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Background Analysis: US FDA Advisory Committee to Review Lofexidine to Treat the Symptoms of Opioid Withdrawal and to Facilitate Discontinuation of Opioids – MAR 27, 2018 (PDAC)

Announcement

The US FDA has scheduled a Psychopharmacologic Drugs Advisory Committee (PDAC) meeting for Tuesday, March 27, 2018, to discuss a new drug application (NDA) for lofexidine hydrochloride, submitted by US WorldMeds, LLC (US WorldMeds), for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment.

Indication Background

Description of Indication

The physical symptoms of opioid withdrawal include chills, sweating, stomach cramps, muscle pain and runny nose. These symptoms can be a significant barrier for patients trying to achieve opioid independence.

Product Background

Description of Drug Class

Medication-assisted treatment (MAT) is the name used to describe the class of medications that are used in combination with counseling and behavioral therapies to treat substance use disorders and prevent opioid overdose.

As of February 27, 2018, FDA-approved MATs have contained the following active ingredients: methadone, buprenorphine, naltrexone and naloxone. One benefit for lofexidine, if it were to become another approved MAT, is that it does not contain an opioid.

Description of Product

Mechanism of Action.

Lofexidine is an orally administered, adrenergic alpha-2-receptor agonist that works by inhibiting the release of norepinephrine in the central and peripheral nervous system.  An excess of norepinephrine during opioid withdrawal is thought to contribute to the aforementioned physical symptoms of opioid withdrawal.

Hypertension

According to product labeling for BritLofex, a lofexidine-containing product that is currently marketed in the United Kingdom (UK), lofexidine is believed to have a high affinity for 2A receptor subtypes, resulting in less anti-hypertensive activity than clonidine, a non-selective alpha-2-receptor agonist. The labeling notes, however, that hypotension may occur in susceptible subjects, accompanied by a decrease in heart rate and that abrupt discontinuation of lofexidine has been, in some cases, associated with a transient increase in blood pressure to higher than pre-treatment levels.

Regulatory Considerations

Curbing the epidemic of opioid abuse in the US has become a priority of many US governmental agencies. On February 4, 2016, the FDA announced their official action plan. One of the actions was to support new classes of pain medicine without the same risks as opioids, safer use of opioid prescribing, and broader access to overdose treatment. Other steps were to expand the use of advisory committees to review opioids that lack abuse-deterrent properties (ADP), require label warnings for immediate-release (IR) opioids, strengthen postmarket requirements for opioid medications, update Risk Evaluation and Mitigation Strategies (REMS) for both IR and extended-release opioids, expand access to abuse-deterrent property (ADP) opioids, and reassess the risk-benefit approval framework for opioid use.

On February 24, 2018, the Secretary of the US Department of Health and Human Services, Dr. Alex Azar, highlighted the topic of MAT in his plenary address to the National Governors Association meeting. As part of his speech, he announced that the FDA would soon release two new guidance documents aimed at helping to improve the quality of, and expand access to, MAT.

One of these guidances is aimed at correcting a misconception that patients must achieve total abstinence in order for MAT to be considered effective. He said that researchers will be invited to develop new measures for evaluating the effects of MAT formulations rather than just relying on patterns of drug use, such as emergency-room visits or overdoses.

On February 25, 2018, the FDA Commissioner, Dr. Scott Gottlieb, retweeted an article about the HHS Secretary’s speech that was published in the NY Times, with a comment stating that “Ending an ‘addiction’ is separate from achieving ‘total abstinence’. Someone may be on lifelong replacement therapy with an approved opioid agonist; but no longer be ‘addicted’ to opioids. Psychological addiction is not synonymous with physical dependence.”

This thinking may factor into the benefit: risk consideration of lofexidine.

Clinical Trials of Proposed Indication

US WorldMeds has stated that the NDA submission for lofexidine is supported by two randomized, double-blind, placebo-controlled clinical trials and several supporting studies to characterize safety in a total of more than 1,000 patients. The company also says that the product's development involved an extensive clinical pharmacology program, including studies to investigate concomitant administration of lofexidine with methadone, buprenorphine, and naltrexone. This development program has been supported by a $15 million grant from the National Institute on Drug Abuse (NIDA).

A search of ClinicalTrialsGov shows that US WorldMeds has completed three phase 3 clinical trials. The results of these trials are not posted at ClinicalTrials.Gov, but the study designs and patient participation numbers are available.

One phase 3 trial was an efficacy, safety, and dose-response study with an initial randomized, placebo-controlled design, followed by open-label trial design in 603 participants (ID: NCT01863186). The primary outcome measure was the area under the curve based on the Short Opiate Withdrawal Scale (SOWS) scores over Day 1 through Day 7. SOWS is a subjective assessment in which patients rate their individual withdrawal experiences. The secondary outcome measure was completion of the 7-day double-blind treatment phase.

A second phase 3 trial was an open-label designed safety study with 286 participants (ID: NCT02363998). The primary outcome measure was the occurrence of adverse events from Day through Day 14 and at the Day 30 post-last-dose follow-up phone call. Secondary outcome measures were vital signs, 12-lead electrocardiograms, pharmacokinetic samplings, Columbia Suicide Severity Rating Scale scores, SOWS scores, Clinical Opiate Withdrawal Scale scores, assessments of completion of pre-defined withdrawal treatment goal, evaluations of subject treatment status 30 days after last dose of study drug, concomitant medication administration and clinical laboratory tests.

The third phase 3 trial was a randomized, placebo controlled trial in 264 participants (ID: NCT00235729). The primary outcome measure was the SOWS score on Day 3.No secondary outcome measure is listed at ClinicalTrials.Gov. In 2008, US WorldMeds reported the top-level results from this trial, saying that that lofexidine demonstrated statistical significance versus placebo in reducing withdrawal symptoms. The company also reported that patients taking lofexidine in the trial stayed in treatment longer than patients taking placebo.

Detailed results of the data provided in the NDA, including the outcomes from the aforementioned trials, will be presented in FDA and Company briefing materials that the FDA will post ahead of the meeting. These data will be summarized on the day they are posted in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

2Q 2018 – PDUFA date

November 21, 2017– US WorldMeds announced the submission of NDA 209229

Priority Review

Ex-US Regulatory Background

Lofexidine is currently marketed for opioid withdrawal using the brand name BritLofex in the UK and using the brand name Kai Er Ding in China.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: US WorldMeds, LLC Drug Name: lofexidine Drug Class:  adrenergic alpha-2-receptor agonist Indication: opioid withdrawal symptoms


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.