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Archive for ‘MS Research News

Mar 29 2019 Mavenclad FDA-approved: Infrequent Oral Tablets for MS Treatment

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.

Mar 26 2019 Mayzent (siponimod) FDA-approved: Option for Secondary Progressive MS

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.

May 29 2017 A New Era of Multiple Sclerosis Treatment

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.

Mar 28 2017 Ocrevus (ocrelizumab) Approved!

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.

 

 

 

Sep 25 2016 ECTRIMS Meeting in London: Interview with Dr. Barry Singer

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

May 27 2016 A New Option: Zinbryta (daclizumab) is FDA-approved

Zinbryta is an antibody therapy that binds onto a receptor (interleukin-2) on the surface of T immune cells.  The SELECT trial studied 621 relapsing-remitting multiple sclerosis patients randomized to placebo and Zinbryta 150 mg [daclizumab high-yield process (HYP)] injected under skin every 4 weeks for 1 year.  Relapses were reduced 54% for patients on Zinbryta compared to placebo. Zinbryta treatment was associated with 57% less disability progression compared to placebo.

In the DECIDE study of 1841 relapsing-remitting multiple sclerosis patients, Zinbryta under skin every 4 weeks was directly compared to Avonex weekly injections into muscle over 96 to 144 weeks of treatment.  Patients on Zinbryta had 45% less relapses than Avonex.  Less MRI activity was seen in people treated with Zinbryta (54% reduction on new or newly enlarging T2 lesions and 60% reduction on contrast-enhancing lesions).

Zinbryta can cause severe liver injury including liver failure and autoimmune hepatitis.  Liver blood tests are required monthly and up to 6 months after last dose. Other immune-mediated disorders can occur including skin reactions, enlarge lymph nodes, and colon inflammation (colitis). These conditions may require treatment with steroids or immunosuppressive medication.

Most common side effects from Zinbryta (compared to Avonex) included upper respiratory infections, rash (37% of patients) and enlarged lymph nodes. Before starting Zinbryta, testing should be performed for viral hepatitis B and C as well as tuberculosis. Because of its safety profile, Zinbryta should generally be reserved for patients who have had inadequate response to 2 or more MS treatments.

READ ABOUT OTHER TREATMENT OPTIONS

May 15 2016 American Academy of Neurology Meeting Vancouver April 2016

IMG_0021Here’s a few highlights of the meeting:

Multiple sclerosis genetically clusters with other autoimmune diseases, especially Crohn’s and Celiac diseases.  Genetic research shows that T regulatory cells and B cells (both types of a white blood cells called lymphocytes) are important in multiple sclerosis.  High salt diet may cause immune dysregulation, leading to increased inflammation.

Remyelination (recoating the nerves with myelin) was a focus of  a great 4 hour afternoon session.  Approximately 5% of the cells in the brain are immature cells called OPCs (oligodendrocyte precursor cells) that potentially could make myelin.  These cells may be important for learning and not just remyelination.  Why does remyelination fail in MS?  May be due to factors that block remyelination,  damage to the nerve (axon section) itself, and the timing of repair.

To test compounds for myelin repair,  remyelination can actually be visualized in translucent Zebra fish.  Micropillars of immature myelin-making cells is another interesting approach to screen for effective compounds to increase new myelin production.  The technique involves upside down cones coated with OPCs.  Clemastine and benzatropine compounds worked in this model.  To see if remyelination works in humans, imaging techniques being examined include PET with MRI scans, myelin water imaging and magnetic transference ratio analyses.

More data was presented on high efficacy treatments.  In the OPERA trials of ocrelizumab (Orevus), 48% of patients had no evidence of disease activity (called NEDA) over 2 years in comparison to 25-29% of Rebif patients.  NEDA means no relapses, no change in disability and no new MRI activity.  Alemtuzumab (Lemtrada) was shown to very effective over 5 years in highly active MS patients whether previously treated with MS treatments or new to MS treatment.

 

Sep 28 2015 WOW! Ocrelizumab effective in primary progressive MS!

