KCP506

First-in-class non-opioid for chronic neuropathic pain

KCP506 is a long-acting α9α10 nicotinic acetylcholine receptor (nAChR) antagonist in development for the treatment of chronic neuropathic pain.  KCP506 has demonstrated robust analgesic, anti-neuroinflammatory and neuroprotective effects across multiple preclinical chronic pain models.  The combination of these effects provides KCP506 with the potential to be a disease modifying therapy that may slow or halt the progression of chronic pain.  KCP506 was non-addictive and non-tolerizing in preclinical studies and therefore may offer a safer alternative to opioids or gabapentinoids.  KCP506 is being developed as a once weekly subcutaneous injectable therapy and is currently in Phase 1 clinical studies to evaluate the safety, tolerability, and pharmacokinetics of the drug.

Target

The α9α10 nAChR drug target is expressed primarily in the peripheral nervous system and some immune cell subsets, but not the central nervous system where opioids, gabapentinoids and other marketed pain therapies are active. Preclinical data suggest that α9α10 nAChR is a critical mediator of peripheral nerve injury-induced inflammation and pain.  Blocking the α 9α10 nAChR at the site of injury in the peripheral nervous system will potentially inhibit the complex interaction between damaged nerves and the immune system providing pain relief, reducing neuroinflammation and protecting of the nerves from further damage.  With target expression taking place in the peripheral nervous system, therapeutics blocking α9α10 nAChR have not demonstrated issues of effect tolerance, addiction, and unintentional overdose as seen with drugs that work in the central nervous system like opioids.

Market

The opioid overdose epidemic has become a public health crisis in the United States.  Over 840,000 people have died since 1999 from a drug overdose.1   While synthetic opioids like fentanyl have become the main driver of drug overdose deaths, nearly 247,000 people died from overdoses involving prescription opioids between 1999-2019.2

An estimated 50 million adults in the United States suffer from chronic pain.3 Current therapies offer limited efficacy, unfavorable side effects and the potential of addiction and overdose. There remains a tremendous unmet need for patients with chronic pain.

The global neuropathic pain market totaled $10.8 billion in 2020 and is forecast to grow to $25.2 billion by 2027.4  KCP506 may potentially be an effective treatment for many types of neuropathic pain including radiculopathy (lower back pain associated with pinched nerves), chemotherapy-induced peripheral neuropathy, and diabetic neuropathy.  There is a tremendous unmet need for the approximately 560,000 patients who are diagnosed with chronic neuropathic pain in the United States.5  This represents a significant commercial opportunity for KCP506.

Partner

Kineta initially established a strategic partnership in April 2018 with Genentech, a member of the Roche Group. The research collaboration is focused on developing first in class α9/α10 nicotinic acetylcholine receptor (nAChr) antagonists for the treatment of chronic pain.  In November 2019, Kineta and Genentech extended our research collaboration to advance KCP506 through Phase 1 clinical studies.

Publications

Romero HK, Christensen SB, Di Cesare Mannelli L, Gajewiak J, Ramachandra R, Elmslie KS, Vetter DE, Ghelardini C, Iadonato SP, Mercado JL, Olivera BM, McIntosh JM. Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):E1825-E1832. doi: 10.1073/pnas.1621433114. Epub 2017 Feb 21. PMID:28223528 PNAS Full Text.

Di Cesare Mannelli L, Cinci L, Micheli L, Zanardelli M, Pacini A, McIntosh JM, Ghelardini C. alpha-Conotoxin RgIA protects against the development of nerve 4 injury-induced chronic pain and prevents both neuronal 5 and glial derangement. PAIN 2014 Jul 5. pii: S0304-3959(14)00312-1. doi: 10.1016/j.pain.2014.06.023. [Epub ahead of print] PubMed PMID: 25008370.

Ernesto J. Muñoz, Elizabeth Bromley, David W. Peckham, Kayla Norton, Jose Mercado, Shawn Iadonato. NOVEL, NON-OPIOID COMPOUNDS FOR CHRONIC PAIN (Poster).

Pain Management Task Force Final Report: Providing a Standardized DoD and VHA Vision and Approach to Pain Management to Optimize the Care for Warrior and their Families. Office of the Army Surgeon General. May 2010.

Halai R, Clark RJ, Nevin ST, Jensen JE, Adams DJ, et al. Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor. J Biol Chem 2009 284: 20275–20284. doi:10.1074/jbc.M109.015339. PMID: 19447885

McIntosh JM, Absalom N, Chebib M, Elgoyhen AB, Vincler M. Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem Pharmacol 2009 78: 693–702. doi:10.1016/j.bcp.2009.05.020. PMID: 19477168

Ellison M, Feng Z-P, Park AJ, Zhang X, Olivera BM, et al. Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol 2008 377: 1216–1227. doi:10.1016/j.jmb.2008.01.082.PMID: 18295795

Clark RJ, Daly NL, Halai R, Nevin ST, Adams DJ, et al. The three-dimensional structure of the analgesic alpha-conotoxin, RgIA. FEBS Lett 2008 582: 597–602. doi:10.1016/j.febslet.2008.01.027. PMID: 18242183

Vincler M, Wittenauer S, Parker R, Ellison M, Olivera BM, McIntosh JM. Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17880-4. Epub 2006 Nov 13. PubMed PMID: 17101979PMCID: PMC1635975.

Clark RJ, Fischer H, Nevin ST, Adams DJ, Craik DJ. The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1. J Biol Chem 2006 281: 23254–23263. doi:10.1074/jbc.M604550200. PMID: 16754662

Ellison M, Haberlandt C, Gomez-Casati ME, Watkins M, Elgoyhen AB, et al. Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR. Biochemistry 2006 45: 1511–1517. doi:10.1021/bi0520129.PMID: 16445293

Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 2006 51: 240–264. doi:10.1016/j.brainresrev.2005.11.004. PMID: 16388853

Olivera, B. M. Conus peptides: biodiversity-based discovery and exogenomics. J Biol Chem 2006 281, 31173-7. PMID: 16905531

McIntosh JM, Plazas PV, Watkins M, Gomez-Casati ME, Olivera BM, et al. A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors. J Biol Chem 2005 280: 30107–30112. doi:10.1074/jbc.M504102200. PMID: 15983035

McMahon SB, Cafferty WBJ, Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol 2005 192: 444–462. doi:10.1016/j.expneurol.2004.11.001. PMID: 15755561

Olivera, B.M., J. Rivier, C. Clark, C.A. Ramilo, G.P. Corpuz, F.C. Abogadie, E.E. Mena, S.R. Woodward, D.R. Hillyard and L.J. Cruz. Diversity of Conus neuropeptides. Science 1990 249:257-63. PMID: 2165278

Baker ER, Zwart R, Sher E, Millar NS. Pharmacological properties of alpha 9 alpha 10 nicotinic acetylcholine receptors revealed by heterologous expression of subunit chimeras. Mol Pharmacol 2004 65: 453–460. doi:10.1124/mol.65.2.453. PMID: 14742688

Terlau, H., K. Shon, M. Grilley, M. Stocker, W. Stühmer and B.M. Olivera. Strategy for rapid immobilization of prey by a fish-hunting cone snail. Nature 1996 381:148-51. PMID: 12074021

References:
1.  Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2017
2.  Mattson CL et al. Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths — United States, 2013–2019. MMWR Morb Mortal Wkly Rep 2021;7 0:202–207.
3.  2016 National Health Interview Survey (NHIS) data
4.  GlobalData; Global Pain Therapeutics Market Overview, May 2021
5.  Datamonitor diagnosed neuropathic pain forecast 2020 (United States incidence)