In a second Phase 2 strikeout, the small-molecule drug ladostigil missed its primary endpoint of curbing progression from mild cognitive impairment to AD, though people on a low-dose regimen did have less brain shrinkage over three years than those on placebo. First announced by Avraham Pharmaceuticals of Yavneh, Israel, in 2016, the trial results were formally published September 6 in Neurology.
- Low-dose ladostigil did not significantly affect progression from MCI to dementia.
- The treatment group had less brain shrinkage than the placebo group.
- Ladostigil seemed well-tolerated.
Ladostigil inhibits both monoamine oxidase (MAO) and acetylcholinesterase. Based on the premise that this would boost cholinergic transmission, ladostigil was tested in 200 people with mild to moderate AD, but 80 mg of the drug twice daily for one year did not slow cognitive decline (see clinicaltrials.gov).
At 20-fold lower doses, ladostigil reportedly bolsters mitochondria against oxidative stress and stifles proinflammatory cytokine release from microglia (Maruyama et al., 2003; Panarsky et al., 2012). Middle-aged rats treated with a low dose of the drug—on par with a 10 mg daily dose in people—had less age-related memory loss over six months (Weinstock et al., 2013). These low-dose effects formed the basis of the next Phase 2.
Run by the Ladostigil Study Group, the trial enrolled 99 and 103 participants who received 10 mg daily ladostigil or placebo, respectively, for three years. They came from 16 clinics in Austria, Germany, and Israel, and ranged from 55 to 85 years of age. All met clinical criteria for MCI, but were not tested for AD biomarkers. They underwent cognitive testing at eight visits throughout the study period. A third of participants from each group withdrew from the study early, without developing dementia.
Over three years, 21 participants in the placebo group progressed to dementia, compared with 14 in the ladostigil group. The difference was not significant. In a planned exploratory analysis, the researchers found that among ApoE4 noncarriers, 18 percent in the placebo group developed dementia, compared with 8 percent in the treatment group. About a quarter of ApoE4 carriers converted to dementia regardless of treatment group.
No significant differences emerged on secondary or exploratory outcomes of cognition. However, people in the ladostigil group had significantly less whole-brain and hippocampal volume loss than those in the placebo group. What this means is unclear.
The ladostigil group had slightly more adverse events in total than the placebo group, while the placebo group had slightly more serious adverse events than the ladostigil group. The researchers deemed the drug safe and well-tolerated.—Jessica Shugart
- Maruyama W, Weinstock M, Youdim MB, Nagai M, Naoi M. Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci Lett. 2003 May 8;341(3):233-6. PubMed.
- Panarsky R, Luques L, Weinstock M. Anti-inflammatory effects of ladostigil and its metabolites in aged rat brain and in microglial cells. J Neuroimmune Pharmacol. 2012 Jun;7(2):488-98. PubMed.
- Weinstock M, Bejar C, Schorer-Apelbaum D, Panarsky R, Luques L, Shoham S. Dose-dependent effects of ladostigil on microglial activation and cognition in aged rats. J Neuroimmune Pharmacol. 2013 Mar;8(1):345-55. Epub 2013 Jan 17 PubMed.
No Available Further Reading
- 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.