お知らせ • Jun 21
Trevena, Inc. Announces Preclinical TRV045 Data Providing Insight Into Novel Mechanism of Analgesic Effect in Chronic Neuropathic Pain Model and Demonstrating Statistically Significant Anti-Seizure Activity in Epilepsy Models
Trevena, Inc. announced preclinical data from two separate research collaborations. The first from a series of experiments conducted in collaboration with scientists at Virginia Commonwealth University and presented at the recent annual meeting of the American Society for Pharmacology and Experimental Therapeutics in May 2024. These studies examined the cellular mechanism of analgesic effects of TRV045, a novel S1P1 receptor modulator, in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The second set of studies was from a separate, ongoing collaboration, with the NIH-supported Epilepsy Therapy Screening Program (ETSP) which studied the use of TRV045 in three different preclinical models examining its potential effects on acute seizure protection and its potential ability to modify seizure development, or epileptogenesis. This newly reported preclinical data, presented as a poster at the recent annual meeting of the American Society for Pharmacology and Experimental Therapeutics in May 2024, provides further insight into TRV045’s mechanism of action and its potential as a differentiated long-term therapeutic for neuropathic pain. In this study, TRV045 did not cause S1P1R functional desensitization or S1PR1 protein reduction despite repeated dosing over 14 days. In contrast, fingolimod, an approved S1PR modulator, demonstrated both significant S1P1R functional desensitization and protein reduction in this same model. As a result, the Company believes TRV045 may represent a differentiated mechanism to provide sustained S1P1R agonism and analgesic effect, unlike other S1PR modulators, such as fingolimod, that demonstrate initial agonism but long-term functional antagonism due to S1PR desensitization and protein reduction. In this new study, S1PR1 functional desensitization was measured by S1PR1 stimulated 35SGTPgS binding in membrane homogenates of spinal cord prepared from drug treated mice. Repeated fingolimod (1 mg/kg, once a day for 14 days) dosing decreased such 35SGTPgS binding by approximately 70% compared with vehicle, while repeated TRV045 oral dosing (10 mg/kg, once a day for 14 days) had no effect. S1PR1 protein expression measured by Western immunoblotting indicated that repeated fingolimod treatment caused an approximately 30% reduction in S1P1R protein in spinal cord while repeated TRV045 treatment had no effect. Similar effects were seen in the region of the periaqueductal gray; both of these regions play important roles in pain transmission. The company believe these studies indicate that, unlike fingolimod, TRV045 does not cause S1PR1 protein reduction or S1PR1 functional desensitization, suggesting that sustained TRV045 agonism is the underlying mechanism for its analgesic effects. Trevena has previously reported that, in a validated mouse model of CIPN, oral administration of TRV045 (1 mg/kg, 3 mg/kg, and 10 mg/kg) reduced mechanical and cold stimulus-evoked nociception in a statistically significant, dose-related manner (at the 3 mg/kg and 10 mg/kg doses only). These effects were present after acute single dose administration of TRV045 in both male and female mice and after repeated treatment (once daily for 7 days). Trevena has previously observed that TRV045, unlike other known S1P-targeted compounds, exerted these analgesic effects in the absence of any reduction in circulating peripheral lymphocytes, suggesting that TRV045’s analgesic effects may not be due to receptor down-regulation. In a preclinical study using a validated model of seizure induction in mice, known as the intravenous Pentylenetetrazol (ivPTZ) Seizure Threshold Test, one of four doses of TRV045 (5, 10, 20 or 30mg/kg) or vehicle was orally administered to ten mice per dosage level. At one hour after test drug administration, 0.5% PTZ solution, a known seizure-inducing compound, was administered via iv infusion. Outcome measures included time to the first myoclonic (whole-body) twitch, and time to generalized clonus (seizure). At the 30mg/kg dose, TRV045 demonstrated a statistically significant increase in time to first myoclonic twitch (31.6 seconds TRV045 vs 26.0 seconds vehicle, p=0.02). This dose of TRV045 also demonstrated an increase in time to generalized clonus (33.9 seconds TRV045, vs 28.7 seconds vehicle, p=0.056). A separate study used a validated model of acute anti-seizure effect in rats, the maximal electroshock (MES) model. In this test, 60 Hz of alternating current (150 mA) is delivered for 0.2 sec by corneal electrodes after application of local anesthesia. Protection from MES-induced seizures is shown by abolition of the hindlimb tonic extensor component of the seizure episode. Rats (N=8 per group) were tested at four doses of TRV045, administered by intra-peritoneal (IP) injection (10, 15, 20 and 30 mg/kg). There was a dose-dependent protection observed across the dose range, reaching 7 of 8 rats protected at the 30 mg/kg dose level, and an estimated effective dose for 50% of the population (ED50) of 18 mg/kg. Finally, TRV045 was screened in a preliminary study to evaluate the potential for TRV045 to exert an antiepileptogenic effect, or to prevent the emergence of epilepsy. In this model, rats underwent repeated low-dose IP injection of kainic acid to induce status epilepticus (SE), which leads to the development of spontaneous recurring seizures weeks later. Administration of test compounds immediately after the induction of SE, and before the development of spontaneous seizures, provides insight into the potential disruption of the process of seizure development, or epileptogenesis.