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.
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.
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.
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.
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.
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
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
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
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
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
Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR. Biochemistry 2006 45: 1511–1517. doi:10.1021/bi0520129.PMID: 16445293
Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 2006 51: 240–264. doi:10.1016/j.brainresrev.2005.11.004. PMID: 16388853
Conus peptides: biodiversity-based discovery and exogenomics. J Biol Chem 2006 281, 31173-7. PMID: 16905531
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
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
Diversity of Conus neuropeptides. Science 1990 249:257-63. PMID: 2165278
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
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)