Self-administered pain therapy by way of a patient-controlled analgesia (PCA) device in Trevena Inc.'s phase IIb trial let TRV130's attention-getting safety profile emerge, and Wall Street didn't miss the significance, pushing the shares (NASDAQ:TRVN) by the end of the day to $9.05, up $3.05, or 50.8 percent.

"We saw what we expected, and we do believe it was because of the way the drug was given," CEO Maxine Gowen told BioWorld Today. "That was really the whole theoretical basis for starting the program."

The biased mu opioid receptor ligand/opioid receptor modulator was tested in moderate to severe acute postoperative pain after abdominoplasty (otherwise known as a tummy tuck), hitting the primary endpoint of statistically significant reduction in pain over 24 hours. The drug proved superior to morphine in pre-specified secondary measures, too, cutting back on nausea, vomiting and hypoventilation.

Focused on developing the next generation of G protein-coupled receptor-targeted medicines, King of Prussia, Pa.-based Trevena in November 2014 reported phase IIa/b data with TRV130 that was called "striking" by Jefferies analyst Biren Amin at the time. The study used a fixed-dosing regimen for post-bunionectomy pain. Brean Capital LLC's Jonathan Aschoff said that since "abdominoplasty generally involves less pain than bunionectomy, it was important to have a useful floor for baseline pain, as it should help trial arms differentiate from one another in terms of efficacy, and the abdominoplasty trial had baseline pain (by the Numeric Pain Rating Scale [NPRS]) of 7.7 out of 10, clearly severe baseline pain," he wrote in a Tuesday research report.

The NPRS score beat the bunionectomy trial's score of 7, Gowen noted. Cutting off bunions is "quite a brutal bony surgery, and it does cause a great deal of pain," she said. At the same time, "'tummy tuck' makes [abdominoplasty] sound less than it is. Really, this is a very large incision, two incisions actually, all the way across the abdomen, with quite a large rescission of flesh as well." A factor to keep in mind about the earlier, fixed-dose experiment is that "the patients got dosed every three hours for 48 hours whether they were still in a great deal of pain or not," she added, and this "had the effect of accentuating the side effects and minimizing, if you like, the efficacy at the later time frame. This time around, the patients were able to dose themselves to comfort and to take into consideration if they were not feeling too well on the drug. They were balancing off both efficacy and safety. The way dosing turned out – and this obviously wasn't something we could control – was that they took a lot less of TRV130 than they took of morphine, in terms of milligram doses, and they saw very similar efficacy."

Two regimens of TRV130 were included. The first consisted of a 1.5 mg intravenous loading dose with 0.1 mg self-administered, on-demand doses as often as every six minutes using a PCA device. In the second, a 1.5 mg loading dose with 0.35 mg on-demand doses were given using a PCA device. A commonly used morphine PCA regimen was also tried, consisting of a 4 mg loading dose with 1 mg on-demand doses. Placebo was administered as a loading dose and on-demand doses that were volume-matched to the active regimens.

TRV130 turned up statistically significant pain reduction compared to placebo and comparable efficacy to morphine. The TRV130 0.1 mg regimen reduced average pain scores (least squares mean change in time-weighted average over 24 hours) by 2.3 points (p<0.0001 vs. placebo). The TRV130 0.35 mg regimen knocked down average scores by 2.1 points (p = 0.0003 vs. placebo), similar to morphine, which reduced average pain scores by 2.1 points (p = 0.0001 vs. placebo). Onset was faster than morphine as well, which is consistent with earlier clinical work.

BUILDING OUT THE FOUNDATION

Use of rescue analgesics was similar for TRV130 and morphine, and less than half the rate of rescue analgesic use for placebo. The proportion of patients using a rescue analgesic was 64 percent with placebo, 31 percent with TRV130 0.1 mg, 21 percent with TRV130 0.35 mg and 25 percent with morphine (post hoc p<0.0005 for all three active arms vs. placebo).

Placebo effects often confound trials with analgesics, Gowen acknowledged, but Trevena's drug has met no such hitches, although outcomes in the latest experiment related to rescue medication "suggests they were getting some kind of placebo effect." In general, "I think when studies run into problems, it's when the drug doesn't really work very well," she said. "Our drug has always been extremely effective, and I think that's why we've never had an issue with the placebo problem."

The TRV130 groups had a significantly lower prevalence (by percentage of patients) of hypoventilation events, nausea and vomiting than the morphine group (post hoc p<0.05 for both TRV130 regimens vs. morphine). Cowen and Co. analyst Ritu Baral hailed the safety outcome, calling it a vital factor in the marketplace. A key opinion leader cited "improved respiratory [risk as] a critical differentiator for any post-op analgesic," Baral wrote in a research report. "One consultant suggested that normally highly cost-conscious hospitals would willingly pay for a post-op analgesic with better respiratory safety rather than one with 'merely' improved gastrointestinal symptoms. We think there is a significant need for safer analgesics in hospitals and clinics, especially given post-op deaths occur in obese/opioid-tolerant patients who require greater amount of opioid, but whose bodies cannot cope with the ensuing respiratory depression."

Jefferies' Amin echoed the praise of Baral, pointing out that patients "appeared to need much less TRV130 overall than morphine to manage their pain, yet still experienced a better safety profile, which we view as a win."

Roth Capital Partners analyst Michael Higgins asked rhetorically in a research report, "Is it a pain drug that's safer than opioids with comparable efficacy, or a pain drug that's more effective than opioids with comparable safety? Neither: While it may seem more of the former, as we noted above, by pressing the IV PCA button half as often as morphine to achieve the same pain results suggests to us the reliance on rescue doses and/or under-dosing of TRV130 limited our view of its full efficacy potential. Regardless of the color of this zebra's stripes, in our view, the phase IIa and phase IIb results bode well for the phase III trial."

CEO Gowen said Trevena next will ask the FDA to schedule an end-of-phase-II meeting. "We would love to squeeze it into this year," she said. "If not the end of this year then early next year we would expect it to happen. We feel very comfortable with the models we've used to this point. They certainly would fulfill the guidance, we believe, that's given" for trials in pain. "I think we have a great foundation where we are right now and we'll build out from there," she said. The PCA is "something we will be discussing with the agency for sure. It's very important for us to target very flexible dosing and administration in our labeling, because that's exactly how opioids are given," she noted, and TRV130's profile suggests it's a drug the likes of which doctors as well as their patients have wanted "for a very long time."

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