Reporting positive and eagerly anticipated, potentially wider label-enabling data from a pair of phase IIb trials, Heron Therapeutics Inc.'s non-opioid HTX-011 took another leap forward on the road to marketing approval in postoperative pain, leaving farther behind any concerns regarding the recent add-on indication for Exparel (bupivacaine liposome injectable suspension) from Pacira Pharmaceuticals Inc.

San Diego-based Heron's Study 209 tested the compound – awarded breakthrough status by the FDA – when locally administered in total knee arthroplasty (TKA). HTX-011 is "on its way to approval in 2019 and I can't wait for my ski trip in 2020," crowed Jefferies analyst Biren Amin in a report. The second trial, Study 211, examined efficacy in instillation or pectoral pocket nerve block in breast augmentation. HTX-011 achieved the primary pain reduction endpoints in both studies. The company expects to submit an NDA in the second half of this year. Shares of the company (NASDAQ:HRTX) closed Thursday at $39.95, up $9.25, or 30 percent.

CEO Barry Quart, in a conference call with investors, reminded listeners that the company has "no guarantee of priority review, even with breakthrough or fast track designation." But getting the former, a development that was also disclosed Thursday, "now that the agency has seen all of the clinical data, certainly indicates that they considered that the product met the standard of demonstrating superiority over all available therapy," which suggests "a high opportunity for priority review," he said.

In March, Heron disclosed results from dual phase III trials examining HTX-011 to control postoperative pain in patients following bunionectomy and hernia repair. Top-line data showed that the drug achieved its primary and key secondary endpoints, producing statistically significant reductions in both pain intensity and need for opioids through 72 hours post-surgery compared both to placebo and to bupivacaine solution. Fewer patients who received HTX-011 reported severe pain at any post-op time point, and more who received HTX-011 were opioid-free through 72 hours past surgery. (See BioWorld, March 20, 2018.)

HTX-011, which emerged from Heron's Biochronomer delivery platform, is a long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory drug meloxicam. Evercore ISI analyst Joshua Schimmer noted in an email alert to investors that, "impressively (again), HTX-011 not only demonstrated the required safety and pharmacokinetic [PK] profile to support a broad label, but results showed clear clinical benefit over both placebo and bupivacaine."

Study 209 was a randomized, placebo- and active-controlled, double-blind experiment in unilateral TKA. After a dose-escalation phase, 222 patients were randomized to receive: (1) HTX-011 400 mg administered via instillation into the surgical site (HTX-011 alone); (2) HTX-011 400 mg administered via instillation into the surgical site with a low dose of ropivacaine injected into the posterior capsule (HTX-011 combination); (3) bupivacaine 125 mg administered via multiple injections into the surgical site; and (4) placebo. The study included a pre-specified hierarchical testing strategy for the primary and key secondary endpoints for the HTX-011 400-mg treatment groups. The primary endpoint was pain intensity as measured by the area under the curve (AUC) from zero to 48 hours post-surgery (AUC 0-48) for HTX-011 compared to placebo. The key secondary endpoint was pain intensity as measured by the AUC from zero to 72 hours post-surgery (AUC 0-72) for HTX-011 compared to placebo.

Along with the primary endpoint, key secondary endpoints were achieved. The HTX-011 combination and HTX-011 alone resulted in reductions of 23 percent and 19 percent, respectively, in pain intensity measured at rest through 48 hours when compared to placebo (p<0.0001 and p=0.0002, respectively). Those pain reductions from HTX-011 were approximately double that of bupivacaine, which resulted in a reduction of 11 percent. The HTX-011 combination reduction was significantly better than that of bupivacaine (p=0.0212).

The HTX-011 combo and HTX-011 alone resulted in reductions of 22 percent and 19 percent, respectively, in pain intensity measured at rest through 72 hours when compared to placebo (p<0.0001 and p=0.0004, respectively). The pain reductions from HTX-011 were also about double that of bupivacaine, which resulted in a drop of 11 percent. The HTX-011 combo reduction turned up significantly better than that of bupivacaine through 72 hours (p=0.0325).

