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Research Paper

Efficacy and safety of EMA401 in peripheral neuropathic pain: results of 2 randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy

Rice, Andrew S.C.a; Dworkin, Robert H.b; Finnerup, Nanna B.c; Attal, Nadined,e; Anand, Praveenf; Freeman, Royg; Piaia, Alessandroh; Callegari, Francescai; Doerr, Christiej; Mondal, Subhayank; Narayanan, Nishak; Ecochard, Laurenti; Flossbach, Yaninai; Pandhi, Shalooi,*

Author Information
doi: 10.1097/j.pain.0000000000002252

1. Introduction

Existing treatments for peripheral neuropathic pain (PNP) have modest efficacy and are often not well tolerated, and the development of improved treatments for these common chronic pain conditions is recognised as a significant unmet need. According to the latest definition of the International Association for the Study of Pain, PNP (ICD 11 code: MG30.51) is defined as “pain caused by a lesion or disease of the peripheral somatosensory nervous system.”13,16 Based on a recent systematic review of epidemiological studies in neuropathic pain (NP), the prevalence of NP globally ranges from 0.9% to 17.9%, with the overall incidence rate for NP at 8.2/1000 person-years (PY; 95% confidence interval [CI]: 8.0-8.4).31 Postherpetic neuralgia (PHN; 1E91.5)13 is a frequent complication of herpes zoster in immunocompromised patients. About 20% of patients with herpes zoster report pain at 3 months after the onset of symptoms and 15% report pain at 2 years.17 Painful diabetic neuropathy (PDN; 8C03.0)13 is a disabling clinical manifestation of diabetic peripheral neuropathy; a prevalence ranging from 8% to 30% has been reported in multiple studies in patients with a long duration of diabetes (8-17 years).12 Overall incidence of PHN was recently reported at 3.9 to 42.0/100,000 (PY); for PDN, this was 15.3 to 72.3/100,000 (PY).31

Recommendations from the NP Special Interest Group for the pharmacotherapy of NP include the use of tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (eg, duloxetine and venlafaxine), pregabalin, and gabapentin as first-line agents. Second-line therapy includes topical lidocaine patches, high-concentration topical capsaicin, and tramadol.10 However, existing treatments have modest and variable efficacy and limited tolerability, especially in vulnerable populations. Furthermore, current evidence suggests that there are no disease-modifying therapies available for established PHN or PDN.11,15 Despite advances in antiviral therapy during acute herpes zoster infection, and the more recent introduction of vaccination against the varicella-zoster virus, PHN continues to be a significant clinical problem.18

Following the first report that small molecule angiotensin II type 2 receptor (AT2R) antagonists are novel analgesics for NP and other pain conditions,27 several preclinical studies suggested that AT2R contributes to pathogenesis of NP and that AT2R antagonists could have analgesic efficacy in these conditions.2,3,19,23,26 Recent preclinical studies indicated that modulating macrophage-mediated neuroimmune interactions may explain the analgesic properties of AT2R antagonists.24,25

EMA401/olodanrigan is a selective AT2R antagonist. The available preclinical data, results of the phase 2a placebo-controlled study in PHN,22 and an open-label phase 2a study in chemotherapy-induced NP1 all supported the initiation of 2 phase 2b studies with EMA401 in patients with PHN (EMPHENE [NCT03094195]) and PDN (EMPADINE [NCT03297294]). However, based on the results of the 39-week twice-daily repeat dosing toxicity study conducted in cynomolgus monkeys (Macaca fascicularis; Novartis Study no. 1570321, unpublished data), all clinical studies that were ongoing at that time—including these 2 studies—were terminated. Here, we report the safety and efficacy results of EMPHENE and EMPADINE.

2. Methods

2.1 Study design and participants

EMA401 in reducing 24-hour average pain intensity score in patients with post-herpetic neuralgia (EMPHENE, dose-ranging study to determine the safety and efficacy of 3 dose levels of EMA401 in reducing 24-hour average pain intensity score in patients with postherpetic neuralgia) and EMA401 100 mg b.i.d. in reducing 24-hour average pain intensity score in patients with painful diabetic neuropathy (EMPADINE, study to determine the safety and efficacy of EMA401 100 mg b.i.d. in reducing 24-hour average pain intensity score in patients with painful diabetic neuropathy) were both double-blind, randomised, placebo-controlled, parallel treatment studies. The design of both studies was aligned with the respective chosen primary estimand.6 Participants were recruited from 45 (EMPHENE) and 49 (EMPADINE) sites, respectively (including pain and neurology clinics in hospitals and clinical trial facilities), across 19 countries (see Appendix S1 in the Supplemental Digital Content, available at http://links.lww.com/PAIN/B317).

Participants aged ≥18 years with PHN and those with type I or type II diabetes mellitus with painful distal symmetrical sensorimotor neuropathy of ≥6 months' duration were included in the EMPHENE and EMPADINE, respectively. For both the studies, participants had to have moderate to severe NP across the screening epoch (numeric rating scale [NRS] ≥4). The assessment of moderate to severe pain was made using a proprietary screening algorithm device. General principles of the algorithm were to exclude participants with scores below the minimum mean baseline pain intensity of 4 (NRS scale) and those who were not compliant in completing the required data or had unacceptable variability in their baseline intensity. In addition, a score of ≥4 on the Douleur Neuropathique 4 Questions at screening was required to be included in EMPADINE. For both studies, participants were required to complete a daily electronic diary (eDiary) as defined in the protocol.

Participants were allowed to continue taking either pregabalin or gabapentin (EMPHENE) and pregabalin or duloxetine (EMPADINE) for managing their NP, as long as dosing had been stable for at least 2 weeks before the randomisation (EMPHENE)/screening (EMPADINE) visit and that dose was maintained for the duration of the study. List of inclusion and exclusion criteria and the rules for concomitant drugs is provided in the Supplemental Digital Content (see Table S1, available at http://links.lww.com/PAIN/B317). Participants were also allowed to take up to 3 g paracetamol daily for relief of incidental pain (for any reason during the studies).

Participants provided written informed consent before participation. The Independent Ethics Committee or Institutional Review Board reviewed the study protocol for each centre. The approved protocols for both studies are provided in the Supplemental Digital Content (see Table S2, available at http://links.lww.com/PAIN/B317). The studies were conducted according to the ICH E6 Guideline for Good Clinical Practice that has its origins in the Declaration of Helsinki.

