CHESTERBROOK, PA — Trevena, Inc. (Nasdaq: TRVN), a biopharmaceutical company, recently announced preliminary topline data from two Phase 1 proof-of-concept studies of TRV045, a novel sphingosine-1-phosphate receptor modulator selective for the S1P receptor subtype 1.
“We’re very excited about the progress we’ve made with TRV045 and I’m pleased that both proof-of-concept studies demonstrated CNS target engagement. This dataset marks another significant milestone for Trevena and our ongoing commitment to focus on innovative new therapies,” said Carrie Bourdow, President and CEO of Trevena. “As a novel, non-opioid therapy, we believe TRV045 has the potential to make a meaningful difference in the lives of patients and we look forward to advancing TRV045, on our own or with a strategic partner, for potential treatment of neuropathic pain and other CNS disorders.”
Data from both studies demonstrated CNS penetration and target engagement, as well as plasma exposures in the anticipated active dose range, supporting the therapeutic potential of TRV045. In a capsaicin-induced neuropathic pain model, a validated model of neuropathic pain, TRV045 showed a statistically significant, dose-dependent treatment effect. In the transcranial magnetic stimulation (TMS) proof-of-concept study, TRV045 demonstrated statistically significant changes in the power spectral density in several bands.
“These preliminary studies strongly suggest to me that this compound has an impact on the central processing of pain, and is potentially working by reducing neural hyperexcitability,” said Daniel Clauw, MD, Professor of Anesthesiology, Medicine and Psychiatry at the University of Michigan. “There is a clear need for innovative new medications for the treatment of chronic pain. TRV045’s novel mechanism of action, accompanied by the early data suggesting it is well tolerated, make this an exciting new potential therapeutic approach.”
Target Engagement (PainCart®) POC Study
The Target Engagement POC study was a randomized, double-blind, placebo-controlled, single dose four-way cross-over study (n=25 subjects) designed to evaluate evidence of target engagement for TRV045, using a select battery of pharmacodynamic outcomes. The study used the validated PainCart® set of analgesic tests to evaluate potential central and peripheral nervous system effects and to provide insight into the potential anti-inflammatory actions of TRV045. Each subject received three different single doses of TRV045 (50mg, 150mg and 300mg) and placebo on four separate visits across the study duration. Plasma exposures of TRV045 in this study were comparable to levels seen in the previously reported Phase 1, FIH study and reached the anticipated targeted active dose range.
TRV045 demonstrated a statistically significant, dose-dependent reduction in mechanical allodynia following topical capsaicin application at 150mg and 300mg v. placebo. Allodynia was assessed by cutaneous pain sensation upon mechanical stimulation with Von Frey hair filaments, a validated model of neuropathic pain. The difference was measured for each dose of TRV045 compared to placebo as the change from baseline in both the secondary area of allodynic sensation and the total area of allodynia across 10 hours following the dose of study medication. The change from baseline in painful surface area at the final 10 hour timepoint is shown below, along with the associated P-values for each treatment difference across the entire 10 hour period of observation. Differences were evident for both the 150mg and 300mg doses beginning at hour 2 and continuing through the entire period of study observation at hour 10.
Baseline in Painful
Surface Area at
Final 10 Hour
|P-Value for Overall
|Total Allodynic Area (mm2)||Placebo||-67.19|
|Secondary Allodynic Area (mm2)||Placebo||-15.79|
TRV045 further demonstrated a dose-dependent trend in change from baseline in the cold pressor test, and also demonstrated trends in reduction to heat pain detection threshold on both unexposed and capsaicin-treated forearm skin, on heat pain detection threshold on unexposed skin on the upper back, and pain tolerance in the electrical burst stimulation test, though these endpoints did not achieve statistical significance. TRV045 did not show a statistically significant difference or trend compared to placebo in other pain modalities.
TMS POC Study
The TMS POC study was a randomized, double-blind, placebo-controlled, multiple dose, two-way cross-over study (n=25 subjects) designed to evaluate the pharmacodynamic effects of TRV045 (250mg) on cortical excitability in healthy male adults, using both EEG and EMG to measure the impact of TRV045 on the electrical excitation of the brain. The goal of the study was to provide further insight into TRV045 CNS target engagement and mechanism of action for the potential treatment of epilepsy and other CNS disorders. Each subject received one of two treatment sequences in random order: TRV045 at a dose of 250mg, followed by placebo; or placebo followed by 250mg of TRV045, each treatment sequence given once daily for four consecutive days. Plasma exposures of TRV045 in this study were comparable to levels seen in the previously reported Phase 1, FIH study and reached the anticipated targeted active dose range.
Among the EEG-related endpoints measured in the study, resting state EEG obtained before and after administration of TRV045, demonstrated statistically significant increases in the power spectral density on day 4 in several of the middle to higher frequency bands including alpha, beta and gamma waves. The changes in alpha waves are generally considered to be associated with conscious arousal and alertness, while beta waves are thought to be associated with GABA-mediated inhibitory cortical neurotransmission, and gamma waves are generally associated with cognitive processing, learning and memory. Alpha waves demonstrated this statistically significant increase in power in the frontal region (P=0.0164), as well as both left parietal (P=0.0047), and right parietal (P=0.0418) regions. This statistically significant increase in power was observed in the frontal region for beta waves (P=0.0235) and gamma waves (P=0.0343).
With respect to slow brain waves, which are generally associated with sedation or sleep, TRV045 showed a statistically significant decrease in the delta brain waves on day 4 in the right parietal region (P=0.0432), and no significant difference in theta brain waves at any of the three observed regions.
Among the EMG-related endpoints measured in the study, TRV045 demonstrated evidence of reduction in cortical excitability, as measured by change in peak motor-evoked potential (MEP) amplitude, on Day 1 comparable in magnitude to the reduction in cortical excitability reported in similar test conditions in the same laboratory for approved anti-epileptic drugs, though this result did not achieve statistical significance. There was no difference in mean peak MEP amplitude on Day 4, and no difference in resting motor threshold (RMT) on Day 1 or Day 4 or other EMG-related endpoints.
There were no serious adverse events reported, and no drug-related discontinuations from either study. Full safety and tolerability data for these studies are not yet available. This data is expected in early 4Q 2023. In the previously reported Phase 1 study of TRV045, the only adverse event assessed by study investigators as probably or definitely related to drug was headache in four subjects across all three parts of the study (n=53, n=27, n=9).
Subjects in both studies were enrolled outside of the United States, and the studies were not conducted under the Investigational New Drug Application for TRV045.
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