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Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a
M Segerdahl1,2, M Rother1, M M Halldin1
1AlzeCure Pharma AB, Huddinge, Sweden.
Background:
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.
Methods:
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 CO2 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(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440.
Results:
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.
Conclusions:
Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development.
Significance:
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.
Insights
Topical ACD440 Gel effectively reduced pain signals in healthy subjects, demonstrating significant analgesic effects without adverse events. This topical TRPV1-antagonist shows promise for treating skin pain conditions.
Area of Science:
- Pharmacology
- Pain Research
- Dermatology
Background:
- Transient Receptor Potential Vanilloid 1 (TRPV1) receptors are crucial in pain signaling.
- Previous oral TRPV1-antagonist development faced challenges with systemic side effects like altered body temperature.
- Topical ACD440 Gel was investigated for localized pain management.
Purpose of the Study:
- To evaluate the efficacy and safety of topically applied ACD440 Gel in healthy subjects.
- To assess ACD440 Gel's impact on pain perception and laser-evoked potentials (LEPs).
- To determine the plasma exposure and pharmacokinetics of topical ACD440 Gel.
Main Methods:
- A randomized, double-blind, placebo-controlled, crossover study in 24 healthy subjects.
- ACD440 Gel or placebo applied daily for 5 days to normal, optimized, and UVB-irradiated skin.
- Pain assessed via LEPs, Visual Analog Scale (VAS), and pinprick tests; plasma pharmacokinetics analyzed.
Main Results:
- ACD440 Gel significantly reduced LEP amplitude and VAS pain scores across all skin conditions (p < 0.001).
- A significant reduction in UVB-induced pinprick pain was observed (p = 0.047).
- No adverse events or skin redness were reported; systemic exposure was minimal.
Conclusions:
- Topical ACD440 Gel exhibits significant analgesic properties for skin-related pain.
- Low systemic exposure suggests a favorable safety profile for localized treatment.
- ACD440 Gel warrants further clinical development for conditions like chronic peripheral neuropathic pain.
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