Dr. Ganesh presents the fascinating story of how a powerful "bench-to-bedside" research collaboration in Calgary led to an affordable new treatment for patients at risk of developing multiple sclerosis.
I’m sitting with Mia*, a 22-year-old college student, reviewing the results of her brain scan. She recently experienced a terrifying episode where she lost the vision in her right eye over a few days followed by a gradual recovery over a few weeks.
Her brain scan showed spots in a couple of locations typically associated with multiple sclerosis (MS) – an autoimmune disease of the central nervous system that attacks the protective covering of the nerves (myelin) and disrupts the transmission of nerve impulses (known as “demyelination”).
Over time, most patients with MS can experience additional attacks affecting different parts of the central nervous system, followed by a gradual progression of their disability. Fortunately, Mia doesn’t have MS yet.
She has had a single attack affecting the nerve in her eye (optic neuritis) and her brain shows a few spots but as of now, there isn’t clear evidence of previous attacks or additional lesions building up over time. So she has what we call a Clinically Isolated Syndrome (CIS).
But unfortunately, patients like her have a high risk of developing MS – over 60 per cent experience a second attack or develop additional lesions within 6 months, and over 80 per cent do so within 2 years.
So of course, Mia is frustrated: “You’re saying I don’t have MS right now, but I could get it later? What can I do about it?”
Patients diagnosed with CIS often feel like they have the sword of Damocles dangling over their heads, knowing that they are at risk for developing MS but feeling powerless to influence the outcome.
Over the last decade, a few different drug options have been tested to try and prevent or delay the onset of MS in patients with CIS, including drugs approved for the treatment of MS like interferons, glatiramer acetate, and teriflunomide, as well as other drugs like the chemotherapy agent cladribine.
Although these have been found to delay the conversion from CIS to MS, they haven’t been widely used, largely due to the challenge of justifying cost and safety concerns against the uncertainty of long-term benefit.
In Canada, such medications would cost about $20,000-40,000 a year. Now, thanks to the efforts of a remarkable collaboration between clinicians and scientists in Calgary, patients with CIS can get the same shot at delaying MS for just about $600/year and minimal side effects.
Calgary’s “Bench-to-Bedside” Collaboration for MS Research
The story begins back in the late 1990s when Dr. V. Wee Yong (Professor at the Hotchkiss Brain Institute and Departments of Clinical Neurosciences and Oncology, Canada Research Chair in Neuroimmunology) moved to the Cumming School of Medicine in Calgary to set up his research laboratory, and started collaborating with Dr. Luanne Metz (Professor and Head of Division of Neurology), a neurologist passionate about MS care. Their collaboration was based on the crucial insight that great progress in the treatment of neurological diseases can be achieved by using laboratory discoveries (at the “bench”) to inform the development and eventual testing of therapies in patients (at the “bedside”)
What Dr. Yong brought to the table was a strong understanding of the cellular and molecular mechanisms behind the development of MS, and of how different therapies might work at this level. He was initially studying how interferons (which were already being used in MS patients) actually work at the molecular level.
He found that one of the ways they work is by inhibiting proteins called matrix metalloproteases (specifically MMP-9), which break down the blood-brain barrier (BBB) and allow inflammatory cells to cross over into the brain, propagating the autoimmune attack on the nervous system that partly drives MS. To further study this process, the Yong lab developed an in vitro (“test-tube”) model of the BBB that they could use to assess the ability of different agents to protect or harm the BBB.
On searching the medical literature to find other agents that could also inhibit MMP-9, they happened to come across an old paper on minocycline, reporting that it could do just that. Minocycline is an old, cheap antibiotic that has been used for many years for the treatment of acne. The possibility that it could have a meaningful effect in MS was exciting.
The team proceeded to test minocycline in their in-vitro model of the BBB, and then in a mouse model of MS, where they found that the drug indeed decreased both the severity of the animals’ symptoms as well as the inflammation and damage to their brains. They were further encouraged by the finding that minocycline also reduced nervous tissue damage and promoted recovery after spinal cord injury in mice. This initial work – back in 2002 – was supported by pilot funding from the MS Society, and the encouraging findings led to a team grant from the Canadian Institute for Health Research to further study the drug in patients with MS.
This is where Dr. Metz’s clinical expertise in MS directly came into play.
In 2004, the team published the results of a trial of minocycline (given for six months) in 10 patients with relapsing-remitting MS (RRMS), evaluating the safety of the drug and its effect on MRI markers of the disease. They found that minocycline reduced the number of active MRI lesions.
On returning to the lab with serum samples from these patients, they observed that the clinical response to minocycline was accompanied by beneficial immune changes and specifically that MMP-9, the enzyme they hoped to inhibit, had very little activity during minocycline treatment, further supporting a favourable treatment effect. The team continued the evaluation of minocycline in these 10 RRMS patients for three years and found that the drug was well-tolerated over this longer duration and potentially beneficial, with the number of brain lesions and brain volume remaining stable in these patients.
