#ECTRIMS2018 – Finding Best Treatment for ‘Right Patient’ and Progressive MS Among Work of Interest, Cleveland Clinic Doctors Say

#ECTRIMS2018 – Finding Best Treatment for ‘Right Patient’ and Progressive MS Among Work of Interest, Cleveland Clinic Doctors Say

Tailored, highly effective therapies early in the disease’s course may be a way forward in multiple sclerosis (MS) treatment, according to Cleveland Clinic neurologist Robert Bermel.

Another neurologist with the Cleveland Clinic, Robert Fox, talked about potential and upcoming progressive MS treatments. 

In interviews with Multiple Sclerosis News Today at the recent 34th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in Berlin, Bermel and Fox also discussed stem cells and potential disease markers.

“Early, highly effective treatment would be a good idea in MS,” said Bermel, who is also the director of the clinic’s Mellen Center for Multiple Sclerosis“The reason why we haven’t used that strategy for all patients in the past was because of issues of risk.”

Such concerns, he said, had clinicians preferring the so-called dose-escalation therapy approach, which starts with an “older, time-tested therapy — even if it’s not as effective” because it’s known to be safer, with fewer side effects.

Robert Bermel, Cleveland Clinic
Robert Bermel, a neurologist and medical director of the Mellen Center for Multiple Sclerosis. (Photo by BioNews Services)

But recent advances encourage a change in thinking.

“What’s evolved in last couple of years is the arrival of newer therapies of high efficacy and with what looks like have outstanding safety data as well,” Bermel said. Immune B-cell depleting therapies, especially Ocrevus (ocrelizumab, by Genentech), were key among these game-changers. Besides being more convenient for patients, as infusions are only given every six months, Ocrevus and other newer treatments “may actually be safer than some of our older therapies.”

Having about six or seven years of practice with oral therapies has brought “a comfort level with [their] safety profile,” Bermel said. Besides Ocrevus, he mentioned treatments that include Tecfidera (dimethyl fumarate) and Tysabri (natalizumab), both by BiogenGilenya (fingolimod) by Novartis; and Aubagio (teriflunomide), by Sanofi Genzyme.

In essence, it’s becoming easier “to weave through the potential risks and the potential benefits,” so as to provide patients with therapies that might be most effective early on, Bermel said.

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“What we’re trying to do is match the right treatment to the right patient,” he added.

Finding the best approach

But treating patients, including those newly diagnosed, is a bit of “a trial and error approach,” Bermel said. This means that, for each patient, only time can tell how well a given treatment enables disease control.

Bermel is certain that early treatment is important to patients: If “we’re certain they’ve had a recent MS attack and we can with confidence make the diagnosis, we think that person should get on treatment right away, within a month or two of diagnosis,” he said.

But, he notes, what’s lacking is rigorous evidence as to which patients would be best served by early use of higher efficacy treatments as opposed to standard ones. “We’re testing that now” using two approaches, he said.

One is by randomized, controlled studies, such as two large clinical trials funded by the Patient-Centered Outcomes Research Institute (PCORI). Both will compare early, effective treatment use to dose-escalation approaches in patients with relapsing-remitting MS (RRMS). Within each treatment category, doctors and patients will choose the specific medicine used.

The first of these studies is the recently launched DELIVER-MS Phase 4 trial (NCT03535298), being conducted at the Cleveland Clinic in Ohio and at the University of Nottingham in the U.K.

A first enrollment, in what is expected to be an 800-patient study, will take place “probably this or next month,” Bermel said, adding that the Cleveland Clinic treats about 9,000 MS patients.

Scientists will primarily focus on changes in brain atrophy, or shrinkage, three years after starting the medication. “We want to know if starting a higher efficacy medicine first confers lower brain atrophy rates, basically.”

The second study, taking place at sites across 12 U.S. states, is called TREAT-MS (NCT03500328) and is led by Johns Hopkins University. Currently enrolling about 900 patients — more information is here — it will compare early use of more highly effective and standard first-line therapies in patients either at higher or lower risk of disability accumulation. Its goal is treatment impact on disability risk .

TREAT-MS will also analyze if switching from a first-line to a higher efficacy treatment after disease progression lessens disability risk compared to changing to a different first-line option.

