Therapeutics

ALDHs are a family of enzymes known primarily for their critical role in ethanol (EtOH) metabolism; ALDH2-induced metabolism of acetaldehyde (ACD) is the rate-limiting step in EtOH metabolism. Inherited human ALDH2 deficiency causes an accumulation of ACD when alcohol is consumed, leading to a highly aversive reaction (ethanol reaction [ER]), which reduces the risk for an AUD. The ER in human ALDH2 deficiency also underlies the mechanism by which the FDA-approved treatment for AUD, disulfiram, deters alcohol consumption. Disulfiram irreversibly and non-selectively inhibits both ALDH1 and ALDH2, resulting in ACD accumulation and the corresponding aversive ER. In contrast to disulfiram, selective and reversible ALDH2 inhibitors reduce alcohol consumption and prevent alcohol-induced dopamine release in the brain independent from increasing ACD levels. Selective ALDH2 inhibitors also decrease norepinephrine (NE) release, which likely underlies the anxiolytic properties of ALDH2 inhibition in animal models of anxiety. Not only is elevated NE associated with alcohol withdrawal and a critical treatment component for preventing alcohol use relapse, it is also implicated in the pathophysiology of PTSD. ANS-6637 is being developed by Amygdala Neurosciences as an aid for substance use disorders based on its mechanism of action in the brain to prevent pathophysiologic dopamine surge without changes to basal dopamine. Unfortunately, an early Phase 2 clinical trial conducted by NIAAA recently uncovered liver toxicity that halted PASA plans to start a similar clinical trial examining it for alcohol use disorder and PTSD.

Alpha-1 adrenergic blockers like doxazosin and alpha-2 adrenergic agonists like BXCL501 have a MOA that reduces the excessive adrenergic activity characteristic of PTSD and AUD and withdrawal. Doxazosin, an alpha-1 specific blocker is FDA approved for prostate hyperplasia and hypertension, and has been shown to reduce PTSD in clinical studies and reduce AUD in preclinical and clinical studies. It has a longer half-life than prazosin which is another alpha-adrenergic blocker that has been shown to also reduce PTSD symptoms (nightmares). Lofexidine is in contrast an alpha2-adrenergic receptor agonist. Like doxazosin it can be used as an anti-hypertensive, but is mostly used to help relieve symptoms of heroin or opiate withdrawal in opiate dependency. It also has broader efficacy in reducing all types of adrenergic activity through feedback inhibition of adrenergic neurons. BXCL501 (dexmedetomidine-DEX on a sublingual film), is a selective and potent alpha2-adrenergic receptor agonist. Other alpha2-adrenergic agonists have been developed for clinical use including clonidine, lofexidine and guanfacine; however, DEX is more potent than these other alpha2-adrenergic agonists and achieves higher free brain levels after dosing suggesting it may have superior pharmacological and pharmacokinetic properties. BioXcel is currently developing BXCL501 for the treatment of acute agitation in patients with schizophrenia and bipolar disorders. The properties of BXCL501 indicate it may be an effective therapeutic for the treatment of patients with PTSD, especially those that are undergoing treatment for ASUD. DEX exerts its effects by preventing release of the neurotransmitter norepinephrine from neurons in the locus coeruleus (LC). LC neurons and norepinephrine are responsible for stress-related agitation as a result of hyper-arousal of the sympathetic nervous. Because PTSD is associated with hyper-arousal and high sympathetic nervous system activity, BXCL501 has the potential to alleviate agitation that occurs in PTSD. Doxazosin is a direct blocker (antagonist) of post-synaptic alpha1-adrenoreceptors, while lofexidine and BXCL501 are agonists at pre-synaptic or auto- alpha2-adrenoreceptors. Lofexidine and BXCL501 have a much broader effect than doxazosin in reducing brain adrenergic activity because lofexidine and BXCL501 not only reduce activity at alpha-1 receptors, but also reduce activity at all the four types of both alpha and beta adrenroreceptors.

N-acetylcysteine is a type of amino acid that is synthesized in the liver for its anti-oxidant properties, since oxidizing agents are generally toxic. It was considered as part of a planning grant but a clinical trial was ultimately not funded based on the past history of the compound failing in most studies with PTSD, AUD and other abused drugs.

Direct cortisol blockers like PT150 have a MOA that are relevant due to the significant dysregulation of the Hypothalamic-Pituitary-Adrenal axis in both AUD and PTSD leading to elevated cortisol activity. Indirect cortisol blockers like SAFit2 (a highly specific small molecule that crosses the blood brain barrier) and benztropine mesylate (more broad acting and FDA-approved for Parkinson's disease) are compounds that potentially target stress related molecular pathways. FKBP5 is a co-chaperone that interacts with the glucocorticoid receptor (GR)/heat shock protein 90 complex and thus interferes with glucocorticoid (GC) binding to its receptor. Therefore, FKBP5 regulates GC signaling, including hypothalamic‐pituitary-adrenal (HPA)-axis negative feedback. Dysregulation of the HPA-axis and extrahypothalamic GR are well established in PTSD and AUD. FKBP5 inhibitors could be repurposed for the treatment of PTSD/AUD and a meta-analysis of 14 studies with >15,000 volunteers found that FKBP5 gene variants predict PTSD rates.

