Our Focus

Therapeutics

Therapeutics for Future Focus
Two PASA-funded Aim 1 non-clinical studies (In-silico research for OUD/PTSD, Electronic Medical Record [EMR] data for ASUD/PTSD) have been funded to use big-data approaches based on genomic and electronic health data respectively to develop a library of therapeutics available for potential repurposing. To obtain access to the interactive library for generating ideas for funding application development, please email pasa@rti.org.

Therapeutics Investigated

The following pharmaceutical agents have been or are being studied by PASA for their effects on ASUD in individuals with comorbid PTSD:
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 award 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.
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.
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.
GABA systems have been implicated as targets for ethanol at the cellular, molecular and behavioral level. The MOA relevant to modulating the GABAB receptor to increase its activity, which decreases alcohol responding and like the prototypic agonist, baclofen, reduces the self-administration of alcohol. The GABAB receptor allosteric modulator, ASP8062 reduced voluntary responding for 10% ethanol in a dose-related manner in initial animal studies. Increased GABA activity can increase depleted dopamine levels and possibly reduce drug cravings. A reduction in GABAB activity is also characteristic of PTSD and augmentation of this activity should reduce PTSD symptoms. Astellas has now begun enrolling subjects in an outpatient Phase II study of ASP8062 for alcohol use disorder and comorbid PTSD, another indication of the success of the PASA in moving new medications into treatments for substance use disorders.
Allopregnanolone (ALLO), a neurosteroid with anxiolytic and antidepressant action, offers a promising treatment target due to shared stress-related neurobiological mechanisms that underlie PTSD/AUD. Specifically, men and women with PTSD have lower levels of ALLO and women have a blunted ALLO response to acute stressors. Additionally, levels of plasma ALLO fall in response to alcohol administration and ALLO levels are correlated with subjective alcohol effects. This evidence suggests that brexanolone (an exogenous, synthetic form of ALLO and GABAA modulator) may target stress, an underlying mechanism of PTSD and AUD, and thus prove to be a novel treatment.
The development of long-lasting glucagon-like peptide 1 (GLP-1) receptor agonists (GLP1RAs) has led to rapid innovation in the clinical management of diabetes and obesity. The increasing popularity and clinical utilization of semaglutide (Ozempic, Wegovy, Rybelsus) has been accompanied by clinical and anecdotal reports that alcohol drinkers often experience reductions in alcohol consumption during treatment with semaglutide. These observations suggest that that GLP1RAs (a class of incretin memetics with satiety-inducing properties) reduce alcohol motivation and intake in rodent and nonhuman primate models. Preclinical studies further suggest that GLP1RAs can reduce motivation for nicotine and other drugs (e.g., stimulants, opioids), indicating the potential for generalized effects on drug-seeking.
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. Selective KCa2 channel positive allosteric modulators (PAMs) reduced excessive drinking and aberrant behaviors in a preclinical model for the study of alcohol-stress interactions. Recent studies identified Kcnn3, the gene that encodes KCa2.3 channels, as a critical mediator of excessive alcohol drinking and anxiety-like behavior in mice. Thus, KCa2.3 channel-selective PAMs are currently being pursued pre-clinically as a potential pharmacogenetic target to treat individuals with AUD and may be particularly effective at treating those with comorbid mood disorders, such as 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 aticaprant (LY2456302; CERC-501; JNJ-67953964) 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.
Xenon (Xe) is a mostly inert, noble gas and has applications in a variety of medical indications. It is thought that Xe, by inhibiting memory reconsolidation, will blunt appetitive (alcohol cravings, urges) and aversive (memory drivers of AUD+PTSD. Inhaled Xe gas already is used clinically for blood flow and lung imaging studies and at the low concentrations has no abuse liability and induces few side effects.
Buprenorphine itself is an opioid, but the maximal effects are less than other more dangerous opioid agonists, like methadone and heroin, and is FDA-indicated for the treatment of opioid dependence, because it is a partial rather than full agonist of the mu receptors. More importantly for the proposed human studies, buprenorphine is the only clinically available medication that acts as an antagonist of the KORs. Kappa opioid antagonists in animal models and buprenorphine in preliminary human studies have reversed PTSD symptoms more effectively than the currently FDA approved selective serotonin reuptake inhibitors (SSRIs) used for treating PTSD (sertraline and paroxetine). The agonist buprenorphine had not been tested for reducing alcohol use previously, but it was tested in a recently completed PASA clinical trial and was ineffective.
Naltrexone reverses the effects of opioid analgesics by binding to the various opioid receptors in the central nervous system, including the mu, kappa and delta-opioid receptors. This leads to an inhibition of the typical actions of opioid analgesics, including analgesia, euphoria, sedation, respiratory depression, miosis, bradycardia, and physical dependence. Naltrexone is longer-acting and more potent compared to naloxone (Narcan). Naltrexone is used to block cravings for both opioids and alcohol (FDA-indicated for the treatment of alcohol dependence) but naloxone is not. Both drugs block the analgesic and respiratory depressant actions of exogenous opioids and the pleasure response of endogenous endorphins, which are released when drinking alcohol. However, to treat an overdose naltrexone does not act quickly enough, while naloxone is both quick and short acting for opioid overdose treatment. While naltrexone cannot be used to rescue someone from an opioid overdose, it can help people who are addicted to opioids have less craving for them (FDA-indicated for the prevention of relapse to opioid dependence following detox).
In order to broadly explore treatment of ASUD and PTSD, we have selected compounds with a range of non-overlapping mechanisms of action (MOA) that have been shown relevant in these diseases. Some medications are positive controls (e.g., baclofen for its action in reducing alcohol use, doxazosin for its efficacy reducing alcohol use and PTSD symptoms, and naltrexone for its efficacy in reducing alcohol).

Investigational Details


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