Archive for ‘MS Research News’

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Omicron variant of the SARS-CoV-2 virus that causes COVID-19 is now taking off in South Africa with scattered cases already in Europe. With over 30 mutations to the spike protein on the surface of the virus, unanswered questions arise. Will the vaccines still be protective? Is this version of the virus more infectious and more lethal? Africa was vulnerable due to only 6% of the population being vaccinated due to global health disparities.

People living with multiple sclerosis deserve highly-effective therapy, which has been shown to prevent future physical and cognitive disability. Many of these medications that prevent the autoimmune attack on the brain and cervical spine are immunosuppressive. Under normal circumstances, the benefits generally outweigh the risks.  During the COVID-19 pandemic, individuals on immunosuppressive MS disease-modifying therapies have had to be extra careful to avoid infection and may be at risk for more serious COVID-19. It’s been a substantial sacrifice for them; missing out on some family gatherings, limited time with friends, remote work or high-risk exposure at work and avoiding critical exercise at classes, gym or the pool. Anxiety and depression in the MS community has been very high during the pandemic.

Sacrifice for 2 years is hard enough, but what if COVID-19 doesn’t go away? COVID-19 could stay around as an “endemic” disease. The best case scenario is that enough people become vaccinated (with regular boosters) or infected naturally that there will be a dramatic decrease in cases over the coming years. An influenza A virus H1N1 caused the 1918 Spanish flu, killing 50 million people globally. Influenza viruses are still around, resulting in 20-60,000 American deaths annually.  However, flu vaccines are not nearly as protective as COVID-19 vaccines and new and emerging treatments for COVID-19 are quite effective.

At some point, each person with multiple sclerosis will need to make a calculated decision with their healthcare providers about their future treatment strategy. I anticipate most people would rather adapt their lifestyle so they can continue on highly effective treatment to prevent future physical and cognitive impairment. Other people living with multiple sclerosis may prefer de-escalation of treatment, using a medication that may be less effective but less or not immunosuppressive. Induction therapy might also become more attractive with temporary immunosuppression followed by “rebooting” the immune system such as with Mavenclad or Lemtrada.  Risk factors for worse COVID-19 disease will need to be considered such as older age and other medical problems like hypertension.

The bottom line:  We will get through this challenging time together as a MS community with open communication between those of you living with multiple sclerosis and the healthcare professionals that show up in a mask everyday to care for you.

Ponvory (ponesimod) is an oral S1P1 medication which traps certain causes types of lymphocytes (a type of white blood cell) in lymph nodes and keeps them out of the brain and spinal cord.  In the OPTIMUM multicenter, double-blind trial, 1133 relapsing multiple sclerosis patients were randomized to Ponvory or Aubagio oral medication daily.  Relapses were 30.5% lower on Ponvory than Augabio.  New lesions were reduced by 56% on Ponvory compared to Auabigo.  No statistically significant difference was seen on disability progression on the 2 medications.

Risks that were higher on Ponvory than Aubagio in clinical trial included high liver blood tests, nasopharyngitis, upper respiratory infections, respiratory symptoms and increased blood pressure.  This class of medications has been associated with rare serious infections including PML and cryptococcal meningitis.  In clinical trial, the dose was increased to full dose of 20 mg over 2 weeks to reduce risk of slowing heart rate or irregular heart rate with first dose.

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Background:

Our immune system includes a type of cell called lymphocytes. T lymphocytes target other cells such as cells infected with viruses or cancerous cells. They are called “T” cells since they mature in the thymus gland in the upper chest. Normally T cells that would attack our own cells are destroyed in the thymus gland before being released into the circulation. In autoimmune diseases such as multiple sclerosis, these T cells escape and can lead to the immune attack on myelin.

B cells mature in the bone marrow in humans, but were named after a specialized organ where B cells mature in birds known as the bursa of Fabricius. B cells can change into plasma cells which make antibodies. Antibodies are like targeted arrows that can help attack germs such as viruses or bacteria that are invading our bodies. In multiple sclerosis, B cells turn against their human by creating antibodies that attack myelin and revving up autoimmune T cells.

Role of T and B cells in Vaccination:

Vaccines work by imitating a serious infection. Vaccines can cause minor symptoms, but do not cause the actual disease. The vaccine triggers the development of specific-targeted T and B cells that remember the infection. When someone is then exposed to the real life-threatening virus or bacteria in the future, they can mount a highly effective defense against the infection due to these “memory” T and B cells. For example, children are vaccinated with a weakened, live chicken pox virus called the varicella-zoster virus. The immune system then develops T cells and antibodies specific for this varicella virus. The vaccine has been shown reduce the risk of getting chicken pox later in life by 92%. If someone is immunosuppressed, important to avoid live, weakened (attenuated) viruses.

