Name:	EHT 0202
Other Names:	Etazolate
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral, small molecule
Mechanisms:	Stimulates the neurotrophic α-secretase (non-amyloidogenic) pathway and inhibits β-amyloid induced-neuronal death.
Development Status:	investigational outside U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	Inhibitor of cyclic 3'5-nucleotide phosphodiesterase and subtype-selective GABAA receptor modulator. Stimulates the neurotrophic α-secretase (non-amyloidogenic) pathway and inhibits β-amyloid-induced neuronal death. May ultimately reduce amyloid plaques.
Role in Alzheimer's Disease:	EHT 0202 redirects APP processing toward the non-amyloidogenic pathway, providing symptomatic relief and modifying disease progression. In vitro, EHT 0202 (0.2-2 μM) is neuroprotective against Aβ42 and associated stresses in a GABAA-dependent manner, and neuroprotection is associated with sAPPα induction (Marcade et al., 2008). EHT 0202 demonstrated procognitive properties in various rodent preclinical models. In humans, blood exposure is fully relevant to preclinical efficacy models. EHT 0202 also showed efficacy in a scopolamine Phase 1 study in healthy volunteers. A Phase 2A study is currently ongoing to assess EHT 0202 safety, tolerability, and preliminary efficacy on cognition and behavior in AD patients, as well as quantification of sAPPα in blood.
Pharmacological Role:	EHT 0202 modulates GABAA receptors and weakly inhibits PDE4. GABAA receptors regulate LTP in hippocampus. APP processing and sAPPα production is controlled by neuronal electrical activity, agents that induce LTP. In turn, sAPPα stimulates LTP in hippocampus. EHT 0202 regulates α-secretase pathway, stimulating sAPPα production. EHT 0202 is neuroprotective in a GABAA-dependent manner.
Side Effects:	Phase 1 clinical studies established that EHT 0202 is a well-tolerated drug. Overall tolerability was good up to 60 mg bid, with no emetic or sedative effect in 8-day repeated doses. Dosing in elderly volunteers had minor adverse effects: “feeling abnormal” (2/9), balance disorder (1/9) with no dropout of either young or elderly volunteers in repeated dose groups prior to completion of dosing regimen.
Evidence pro its efficacy:	In Phase 1 clinical study, cognitive improvement in scopolamine-induced memory loss was observed at 80 mg dose (p <0.04) at all times post-dose. Maximum effect of EHT 0202 80 mg occurred at 4h15 post-dose and was associated with the ability to restore working memory function, while deleterious effect of scopolamine reached its peak (p <0.02). Working memory was assessed by the analysis of P300 peak amplitude in EEG.
Companies:	ExonHit Therapeutics
Notes:	A Phase 2A study is currently ongoing to assess EHT 0202 safety, tolerability, and preliminary efficacy on cognition and behavior in AD patients, as well as quantification of sAPPα in blood. This multicenter study is currently taking place in France, and is registered in the EudraCT clinical trial database (EudraCT number : 2007-005549-39). Enrollment is complete for this study. Study results will be communicated in Q4 2009. This record was entered March 31, 2009.

References

Pando M, Marcade M, Peillon H, Rayer A, Drouin D, Desire L. An alpha-secretase stimulator drug for cognitive disorders associated with neurodegeneration. Presented at the 12th congress of the European Federation of Neurological Societies; 23-26 August, 2008; Madrid, Spain.

Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer A, Drouin D, Schweighoffer F, Désiré L. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem. 2008 Jul;106(1):392-404. Abstract