Drugmakers, regulators and legislators have put enormous effort towards bringing abuse-proof painkillers to market over the past decade or more, with little to show for it. So the 43% rise in Nektar Therapeutics’ stock yesterday – the shares cracked the $22 mark for the first time in more than a decade – is understandable after data suggested that NKTR-181 might be the closest thing yet to this long-sought goal.
Nektar has long claimed that NKTR-181, a mu-opioid agonist, does not produce the euphoria seen with other opioids and thus would be less tempting to addicts, but its efficacy had been in doubt after a 2013 failure in arthritis. These doubts have, it seems, been swept away by a resounding hit in the phase III Summit-7 trial in chronic lower back pain, and though it will take some years to launch ’181 Nektar could well have its pick of marketing partners.
Mu and improved
In Summit-7, 610 opioid-naive patients with moderate to severe chronic low back pain were titrated to a tolerated effective dose of NKTR-181 of between 100mg and 400mg twice-daily, cutting average pain scores by 65%. Patients then entered a double-blind, placebo-controlled phase in which they were randomly assigned to continue on their dose of ’181 or to receive placebo for 12 weeks.
The primary efficacy endpoint, better pain relief with NKTR-181 than placebo over the 12-week placebo-controlled period, was met with a p value of 0.0019: average pain scores were 1.46 for placebo versus 0.92 for NKTR-181. Among the 83% of patients who completed the 12-week treatment period, average pain scores were 1.25 for placebo versus 0.56 for NKTR-181. The p value here was less than 0.0001.
The dropout rate during the titration phase was 12%; in phase II trials it had reached 18%. Side-effects were mild enough, with nausea in 10% of patients and constipation in 8.7%. The latter effect was eased by use of Nektar’s opioid-induced constipation drug Movantik, perhaps providing a neat bundling opportunity should ’181 reach the market.
The USP of ’181 is its alleged lack of appeal to addicts at a time when the abuse of opioid painkillers is the subject of a great deal of hand-wringing, particularly in the US. Just last week an FDA adcom decided that Endo International’s oxymorphone formulation Opana ER was no longer worth the candle (Snippet roundup: Medica and Cell Medica are in the money, but Endo and Valeant feel the pain, March 17, 2017).
The Nektar project crosses the blood-brain barrier brain more slowly than conventional opioids, the company says, and thus neither produces a high nor requires a special formulation to deter abuse. Nektar points to a recent study in which the same doses of NKTR-181 used in Summit were given similar scores to placebo for “drug liking” and “feeling high”, and were rated significantly lower than 40mg of oxycodone on the same measures.
Staying the course
The failure of a phase II study in osteoarthritis of the knee four years ago hurt Nektar badly, and its decision to stick with this asset, throwing large sums of money at clinical trials, raised eyebrows over the past three and a half years (Nektar’s faith in pain project hurts share price, September 27, 2013).
It is doubtful that the Summit-7 data will be enough for FDA approval – for a start another opioid might have been a more convincing comparator – but they could allow Nektar to hook a partner and therefore avoid the costs of any further studies the FDA does request. Roth analysts pick Purdue Pharma as the most likely licensee of ’181, with Pfizer, Horizon Pharma and Mallinckrodt also in the running.
Analysts from Janney reckon '181 will be launched in 2021, and could see peak sales of $800m to $1bn five years later. Nektar’s tenacity in developing it could pay off handsomely.