Most vaccines are inactivated vaccines which means they do not contain live viruses or bacteria. Vaccines that inject killed whole virus include polio, hepatitis B and rabies.  Many inactivated vaccines include only sugar molecules (polysaccharides) that are found on the surface of bacteria or surface proteins that are found on viruses. These components of the infectious agent lack the ability to replicate since they do not contain disease-spreading genetic material (RNA or DNA).

COVID-19 vaccines:

For COVID-19, the Pfizer and Moderna vaccines are mRNA vaccines. The mRNA contains instructions for our own body to make a harmless “spike” protein.  This spike protein is on the surface of the COVID-19 virus. The spikes on the surface of this COVID-19 coronavirus creates a “corona” (derived from the latin word for crown).  The mRNA is surround by a lipid (fatty) nanoparticle that allows it to enter cells of the body when injected in the muscle.  Once mRNA is in the cells, the cells can create their own spike proteins on their surface. The body’s immune system that reacts to these foreign spike proteins leading to immunity with memory T and B cells.  These COVID-19 vaccinations result in a robust immune response to this spike protein that provides up to 95% immunity from the real COVID-19 infection, caused by the SARS-CoV-2 virus.

The AstraZeneca and Sputnik V vaccines use a type of virus called an adenovirus to insert DNA into the cell nucleus.  The double-stranded DNA does not get into our own DNA, however.  The DNA strand allows the cell to also make only the spike protein.  The DNA in the adenovirus has been altered so the adenovirus lacks to the ability to replicate (divide) in the body.

MS Living Well values educating people living with MS globally since 2007.  In this developing coronavirus pandemic, the goal is provide information specific to those living with MS to help determine your risks and ways to protect yourself.  For more info see the CDC’s website on COVID-19.

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EVALUATE YOUR RISK:

A.  LOCATION: plays a major factor.  Higher risk countries are changing: now Europe, United States and Iran have the most new cases (updated March 19, 1920).  The situation is changing rapidly so important to be aware of local evolving risk.  Many people may be carriers of the virus without symptoms.  People can become infected if within 6 feet of someone infected with the coronavirus who coughs or sneezes or by touching surfaces infected and then touching your face, nose or possibly your eyes.

B. IMMUNE STATUS:  Many multiple sclerosis medications could put a person at increased risk of serious complications from coronavirus infection including pneumonia or even death.  All FDA-approved medications to change the disease course of multiple sclerosis impact the immune system.  As a consequence, your ability to fight the viral infection may not be as robust.  Many MS medications have been studied to make sure that people can still mount an immune response to new virus while the medication is being taken.

Ocrevus, Gilenya and Mayzent have been associated with an increased risk of respiratory infections in clinical trials and might make MS patients on these medications at increased risk of coronavirus complications.   Lemtrada and Mavenclad could also potentially put people with MS at higher risk of serious complications during the year after the last treatment course.  Whether Tecfidera, Vumerity or Tysabri treatment would impact susceptibility to coronavirus complications is unclear.  Teriflunomide is likely low risk for increased complications.  Copaxone and interferons (Avonex, Betaseron, Extavia, Plegridy and Rebif) are likely quite safe as well.  NEVER STOP YOUR MS MEDICATION ON YOUR OWN SINCE COULD LEAD TO PERMANENT SEVERE DISABILITY. ALWAYS CONSULT WITH YOUR HEALTHCARE PROVIDERS BEFORE MAKING TREATMENT DECISIONS.

C. AGE and DISABILITY:   Elderly patients are at greater risk of death.  Overall, the risk of death is estimated at 2-3% of infected COVID-19 patients.  People with MS with higher levels of disability such as with moderate to severe weakness in arms and legs may be more vulnerable to coronavirus complications.

PROTECT YOURSELF:

A.  Avoid close contact with people who are sick.

B.  Avoid touching your eyes, nose, and mouth.

C. Cover your cough or sneeze with a tissue, then throw the tissue in the trash.

D. Clean and disinfect frequently touched objects and surfaces using a regular household cleaning spray or wipe.  The virus can linger for a few days on plastic and steel.

E. Facemasks are not recommended by the CDC for people that are healthy.  N95 masks are effective but generally reserved for healthcare works treating sick coronavirus patients.

