As Impact of Substance Use Disorders Rise, so Do Innovative Solutions

18 Sep 2023
www.biospace.com
Drug ApprovalClinical Study
Pictured: A vial of Fentanyl/iStock, nito100 In July, the FDA approved a first-in-human clinical trial of a monoclonal antibody investigated by Cessation Therapeutics that aims to prevent fentanyl overdose. That same month, the regulator greenlighted an over-the-counter nasal spray formulation of naloxone—a staple in reversing opioid overdose since its FDA approval in 1971—from Harm Reduction Therapeutics, a nonprofit biopharma. These are but two examples of a wide-ranging push to address the broader issue of substance use disorder (SUD). Currently, the National Institutes of Health’s clinical trial database lists 714 active studies investigating treatments for SUD. “You can’t treat a dead person,” Cessation CEO Tracy Woody told BioSpace. “We are trying to keep these people alive and bridge them to other treatments.” SUD is a disease that affects a person’s brain and behavior, leading to the uncontrollable use of harmful substances like alcohol, opioids and illicit drugs. More than 40 million Americans aged 12 or older had a SUD in 2019, according to 2020 data collected by the Substance Abuse and Mental Health Services Administration, and CDC data show that over 150 people die every day from overdoses related to synthetic opioids alone. Here, BioSpace explores a few of the many drug development efforts that aim to reduce these tragic numbers. Neutralizing Fentanyl Dubbed CSX-1004, Cessation’s therapeutic works by neutralizing fentanyl molecules as they enter the bloodstream, preventing the opioid from impacting the brain and causing overdose. This effectively halts respiratory depression, which is fatal. “We have done a lot of studies in nonhuman primates with our collaborators at Harvard to evaluate fentanyl-induced respiratory depression, and we showed with this antibody that a single dose could prevent the respiratory effects of fentanyl for about 30 days,” said Andy Barrett, CSO of Cessation Therapeutics. Woody noted that a monoclonal antibody option for preventing overdose could also mean broader accessibility. Some treatments for substance use disorder, such as buprenorphine, are classified as controlled substances by the Drug Enforcement Agency, but a monoclonal antibody would not be, minimizing some barriers to access for clinics. Lowering Costs to Increase Accessibility Harm Reduction Therapeutics’ over-the-counter therapeutic, RiViveRiVive, is an opioid receptor antagonist that works similarly to generic naloxone nasal sprays currently available via prescription. Specifically, it prevents overdose by binding to opioid receptors, which reverse or block the effects of opioids that have been taken. This process helps to prevent respiratory depression. Naloxone’s original approval required a prescription, which could be a potential barrier to accessing the life-saving drug as it required seeing a medical professional. The price of naloxone has also escalated in tandem with the opioid epidemic. For example, the price of a vial of injectable naloxone manufactured by Hospira increased 129% from 2014 to 2016, as reported in The New England Journal of Medicine. A two-pack of Narcan, a name brand of naloxone, can cost $145 for uninsured patients, according to Naloxone Exchange. RiViveRiVive, on the other hand, is set to be available for $36 for a box of two doses. Ten percent of the cost goes to funding free doses for those who can’t afford it—the company is partnered with Remedy Alliance to donate 200,000 naloxone doses for distribution. “Harm Reduction Therapeutics exists to fix a problem that, in an ideal market, wouldn’t exist,” Michael Hufford, the company’s co-founder and CEO, told BioSpace. “In an ideal market, the price of an old, established drug like naloxone should fall [over time]. It didn’t, so we helped correct that.” Blocking the Cravings that Drive Addiction Focusing on another addictive substance, alcohol, Addex Therapeutics and Indivior are looking to reduce the desire to drink in the first place. “In the U.S. alone, there are about 14 million people diagnosed with alcohol use disorder, and the number one issue is cravings,” Indivior CEO Mark Crossley told BioSpace. “If we could intervene on cravings, we think there’s a chance to reduce alcohol usage.” Alcohol intake disrupts the brain’s GABA transmission, particularly the GABAB receptor, which is associated with the development and maintenance of addiction. Robert Lütjens, head of discovery–biology at Addex, said that agonists of the receptor have been studied extensively in the context of substance use. “[Agonists] that have been tested in preclinical models have shown that GABAB receptor activation can reduce addiction and addictive behavior,” he told BioSpace. However, approved agonists, such as Baclofen, come with side effects like sedation, and patients can become tolerant, requiring higher dosing, Lütjens said. To avoid these drawbacks, Addex and Indivior entered into a strategic collaboration to develop GABAB-positive allosteric modulators (PAMs) for alcohol use disorder. PAMs differ from agonists in that they work to enhance the activity of GABAB receptors only when the GABA neurotransmitter activates the receptor. “In my mind, I think of [PAMs] as working when the patient needs it,” Crossley said. “The neat thing about a PAM is that it doesn’t sit on the receptor all the time, which helps to resolve a lot of the side effects.” The companies plan to have a lead asset from their GABAB PAM development program ready for clinical trials in Q4 of 2023, Crossley added. Hayley Shasteen is a freelance science writer based in Northeastern Ohio. You can reach her at hayleyshasteen@gmail.com, or follow her on LinkedIn.
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