2.2. Randomisation and masking

2.2.1. Original plan

Overall, 360 and 400 participants, respectively, were planned to be enrolled in the EMPHENE and EMPADINE studies. Details of the original plan of randomisation for the 2 studies are provided in the Supplemental Digital Content (see Appendix S1 and S2, available at http://links.lww.com/PAIN/B317; Fig. 1). At baseline, all eligible participants were randomised via interactive response technology to one of the treatment arms in the double-blind treatment epoch and to one of the treatment arms in the double-blind treatment withdrawal epoch as per the prespecified randomisation scheme. Patients, investigator staff, persons performing the assessments, and data analysts were masked to treatment assignment.

Figure 1.
Figure 1.:
(A) Study design: EMPHENE (proposed study design). (B) Study design: EMPHENE: (actual study design); EMPADINE (proposed and actual study Design). In the EMPHENE study, the second cohort was not initiated as the studies were prematurely terminated. In the EMPADINE study, the study design was the same as planned but the number of participants recruited was lower due to premature study termination. pts, participants.

Both studies were terminated early in February 2019, and the details of the safety measures instituted as part of the urgent-safety measure (USM) are provided in the Supplemental Digital Content (see Appendix S3, available at http://links.lww.com/PAIN/B317).

2.2.2. Final design post termination

Due to the early termination, the second cohort of the EMPHENE was not initiated and no participant was randomised to a high-dose of EMA401 300 mg b.i.d. Fewer participants than planned were randomised for both studies.

2.3. Procedures

Both studies consisted of 3 epochs, that is, screening, double-blind treatment, and double-blind treatment withdrawal (Figs. 1A and B). During screening, participants went through an eligibility assessment and training on how to use the eDiary for daily reporting. Eligible participants who completed the preliminary screening assessments received an eDiary. Details on completing the eDiary device is provided in the Supplemental Digital Content (see Appendix S4, available at http://links.lww.com/PAIN/B317). At the screening/baseline visit, eligible participants were randomised 1:1:1 to either oral placebo, EMA401 25 mg, or EMA401 100 mg b.i.d. in the EMPHENE and 1:1 to oral placebo or EMA401 100 mg b.i.d. in the EMPADINE for 12 weeks. The NP Symptom Inventory (NPSI) score was to be completed by participants using the electronic tablet at the site at the specified visits every 4 weeks. EMA401 and placebo were provided as capsules to be self-administered orally b.i.d., consisting of a morning dose and an evening dose. At the end of the 12-week double-blind treatment epoch, there was a 1-week double-blind treatment withdrawal epoch. Participants completed the pain diary each day during each epoch. Details of the double-blind treatment withdrawal epoch are provided in the Supplemental Digital Content (see Appendix S5, available at http://links.lww.com/PAIN/B317).

As part of the USM, all participants who received treatment were requested to return for 2 follow-up visits one between 4 and 8 weeks and then between 12 and 16 weeks after discontinuation of treatment. They underwent laboratory assessments in addition to the assessments already specified in the protocol.

2.4. Outcomes

The primary outcome for both studies was change in the weekly mean of the 24-hour average pain intensity score, using an 11-point NRS, from baseline to week 12 in participants with PHN (EMPHENE) and PDN (EMPADINE). The parameters that were evaluated using the 11-point NRS were 24-hour average pain intensity score and 24-hour worst pain score. The NPSI (key secondary outcome of the EMPADINE) is a 12-item patient-reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain, and paraesthesia/dysaesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms.5 The list of primary, secondary, and safety outcomes measured in both studies is provided in the Supplemental Digital Content (see Table S3, available at http://links.lww.com/PAIN/B317).

As part of the USM after study termination, all participants who were exposed to the EMA401 or placebo were required to return for laboratory assessments (full haematology including coagulation and clinical chemistry panel) in addition to the specified assessments. All newly occurring or ongoing adverse events (AEs; including liver laboratory triggers and liver events) were followed up until resolution. The timings of study procedures and assessments are summarised in the Supplemental Digital Content (see Table S4, available at http://links.lww.com/PAIN/B317).

2.5. Statistical analysis

2.5.1. Sample size determination

A sample size of 90 participants per group in the EMPHENE yielded 77% power for the primary variable (NRS change from baseline to week 12) assuming candidate shapes for the dose-response using MCP-Mod (Multiple Comparison Procedure—Modelling) methodology with the alpha equal to 0.025 (one-sided). For the EMPADINE, a sample size of 200 participants per group yielded 85% power for the primary efficacy variable (NRS change from baseline to week 12) and 84% power for the key secondary variable (NPSI change from baseline to week 12) to show that EMA401 100 mg is statistically significant over placebo, using a hierarchical testing procedure. Therefore, 360 (EMPHENE) and 400 (EMPADINE) participants were planned to be recruited. More details on the sample size calculation are provided in the Supplemental Digital Content (see Appendix S6, available at http://links.lww.com/PAIN/B317).

2.5.2. Methods for statistical analysis

Due to the premature termination of the studies, not all planned participants were enrolled (N = 129 EMPHENE and N = 137 for EMPADINE) and this had an impact on the power for the final efficacy analysis of EMA401 in both studies. For this reason, the P values reported for the primary and key secondary outcomes are intended only as descriptive measures and should be interpreted with caution. In the EMPHENE, because the EMA401 300 mg dose could not be initiated due to the premature study termination, the dose-response characterisation via the MCP-Mod methodology was not performed. As a result, the first secondary objective was evaluated to compare the efficacy of the 2 doses (25 and 100 mg) of EMA401 vs placebo in the 24-hour average pain intensity score at week 12 using the 11-point NRS. In the EMPADINE, a hierarchical testing procedure (sequentially rejective, weighted Bonferroni-type test using graphical approach) was planned to control the family-wise type I error rate at the one-sided 2.5% significance level between primary and key secondary efficacy measure.

In both studies, the full analysis set (FAS) included all randomised patients and was the primary efficacy analysis population. The modified FAS (mFAS) included all participants who could have completed week 12 by the study termination date of February 25, 2019. All participants who were randomised at least 12 weeks before February 25, 2019, were included in the mFAS. The mFAS was used for sensitivity analyses. The safety population included all participants who took at least one dose of the study medication and who had at least one post-baseline safety assessment. The primary estimation method for the primary endpoint was based on an analysis of covariance model including region (eg, America or Europe, Australia, and Asia for the EMPHENE and America or Europe and Australia for the EMPADINE), treatment, sex, and use of concomitant pain medication for PHN/PDN (yes/no) as factors and age and baseline (mean pain intensity) score as covariates. The primary analysis accounted for different intercurrent events (ie, events that occurred post-randomisation) in alignment with the chosen primary estimand.20 Furthermore, details on handling of intercurrent events are included in the Supplemental Digital Content (see Appendix S7, available at http://links.lww.com/PAIN/B317). Methods for sensitivity analyses for the primary estimand and for supplementary analyses targeting a supplementary estimand are presented in the Supplemental Digital Content (see Appendix S10, available at http://links.lww.com/PAIN/B317).

