Analgesia Program The treatment of acute and chronic pain remains a significant challenge, due to insufficient efficacy, negative side effects and abuse potential of currently available therapeutics. Chromocell’s discovery and development programs are focused on development of breakthrough therapeutics for neuropathic and nociceptive pain. Our lead candidate, CC8464, which is partnered with Astellas Pharma, is expected to begin Phase 1 clinical development in 2016.
Peripheral Neuropathic Pain: Patients suffering from neuropathic pain conditions, such as diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia and chemotherapy induced neuropathies, are a highly underserved patient population. Currently available drugs specific for neuropathic pain are only partially effective and often have side effects that are difficult to tolerate, particularly CNS side effects. Many patients resort to narcotics to obtain pain relief, risking severe side effects and addiction.
Nociceptive Pain: Conditions such as osteoarthritis, chronic back pain and fibromyalgia continue to be disorders where patients suffer from chronic pain and current therapeutics are not sufficiently effective.. Treated patients often find they have intolerable side effects to their drugs or must take stronger medications with addiction liabilities. In addition, patients and physicians are seeking alternatives to opioids for the treatment of acute, peri-surgical pain due to the acute opioid effects on respiratory and GI systems.
Discovery
Voltage-Gated Sodium Channel (NaV) Program Chromocell focused its drug discovery program in pain on Nav1.7, a voltage-gated sodium ion channel expressed on nociceptors, the neurons that transmit pain responses. Specifically, NaV1.7 channels are primarily found on pain transmitting sensory neurons and on sympathetic ganglion cells. Patients with chronic insensitivity to pain, CIP, have mutations in the NaV1.7 genes that result in under-active or non-functional channels; they experience no pain but have normal touch and can sense changes in temperature. Other patients have NaV1.7 mutations resulting in chronic pain; many of these patients have “gain-of-function” mutations in the NaV1.7 genes that increase neuronal excitability resulting in rare small fiber neuropathic pain conditions including primary erythromelalgia (iEM) and paroxysmal extreme pain disorder (PEPD). iEM is an autosomal dominant disorder in which patients suffer from burning pain in limbs. PEPD is characterized by skin redness and bouts of extreme pain that can last minutes or hours. A high incidence of “gain-of-function” mutations have also been found in patients with idiopathic small fiber neuropathy, chronic back pain, osteoarthritis and post herpetic neuralgia. Because patients with NaV1.7 related mutations have various pain syndromes, there is tremendous interest and excitement in the medical community for developing therapeutics that specifically inhibit the activity of this channel. Chromovert® technology has enabled the creation of cell lines that not only express the pore forming alpha subunit, but also auxiliary beta subunits critical for physiological activity of Nav1.7. Chromocell has been using its Chromovert platform to express a number of multi- and single-subunit sodium voltage-gated channel subtypes as a foundation for its analgesia programs. The existence of this array of cell lines has proven to be a significant competitive advantage in this field.
CC8464 Chromocell’s lead candidate, CC8464, is a potent and highly selective NaV1.7 antagonist of the inactivated state of the channel. CC8464 is orally bioavailable, peripherally restricted and efficacious in multiple preclinical models of neuropathic and inflammatory pain including models of pain from nerve injury, diabetic neuropathy, chemotherapy induced pain and visceral pain. IND enabling toxicology studies have not demonstrated any significant safety signals. Chromocell has a pipeline of NaV1.7 inhibitor back-ups.
Development
CC8464 It is anticipated that CC8464 may be useful in treating chronic and acute pain in both rare, currently untreated diseases, and in several large unmet or poorly served pain markets.
Conditions, diseases and indications: There are a number of serious pain conditions where CC8464 is expected to be beneficial and potentially superior to currently available treatments;
Diabetic neuropathic pain – Diabetes affects almost 30 million Americans and almost 400 million people worldwide and up to 70% of diabetics have some sort of neuropathy. The resulting neuropathic pain is believed to be at least partially due to damage to the nerve fibers that express NaV1.7. CC8464 has been able to both prevent and treat diabetic neuropathic pain in animal models of Type I diabetes.
Chemotherapy-induced pain – Depending on the chemotherapeutic, up to 90% of patients, suffer from chronic pain following treatment, and there are few, if any, effective treatments. CC8464 appears effective in preventing neuropathic pain in animal models of chemical toxin-induced neuropathies.
Chronic back pain/sciatica – Affecting up to 70% of the world’s population at some time during their lifetime and 5% of adults in any given year, chronic back pain is a major health problem. CC8464 has been shown to be effective in animal models of nerve pain due to sciatic nerve ligation.
Osteoarthritis – Affecting at least 27 million Americans, osteoarthritis is one of the most prevalent pain disorders. CC8464 has been efficacious in several animal models believed to be predictive of efficacy in treating osteoarthritis.
Burn pain – In the U.S. almost 500,000 medically treated burns occur each year requiring 40,000 hospitalizations. Research has demonstrated an association with NaV1.7 activity and burn-induced sensory pain and CC8464 has been shown to reduce thermal hypersensitivity in animals.
Other disorders amenable to modulation of NaV1.7 by CC8464 include genetically linked disorders such as primary erythromelalgia and idiopathic small fiber neuropathy, as well as trigeminal neuralgia, prevention and treatment of peri-surgical pain, and pruritic syndromes like psoriasis. The utility of CC8464 is likely to be extended by additional formulations, such as IV and topical applications. CC8464 is also expected to be beneficial in veterinary disorders with symptoms of severe itch or pain.
CC8464 Commercialization CC8464 is part of a license and collaboration agreement with Astellas Pharma for the development and commercialization of therapeutics to treat neuropathic and other pain conditions. Chromocell will conduct all development of CC8464 through the initial Phase 2a proof-of-concept clinical trial in neuropathic pain. Astellas Pharma will lead further development activities through to commercialization of CC8464 for the treatment of peripheral neuropathic pain. Under a co-development arrangement, Chromocell may initiate studies for additional indications such as rare diseases and non-oral formulations of the drug candidate. Astellas Pharma has the right to opt-in for development and commercialization for such additional indications. Chromocell’ opt-in will trigger additional payments to Chromocell, and co-promotion rights in the U.S.
In 2016 an IND for CC8464 will be submitted and Phase 1 studies are expected to begin.
Respiratory Disorders Chromocell has a discovery program to identify compounds for the treatment of pulmonary pathologies. The target is the epithelial sodium channel, ENaC, an ion channel comprising three distinct subunits which has never been reduced to a cell-based assay due to the toxicity of its over-expression. Modulation of this channel impacts several pulmonary conditions, including pulmonary edema, COPD and cystic fibrosis. Applying Chromovert technology and a multi-pronged approach exploring various cell backgrounds and media formulations, we have been able to isolate functional and viable clonal cell lines for this target. A high-throughput screening campaign has been carried out and hits were identified representing agonists, antagonists and positive modulators. The most promising compounds are being progressed through lead optimization to candidate selection.
Additional Programs Drug discovery and development at Chromocell is focused on complex and challenging potential drug targets for which our Chromovert platform offers a competitive advantage in drug screening and discovery. These efforts include therapeutics targeting additional NaV subtypes. Chromocell is actively seeking partners interested in collaborating on the Chromovert platform and on current products in the discovery and development pipeline.
