AlzeCure Pharma AB, Huddinge, Sweden.
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden.
Eur J Pain. 2024 Nov;28(10):1656-1673. doi: 10.1002/ejp.2299. Epub 2024 Jun 12.
The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects.
The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC. In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440.
ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400.
Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development.
This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.
TRPV1 受体是疼痛产生的关键分子。先前开发的口服 TRPV1 拮抗剂因全身热感觉迟钝和体温改变而停止。本 1b 期研究旨在评估一种局部应用的 TRPV1 拮抗剂（ACD440 凝胶）在健康受试者中的疗效、安全性和血浆暴露情况。
该研究包括两部分。在第 1 部分中，24 名健康受试者被纳入这项随机、双盲、安慰剂对照、交叉试验。ACD440 凝胶或安慰剂每天应用一次，在 1 小时后擦拭干净，连续应用 5 天。评估在正常皮肤、经渗透优化的皮肤（通过剥脱和封闭性凝胶应用）和 UVB 照射的皮肤中进行。热伤害性 CO 激光脉冲诱导的疼痛产生激光诱发电位（LEP），通过顶点 EEG 的峰间（PtP）幅度读数和视觉模拟量表（0-100）进行疼痛评估。终点包括给药后 1 小时的影响、AUC（第 1-5 天）和 AUC。在 UVB 照射的皮肤中，还评估了刺痛和皮肤发红引起的疼痛。第 2 部分探索了 ACD440 的血浆药代动力学。
ACD440 凝胶降低了 LEP PtP 幅度和 VAS 疼痛，与安慰剂相比，在所有皮肤状况下均有统计学意义（p<0.001）。在 UVB 照射的皮肤中，刺痛疼痛也有所减轻（p=0.047）。在 1 小时后，效果显著，至少持续 9 小时。没有不良反应或药物引起的红斑。ACD440 的血浆暴露量太低，无法确定 ACD400 的消除半衰期。
局部应用 ACD440 凝胶在 LEP、VAS 评分和刺痛疼痛方面显示出显著的镇痛效果，全身暴露量低，支持进一步的临床开发。
这项研究表明，局部应用 TRPV1 拮抗剂 ACD440 凝胶具有成为治疗影响皮肤的疼痛性疾病（如慢性周围神经性疼痛）的新疗法的潜力，且无局部或全身副作用。