Observational studies make up the other approach highlighted by Bermel. “We’re actively following thousands of patients in our clinic, who are everyday making these choices with their providers — either starting on standard efficacy therapy or high efficacy therapy,” he said.

“High quality data from clinical practice” may be pooled to determine how these patients do over time.

Work in progressive MS

While RRMS patients have various treatments available, those with progressive disease have more limited options. In fact, Ocrevus is their only specific disease-modifying medication, approved by the U.S. Food and Drug Administration for both forms of relapsing MS and primary progressive MS (PPMS) in March 2017.

“Clearly, our biggest unmet need is developing treatments for progressive MS. That is the biggest hole in our treatment armamentarium,” Fox said. Among other candidates, “ibudilast is a therapy that I’ve been involved in that looks promising,” he added.

Robert Fox, Cleveland Clinic
Robert Fox, a neurologist with the Cleveland Clinic. (Photo courtesy of Cleveland Clinic)

In a recent interview with Multiple Sclerosis News Today, Fox discussed the findings of the 96-week Phase 2 SPRINT-MS study (NCT01982942), which reported that use of ibudilast — an oral treatment developed by MediciNova — slowed the progression of brain atrophy by 48 percent relative to placebo in patients with either primary or secondary progressive MS (SPMS).

Although a Phase 3 trial would be essential to properly assess therapeutic benefit, this result compared favorably with those of prior studies with Ocrevus in RRMS and progressive MS, and with the investigational progressive MS treatment siponimod (by Novartis), Fox said.

The U.K.-based Phase 2b MS SMART trial (NCT01910259), also detailed at ECTRIMS, compared the efficacy of three neuroprotective treatments — riluzole (marketed as Rilutek and Tiglutik for amyotrophic lateral sclerosis), the diuretic amiloride and fluoxetine — to placebo in 445 SPMS patients. Results failed to show therapeutic effect for either medication, but the design demonstrated “the utility of a four-arm trial that evaluates three different therapies,” he said.

MD1003, a high-dose biotin being developed by MedDay,  may hold more “promise for progressive MS,” Fox said. Results of the MS-SPI trial (NCT02220933) showed that MD1103 lessened patients’ disability, especially with walking, over three years. The follow-on Phase 3 study, which is due to conclude in September 2019 according to the MS Society,  may not have results ready for release at next year’s ECTRIMS, Fox said, but will more clearly define benefit.

“So, there is a lot that I think we’ll be seeing over the near future for therapies that may protect the brain in progressive MS,” he said.

Stem cells and disease markers

An alternative MS treatment strategy, but one with little presence at this year’s ECTRIMS congress, is stem cells. Work here as a way to go, Fox said, a point echoed by other MS researchers.

“The most promising part of stem cell therapy, to me, is not stem cells to go in and be neurons,” Fox said, “but rather stem cells that can provide some sort of growth, stabilization, something to make the brain a healthier place.”

Researchers still lack information on “what those molecules are,” and how to make the cells that might reach the brain and the spinal cord and provide therapeutic benefit. “We really don’t know,” Fox said.

Scientists are also looking to develop better markers of disease progression, damage, and treatment response. Serum neurofilament light (sNfL), a potential blood biomarker, has been a focus of studies as a relatively easy way to make such assessments — although outcomes to date are mixed.

“[sNfL] is our leading candidate biomarker for treatment response,” said Fox, who discussed sNfL in an interview with Multiple Sclerosis News along with neurologists Jerry S. Wolinsky and Bernd Kieseier. But besides not being specific to MS, sNfL still lacks a suitable assay and may be better for relapsing than for progressive forms of MS, the scientists noted.

Fox sees more likely progress — at least for the near future — coming out of work into advanced imaging approaches, like those explored in the SPRINT-MS trial of ibudilast. “Cortical atrophy,” Fox said, “showed particular promise as being a sensitive measure of a treatment response, at least a treatment response in progressive MS.”

Overall, advanced imaging approaches may help find “a more sensitive measure of neuroprotection so that we can do trials more quickly and with fewer patients,” he concluded.