Secondary outcomes analyses included responder analyses (based on at least a 30% or 50% improvement from baseline on the NRS), analyses on NPSI total score, Brief Pain Inventory Short Form (BPI-SF) interference total score, the weekly mean of the 24-hour worst NRS pain, Insomnia Severity Index (ISI), and Patient Global Impression of Change (PGIC). Details of the analysis methods are provided in the Supplemental Digital Content (see Appendix S11, available at http://links.lww.com/PAIN/B317). The safety analysis was conducted using the safety population, and the participants were analysed by the actual treatment they received. An external independent data monitoring committee had access to unblinded data to conduct quarterly safety reviews. Further details on the safety analysis are provided in the Supplemental Digital Content (see Appendix S12, S13 and S15, available at http://links.lww.com/PAIN/B317). The clinical trials are registered with ClinicalTrials.gov with trial registration numbers NCT03094195 (EMPHENE) and NCT03297294 (EMPADINE).

2.6. Role of the funding source

Novartis (sponsor) designed the study in collaboration with the study steering committee and was responsible for the trial monitoring, data collection, reporting, and analysis. Retrieval, analyses of collected data, and writing of the report were performed by employees of Novartis along with an independent contract research organisation who had access to unblinded data. All authors had full access to the clinical study reports and have final responsibility for the decision to submit the manuscript for publication. All authors reviewed and approved the final version of the manuscript for submission. As per ICMJE criteria, none of the authors received any remuneration for writing/reviewing of the manuscript.

3. Results

Between June 27, 2017, and March 7, 2019, for the EMPHENE, and March 14, 2018, and March 25, 2019, for the EMPADINE, 129 (EMPHENE) and 137 (EMPADINE) participants were enrolled. Based on the results of the preclinical safety studies, it was decided to implement an USM to stop the dosing of all participants and to terminate studies on February 22, 2019.

For the EMPHENE, 129 of 230 screened participants were randomised across the 3 treatment arms, of whom 87 (67.4%) completed the double-blind treatment epoch and 80 (62.0%) completed the treatment during the double-blind treatment epoch (Fig. 2). Overall, 80 participants continued in and completed the treatment-withdrawal epoch. The primary reason for treatment discontinuation during the double-blind treatment epoch was study termination by the sponsor (n = 33 out of 129, 25.6%). Other reasons for treatment discontinuation occurred with lesser frequency and are mentioned in Figure 2.

Figure 2.
Figure 2.:
Trial Profile. *Study completer. Participants could discontinue from the study treatment but continue participating in the study, therefore “Study completer” includes all participants who completed the treatment epoch whether or not they completed study treatment.

For the EMPADINE, 137 of 306 screened participants were randomised across the 2 treatment arms, of whom 62 (45.3%) completed the double-blind treatment epoch and 52 (38.0%) completed the study treatment during the double-blind treatment epoch (Fig. 2). Overall, 53 participants continued in the treatment withdrawal epoch, of whom one participant discontinued the treatment withdrawal epoch due to study termination by the sponsor and 52 participants completed it. The primary reason for treatment discontinuation during the double-blind treatment epoch was study termination by the sponsor (n = 61 out of 137, 44.5%). Other reasons for treatment discontinuation occurred with lesser frequency and are mentioned in Figure 2.

Baseline demographics were well balanced across the treatment arms for both studies (Table 1). In EMPHENE, randomised participants had a median PHN duration of 2.2 years and a mean baseline NRS score of 5.8. In EMPADINE, randomised participants had a median PDN duration of 5.7 years and a mean baseline NRS score of 5.5. About 88% (EMPHENE) and 97% (EMPADINE) participants, respectively, in both studies were on concomitant therapy for treatment of NP and the majority of participants were on antiepileptic therapy (eg, valproic acid, carbamazepine, phenytoin; 95.3%[EMPHENE] and 59.1% [EMPADINE]). Lack of efficacy ([79.1%; EMPHENE] and [44.5%; EMPADINE]) was the primary reason for discontinuation of antiepileptic therapy in most participants.

Table 1 - Patient demographics and clinical characteristics.
EMPHENE (PHN), N = 129 EMPADINE (PDN) N = 137
EMA401 (25 mg b.i.d.) N = 43 EMA401 (100 mg b.i.d.) N = 43 Placebo (b.i.d.) N = 43 EMA401 (100 mg b.i.d.) N = 70 Placebo (b.i.d.) N = 67
Age (y) 72.7 (9.1) 70.5 (9.3) 70.9 (8.3) 64.6 (7.9) 65.5 (10.7)
Sex, n (%)
 Male 23 (53.5) 28 (65.1) 13 (30.2) 50 (71.4) 43 (64.2)
 Female 20 (46.5) 15 (34.9) 30 (69.8) 20 (28.6) 24 (35.8)
Ethnic origin, n (%)
 Caucasian 33 (76.7) 32 (74.4) 32 (74.4) 70 (100) 63 (94.0)
 Asian 9 (20.9) 10 (23.3) 10 (23.3) 0 1 (1.5)
 Other 1 (2.3) 1 (2.3) 1 (2.3) 0 3 (4.5)
Clinical characteristics of the population
 Duration of PHN/PDN (y)* 3.5 (3.4) 2.9 (2.7) 4.1 (4.9) 6.5 (5.4) 6.7 (5.1)
 Baseline NRS score 5.9 (1.3) 5.7 (1.1) 5.9 (1.3) 5.3 (1.4) 5.6 (1.2)
No. of prior medications, n (%)
 2 9 (20.9) 11 (25.6) 10 (23.3) 10 (14.3) 11 (16.4)
 3 10 (23.3) 8 (18.6) 7 (16.3) 8 (11.4) 5 (7.5)
 4 8 (18.6) 9 (20.9) 9 (20.9) 4 (5.7) 5 (7.5)
 ≥5 16 (37.2) 15 (34.9) 17 (39.5) 5 (7.1) 4 (6.0)
Use of stable concomitant medications, n (%)
 Pregabalin 18 (41.9) 16 (37.2) 15 (34.9) 13 (18.6) 20 (29.9)
 Gabapentin 5 (11.6) 4 (9.3) 6 (14.0) NA NA
 Duloxetine NA NA NA 3 (4.3) 3 (4.5)
Data are mean (SD) unless otherwise stated.
*Duration of PHN/PDN was calculated from the start date of PHN/PDN as recorded on the eCRF until the date of Screening Visit.
b.i.d., twice daily; eCRF, electronic case report form; N, total number of participants; n, participants per treatment arm; NA, not applicable; NRS, numeric rating scale; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; SD, standard deviation.

