Drug makers leave the pain behind
Developing non-opioid analgesics remains one of the hardest tasks in biopharma.
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.
|Pain projects: what's gone...|
|Ampion||Ampio||TLR 7 agonist||Abandoned Aug 3 following failure of most recent ph3 osteoarthritis trial|
|LY3016859||Lilly||TGF alpha & epiregulin MAb||Dropped from pipeline in Q1; no explanation|
|ACP-044||Acadia||Redox modulator||Abandoned Aug 8 based on data from a previous ph2 bunionectomy study|
|ETX-810||Eliem||Prodrug of palmitoylethanolamide||Abandoned Aug 2 following failure of ph2a lumbosacral radicular pain trial|
|NYX-2925||Aptinyx||NMDA modulator||Abandoned Aug 12 following failure of ph2b fibromyalgia trial|
|Source: Evaluate Pharma, clinicaltrials.gov & company statements.|
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.
|… and what's still going|
|Anti-NGF MAb||Update on plans awaited|
|VER-01||Vertanical||Cannabis extract||Ph3 ongoing (in Germany only) in chronic lower back pain; ct.gov record has not been updated since Sep 2021|
|VVZ-149||Vivozon||5-HT2A receptor antagonist; GlyT2 inhibitor; PX2 purinoceptor 3 antagonist||Ph3 trials in postoperative pain ongoing in S Korea and the US|
|VX-548||Vertex||Nav1.8 sodium channel blocker||Ph3 in acute pain and ph2 in neuropathic pain to start in Q4 2022|
|BIIB074 (vixotrigine)||Biogen||Nav1.7 sodium channel blocker||2 ph3 trials in trigeminal neuralgia, Surge-1 and Surge-2, registered with late 2022/early 2023 start dates|
|LY3526318||Lilly||TRPA 1 antagonist||Data from 3 ph2 trials, in OA, DPNP and low back pain, could emerge in 2022|
|LY3556050||Lilly||SSTR4 agonist||Ph2 in DPNP terminated in Jul 2022 on slow enrolment; plans unclear|
|MEDI7352||Astrazeneca||Anti-NGF/TNF bispecific MAb||Data due in 2023 from 2 ph2 trials in DPNP and OA|
|BAY2395840||Bayer||Bradykinin B1 receptor antagonist||Ph2 in diabetic nerve pain started this year|
|GRC 17536||Glenmark||TRPA 1 antagonist||Ph2b in DPNP with preserved small nerve fibre function said to have been planned for Q2 2022 but has not begun|
|OLP-1002||Olipass||Nav1.7 sodium channel 9a antisense||Small ph2 in OA ongoing (Australia only)|
|Novaremed||TYK regulator||Eppic-Net, investigator-sponsored ph2 trial in DPNP, to begin 2022|
|MP-101||Novaremed||NMDA receptor antagonist||Ph2 trial in chemotherapy-induced neuropathy and neuropathic pain to begin Q1 2023|
|GSK3858279||GSK||CCL17 inhibitor||Ph1 in OA ongoing (Australia only)|
|ST-2427||Siteone Therapeutics||Nav1.7 sodium channel blocker||Ph1 in healthy volunteers ongoing; agent is intended for chronic, acute and ocular pain|
|Trichomylin||Zyus Life Sciences/
|Cannabinoid agonist||Hope, ph1 in OA, ongoing (Australia only)|
|DPNP=diabetic peripheral neuropathic pain. OA=osteoarthritis. Excludes gene and cell therapies. Source: Evaluate Pharma, clinicaltrials.gov & company statements. Phase 1 projects were selected based on a novel mechanism and an ongoing, active trial that was started in the last two years.|