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.
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.
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.
Multiple sclerosis in children is becoming increasingly recognized. The focus has been on earlier diagnosis. Many children can have only one attack such as optic neuritis or ADEM (acute disseminated encephalomyelitis) in which multiple active areas of inflammation occurred in the brain and spinal cord. Data was presented on MRI findings and environmental factors (low vitamin D levels and Epstein-Barr virus exposure) that predict risk of developing multiple sclerosis.
Daclizumab data was presented. In the DECIDE Trial, 1841 patients were randomized to daclizumab or Avonex. Daclizumab reduced new relapses by 54%, reduced contrast-enhancing lesions by 65% and reduced confirmed progression of disability at 6 months by 27%. Infections and skin reactions (37%) were higher on daclizumab.
SMART study examined 2455 multiple sclerosis patients treated with Gilenya. Only one patient had symptoms from low pulse. LONGTERMS study of patients on Gilenya for an average of 4 years results showed no increase risk of infection in patients with low lymphocyte (type of white blood cell) counts. Low lymphocytes was defined as absolute lymphocyte count <0.4 for 60% or more of labs checked on treatment.
Lemtrada-treated patients with no previous treatment with multiple sclerosis treatment generally had good 4 year response. Forty-two percent of patients actually had improvement in disability and 31 % of patients remained stable despite very active disease entering the trial.
JC virus index has been useful in examining PML risks. Of a group of 68 patients with PML without previous immunosuppressive medication exposure, only 2 patients (2.9%) had a JC virus index less than or equal to 0.9. Since PML can be fatal, Tysabri risks must be weighed against treatment benefits.
Approximately 10% of patients with multiple sclerosis have a slow progressive course of worsening disability without a history of attacks or relapses call primary progressive MS (PPMS). Previous attempts to slow down the progression for this form of the disease have failed including trials with Copaxone, Novantrone and Rituxan. Since Gilenya has direct effects on cells in the central nervous system and reduces the risk of brain atrophy, there was hope that Gilenya might work for primary progressive MS.
The INFORMS study was a 3 year study of 970 primary progressive multiple sclerosis patients. Patients were randomized in a double-blind study to Gilenya versus placebo in 148 clinical trial sites in 18 countries.
The primary endpoint was to evaluate the effect of fingolimod versus placebo on reducing the risk of disability progression based on a composite measure of Expanded Disability Status Scale (EDSS), assessment of upper limb function (9-Hole Peg Test), and walking speed (25-foot Timed Walk Test).
The Phase III INFORMS study in primary progressive multiple sclerosis (PPMS) did not show a significant difference between fingolimod and placebo on a combination of disability measures.
A case of a brain viral infection called progressive multifocal leukoencephalopathy (PML) was just reported in a patient treated with Tecfidera for 4 1/2 years. This patient had low lymphocyte counts (a type of white blood cell) for over 3 1/2 years while on treatment. Approximately 6 percent of patients on Tecfidera may have a temporarily low lymphocyte count, but only 2% of patients on Tecfidera have a chronically low lymphocyte counts (<500 cells/mcl). This patient’s lymphocytes fluctuated between 290 and 580 cells/mcl. The patient died from pneumonia.
Over 100,000 people have been treated with Tecfidera. The risks of treatment must be balanced against the benefits of therapy. Consult with your healthcare provider before making any changes in therapy.
Daclizumab. DECIDE Trial of 1841 patients showed that daclizumab antibody therapy given under the skin every 4 weeks lower relapses by 45% as compared to Avonex. Contrast-enhancing lesions were 65% lower on daclizumab than Avonex. Daclizumab benefit also noted on disability prevention (6 month confirmed disability) compared to Avonex . Daclizumab side effects include 37% skin reactions, 6% high liver blood tests (>5 times upper limit of normal), and 2% serious infections.
Oral vs. IV steroids. Oral vs. IV 1000 mg per day methylprednisolone for 3 days was compared in a French study. Double-dummy design: every one received a daily infusion and 10 capsules (but one was placebo). Seventy-eight percent of patients in either group responded to steroids with improvement at Day 28 after treatment onset. 6 month recovery and gastrointenstinal side effects were similar between the two groups.
Gut Microbiome. People with MS have an increase in a type of Archea, a single-cell organism, in the gut. This organism, Methanobrevabacter, could potentially play a role influencing the immune system in multiple sclerosis. Some gut bacteria increase in numbers with certain MS treatments in early studies.
A new form of interferon beta-1a (the active ingredient in Avonex and Rebif) is now available in a pegylated form. A tail was added to the interferon molecule so injection under skin can be given only once every 2 weeks.
In the ADVANCE Trial, 512 patients received 125 micrograms of Plegridy and 500 patients received placebo every 14 days under the skin over 48 weeks. MS attacks (annualized relapse rate) dropped by 36%. Risk of disability progression was reduced by 38%. Sixty-seven percent less new or enlarging T2 lesions and 86% less contrast-enhancing T1 lesions.
Risks of Plegridy are similar to other interferons and can include injection site reactions, flu-like symptoms, liver injury, depression and allergic reactions. Plegridy comes in a single-dose prefilled pen or prefilled syringe.
American Academy of Neurology meeting in Philadelphia just wrapped up. Here’s some new information presented at the meeting.
1. Estriol, a pregnancy hormone, was studied in addition to Copaxone. During the last trimester of pregnancy, estriol levels increase and relapses decrease. In a double-blind trial of 164 multiple sclerosis patients, relapses decreased 47% over one year on estriol and Copaxone compared to placebo and Copaxone (p=0.0326). However, relapses dropped only 32% at 2 years which was not statistically significant (p=0.015). No significant impact on MRI imaging was seen at 2 years.
2. Alfacalcidol, synthetic compound with similarities to Vitamin D, reduced fatigue compared to placebo in a study of 158 MS patients. More patients on Alfacalcidol remained relapse-free.
3. B cells are a type of lymphocyte (white blood cell) that play a role in MS disease. Data was presented on ofatumumab injected under the skin. This antibody therapy knocks out B cells by attached to a B-cell marker CD20. Significant impacts were seen on MRI activity based on doses studied. Risks included injection-related reactions, low potassium and one patient had a cytokine release syndrome.
4. The gut plays an important role in the body’s immune system. Researchers found that MS patients have a higher levels of methnobrevibacter in stool samples. This bowel bug is not a bacteria, but considered an archaea. Methane breathing test might eventually be useful in multiple sclerosis.
5. Melatonin can help with sleep, but what about a role in MS? High relapse rates are associated with low melatonin levels in urine. Melatonin may have positive effects on immune cells (IL-17 cells) by making them less inflammatory.
6. Men with MS: How’s your testosterone level? 40% of men are deficient in a study of multiple sclerosis patients, early in the disease course.