US Worldmeds LLC has landed the first FDA approval of a non-opioid treatment for the management of opioid withdrawal symptoms, giving U.S. doctors a tool that has long helped U.K. doctors provide relief to patients going off the powerful medicines.

US Worldmeds LLC has landed the first FDA approval of a non-opioid treatment for the management of opioid withdrawal symptoms, giving U.S. doctors a tool that has long helped U.K. doctors provide relief to patients going off the powerful medicines. The Louisville, Ky.-based specialty pharma said it expects to begin marketing the drug, Lucemyra (lofexidine), in August. Pricing has yet to be determined.

The regulatory success, marking Worldmeds' first new drug application approval, was hastened by an FDA fast track designation and covers use of the treatment for up to 14 days at the lower of two doses Worldmeds had proposed marketing.

Opioid withdrawal symptoms – such as anxiety, agitation, sleep problems, muscle aches, runny nose, sweating, nausea, vomiting, diarrhea and drug craving – occur after stopping or reducing the use of opioids in anyone with physical dependence on the drugs.

"When opioids are on board, the brain essentially recalibrates so that it's able to maintain normal function," Mark Pirner, Worldmeds' senior medical director, clinical research, told BioWorld. When opioids are withdrawn, that extra capacity "goes crazy with a massive surge of signaling that drives withdrawal symptoms," he said. Lucemyra, an oral, selective alpha 2-adrenergic receptor agonist, reduces the release of norepinephrine to quell the root drivers of withdrawal symptoms.

"We know that the physical symptoms of opioid withdrawal can be one of the biggest barriers for patients seeking help and ultimately overcoming addiction, FDA Commissioner Scott Gottlieb said, in a statement accompanying the approval. "The fear of experiencing withdrawal symptoms often prevents those suffering from opioid addiction from seeking help," he said.

Though Lucemyra can help mitigate those symptoms, like its U.K. counterpart, Britannia Pharmaceuticals Ltd.'s Britlofex, it's not known to alleviate opioid cravings. Accordingly, the FDA approval specifically excludes use of the medicine as the sole element of treatment for opioid use disorder, or addiction.

The successful approval was due in large part to a long-running collaboration with the National Institute on Drug Abuse (NIDA), Pirner said. As far back as 1996, NIDA had laid plans to run a phase III study testing Britlofex in cooperation with Britannia, eventually meeting with such clear success in 2002 that, "due to overwhelming evidence of efficacy in the Britlofex treatment group," the trial was stopped early.

Worldmeds licensed lofexidine from Britannia in 2003 under undisclosed terms shortly after its founding by CEO Paul Breckinridge Jones in March 2001. Building on NIDA's progress, Worldmeds ran its own randomized, double-blind, placebo-controlled clinical trials to evaluate the drug in 866 adults physically dependent on opioids and undergoing abrupt opioid discontinuation – the population that the current approval covers. Short Opiate Withdrawal Scale of Gossop scores were lower for patients treated with Lucemyra compared to placebo in the studies and more patients completed the treatment period of the studies in the Lucemyra group compared to placebo.

In light of evidence favoring the drug, the FDA's Psychopharmacologic Drug Advisory Committee (PDAC) voted near-unanimously in March to support approval for a 2.4-mg/day regimen, with some flexibility allowed. Despite the strong support, some members expressed concerns about the drug's cardiac risks, especially in those patients with existing cardiac issues or those who are taking other drugs that may have similar risks. (See BioWorld, March 28, 2018.)

Pirner said the FDA has been "very involved and engaged," ultimately approving a label that both "appropriately and accurately" calls out warnings and precautions while, at the same time allowing for broad and safe access to lofexidine for patients and providers.

The FDA is requiring an unusually high 15 postmarketing studies for the drug in hopes of getting more definition around pediatric and longer-term use of the medicine – another issue some PDAC members expresses concern about – in the context of gradual opioid taper. "I think that's the place where FDA would like us to go next," Pirner said.

Studies will also gather additional safety data on the effects of lofexidine on the liver, effects on blood pressure after lofexidine is stopped, and in different age groups of children who have opioid withdrawal.

Pirner said he sees Lucemyra as addressing a problem that has largely gone undiscussed. "Raising awareness of opioid withdrawal and the role it has in perpetuating opioid use, and having an FDA-approved non-opioid new tool is very exciting," he said. "Hopefully, this opens the door to a broader discussion, allowing people who were maybe afraid or didn't want to talk about getting treatment [who] now may have the encouragement or the hope they need to try to get help," he said.

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