F. Wash your hands often with soap and water for at least 20 seconds, especially after going to the bathroom; before eating; and after blowing your nose, coughing, or sneezing.  If soap and water are not readily available, use an alcohol-based hand sanitizer with at least 60% alcohol.

G. Stock up on supplies at home if you are at higher risk for complications.  As infection rates soar, you will be prepared to avoid public places for shopping.

H. Would avoid travel including airplane flights and cruises. Avoid attending group gatherings such as meetings, religious events and sporting events in higher risk areas.

I. Notify your healthcare providers immediately if having fever, cough or shortness of breath.

Vumerity is a twice a day oral medication for patients with multiple sclerosis.  The active ingredient of Vumerity is diroximel fumarate, which  is rapidly converted to monomethyl fumarate in the body.  Similarly dimethyl fumarate (Tecfidera) is also converted to monomethyl fumarate.  Therefore, Vumerity would be expected to the same benefits as Tecfidera on multiple sclerosis such as 53% reduction of relapses, 38% reduction in likelihood of disability progression and 90% reduction on active contrast MRI lesions (DEFINE trial).

Full results of the EVOLVE-MS trials are pending including the EVOLVE-MS-1 study, a Phase 3, open-label, two-year safety study and the EVOLVE-MS-2 study, a Phase 3, five-week randomized, prospective, double-blind, multi-center study that assessed the gastrointestinal (GI) tolerability of VUMERITY and TECFIDERA using self-administered GI questionnaires.  Based on preliminary results of EVOLVE-MS-1 study that I presented at ECTRIMS in September 2019, approximately 30% of Vumerity had gastrointestinal side effect but less than 1% discontinue due to this side effect.  Lymphocyte (type of white blood cell) monitor is important to reduce potential risk of PML, a brain viral infection.  Thanks to all of our patients who participated in the clinical trials.

Mavenclad is an oral medication approved for relapsing-remitting and secondary progressive multiple sclerosis.   The oral treatment course consists of two yearly courses of 2 cycles of 1-2 tablets per day for 4-5 days depending on the patient’s weight.

In the CLARITY study, 1326 multiple sclerosis patients were randomized to a total dose of 3.5 mg/kg (FDA-approved dose), 5.25 mg/kg or placebo.  Mavenclad 3.5 mg/kg total dose reduced relapses by 58% compared to placebo.  Likelihood of progression of disability was reduced by 33% on Mavenclad.  On MRI, Mavenclad reduced contrast-enhancing lesions by 86% and new or enlarging T2 lesions by 73% compared to placebo.

Risks of Mavenclad include low white blood cell counts, serious infections, anemia, potential fetal harm and possible malignancy.  Per prescribing information, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS due to its safety profile.

Mayzent (siponimod) is a tablet medication to treat people with both relapsing-remitting multiple sclerosis and secondary-progressive patients with active disease such with new relapses or new MRI activity.

In the EXPAND trial, 1651 multiple sclerosis patients with secondary-progressive multiple sclerosis were randomized to once-daily oral Mayzent 2 mg daily or placebo for up to 3 years (2/3 of patients received Mayzent).  Patients on Mayzent had a 21% less risk of disability progression than those patients on placebo.  Mayzent reduced relapses by 55% compared to placebo.  Patients on Mayzent were more likely to be free of contrast-enhancing lesions (89% vs 67% on placebo) and free of new or enlarging T2 lesions (57% vs. 37% on placebo).

Medication risks include elevation of liver blood test, swelling back of eye (called macular edema), increase in blood pressure and potential serious infections.

Prior to 1993, no approved treatments were available for multiple sclerosis (MS). People who developed MS prior to the first treatments, unfortunately, had damage to their brain and spinal cords which often led to progressive disability. MS relapses are bouts of neurological symptoms such as numbness, weakness, imbalance and visual loss that can last days to months.

The first generation of self-injected medications reduced relapses by about one-third and as much as 80% of new brain disease seen on MRI (magnetic resonance imaging) scans. These medications fight the immune attack on the brain and spinal cord without compromising the body’s ability to fight infections.  Tysabri (natalizumab), an infusion therapy  given in the vein monthly, dropped relapses by 68% compared to placebo in clinical trial and has been available for treatment for over a decade.

