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Quantitative Sensory Testing of SR419, a First-in-Class Oral α5-GABAA Receptor Negative Allosteric Modulator, in Neuropathic Pain Patients

P-071 - (Poster #71) Quantitative Sensory Testing of SR419, a First-in-Class Oral α5-GABAA Receptor Negative Allosteric Modulator, in Neuropathic Pain Patients

Thursday, September 4, 2025

4:00 PM - 5:30 PM PST

Location: Exhibit Hall (Level 4)

Author/Presenter(s)

QH

Qinyu Han, n/a

Medical Manager
Shanghai SIMR Biotechnology Co., Ltd.
Shanghai, Shanghai
CF

Cuifang Fei, n/a

Research and Development Manager
Shanghai SIMR Biotechnology Co.,Ltd
Shanghai, Shanghai
LW

Li Wang, MD. PhD

Associate Director
Shanghai SIMR Biotechnology Co.,Ltd
Shanghai, Shanghai
XG

Xuechun Gong, n/a

Clinical pharmacology
Shanghai Simrbio Tech.
Shanghai, Shanghai
FW

Fei Wang, n/a

VP
Shanghai SIMR Biotechnology Co., Ltd.
Shanghai, Shanghai
SL

Shuai Li, n/a

Founder & CEO
Shanghai SIMR Biotechnology Co., Ltd.
Shanghai, Shanghai

Background: Neuropathic pain, caused by lesions or diseases affecting the somatosensory nervous system, affects 7-10% of the global population. However, due to the limited efficacy of current treatments and opioid-related adverse effects, over 50% of patients fail to achieve adequate pain control. Preclinical studies demonstrate that α5-GABAA receptors are involved in neuropathic pain pathogenesis, highlighting the therapeutic potential of α5-GABAA receptor negative allosteric modulators (NAMs). Following sensory nerve injury, dorsal root ganglion neurons exhibit significant upregulation of extra-synaptic α5-GABAA receptors, which correlates with the progression of hyperalgesia. Notably, peripherally restricted α5-GABAA receptor NAMs have been shown to effectively attenuated mechanical allodynia and hyperalgesia in formalin-induced neuropathic pain models, supporting their therapeutic potential. SR419, a potent α5-GABAA receptor NAM, demonstrated dose-dependent analgesia in rat neuropathic pain models (SNI/CCI/pIONL) with a minimal efficacious dose of 0.1 mg/kg. In a completed Phase 1 trial (NCT04021563), SR419 demonstrated favorable safety and tolerability in healthy volunteers. It achieved peak concentration at 1-1.5 hours post-dose, with a terminal half-life of 1-3 hours. The exposure (Cmax and AUC) of SR419 was approximately dose-proportional from 1 to 30 mg. These data support SR419 as a promising therapeutic candidate for neuropathic pain with optimized target engagement and favorable safety profiles.

Purpose/Objectives: Preclinical and completed clinical data demonstrated that SR419 has the potential to provide rapid efficacy without CNS-related liabilities in the treatment of neuropathic pain. Here we report the results from a multi-center, 3-period, complete crossover, double-blind, randomized, placebo- and active-controlled trial (conducted in Australia) to evaluate the preliminary efficacy of a single dose of SR419 compared to placebo and active control (pregabalin) in participants with postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), or unilateral sciatica (NCT04494815). The study also evaluated the safety, tolerability and pharmacokinetics (PK) of single-dose SR419 in participants with peripheral neuropathic pain. Eligible participants completed the pain DETECT questionnaire to detect and quantify neuropathic pain, as part of the translational study to identify the optimal patient population for SR419 therapy.

Methods: Participants clinically diagnosed with PHN, DPN, or unilateral sciatica, experiencing moderate-to-severe pain (defined as an average daily pain score ≥4 on the 11-point Numeric Rating Scale [NRS] during the week prior to screening), were randomized into one of six treatment sequences, each involving three treatments across three treatment periods. The primary endpoint was the quantitative sensory testing (QST) component scores in the affected area for SR419, placebo and pregabalin. The QST included thermal and mechanical tests adapted from the German Research Network on Neuropathic Pain. The following parameters were tested: thermal detection thresholds for the perception of cold (cold detection threshold [CDT]) and warmth (warm detection threshold [WDT]), thermal pain thresholds for cold (cold pain threshold [CPT]) and hot stimuli (heat pain threshold [HPT]), mechanical detection threshold (MDT), mechanical pain threshold (MPT), and dynamic mechanical allodynia (DMA). Secondary efficacy endpoints included spontaneous pain scores (SPS), QST component scores in the unaffected area, safety, tolerability, and PK.

Results:
Participants had a mean age of 66.8 ± 9.31 years (range: 50-81 years), with 80% being male.

Following administration of a single dose of SR419 (20 mg), pregabalin (150 mg or 300 mg), or placebo to patients with DPN (n = 10), PHN (n = 6), or idiopathic neuropathy (n=8), no significant differences were observed in QST components (DMA, MDT, MPT, WDT, CDT, HPT, CPT) or the overall QST score (△QST) at the affected area across treatment groups, based on parameters including absolute value, Emax, and AUC. SR419 and pregabalin exhibited similar effect profiles on QST parameters, although pregabalin demonstrated greater efficacy than SR419 at the affected site. Notably, in DPN participants, SR419 trended toward improving the DMA, mechanical (MDT, MPT), cold (CDT, CPT) sensation/pain and △QST, with no impact on the warm (WDT) and heat (HPT) sensation/pain. In PHN patients, although SR419 had weaker effects on ΔQST, it appeared to demonstrate an improvement with mechanical (MPT) pain and cold (CDT) sensation. At the unaffected side, both SR419 and pregabalin showed QST profiles similar to placebo for all components and △QST. In DPN patients, SR419 appeared to decrease SPS more than pregabalin and placebo (using the SPS vs. time curve with screening as baseline). However, pregabalin demonstrated more pronounced effects on SPS in PHN patients compared to SR419 and placebo.

SR419 plasma concentration at 1.5 hours post-dose in neuropathic pain patients was comparable to Cmax values observed in healthy volunteers (20 mg dose, historical data), and declined rapidly by approximately 6.5 hours post-dose.

SR419 was generally well tolerated, with most treatment-emergent adverse events (TEAEs) were mild. Two moderate TEAEs occurred (one case each of sedation and somnolence), with no severe TEAEs, serious AEs, AEs leading to discontinuation, or deaths reported.

Conclusions/Implications for future research and/or clinical care: In this study, SR419 demonstrated an efficacy trend similar to pregabalin in △QST and SPS in the DPN, PHN and idiopathic patients. Meanwhile, SR419 was well-tolerated at 20 mg dose in neuropathic pain patients, with no major safety concerns. In conclusion, the positive efficacy results, and favorable safety and PK profiles, support further clinical development of SR419 for neuropathic pain.