2018 Year in Preview

Opioids, Part 2

Thomas Reinke
Contributing Editor
Gabriella Santamaria, 9, holds up a picture of her uncle who died from a heroin overdose during a candlelight vigil for victims of drug addiction on Aug. 24, 2017, in Staten Island, N.Y. (Spencer Platt/Getty Images)

An all-hands-on-deck response to the opioid epidemic will continue to be one of the major health care stories in 2018. But the epidemic took off partly because pain and its control are a black box that has resisted firm scientific understanding and safe and effective treatment. Drugmakers, for the most part, have continued to rely on opioid receptor agonists for their new medicines, although that could change next year.

So far, though, most of the new pain drugs coming from manufacturers have been iterations of the legacy opioids with extended-release (ER) and abuse-deterrent (ADF) formulations. Examples include Xtampza ER, an extended-release, abuse-deterrent form of oxycodone; Vantrela ER, a hydrocodone bitartrate; Arymo ER, a morphine sulfate; and Troxyca ER, an extended-release formulation of oxycodone and naltrexone.

The ADF opioids incorporate ingredients that extend the release and lower the maximum concentration of the agonist, which is supposed to thwart the effect of crushing the drugs and snorting, smoking, or injecting them to achieve high concentrations that provide a high. While this sounds good, the problem is that these formulations do not address the most common form of abuse—simply swallowing more of the pills. In fact, the extended-release products may actually contribute to increased opioid overdoses and deaths because they extend the opioid level overtime to dangerous levels as individuals take repeated doses.

“The ADF products are not a magic bullet—and they are very expensive,” says Mary Lynn McPherson, a pharmacy professor at the University of Maryland. “Most payers do not pay for them as first- or second-line therapies.” The low-cost formularies offered by PBMs typically rely on the legacy generic opioids.

The unmet need in pain management is for truly novel agents. The opioids remain the go-to products because they target the mu opioid receptor, which has been shown to be the most effective pathway to reduce pain. The holy grail for drug developers is an agent that stifles pain without producing the euphoria and addiction of opioids, says McPherson. To that end, she says, there is renewed interest in ketamine, which has a unique mechanism of action and has been used on battlefields.

Christopher Milne at Tufts’ Center for the Study of Drug Development says tanezumab is a new pain drug in development that should be watched in 2018. The monoclonal antibody has a novel mechanism of action that targets nerve growth factor (NGF) rather than the opioid receptors. NGF levels increase as a result of injury, inflammation, or chronic pain. Tanezumab selectively binds to nerve growth factor, limiting the protein’s ability to stimulate pain-signaling neurons. Tanezumab is being jointly developed by Pfizer and Lilly and is being tested in osteoarthritis and chronic low back pain. It was granted fast-track status by the FDA in June 2017. The phase 3 global clinical development program for tanezumab is currently ongoing with six studies in approximately 7,000 patients. We may see some results reported in the coming year.

It has been a fairly bumpy road for tanezumab. The FDA imposed a partial clinical hold on it and all other anti–nerve growth factor antibodies in December 2012 because of changes in the sympathetic nervous system of mature animals. In early 2015, the FDA lifted the hold on the tanezumab development program after a thorough review of nonclinical data characterizing the sympathetic nervous system response.

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