NeuroImmunology

Highlights

 

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Ruth Arnon and Michael Sela profoundly influenced the development of a model system to test new therapies in multiple sclerosis.

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By measuring clinical, pathologic, and immunologic outcomes, the biological implications of new drugs could be elucidated.

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The pioneering research on Copaxone using the EAE model, paved the way for the discovery of other therapeutics in MS.

Via Krishan Maggon

ABSTRACT

Objective: This study evaluated the efficacy and safety of ATL1102, an antisense oligonucleotide that selectively targets the RNA for human CD49d, the α subunit of very late antigen 4, in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: In a multicenter, double-blind, placebo-controlled randomized phase II trial, 77 patients with RRMS were treated with 200 mg of ATL1102 subcutaneously injected 3 times in the first week and twice weekly for 7 weeks or placebo and monitored for a further 8 weeks. MRI scans were taken at baseline and weeks 4, 8, 12, and 16. The primary endpoint was the cumulative number of new active lesions (either new gadolinium-enhancing T1 lesions or nonenhancing new or enlarging T2 lesions) at weeks 4, 8, and 12.

Results: A total of 72 patients completed the study and 74 intention-to-treat patients were assessed. ATL1102 significantly reduced the cumulative number of new active lesions by 54.4% compared to placebo (mean 3.0 [SD 6.12] vs 6.2 [9.89], p = 0.01). The cumulative number of new gadolinium-enhancing T1 lesions was reduced by 67.9% compared to placebo (p = 0.002). Treatment-emergent adverse events included mild to moderate injection site erythema and decrease in platelet counts that returned to within the normal range after dosing.

Conclusions: In patients with RRMS, ATL1102 significantly reduced disease activity after 8 weeks of treatment and was generally well-tolerated. This trial provides evidence for the first time that antisense oligonucleotides may be used as a therapeutic approach in neuroimmunologic disorders.

Classification: This study provides Class I evidence that for patients with RRMS, the antisense oligonucleotide ATL1102 reduces the number of new active head MRI lesions.

Via Krishan Maggon

ABSTRACT

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS).

Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1–100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3–100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated.

Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low.

Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders.

Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0–7.6%).

Via Krishan Maggon

Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinic pharmacology, ... http://t.co/GmAivJZDRp

 

Multiple sclerosis (MS) is an inflammatory condition of the CNS presumably induced by an environmental trigger(s) in a genetically susceptible individual. Inflammation is prominent and most susceptible to intervention early in MS, so early treatment with disease-modifying therapies is recommended to reduce relapses and new MRI activity (both markers of inflammation) with the goal of delaying disability progression. Unfortunately, the response to the disease-modifying therapies is variable and often falls short of stopping observable disease activity, so the search for more effective agents continues. Alemtuzumab is a monoclonal antibody against CD52 that has exhibited significant efficacy throughout its clinical trial program in MS; uniquely, some of the studies have demonstrated a sustained reduction in disability in MS patients. Countering this impressive efficacy is an associated high risk of autoimmune events (especially thyroid) and concerns for infection or malignancy given prolonged immunosuppression after treatment with alemtuzumab.


Read More: http://informahealthcare.com/doi/abs/10.1586/1744666X.2014.951332

Via Krishan Maggon

Biogen Idec’s PLEGRIDY™(Peginterferon Beta-1a) Approved in the US for the Treatment of Multiple Sclerosis

 

Reduces Relapses, Disability Progression and Brain Lesions with a Favorable Safety Profile −

− Only Pegylated Interferon in MS, Dosed Once Every Two Weeks –

− Complements Biogen Idec’s Industry-Leading Portfolio of MS Products –

CAMBRIDGE, Mass.Today Biogen Idec (NASDAQ: BIIB) announced that the U.S. Food and Drug Administration (FDA) has approved PLEGRIDYTM (peginterferon beta-1a), a new treatment for people with relapsing forms of multiple sclerosis (RMS). PLEGRIDY, the only pegylated beta interferon approved for use in RMS, is dosed once every two weeks and can be administered subcutaneously with the PLEGRIDY PEN, a new, ready-to-use autoinjector, or a prefilled syringe.

 

The FDA approval of PLEGRIDY is based on results from one of the largest pivotal studies of beta interferon conducted, ADVANCE, which involved more than 1,500 MS patients. ADVANCE was a two-year, Phase 3, placebo-controlled (in year one) study that evaluated the efficacy and safety of PLEGRIDY administered subcutaneously. The analysis for all primary and secondary efficacy endpoints occurred at the end of year one. After the first year, patients on placebo received PLEGRIDY for the duration of the study.

In the first year of the ADVANCE clinical trial, PLEGRIDY dosed once every two weeks significantly reduced annualized relapse rate (ARR) at one year by 36 percent compared to placebo (p=0.0007). PLEGRIDY reduced the risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, by 38 percent (p=0.0383) compared to placebo. PLEGRIDY also significantly reduced the number of new gadolinium-enhancing [Gd+] lesions by 86 percent (p<0.0001) and reduced new or newly enlarging T2-hyperintense lesions by 67 percent (p<0.0001) compared to placebo.

 

The most common adverse reactions were injection site reaction, flu-like illness, fever, headache, muscle pain, chills, injection site pain, weakness, injection site itching and joint pain. The ADVANCE two-year safety data were consistent with safety results observed in year one.

Via Krishan Maggon

Abstract

Multiple sclerosis (MS) often results in chronic inflammatory and autoimmune disorders, and recent developments in understanding the disease pathogenesis has lead to newer therapeutic options for the treatment of the disease. The development of small molecule drugs with improved efficacy, better tolerability, and oral administration has received a new impetus with the discovery of newer classes of drugs. In this review, we have summarized the hitherto known synthetic strategies of fingolimod, laquinimod, cladribine, and teriflunomide reported in the literature which are the key small molecules and the first oral drug candidates for MS in various stages of clinical development or have been launched in the market.

Via Krishan Maggon