Eli Lilly has quietly removed another experimental pain drug from its research pipeline after disappointing Phase II results, marking the second mid-stage analgesic program the pharmaceutical giant has discontinued in recent months.
The discontinued drug, LY3857210, is an orally available inhibitor of the P2X7 receptor found on various immune cells and considered a key player in chronic pain pathology. The compound had completed a Phase II master protocol study evaluating its safety and efficacy across three chronic pain conditions: chronic low back pain, osteoarthritis pain, and diabetic peripheral neuropathic pain.
Clinical Development Setback
According to Lilly spokesperson Ashley Hennessey, data from LY3857210's development "did not meet our high internal bar for success." While the company is "assessing next steps for the program, including possible additional indications," the drug has been removed from its pain pipeline for now.
LY3857210 entered Lilly's portfolio in early 2021 through a licensing agreement with Japan's Asahi Kasei. The deal involved a $20 million upfront payment and promised up to $210 million in milestone payments for the drug, originally designated AK1780. Despite the discontinuation of the pain program, the partnership with Asahi Kasei remains active, according to a company spokesperson.
Pattern of Pain Pipeline Challenges
This discontinuation follows Lilly's August decision to shelve mazisotine, a Phase II oral SSTR4 agonist that had also completed a chronic pain master protocol study testing osteoarthritis, low back pain, and diabetic peripheral neuropathic pain. The pattern underscores the persistent challenges in pain drug development, even for well-resourced pharmaceutical companies with extensive nervous system research experience.
The difficulties extend beyond Lilly. Vertex Pharmaceuticals, a major competitor in the pain space, recently lost billions in market value after reporting that a potential successor to its pioneering pain medicine Journavx failed a key mid-stage trial. Vertex also announced it would not proceed with a late-stage study of Journavx in sciatica, derailing expansion plans into peripheral neuropathic pain.
Continued Investment Despite Setbacks
Despite these setbacks, Lilly continues to deepen its pain portfolio investments. In May, the company acquired SiteOne Therapeutics in a deal potentially worth up to $1 billion, gaining access to non-opioid pain drugs. The acquisition's centerpiece is STC-004, a Nav1.8 blocker currently in Phase I development, according to Lilly's Q3 presentation.
Carter Gould, an analyst at Cantor Fitzgerald, noted that "Lilly has had a persistent interest in pain in recent years ... but with little tangible success." However, he characterized the SiteOne acquisition as "a reasonable move" given the deal terms and strategic interest, despite outstanding commercial and clinical questions surrounding the drug class.
Broader Pain Pipeline
Beyond the SiteOne acquisition, Lilly maintains several other pain development programs. The company has a Phase I AT2R blocker targeting neuropathic pain and an anti-epiregulin antibody in mid-stage development for chronic pain treatment.
Additionally, Lilly is positioning orforglipron, its closely watched oral obesity asset, for knee osteoarthritis pain. Late-stage studies for this indication are currently underway, with completion expected in 2027. The company is also evaluating whether retatrutide, another experimental diabetes and weight loss therapy, could prove useful against osteoarthritis or chronic lower back pain.
BMO Capital Markets analysts suggested in a May note that the pain pipeline investments will help Lilly achieve "diversification and growth beyond GLP-1s," referring to the company's blockbuster diabetes and obesity franchise.
Market Context
The pipeline adjustments were overshadowed by Lilly's strong financial performance, with the company reporting that its tirzepatide weight-loss franchise has unseated Merck's Keytruda as the world's top-selling drug. The sister brands Mounjaro and Zepbound generated $10.1 billion worldwide in the third quarter, surpassing Keytruda's $8.1 billion in Q3 earnings.
