Trevena Inc. reported top-line results from its pivotal phase III APOLLO-1 and -2 efficacy studies of lead candidate oliceridine (previously TRV-130) in moderate to severe acute pain following bunionectomy and abdominoplasty (commonly known as a tummy tuck), respectively, showing that all dose regimens across both trials achieved the primary endpoint of statistically greater analgesic efficacy than placebo, as measured by responder rate. Oliceridine, branded Olinvo, also showed dose-related trends of improvements vs. morphine on multiple measures of respiratory safety and gastrointestinal tolerability in acute pain management.

The findings, part of an intricate phase III development program, were greeted with a solid retreat by the company's shares (NASDAQ:TRVN), which lost more than one-third of their value in heavy trading as analysts quizzed company officials about a differentiated profile for the opioid receptor mu agonist, designed as a next-generation intravenous (I.V.) analgesic to manage acute pain in hospital and similar settings. Shares closed at $4.27 for a loss of $2.86, or 40.1 percent. Volume of nearly 10.4 million shares was more than 20 times the company's three-month moving average.

Some concerns were related to what Cowen and Co. analyst Ritu Baral characterized as "murkier than expected" safety findings. Only the low 0.1-mg oliceridine dose showed consistent statistically significant improvements on respiratory safety, including O2 desaturation, use of supplemental oxygen and the engineered respiratory safety burden (RSB), Baral pointed out.

Nevertheless, she voiced confidence in the drug's profile.

"While the 0.35-mg and 0.5-mg doses did not reach statistical significance (with a narrow miss of p=0.07 on RSB in the 0.35-mg dose in APOLLO-1), we note clear dose-related trends on all safety metrics," Baral wrote. "We are impressed with the magnitude of reduction on the safety measure, which greatly exceeded our previously published 20 percent reduction expectation (TRVN's slides suggest 25-80 percent dose-dependent reduction across measures and trials), although high variability and underpowering clearly complicates interpretation. We think any incremental benefit on safety without a sacrifice on efficacy (suggested especially by the 0.35-mg dose data) would be meaningful for both patients and physicians, and continue to view oliceridine's profile as a solid improvement over current standard of care."

The multicenter, randomized, double-blind, placebo- and active-controlled APOLLO-1 and -2 studies evaluated the efficacy of oliceridine for 48 hours following bunionectomy and 24 hours following abdominoplasty, respectively. During the study period, a loading dose of placebo, morphine (4 mg) or oliceridine (1.5 mg) was administered first. Patients then used a patient-controlled analgesia (PCA) button to dose themselves as often as every six minutes with either 1 mg morphine or 0.1 mg, 0.35 mg or 0.5 mg oliceridine.

If PCA dosing was inadequate to control pain, patients could request supplemental study medication (0.75 mg oliceridine or 2 mg morphine, no more than once an hour). If the study medication regimen did not adequately manage pain, patients could opt for an NSAID rescue analgesic.

Placebo loading, demand and supplemental doses were volume-matched to study drug or morphine.

Endpoints were the same in both studies. Efficacy was measured by a responder analysis that defined a responder as experiencing at least a 30 percent reduction in their sum of pain intensity difference at the end of the treatment period without either early discontinuation for lack of efficacy or safety or use of rescue medication. Noninferiority to morphine and superiority to morphine were key secondary endpoints. Respiratory safety events were defined as clinically relevant worsening of respiratory status, with the product of the frequency and conditional duration of those events reported as RSB. Additional measures of respiratory safety included prevalence of oxygen saturation less than 90 percent and prevalence of supplemental oxygen use.

Measures of gastrointestinal tolerability included use of rescue antiemetics, incidences of vomiting and instances of spontaneously reported nausea.

'THERE'S A LOT MORE ANALYSIS TO BE DONE'

In APOLLO-1, the three on-demand oliceridine regimens showed statistically superior responder rates compared to placebo at 48 hours (p<0.0001, adjusted for multiplicity). The 0.35-mg and 0.5-mg regimens showed efficacy comparable to morphine at 48 hours based on responder rate (both doses p<0.005 for noninferiority to morphine), and both doses were comparable to morphine for rates of rescue analgesic use, David Soergel, senior vice president of clinical and chief medical officer, explained on the company's conference call.

Following the 1.5-mg initial loading dose, the oliceridine regimens also showed rapid onset and achieved statistically significant efficacy by five minutes (p<0.05).

Oliceridine was associated with dose-related RSB in the three regimens (p<0.05 for the 0.1-mg regimen vs. morphine), and showed dose-related trends of reduced prevalence of oxygen desaturation (O2 < 90 percent) and lower prevalence of supplemental oxygen use (p<0.05 for the 0.1-mg regimen vs. morphine for both measures).

Oliceridine also showed a dose-related trend of less antiemetic use compared to morphine (p<0.05 for all oliceridine regimens vs. morphine) and dose-related trends of lower prevalence of nausea and vomiting across the three oliceridine regimens (p<0.05 for the 0.1-mg regimen vs. morphine).

In APOLLO-2, the three oliceridine regimens also showed statistically superior responder rates compared to placebo (adjusted p<0.05 for the 0.1-mg regimen; adjusted p<0.001 for the 0.35-mg and 0.5-mg regimens). The 0.35-mg and 0.5-mg regimens showed efficacy comparable to morphine at 24 hours based on responder rate (p<0.05 for noninferiority of the 0.35-mg regimen vs. morphine), and both doses were comparable to morphine for rates of rescue analgesic use.

