Trevena, Inc. (Trevena) is a biopharmaceutical company focused on developing and commercializing novel medicines for patients affected by central nervous system, or CNS, disorders.
The company’s product, OLINVYK (oliceridine) injection, or OLINVYK, was approved by the United States Food and Drug Administration, or FDA, in August 2020. The company initiated commercial launch of OLINVYK in the first quarter of 2021. OLINVYK is an opioid agonist for use in adults for the management of acute pain s...
Trevena, Inc. (Trevena) is a biopharmaceutical company focused on developing and commercializing novel medicines for patients affected by central nervous system, or CNS, disorders.
The company’s product, OLINVYK (oliceridine) injection, or OLINVYK, was approved by the United States Food and Drug Administration, or FDA, in August 2020. The company initiated commercial launch of OLINVYK in the first quarter of 2021. OLINVYK is an opioid agonist for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. OLINVYK is the first new chemical entity, or NCE, in this intravenous, or IV, drug class in decades and it offers a differentiated profile that addresses significant unmet needs in the acute pain management landscape. OLINVYK delivers IV opioid efficacy with a rapid 1-3 minute median onset of action. In addition, OLINVYK requires no dosage adjustments in patients with renal impairment, a large patient population with significant medical complications. The U.S. Drug Enforcement Administration, or DEA, has classified oliceridine as a Schedule II controlled substance.
In April 2024, the company announced that OLINVYK remains available for purchase by customers, but that the company is reducing commercial support for the product to preserve capital as the company conducts a process to explore a range of strategic alternatives for OLINVYK. Potential alternatives that may be explored or evaluated include, but are not limited to, a sale, license, or divestiture of OLINVYK. There can be no assurance regarding the schedule for the completion of the strategic review process, that this strategic review process will result in the company pursuing any transaction or that any transaction, if pursued, will be completed.
Using the company’s proprietary product platform, the company also has identified and is developing the following product candidates:
TRV045: TRV045 is the company’s novel sphingosine-1-phosphate, or S1P, receptor modulator that may offer a new, non-opioid approach to managing chronic pain, as well as for treating epilepsy and seizure disorders. TRV045 has also demonstrated an anti-inflammatory effect in nonclinical studies that may have broad potential application in CNS disorders, autoimmune disease and inflammatory disease. TRV045 targets the S1P subtype 1 receptor and data suggests that TRV045 may effectively reverse neuropathic pain and reduce seizure risk without the immune-suppressing activity, or lymphopenia, observed with approved therapeutics targeting S1P receptors.
In September 2023, the company announced positive data from two clinical proof-of-concept studies. TRV045 demonstrated statistically significant analgesic effect in a capsaicin-induced model of neuropathic pain. TRV045 also demonstrated a statistically significant evidence of CNS activity as measured by resting state EEG power spectral analysis in a transcranial magnetic stimulation, or TMS, study. 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.
TRV045 was well tolerated in these proof-of-concept studies, with no drug-related adverse events and no serious adverse events reported. In addition, no drug-related lymphopenia, bradycardia, or change in blood pressure, adverse events generally observed with approved therapeutics targeting S1P receptors, were reported.
TRV734: The company also has identified and has completed the initial Phase 1 studies for TRV734, an NCE targeting the same novel mechanism of action at the mu opioid receptor, or MOR, as OLINVYK. TRV734 was designed to be orally available, and its mechanism of action suggests it may offer valuable benefits for two distinct areas of important unmet medical need: acute and chronic pain, and maintenance-assisted therapy for patients with opioid use disorder, or OUD. The company is collaborating with the National Institute on Drug Abuse, or NIDA, to further evaluate TRV734 for the management of OUD, and NIDA initiated a proof-of-concept study for this indication in December 2019. In June 2021, the company announced that the study, which had been paused due to the global COVID-19 pandemic, had resumed recruiting patients. The company intends to continue to focus its efforts for TRV734 on securing a development and commercialization partner for this asset.