Meanwhile, Dr Yong’s team showed that combining minocycline with glatiramer acetate (an approved MS drug) was beneficial in mice. In 2009, Dr. Metz and the team examined the effect of adding minocycline (versus placebo) to 42 patients with RRMS who were starting treatment with glatiramer acetate, and found that patients on the combination treatment tended to develop fewer new MS lesions on MRI and had fewer relapses.
All these findings taken together raised an exciting possibility: If minocycline could reduce the disease activity in patients who already had MS, could it delay the onset of MS in patients with CIS?
What’s quite apparent from this story is the non-linear track that the team took getting from where their collaboration started to where they ended up. They set out trying to understand the mechanisms of MS and responses to existing therapies and searched widely for different treatment options to target these mechanisms, before honing in on minocycline.
This is a fundamental fact of medical science that policy-makers can fail to appreciate. We won’t find new therapies if we just keep looking in the same tried-and-tested places without a freedom to roam and to broaden our understanding of the diseases we’re trying to tackle. Searching for new therapies can seem like looking for a needle in a haystack, but without the guidance of basic science we might just keep looking in the wrong haystack and never have the unexpected joy of finding hidden gems.
It’s this “evidence-guided serendipity” that we rely on. This can be an uncomfortable fact to acknowledge in economically challenging times. When such findings occur in the context of a scientifically methodical bench-to-bedside collaboration, the benefits can be profound. As Dr. Metz puts it, “We were doing things in parallel – lab studies would support clinical studies but it is also of importance that clinical studies facilitated further lab studies to identify biomarkers and additional treatment ideas.”
The Minocycline in MS Study
In 2008, the Calgary team led a randomized, double-blind, placebo-controlled trial conducted at 12 Canadian MS clinics. Over the next several years, adult patients who had a CIS event – like optic neuritis, or a brainstem, cerebral, cerebellar, or myelopathy (spinal-cord) syndrome – within the previous six months and at least two MRI lesions consistent with demyelination. These patients were randomized to receive either 100 mg of minocycline or placebo twice daily for 24 months or until they were known to have converted to MS.
The primary endpoint of the trial (the basis on which it would be judged positive/negative) was set as the proportion of patients who converted to MS within six months. Forty-one patients who received placebo but only 23 who received minocycline converted to MS within six months – this was a significant absolute difference of 18.5 per cent.
MRI markers of the disease, including change in lesion volume and number of new active lesions, also favoured minocycline at six months. These differences were no longer statistically significant when the patients were re-assessed at two years, but the implication was clear – the trial had successfully shown that the onset of MS could be delayed using minocycline in patients with CIS. The trial results were recently published in the New England Journal of Medicine.
In thinking about the three key questions we must ask when considering any new medical innovation, minocycline ticks all the boxes:
- Where is the evidence? As noted above, there’s a robust trail of evidence all the way from the lab to high-quality randomized-controlled trials on the effectiveness of minocycline. Thanks to Dr. Yong’s lab, we understand how the drug probably works in MS at a molecular level, and thanks to Dr. Metz’s clinical leadership, we now understand that it can also delay the onset of MS in CIS patients.
- What are the risks versus benefits? The difference that minocycline made in the rate of conversion to MS at six months (“effect size”, 18.5 per cent) was pretty similar to that observed in trials of previous agents like interferons, teriflunomide, and cladribine. However, it is far cheaper, about $600/year. And although many of the patients receiving minocycline in the recent trial experienced one or more side-effects, these were generally mild to moderate and exactly what we know to expect from this drug which has been around for a long time (rash, dental discoloration, dizziness).
- Are there relevant conflicts of interest? Importantly, the CIS trial was not funded by any pharmaceutical companies but rather by the Multiple Sclerosis Society of Canada. This is quite rare in modern medicine, owing to the immense expenses of getting a drug all the way across the pipeline from lab-based testing to clinical trials (the so-called “valley of death”). The MS Society’s championing of this trial deserves to be commended and will hopefully encourage other non-pharma groups to invest in high-quality, pioneering trials.
Boosted by this success, the Calgary MS team is now eager to solidify the case for starting minocycline in patients with CIS as well as using it in RRMS patients. Inexpensive therapies like minocycline can have an even bigger impact in the developing world, where the prices for typical MS drugs are simply prohibitive for most patients. Furthermore, by understanding the mechanisms involved, and proving the clinical benefit of minocycline in one condition, this work has led to an ongoing international clinical trial of minocycline in acute spinal cord injury, another devastating condition with no treatment. This trial is led by Dr Steve Casha, a neurosurgeon and Associate Professor from the Department of Clinical Neurosciences and the Hotchkiss Brain Institute of the Cumming School of Medicine.
Meanwhile, Mia, who has suffered from acne since her teenage years, has heard about minocycline previously from her dermatologist. She’s now eager to give it a try – and thanks to the Calgary MS team’s fruitful collaboration, patients with CIS all over the world have an affordable and effective option to try and delay the onset of MS.
*Details altered to protect patient confidentiality.
Dr Aravind Ganesh is a neurology resident-physician at the University of Calgary, currently working with the University of Oxford’s Centre for Prevention of Stroke and Dementia. He has co-founded the mHealth venture SnapDx and the patient-monitoring service Advanced Health Analytics.
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