Following the 1.5-mg initial loading dose, the oliceridine regimens achieved statistically significant efficacy by five to 15 minutes (p<0.05).

Oliceridine showed a dose-related trend of improved RSB across the three doses (p<0.05 for the 0.1-mg regimen vs. morphine), and dose-related trends of reduced prevalence of oxygen desaturation (O2 < 90 percent) and lower prevalence of supplemental oxygen use (p<0.05 for the 0.1-mg regimen vs. morphine for both measures).

Also similar to APOLLO-1, oliceridine was associated with a dose-related trend of less antiemetic use than morphine across the three regimens (p<0.05 for 0.1-mg oliceridine) and dose-related trends of lower prevalence of nausea and vomiting (p<0.05 for the 0.1-mg regimen vs. morphine for both nausea and vomiting; p<0.05 for 0.35 mg vs. morphine for vomiting).

Oliceridine was generally safe and well-tolerated in both studies, with nausea, vomiting, headache and dizziness as the most common drug-related adverse events, according to Trevena, of King of Prussia, Pa. Officials said they plan to present full results at future scientific conferences and peer-reviewed publications, with analysts suggesting the first full look may come in April at the American Society of Regional Anesthesia and Pain Medicine regional meeting in San Francisco.

"We believe we have demonstrated oliceridine's performance in terms of the side effect profile in comparison with morphine in a way that will really resonate with the end users – with the physicians who will be prescribing the drug," Maxine Gowen, Trevena's founding president and CEO, told BioWorld Today. "These are only the top-line data. There's a lot more analysis to be done."

Enrollment is on track for the phase III ATHENA multi-procedure safety study, with more than 400 patients treated with oliceridine to date without apparent off-target or unexpected adverse effects. In addition, a recently completed renal impairment study suggested that no dose adjustment will be required in renally impaired patients, and a metabolism study showed no evidence of active metabolites.

A phase IIb study of oliceridine in moderate to severe acute postoperative pain after abdominoplasty previously hit its primary endpoint of statistically significant reduction in pain over 24 hours. (See BioWorld Today, Sept. 2, 2015.)

"We believe we have a very powerful analgesic here that's as effective as conventional opioids, like morphine," Gowen said. "We think we've established that over a number of studies."

Clinical, nonclinical and manufacturing activities for oliceridine – which has FDA breakthrough therapy designation – are on track to support a new drug application submission in the fourth quarter. The company anticipates that oliceridine is approvable at all three dose regimens.

To that end, Trevena is beginning to build its sales force and medical affairs team, which Gowen called "appropriately sized" for 18 months from launch.

Perhaps somewhat dampening analyst enthusiasm, Trevena expects the FDA to review the drug as a schedule II controlled substance and has no plans for a schedule III filing. On the upside, the company is confident that oliceridine not only addresses the need for acute pain relief but also offers the potential to reduce hospital costs by minimizing side effects.

"Not only do we expect the profile of oliceridine to make the administration of analgesia more straightforward for physicians and much better tolerated by patients, but we also believe there is a potential for improving the costs of the procedures that these patients are undergoing," Gowen said. Better pain relief, with fewer side effects, could lead to faster ambulation and earlier discharges, for instance, she suggested.

"We are certainly going to be pursuing the health economics aspect of the use of oliceridine, as well," Gowen said.

Although the company declined to provide specifics on launch plans, Carrie Bourdow, senior vice president and chief commercial officer, said on the company's call that benchmark pricing falls in a range of $60 to $140 per day, which Baral deemed "reasonable."

Trevena also has the support of key opinion leaders (KOLs) – anesthesiologists and surgeons – in networking with prescribers. "KOLs have indicated to us that they still see oliceridine as a very viable, and very promising commercial product in post-op pain relief: a product that they would very much like to use in higher-risk patients, and would if it is priced within reach," Baral wrote. "Our two anesthesiology consultants that we have spoken to this morning strongly believe the drug has equivalent pain control to morphine, with likely faster onset of action. In particular, our consultants were impressed with oliceridine's respiratory safety profile."

"We would note that of the $562/patient of costs related to opioid-related adverse events, approximately three quarters of those costs are driven by respiratory-related adverse events," added Jefferies Group LLC analyst Biren Amin in a flash note. He pronounced oliceridine's clinical profile sufficiently compelling to justify a health outcomes benefit.

"As we have previously noted, we believed a minimum of 25-30 percent risk reduction on nausea/vomiting and respiratory safety burden was needed for oliceridine vs. morphine to have a compelling enough profile for P&T committees to have a favorable view of the drug and drive hospital uptake among physicians," Amin wrote. Although he cited the 0.35-mg dose as "the one to offer the most compelling profile vs morphine," with similar efficacy and improved rates of certain safety endpoints, Amin also was impressed with efficacy, safety and tolerability data consistency across APOLLO-1 and -2, "demonstrating applicability across different surgery types."

As it preps for filings and commercialization, Trevena could face down Cara Therapeutics Inc., of Shelton, Conn., which is advancing the I.V. formulation of its peripherally acting kappa opioid receptor agonist, CR845, in a phase III trial in acute pain and its oral formulation for chronic osteoarthritis pain in a phase IIb trial. Cara last year saw a delay in its phase III adaptive pivotal trial of CR845 to treat postoperative pain when the FDA placed a hold triggered by a pre-specified protocol measure based on elevated serum sodium levels greater than 150 mmol/L (normal is 135 to 146). That effect turned up in four patients, two of whom counted as protocol violations. (See BioWorld Today, Feb. 29, 2016.)