Product and Pipeline
OLINVYK (oliceridine) Injection
OLINVYK is a G-protein biased MOR ligand approved for acute pain in adults that is severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. It is an NCE with a novel mechanism of action.
Pain Treatment Options
Approximately 165 million units of IV opioids were used on average over the last three years, according to 2021 IQVIA data. Conventional IV opioid analgesics, such as morphine, fentanyl, and hydromorphone, have been core components of pain management protocols in the immediate postoperative period. The effectiveness of conventional opioids agonists is limited by severe dose dependent side effects such as respiratory depression, nausea, vomiting, constipation, and sedation which can be exacerbated by accumulation of active metabolites and by reduced renal clearance in patients with impaired kidney function. These shortcomings of conventional IV opioids create substantial challenges for healthcare providers in certain clinical practice situations.
Injectable non-opioid analgesics are often used together with IV opioids in multimodal protocols for post-surgical pain management. However, these drugs, such as IV non-steroidal anti-inflammatory drugs, or NSAIDs, IV acetaminophen, or local anesthetics such as bupivacaine, have their own potential for cardiovascular, hepatic and gastrointestinal side effects. In addition, none of these non-opioid analgesics offers sufficient efficacy to manage severe acute pain as a monotherapy in many patients.
OLINVYK addresses a significant unmet need for a highly effective IV opioid analgesic agent with a differentiated safety, tolerability, and PK/PD profile. OLINVYK delivers IV opioid efficacy with a rapid 1-3 minute median onset of action and requires no dosage adjustments in patients with renal impairment, a large patient population with significant medical complications.
OLINVYK was approved by the FDA in August 2020 for both bolus and patient-controlled analgesia, or PCA, delivery and the company initiated commercial launch of OLINVYK in the first quarter of 2021. The DEA has classified oliceridine as a Schedule II controlled substance. Like other opioids, the label for OLINVYK contains a ‘boxed’ warning and important safety information. Please consult www.olinvyk.com to view the prescribing information together with important safety information and boxed warning.
OLINVYK VOLITION Post-Approval Study
In 2023, the company announced OLINVYK data from the VOLITION study, a 203-patient, real world, open-label, multi-site study led by clinical outcomes research experts from Cleveland Clinic and Wake Forest Baptist Health Medical Center. OLINVYK was dosed as the first-line analgesic during post-operative care, with a 1.5mg loading dose of OLINVYK at surgical closure, and 0.35mg to 0.5mg of OLINVYK, as needed, administered with a PCA device, with a 6-minute lockout period. Additional boluses (=1 mg) of OLINVYK were available if needed as soon as 15 minutes after the initial 1.5 mg loading dose.
OLINVYK demonstrated a 22.8% respiratory compromise, defined as any one of five pre-specified respiratory events over 48 hours of continuous monitoring. As with all opioids, serious, life-threatening, or fatal respiratory depression may occur in patients treated with OLINVYK, as indicated in the boxed warning. OLINVYK also demonstrated a 52.2% GI complete response rate, defined as no vomiting and no antiemetic use throughout the post-operative period. Over 90% of OLINVYK-treated patients reported feeling ‘alert and calm’ from the morning of the first post-operative day and at every observation point thereafter, based on the Richmond Agitation-Sedation Scale, and 3.9% of OLINVYK-treated patients exhibited symptoms suggesting delirium at any point in the 48-hour post-operative period, based on the validated 3D-CAM screening tool. Sedation is an established risk of opioids including OLINVYK.
OLINVYK ARTEMIS Post-Approval Electronic Medical Records Study
In 2023, the company also announced OLINVYK data from the ARTEMIS electronic medical records, or EMR, analysis that compared the health outcomes of VOLITION study patients with a matched population of patients, who underwent similar surgical procedures but were treated with other IV opioids, at the same institutions and during the same general time period as VOLITION. Matching was conducted with a greedy matching algorithm, using a propensity scoring method with eight different demographic and clinical characteristics including age, sex, type and duration of surgery, measures of overall surgical and medical morbidity, and type of hospital insurance.