The majority of the randomised participants in both the studies were exposed to the treatment for at least 12 to 13 weeks. Treatment exposure was 53.5% (EMA401 25 mg), 60.5% (EMA401 100 mg) and 58.1% (placebo) in the EMPHENE; median exposure was 85 days in both the active arms and 84 days in the placebo arm. Treatment exposure in the EMPADINE was 40.6% (EMA401 100 mg) and 39.4% (placebo) with a median exposure of 56 days and 60.5 days in the active and placebo arms, respectively.

For both studies, the least square means for the change from baseline in the weekly mean of the 24-hour average NRS pain score over 12 weeks illustrated reduction in the NRS pain score in all of the treatment arms. Detailed results of the primary and secondary endpoints are presented in Table 2. The 24-hour average NRS pain score during the treatment withdrawal epoch is presented in the Supplemental Digital Content (see Table S5, available at http://links.lww.com/PAIN/B317). For the EMPHENE, at week 12, the treatment difference (TD) between EMA401 25 mg and placebo for the primary efficacy endpoint was −0.2 (95% CI: −1.3 to 0.9; P value: 0.689), whereas the TD between EMA401 100 mg and placebo was −0.5 (95% CI: −1.6 to 0.6; P value: 0.350), numerically (based on the point estimate) in favour of EMA401. The adjusted P value for the comparison of at least one active dose vs placebo was 0.689 (Fig. 3).

Table 2 - Summary of primary and secondary efficacy outcome results at week 12.
EMPHENE (PHN), N = 129 EMPADINE (PDN), N = 137
EMA401 (25 mg b.i.d.), N = 43 EMA401 (100 mg b.i.d.), N = 43 Placebo (b.i.d.), N = 43 EMA401 (100 mg b.i.d.), N = 70 Placebo (b.i.d.), N = 67
Primary outcome
 Primary analysis: Weekly mean of the 24-hour average pain score using NRS change from baseline to week 12 (LS mean [SE]) −0.9 (0.40) −1.2 (0.38) −0.7 (0.40) −1.9 (0.31) −1.3 (0.27)
 TD (LS mean) −0.2 (95% CI: −1.3 to 0.9; P value: 0.689) −0.5 (95% CI: −1.6 to 0.6; P value: 0.350) NA −0.6 (95% CI: −1.4 to 0.1; P value: 0.101) NA
Secondary outcomes
 At least 30% pain reduction at week 12* 22.3% (6/25) 29.6% (11/26) 23.6% (10/24) 52.7% (14/32) 40.4% (12/31)
 Odds ratio 0.9 (95% CI: 0.3 to 3.2; P value: 0.908) 1.4 (95% CI: 0.4 to 4.5; P value: 0.609) NA 1.6 (95% CI: 0.7 to 3.9; P value: 0.255) NA
 At least 50% pain reduction at week 12* 12.0% (4/25) 13.4% (7/26) 10.3% (5/24) 31.4% (8/32) 14.1% (4/31)
 Odds ratio 1.2 (95% CI: 0·3 to 4·5; P value: 0·800) 1·3 (95% CI: 0·4 to 4·8; P value: 0·653) NA 2.8 (95% CI: 0.8 to 9.6; P-value: 0.100) NA
 24-hour worst NRS pain score change from baseline to week 12 −1.0 (1.9) −2.0 (2.4) −1.5 (2.2) −1.6 (1.8) −1.3 (1.6)
 Change from baseline to week 12 in BPI-SF interference total score −8.2 (13.0) −15.0 (13.3) −14.1 (12.5) −12.0 (13.3) −10.8 (14.6)
 PGIC at week 12 (“very much improved” or “much improved”) 7% 11.6% 20.9% 15.7% 19.4%
 Change from baseline to week 12 in NPSI total score; TD (LS mean) 0.6 (95% CI: −0.4 to 1.6; P value: 0.225) 0.1 (95% CI: −1.0 to 1.1; P value: 0.914) NA −0.5 (95% CI: −1.3 to 0.2; P-value: 0.168 NA
 Change from baseline to week 12 in ISI −1.3 (4.5) −4.1 (5.1) −3.4 (4.2) −4.0 (4.9) −1.0 (6.3)
Data are mean (SD) unless otherwise stated.
For NRS, NPSI, BPI, and ISI: A negative (positive) treatment difference indicates an advantage (disadvantage) over placebo.
*Model-adjusted rates are presented as percentages; in brackets are the actual number of patients with observed response.
b.i.d., twice daily; BPI-SF, brief pain inventory short form; CI, confidence interval; ISI, insomnia severity index; LS, least square; NA, not applicable; NPSI, neuropathic pain symptom inventory; NRS, numeric rating scale; PDN, painful diabetic neuropathy; PGIC, Patient Global Impression of Change PHN, postherpetic neuralgia; SE, standard error; TD, treatment difference vs placebo.

Figure 3.
Figure 3.:
Change in the weekly mean of the 24-hour average pain score using the NRS during post-baseline visits in the double-blind treatment epoch (FAS). Note: Multiplicity adjustment for the pairwise comparisons has been performed using the Hochberg procedure. b.i.d., twice daily; CI, confidence interval; FAS, full analysis set; LS, least squares; NRS, numeric rating scale.

For EMPADINE, at week 12, the TD between EMA401 100 mg and placebo was −0.6 (95% CI: −1.4 to 0.1; P value: 0.101) for the primary efficacy endpoint, which was numerically in favour of the EMA401 treatment arm. The P value for the treatment comparison of EMA401 100 mg with placebo for the key secondary endpoint of the change from baseline to week 12 in the NPSI total score was calculated nonetheless and was 0.168. The pattern of pain reduction in the NRS was different for EMA401 100 mg and placebo with a separation in the pattern starting at week 4 and reaching the maximum at week 12 (Fig. 3). For both the studies, the pattern of pain reduction in the supplementary (see Figure S1 in the Supplemental Digital Content, available at http://links.lww.com/PAIN/B317) and sensitivity analysis was consistent with the primary analysis as described in the Supplemental Digital Content (see Appendix S10, available at http://links.lww.com/PAIN/B317). In the EMPADINE, reduction in NPSI total score compared to placebo was seen in the EMA401 100 mg treatment arm at the end of week 12 (Table 2). In the EMA401 100 mg arm, the reduction in NPSI dimensional scores at week 12 was higher as compared to the placebo arm for all of the dimensions (see Table S6, Appendix S11 in the Supplemental Digital Content, available at http://links.lww.com/PAIN/B317).

