Background

Sembragiline is an inhibitor of monoamine oxidase B (MAOB), a mitochondrial enzyme that inactivates the neurotransmitter dopamine, and in the process generates reactive free oxygen radicals. MAOB expression is increased in Alzheimer's brain, particularly in reactive astrocytes near amyloid plaques (Saura et al., 1994; Gulyas et al., 2011).

RG1577 was developed by Roche but first licensed to Evotech AG, which began developing it as EVT302 for the treatment of nicotine dependence. That development was discontinued in Phase 2 (see Berlin et al., 2012).

Evotech AG claimed on its website that EVT302 was safer and more tolerable than other MAOB inhibitors marketed for the treatment of Parkinson's disease (see company press release). The compound was reported to be more selective for MAOB over MAOA, a related enzyme that helps metabolize tyramine, a component of certain foods and beverages. For a review on MAO inhibitors, see Finberg, 2014. 

Roche and Evotech partner in the development of EVT302/RG1577 for Alzheimer's disease, both to reduce oxidative stress in the brain and to treat dopamine-related symptoms in AD. Roche scientists reported that the compound in enzyme assays is 500-fold selective for human MAOB over MAOA, dose-dependently inhibits MAOB in rat brain at low doses, does not elevate blood pressure in the presence of tyramine, and reduces H2O2 production near amyloid deposits in AD brain sections (Borroni et al., 2013).

Findings

Between 2012 and 2014, Roche conducted four Phase 1 trials of RG1577 in Sweden, the Netherlands, and the United States. One assessed pharmacokinetics and elimination of the compound in six healthy men; one assessed its effect on the liver enzyme complex P450 with a probe compound, the antifungal ketoconazole, in 34 healthy men; and one measured target engagement of a multiple-dose regimen in the brain with a PET tracer in 17 healthy elderly men. The largest Phase 1 trial enrolled 183 healthy men and women in the United States; it is a two-part study to probe the safety of RG1577 at doses higher than the therapeutic dose and assess whether the compound affects cardiac function. In July 2014, the Japanese company Chugai was also testing this compound in Phase 1 (see pipeline).

In 2012, Roche began the MAyflOwer RoAD study. This is a Phase 2 trial to evaluate the safety and efficacy of RG1577 as an adjunct to cholinesterase inhibitor and/or memantine therapy. The trial enrolled 544 patients with moderate to severe Alzheimer's disease at 141 sites in North America, Australia, South Korea, and Europe. Participants received one of two doses of RG1577 or placebo for one year and were assessed on change in the ADAS-Cog-11, ADCS-ADL, and global and behavioral measures. In summer 2015, Roche announced that sembragiline, while safe, fell short of its primary endpoint in this trial (see July 2015 news) and, in October, removed it from its development pipeline. At CTAD in November, data were presented to indicate a possible benefit on behavioral symptoms in a more severely affected subpopulation. 

For all clinical trials of this compound, see clinicaltrials.gov.