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BOSTON -- An investigational medication that, if approved, would be a first-in-class treatment for post-herpetic neuralgia (PHN) still has a future despite missing the primary efficacy endpoint in a phase II study, a researcher said here.

Called LX9211, the non-opioid drug inhibits adapter protein 2-associated kinase-1 (AAK1), which earlier studies had established as a mediator of neuropathic pain, explained Anand Patel, MD, of Conquest Research in Winter Park, Florida.

Patients receiving it in the 79-patient phase II study -- the second completed thus far -- showed a mean decrease of 2.42 points in average daily pain scores at week 6, which have a range of 0-11 and served as the primary efficacy endpoint, Patel reported at the American Academy of Neurology annual meeting. Scores in a placebo group declined 1.62 points on average.

However, the difference failed to reach statistical significance (P=0.12) and thus the endpoint was missed.

Part of the reason may be the smallish sample size, but Patel said a high rate of adverse events leading to early dropouts was an important factor. He said another study is in the works that would try to optimize the dosing.

AAK1 emerged in the previous decade as a tempting target for neuropathic pain therapy. In a mouse study employing a shotgun approach to identify novel targets, via knockout for their relationship to neuropathic pain, and the one encoding AAK1 was the winner. As a kinase enzyme, a small-molecule inhibitor approach was feasible and early clinical tests supported it.

LX9211's developer, Lexicon Pharmaceuticals, sponsored an initial placebo-controlled phase II study in diabetic neuropathy pain for which last June. With 319 patients enrolled, it found significant reductions in pain scores with the drug versus placebo.

For the new trial, called Patel and colleagues randomized 79 patients 1:1 to LX9211 or placebo. It started with a 2-week, single-blind, run-in period in which all patients received placebo. This was followed by 6 weeks of double-blind treatment with the assigned agents: LX9211 started with a 200-mg loading dose on day 1 followed by 20 mg/day from day 1 onward. After week 6, all patients were switched back to single-blind placebo for a 5-week safety follow-up.

Mean patient age was 65, and roughly three-quarters had pain scores of 5-7 at baseline; scores were in the range of 8-9 for the remainder. About one-third were taking some type of painkiller and those using gabapentin, pregabalin (Lyrica), or tricyclic antidepressants for PHN pain were allowed to continue with one of these during the trial. (Patel said that this, too, might help account for the missed efficacy endpoint, as responses in the placebo group particularly had "quite a bit of variability.")

One secondary outcome clearly favored LX9211. When analyzed across the entire 6-week treatment period -- during which average pain scores were numerically lower with the drug versus placebo at every weekly evaluation -- the average difference was 0.8 points with a P value of 0.032.

Adverse events were far more common with the active agent. Dizziness was reported by 29% of those on LX9211, compared with 5% of the placebo group. Headache occurred in 11% and 5%, respectively. Similarly, 19% of the LX9211 group had gastrointestinal complaints versus 7% of those taking placebo.

However, said Patel, most of these events were reported during the first week of treatment. He said his group suspects that the very large loading dose may have been responsible. Moreover, these events drove a number of early discontinuations that diminished LX9211's apparent effectiveness under the prespecified statistical analysis. The investigators therefore are now developing another trial to test other dosing regimens that may reduce this effect.

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