In the EMPHENE, the TD of the NPSI total score between both EMA401 doses and placebo at week 12 was numerically in favour of placebo (Table 2). In the EMA401 treatment arms, the reductions in NPSI dimensional score at week 12 were lower compared to placebo for all dimensions except for deep/pressing pain (see Table S6, Appendix S11 in the Supplemental Digital Content, available at http://links.lww.com/PAIN/B317). In the EMPHENE, the proportion of participants meeting the responder criteria of at least 30% pain reduction from baseline to week 12 in all the 3 treatment arms was <30%; however, for the responder criteria of at least 50% pain reduction, the proportion of participants was <15% (Table 2; Supplemental Figure S2, available at http://links.lww.com/PAIN/B317).

In the EMPADINE, both the 30% and 50% responder criteria overall were numerically in favour of the EMA401 100 mg arm (Table 2; Supplemental Figure S2, available at http://links.lww.com/PAIN/B317). In both the EMPHENE and EMPADINE at week 12, the proportions of participants in the “very much improved” or “much improved” PGIC categories were highest in the placebo arm compared to the EMA401 arms. In both studies, the mean change from baseline for the 24-hour worst NRS pain score, BPI-SF interference total scores and ISI scores were numerically in favour of EMA401 100 mg compared with placebo (Table 2).

For the EMPADINE, the proportion of participants using paracetamol for incidental pain at least once during the double-blind treatment epoch was similar in both treatment arms (20.0% with EMA401 100 mg and 19.4% with placebo). The number of days (median) that the participants were at risk from the start of the treatment until the event (first intake of paracetamol) was 44.0 (range: 2-90) days for those treated with EMA401 100 mg and 56.5 (range: 2-92) days for those treated with placebo.

Detailed safety results for the 2 studies are presented in Table 3. The most frequently reported treatment-emergent AEs (TEAEs) during the double-blind treatment epoch in the EMPHENE and EMPADINE are described in the Supplemental Digital Content (see Appendix S12, available at http://links.lww.com/PAIN/B317). None of these events were reported as serious in both studies. The severity of the TEAEs was generally mild across treatment arms in both studies except for 3 events (2 of increased lipase and one of upper abdominal pain) that were of moderate severity in the EMPADINE. No deaths were reported during the studies. Liver function parameters were within normal limits for all participants in both studies. Details are described in the Supplemental Digital Content (see Appendix S15, available at http://links.lww.com/PAIN/B317).

Table 3 - Adverse events in the double-blind treatment epoch.
EMPHENE (PHN) N = 129 EMPADINE (PDN) N = 137
EMA401 (25 mg b.i.d.) N = 43 EMA401 (100 mg b.i.d.) N = 43 Placebo (b.i.d.) N = 43 EMA401 (100 mg b.i.d.) N = 69 Placebo (b.i.d.) N = 66
Participants with at least one AE 25 (58.1) 27 (62.8) 28 (65.1) 44 (63.8) 30 (45.5)
Participants with at least one SAE 0 3 (7.0) 3 (7.0) 5 (7.2) 3 (4.5)
Deaths 0 0 0 0 0
Most frequent (at least 3.0% in any treatment arm) TEAE
 Diarrhoea 3 (7.0) 2 (4.7) 3 (7.0) 3 (4.3) 1 (1.5)
 Nasopharyngitis 3 (7.0) 2 (4.7) 4 (9.3) 4 (5.8) 6 (9.1)
 Flatulence 2 (4.7) 0 1 (2.3) NA NA
 GGT Increased 2 (4.7) 0 2 (4.7) 4 (5.8) 1 (1.5)
 Muscle spasms 2 (4.7) 0 0 NA NA
 Pruritus 2 (4.7) 0 1 (2.3) NA NA
 Amylase increased 1 (2.3) 2 (4.7) 0 NA NA
 Dizziness 1 (2.3) 1 (2.3) 3 (7.0) 3 (4.3) 2 (3.0)
 Fatigue 1 (2.3) 0 2 (4.7) NA NA
 Lipase increased 1 (2.3) 3 (7.0) 0 6 (8.7) 0
 Nausea 1 (2.3) 1 (2.3) 2 (4.7) 4 (5.8) 1 (1.5)
 Back pain 0 0 2 (4.7) NA NA
 Blood creatinine increased 0 2 (4.7) 0 2 (2.9) 2 (3.0)
 Blood triglycerides increased 0 2 (4.7) 0 NA NA
 Dyspepsia 0 3 (7.0) 1 (2.3) NA NA
 Headache 0 2 (4.7) 3 (7.0) 4 (5.8) 4 (6.1)
 Urinary tract infection 0 2 (4.7) 3 (7.0) NA NA
 Abdominal pain upper NA NA NA 5 (7.2) 0
 Abdominal pain NA NA NA 2 (2.9) 3 (4.5)
 Constipation NA NA NA 1 (1.4) 3 (4.5)
 Hypertension NA NA NA 1 (1.4) 2 (3.0)
Data are presented as n (%).
Only AEs reported during the double-blind treatment epoch and within 21 d of the end of study date are included.
MedDRA Version 22.0 was used for the reporting of AEs.
AE, adverse event; b.i.d., twice daily; GGT, gamma-glutamyltransferase; NA, not applicable; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

In the EMPHENE, no SAE was reported in the EMA401 25 mg treatment arm, whereas SAEs were reported in the EMA401 100 mg and placebo arms with the same incidence of 7.0%. No SAE was deemed to be related to the study treatments, as assessed by the investigators. SAEs were reported in both treatment arms in the EMPADINE with low incidence (7.2% [EMA401 100 mg] and 4.5% [placebo]). Product intolerance and cholelithiasis were considered to be related to treatment, and no other SAEs were considered to be related to the investigational treatment as assessed by the investigators. Details of SAEs reported in both studies are described in the Supplemental Digital Content (see Appendix S13, available at http://links.lww.com/PAIN/B317).

