Synonyms: EVP 0015962
Therapy Type: Small Molecule
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Phase 2), Mild Cognitive Impairment (Phase 2)
Company: FORUM Pharmaceuticals Inc. (was EnVivo Pharmaceuticals)
EVP-0962 is a γ-secretase modulator. The rationale behind this approach is that γ-secretase modulators affect the enzyme complex differently than inhibitors: They shift its processive cleavage mechanism away from generating Aβ42 and other long forms of this peptide and toward generation of Aβ38 and other short forms of Aβ. Gamma-secretase modulators are designed to selectively reduce the amount of Aβ42 while letting cleavage of the Notch substrate proceed unimpeded. Aβ42 is the most aggregation-prone form of the peptide and lies upstream of the amyloid cascade. Inhibition of Notch cleavage is thought to have been largely responsible for the toxic side effects on the skin, immune, and gastrointestinal systems that occurred with γ-secretase inhibitors. In addition, γ-secretase inhibition does not affect the total amount of Aβ in the brain.
EVP-0962 is an NSAID derivative without activity on the classic NSAID targets Cox 1 or 2. In preclinical studies, EVP-0962 was reported to decrease Aβ42, increase Aβ38, but leave the total Aβ load or Notch processing unchanged in four different cell types. In the brains of wild-type and Tg2576 mouse models of Alzheimer’s amyloidosis, it reduced Aβ42, neuroinflammation measured as astrocyte and microglial activation, and plaque load in the hippocampus. EVP-0962 reversed memory deficits in contextual fear-conditioning tests. All effects were reported to be dose-dependent (see Apr 2011 conference story; Rogers et al., 2012).
In 2011, FORUM Pharmaceuticals Inc. (formerly called EnVivo Pharmaceuticals), ran an ascending single- and multiple-dose Phase 1 study to assess safety, tolerability, pharmacology, and food effect of EVP-0962 in healthy volunteers (see company press release).
In November 2012, FORUM Pharmaceuticals started a single-center Phase 2 study in 52 participants. This is a two-part study. The first part evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating EVP-0962 doses of 10, 50, 100, and 200 mg taken once daily for two weeks in healthy participants. The data from this part of this trial will serve to select one or several doses for part two. It will evaluate the same parameters following once-daily administration for two weeks in patients with mild cognitive impairment due to AD as defined in the NIA-AA proposed criteria. Adverse events are a primary outcome of this study, as are the rate of synthesis and concentration of CSF Aβ in response to EVP-0962 monitored for 36 hours after dosing.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|FORUM Pharmaceuticals Inc. (was EnVivo Pharmaceuticals)||NCT01661673||
Research Models Citations
- Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F, Lee W, Hopp S, Miller MJ, Spaulding D, Yang Z, Hodgdon H, Nolan S, Wen M, Costa D, Blain JF, Freeman E, De Strooper B, Vulsteke V, Scrocchi L, Zetterberg H, Portelius E, Hutter-Paier B, Havas D, Ahlijanian M, Flood D, Leventhal L, Shapiro G, Patzke H, Chesworth R, Koenig G. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol Neurodegener. 2012;7:61. PubMed.
No Available Further Reading