Chronic pain is pain that persists beyond the pain caused by an underlying injury or illness. It is pain that persists past the normal healing time and lacks the warning function of acute pain, which acts as a protective mechanism. Usually, pain is regarded as chronic when it lasts or recurs for more than three to six months. In addition, this type of pain is independent of the original cause of pain. The Institute of Medicine report “Relieving Pain in America” (2011) stated that chronic pain affects at least 100 million adults in the U.S., costing $560-$635 billion annually. The World Health Organization estimates that 22 percent of the global population suffers from chronic pain, which includes neuropathic pain (caused by a lesion on or disease of the nervous system), such as diabetic neuropathy, musculoskeletal pain (including osteoarthritis) as well as pain due to cancer, trauma, and pain that originates from internal organs.
The development of chronic pain is a result of changes in the nervous system that increase its reactivity, a process called sensitization. During the process of sensitization, increased responsivity of the peripheral sensory system is followed by sensitization of the central nervous system (spinal cord and brain). There is increasing evidence for the role of peripheral (non-central nervous system) mechanisms in the development of chronic pain, and the systems involved are candidate targets for treatment of chronic pain. Kindolor is a multi-target drug that simultaneously inhibits two of the peripheral systems whose over-activity is involved in chronic pain syndromes. Kindolor’s actions are confined to the peripheral nervous system, reducing the possibility of deleterious central nervous system effects and alleviating the potential for addiction. Kindolor controls the hyperalgesia of chronic pain without eliminating normal, protective pain responses, and Kindolor has been shown to have anti-hyperalgesic effects in five animal models of chronic pain. Not only can Kindolor act on its own, but it can also effectively enhance the action of centrally acting analgesics for controlling chronic pain. Lohocla has received a grant from the National Institute on Drug Abuse/National Institutes of Health to take Kindolor through Phase I clinical trials. We have developed an appropriate formulation for Kindolor administration and are currently completing the preparation of an IND application for submission to the FDA in the second quarter of 2022.
Alcohol Use Disorder (AUD) is defined as a chronic relapsing brain disease, characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, and/or health consequences. The National Survey on Drug Use and Health estimated in 2015 that 15.1 million adults in the United States had AUD, and an estimated 88,000 individuals die from alcohol-related causes annually, making alcohol the third leading preventable cause of death in the United States. Globally, in 2012, 3.3 million deaths were attributable to alcohol-related causes (including cancer, liver failure, and accidents resulting from impairment). In the U.S., only about 6.7 percent of adults with AUD receive treatment annually. “Talk therapy,” such as Alcoholics Anonymous, and pharmacotherapy are often employed. The fifth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-5) includes the criterion of “craving” for alcohol (a strong desire or urge to use alcohol). Available pharmacological treatments for AUD, which are administered along with behavioral support and are aimed at reducing craving in order to reduce or eliminate alcohol consumption, have only modest efficacy accompanied by many adverse side effects.
These drugs are currently used by a relatively small percentage of alcohol dependent individuals due to lack of awareness by patients or care providers, lack of efficacy, and problems with compliance. Our focus is on the use of rational, evidence-based drug design for development of therapeutics to reduce craving and relapse to alcohol consumption in alcohol-dependent individuals, with the overall aim of reducing alcohol-related negative consequences and deaths. Nezavist, the lead medication for this indication from Lohocla Research, is a novel enhancer of the effect of GABA, the major inhibitory neurotransmitter at the GABA-A receptor. Changes in this receptor that occur during ethanol withdrawal have been proposed to contribute to craving for alcohol, and Nezavist is postulated to rectify these alcohol-induced changes. In several animal models of withdrawal-induced alcohol craving, Nezavist is effective in reducing the increased alcohol consumption that accompanies withdrawal in alcohol-dependent animals. Nezavist is therefore proposed to prevent relapse in those addicted to alcohol and wishing to recover. Nezavist itself has few side effects, and shows no signs of potential for producing addiction. Lohocla has received funding from the National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health to bring Nezavist to clinical trials. We have completed preclinical toxicology and safety studies and will be submitting and IND application in first quarter 2022, with first-in-human trials beginning in the latter part of the year.