The overall incidence of AEs leading to discontinuation was low in both studies (EMPHENE 7.0% in each of the active treatment arms and 2.3% in the placebo arm; EMPADINE 11.6% [EMA401 100 mg] and 4.5% [placebo]). Details of the TEAEs reported in the treatment withdrawal epoch are described in the Supplemental Digital Content (see Appendix S14 and Table S7, available at http://links.lww.com/PAIN/B317). No suicidal ideation or behaviour was reported in any of the participants in both studies. Detailed safety results of physical examination and vital signs, laboratory parameters, Electrocardiogram, withdrawal and rebound effects, and suicidality evaluations are provided in the Supplemental Digital Content (see Appendix S7, available at http://links.lww.com/PAIN/B317). The overall incidences of TEAEs were low during the USM follow-up in both studies (see Table S8 in the Supplemental Digital Content, available at http://links.lww.com/PAIN/B317).

4. Discussion

The purpose of these studies was to evaluate the safety and efficacy of EMA401 compared with placebo in participants with PHN (EMPHENE) and PDN (EMPADINE). Premature study termination had an impact on power for the final efficacy analysis; hence, P values were only reported for descriptive purposes and should be interpreted with caution. Change in the weekly mean of the 24-hour average pain intensity from baseline to week 12 was the primary outcome for both studies. In both trials, decreases in pain intensity from baseline were numerically greater in the patients administered EMA401 compared with those administered placebo. The results of majority of the secondary outcomes were numerically in favour of EMA401 compared with placebo (Table 2). Although participants were allowed to use paracetamol for incidental pain in both the studies, only 6.2% (EMPHENE) and 8.1% (EMPADINE) participants used paracetamol during these studies.

To better understand the results of the primary endpoint in the context of the historical pain trials, the standardised effect size measure (SES) has been considered. Caution needs to be exercised in making comparisons against historical trials, due to the differences in the underlying estimands and in the corresponding methods of analyses. A SES of −0.20 for EMPHENE (EMA401 100 mg dose vs placebo) and −0.27 for EMPADINE (EMA401 100 mg dose vs placebo) was observed. A recent review by Smith et al.29 compared the SES of 23 studies (including 27 instances of comparison of an active treatment vs placebo) and estimated the mean SES for change in average pain intensity as −0.38 (95% CI: −0.439 to −0.299). The studies included 35% patients with PDN and 9% patients with PHN and almost all the studies except one used the 11-point NRS similar to our studies to measure the average pain intensity.29 Again, the mean SES is approximately 0.3 for the most recently published chronic pain studies.28 Therefore, the SES achieved in the EMPHENE and EMPADINE may be considered as clinically meaningful and comparable with the signals achieved in the efficacious trials of present times. The statistical analysis was aligned with the chosen estimand and in accordance with health authority guidances.6

The safety and tolerability observed in these phase 2b studies were in line with the EMA401 profile previously observed in the PoC study.22 The EMPHENE and EMPHADINE were terminated due to potentially serious and unexpected preclinical histopathological observations (minimal to marked periportal inflammation, bile duct hyperplasia, periportal fibrosis, and hepatocellular single cell necrosis) in the liver from the 39-week toxicity study conducted in cynomolgus monkeys (M. fascicularis). The evaluation of haematological parameters revealed minimal increase in one or more indicators of inflammation (white cell blood count, neutrophils, lymphocytes, monocytes, and/or eosinophils), correlating with the liver inflammation. The evaluation of biochemical parameters demonstrated drug-related changes in liver parameters (at ≥15 mg/kg b.i.d. dose of EMA401), characterised by mild to marked increases in alanine aminotransferase (up to 8-fold pre-test, dose-dependent), aspartate aminotransferase (up to 4-fold pre-test), and gamma glutamyltransferase in individual male and female animals starting from day 85. There were no drug-related changes in the other liver parameters measured including total bilirubin and alkaline phosphatase.

The safety profile of EMA401 during the USM safety follow-up was similar with the safety profile reported during the treatment epoch and treatment withdrawal epoch of the 2 studies and also compared well with the earlier phase 2 study of EMA401 conducted in PHN patients.22 Therefore, it is unclear whether the hepatic safety signal observed in monkeys is relevant to patients treated with EMA401. We did not observe changes in liver biochemical parameters during or after our studies (as observed in the USM). However, the limitation is exposure in our clinical studies was only of 13 weeks' duration. Based on recent studies,23,25 it is known that AT2R is unlikely to be expressed in the liver. In the absence of specific data on the safety of the overall class of AT2R antagonists, we cannot therefore comment on their overall safety. In addition, it is also known that EMA401 was metabolised into acylglucuronide metabolites.20 Acylglucuronide metabolites are known to be toxic,14 but the definitive evidence of the reason for EMA401 toxicity finding in monkeys is unknown.

One of the major limitations of our studies was premature termination. Also, the baseline NRS pain scores in our studies were lower compared to PoC study (EMA401 100 mg vs placebo: 6.31 [1.02] vs 6.33 [1.09]).22 We recognise that the relatively low baseline pain at randomisation might have attenuated the efficacy signal in our trials, given the evidence that higher baseline pain intensity may be associated with greater assay sensitivity.9 Another limitation of our studies is that we did not use sensory profiles to phenotype patients, which are currently of increased interest in pain trials7 and suggest that patients classified into different mechanistic groups may respond to treatments differently.4,8,32

The placebo effect was lower in the primary outcome over 12 weeks in these 2 phase 2b studies compared with the PoC study (4 weeks).22 Lower placebo effect was also observed for most of the secondary outcomes for both studies. Several pain studies in the past have failed due to high placebo response,30 suggesting that the measures taken in these 2 studies to reduce the placebo response, such as screening algorithm to detect participants at risk of a high placebo response, was worthwhile. However, we understand that the measures taken to reduce the placebo response were adequate for NRS pain intensity but did not impact the PGIC,21 which is a more global measure of improvement.

The efficacy of EMA401 could not be confirmed in these studies due to the premature termination, and the data are indicative of reduction in pain intensity after EMA401 in the treatment of NP in comparison with placebo. There is no intent to continue development of EMA401 in PNP but the possibility that other therapeutics of this class are being developed for analgesia cannot be ruled out at this stage. To the best of our knowledge, currently, there are no ongoing clinical trials going on for this class. However, given the paucity of multicentric studies, this article provides the readers useful information about methods and observed effect with AT2R antagonists across 2 different indications and can support much needed future research efforts in development of analgesics.

In conclusion, EMA401 was well tolerated in PHN and PDN participants at the tested doses, and reductions in pain from baseline were numerically greater in the EMA401 treatment arms compared with placebo over the 12 weeks of treatment. Considering the global unmet need for the treatment of NP, and the lack of novel nonopioid treatments emerging for more than a decade, the consistent clinical improvement in pain intensity reduction across 3 studies (2 phase 2b and PoC) with EMA401 deserves further consideration. Further studies may be needed to further understand the exact reasons for observed toxic findings in monkeys and its relevance to the AT2R antagonists as a class.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/B317.

