Repurposed drugs fail to slow disease progression in ALS trial
Memantine, tradozone groups pulled from platform trial
Neither memantine nor trazodone, two medications approved to treat other conditions, was able to slow disease progression in people with amyotrophic lateral sclerosis (ALS) who took part in a platform clinical trial, a study concluded.
Based on the lack of benefits in the trial’s interim analysis, the two treatment groups have been discontinued. The trial has since added a third treatment arm to test another investigational therapy, amantadine.
The study, “Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial,” was published in The Lancet Neurology.
ALS, often called motor neuron disease in the U.K., is a neurological disorder marked by symptoms such as muscle weakness and wasting. Although a few treatments are already approved to slow ALS progression, their efficacy is limited.
Memantine, sold under the brand name Namenda and others, is a drug approved to treat some types of dementia. Trazodone, available as generics only, is a type of antidepressant used in the management of certain mental health conditions.
Disease progression main focus for treatment pair
A platform clinical trial called MND-SMART (NCT04302870) was launched in 2020 to test if certain medicines might be repurposed to slow the progression of ALS. Repurposing medicines that are already approved for other conditions, and therefore have well-established safety profiles, is generally faster than bringing a brand-new therapy to approval.
The trial was designed to test multiple drugs at the same time and compare them with a shared placebo group, with the aim of accelerating the development of new therapies for ALS while also cutting costs. If an included treatment fails to show benefits in people with ALS, that treatment arm can be dropped, and new medicines can be added at any time if they show promise.
Memantine and trazodone were the first two medications selected for inclusion into MND-SMART. The present analysis covered data from 530 participants who participated in those two treatment arms or were given placebo.
The study’s main goal was to assess whether either of the two therapies slowed the progression of ALS, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R). Results showed, however, that neither medication significantly slowed disease progression compared with a placebo. After a year of treatment, average scores worsened by 0.65 points per month with memantine, 0.625 with trazodone, and 0.655 with a placebo.
Survival rates also showed no significant difference between patients given memantine, trazodone, or a placebo. Safety issues judged to be possibly related to treatment were reported in half of the patients given trazodone and about one-third of those given memantine or a placebo.
“The findings of this prespecified interim analysis from the MND SMART trial showed that both memantine and trazodone had little or no effect on the primary outcome of rate of change in the ALSFRS-R at the doses evaluated, compared with placebo,” the researchers wrote. “Additionally, there was no evidence of a survival difference between these intervention groups and placebo.”
Based on the negative findings, the MND-SMART trial has stopped testing the two therapies.
Although the results were disappointing, the researchers said that getting conclusive results 3.5 years after the trial launched, even with interruptions due to the pandemic, is itself a noteworthy achievement.
This was only possible, they said, due to the platform design of the trial that allowed testing of multiple therapies simultaneously. If each drug had been tested in its own trial, the researchers said, it would probably have taken about eight years to get the same results.
“Importantly, this trial was powered to be definitive and, therefore, unlike many other underpowered trials in motor neuron disease, means that neither of these drugs needs be tested again in motor neuron disease at the doses evaluated,” the team concluded.
About the Author
