Background & Aims

Osteoarthritis (OA) pain in the knee and chronic low back pain (CLBP) are the most common reasons for chronic pain (1,2). Adequate treatment of these conditions is severely hindered as available treatment options either have limited efficacy, access issues, or safety concerns. Somatostatin is a neuromodulatory peptide released by sensory neurons and acts to inhibit peripheral neuronal activity via the SST4 receptor (SSTR4) (3,4). Activation of SSTR4 with selective agonists in nonclinical studies have shown to reduce mechanical sensitivity of peripheral nociceptors, activity of spinal neurons, and behavioral hyperalgesia in models of neuropathic, and bone cancer pain (3-5). LY3556050 is a selective and potent SSTR4 agonist and is being evaluated as an oral analgesic for chronic pain. We report results from 2 Phase 2, double-blind, placebo-controlled studies of LY3556050 to test whether LY3556050 is efficacious in relieving OA pain in the knee (NCT04627038) and CLBP (NCT04874636).

Methods

In both studies, eligible participants were randomized (2:1) to receive LY3556050 or placebo via oral administration; LY3556050 was titrated from 200 mg twice daily (BID) up to a maximum of 600 mg BID based on tolerability. Limited use of acetaminophen was the only rescue medication allowed during the study. Primary endpoint was the mean change from baseline to Week 8 in average pain intensity (API) measured by the Numerical Rating Scale (NRS). Key secondary endpoint included mean change in pain intensity from baseline at Week 8 using the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain subscale (OA study only). A Bayesian mixed model repeated measures analysis was used to evaluate the change from baseline in the comparison between the treatment and placebo group. Safety and tolerability were monitored throughout the study and the LY3556050 plasma concentrations were assessed throughout the study.

Results

Eligible participants with OA (N=202) and CLBP (N=153) were randomized. Demographics, disease history, and baseline characteristics were balanced across groups. LY3556050 was not superior to placebo in change from baseline in API at Week 8 in both studies; posterior mean change difference (95% credible interval [CrI]): 0.09 (-0.51, 0.67) for OA and 0.08 (-0.59, 0.75) for CLBP. In addition, LY3556050 was not superior to placebo on the WOMAC® pain subscale (posterior mean change difference [95% CrI]: 0.95 [-0.07, 1.96]). In both studies, numerically higher proportion of participants in LY3556050 vs. placebo group reported at least 1 treatment-emergent adverse event (TEAE). Most commonly reported TEAEs in the LY3556050 group in either study were constipation, nausea, diarrhea, dizziness, fatigue, and headache. At Week 8, trough LY3556050 plasma concentrations (mean±SD) following 600 mg BID was 1530±880 ng/mL and 1960±939 ng/mL in participants with CLBP (n=32) and OA (n=45), respectively.

Conclusions

In both studies, there was no statistical evidence that LY3556050 600 mg BID was superior to placebo in relieving OA pain in the knee or CLBP. The overall safety profile was generally consistent for both studies. Most common TEAEs were constipation, nausea, dizziness, fatigue, and headache; most were mild to moderate. LY3556050 was associated with a higher number of discontinuations due to AEs in the OA study, mostly driven by nausea, dizziness, and fatigue. Plasma LY3556050 concentrations were generally consistent across OA and CLBP study participants. Based on these findings, LY3556050 was not superior to placebo in 2 disease states of chronic pain i.e., knee pain due to OA or CLBP.

References

1. Mills SEE, Nicolson KP, and Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273-e283.
2. Cohen SP, Vase L, and Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082-2097.
3. Sándor K, Elekes K, Szabó A, et al. Analgesic effects of the somatostatin SST4 receptor selective agonist J-2156 in acute and chronic pain models. Eur J Pharmacol. 2006;539(1-2):71-75.
4. Schuelert N, Just S, Kuelzer R, et al. Somatostatin receptor 4 agonist J-2156 reduces mechanosensory peripheral nerve afferents and spinal neurons in an inflammatory pain model. Eur J Pharmacol. 2015;746:274-281.
5. Shenoy PA, Kuo A, Khan N, et al. The somatostatin receptor-4 agonist J-2156 alleviates mechanical hypersensitivity in a rat model of breast cancer induced bone pain. Front Pharmacol. 2018;9:495.

Presenting Author

Stacey Layle

Poster Authors

Stacey Layle

MD

Artemis Institute for Clinical Research Study, CA, USA

Lead Author

E-mail

Judith Krikke

PhD

Eli Lilly and Company

Lead Author

E-mail

Heather Shi Zhao

PhD

Eli Lilly and Company, Indianapolis, IN, USA

Lead Author

E-mail

AnnCatherine M. Downing

PharmD

Eli Lilly and Company

Lead Author

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William Kielbasa

PhD

Eli Lilly and Company, Indianapolis, IN, USA

Lead Author

E-mail

Eric Pearlman

Eli Lilly

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Inflammatory