Supplemental video content

A video abstract associated with this article can be found at http://links.lww.com/PAIN/B318.

Acknowledgments

This study was funded by Novartis Pharma AG, Basel, Switzerland. The authors thank the study investigators and participants for their participation and commitment to this work. The authors also thank the statisticians from ICON for their support in retrieval, analyses of collected data, and writing of the clinical study report. Medical writing support was provided by Preethi Bheereddy, Novartis Healthcare Pvt. Ltd, India.

Author contributions: A.S.C. Rice, R.H. Dworkin, N.B. Finnerup, N. Attal, P. Anand, and R. Freeman were involved in the design, conduct, and interpretation of EMPHENE and EMPADINE. A. Piaia was responsible for the preclinical safety studies and data reported in the manuscript. As per ICMJE criteria, none of the authors received any remuneration for writing/reviewing of the manuscript. F. Callegari and S. Mondal were involved in the design of the studies and were responsible for statistical analysis and data interpretation. C. Doerr participated in design of the studies. L. Ecochard, Y. Flossbach, and S. Pandhi were involved in the overall design and conduct of the studies. N. Narayanan provided medical writing support for drafting and revision of the manuscript. All authors' interpreted data, agreed on the content of the manuscript, reviewed drafts, and approved the final version.

A.S.C. Rice undertakes consultancy and advisory board work for Imperial College Consultants-in the past 24 months, this has included remunerated work for: Abide, Pharmanovo, Lateral, Novartis, Pharmaleads, Mundipharma, Orion, Asahi Kasei & Toray -. Was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015 and from which payments continued until 2019. Named as an inventor on patents: WO 2005/079771 & WO2013/110945. Grant funding includes a number of Innovative Medicines Initiative grants. R.H. Dworkin, PhD, has received in the past 5 years research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, AstraZeneca, Biogen, Biohaven, Boston Scientific, Braeburn, Celgene, Centrexion, Chromocell, Clexio, Concert, Coronado, Daiichi Sankyo, Decibel, Dong-A, Editas, Eli Lilly, Eupraxia, Glenmark, Grace, Hope, Hydra, Immune, Johnson & Johnson, Lotus Clinical Research, Mainstay, Medavante, Merck, Neumentum, Neurana, NeuroBo, Novaremed, Novartis, NSGene, Olatec, Periphagen, Pfizer, Phosphagenics, Quark, Reckitt Benckiser, Regenacy (also equity), Relmada, Sanifit, Scilex, Semnur, SK Life Sciences, Sollis, Spinifex, Syntrix, Teva, Thar, Theranexus, Trevena, Vertex, and Vizuri. N.B. Finnerup has received an honorarium from Novartis for consulting on these two studies. She also reports personal fees from Mitshubishi Tanabe Pharma, Merck, Almirall, and NeuroPN, and research grant from EU IMI Paincare, an EU IMI 2 (Innovative medicines initiative) public-private consortium and the companies involved are: Grunenthal, Bayer, Eli Lilly, Esteve, and Teva outside the submitted work. N. Attal reports personal fees from Grunenthal, Aptynix, Ipsen, Sanofi MSD, MSD, and Lilly over the past 36 months outside the submitted work. P. Anand received fees for consultancy and serving on scientific advisory boards from Averitas, Biogen, Grunenthal, GW Pharma, LifeArc, Novartis, Sapphire, Spinifex, and Tilray. R. Freeman received personal compensation for serving on scientific advisory boards of Abide, Averitas, Applied Therapeutics, Clexio, Ceracor, Cutaneous NeuroDiagnostics, GW Pharma, Lundbeck, Novartis, NeuroBo, Regenacy, Toray, Theravance, and Vertex. A. Piaia, Y. Flossbach, L. Ecochard, S. Pandhi, F. Callegari, C. Doerr, and S. Mondal are employees and own stock of Novartis; N. Narayanan is an employee of Novartis Healthcare Pvt. Ltd, Hyderabad, India, during conduct of the study and writing of this manuscript and is currently affiliated with Eli Lilly Services India Private Limited.

Qualified researchers can request access to patient-level data and related study documents, including the study protocol and the statistical analysis plan. Patient-level data will be deidentified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email [email protected] to make your request. The protocol and statistical analysis plan are available through ClinicalTrials.gov (NCT03094195, NCT03297294) from June 2020.