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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10 comments

  1. Jason says:

    So the best treatment is, for example, Gilyena? The same company that has increased the price from 62,000 per year in 2013 to 98,000 to now…that one? Seams like you misinformed. I shouldn’t have gone with chemo and stem cells because “we” don’t know enough right now? America is coming in last to the world. We’re losing because the we’re collecting paychecks from pharmaceutical companies and the world has passed us by.

  2. Joan Quilter says:

    I still find nothing new in your newsletters. I know this is because there is nothing new out there, and when a new “drug” appears, there are too many risks and side effects for many to chance it. The focus should, really, be on remyelination so that people with crippling disabilities can hope for a normal life.

    • Mary Ann Cincinnati says:

      I agree with you 100% Joan!!! I have PPMS and my doc wanted to put me on Ocrevus, which causes breast cancer. I said no, I’m done. My mom died of breast cancer the month of her 50th birthday. I no longer see a neurologist, and I’ve given it all to God. In my opinion, it’s all a money making business, and they don’t want to find a cure. I’ve had MS for 22years, and I’m tired of going from one med to the next. The only way I’d go on another one is if it caused remyelination. Finding a cure for diseases would put the pharmaceutical companiesout of business. They’d rather poison the population!

  3. Kirby says:

    Diagnosed in 2001 and still working and walking, I feel fortunate. Was it the 7 years of Copaxone, the 7 years that followed of monthly infusions of Tysabri, and then the two 1 year infusions of Lemtrada? I don’t know. But I can’t believe I would be better off with no treatments at all. I appreciate the cynicism expressed towards big Pharma, but if $$ didn’t talk I bet you I couldn’t walk. Do I feel well, no. Have I been fortunate, yes. I guess we should just be thankful.

  4. Reni says:

    wow it’s been the same bull for years! once you have MS its over, you will progress and they will never ever cure it, we are a cash cow for these companies

  5. Dessie says:

    Joan,Mary Ann and Reni all have expressed excellent points.I feel that some of the information in these newsletters just sounds ridiculous.The money that pharmaceutical companies are raking in is obscene.And we do continue to hear a lot of the same “bull” over and over.Many neurologists seem to be tossing around ideas until something sticks or flat out tell you they can’t help(I am seeing # 6).Two things are certain,they don’t have a clue what causes MS and every individual with this disease is different relating to type,symptoms,pain,progression,etc.I have PPMS that took two years to diagnose and have been steadily declining since 2013.I have had 3 rounds of Ocrevus and feel that it has only sped up my decline.I am so very tired of the useless information overload and waste of money and resources.Why can’t more collective focus be placed on things that they know for sure are affecting every MS patient,like demyelination.More HSCT trials could be helpful.Other countries are performing this procedure successfully,why not the USA.I would surely live a more positive life thinking I might be able regain use of my arms and legs than to die slowly while they do more studies to determine such things as if environmental factors I was exposed to as a child may have caused my MS.

  6. Susan M says:

    I get more useful & relevant information by reading actual MS folk’s experiences with the various therapies, etc. than I get from the newsletter articles!

    Big thanks to those of you who share your experiences!

  7. Reni says:

    We live in a “me” world so yes there are people who have a generally ok life with the disease therefore they are pleased with their medication and neurologists and go on living without thinking about anyone else with this illness that may be going through a tougher outcome, and these are the people that always get highlighted so the medical community just goes on feeding us medication that may, just may have a 40% chance of working and we will just take it in the hopes that we are part of that 40% the only reason that they found an almost cure for AIDS was because people and gay men marched and demanded that they find a cure! shouting, marching, being angry and bringing more focus is what will force them to find a cure.

  8. neal yarm says:

    I know one thing for sure. I will get worse. I am already very bad. There is nothing in the pipe line that will reverse or repair this disease. The PPMS teatments in the pipeline are all a dead end. I have never gotten any benifits from all the treatments I have taken. Now I am deciding on Ocrevus. I’m thinking why. No upside and potentil risk. We all want to walk again. I don’t care about any of these drugs if improving my disability is not a projected goal. “I won’t get any worse” You have to be kidding me. I can’t make it to the bathroom sometimes. Forget leaving the house in the summer. This is a fifteen year nightmare. I have one qestion, why are they still funding and developing disease modifying drugs.

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