NR Times speaks to UCLA researcher Dr Kevin Patel about the potential of metformin in MS care and an upcoming human trial assessing its efficacy.
Metformin is a well-understood medicine. Derived from the French lilac flower, the compound has been known for over a century and was first used to treat type 2 diabetes in the early 1990s.
More recently, interest in the drug has been growing in the scientific community for its potential to treat neurological conditions, notably multiple sclerosis (MS).
While there are over 20 medications on the market for relapsing remitting MS (RRMS), there are far fewer options for people suffering from progressive MS.
RRMS is characterised by inflammatory attacks that cause symptoms to worsen followed by a period of recovery, or remission, in which symptoms improve.
Progressive MS, on the other hand, is caused by a gradual worsening of symptoms over time without remission.
Dr Kevin Patel, an MS specialist and assistant professor at UCLA, told NR Times: “We have fantastic treatments that can stop those relapses from occurring, but there’s a second way in which MS causes problems; that’s called disease progression.
“When folks have disease progression they don’t have a sudden onset problem, they don’t wake up and notice that something is different.
“They don’t notice something is different over the course of a week, a month or several months, but they have this very, very gradual worsening.
“Existing treatments for progressive MS are not only less numerous, they are also shown to be less effective. Ocrelizumab is the first approved drug to work against primary progressive MS, but its effect is still only classed as ‘moderate’ with one trial finding that progression was slowed down by 25 percent compared to placebo.
“If you look at disability for multiple sclerosis over the course of a lifetime, progressive MS is the thing that really causes folks to experience significant disability,” Dr Patel said.
“It causes real walking disability, it causes people to become wheelchair dependent or become bed-bound over time.
“Our current treatments just don’t have very much efficacy as far as that’s concerned […] metformin has the real potential to take a bite out of that problem which just isn’t being addressed.”
Symptoms of progressive multiple sclerosis are caused by the stripping away of the insulating layer of nerve fibres known as myelin. If myelin can be repaired, the progression of the disease could be slowed significantly.
Early research involving lab and animal models have shown promise for metformin as a new treatment. According to one study, metformin has been found to rejuvenate the remyelinating capacity of oligodendrocytes, the name given to cells that support neurons in the brain.
Another study showed that metformin had the ability to down-regulate a range of cytokines, pro-inflammatory signalling molecules that aid the body’s immune and inflammation responses. Further, it’s been shown in lab models, that metformin restricts the inflammatory cell, microglia from entering the space around the brain.
One major theory claims that the inflammation that causes progressive MS is completely separate from the immune problems that cause relapse episodes.
Existing treatments address the inflammation associated with inflammatory episodes, but metformin may offer something new by targeting the microglia that are thought to play a greater role in the progressive elements of the disease.
With a growing body of evidence behind it, researchers at UCLA are preparing a first-of-its-kind clinical trial examining whether metformin affects disease progression. Other human trials that are currently running
Dr Patel, the principal investigator in the trial said: “There’s a lot of suspicions these days that [microglia] may be involved in progressive MS, which we historically have not been able to make any headway into treating.
“The hope is that by reducing this microglial, mononuclear activation, we might be able to help these folks that have this progressive disease. It’s been tried in animal models of multiple sclerosis, and it’s been shown to help in mice. We’re moving forward with trialling this in humans.”
This study is among the first to test metformin as an MS treatment in humans. A previous small study looked at metformin and pioglitazone – another diabetes treatment – in an obese MS population examining whether these treatments may reduce MS relapses.
Meanwhile, there are two ongoing studies examining whether metformin may help in remyelination after relapses. One involves a pediatric population while the other is looking at the efficacy of metformin used in combination with an antihistamine.
More broadly, metformin has been shown to have anti-ageing properties and neuroprotective capacity, which has made it an area of interest for treating other neurological conditions such as Alzheimer’s and Huntington’s disease.
Retrospective studies have suggested that for type 2 diabetes patients, metformin not only improves their condition but also produces better cognitive outcomes.
“In folks that have diabetes, they can develop small vessel disease and they can develop problems related to thinking from small vessel disease,” Dr PAtel explained.
“There’s an entity called vascular dementia that often develops in folks that have high cholesterol or high blood pressure and diabetes.
“There is this thought that Metformin may be helping in those patients because of that, but that’s not a settled mechanism. There are other [people] that feel as though there may be some effect that’s occurring that is preventing folks from developing neurodegenerative diseases, like Alzheimer’s and other types of neurodegenerative problems that develop in later age.”
The UCLA trial is underway with patients currently being screened and a number of participants already enrolled, taking either placebo or Metformin.
Around 44 participants will be on treatment for 12 months and will be seen on a regular basis for imaging and MRI tests, cognitive testing and blood testing.
“We’re doing a wide range of studies and following patients as they move forward through this process,” Dr Patel said.
“In addition to being able to do state-of-the-art MRI work with these patients, we’re also doing a large cognitive battery [tests] in these patients.
“We’re doing very specialised bloodwork with our collaborators that are looking at particular investigational blood markers, which are indicative of neurodegeneration.”
The study is funded by Race to Erase MS, a nonprofit dedicated to the treatment and ultimate cure of multiple sclerosis.
Its Center Without Walls program includes renowned scientists in neurology, including Yale, UCLA, Harvard and Cedars-Sinai who are leading research to find a cure for MS.
The organisation has raised over US$50 million for MS research and has helped bring over 20 FDA-approved therapies to the market.
“It’s largely because of the support that we have from the Race to Erase MS that we’re able to push forward with this sort of work,” Dr Patel said.
It will be another two to three years before the results of the trial are published. Depending on the outcome, a larger trial is expected to follow testing the efficacy of the drug on a wider cohort.
For Dr Patel, it is an “incredibly exciting time” to be working in the MS research space.
“If you look at where we were 20 years ago, we had these treatments that barely had any effect on multiple sclerosis,” he said.
“Over the course of the last 15 to 20 years, there have been a wide array of new agents developed that essentially can stop this inflammatory component from occurring.
“I’m very optimistic about our ability to develop treatments for [progressive MS],” he added.
“Even though the problem right now seems rather hard to solve, the problem of relapsing remitting MS seemed hard to fix 20 years ago and we’ve made so much in the way of gains as far as that’s concerned.
“I think that we have reason to be really optimistic with regards to this as well.”