References

[1]. Anand P, Privitera R, Yiangou Y, Mishra P. Angiotensin II Type 2 receptor antagonist EMA401 for the treatment of pain in patients with chemotherapy-induced peripheral neuropathy: efficacy and nerve biomarkers in skin biopsies. Eur J Neurol 2016;23(suppl. 2):634.
[2]. Anand U, Facer P, Yiangou Y, Sinisi M, FoX M, McCarthy T, Bountra C, Korchev YE, Anand P. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. Eur J Pain 2013;17:1012–26.
[3]. Anand U, Yiangou Y, Sinisi M, Fox M, MacQuillan A, Quick T, Korchev YE, Bountra C, Tom McCarthy T, Anand P. Mechanisms underlying clinical efficacy of angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies. Mol Pain 2015;11:38.
[4]. Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu G, Finnerup NB, Haanpää M, Hansson P, Hüllemann P, Jensen TS, Freynhagen R, Kennedy JD, Magerl W, Mainka T, Reimer M, Rice ASC, Segerdahl M, Serra J, Sindrup S, Sommer C, Tölle T, Vollert J, Treede RD. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. PAIN 2017;158:261–72.
[5]. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F. Development and validation of the neuropathic pain symptom inventory. PAIN 2004;108:248–57.
[6]. Callegari F, Akacha M, Quarg P, Pandhi S, Raison FV, Zuber E. Estimands in a chronic pain trial: challenges and opportunities. Stat Biopharm Res 2019;12:39–44. doi: 10.1080/19466315.2019.1629997.
[7]. Committee for Medicinal Products for Human Use. Guideline on the clinical development of medicinal products intended for the treatment of pain. 2016. EMA/CHMP/970057/2011. Committee for Medicinal Products for Human Use (CHMP). An agency of the European Union: Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-medicinal-products-intended-treatment-pain-first-version_en.pdf
[8]. Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB, Jensen TS, Sindrup SH. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. PAIN 2014;155:2263–73.
[9]. Dworkin RH, Turk DC, Peirce-Sandner S, Burke LB, Farrar JT, Gilron FI, Jensen MP, Katz NP, Raja SN, Rappaport BA, Rowbotham MC, Backonja M, Bardon R, Bellamy N, Bhagwagar Z, Costello A, Cowan P, Fang WC, Hertz S, Jay GW, Junor R, Kerns RD, Kerwin R, Kopecky EA, Lissin D, Malamut R, Markman JD, McDermott MP, Munera C, Porter L, Rauschkolb C, Rice ASC, Sampaio C, Skljarevski K, Stacey BR, Steigerwald I, Tobias J, Trentacosti AM, Wasan AD, Wells GA, Williams J, Witter J, Ziegler D. Considerations for improving assay sensitivity in chronic pain clinical trials:IMMPACT recommendations. PAIN 2012;153:1148–58.
[10]. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73.
[11]. Forstenpointner J, Rice ASC, Finnerup NB, Baron R. Up-date on clinical management of postherpetic neuralgia and mechanism-based treatment: new Options in Therapy. J Infect Dis 2018;218(suppl 2):S120–6.
[12]. Gylfadottir SS, Christensen DH, Nicolaisen SK, Andersena H, Callaghana BC, Itania M, Khana KS, Kristensena AG, Nielsenh JS, Sindrupa SH, Anderseni NT, Jensena TS, Thomsenc RW, Finnerupa NB. Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes. PAIN 2020;161:574–83.
[13]. ICD-11 Coding Tool. Mortality and morbidity statistics (MMS). 2019. Available at: https://icd.who.int/ct11/icd11_mms/en/release. Accessed June 29, 2020.
[14]. Iwamura A, Nakajima M, Oda S, yokoi T. Toxicological potential of acyl glucuronides and its assessment. Drug Metab Pharmacokinet 2017;32:2–11.
[15]. Javed S, Hayat T, Menon L, Alam U, Malk RA. Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late. Diabet Med 2020;37:573–79.
[16]. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice ASC, Treede RD. Commentary: a new definition of neuropathic pain. PAIN 2011;152:2204–5.
[17]. Johnson RW, Rice ASC. Clinical practice. Post-herpetic neuralgia. N Engl J Med 2014;371:1526–33.
[18]. Lecrenier N, Beukelaers P, Colindres R, Curran D, Kesel CD, De Saegher J, Didierlaurent AM, Ledent EY, Mols JF, Mrkvan T, Normand-Bayle M, Oostvogels L, Da Silva FT, Vassilev V, Vinals C, Brecx A. Development of adjuvanted recombinant zoster vaccine and its implications for shingles prevention. Expert Rev Vaccin 2018;17:619–34.
[19]. Muralidharan A, Wyse BD, Smith MT. Analgesic efficacy and mode of action of a selective small molecule angiotensin II type 2 receptor antagonist in a rat model of prostate cancer-induced bone pain. Pain Med 2014;15:93–110.
[20]. Murgasova R, Carreras ET, Suetterlin-Hachmann M, da Silva Torrao LR, Kittelmann M, Alexandra V, Fredenhagen A. Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist. Biopharm Drug Dispos 2020;41:166–83.
[21]. Perrot S, Lantéri-Minet M. Patients' Global Impression of Change in the management of peripheral neuropathic pain: clinical relevance and correlations in daily practice. Eur J Pain 2019;23:1117–28.
[22]. Rice ASC, Dworkin R, McCarthy T, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, Raff M. For the EMA401-003 study group. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 2014;383:1637–47.
[23]. Rice ASC, Smith MT. Angiotensin II Type 2-Receptor: new clinically validated target in the treatment of neuropathic pain. Clin Pharmacol Ther 2015;97:128–30.
[24]. Shepherd AJ, Copits BA, Mickle AD, Karlsson P, Kadunganattil S, Haroutounian S, Tadinada SM, de Kloet A D, Valtcheva MV, McIlvried LA, Sheahan TD, Jain S, Ray PR, Usachev YM, Dussor G, Krause E, Price TJ, Gereau RW, Mohapatra DP. Angiotensin II triggers peripheral macrophage-to-sensory neuron redox crosstalk to elicit pain. J Neurosci 2018a;38:7032–57.
[25]. Shepherd AJ, Mickle AD, Golden JP, Mack MR, Halabi CM, Kloet AD, Samineni VK, Kim BS, Krause EG, Gereau IVRW, Mohapatra DP. Macrophage angiotensin II type 2 receptor triggers neuropathic pain. Proc Natl Acad Sci U S A 2018b;115:E8057–66.
[26]. Smith MT, Woodruff TM, Wyse BD, Muralidharan A, Walther T. A small molecule angiotensin II type 2 receptor (AT2R) antagonist produces analgesia in a rat model of neuropathic pain by inhibition of p38 mitogen activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia. Pain Med 2013b;14:1557–68.
[27]. Smith MT, Wyse BD, Edwards SR. Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radio ligand binding, and efficacy in rats. Pain Med 2013a;14:692–05.
[28]. Smith SM, Fava M, Jensen MP, Mbowe OB, McDermott MP, Turk DC, Dworkin RH. John D. Loeser Award Lecture: size does matter, but it isn't everything: the challenge of modest treatment effects in chronic pain clinical trials. PAIN 2020;161:S3–13.
[29]. Smith SM, Jensen MP, He H, Kitt R, Koch J, Pan A, Burke LB, Farrar JT, McDermott MP, Turk DC, Dworkin RH. A comparison of the assay sensitivity of average and worst pain intensity in pharmacologic trials: an ACTTION systematic review and meta-analysis. The J Pain 2018;19:953–60.
[30]. Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweinhardt P, Bennett GJ, Mogil JS. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. PAIN 2015;156:2616–26.
[31]. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. PAIN 2014;155:654–62.
[32]. Vollert J, Maier C, Attal N, Bennett DLH, Bouhassira D, Enax-Krumova EK, Finnerup NB, Freynhagen R, Gierthmühlen J, Haanpää M, Hansson P, Hüllemann P, Jensen TS, Magerl W, Ramirez JD, Rice ASC, Schuh-Hofer S, Segerdahl M, Serra J, Shillo PR, Sindrup S, Tesfaye S, Themistocleous AC, Tölle TR, Treede RD, Baron R. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. PAIN 2017;158:1446–55.
Keywords:

EMA401; Olodanrigan; Painful diabetic neuropathy; Peripheral neuropathic pain; Postherpetic neuralgia

Supplemental Digital Content

© 2021 International Association for the Study of Pain