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(NMDA) Receptor Glutamate Synapse Functional NMDA receptor-based target engagement biomarkers for schizophrenia research Daniel C. Javitt, M.D., Ph.D. Professor & Director, Division of Experimental Therapeutics Columbia University Medical Center Director of Schizophrenia Research Nathan Kline Institute Disclosures • Consultant: Pfizer, FORUM, Autifony, Glytech, Lundbeck, Concert, Cadence • Scientific Advisory Board: Promentis, NeuroRx, Phytecs • Equity: Glytech, AASI, NeuroRx • Intellectual property rights: Glycine, D-serine and glycine transport inhibitors in Sz; D-cycloserine, combined NMDAR/5-HT2AR antagonism in depression & PTSD; visual ERP for early diagnosis of Alzheimer disease • Off-label treatment: pomaglumetad Functional target engagement biomarkers The challenge • Glutamatergic theories of schizophrenia have become increasingly established over the past 25 years • Many glutamate-base pharmacological approaches show encouraging effects in preclinical models • To date, none has translated into an effective medication The solution • Need target engagement biomarkers to permit better translation from animals to humans • Allow “FAST fail” decisions regarding mechanism of action: • No target engagement - “fail” drug • Target engagement but no beneficial clinical effect – “fail” mechanism • Permit informed dose selection Academia, Government, and Pharma contributions Sci Transl Med. 3:102mr2, 2011 TRANSLATION TYPE (Institute of Medicine, 2013) NMDAR-based treatment development Background • NMDAR antagonists such as phencyclidine (PCP) and ketamine induce symptoms, neurocognitive deficits and neurophysiological deficits that closely resemble schizophrenia • Acute NMDAR blockade is associated with an increase in presynaptic glutamate release (“glutamate surge”) • Hypothesis 1: Symptoms/neurocognitive deficits results from NMDAR hypofunction • Hypothesis 2: Symptoms/neurocognitive deficits result from “glutamate surge” N-methyl-D-aspartate (NMDA) receptor Glutamate synapse Treatment targets - Javitt & Zukin, Am J Psychiatry, 148: 1301-8, 1991 - Moghaddam & Javitt., Neuropsychopharmacol Rev, 2011 NMDAR-based treatment development Background • NMDAR antagonists such as phencyclidine (PCP) and ketamine induce symptoms, neurocognitive deficits and neurophysiological deficits that closely resemble schizophrenia • Acute NMDAR blockade is associated with an increase in presynaptic glutamate release (“glutamate surge”) • Hypothesis 1: Symptoms/neurocognitive deficits results from NMDAR hypofunction • Hypothesis 2: Symptoms/neurocognitive deficits result from “glutamate surge” Potential treatment approaches Glutamate synapse Hypothesis 2: Desired solution - ↓ presynaptic glutamate release Treatment targets Hypothesis 1: Desired solution – ↑ postsynaptic NMDAR activity - Moghaddam & Javitt., Neuropsychopharmacol Rev, 2011 Effect of metabotropic glutamate receptors: preclinical models • Treatment with an NMDAR antagonist (PCP) leads to significant increases in glutamate & dopamine release in prefrontal cortex, along with increases in locomotion • Pretreatment with the mGluR2/3 agonist LY354740 blocks both the increases in glutamate and locomotion • PCP-induced increases in dopamine release also inhibited but not blocked Moghaddam et al., Science. 281:1349-52, 1998 Clinical effects of pomaglumetad (LY21400230) Initial positive result Subsequent failures to replicate 15 80 mg 10 5 0 -5 -10 -15 % Change PANSS Total Total % Change PANSS % Change PANSS Total Total % Change PANSS -20 -25 0 1 2 3 4 Week Week Patil et al., Nat Med. 13:1102-7, 2007 Downing et al., BMC psychiatry. 14:351, 2014 FAST-Fail: Psychotic disorders Questions • Why don’t mGluR2/3 agonists work in people, even though they work in rodent models? • Were doses used in the clinical studies sufficient to adequately test the hypothesis? • What biomarkers can be used to test target engagement? NIMH FAST-psychosis spectrum (FAST-PS) biomarker project • Phase I: Biomarker selection • Selected measures potentially sensitive to the glutamate “surge” • PharmacoBOLD, Glutamate MRS, task-based fMRI • Phase II: Target engagement studies with pomaglumetad (healthy volunteers) Phase I biomarker validation JAMA Psychiatry. 