Insys May Need Convenience Argument To Save Sublingual Buprenorphine Spray

US FDA advisory committee will hear agency's concerns with Buvaya's effectiveness, safety, and abuse potential. 

Insys Therapeutics Inc. may need to lean on the convenient sublingual route of administration of its buprenorphine spray Buvaya to win the hearts of a US FDA advisory panel and save the non-abuse deterrent opioid from an unfavorable review outcome, as the agency has made no secret about the sour taste it has in its mouth regarding the product.

The Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee will convene in a joint session May 22 and vote on the risk/benefit profile of Buvaya after first addressing a series of discussion questions. (See chart below.) Insys is specifically seeking an indication for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

FDA, however, conveyed a clear signal about its feelings on the drug in briefing documents released May 18 in advance of the meeting.

"The totality of data submitted by the Applicant does not support the use of this product in an acute pain setting, based on both efficacy and safety findings," the briefing documents state.

But Insys contends that an easier alternative to the currently available injectable formulations is needed, as the only available buprenorphine formulation in the acute setting is the injectable Buprenex (buprenorphine hydrochloride).

"The only formulation currently available for the treatment of acute pain requires parenteral administration limiting its use despite two buprenorphine products available for chronic pain," the drugmaker says in its own briefing documents. "Buprenorphine Sublingual Spray offers an alternative that allows physicians to take advantage of the unique pharmacology and safety profile in an easy-to-administer non-parenteral formulation for cases of moderate to severe acute pain."

Insys adds that there is still a role for opioids until non-opioid pain medications are sufficient to manage moderate to severe pain, and contends that buprenorphine has lower abuse potential than Schedule II opioids.

The drug is intended to be dosed at 0.125 mg, 0.25 mg, or 0.50 mg, and sprayed sublingually every eight hours as needed for pain.

The 505(b)(2) new drug application (NDA) is currently undergoing a standard 10-month review with a user fee goal date of July 28.

FDA is proposing a risk evaluation and mitigation strategy (REMS) for Buvaya, as it is an immediate-release (IR) opioid analgesic expected to be used in the outpatient setting. The agency's proposed REMS includes a medication guide, and elements to assure safe use (ETASU) that includes mandatory training for prescribers of the drug and providers involved in treating patients on the drug.

Question To Advisory Committees

Discussion: Discuss whether based on the available data, the efficacy findings support the indication “management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.”

Discussion: Based on the available safety data, discuss whether the safety profile of Buvaya is acceptable for the proposed indication.

Discussion: Discuss any concerns you may have regarding the abuse or misuse of Buvaya and whether, based on the available data, the benefits to patients are expected to outweigh public health risks related to abuse and misuse.

Vote: Overall, do the benefits of Buvaya outweigh the risks for the indication, “the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate,” supporting approval of Buvaya?

Insufficient Efficacy

One of the agency's primary concerns involves the adequacy of Buvaya's efficacy profile.

In the Phase III pivotal trial, Buvaya met the primary endpoint of the summed pain intensity difference over 48 hours (SPID-48), which is a weighted average of the change in pain from baseline to multiple time points at intervals through 48 hours after the first dose.

The problem, FDA explains, is that "there is an expectation that meaningful pain relief will be experienced soon after taking the first dose of drug (generally within one hour)." Less than half of patients receiving the .125 mg dose or the .25 mg dose experienced meaningful analgesia, according to the briefing documents.

Additionally, the median time to onset of meaningful pain relief was 92 minutes for the 0.5 mg dose of Buvaya, and more than one-third of patients on the highest dose were either re-dosed with study drug or received rescue prior to experiencing analgesia.

"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," the briefing documents state.

FDA further doubts Buvaya's utility in the acute pain setting because the rates of rescue analgesia use in patients on the 0.125 mg and 0.25 mg doses were similar to the rate in the placebo arm.

An Imbalance In Adverse Events

On the safety side, there were higher rates of nausea, vomiting and dizziness in patients taking Buvaya in all three trials of post-surgical patients.

Although these adverse events are expected from patients taking opioids, FDA noted that the patients taking the 0.5 dose had higher rates of nausea, vomiting and dizziness compared with the morphine/oxycodone opioid regimen selected by Insys.

Buvaya was also associated with higher rates of hypoxia compared with the morphine/oxycodone regimen.

Uncertain Abuse Potential

Another strike going against Buvaya is the uncertainty surrounding its abuse potential in a period where FDA, led by Commissioner Scott Gottlieb, has made curbing opioid abuse one of the agency's top priorities. (Also see "Initiator Or Facilitator? Gottlieb Reflects On First Year As Head Of US FDA" - Pink Sheet, 11 May, 2018.)

The Office of Surveillance and Epidemiology conducted a literature review to evaluate the drug's abuse potential, and found very little to support the review of the Division of Anesthesia, Analgesia, and Addiction Products.

For instance, the office found only one study on the abuse of opioid sublingual spray dose forms, which was a small French study of 160 patients prescribed intranasal fentanyl.

Regarding the risk of abuse and overdose associated with the currently marketed buprenorphine analgesic products, Butrans and Belbuca, the agency found that Butrans had among the lowest rates of abuse compared with other buprenorphine and opioid analgesic formulations, and that there were few cases of abuse of Belbuca. Belbuca, however, has only been on the market for a short period of time, FDA noted, which complicates the assessment.

"Overall, the epidemiologic data provide very limited insight on the risks of misuse, abuse, or overdose associated with buprenorphine sublingual spray compared to other buprenorphine products or other opioid analgesics," according to the briefing documents.

Given the difficulties of characterizing the abuse potential, it may be a hard sell to both the advisory panel and FDA that the convenience is reason enough to approve Bubaya amid an opioid epidemic, especially since there is a relevant reference product in Buprenex.

Repairing A Bad Reputation

Near the beginning of Insys' briefing documents, the drugmaker includes a statement addressing the reputation hit it has taken after the Department of Justice alleged former company executives and managers created a reimbursement unit to increase prior authorizations for the fentanyl-based spray Subsys. (Also see "Insys ‘Reimbursement Unit’ Fraudulently Boosted Fentanyl Rxs, DOJ Charges" - Pink Sheet, 9 Dec, 2016.)

Insys says it is "a markedly different company today" than it is made out to be in media reports.

"The company is led by a new management team that has significantly strengthened compliance protocols to foster an organizational culture of high ethical standards and strives to puts the best interests of patients at the center of the process for making business decisions," the company states. "In fact, more than 90% of the management team and commercial organization, including the sales force, is new to the company since 2015."

Insys added that CEO Saeed Motahari joined the company in April 2017, and that there are four new members on the board of directors.