Eli Lilly Discontinues P2X7 Inhibitor for Pain, Reshaping Pipeline Strategy

Eli Lilly, a leading pharmaceutical company, has announced the discontinuation of its phase 2 P2X7 inhibitor, LY3857210, for pain indications. This decision marks another significant pivot in the company's pain pipeline, following recent adjustments earlier this year.

P2X7 Inhibitor Falls Short of Expectations

LY3857210, originally licensed from Asahi Kasei Pharma in 2021 for $20 million upfront, failed to meet Lilly's internal benchmarks for success in pain treatment. A Lilly spokesperson stated, "P2X7 data did not meet our high internal bar for success and is being removed from the pipeline for pain." The company is currently evaluating potential next steps for the program, including exploring additional indications beyond pain management.

The asset had been undergoing evaluation for osteoarthritis, diabetic neuropathic pain, and chronic back pain as part of Lilly's phase 2 chronic pain master protocol. Despite the setback in pain indications, the licensing agreement with Asahi Kasei Pharma remains intact, as confirmed by an Asahi Kasei spokesperson.

Lilly's Evolving Pain Pipeline

This recent development follows a pattern of strategic pipeline adjustments at Eli Lilly. Earlier this year, the company discontinued mazisotine, another non-opioid pain candidate licensed from Centrexion Therapeutics in 2019 for $47.5 million upfront.

In response to these changes, Lilly has introduced new candidates to its pain pipeline:

1. A phase 1 NaV1.8 inhibitor (STC-004) from the SiteOne Therapeutics acquisition, targeting the same mechanism as Vertex's recently approved pain treatment, Journavx.
2. A phase 1 AT2R antagonist licensed from Confo Therapeutics in 2023.
3. Fepixnebart, a phase 2 epiregulin-targeting antibody.
4. Orforglipron, an oral GLP-1 candidate currently in two phase 3 osteoarthritis pain trials.

Challenges in P2X7 Receptor-Targeted Therapies

The discontinuation of LY3857210 highlights the ongoing challenges in developing P2X7 receptor-targeted therapies. Despite the receptor's implication in various diseases, including neurodegenerative conditions and cancer, no drugs targeting P2X7 have yet received regulatory approval.

Previous attempts by other pharmaceutical companies to develop P2X7-targeted therapies have also faced obstacles. GSK's efforts in chronic pain over a decade ago were halted after disappointing phase 1 results. Similarly, AstraZeneca's P2X7 candidate for rheumatoid arthritis failed to outperform placebo in phase 2 trials, leading to its discontinuation.

As Eli Lilly continues to refine its pain management portfolio, the pharmaceutical industry watches closely to see how these strategic shifts will shape the future of pain treatment development.