Currently CMO at Gilgamesh Pharmaceuticals, since Sept. 2021. Previously, I had spent 20 years in the pharmaceutical industry at Pfizer, Eli Lilly, AbbVie, and Astellas. Outside of 4 years where I was the CSO of the Psychiatric Disorders Drug Hunting Team at Lilly, I have worked as a clinician for programs developing drugs for neuropsychiatric disorders and rare neuromuscular disorders. Before that, I completed a psychiatric residency at the Yale University School of Medicine and completed post-doctoral with George Aghajanian, which was followed by assuming a junior faculty position at Yale in the Department of Psychiatry. I completed my MD, PhD training at the University of Chicago Pritzker School of Medicine. My PhD thesis demonstrated serotonergic mediation of antidepressant drugs on a behavioral screen for antidepressant drugs, the differential reinforcement of low rate 72-s (DRL 72-) schedule of reinforcement. Phone: 224-292-8419 Address: 217 Lexington Court Grayslake, IL 60030-3701
Background: There is an unmet need for therapeutics with greater efficacy and tolerability for th... more Background: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD. Aims: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®). Methods: In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1–4; maintenance, Days 5–18; downward titration, Days 19–26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK. Results: Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug–drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N. Conclusions: In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine. Trial registration: Clinicaltrials.gov identifier: NCT04447287.
Background: Recent increases in opioid use and subsequent opioid use disorder are a major public ... more Background: Recent increases in opioid use and subsequent opioid use disorder are a major public health crisis in the United States. Aims: This phase 1 randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics (PKs) of ASP8062, a γ-aminobutyric acid B receptor-positive allosteric modulator, with and without administration of morphine in participants who used opioids recreationally. Methods: Participants were randomly assigned (2:1) to daily dosing with ASP8062 25 mg or placebo on days 1–10. On day 10, all participants received morphine as a single oral dose of 45 mg; assessments were performed on days 11–16. The primary end point was safety, evaluated as the nature, frequency, and severity of adverse events, and end-tidal CO2 levels. PK end points were a secondary outcome measure. Results: A total of 24 participants (aged 21–54 years) received ASP8062 ( n = 16) or placebo ( n = 8). There were no deaths or serious adverse events leading to treatment discontinuation during the study. Most adverse events were mild, with numerically lower absolute number of adverse events reported with ASP8062 plus morphine versus placebo plus morphine. ASP8062 plus morphine did not increase respiratory depression, potential drug abuse- or withdrawal-related adverse events. There were no significant PK interactions. Conclusions: In this phase 1 study, we did not observe any unexpected safety signals or notable PK interactions with concomitant morphine administration. These data suggest a potentially low risk for an increase in drug abuse- or withdrawal-related adverse events or respiratory distress in participants exposed to ASP8062 and morphine.
Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clin... more Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.
Purpose ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing ... more Purpose ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects. Patients and Methods In this phase 2a, double-blind trial (NCT03056690), adults meeting fibromyalgia diagnostic criteria were randomized 1:1 to receive either 15 mg/day of oral ASP0819 (n=91) or placebo (n=95). The primary endpoint was the change from baseline to Week 8 in the mean daily average pain score. Changes in the Fibromyalgia Impact Questionnaire Revised (FIQR) symptoms, function, and overall impact subscales, as well as changes in the patients’ global impression of change, were secondary endpoints; treatment effects on FIQR total score and impact on sleep were exploratory analyses. Results There was no statistically significant difference between ASP0819 and placebo for the primary endpoint (P=0.086); however, ASP0...
There is substantial pharmacological evidence that glutamate can modulate the effects of 5-hydrox... more There is substantial pharmacological evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 receptor...
The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Admini... more The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Administration of a hallucinogenic 5-HT2A /2Creceptor agonist, but not a 5-HT1Areceptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A /2Creceptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A /2Creceptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A /2Creceptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2Areceptor mediates this e...
The Journal of pharmacology and experimental therapeutics, Jan 23, 2015
Cognitive dysfunction may be a core feature of major depressive disorder (MDD) including affectiv... more Cognitive dysfunction may be a core feature of major depressive disorder (MDD) including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically-derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision-making. The differential-reinforcement-of low rate 72-s (DRL 72-s) schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from non-antidepressant drugs. However, a theoretical basis for this empirical relationship has been la...
Background: There is an unmet need for therapeutics with greater efficacy and tolerability for th... more Background: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD. Aims: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®). Methods: In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1–4; maintenance, Days 5–18; downward titration, Days 19–26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK. Results: Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug–drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N. Conclusions: In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine. Trial registration: Clinicaltrials.gov identifier: NCT04447287.
Background: Recent increases in opioid use and subsequent opioid use disorder are a major public ... more Background: Recent increases in opioid use and subsequent opioid use disorder are a major public health crisis in the United States. Aims: This phase 1 randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics (PKs) of ASP8062, a γ-aminobutyric acid B receptor-positive allosteric modulator, with and without administration of morphine in participants who used opioids recreationally. Methods: Participants were randomly assigned (2:1) to daily dosing with ASP8062 25 mg or placebo on days 1–10. On day 10, all participants received morphine as a single oral dose of 45 mg; assessments were performed on days 11–16. The primary end point was safety, evaluated as the nature, frequency, and severity of adverse events, and end-tidal CO2 levels. PK end points were a secondary outcome measure. Results: A total of 24 participants (aged 21–54 years) received ASP8062 ( n = 16) or placebo ( n = 8). There were no deaths or serious adverse events leading to treatment discontinuation during the study. Most adverse events were mild, with numerically lower absolute number of adverse events reported with ASP8062 plus morphine versus placebo plus morphine. ASP8062 plus morphine did not increase respiratory depression, potential drug abuse- or withdrawal-related adverse events. There were no significant PK interactions. Conclusions: In this phase 1 study, we did not observe any unexpected safety signals or notable PK interactions with concomitant morphine administration. These data suggest a potentially low risk for an increase in drug abuse- or withdrawal-related adverse events or respiratory distress in participants exposed to ASP8062 and morphine.
Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clin... more Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.
Purpose ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing ... more Purpose ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects. Patients and Methods In this phase 2a, double-blind trial (NCT03056690), adults meeting fibromyalgia diagnostic criteria were randomized 1:1 to receive either 15 mg/day of oral ASP0819 (n=91) or placebo (n=95). The primary endpoint was the change from baseline to Week 8 in the mean daily average pain score. Changes in the Fibromyalgia Impact Questionnaire Revised (FIQR) symptoms, function, and overall impact subscales, as well as changes in the patients’ global impression of change, were secondary endpoints; treatment effects on FIQR total score and impact on sleep were exploratory analyses. Results There was no statistically significant difference between ASP0819 and placebo for the primary endpoint (P=0.086); however, ASP0...
There is substantial pharmacological evidence that glutamate can modulate the effects of 5-hydrox... more There is substantial pharmacological evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 receptor...
The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Admini... more The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Administration of a hallucinogenic 5-HT2A /2Creceptor agonist, but not a 5-HT1Areceptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A /2Creceptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A /2Creceptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A /2Creceptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2Areceptor mediates this e...
The Journal of pharmacology and experimental therapeutics, Jan 23, 2015
Cognitive dysfunction may be a core feature of major depressive disorder (MDD) including affectiv... more Cognitive dysfunction may be a core feature of major depressive disorder (MDD) including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically-derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision-making. The differential-reinforcement-of low rate 72-s (DRL 72-s) schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from non-antidepressant drugs. However, a theoretical basis for this empirical relationship has been la...
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