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Nektar advances abuse-proof opioid

Biotech firm uses PEGylation to stem euphoria effect

by Michael McCoy
July 19, 2017 | A version of this story appeared in Volume 95, Issue 30

Credit: Nektar
Nektar’s R&D labs in San Francisco.
A photo of Nektar’s R&D labs in San Francisco.
Credit: Nektar
Nektar’s R&D labs in San Francisco.

Nektar Therapeutics is advancing a new drug that uses polymer chemistry to reach an elusive public health goal: relief from chronic pain with little potential for abuse.

The San Francisco-based biotech firm has released results of a study showing that its developmental opioid, NKTR-181, provides pain release without the high levels of euphoria that can lead to abuse and addiction with standard opioids. Nektar previously reported that the drug significantly reduces pain in patients with chronic lower back pain.

Pain, particularly back pain, is a big problem for millions of Americans. But abuse of opioid pain relievers is arguably a bigger problem. In 2014, nearly 2 million Americans either abused or were dependent on prescription opioid pain relievers, Nektar says.

Marketers of oxycodone and other opioids have confronted abuse with formulas intended to make their pills resistant to crushing and snorting. But drug abusers often find ways to thwart the controls and extract the pills’ active ingredients.

Nektar’s approach is to covalently bond, through an ether linkage, a short-chain polyethylene glycol to a five-ring morphinan, explains Chief Scientific Officer Stephen K. Doberstein. The molecule, whose structure will be published in the coming weeks, crosses the blood-brain barrier slowly, preventing the “rush” that abusers seek. “The speed of onset is super important,” Doberstein says.

Moreover, the ether linkage is more stable than the morphine ring, according to Doberstein. Thus, a potential abuser can’t use chemistry to break the linkage without denaturing the molecule’s active half.

NKTR-181 represents only the second example of a PEGylated small-molecule drug, Doberstein says. The first is naloxegol, a derivative of α-naloxol that Nektar licensed to AstraZeneca in 2009. FDA approved it in 2014 for the treatment of opioid-induced constipation.

Nektar continues to study the long-term safety of NKTR-181 in a Phase III clinical trial. Given its potentially large market, the company will seek a partner with pain drug experience. “We are talking to multiple companies,” Doberstein says.



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