Manufacturing
The company has completed process development of the active pharmaceutical ingredient, or API, in OLINVYK and has manufactured multiple commercial-scale batches under current good manufacturing practices, or cGMP. The company also has completed drug product process development and have manufactured multiple commercial-scale batches of drug product under cGMP conditions.
For OLINVYK, the company has established commercial supply agreements for the manufacture of the API and finished (compounded, filled and packaged) drug product. Sterling Pharma Solutions (formerly Alcami Corporation), or Sterling, is contracted to supply all of the company’s commercial API from its Germantown, WI manufacturing facility. The company has existing commercial supply agreements with two separate companies for the supply of drug product. Alcami Corporation, or Alcami, is contracted to supply commercial drug product from its facilities in Charleston, SC and Wilmington, NC and was included as part of the company’s approved new drug application, or NDA, submission. Pfizer CentreOne (formerly Hospira) is also contracted to supply commercial drug product in the future, but was not included in the company’s NDA submission.
In October 2020, the company announced that the DEA has classified OLINVYK as a Schedule II controlled substance. All third-party facilities throughout the supply chain have the appropriate licenses from the DEA for handling Schedule II controlled substances according to each of their respective contractual roles (manufacturing, testing, distribution, etc.).
Intellectual property
The company wholly owns the OLINVYK patent portfolio, including six issued U.S. patents (U.S. Patent Nos. 8,835,488; 9,309,234; 9,642,842; 9,849,119;11,077,098; and 11,931,350), which claim, among other things, OLINVYK, compositions comprising OLINVYK, and methods of using OLINVYK. The issued patents are expected to expire no earlier than 2032, subject to any disclaimers or extensions, and any U.S. patent to issue in the future is also expected to expire no earlier than 2032, subject to any disclaimers or extensions. The company also has issued patents in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Macau, Israel, Japan, India, South Korea, and New Zealand, which claim, among other things, OLINVYK, compositions comprising OLINVYK and methods of making or using OLINVYK. The company has patent applications pending in the United States, Europe and Japan. The issued patents and patents that could issue in the future from these allowed or pending applications outside the United States are expected to expire no earlier than 2032, subject to any disclaimers or extensions. Following the FDA approval of OLINVYK, the FDA has added four issued U.S. patents to the Orange Book of Approved Drug Products with Therapeutic Equivalence Evaluations (U.S. Patent Nos. 8,835,488, 9,309,234, 9,642,842, and 11,077,098) and the company expects the FDA to add a fifth patent (U.S. Patent No. 11,931,350) in the coming months. In addition, the company has filed Patent Term Extension applications with the United States Patent and Trademark Office that could extend the life of one of the patents until 2034. Finally, the FDA has designated OLINVYK as an NCE in the Orange Book and it will therefore receive the exclusivity and protections afforded to NCE’s.
TRV045 (S1P Modulators)
TRV045 is the company’s novel sphingosine-1-phosphate, or S1P, receptor modulator that may offer a new, non-opioid approach to managing chronic pain, as well as for treating epilepsy and seizure disorders. TRV045 has also demonstrated an anti-inflammatory effect in nonclinical studies that may have broad potential application in CNS disorders, autoimmune disease and inflammatory disease. TRV045 targets the S1P subtype 1 receptor and nonclinical data suggests that TRV045 effectively reverses neuropathic pain and reduces seizure risk without the immune-suppressing activity, or lymphopenia, observed with approved therapeutics targeting S1P receptors.
Target Engagement, Neuropathic Pain Proof-of-Concept Study
In September 2023, the company announced data from its Target Engagement proof-of-concept study in a validated model of neuropathic pain. The 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.
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.
Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, with pain in the extremities being one of the main symptoms. Other symptoms may include numbness, tingling, allodynia and hyperalgesia. Diabetic neuropathic pain, or DNP, is usually characterized as moderate to severe in nature and can substantially affect patients’ quality of life, as well as their social and psychological well-being. Approximately one quarter of people with diabetes are affected by DNP, totaling over 5 million people in the United States. During their lifetime, approximately 50% to 70% of diabetic patients may experience symptoms of DNP.