Ocrelizumab becomes the FIRST therapy to show positive results in a Phase III clinical trial in PRIMARY PROGRESSIVE multiple sclerosis after numerous other failed trials with other medications.

In the ORATORIA study,  ocrelizumab infusions in the vein reduced the risk of clinical disability progression compared to placebo in patients with primary progressive multiple sclerosis. The most common side effect was mild-to-moderate infusion-related reaction.  The incidence of serious side effects (adverse events), including serious infections, was similar to placebo.

ORATORIO is a Phase III, randomized, double blind trial comparing ocrelizumab infusions to placebo in 732 primary progressive multiple sclerosis.  The primary endpoint of the study was the time to onset of confirmed disability progression, sustained for at least 12 weeks.  Ocrelizumab was given in the vein every 6 months as two 300 mg infusions two weeks apart.

Ocrelizumab targets specifically B-cells, a type of white blood cell lymphocyte.  Another B-cell therapy, rituximab had failed in a previous primary progressive multiple sclerosis trial. Full abstract results coming next week at ECTRIMS in Barcelona.

Jul 12 2015 Antibody Therapies in Clinical Trials: Key to Remyelination?

Myelin repair strategies are being pursued to repair old myelin damage in multiple sclerosis patients and to improve remyelination after an acute exacerbation.  Encouraging to see these potential remyelinating treatments enter clinical trial phases! Clearly, a huge need is treatment to repair myelin and hopefully improve disability for those living with MS.

Through screening over 125,000 Mayo Clinic patient blood samples, a human monoclonal antibody was found that promoted remyelination in animal models of MS.  A phase 1, multi-center, double-blind randomized study was conducted using a recombinant version of this antibody, rHIgM22.  A single dose of rHIgM22 was given in the vein to 55 MS patients and 17 patients received placebo.  Headache and contact dermatitis were reported, but no MRI or laboratory safety issues.  The MS Center for Innovations in Care at Missouri Baptist Medical Center was one of the sites for this phase 1 clinical trial.  A second phase 1 trial is planned to assess the safety and tolerability of rHIgM22 immediately following a relapse.

LINGO-1 is a glycoprotein on neurons and oligodendrocytes (myelin-making cells) in the central nervous system that blocks myelination. In the RENEW Trial, 82 patients with acute optic neuritis affecting one eye were randomized anti-LINGO-1 antibody BIIB033 or placebo infusions every 4 weeks for 6 total doses. Anti-LINGO-1 treatment had better outcomes than placebo on the full-field visual evoked potentials (P=0.05).  An ongoing phase 2 trial of anti-LINGO-1 treatment is being examined in patients with relapsing multiple sclerosis while staying on Avonex.

Semaphorin 4D signaling blocks remyelination. Anti-semaphorin 4D (Anti-SEMA 4D) monoclonal antibody protects against loss of myelin and enhancing myelin repair in animal models of MS.  A phase 1 study of VX15/2503, an anti-SEMA 4D antibody, showed that the antibody treatment was well-tolerated without serious safety issues.

Jun 30 2015 Ocrelizumab Outperforms Rebif

Ocrelizumab is an anti-CD20 antibody therapy given as an infusion every 6 months.  Ocrelizumab temporarily knocks out B cells, an important immune cell involved in causing damage in multiple sclerosis.  Two Phase 3 clinical trials (OPERA I and II) were conducted to evaluate ocrelizumab in relapsing multiple sclerosis.   In both trials, patients were randomized to Rebif or ocrelizumab 600 mg intravenously every 24 weeks. Only the first dose of ocrelizumab was divided into 300 mg on Day 1 and Day 15. OPERA I and II randomized 821 and 835 patients, respectively.

Treatment with ocrelizumab significantly reduced the number of relapses per year (annualized relapse rate), the risk of disability progression and reduced the number of brain lesions compared to Rebif treatment.  Results were just announced in a press release.  Exact difference will be presented at a future scientific meeting.

The most common side effects of ocrelizumab were mild-to-moderate infusion-related reactions. The incidence of serious infections on ocrelizumab was similar to Rebif.

The MS Center for Innovations in Care was a site for the OPERA clinical program.