DORAs block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. In addition to the well-established effects in regulating sleep, 15+ years of preclinical data evince a key role of the orexin system and DORAs in attenuating (1) drug seeking and self-administration (including alcohol), and (2) PTSD-relevant symptoms including reductions in stress/anxiety. Suvorexant has two key advantages over more traditional somnolent medications (e.g., benzodiazepines) in this population: (1) it uniquely re-regulates PSG-measured sleep architecture rather than simply improving onset latency and total sleep time, moving sleep patterns towards homeostasis; and (2) it does not potentiate CNS depression with alcohol.

Zonisamide is an anticonvulsant sulfonamide. Zonisamide's MOA alters the fast inactivation threshold of voltage dependent sodium channels, and it reduces the sustained high-frequency repetitive firing of action potentials. Zonisamide also inhibits low-threshold T-type calcium channels in neurons, which may prevent the spread of seizure discharge across cells. Both alcohol and zonisamide regulate/modulate the activity of the same neurotransmitter systems. Zonisamide in repeated doses decreases the sensitivity of the hippocampus to ethanol. Its MOA for reducing PTSD symptom is less clear and was tested in a rodent study, where it showed little efficacy, thereby leading to cancellation of a planned human study using it for alcoholism and PTSD.

Endogenous opioid systems in the brain are involved in regulation of mood, stress modulation, and cravings. KORs are densely localized in limbic and cortical areas comprising the brain reward system, which play a role in modulating stress and in promoting addictive behaviors. The MOA for KOR antagonists like CERC-501 involve blocking the increased dynorphin A (endogenous ligand for KOR) and increased KOR signaling in the amygdala with AUD. This excessive signaling in the dynorphin/KOR system during the stress response contributes to the anxiogenic and dysphoric responses to stress which directly produce negative emotional/mood states that accompany alcohol withdrawal and contribute to excessive alcohol consumption to avoid withdrawal. KOR antagonists block the actions of endogenous dynorphins and alleviate the negative mood states from AUD. Similar actions are postulated for reduction in PTSD symptoms. CERC-501 is currently being pursued for major depression as the first approved indication.

The ketamine metabolite, hydroxynorketamine (2R,6R-HNK), produces comparable effects to ketamine in preclinical models of stress and pain, without producing sedation, gait impairment, or rewarding effects. Ketamine metabolites reverse the behavioral deficits associated with models of traumatic stress, attenuate alcohol consumption and compulsive drinking in ethanol dependent animals and diminish the negative affective behavior associated with abstinence in murine models of PTSD and AUD.

Upregulation of the nociceptin opioid peptide (NOP) receptor and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) has been associated with both excessive alcohol consumption and development of PTSD symptoms in rodent models. NOP receptor antagonists have been shown to prevent development of PTSD symptoms including anxiety, pain, depression and hypocortisolism, generated by single prolonged stress (SPS) in rats. Binge alcohol drinking has also been shown to be reversed by pharmacological blockade of NOP receptors in mice. PPL-138, formerly named BU10038, is a recently identified bifunctional NOP/mu partial agonist with potent antinociceptive activity and fewer side effects than other opioid analgesics.

An Anti-fentanyl vaccine (CRM-GFEN+Alum+dmLT [CRM197-glutaryl fentanyl plus the adjuvant dmLT]) is composed of fentanyl attached to the carrier protein CRM197, which is derived from pertussis toxoid, and then added to a new vaccine adjuvant dmLT, which is currently in human studies world-wide for increasing antibody responses to various vaccines. This vaccine produces antibodies in the blood that attach to fentanyl, if it is ingested, and this large antibody-fentanyl complex cannot get out of the bloodstream to enter the brain, heart or other vulnerable organs to produce psychological effects, analgesia or respiratory depression. Thus, these antibodies prevent both abuse of fentanyl and overdose. These blocking effects are critical because our existing FDA approved treatments for opioid relapse prevention and overdose - methadone, buprenorphine and naltrexone - are not able to block fentanyl's effects. Overall, preventing fentanyl overdose has two critical roles for the DOD. First, it can prevent the high rate of overdoses and deaths occurring among Veterans with opioid use disorders. Second, it can prevent terrorist or related combat attacks using aerosolized fentanyl. This vaccine is moving towards human use in FDA testing during the next couple of years with this DOD and NIH support. The dmLT adjuvant is being provided at no cost for animal and later human studies from the WHO and PATH foundation through NIH. Human studies are now actively being pursued using PASA funds for early manufacturing, stability and toxicology testing in preparation for IND filing to do a Phase 1 human clinical trial in about 2 years.