The Rocky Mountain MS Center and our partners at the Rocky Mountain MS Center at University of Colorado advocate for a fundamental philosophy of maximizing lifelong brain health through early and effective treatment and adoption of a healthy lifestyle. This philosophy drives a core treatment model focused on early, highly effective treatment of the disease. The strategy starts with identifying MS as early as possible – in many cases, even before significant symptoms are apparent. Patients are treated with the latest and most effective MS drugs at the very earliest signs of MS, in an effort to slow or even stop the disease before it has the opportunity to do much lasting damage.
The maximizing lifelong brain health philosophy and treatment approach is based on the fundamental understanding of neurological reserve. The brain has a built-in capacity to compensate for injury or damage, including the damage caused by MS. When an area of the brain is compromised, this neurological reserve essentially acts as a buffer, working to make up the difference. As we get older, we all lose brain volume – that’s just a natural part of the aging process. But as our brains get smaller, we’re also losing the neurological reserve that protects our brains from injury.
In people with MS, their neurological reserve compensates for the effects of the disease, leaving them with less neurological reserve as they age. Less neurological reserve means less ability to compensate for the next bout of disease activity, which can lead to a worsening of MS symptoms, or to an increased risk for disability. It also means less reserve to compentate for normal aging. Therefore, it’s critical that we do everything we can to lessen the damage MS can do in its very earliest stages.
“And we have reasonable evidence that patients on more highly-effective therapies have a much better chance of actually having long term improvement of symptoms,” said Vollmer. “And, if they have relapsing-remitting disease – many even appear to be in full disease remission with no symptoms of MS.”
Fortunately, we have a number of highly-effective disease modifying therapies today that can do just that – dramatically slow MS, or even stop it in its tracks. For most MS patients, highly-effective treatment options at the earliest stages of their disease, coupled with maintaining an active lifestyle and eating healthfully is the best way to protect their neurological reserve and maximize their lifelong brain health.
The benefits of effective disease modifying therapies are wide-ranging and significant. We know that effective DMTs have impact in both the short-run and long-run. DMTs decrease relapses; decrease new and active MRI lesions; decrease brain volume loss; decrease disability progression due to attacks; decrease the number failing No Evidence of Disease Activity (NEDA); and decrease cognitive deterioration. “It’s often stated that more effective therapies for MS also have higher risks. This is not true,” says Vollmer. “However, the potential risk for each disease modifying therapy for an individual patient has to be assessed so that the treatment with the best benefit/risk ratio for the individual patient is identified. Once patients start a therapy they must also be followed by a predetermined and strict safety protocol such that any problems can be detected early before they become serious.”
DMTs are approved for Relapsing Remitting MS (RRMS) by the US Food and Drug Adminstration (FDA) and other regulatory agencies in countries throughout the world. Ocrelizumab (Ocrevus) is the only drug approved for Primary Progressive MS (PPMS). The 2019 approval of siponimod (Mayzent) and cladribine (Mavenclad) for Clinically Isolated Syndrome (CIS), RRMS, and Secondary Progressive MS with activity reflects an important recognition that there is a continuum from RRMS into Progressive MS and that Secondary Progressive MS is just a form of RRMS.
Some Potential Advantages of Newer DMTs
There are some potential advantages of the newer DMTs compared to older drugs. Ofatumumab (Kesimpta) perhaps offers greater convenience than ocrelizumab (Ocrevus) or rituximab (Rituxan) for some patients because it is given by injection at home once each month and a patient does not need to go in for infusions. This convenience can be a very important factor especially if a person lives in a rural community and needs to travel greater distances for infusions. However, many patients prefer the once every six months infusion schedule of Ocrevus and rituximab so that don’t have to deal with MS more than necessary. There is a study being conducted to test extended dosing in natalizumab (Tysabri) which would extend the time between infusions from 4 weeks to 6 weeks. That would reduce the number of infusions by about one third, increasing the convenience for patients.
Diroximel fumarate (Vumerity) and monomethyl fumerate (Bafiertam) have less GI tract side effects compared to dimethyl fumarate (Tecfidera). Siponimod (Mayzent) and ozanimod (Zeposia) are a little easier to start than fingolimod (Gilenya) which requires a first-dose monitoring of 6-8 hours in the clinic. Zeposia doesn’t require that, nor does it require the genetic testing that Mayzent requires. Fingolimod, glatiramer acetate and dimethyl fumarate generics are cheaper which offers cost-savings benefits for insurance companies and health care cost savings so as long as they are equivalent. Shortly, there will be a number of generics or biosimilar drugs entering the market for several of the MS drugs.
Off Label Use of Medication
ff-label use of medication occurs when a drug is approved by FDA or other regulatory agency for one condition, but presumably due to the mechanism of action or the fact that condition X bears similarities to condition Y, the drug is tried in large numbers of people with condition Y. In the world of off-label use in MS, rituximab was approved to treat lymphoma, rheumatologic arthritis, and other rheumatologic conditions. The mechanism of action is depletion of B lymphocytes. The drug was studied in MS, showed some benefit, but was abandoned because its patent was about to run out, and ultimately led to approval of ocrelizumab (Ocrevus) and ofatumumab (Kesimpta).
What About Generics and Biosimilars?
Generic DMTs are copies that one company makes of a brand-name drug developed by another company if the patent has expired. These generic drugs have the same active ingredients and work the same way with the same risks and benefits. They are equivalent in dosage, safety, strength, route of administration, quality, and performance characteristics. They have the same label as brand-name medication. The FDA does not require trials to prove effectiveness of generic drugs.
