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Minocyline Found to Have a Role in Early MS Treatment

Fitzgerald, Susan

doi: 10.1097/01.NT.0000521713.03202.29
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A new study found that minocycline may slow the progression of multiple sclerosis (MS) in patients who have early signs of the disease, but independent MS experts disagree about the efficacy of the treatment.

Minocycline, an inexpensive decades-old antibiotic, may slow the progression of multiple sclerosis (MS) in patients who have early signs of the disease, according to a randomized, controlled trial reported in the June 1 issue of The New England Journal of Medicine.

The study found that minocycline reduced the risk of conversion from a first demyelinating event, also known as clinically isolated syndrome (CIS), to a diagnosis of MS compared with placebo over six months.

Minocycline, traditionally used to treat severe acne, has been shown in animal and laboratory studies to have anti-inflammatory and neuroprotective effects, and a few smaller human trials suggested it may have a place in MS treatment, either alone or in combination with other drugs. The results from this new trial conducted in Canada created a buzz in the MS community, but opinions vary on whether minocycline is poised to become part of the standard lineup of MS drugs.

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The study, funded by the Multiple Sclerosis Society of Canada and carried out at 12 Canadian MS clinics, was designed to assess whether minocycline reduced the risk of conversion from a first clinical demyelinating event to a diagnosis of MS as defined by the 2005 McDonald criteria, which were in effect when the study began in 2009. Patients were eligible for the study if they had had a single clinically isolated demyelinating event such as optic neuritis or a brainstem, cerebral, cerebellar or myelopathy syndrome within the previous 180 days, and had at least two lesions larger than 3 mm in diameter on T2-weighted magnetic resonance imaging (MRI) of the brain. (One lesion had to be ovoid, periventricular or infratentorial, which is typical of demyelinating disease.)

A total of 142 patients were randomized to 100 mg of minocycline twice daily (72) or placebo (70). The primary endpoint was conversion to MS based on the 2005 McDonald criteria within six months. Secondary outcomes included conversion to MS within 24 months and changes on MRI at six months and 24 months — change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI, and cumulative combined number of unique lesions.

The unadjusted risk of conversion to MS within six months was 33.4 percent in the minocycline group compared to 61 percent in the placebo group. After adjusting for the number of enhancing lesions at baseline, the risk of conversion at six months was 43 percent for minocycline, 61.5 percent for placebo.

“The adjusted risk difference of 18.5 percentage points at 6 months is similar to that with other disease-modifying therapies for multiple sclerosis,” reported the researchers, led by Luanne Metz, MD, section chief of neurology and program leader for multiple sclerosis for the University of Calgary and Alberta Health Services.

Analysis of the data was complicated by the fact that during the trial period the 2005 McDonald criteria for MS were replaced by 2010 criteria, “which would have reclassified some of the participants in this trial as having multiple sclerosis at the initial presentation,” the researchers reported.

Dr. Metz said that minocycline continued to show a positive effect even when that point was taken into consideration. “I would say that whatever way we analyzed the data, we came out with similar results,” she said.

Those who received minocycline were more likely to drop out of the trial and to have side effects including rash, dizziness and teeth discoloration, though Dr. Metz said such side effects “aren't any worse than those found with other therapies and they are not serious.”

Dr. Metz said she believed there is now sufficient Level I evidence to support the use of minocycline in early MS treatment, if only as an interim drug as an MS diagnosis is being sorted out.

She noted that MS drugs can cost over $50,000 annually, as opposed to $500 or so for minocycline. “Most of the people in the world can't afford those drugs,” she said, and minocycline is taken orally, not injected, which is another advantage. “If we look globally, minocycline is an important consideration.”

Dr. Metz said her team is considering whether to do additional clinical testing of minocycline for either CIS or relapsing-remitting MS, but she said it would be unethical to do a placebo-controlled trial since there are proven treatment options for patients.

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Bianca Weinstock-Guttman, MD, professor of neurology at the State University of New York University at Buffalo and director of the Jacobs MS Center for Treatment and Research, said that while the study on minocycline was interesting, it was “difficult to imagine this would go further” and become a routine part of clinical care. A larger, longer-term study would be needed to further assess the drug's effectiveness for MS, she said, and even then, patients and clinicians would be prone to wanting newer MS drugs.

For now, “you really can't go and recommend this to patients,” Dr. Weinstock-Guttman told Neurology Today.

On the other hand, Amit Bar-Or, MD, FRCPC, professor of neurology, director of the Center for Neuroinflammation and chief of the multiple sclerosis division at the University of Pennsylvania Perelman School of Medicine, said the study is important and “provides a rationale for pursuing minocycline as a potential therapy for MS.”

He said the oral antibiotic is “generally safe and well-tolerated and is also quite inexpensive compared to the existing MS medications.”

Dr. Bar-Or said the minocycline study was a nice example of translational medicine – taking laboratory and animal research findings and testing them in the clinical setting. He also complimented the MS Society of Canada for sponsoring the study, an important step because the pharmaceutical industry is typically less attracted to “a molecule that will not be sold under patent for a higher price.”

Dr. Weinstock-Guttman noted, however, that the exact mechanisms by which minocycline may impact MS are not fully understood, but it is known that the drug can penetrate the blood-brain barrier and research in animal models supports that it has anti-inflammatory, neuroprotective effects. The neuroprotective effect may be related to anti-apoptotic properties and inhibitory activity on microglia, she said. The drug may also help in MS by preventing T-cell migration into the central nervous system, she added.

She said the latest results from Canada still leave many clinical questions unanswered about the potential role of minocycline in MS therapy, including whether the drug in the long run can reduce disease activity and limit disability.

The study, whose enrollment stretched from 2009 to 2013 due to some enrollment difficulties, was in some ways overtaken by advances in MS drug therapy and a growing tendency in MS practice to begin treatment at the earliest possible signs of disease.

A study published last year with 11 years of follow-up found an advantage to starting treatment with interferon beta 1-b at the time of CIS diagnosis instead of waiting until a patient converted to MS. The study did not look at other MS drugs. The dilemma for clinicians is that it's not necessarily easy to predict which patients with will go on to MS, though over two-thirds of people do over a period of eight to ten years.

Emmanuelle Waubant, MD, PhD, FAAN, professor of neurology at the University of California, San Francisco and the Race to Erase MS medical director, said she thought the Canadian results were partially muddled by the fact that “the placebo group had more active disease at the beginning, which means they were more likely to convert to MS than the minocycline group.”

Dr. Waubant said that at least six new MS drugs have come on the market since the study was launched, all with higher effectiveness and tested over longer periods of time in larger studies. Given that patients now have many options, the likelihood of minocycline becoming commonly used for MS is “close to nil,” Dr. Waubant said. “However, having this proof-of-concept study may help develop new treatment strategies.”

In addition to more therapy options, the criteria for diagnosing CIS and MS also continue to evolve, with new revised McDonald criteria in the works, she said.

“The landscape is constantly changing, and that is a challenge when you conduct clinical trials,” Dr. Waubant said.

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•. Metz LM, Li DKB, Traboulsee AL, et alfor the Minocycline in MS Study Team. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis http:// N Engl J Med 2017;376:2122–2133.
© 2017 American Academy of Neurology