Functional NMDA receptor-based target engagement biomarkers for - - PowerPoint PPT Presentation

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

Di 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

Functi tional tar arget en engagement bi 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
• 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

The solution

Ac Academia, Go Government, and and Phar harma con

• ntributions

Sci Transl Med. 3:102mr2, 2011

TRANSLATION TYPE (Institute of Medicine, 2013)

NM NMDAR-based tr trea eatment de development

N-methyl-D-aspartate (NMDA) receptor

• Javitt & Zukin, Am J Psychiatry, 148: 1301-8, 1991

Treatment targets

• Moghaddam & Javitt.,

Neuropsychopharmacol Rev, 2011

Glutamate synapse 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”

NM NMDAR-based tr trea eatment de development

Potential treatment approaches

Treatment targets

• Moghaddam & Javitt.,

Neuropsychopharmacol Rev, 2011

Glutamate synapse 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”

Hypothesis 2: Desired solution - ↓ presynaptic glutamate release Hypothesis 1: Desired solution – ↑ postsynaptic NMDAR activity

Effect ct of

• f metabotropic glutamate rece

eceptors: pr precl clinical mod

• dels

Moghaddam et al., Science. 281:1349-52, 1998

• 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

Cl Clinical effects of

• f pom

pomaglumetad (LY21400230)

Downing et al., BMC psychiatry. 14:351, 2014

% Change PANSS Total Subsequent failures to replicate

Week Patil et al., Nat Med. 13:1102-7, 2007 0 1 2 3 4 Week

% Change PANSS Total 80 mg Initial positive result

15 10 5

• 5
• 10
• 15
• 20
• 25

FAST-Fail: : Psychotic c di diso sorders

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)

Pha hase I bi biom

• mark

rker val alidation

JAMA Psychiatry. 75:11-19, 2018

• 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

Design

Magn agnetic reso esonance spe pectroscopy (MRS): Methods

Abdallah et al., Neuropsycho-pharmacology 43: 2154-2160, 2018.

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

Magn agnetic reso esonance spe pectroscopy (MRS): Results

Abdallah et al., Neuropsychopharmacology 43: 2154-2160, 2018.

Mechanism of action

• 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

*

Results

• Significant increase in Glx content at 15 min
• BUT: Moderate effect size (d=.64)
• Not sufficiently robust to be able to detect a

drug effect even if present

Phar harmacoBOLD

Abdallah et al., Neuropsycho-pharmacology 43: 2154-2160, 2018.

Mechanism of action

• Increase in presynaptic glutamate release leads to a

rapid increase in glutamate synthesis from glucose

• The increased metabolic rate leads to an acute increase

in BOLD reponse

Results

• Extremely large effect (d=5.4)
• Sufficient to detect a change, if present

Pha hase 2 stu tudy: 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

Pha hase 2 Pom

• maglumetad stu

tudy: : results

%change dACC peak

High Dose Low Dose Placebo

Treatment Group

• 0.2
• 0.4
• 0.6
• 0.8
• 1.0

dACC pharmacoBOLD

High Dose Low Dose Placebo

Treatment Group

Mean change in BPRS Total

• 1
• 2
• 3

Clinical ratings (BPRS)

d=-.14, p=.52

• vs. placebo

Main effect of treatment: p=.80 Placebo Low-dose High-dose (40 mg BID) (160 mg BID) d=-.33, p=.15

• vs. placebo

Placebo Low-dose High-dose (40 mg BID) (160 mg BID) Main effect of treatment: p=.33

mGluR/3 ag agonist de development in n Sz 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 T2 tr translation: Mismatch ne negativity (MMN)

ERP Biomarker Qualification Consortium

www.erpbiomarkers.org

• 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
• utcome
• 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)

• Avissar et al., Schizophr Res. 191:25-34; 2018

Col Collaborators

Columbia Jeff Lieberman (PI) Josh Kantrowitz Larry Kegeles Jack Grinband Ragy Girgis Melanie Wall Tse Hswei Choo Marlene Carlson Jim Robinson (NKI) Biomarker validation Yale University John Krystal Phil Corlett Graeme Mason Douglas Rothman Maolin Qui UC Davis Cameron Carter

• J. Daniel Ragland

Richard Maddock Costin Tanase Tyler Lesh Pomaglumetad UCLA Steve Marder Junghee Lee Michael Green NYU Don Goff Fernando Boada Erica Diminich UA Birmingham Adrian Lahti David White Mark Bolding MMN Consortium