Late-stage pain pipeline refuses to swell
Setbacks from Eliem, Ampio and Acadia thin an already sparse pain pipeline, which remains lacking in serious interest from big developers.
Pain research is notorious for its failures. Despite a huge unmet need for new approaches few developers are seriously committed to the field, and setbacks in the last few weeks from Eliem, Acadia and Ampio show why investors also steer clear.
True, Vertex had a mid-stage success last month with a novel sodium channel blocker; the company also stands out as a rare large developer working in the space. Another big name to watch is Lilly, which has three projects due to yield phase 2 data in the coming months.
A look at the late-stage pipeline shows that, of the large pharma groups, Lilly is one of the most invested in this area. However, having been burned by what must have been the very costly failure of tanezumab, decisions to push forward with any new asset will not be taken lightly.
Tanezumab was Pfizer’s anti-NGF MAb on which Lilly had partnered; it was finally abandoned last year after a lengthy clinical programme that failed to convince the FDA.
Serious adverse effects including rapidly progressive osteoarthritis mean that the anti-NGF class is most likely dead, although Regeneron and Teva’s fasinumab technically remains standing. The partners on the asset confirmed to Evaluate Vantage that discussions with regulators are ongoing and longer-term data still being analysed.
Hopes are low that this mechanism will ever reach the market, although it is interesting to see that Astrazeneca is pushing forward here, albeit with a twist. It has two fairly large phase 2 studies running with MEDI7352, a bispecific that hits TNF as well as NGF.
Big hopes had built behind blocking nerve growth factor, a protein involved in the activation of pain sensation – perhaps this combination approach might finally offer a safe way forward. TNF or tumour necrosis factor has been shown to reduce pain in inflammatory joint diseases, and is thought to play a role in the mediation of neuropathic pain.
As for Lilly, the focus of its pain research has turned elsewhere. LY3016859 hits targets more commonly associated with cancer – TGF-α and epiregulin are ligands that can bind EGFR – although they have also been associated with pain processing. Several phase 2 trials concluded last year, however; at time of publishing the company had not replied to Vantage’s questions about when we might see these data.
Studies with the other two projects are ongoing. TRPA 1, the target of LY3526318, is an ion channel known to be a pain receptor, while LY3556050 is directed at a somatostatin receptor, which are thought to be involved in inflammatory and pain pathways.
|Painful progress: the mid to late-stage pain pipeline|
|Fasinumab||Teva/Regeneron||Anti-NGF MAb||Update on plans awaited|
|Ampion||Ampio||TLR 7 agonist||New ph3 required by FDA; several studies conducted over last decade|
|VER-01||Vertanical||Cannabis extract||Ph3 ongoing (in Germany only) in chronic lower back pain|
|VX-548||Vertex||Nav1.8 sodium channel blocker||Ph3 to start later in 2022 after successful ph2|
|BIIB074 (vixotrigine)||Biogen||Nav1.7 sodium channel blocker||2x ph3 trial in trigeminal neuralgia registered with late 2022/early 2023 start dates|
|LY3016859||Lilly||TGF alpha & epiregulin MAb||Several ph2 trials completed, plans unclear|
|LY3526318||Lilly||TRPA 1 antagonist||Data could emerge from two ph2 trials in chronic pain later this year|
|LY3556050||Lilly||SSTR4 agonist||Ph2 in DPNP could report later next year|
|MEDI7352||Astrazeneca||Anti-NGF/TNF bispecific MAb||Data due in 2023 from 2x ph2 trials in DPNP and osteoarthritis|
|ACP-044||Acadia||Redox modulator||Ph2 postop pain trail failed; ph2 osteoarthritis pain due H1'23|
|ETX-810||Eliem||Prodrug of palmitoylethanolamide||PoC ph2a in DPNP failed; sciatica data due Q3'22|
|BAY2395840||Bayer||Bradykinin B1 receptor antagonist||Ph2 started this year in diabetic nerve pain|
|TRPA 1 antagonist||Ph2a completed in DPNP, company plans ph2b in DPNP with preserved small nerve fibre function this year|
|OLP-1002||Olipass||Nav1.7 sodium channel 9a antisense||Small ph2 ongoing in chronic pain since early 2021 (Australia only)|
|NYX-2925||Aptinyx||NMDA modulator||Ph2b in DPNP failed; ph2b in fibromyalgia due Q3'22|
|DPNP=diabetic peripheral neuropathic pain. Source: Evaluate Pharma, clinicaltrials.gov & company statements.|
Biogen is another big name with a long interest in pain – it bought Glaxosmithkline’s pain-focused spin out Convergence in 2015 – but the future of the lead asset from that move, vixotrigine, looks doubtful. Mid-stage results have been mixed at best, and although two phase 3 trials are listed on CT.gov in trigeminal neuralgia (TGN), it is unclear whether they will ever start.
Last year the group took a $44m impairment charge on the project – at time of publishing Biogen had not replied to enquiries about its plans here.
It is also worth nothing that Bayer, famously the originator of aspirin, joined the pipeline above a couple of months ago with a project that blocks bradykinin B1, a receptor that has been shown to play a role in pain perception.
And all the rest...
A string of failures from small groups working in this field suggests that hopes for progress must rest in the occasional asset found in the pipeline of a large developer.
A case in point is one of the rare pivotal stage projects, Ampion, which its tiny developer will surely struggle to continue funding. Last week the FDA told Ampio that it would not accept the phase 3 Ap-103 trial as a second, confirmatory pivotal study, a mess that appears to be of the company’s making.
The endpoints and statistical analysis of the trial were changed after the pandemic caused disruptions, alterations that the agency said it should have been consulted on before the data were unblinded.
This followed the failure earlier in the month of Acadia's ACP-004 in post-surgical pain, and another setback from Aptinyx with its NMDA modulator NYX-2925. Both companies are now relying on radically different readouts from these assets' next set of studies, but hopes are very low.
And yesterday Eliem saw its stock crash 56% after announcing the failure of ETX-810 in diabetic peripheral neuropathic pain, with a setback with a separate asset also contributing to the plunge.
The company made no attempt to polish results which showed no separation between placebo and ETX-810 treated patients, admitting that the control group responded as expected. Development in DPNP has been scrapped and the future of the project rests on an ongoing trial in sciatica due later this year.
The project is a prodrug of palmitoylethanolamide, also known as PEA, an endogenous lipid that has been widely studied for its purported anti-inflammatory and pain relieving properties. Lack of firm evidence of efficacy has consigned its use to an over-the-counter “nutraceutical", though Eliem contends that the ETX-810 formulation allows for greater bioavailability and systemic exposure.
This series of setbacks will make it incredibly hard for other small developers to win investor support in this field. Success is desperately needed, from anywhere in the pipeline.