Download A positive allosteric modulator (PAM)

A positive allosteric modulator (PAM)
of the metabotropic glutamate receptor 2 (GluR2)
Licensing opportunity
Positive Allosteric Modulator (PAM) of the metabotropic Glutamate receptor 2 (mGluR2)
compound key points:
Therapeutic Areas: Schizophrenia (SZ), Cognitive impairment associated with SZ (CIAS)
and/or Alzheimer ’s disease.
● Mechanism of Action: Potent and selective PAM of mGluR2, reducing excessive
glutamatergic transmission, which is characteristic of a pathophysiological state.
● Planned indications: Improvement of CIAS and reduction of positive symptoms of
schizophrenia.
● Patent protection: US/EU/JP until September 2030 (not including 5-year extension)
● Route of administration: Oral
● Development Phase: Preclinical
1. RATIONALE AND BACKGROUND
Cognitive impairment is a core feature of schizophrenia (SZ) not addressed by current
medications. It contributes significantly to the residual disability burden of the disease. These
deficits are broad, involving nearly all aspects of cognition, including attention deficit,
executive dysfunction, impairment of working and episodic memory and inability to filter
pertinent information.
It is now widely accepted that the mechanisms underlying schizophrenia involve
dysfunctions of two main neurotransmitter systems: dopamine and glutamate. All marketed
antipsychotics block dopamine receptors, with the D2 receptor playing a major role in the
alleviation of psychotic symptoms. However, D2 blockers do not improve the cognitive
deficits associated with schizophrenia and are generally associated with various side-effects
including sedation, extrapyramidal symptoms (impairment of control of movements),
hormonal side effects such as hyperprolactinemia, and weight gain. Recent research has
highlighted new targets for drug development based on mechanisms leading to glutamate
system dysfunction. Normalizing excess glutamate levels by metabotropic glutamate group
2/3 receptor (mGluR2/3) agonists has led to potential identification of the first nonmonoaminergic target with efficacy comparable to that of conventional antipsychotic drugs
for treating positive and negative symptoms of SZ. In addition, intrinsic modulatory sites such
as positive allosteric modulation (PAM) of the mGluR2 provide a novel way to regulate
glutamatergic function, being active targets for both symptoms of SZ and cognition. To date,
most studies have used pure agonists (orthosteric) at specific sites. However, PAMs of
mGluR2 may constitute an emerging class of orally therapeutic agents and expect to have
competitive advantages over orthosteric drugs:
 They only enhance the function of receptors activated by the agonist at the same time,
effects which are therefore dependant of the pathophysiological state and which are
devoid of activity in absence of endogenous ligands.
 This approach confers a greater selectivity and better glutamate modulatory control at
disease mediating receptors. Thus, this mechanism may offer a clinical advantage to
maximize therapeutic activity while limiting undesirable side-effects or toxicity.
 The possibility to combine PAMs with orthosteric classical drugs could be used to
potentiate an orthosteric agonist therapeutic effect
Studies in animals have shown that mGluR2 agonists are able to improve cognitive
impairment produced by psychotomimetics, and are active in several models related to the
positive symptoms of schizophrenia. These findings are now substantiated by studies in
healthy volunteers, which demonstrated that mGlu2/3 receptor agonists can reduce the
impairment in cognitive functions following the administration of ketamine (Krystal et al,
2005, Psychopharmacology 179: 303–309.). More recently, the first clinical trials published
in Nature Medicine confirmed expectations that mGluR2/3 agonists possess clinically
significant antipsychotic efficacy for treating negative and positive symptoms without the
metabolic and motor-related side-effects generally associated with antipsychotic drug (Patil
ST, Zhang L et al (2007), Nat Med 13: 1102–1107).
2. MARKET
Schizophrenia is a chronic progressive highly disabling and distressing psychiatric disease.
The prevalence of schizophrenia is estimated at 1.2% of the European population (Eur.