TMS Proof-of-Concept Study
In September 2023, the company also announced data from its transcranial magnetic stimulation, or TMS, proof-of-concept study for epilepsy. The TMS 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.
Epilepsy, one of the most common neurological diseases in the world, is a chronic disorder characterized by recurrent seizures. Nearly 50 million people suffer from epilepsy worldwide, including 3 million adults and 470,000 children in the United States. 150,000 new cases of epilepsy are reported in the United States each year. According to the CDC, 56% of adults living with diagnosed epilepsy continue to have seizures.
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.
TMS Proof-of-Concept Studies – Safety and Tolerability
There were no drug-related adverse events and no serious adverse events were reported in either proof-of-cponcept study. Of the adverse events, 98% (102 of 104) were reported as mild in the Target Engagement study, and 99% (79 of 80) were reported as mild in the TMS study. The most common adverse events reported were headaches, somnolence, dizziness and fatigue.
In screening and follow-up physical exams, including ophthalmologic exams, there were no clinically significant observations. Laboratory results also showed no clinically significant reduction in total lymphocyte count, no clinically significant changes in heart rate or blood pressure, and no clinically significant changes in ECG interval measures (including no prolongation of PR or QTcF intervals).
This safety and tolerability data in 50 subjects is generally consistent with, and further builds upon, the 89-subject data from the first-in-human study of TRV045 reported in November 2022. The data supports the company’s belief that TRV045 has the potential to effectively target indications, such as neuropathic pain and epilepsy, without adverse events such as lymphopenia, bradycardia, pulmonary adverse events and ophthalmologic adverse events, which have been reported with other S1P receptor modulators.
Intellectual Property
The company wholly owns the S1P patent portfolio, including one pending provisional application, two issued U.S. patents (U.S. Patent Nos. 11,912,693 and 11,884,655) claiming S1P receptor modulators and/or methods of making or using the same. The company also has issued patents in Japan, India, Israel, and South Africa; and pending applications in the United States, Australia, Brazil, Canada, China, Europe, Israel, India, Japan, South Korea, Hong Kong, Russia, the United Arab Emirates, Mexico, and New Zealand. The applications are directed to, amongst other things, compounds that modulate the S1P receptor and methods of making or using these compounds, including methods of treating pain, epilepsy, mood disorders, anxiety disorders, and trauma-and stressor-related disorders. Patents that could issue in the future from the national phase applications would be expected to expire no earlier than 2038 subject to any disclaimers or extensions.
The company is aware of a certain U.S. patent owned by a third party with claims that are broadly directed to a method of treating chemotherapy induced neuropathic pain with an S1P receptor agonist or an S1P receptor antagonist.
TRV734
TRV734 is a small molecule G-protein biased ligand of the MOR that the company discovered and has developed through Phase 1 as a first-line, orally administered compound for the treatment of moderate-to-severe acute and chronic pain. Like OLINVYK, TRV734 utilizes a well-established mechanism of pain relief by targeting the MOR. Also like OLINVYK, it does so with enhanced selectivity for the G-protein signaling pathway, which in nonclinical studies was linked to analgesia, as opposed to the beta-arrestin signaling pathway, which in nonclinical studies was associated with the development of side effects. Subject to successful nonclinical and clinical development and regulatory approval, TRV734 may have an improved efficacy and side effect profile as compared to current commonly prescribed oral analgesics, such as oxycodone. In addition, TRV734’s mechanism of action suggests it may offer valuable benefits for another unmet medical need: the management of opioid dependence associated with OUD. The company intends to continue to focus its efforts for TRV734 on securing a development and commercialization partner for this asset.
