online], 2014. Available 14. Tesfaye S, Vileikyte L, Rayman G, et al.; To- ment for painful diabetic peripheral neuropathy: from http://www.ema.europa.eu/docs/en_GB/ ronto Expert Panel on Diabetic Neuropathy. findings from seven randomized, controlled trials document_library/EPAR_-_Scientific_Discussion/ Painful diabetic peripheral neuropathy: consen- across a range of doses. Diabetes Care 2008;31: human/000546/WC500046600.pdf. Accessed 6 sus recommendations on diagnosis, assessment 1448–1454 February 2014 and management. Diabetes Metab Res Rev 20. Rosenstock J, Tuchman M, LaMoreaux L, 27. Vinik A, Emir B, Parsons B, Cheung R. Pre- 2011;27:629–638 Sharma U. Pregabalin for the treatment of painful diction of pregabalin-mediated pain response by 15. Bril V, England JD, Franklin GM, et al.; Amer- diabetic peripheral neuropathy: a double-blind, severity of sleep disturbance in patients with ican Academy of Neurology; American Asociation placebo-controlled trial. Pain 2004;110:628–638 painful diabetic neuropathy and post-herpetic of Neuromuscular and Electrodiagnostic Medi- 21. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, neuralgia. Pain Med 2014;15:661–670 cine; American Academy of Physical Medicine Poole RM. Clinical importance of changes in 28. Merante D, Skouteris G, Malik R. Develop- and Rehabilitation. Evidence-based guideline: chronic pain intensity measured on an 11-point ing new molecules for the treatment of painful treatment of painful diabetic neuropathyd numerical pain rating scale. Pain 2001;94:149–158 diabetic peripheral neuropathy: Is it feasible report of the American Association of Neuro- 22. Farrar JT. What is clinically meaningful: out- given the magnitude of the placebo response muscular and Electrodiagnostic Medicine, the come measures in pain clinical trials. Clin J Pain in proof of concept clinical studies? J Diabetes American Academy of Neurology, and the 2000;16(Suppl.):S106–S112 Metab 2013;4:305 American Academy of Physical Medicine & Reha- 23. Tolle¨ T, Freynhagen R, Versavel M, 29. Lyrica (pregabalin) prescribing information. bilitation. Muscle Nerve 2011;43:910–917 Trostmann U, Young JP Jr. Pregabalin for relief New York, Pfizer, 2013