Synonyms: Ladostigil hemitartrate, TV3326
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Discontinued)
Company: Avraham Pharmaceuticals Ltd
Ladostigil is a multimodal, or multifunctional, (MFC) compound that combines two pharmacophores taken from rivastigmine and rasagiline. This "dirty" drug has been reported to be an inhibitor of the enzymes acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B, and to have neuroprotective and antidepressant effects (Weinreb et al. 2008; Youdim 2013; Bansal and Silakari 2014).
Avraham Pharma developed this compound initially for Alzheimer’s disease but later changed to an indication of mild cognitive impairment (MCI).
In 2011 and 2012, Avraham Pharmaceuticals evaluated a six-month course of escalating doses of up to 80 mg twice daily of ladostigil in a Phase 2 study of 201 people with mild to moderate Alzheimer's disease. Conducted in five European countries, this trial missed its primary endpoint of change on the ADAS-cog11, and development for Alzheimer's disease was terminated (see company press release).
In January 2012, the company started a second Phase 2 study, this time evaluating a lower dose for its ability to delay progression from MCI to AD. Conducted in Austria, Germany, and Israel, this trial enrolled 210 people with a clinical diagnosis of MCI. It compared a three-year course of 10 mg of ladostigil once daily to placebo on the primary outcome of conversion from MCI to AD as determined by a clinical dementia rating (CDR) of 1 or greater. In September 2016, the company disclosed that ladostigil missed its primary endpoint in this trial, as well, but trended in the direction of a treatment benefit. Treatment benefits were reported on MRI and select cognitive tests (see company website). Results were formally published in Neurology (Schneider et al., 2019).
Last Updated: 13 Sep 2019
- Schneider LS, Geffen Y, Rabinowitz J, Thomas RG, Schmidt R, Ropele S, Weinstock M, Ladostigil Study Group. Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial. Neurology. 2019 Oct 8;93(15):e1474-e1484. Epub 2019 Sep 6 PubMed.
- Youdim MB. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp Neurobiol. 2013 Mar;22(1):1-10. PubMed.
- Bansal Y, Silakari O. Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem. 2014 Apr 9;76:31-42. Epub 2014 Jan 31 PubMed.
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