Clinical Development
The company has completed three Phase 1 trials of TRV734 in healthy volunteers, including a single ascending dose study, a multiple ascending dose study, and a pharmacokinetic study. In these studies, a total of 127 healthy volunteers were exposed to TRV734 at doses between 2 mg and 250 mg. The company incorporated measures to assess the potential for analgesic efficacy and tolerability advantages in these studies. Based on these data and data for OLINVYK, TRV734 may offer an improved efficacy profile as compared to current opioid therapies or equivalent efficacy with an improved gastrointestinal tolerability and respiratory safety profile.
In collaboration with NIDA, the company intends to pursue a clinical study to determine whether TRV734 decreases symptoms of opioid withdrawal in patients with OUD. The company expects to initiate a randomized, double-blind, four-period, placebo- and positive-controlled study that will enroll approximately 50 opioid-dependent patients undergoing stable methadone maintenance therapy. The primary objective of the study is to assess the ability of TRV734 to reduce acute opioid craving symptoms, as measured by the Subjective Opioid Withdrawal Scale. The study will also evaluate whether TRV734 suppresses withdrawal signs using the Clinical Opioid Withdrawal Scale. Secondary outcomes will include assessments of safety and measures of neurocognitive changes. In June 2021, the company announced that the study, which had been paused since March 2020 due to the global COVID-19 pandemic, had resumed recruiting patients.
NIDA has previously generated nonclinical data in a rodent model of maintenance treatment showing that chronic administration of TRV734 reduced oxycodone-seeking in rats. TRV734 may provide an alternative to existing therapies such as methadone and buprenorphine. Successful therapy with methadone is limited by side effects that include sedation and constipation, while use of buprenorphine is limited by lower maximal efficacy and challenges with initial induction of therapy. It is hypothesized that a MOR-biased agonist may provide high efficacy for preventing symptoms of opioid withdrawal while offering a more benign side-effect profile.
Intellectual Property
The company wholly owns the TRV734 patent portfolio, including two issued U.S. patents (U.S. Patent Nos. 9,044,469 and 10,588,898) claiming TRV734, other compounds and/or methods of making or using the same. These patents are expected to expire no earlier than 2032, subject to any disclaimers or extensions. The company also has issued patents in Australia, Brazil, Canada, China, Europe, Eurasia, Hong Kong, Macau, Israel, Japan, India, South Korea, and New Zealand claiming TRV734, other compounds and/or methods of making or using the same. The company also has patent applications pending in the United States, Europe, and Japan. The issued patents and patents that could issue in the future from these allowed or pending applications outside the United States are expected to expire no earlier than 2032, subject to any disclaimers or extensions.
One of the two issued U.S. patents (U.S. Patent No. 10,588,898) also claims, among other things, methods of using TRV734 or compositions comprising TRV734 for treating drug abuse. The company also has issued patents in Brazil, Canada, Israel, Japan, and South Korea, which claim, among other things, methods of using TRV734 or compositions comprising TRV734 for treating drug abuse. The issued patent (U.S. Patent No. 10,588,898) is expected to expire no earlier than 2032. The issued patents outside the United States are expected to expire no earlier than 2032, subject to any disclaimers or extensions.
Commercialization
The company launched the customer-facing elements of the company’s commercial team in the first quarter of 2021 with Syneos Health, a contract sales organization, to assist in the sourcing, training and deployment of a range of customer-facing roles. In 2022, the company transitioned to an in-house U.S. commercial team. In April 2024, the company announced that OLINVYK remains available for purchase by customers, but that the company is reducing commercial support for the product to preserve capital as the company conducts a process to explore a range of strategic alternatives for OLINVYK. Nowithstanding the company’s reduction of commercial support for OLINVYK, the company will continue to comply with all regulatory requirements, including post-marketing surveillance and reporting obligations.
Government Regulation and Product Approval
OLINVYK has been classified as a Schedule II controlled substance under the Federal Controlled Substances Act of 1970, or CSA.
History
Trevena, Inc. was founded in 2007. The company was incorporated under the laws of the state of Delaware in 2007.
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