Amid need for new pain options, FDA panel rebuffs Nektar’s ‘safer’ opioid

Regulators and physicians are urgently seeking novel pain therapeutics to combat the opioid crisis without compromising treatment availability for chronic pain patients, but according to an FDA panel, Nektar’s oxycodegol shouldn’t make the cut based on available data.

In a meeting of FDA’s Analgesic Drug Products and Drug Safety and Risk Management advisory committees, the joint panel voted unanimously (0-27) against recommending oxycodegol (NKTR-181) to either treat chronic lower back pain or for general extended-release/long-acting opioid analgesic chronic pain indications.

The vote came after market close Tuesday, when Nektar shares were off $4.26 (15%) to $23.70.

The consensus among panelists was that given the public health concerns, the efficacy, safety and abuse potential data were insufficient to support bringing another opioid onto the market.

The μ opioid agonist falls into the highly scrutinized opioid class of analgesics, but Nektar designed its therapy to provide the pain reducing benefits without the CNS side effects responsible for abuse.

Oxycodegol penetrates the blood brain barrier and crosses into the CNS more slowly than other opioid analgesics, and also activates the μ opioid receptor (MOR; OPRM1) more slowly, both of which have been correlated with decreased abuse potential.

The problem is that FDA and the panelists aren’t convinced data from the limited number of studies support that therapeutic profile.

FDA advised Nektar to conduct two pivotal efficacy trials of oxycodegol, but Nektar is seeking approval for the subgroup of pain patients with chronic lower back pain based on one.

At the meeting, panelists and FDA presenters brought up concerns spanning the efficacy, toxicity, and abuse potential of oxycodegol.

Central to the arguments against approval were the data from a human abuse potential trial showing that supratherapeutic doses of oxycodegol have similar potential for abuse as supratherapeutic doses of oxycodone.

31 of 62 (50%) patients in the trial’s 1200 mg oxycodegol arm and 33 of 60 (55%) patients in the 40 mg oxycodone arm experienced euphoric mood. FDA deemed those doses comparable based on the therapeutic doses for each compound, which are higher for oxycodegol due to its lower level of exposure.

The company argued that oxycodegol’s delayed onset of action and the fact that its slow onset is a function of the therapy itself rather than a special formulation should also decrease abuse potential.

Other concerns included hepatic toxicity in the pivotal trial, and the elevated risk that may present to patients who abuse higher doses or abuse multiple substances affecting the liver. The studies also failed to consider IV use and abuse, the panelists said.

For efficacy, panelists were concerned that the therapy was tested in a single pivotal trial in an enriched population, and the improvement in pain scores was modest.

Panelists also worried that if approved, oxycodegol would be marketed as a safer opioid, rapidly expanding its use and possibly shifting guidelines that advise against the use of opioids for chronic lower back pain.

The panelists called for an additional efficacy trial with an active comparator and an expanded patient population, plus safety and human abuse potential trials evaluating higher doses in more diverse populations in order to consider the therapy for approval.

FDA missed the Aug. 29 PDUFA date for oxycodegol after postponing the advisory committee meeting due to scientific and policy issues related to the opioid class of drugs. The therapy, which is being developed through Nektar’s Inheris Biopharma Inc. subsidiary, has Fast Track designation from FDA.

Advisory committee meetings are scheduled for three other pain therapies this week: a fixed dose combination of tramadol and celecoxib from Esteve S.A. and an extended-release oral formulation of oxycodone from Intellipharmaceutics International Inc. (TSX:IPCI; NASDAQ:IPCI) Wednesday, and an extended-release bupivacaine for post-surgical analgesia from Durect Corp. (NASDAQ:DRRX) on Thursday.

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