75:11-19, 2018 Design • 65 Healthy volunteers • Randomized 2:1 to ketamine infusion vs. placebo • 2 MRI sessions per subject • Session 1: Glutamate 1H-MRS, task-based fMRI • Session 2: “PharmacoBOLD” • Psychosis ratings: CADSS, BPRS Magnetic resonance spectroscopy (MRS): Methods Mechanism of action Example spectrum • Increase in presynaptic glutamate release leads to a rapid increase in glutamate synthesis from glucose • The increase in glutamate synthesis , in turn, leads to an increase in total glutamate+glutamine (“Glx”) in brain Abdallah et al., Neuropsycho-pharmacology 43: 2154-2160, 2018. Magnetic resonance spectroscopy (MRS): Results Mechanism of action Results • Increase in presynaptic glutamate release leads to a • Significant increase in Glx content at 15 min rapid increase in glutamate synthesis from glucose • BUT: Moderate effect size (d=.64) • The increase in glutamate synthesis , in turn, leads to an • Not sufficiently robust to be able to detect a increase in total glutamate+glutamine (“Glx”) in brain drug effect even if present * Abdallah et al., Neuropsychopharmacology 43: 2154-2160, 2018. PharmacoBOLD Mechanism of action Results • Increase in presynaptic glutamate release leads to a • Extremely large effect (d=5.4) rapid increase in glutamate synthesis from glucose • Sufficient to detect a change, if present • The increased metabolic rate leads to an acute increase in BOLD reponse Abdallah et al., Neuropsycho-pharmacology 43: 2154-2160, 2018. Phase 2 study: Design overview • 81 healthy volunteer completers across 4 sites (Columbia, NYU, UAB, UCLA) (100 total subjects randomized) • Randomized (1:1:1) double blind administration of a placebo, 40mg bid POMA, or 160mg bid POMA • 40 mg BID = dose used in prior successful clinical trial • 160 mg BID = maximum tolerated dose (limited by nausea, vomiting) • Subjects took POMA or placebo for 10 days • Administered ketamine or placebo on the final day of treatment • Ketamine dose - 0.23 mg/kg bolus over 1 minute • Ketamine-induced prefrontal glutamate activity as measured by resting BOLD fMRI (pharmacoBOLD) • Inclusion criteria: BOLD fMRI response in dACC-ROI > 0.5% at Screening (40 mg BID) (160 mg BID) mg (160 BID) mg (40 (40 mg BID) (160 mg BID) mg (160 BID) mg (40 Placebo Low Placebo dose - High dose - dose - High dose - Low Placebo 1.0 - 3 - : p=.80 : Main effect of treatment of effect Main 0 . 0 0 Main effect of treatment of effect Main : p=.33 p=.33 : Mean change in BPRS Total in BPRS change Mean 0.8 - %change 2 . 0 - e s n o p k s a 2 - e e placebo vs. 1 - R 0.6 P - l a C 4 . 0 - t d= .33, p=.15 .33, C - o vs. placebo vs. T dACC A d S n R i .14, p=.52 .14, - d= P e B 0.4 g - n n i 6 . 0 - a h peak e C g 1 - 2 - n n a a h e C M 0.2 - n a 8 . 0 - e M 0 0 0 . 1 - 3 - o b e c a l P e s o D w o L e s o D h g i H o b e c a l P e s o D w o L e s o D h g i H pharmacoBOLD dACC p u o r G t n (BPRS) e m t a e r T ratings Clinical p u o r G t n e m t a e r T results study: Pomaglumetad 2 Phase mGluR/3 agonist development in Sz: Conclusions Conclusions • The good news is that the bad news may be wrong • At doses used in prior clinical studies, pomaglumetad does not show evidence of significant functional target engagement • Other compounds are presently under investigation • The bad news is that the mechanism may not be viable • Further dose escalation may be precluded by high rates of nausea/vomiting • HOWEVER: Side effects are likely due to local effects in stomach; could be blocked by peripheral antagonists • Future studies with higher doses are needed • “PharmacoBOLD” can be used for T1-type translation to healthy volunteers • Not suitable for T2-T4 translation involving patient groups • Biomarker studies should probably be implemented before, rather than after, intensive phase 3 development T2 translation: Mismatch negativity (MMN) • Elicited in the context of an auditory “oddball” paradigm • Reflects information processing dysfunction at the level of auditory sensory cortex • Consistent deficits in Sz related to impaired functional outcome • Can be assessed in parallel in rodents, monkeys, & humans • Inhibited by NMDAR antagonists (e.g., ketamine) • Improved by putative NMDAR agonists (e.g. D-serine) MMN Meta-analysis (Sz) ERP Biomarker Qualification Consortium www.erpbiomarkers.org - Avissar et al., Schizophr Res. 191:25-34; 2018 Collaborators Columbia Biomarker validation Pomaglumetad MMN Consortium Jeff Lieberman (PI) Yale University UCLA Josh Kantrowitz John Krystal Steve Marder Larry Kegeles Phil Corlett Junghee Lee Jack Grinband Graeme Mason Michael Green Ragy Girgis Douglas Rothman Melanie Wall Maolin Qui NYU Tse Hswei Choo Don Goff Marlene Carlson UC Davis Fernando Boada Cameron Carter Erica Diminich Jim Robinson (NKI) J. Daniel Ragland Richard Maddock UA Birmingham Costin Tanase Adrian Lahti Tyler Lesh David White Mark Bolding.
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