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7/12 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.

6/30 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.

 

 

4/22 Direct from American Academy of Neurology Meeting

Reporting live from Washington, DC.

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.

 

12/1 Another Disappointment for Primary Progressive MS

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.

11/14 Lemtrada now FDA-approved

FDA approved Lemtrada (alemtuzumab) today for relapsing forms of multiple sclerosis.  Because of its safety profile, Lemtrada should generally be reserved for patients who have had inadequate response to two or more other MS medications. Lemtrada is an antibody treatment that is given in the vein over 5 days the first year and 3 days the second year.  Eighty percent of patients do not require treatment in the 3rd year.  Lemtrada removes certain immune cells from the body for months  (approximately 6 months for B lymphocytes and 1 year for T lymphocytes).

In the CARE-MS I Trial, 581 early, active relapsing-remitting patients, who had received no prior MS therapy, were randomized to Rebif or Lemtrada treatment. Compared to those MS patients on Rebif, those individuals on Lemtrada had 55% less relapses.  A low percentage of patients had worsening disability on both treatments without a significant difference between Rebif and Lemtrada (11% and 8% respectively worsened).  In the CARE-MS II Trial,  Lemtrada IV treatment dropped new relapses by half (49%) compared to Rebif in a 2 year trial.   People with MS treated with Lemtrada also were 42%  less likely to progress in disability than on Rebif and have less MRI activity.

Autoimmune disease is a risk of Lemtrada including 34% thyroid disease (including 1% orbital involvement), 2% incidence of low platelets which can lead to serious bleeding complications (thrombocyopenia), and 0.3% serious renal disease (glomerular nephropathies).  Other risks include serious infections (including fungal and herpetic) and  serious infusion reactions including anaphylaxis.  Lemtrada may cause an increase risk of malignancy include thyroid cancer, melanoma and lymphoproliferative disorders.

Safety monitoring includes baseline and monthly complete blood count with differential, serum creatinine and urinalysis with cell counts monthly for 4 years.  At baseline and every 3 months,  blood thyroid function testing (such as TSH) should be checked. In addition, patients need baseline and yearly skin exams to screen for melanoma.

11/11 Tecfidera Safety Update

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.

11/11 3 ECTRIMS Global Meeting Highlights

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.

9/15 Join us for Multiple Sclerosis Breakthroughs Program

Full M cover

Your Invited!  Come to our program on the latest MS treatments along with strategies to reduce MS symptoms and improve quality of life. Groundbreaking research from the world’s largest annual international MS conference will be presented.  Hear about potential future preventative therapies and treatments to repair myelin in attempt to restore function in individuals living with MS.  A question and answer session will follow the presentation.  FREE.  Refreshments will be served.  Presenters: Barry Singer, MD; Mark Tullman, MD and Heather Popham, NP.  Sponsored by Missouri Baptist Medical Center.

Thursday, Oct 30, 2014.  6:30 PM to 8:30 PM. St. Louis Frontenac Hilton.  1355 South Lindbergh.

CALL 314-996-LIFE to REGISTER.

 

8/24 BJC Today Article: Doc gets down and dirty for his patients