Background & Aims

Diabetic neuropathy is a common complication of diabetes and nearly 50% of adults with diabetes present with peripheral neuropathy (1,2). Treatment options for diabetic peripheral neuropathic pain (DPNP) are limited and this represents a significant unmet medical need. Somatostatin is an inhibitory neuropeptide and acts to inhibit peripheral nociceptive activity via the SST4 receptor (SSTR4) (3,4). LY3556050 is a selective and potent SSTR4 agonist being evaluated as an oral analgesic for chronic pain. Herein we report the efficacy, safety, and pharmacokinetic findings from a phase 2, double-blind, placebo-controlled study of LY3556050 in participants with DPNP (ClinicalTrials.gov: NCT04707157).

Methods

Eligible participants had diagnosis of diabetes (type 1 or type 2), had a history of daily symmetrical neuropathic foot pain and met diagnostic criteria for DPNP. 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. Acetaminophen with limited frequency was allowed as rescue medication. Metformin doses were limited to ?1000 mg/day (due to a drug-drug interaction). Primary endpoint was mean change from baseline to Week 8 in average pain intensity (API) measured by the Numerical Rating Scale. Secondary endpoints measured overall improvement in pain and physical functioning. A Bayesian mixed model repeated measures analysis was used to evaluate the change from baseline in the comparison between the treatment and placebo groups. Safety and tolerability were monitored, and the LY3556050 plasma concentrations were assessed, throughout the study.

Results

Of 68 randomized participants (LY3556050: 45, placebo: 23; mean age: 59.5 years), 55.9% were female. LY3556050 600 mg BID was superior to placebo with the posterior mean change difference from placebo in API (95% Credible Interval) of -1.56 (-2.76, -0.38). Results for secondary endpoints were positive and support the primary endpoint. Most commonly reported treatment-emergent adverse events (AEs; ?15% in any group) were diarrhea, constipation, nausea, and increased anion gap; majority were of mild or moderate severity. Two participants in each treatment group reported serious AEs; none were considered related to study drug. No deaths were reported. Numerically higher percentage of participants discontinued treatment due to AE in the LY3556050 (26.7%) vs. placebo group (13.0%). Most common AEs leading to treatment discontinuation were nausea, constipation, and diarrhea. At Week 8, trough LY3556050 plasma concentration (mean ± SD; n=12) following 600 mg BID was 2310 ± 1320 ng/mL.

Conclusions

In this study, treatment with LY3556050 600 mg BID in participants with DPNP was associated with improvement in pain, as demonstrated by a statistically significant improvement in mean change in API from baseline at Week 8 vs placebo and some secondary measures. Furthermore, effectiveness of LY3556050 was demonstrated by Week 2 and was sustained till the end of study. Treatment-emergent AEs due to LY3556050 were mild to moderate in severity. Numerically higher discontinuation rate in the LY3556050 vs. placebo group was driven by nausea, constipation, and diarrhea. LY3556050 plasma concentrations provided insight on an effective exposure sufficient to impact pain outcomes in participants with DPNP. Findings from this study demonstrate that LY3556050 is a novel potential treatment option for DPNP. Further double-blind, placebo-controlled trials are warranted to confirm efficacy and evaluate safety of LY3556050 in DPNP.

References

1. Hicks CW and Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019;19(10):86.
2. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41.
3. Sandor K, Elekes K, Szabo 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.

Presenting Author

Timothy R Smith

Poster Authors

Timothy Smith

StudyMetrix Research

Lead Author

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Judith Krikke

PhD

Eli Lilly and Company

Lead Author

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Heather Shi Zhao

PhD

Eli Lilly and Company, Indianapolis, IN, USA

Lead Author

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William Kielbasa

PhD

Eli Lilly and Company, Indianapolis, IN, USA

Lead Author

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Jennie Lin Francis

MD

Eli Lilly and Company, Indianapolis, IN, USA

Lead Author

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Eric Pearlman

Eli Lilly

Lead Author

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Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral