Drug makers leave the pain behind

August is a time for relaxing, holidaymaking and, apparently, culling unpromising pain projects. This month no fewer than five groups gave up on mid or late-stage agents for various intractable pain conditions, and this included one of the few big pharmas in this space, Lilly. 

Despite the huge underserved need that guarantees rich rewards for any group that can bring a successful novel painkiller to market, a search for new therapies entering the clinic yields precious little. 

The most recent pain candidate to crash out of development was Aptinyx’s NMDA modulator NYX-2925. The agent had lurched from failure to failure, but the company only shifted away from it after the miss in a phase 2b fibromyalgia trial. Even then the group said it would “continue to analyse the data”, even as it refocused on its other products.

In the weeks before, Eliem, Acadia and Ampio had also admitted defeat with their putative painkillers. Ampio had taken its TLR 7 agonist all the way through phase 3, but in April the FDA told it that its most recent phase 3 trial was inadequate. Investors might wonder why it took the cash-strapped, penny-stock company this long to pull the plug, and indeed some have filed lawsuits alleging mismanagement.

At least some groups have managed to keep going. South Korea's Vivozeon stated at the end of May that two phase 3 studies of VVZ-149, one in the US in post-bunionectomy patients and one in its home country in colorectal resection, were ongoing. No reporting date has been given. 

And last month Vertex laid out pivotal plans for VX-548. Two phase 3 studies in moderate to severe acute pain following bunionectomy or abdominoplasty surgery are to start at by the end of the year, comparing the sodium channel blocker with hydrocodone bitartrate plus acetaminophen. A single-arm phase 3 in multiple other types of moderate to severe acute pain is also on the slate, as is a phase 2 in neuropathic pain.

Two in, one out

Three big pharmas are still plugging away in phase 2. Lilly quietly dropped one of its candidates, LY3016859, earlier this year, but expects mid-stage data on its TRPA 1 inhibitor LY3526318 in osteoarthritis, diabetic peripheral neuropathic pain (DPNP) and low back pain in the coming months. 

The SSTR4 agonist LY3556050 remains listed in its pipeline, but a phase 2 trial in DPNP was terminated last month, according to clinicaltrials.gov. It will be interesting to see if this project remains in development when Lilly reports third-quarter results. 

Entirely new entrants into this nightmarishly difficult space are thin on the ground. The private Swiss biotech Novaremed is one of the few brave enough to set foot here with a pain therapy that is neither an opioid nor a reformulation of a long-established analgesic. It plans to take its NMDA receptor antagonist into a mid-stage study next year, and another project is to reach phase 2 sooner, albeit in an academic trial. 

The effort to develop novel painkillers beyond opioid therapy is laudable, but this is undeniably one of the riskiest gambles drug development has to offer. The sad fact is that, for all the companies in the table below, failure is far more likely than success.