Over the past 7 years, an array of new oral and antibody treatments for MS have become available that have unique effects on the immune system to block MS.  Oral therapies are Aubagio, Gilenya and Tecfidera and new monoclonal antibody therapies are Lemtrada, Ocrevus, and Zinbryta.  Some oral therapies have been shown to reduce relapses by more than half compared to placebo.  Gilenya and Zinbryta demonstrated a superior reduction in relapses compared to Avonex.  The advantages of good disease control must be balanced against serious risks of these drugs even if some risks are uncommon or rare.

Lemtrada (alemtuzumab) is a highly effective antibody therapy that in clinical trials has  reduced relapses by half compared to Rebif. On Lemtrada, 43% of patients actually had less disability confirmed at end of 6 years compared to the onset of the study.  Another antibody treatment, Ocrevus (ocrelizumab), also showed in clinical trials to reduced relapses almost in half and reduced contrast MRI activity by 95% compared to Rebif. Lemtrada transiently depletes T and B cells and Ocrevus consistently depletes B cells with potential serious risks including serious infusion reactions and serious infections.

Treatment Stategies

One common approach to treating multiple sclerosis is starting with a self-injected medication with two decades of long-term safety information. These medications including Copaxone (glatiramer acetate) and interferons (including Avonex, Betaseron, Extavia and Rebif )have been effective for many patients without immune compromise. If new relapses, worsening disability or unchecked MRI activity occur, the first medication could be switched to another agent.   The strategy is often referred to as “escalation” of treatment. This approach may be the safest option, but waiting too long to switch therapies may result in irreversible disability.

Another strategy is to seize the moment.   People living with MS without new relapses and without new MRI activity have the best chance of preventing disability progression. One goal of MS treatment is achieving NEDA (No Evidence of Disease Activity) which means a patient is free of relapses, disability progression and MRI activity. Choosing a high-powered medication first to minimize risk of worsening disability to maximize quality of life is another treatment approach. Early in MS there can be changes such as nerve injury that may lead to irreversible disability. This earlier treatment approach  tackles the disease aggressively from the start.  Accepting potential long-term risks of these immune therapies with a lifelong disease is one concern. In addition, the use of some of these immune treatments might restrict the next treatment option. Not all therapies are indicated for first-line therapy in the United States.

Likely the best approach is a combination. This strategy involves stratifying the risk of disease, then matching with an appropriate medication. Some risk factors that increase risk for disability include being male, MS onset after age 40, incomplete recovery from first attack, frequent relapses the first 2 years of disease, spinal cord disease and higher amount of MS changes on initial MRI. Patients with lower risk of disability progression may choose a more conservative medication option. In contrast, someone at higher risk for disability may be willing to accept more risk for more effective treatment. It is critical for individuals living with MS to share their willingness to accept or not accept certain risks to control their disease. Neurologists also vary in their willingness to use higher risk medications which often influences the decision process. Each person living with MS should meet with their neurologist to clarify their individual risk of disability based on their disease.

Research advancements have led to a growing array of new MS therapies. To determine the best individualized treatment plan, being informed and open with healthcare providers is essential.

The FDA has approved Ocrevus tonight for primary progressive and relapsing forms of multiple sclerosis.  The approval is a major breakthrough since no treatments have previously been approved for primary progressive multiple sclerosis.  This monoclonal antibody treatment works by depleted B cells, a type of immune cell. Ocrevus  is given intravenously with half given the first day and a second half given 2 weeks later, followed by a single infusion every 6 months.

In 2 relapsing multiple sclerosis trials (OPERA I and II), patients treated with Ocrevus had 46 to 47% less relapses than Rebif.  In addition, patients treated with Ocrevus were 40% less likely to progress in disability compared to Rebif treated patients.  On MRI scans, the average number of active contrast-enhancing lesions were 94-95% less with Ocrevus treatment than Rebif.  In a primary progressive trial (ORATORIO) of 732 patients, treatment with Ocrevus reduced risk of disability progression by 24% compared to placebo treatment.  A 29% benefit was also seen on the time to walk 25 feet.

The most common side effects in clinical trials were infusion reactions and upper respiratory tract infections, which were mostly mild to moderate in severity. Although PML (progressive multifocal leukoencephalopathy) did not occur in Ocrevus clinical trials, this brain infection, which is potentially fatal, has occurred rarely with another B-cell depleting treatment.  Other serious infections including reactivation of a Hepatitis B infection are risks.  A higher rate of malignancies was seen on ocrelizumab than placebo or Rebif so possible risk of treatment with Ocrevus.

Dr. Singer discusses great progress in multiple sclerosis including on progressive disease and preventing brain size loss.