What one analyst described as Heron Therapeutics Inc.'s "profound benefit" in phase II data with HTX-011 for post-bunionectomy pain triggered speculation about how the findings might translate into a pivotal trial with the compound, a long-acting formulation of the numbing agent bupivacaine in a fixed-dose pairing with the anti-inflammatory therapy meloxicam.
Redwood City, Calif.-based Heron's stock (NASDAQ:HRTX) closed Wednesday at $40.81, up $7.25, or 21.6 percent, on word that HTX-011 handily met primary and secondary endpoints in the experiment that enrolled 64 patients to test the safety and efficacy of 200 mg or 400 mg of the bupivacaine/meloxicam combo compared to placebo. Heron's Biochronomer technology uses bioerodible polymers that, when injected into subcutaneous tissue, undergo controlled hydrolysis for sustained release.
CEO Barry Quart said the goal in pivotal trials would be to show that HTX-011 can beat bupivacaine alone, which "has been a very difficult task for products, because bupivacaine solution works very well early on." During a conference call with investors, he said the key is knocking down pain during "the later hours of the first day, and in the second day particularly," and Heron was "extremely encouraged" by the phase II data in this regard. "If you just look at that second day, you see a very substantial separation between placebo and drug," he said. "I think it is safe to say that you will see, coming up in the future, head-to-head comparisons" between HTX-011 and bupivacaine by itself.
The primary endpoint of the phase II trial was the difference as compared to placebo in pain intensity as measured by the Summed Pain Intensity (SPI) score in the first 24 hours post-surgery (SPI 0-24). Key secondary endpoints included the difference in SPI in the first 48 hours post-surgery (SPI 0-48), the difference in SPI in the first 72 hours post-surgery (SPI 0-72), time to the first use of opiate rescue medication, and the percent of patients who received no opiate rescue medication in the first 72 hours post-surgery.
More effective was the 400 mg dose. Findings with that treatment as compared to placebo found pain intensity in the first 24 hours post-surgery was reduced by 69 percent (SPI of 38.5 vs. 124.2, p<0.0001). Pain intensity in the first 48 hours post-surgery fell 52 percent (SPI of 106.9 vs. 224.8, p<0.0001). And in the first 72 hours post-surgery, pain intensity dropped 40 percent (SPI of 170.2 vs. 285.9, p = 0.0064). With the drug, time to the first use of opiate rescue medication was increased by 488 percent (48.2 hours vs. 8.2 hours, p<0.0001). Thirty-two percent of patients received no opiate rescue medication during the entire 72-hour period post-surgery, compared to 5 percent for placebo (p<0.0001).
HTX-011 proved generally well tolerated, with the most frequent adverse events turning up as headache, nausea, vomiting, erythema, cellulitis, dizziness and hypoxia, none of which was considered drug-related.
Leerink Partners analyst Jason Gerberry focused on the third of patients who took no rescue meds in the 72 hours, and called it a "profound benefit," asking whether the primary endpoint of a registration trial might leverage the finding. Quart was cautious, saying that the idea is "something we will ultimately have to discuss with the [FDA], in terms of acceptability. Clearly, one of the areas you can look at in terms of durability of response and benefit of the product continuing out to 72 hours is that endpoint" but "it's going to be the agency that decides whether or not it's an endpoint they consider valuable for approval."
In a research report later in the day, Gerberry pointed out that efficacy curves for HTX-011 and placebo related to pain intensity "start to converge at around the 55-hour period post-surgery." The FDA, he reminded investors, recently restricted Parsippany, N.J.-based Pacira Pharmaceuticals Inc.'s ability to promote a 72-hour benefit with its drug Exparel (bupivacaine liposome injectable suspension). U.S. regulators said "the difference in mean pain intensity needed to be demonstrated during the 24-72-hour period, not 0-72-hour mean pain intensity," he recalled. "According to the FDA, Exparel's benefit at 24-72 hours was minimal to zero." During the conference call, Heron said it has not received data cuts on 24-48 hour or 24-72 hours from its statisticians, though these may come later. "In our view, there were still many encouraging indicators to suggest HTX-011 may have a more sustained effect," Gerberry wrote.
If there was any blot on the data, it might have been that placebo patients did not require rescue opioid therapy until the eight-hour mark, whereas trials with Exparel showed the need came at around the seven-hour mark. This did little to affect the enthusiasm of Gerberry, who was "ultimately comforted by the fact that we didn't see a strong placebo effect on pain intensity using either a data imputation or non-imputation methodology." He also pooh-pooh'd frets by some investors that the 400 mg dose could turn out toxic. "We disagree," he wrote, since HTX-011 is "a slow-erosion technology" and "there have been no signs of dose-dumping in the phase I or phase II data sets." In phase I, HTX-011 blood levels measured in the 300-500 ng/ml level, well below the toxicity threshold of 1,500 ng/ml. Toxicity blood levels are well established with products such as Marcaine (bupivacaine hydrochloride, Hospira Inc.)