LY3848575 for Neuropathic Pain

Recruiting at 83 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Eli Lilly and Company

Disqualifiers: Uncontrolled diabetes, Cancer, Suicidal, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate how safe and how well a treatment works compared to placebo for people with nerve pain that begins in their feet and moves up the leg to just below the knee. Participation may last up to 30 weeks including screening.

Will I have to stop taking my current medications?

Yes, you will need to stop taking all medications for chronic pain conditions, except for the allowed pain medications specified by the trial.

What data supports the effectiveness of the drug LY3848575 for neuropathic pain?

Research suggests that epiregulin, a component of LY3848575, is linked to pain modulation. In studies, an antibody against epiregulin reduced pain sensitivity in chronic pain models, indicating potential effectiveness for neuropathic pain. ^{1 2 3 4 5}

What makes the drug LY3848575 unique for treating neuropathic pain?

LY3848575 is unique because it targets epiregulin, a growth factor involved in nerve signaling, which may offer a novel approach to managing neuropathic pain compared to existing treatments that primarily focus on pain relief rather than addressing underlying nerve mechanisms. ^{2 3 6 7 8}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 : Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for individuals experiencing nerve pain that starts in the feet and progresses up to just below the knee, known as painful distal sensory polyneuropathy. Participants should be able to commit to a study period of up to 30 weeks.

Inclusion Criteria

Individuals NOT of childbearing potential may participate in the trial. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

Have a Visual Analog Scale (VAS) pain value ≥40 and <95 at screening

I have had painful nerve pain in my feet or legs for over 6 months due to a known or unknown cause.

Exclusion Criteria

I've had a procedure to permanently lose feeling in a specific area within the last 6 months.

I have had cancer within the last 2 years, except for certain skin cancers or cancers that caused nerve pain due to chemotherapy.

My diabetes hasn't been under control for 3 months and my HbA1c level is above 11.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LY3848575 or placebo administered subcutaneously for chronic neuropathic pain

26-28 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• LY3848575 (Other)

Trial Overview The trial is testing LY3848575 against a placebo to determine its safety and effectiveness in treating nerve pain associated with polyneuropathy. The duration of participation may last up to 30 weeks, including screening time.

Participant Groups

Group I: LY3848575 Dose 3 Experimental Treatment 1 Intervention

LY3848575 high dose administered SC.

Group II: LY3848575 Dose 2 Experimental Treatment 1 Intervention

LY3848575 mid dose administered SC.

Group III: LY3848575 Dose 1 Experimental Treatment 1 Intervention

LY3848575 low dose administered subcutaneously (SC).

Group IV: Placebo Placebo Group 1 Intervention

Placebo administered SC.

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

In a phase II trial involving 77 patients with diabetic peripheral neuropathic pain, fulranumab showed a significant dose-dependent reduction in pain, particularly at the 10 mg dose compared to placebo, indicating its potential efficacy as a treatment.

The treatment was generally well tolerated, with common side effects including arthralgia, peripheral edema, and diarrhea, but no serious adverse events like joint replacement or death were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial. Wang, H., Romano, G., Frustaci, ME., et al.[2021]

Chronic constriction injury of the trigeminal nerve in rats leads to mechanical allodynia, which is significantly delayed in transgenic rats lacking neuregulin 1, indicating its role in the development of neuropathic pain.

The ErbB2 inhibitor Lapatinib effectively alleviates mechanical allodynia in wild type rats, suggesting that targeting the Neuregulin 1-ErbB3-ErbB2 signaling pathway could be a promising strategy for treating trigeminal neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trigeminal nerve injury ErbB3/ErbB2 promotes mechanical hypersensitivity. Ma, F., Zhang, L., Westlund, KN.[2021]

The study identified ephrinB1 as a key gene involved in lysophosphatidic acid (LPA)-induced neuropathic pain, confirmed through gene expression profiling in the dorsal root ganglion of nerve injury models.

Blocking ephrinB1 with antisense oligodeoxynucleotides significantly reduced pain responses, indicating its crucial role in pain transmission and suggesting potential therapeutic targets for neuropathic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profiling of BoNT/C3-reversible gene expression induced by lysophosphatidic acid: ephrinB1 gene up-regulation underlying neuropathic hyperalgesia and allodynia. Uchida, H., Matsumoto, M., Ueda, H.[2016]

The study found that ErbB4, a receptor activated by neuregulin-1, plays a crucial role in the development of mechanical allodynia, a common symptom of neuropathic pain, by being activated in spinal parvalbumin interneurons after nerve injury.

Knocking down ErbB4 in the spinal cord not only prevented but also reversed mechanical allodynia in mice, indicating that targeting ErbB4 could be a potential therapeutic strategy for managing neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone. Yu, Y., Wei, G., Zhou, Q., et al.[2022]

A genetic marker in the EREG gene was linked to pain intensity in chronic facial pain patients, showing that a specific allele (rs6836436) was associated with lower chronic pain but higher acute facial pain.

In mouse models, blocking EREG with a monoclonal antibody reduced chronic pain sensitivity but worsened pain during acute pain development, suggesting that EREG plays a complex role in pain modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dichotomous role of epiregulin in pain. Verma, V., Khoury, S., Parisien, M., et al.[2022]

The new compound (S)-17 (UCM-05194) is identified as the most potent and selective agonist for the LPA1 receptor, showing significant efficacy in reducing neuropathic pain in an in vivo model.

By activating the LPA1 receptor, (S)-17 induces internalization of the receptor, leading to its functional inactivation in sensory neurons, which contributes to its ability to attenuate pain perception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration. González-Gil, I., Zian, D., Vázquez-Villa, H., et al.[2021]

In a study using rat models of nerve injury, the expression of neuregulin1 (Nrg1) type I and type II isoforms significantly increased in the dorsal root ganglion (DRG) after spinal nerve ligation, indicating their potential role in nerve injury response.

Conversely, the expression of Nrg1 type III decreased in the DRG, suggesting that changes in Nrg1 isoform expression may be linked to the development of neuropathic pain following nerve injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression changes of the neuregulin 1 isoforms in neuropathic pain model rats. Kanzaki, H., Mizobuchi, S., Obata, N., et al.[2012]

In a mouse model of chronic constriction injury, the expression of EphA1 was found to increase as neuropathic pain progressed, indicating its potential role in the disease's development.

Knocking down EphA1 expression led to significant improvements in pain sensitivity and reduced inflammation, suggesting that targeting EphA1 and its associated signaling pathways could be a promising approach for treating neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice. Li, Q., Li, R., Zhu, X., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Trigeminal nerve injury ErbB3/ErbB2 promotes mechanical hypersensitivity. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Profiling of BoNT/C3-reversible gene expression induced by lysophosphatidic acid: ephrinB1 gene up-regulation underlying neuropathic hyperalgesia and allodynia. [2016]

4. New Zealand pubmed.ncbi.nlm.nih.gov

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

The dichotomous role of epiregulin in pain. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration. [2021]

7. Ireland pubmed.ncbi.nlm.nih.gov

Expression changes of the neuregulin 1 isoforms in neuropathic pain model rats. [2012]

8. Japan pubmed.ncbi.nlm.nih.gov

EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice. [2023]