Peripheral Nerve Hypersensitivity Underlies Cough and Pain Pathophysiology
The peripheral nervous system comprises a network of sensors that are finely tuned to detect harmful conditions in the environment. Over time, due to intrinsic and extrinsic stressors, these sensors fall out of balance and begin to respond to conditions that are non-harmful. The resultant hypersensitivity disorders, such as chronic cough and chronic pain, affect hundreds of millions of patients, are poorly managed by existing treatment regimens and severely impact quality of life. Individuals with chronic cough and chronic pain have an elevated risk of addiction, anxiety, depression and suicidality. The core mission of SiteOne Therapeutics is to advance innovative therapeutics to improve the lives of these patients.
Chronic Cough and Chronic Pain
Chronic cough is defined as a cough that persists for over 8 weeks. In many cases the cough persists for years. Symptoms include breathlessness, wheezing, chest tightness, dyspnea, dysphagia, fatigue and disturbed sleep. The disease takes a major psychological toll as well, leading to bouts of anger, frustration, anxiety or depression. Chronic cough is typically nonproductive, or not due to any sputum expectoration, and patients cough hundreds or even thousands of times per day. In contrast to cough associated with illnesses such as an upper respiratory tract infection (URTI) or bronchitis, in which the symptom is transient and can be treated with over-the-counter antitussives such as dextromethorphan, chronic cough is a persistent disease with debilitating physical and psychological effects. The prevalence of chronic cough in the United States is estimated to be 11%, with women disproportionately affected, accounting for roughly two-thirds of the cases.
Pain is a common condition that affects essentially everyone at some point in their lives. Chronic pain afflicts 50 – 100 million individuals in the United States each year, and is the second most common reason for seeking medical care, behind only the common cold. Pharmaceutical treatments available today, ranging from non-steroidal anti-inflammatory drugs like ibuprofen to morphine-like opioid analgesics do not completely block pain and are effective in only a subset of patients. For example, neither NSAIDs nor opiates are effective in the treatment of nerve injury (neuropathic) associated pain, such as diabetic neuropathy. Meanwhile, massive over-prescribing of opioid drugs has led to an epidemic of abuse and addiction without a quantifiable improvement in the condition of chronic pain patients. In addition to their lack of effectiveness in many pain states, NSAIDs and opiates, as well as acetaminophen are associated with a range of side effects. Opiates frequently lead to nausea, drowsiness, respiratory depression and also have a powerful potential for addiction. Drug overdoses (mainly opioids) are the number one cause of accidental deaths in the US, outpacing auto accidents. NSAIDs can also lead to gastric bleeding, killing an estimated 16,500 patients/year. Acetaminophen (Tylenol) is the leading cause of acute liver failure in the US, causing an estimated 78,000 emergency room visits per year. Thus, there is an acute need for new approaches to the treatment of pain. Although the past several decades have yielded an unprecedented new understanding of chronic pain, these findings have yet to translate into new pain medications. Based on human genetic information, SiteOne is developing a completely new class of non-opioid, non-NSAID pain treatment which selectively targets and interrupts pain signals before they engage the central nervous system. The molecules under development by SiteOne should not only be effective for treating both acute and chronic pain, but should also be devoid of the non-selective side effects associated with other analgesics.
The Role of Voltage-Gated Sodium Channels
Voltage-gated sodium ion channels are essential to electrical signal transmission in the human body. These transmembrane proteins are the target of multiple classes of marketed drugs, such as the local anesthetics, antiepileptics and antiarrhythmics. Existing drugs inhibit all subtypes of the sodium channel with similar potency, leading to side effects that limit their safety and therapeutic utility.
SiteOne Therapeutics is advancing novel drug candidates that exhibit exquisite selectivity for individual sodium channel subtypes, Nav1.7 and Nav1.8. These channels are highly restricted to the peripheral nervous system, where they act as molecular amplifiers to control the sensitivity of biological circuits to noxious input. Nav1.7 and Nav1.8 are validated as targets for pain, cough, itch and other hypersensitivity disorders by an extensive body of preclinical evidence, as well as studies on humans with genetic variants conferring gain- and loss-of-function.
By selectively targeting peripheral nerve fibers, SiteOne’s technology allows the electrical signals responsible for pain, cough and itch to be stopped before they reach the central nervous system. As a result, our drug candidates do not need to enter the brain and are not expected to cause the central nervous system adverse effects (e.g. sedation, nausea, dependence and addition) that plague existing therapeutics such as the opioids and gabapentinoids. The peripheral site of action enables our drug candidates to be effective by both local and systemic routes of administration. Local administration has the advantage of achieving a focused and highly restricted site of drug action.