With a more conservative assessment of pain with activity, the HTX-011 combination and HTX-011 alone resulted in reductions of 16 percent and 12 percent, respectively, in pain intensity measured with activity through 48 hours when compared to placebo (p<0.0001 and p=0.0017, respectively). Such results proved significantly better than that of bupivacaine, which resulted in a reduction of 4 percent (p=0.0012 and p=0.0366, respectively). Both the HTX-011 combination and HTX-011 alone maintained control of pain with activity through 72 hours with a 15 percent (p=0.0002) and 11 percent (p=0.0058) reduction compared to placebo, respectively. The HTX-011 combo significantly reduced opioid use through 48 and 72 hours compared to placebo (p=0.0091 and p=0.0253, respectively).

Citizen's petition 'unpersuasive'

The second trial, Study 211 was a randomized, placebo- and active-controlled, double-blind, dose-finding experiment in patients undergoing augmentation mammoplasty, where HTX-011 was given by instillation into the surgical site or via ultrasound-guided lateral and medial pectoral nerve block before surgery. The study consisted of three cohorts comparing HTX-011 nerve block (60 mg, 120 mg and 240 mg) to the standard dose of bupivacaine 50 mg given as a nerve block and placebo, and a final cohort comparing both HTX-011 400 mg administered by instillation and HTX-011 400 mg delivered as a nerve block to the same two control groups. Enrolled were 243 patients. The primary endpoint was pain intensity as measured by the AUC from zero to 24 hours post-surgery (AUC 0-24) compared to placebo.

HTX-011 400 mg instilled into the surgical site and HTX-011 400 mg given as a nerve block both resulted in reductions of 22 percent in pain intensity measured at rest through 24 hours when compared to placebo (p=0.0023 and p=0.0055, respectively). The reductions with HTX-011 about tripled that of bupivacaine administered as a nerve block, which resulted in a reduction of 8 percent. The HTX-011 400-mg instillation reduction was significantly better than that of bupivacaine (p=0.0383).

With the more conservative measure, HTX-011 400-mg instillation and HTX-011 400-mg nerve block resulted in reductions of 24 percent and 23 percent, respectively, in pain intensity measured with activity through 24 hours when compared to placebo (p=0.0004 and p=0.0015, respectively). Those pain reductions from HTX-011 about doubled that of bupivacaine administered as a nerve block, which resulted in a reduction of 12 percent.

HTX-011 400-mg instillation and HTX-011 400-mg nerve block resulted in reductions in total opioid use of 33 percent and 26 percent, respectively, when compared to placebo (p=0.0093 and p=0.0435, respectively), or about triple that of bupivacaine administered as a nerve block, which resulted in a 10 percent drop. The HTX-011 400-mg instillation reduction was significantly better than that of bupivacaine (p=0.0455). Pain reduction and the PK of HTX-011 correlated nicely in both studies, Heron said.

The drug proved well-tolerated, with a safety profile comparable to placebo and bupivacaine solution. No deaths were recorded, nor were any clinically meaningful differences in overall adverse events (AEs), serious AEs, premature discontinuations due to AEs, potential local anesthetic systemic toxicity-related AEs adverse events, or wound healing.

Cowen analyst Boris Peaker estimated $1 billion-plus in HTX-011 sales by 2025, predicting "the positive data in pivotal phase III and phase II programs (hernia repair, abdominoplasty, bunionectomy, TKA, breast augmentation) will lead to broad usage of the drug," he wrote in a report. "Conversations with surgeons and pain management specialists indicate a high need for alternatives to postsurgical opioids that demonstrate superior efficacy and duration compared to cheap generics."

Parsippany, N.J.-based Pacira's Exparel won FDA clearance in 2011 for local administration to provide postsurgical analgesia, and the April label expansion, allowing for its use as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia following shoulder surgery in adults, caused some speculation about Heron's product – as did the citizen's petition filed the following month by Pacira, trying to derail approval of HTX-011. Evercore's Schimmer said in an email alert that he was "a little puzzled by the strategy, considering the filing hasn't even been submitted to the FDA, and we doubt the FDA will care much about Pacira's perspective regardless – especially as we found the document particularly unpersuasive. It's possible Pacira is simply trying to assuage concerns of investors who, like us, see [HTX-011] as an existential threat to Exparel."

He wrote that his firm does not cover Pacira, but "our general view is that the postoperative pain market is so vast that there can be room for multiple players to succeed, although we do wonder why anyone would use Exparel over HTX-011 in all but select procedures." Schimmer was "surprised to see a company advocate against another drug which clearly brings meaningful value to patients," and opined that it "would be ironic/awesome if Heron responded with its own citizen's petition requesting removal of Exparel from the market, given the fact that it never established noninferiority to the bupivacaine standard of care, although that probably won't happen."

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