Neuropathic cancer pain is characterized by neuronal cell damage and no current treatment has satisfactory results. Advantx‘s candidate ADV502 has been precisely designed to bind Sigma-1 receptors and block the sensory hypersensitivity and increase the antinociception effects, and, at the same time, marginally bind to the mu-Opioid receptor with partial activation, to produce effective analgesia.
Neuropathic Cancer Pain
In neuropathic cancer pain, damage to peripheral nerves results in changes at the cellular and molecular level that cause sensitization of peripheral and central nerve pathways. This can cause painful stimuli to be amplified and prolonged, non-painful stimuli to be interpreted as pain, and spontaneous pain bursts to occur without prior stimulus; the overall effect is an increased sensation of pain with burning, tingling, stabbing, and electric shock sensations, as well as impaired balance and motor weakness.
The cellular mechanisms involved in this central sensitization are the dysfunction of ion channels, activation of N-methyl-D-aspartate receptors (NMDAR), and the activation of microglia specialized cells of the central nervous system involved in the immune response, leading to the release of various substances that enhance pain transmission. Whereas the main mechanisms relevant to chronic neuropathic cancer pain are nuclear DNA damage, oxidative stress-induced mitochondrial damage, glia activation-related neuroinflammation, and gut microbiota-induced inflammation. As for the mechanisms of peripheral sensitization, the proliferation of sodium and calcium intracellular channels stands out, causing an increase in the excitability of nerve fibers and ectopic discharges.
The sigma-1 receptor combined with the mu-opioid receptor (MOR) regulates the transient receptor potential ankyrin 1 (TRP1) and transient receptor potential vanilloid 1 (TRPV1) described as involved in cancer pain and reduces opioid-mediated NMDAR hyperactivity implicated in opioid-induced tolerance, hyperalgesia, and poor response in neuropathic cancer pain. Sigma chaperone activation also contributes to nuclear DNA and mitochondrial damage.
Potential market for Advantx candidate in Neuropathic Cancer Pain
Prevalence>18m people in US/EU/UK/JP
Treated Population>18m patients
Market Growthest. 5.3% CAGR
Neuropathic cancer pain has no effective treatment
The American Cancer Society estimates that more than 17 million Americans have cancer, and one-third of cancer survivors report significant neuropathic pain, either from cancer itself or from treatments. Treatment of this neuropathic cancer pain remains an unmet medical need as patients continue to report inadequate pain relief and physicians continue to have trouble coping with the pharmacologic strategy when first-line therapy fails. Administration of oral opioids or pregabalin does not improve chronic neuropathic pain, quality of life, or mood in cancer patients. For this reason, combination therapy has been a practice adopted for some years, the most frequent combinations being antidepressants with opioids, antiepileptics with opioids, and gabapentinoids plus opioids; however, the results are not very satisfactory.
THE SIGMA SCIENCE
Sigma-1 receptor antagonist compounds have demonstrated high efficacy in pain relief with safety and tolerability in human patients while reducing opioid-associated adverse events. Sigma1 antagonists have also shown promise as adjuvants to opioids in chronic pain indications. Advantx has designed a single molecule that enters into the neuronal cells damaged by cancer acting simultaneously as a potent sigma-1 receptor antagonist, with strong pain relief effects, and a weak opioid agonist, whose activity is enhanced by the adjuvant capacity of the sigma-1 antagonist. At the same time, Sigma-1 antagonist activity reduces reducing opioid-mediated NMDAR hyperactivity implicated in opioid-induced tolerance. Sigma science promises an oral disease-modifying therapy for cancer patients suffering from chronic neuropathic pain.
ADV502 NCP is Advantx’s candidate for the treatment of neuropathic cancer pain.