Heron Receives Rejection from FDA for Non-Opioid Pain Drug

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The U.S. Food and Drug Administration (FDA) issued Heron Therapeutics a Complete Response Letter (CRL) for its New Drug Application (NDA) for HTX-011 for the management of postoperative pain.

The CRL indicated the agency required more non-clinical information, but did not cite any clinical safety, efficacy or CMC issues. The company indicates that four non-clinical issues were noted, none of which were related to toxicity. Three were linked to confirming exposure of excipients in preclinical reproductive toxicology studies. The fourth was related to changing the manufacturing release specification of the allowable level of an impurity based on animal toxicology coverage.

Heron does not think any of the issues will be significant barriers to approval and has requested a Type A meeting with the FDA.

“We are committed to resolving the non-clinical issues outlined in the CRL with the FDA and resubmitting an NDA as soon as possible to bring this important non-opioid analgesic to patients,” said Barry Quart, president and chief executive officer of Heron.

On February 19, 2020, the FDA had extended the review period for the drug for up to three months, with a new target action date of June 26. The agency had issued a previous CRL for HTX-011 on April 30, 2019, related to chemistry, manufacturing and controls and non-clinical information. The contract manufacturing site that manufactured HTX-011 had been reinspected and no Form 384 observations were issued.

HTX-011 is a dual-acting, fixed-dose combination of the local anesthetic bupivacaine with a low dose of the nonsteroidal anti-inflammatory drug meloxicam. It is the first and only extended-release local anesthetic to show in Phase III trials to significantly decrease pain and opioid use through 72 hours compared to bupivacaine solution.

The drug was granted Fast Track designation by the FDA in the fourth quarter of 2018 and Breakthrough Therapy designation in the second quarter of 2018. The original NDA was submitted in October 2018 and received Priority Review designation in December 2018. The first CRL was issued on April 30, 2019. The company resubmitted it in September 2019.

In Europe, the European Medicines Agency validated the company’s Marketing Authorization Application (EMA) in March 2019. Its New Drug Submission was granted Priority Review status by Health Canada in October 2019 and accepted by Health Canada in November 2019.

On June 4, Heron published the results from Study 209, a Phase II trial of HTX-011 in primary unilateral total knee arthroplasty (TKA). It was published in The Journal of Arthroplasty. All primary and key secondary endpoints in the trial were achieved, with the drug demonstrating statistically significant decreases in pain intensity after surgery.

In the study, patients who underwent TKA received a single, needle-free application of HTX-011. Compared to patients receiving placebo or bupivacaine solution through 38 and 72 hours, patients receiving HTX-011 showed superior pain reduction. They also consumed fewer opioids compared to patients receiving placebo or bupivacaine.

“Effective pain management is crucial after TKA to permit earlier mobilization, maximize patient satisfaction and facilitate outpatient surgery,” said Alan J. Rechter, an orthopedic surgeon at Orthopaedic Associates. “Based on my experience in Study 209, the fast and easy needle-free administration of HTX-011 provided patients with effective and improved pain control despite taking fewer opioids.”

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