Neuropsychopharmacology (2011), 21, 655-679). The market is large and fiercely
competitive. Estimates of the costs to society from schizophrenia run at approximately $65
billion per year in the United States. Worldwide sales in top 7 countries + emerging countries
run at 6.5 B€. However, the high continued cost to society, despite the success of marketed
products, indicates that some of the most important symptoms of schizophrenia, such as
cognitive impairment, are poorly addressed by marketed drugs. Cognitive impairment in
schizophrenia patients is a key unmet medical need, which has been recognized by the FDA
and EMEA authorities.
3. COMPOUND PROFILE
The compound is a new chemical entity acting as a potent and selective PAM of the mGluR2,
showing selectivity over a large panel of other CNS targets (receptors, ion channels,
transporters and enzymes), in particular dopamine, serotonin and GABA receptors.
In pre-clinical pharmacology studies the compound is orally effective in a variety of models
related to the cognitive and positive symptoms of schizophrenia in rodents. The results of
these experiments are summarized in Table1.
Table1: Summary of effects in models of the cognitive and positive symptoms of
schizophreniaa.
Model
Species
Symptoms
Outcome
DOI-induced headtwich
Mouse, rat
active
Amphetamine –
induced Hyperactivity
MK-801-disrupted
novel object
recognition
Y-maze –induced
deficit
Mouse
Hallucinogenic-like
model of positive
symptoms
Positive symptom
Visual episodic
memory deficit
active
Amphetamine- induced
auditory evoked
potential gating deficit
Amphetamine- induced
Latent Inhibition
dysfunction
Drug-induced
catalepsy
a
Mouse
inactive
Transgenic mice with Working memory
glutamate transmission deficit
deficit
Rat
Sensory gating
active
Rat
Selective attention
deficit
active
Mouse
Extrapyramidal sideeffects
inactive
active
from data published in: Society for Neuroscience, 2010 San Diego Meeting, P767.1, P767.6, P767.7
The results of these studies showed that the compound was able to improve the cognitive
deficits induced either pharmacologically or naturally observed in a transgenic mouse line.
Moreover, the drug was active in a mouse model relating to certain aspects of hallucinations
observed in schizophrenic patients. Importantly, the compound was devoid of the classical
side-effects observed with antipsychotics, such as sedation or catalepsy. Together, these
findings suggest that the drug may be effective as a monotherapy in schizophrenia (cognitive
and positive symptoms).
4. PRELIMINARY SAFETY AND PHARMACOKINETIC PROFILE
No major issues are anticipated for the compound at preclinical (toxicology and
pharmacokinetic studies) stages. It demonstrated a good preliminary safety profile based on
the following standard non-clinical safety program:
o Genotoxicity : Ames test, in-vitro micronucleus test in mouse lymphoma L5178Y cells
o Frog Embryo: Teratogenesis Assay on Xenopus laevis eggs (FETAX)
o Safety pharmacology : no haemodynamic or electrophysiological effects on;
- hERG channel; Nav1.5 channel ( IC50 > 30µM)
- Ex-vivo CV/haemodynanic studies in isolated guinea pig heart model, and isolated guineapig papillary muscle model
- In vivo CV studies in conscious rats, anaesthetized dogs, and conscious monkeys (iv route)
o Exploratory oral 7-day toxicity study in rats( no findings up to 300 mg/kg/d)
It shows a suitable pharmacokinetic profile for the proposed indication with limited
risk for CYP (3A4, 2D6, and 2C9) competitive inhibition and related drug-drug
interactions, when tested in human hepatic microsomal fraction.
5. VALUE PROPOSITION
The main added therapeutic value of the compound, compared to currently used
antipsychotics, is that it targets a core symptom of schizophrenia, i.e. cognitive deficit.
Moreover, the compound provides an innovative therapeutic solution independent of the
dopamine system, offering efficacy and safety while avoiding the side-effects associated with
dopaminergic therapeutics.
6. CONTACTS
Guy Claude
Anne Marie SIGOT
Vice President Out-Licensing &Special Projects
Senior Manager Out-licensing and Special Projects
Strategy & Business Development
Strategy & Business Development
Corporate Licenses
Corporate Licenses
[email protected]
[email protected]