In the world of MS drugs, several generic DMTs have been introduced in the past several years. The first generic MS DMT was Glatopa which is a generic version of Copaxone. Last year, three different generic versions of fingolimod (Gilenya) were approved for use in the U.S. More recently, additional generic versions of Copaxone and a generic version of dimethyl fumerate (Tecfidera), DMF, was approved.
Biosimilars are “highly similar” and modeled after other biological drugs. Biologicals use living organisms (yeast, bacteria, or animal or plant cells) as important ingredients and involve large, complex molecules. Approval requires it be highly similar, and contain no meaningful clinical differences. Notably, approval does require more clinical testing than generics. The price savings is generally 15-20% compared to the brand name drug. Biologicals in our world include all interferons (Betaseron, Avonex, Rebif, and Plegridy); and all monoclonal antibodies (Tysabri, Lemtrada, Ocrevus, Rituxan, and Kesimpta). Truxima is a biosimilar of rituximab which, as noted above, is not approved for MS but other conditions.
Prodrugs
A drug is a substance used to treat an illness, relieve a symptom, or modify a chemical process in the body for a specific purpose. A prodrug is a drug that is administered in its inactive form that is metabolized by the body into a biologically active compound. In MS, these drugs include dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity) which are both metabolized into monomethyl fumarate, the most active ingredient.
What’s Next?
The next frontier for MS disease modifying therapies will be focused on protecting nerves from degeneration (neurological protection); enhancing normal repair in the central nervous system; and replacing damaged cells in the central nervous system (neurological repair). Some of the potential therapies for Progressive MS, neurological protection, and neurological repair are summarized here:
A new class of medications being studied in MS is Tyrosine Kinase Inhibitors (TKi). TKi are enzymes within cells that cause cells to either turn off or turn on metabolic functions. Metabolic functions include the making of new cells, changing cell function, controlling cell growth, and cell survival. One type of TKi, mastinib, has shown a 37% reduction in progression of disability compared with placebo.
The category that has gathered the most interest is Bruton’s tyrosine kinase Inhibitors (BTKi). These transmit signals through a variety of cell-surface molecules and are being studied in relapsing and progressive MS. In relapsing MS, they may primarily affect B cell proliferation and development. They might also be useful in progressive MS because they may pass through the blood brain barrier and interact directly with cells inside the innate immune system involved in the disease-causing mechanism in progressive MS. It is important to alter or suppress the immune system—which is what DMTs do—but protecting against nerve damage is likely the key to preventing disability. Researchers are looking at why cells die over time. One argument is that disruption in the energy mechanisms is what leads to cell damage and cell death over time. There are also several studies underway to explore potential neuroprotective therapies to help stop the damage of cells in the central nervous system. Unfortunately, a large recent study found that biotin had no significant neuroprotective impact in MS. Currently researchers for the LAP-MS study are exploring alpha lipoic acid, an antioxidant, as a potential neuroprotective therapy in progressive MS. In addition, a large second study in progressive MS is looking at potential neuroprotective effects of Simvastatin, a drug used to control cholesterol levels.
Research in this area is very preliminary and all the studies have been very small. How these sorts of drugs might be helpful and how they might be used—perhaps as add-on therapies to improve the effects of disease modifying drugs—is unknown. But they are causing excitement because they provide indications that neuroprotective strategies are a real possibility for people with MS.
Research studies are also being conducted on potential neuroreparative therapies. Clemastine, an antihistamine drug, has been shown to have modest effects on remyelination in human studies to date. Metformin, a drug for type II diabetes, improved recovery of function in animal models of MS by inducing neuroprotective astrocyte. Metformin and could be an add-on to disease modifying therapies to study the impact on recovery of neurological function in MS patients with higher levels of disability. Human trials of metformin and MS are very likely to be pursued.
Stem cell therapies are also the subject of much interest and research. The area of stem cell research to treat diseases, including MS, is huge. The basic problem in MS is that the immune system is attacking the nervous system. One strategy to fix this would be to get rid of the old, poorly behaving immune cells and replace them –or reboot—with cells that have not been programmed to attack the nervous system. The most publicized stem cell approaches in MS reboot the immune system.
There are lots of different types of stem cells, and they have different qualities and characteristics. They have different abilities to enter the nervous system and to migrate to where you need them to go. They might have different abilities, either to replace cells that are damaged or to stimulate those cells that are already in the nervous system, or help them to function better.
Multiple types of stem cells are under study for MS that may offer potential repair of brain or spine cells. The types of cells that may offer potential benefit in MS could be bone marrow derived cells that re-boot the immune system. Studies show these stem cells likely do benefit younger patients with active disease. Researchers at RMMSC at CU will soon begin participating in a national stem cell therapy study called BEAT MS. RRMS patients with active disease, who are taking standard drugs, will get Hematopoietic Stem Cell transplant after high dose immunoblation therapy – the deletion of the patient’s own immune system with chemotherapy. This treatment will be compared head-to-head to best available therapy (Ocrevus, Rituxan, Tysabri, or Lemtrada) as a comparator. This will be the largest study to date aimed at helping determine whether the potential benefits of this treatment outweighs its significant risks when compared to highly effective DMTs. In addition there are now stem cell studies looking at neural pre-cursor cells to examine whether they could repair brain or spine cells.
For more information on DMTs in MS, please see Dr. Vollmer’s and Dr. John Corboy’s presentations from the MS Center’s Fall 2020 Education Summit. Video and slides can be found in our online archive, available at mscenter.org/edsummit.
