Insys Therapeutics says it will ponder its next steps after acknowledging the FDA’s rejection of its new drug application (NDA) for Buvaya (buprenorphine sublingual spray) as a treatment for moderate-to-severe acute pain.

The FDA has issued a complete response letter (CRL) which, according to the company, restated that some of the company’s data raised safety concerns, even as the clinical development program showed all three proposed doses of Buvaya were statistically significantly different than placebo in providing pain relief.

The safety concerns were among reasons cited by the FDA’s Joint Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee when they voted in May to not recommend approval of the NDA. The FDA typically follows the advice of its advisory panels.

“Overall, the committee agreed that the efficacy findings were not sufficient, because of the delayed time to onset of analgesia, to support the indication of ‘management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate,” the Committees stated in the minutes of their May 22 meeting.

According to the Briefing Document prepared by FDA staffers for the Joint Committee, more than half of the patients treated with the 0.125 and 0.25 mg dosages of Buvaya “never experienced meaningful analgesia.” The median time to onset of meaningful pain relief was 92 minutes for patients treated with the highest, 0.5 mg, dose of Buvaya.

“It is important to note that, while enough high-dose patients experienced meaningful analgesia to estimate a median, over one-third of patients in that group either were redosed with study drug or received rescue prior to experiencing analgesia,” the Briefing Document cautioned.

“For analgesics intended to treat acute pain, there is an expectation that meaningful pain relief will be experienced soon after taking the first dose of drug (generally within one hour). The concern around a delay in onset of pain relief is that, in seeking adequate analgesia, patients may redose with [Buvaya] or use another opioid medication before the next dosing time, which poses the increased risk of adverse opioid-related events or potentially opioid overdose.”

‘Did Not Show Clinical Efficacy’

Thus, the joint committee concluded that despite what it termed “a tremendous public health need for other alternative medications for acute pain,” Buvaya’s delayed time to onset and weak efficacy demonstrated that it “did not show clinical efficacy as a schedule III controlled substance and was compared to having similar efficacy as nonsteroidal anti-inflammatory drugs.”

Steve Sherman, Insys SVP of regulatory affairs, issued the company’s response to the FDA CRL in a statement: “Given the attributes of our proprietary buprenorphine formulation for sublingual delivery, we continue to believe that this drug-device combination could bring value to the management of pain and will assess the next steps in the context of the company’s overall mission.”

The FDA’s rejection of Buvaya caps a turbulent year for Insys, mostly related to one of its marketed drugs, Subsys® (fentanyl sublingul spray). Insys’ founder and majority owner John N. Kapoor, Ph.D., was arrested October 27, 2017, on federal racketeering and conspiracy charges that could, if he is convicted, send him to prison for decades.

Nearly five months later, in March, federal prosecutors indicted five doctors on charges of conspiring to receive bribes and kickbacks from the company, prompting Insys to issue a statement expressing a commitment to “high ethical standards” and cooperation with authorities.

And on May 15, the U.S. Department of Justice announced that it had joined five lawsuits accusing Insys of paying kickbacks to induce physicians and nurse practitioners to prescribe Subsys for their patients. Insys responded with a statement saying it “continues to have an ongoing dialogue with the DOJ” and restating its estimate of $150 million as its minimum liability exposure expected to be paid out over five years in connection with the federal investigation.

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