Trevena Shares TRV045 Preclinical Data on Chronic Pain and Anti-Seizure Effects

TRV045, a novel S1P1 receptor modulator developed by Trevena, Inc., has demonstrated promising results in preclinical studies targeting neuropathic pain and epilepsy. Trevena's recent research collaborations with Virginia Commonwealth University and the NIH-supported Epilepsy Therapy Screening Program (ETSP) have provided significant insights into the therapeutic potential of TRV045.

In studies conducted in collaboration with Virginia Commonwealth University, TRV045 was examined for its analgesic effects in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The results, presented at the American Society for Pharmacology and Experimental Therapeutics annual meeting in May 2024, revealed that TRV045 exhibited sustained, long-term analgesic effects without causing receptor desensitization. Unlike fingolimod, another S1P1 receptor modulator, TRV045 did not lead to a reduction in receptor protein or functional desensitization even after repeated dosing over 14 days. This indicates that TRV045 might offer a differentiated mechanism for providing ongoing analgesia without the drawbacks seen with other S1P1 modulators.

In these experiments, S1PR1 functional desensitization was evaluated by measuring S1PR1-stimulated 35SGTPgS binding in spinal cord membrane homogenates from treated mice. Repeated administration of fingolimod significantly reduced this binding, while TRV045 did not have any impact, even at higher doses. Additionally, fingolimod reduced S1P1R protein levels by approximately 30%, whereas TRV045 had no such effect. These findings suggest that TRV045 maintains its efficacy through sustained S1P1R agonism, positioning it as a potential long-term treatment for neuropathic pain.

In terms of epilepsy research, TRV045 demonstrated significant seizure protection in various preclinical models. In an intravenous Pentylenetetrazol (ivPTZ) Seizure Threshold Test on mice, a 30mg/kg dose of TRV045 significantly delayed the onset of myoclonic twitches and generalized clonus, indicating robust anticonvulsant properties. A separate study using the maximal electroshock (MES) model in rats confirmed dose-dependent seizure protection, with notable efficacy at the higher dose levels.

However, TRV045 did not show a statistically significant effect in an initial study on epileptogenesis, the process of developing epilepsy. This preliminary study involved inducing status epilepticus in rats and then treating them with TRV045 or a vehicle. While two animals in the TRV045 group were seizure-free weeks after treatment, the overall outcomes did not significantly differ from the control group. Despite this, the findings provide a foundation for further exploration in epilepsy prevention and treatment, as suggested by the ETSP.

Trevena's continued focus on CNS disorders is evident in their development pipeline, which includes TRV045 for neuropathic pain and epilepsy, TRV250 for acute migraine treatment, and TRV734 for opioid use disorder. Trevena's approach capitalizes on research findings to develop innovative treatments for these challenging conditions.

In summary, TRV045 has shown substantial promise as a treatment for neuropathic pain and epilepsy in preclinical models. Its unique action on the S1P1 receptor, without causing receptor desensitization or protein reduction, sets it apart from existing treatments like fingolimod. Ongoing and future studies aim to further elucidate and capitalize on TRV045's therapeutic potential, potentially offering new hope for patients with these debilitating conditions.