Hot Topics and MS Research News for May 2014
Pharmaceutical News Across the Pond:
Bad News for Nerventra® (Laquinimod)
On May 23, 2014, The European Medicines Agency - Committee for Medicinal Products for Human Use (CHMP) upheld its January 23, 2014 negative opinion to recommend against approval of Laquinimod (brand: Nerventra) for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the European Union (EU) at this time. Nerventra is a once-daily oral CNS-active immunomodulator that affects the levels of certain cytokines and reduces the passage of immune cells in to the brain and spinal cord. It is being developed for the treatment of RRMS and progressive forms of MS by Teva Pharmaceutical Industries Ltd. and Active Biotech.
CHMP initially ruled that the risk-benefit profile of Nerventra was not favorable based on results from animal studies that showed a higher occurrence of cancers after long-term exposure to the medicine and possible risk to an unborn baby. However, the most common side effects seen in clinical trials include headache, abdominal pain, back and neck pain, appendicitis, and mild, asymptomatic laboratory abnormalities, including liver enzyme elevations, hematological changes, and elevation of CRP or fibrinogen levels.
In two pivotal phase III studies involving over 2432 people with RRMS, ALLEGRO and BRAVO, Nerventra reduced relapses by 21-23% compared to placebo. It was also shown to reduce disability progression and brain volume loss. A third Phase III trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 2,100 patients for up to 24 months. The primary outcome measure will be confirmed disability progression as measured by the EDSS, making CONCERTO the largest MS clinical trial with disability progression as the primary endpoint. In addition, Teva is investigating the potential of Nerventra in progressive forms of MS. The first trial for this indication is planned to be initiated soon.
Good News for Plegridy™ (PEGylated interferon beta-1a)
On May 23, 2014, Biogen Idec received good news as EMA-CHMP released a positive opinion for the marketing authorization of Plegridy, a pegylated interferon administered by subcutaneous injection once every two weeks at a dose of 125 mcg for adults with RRMS. Plegridy offers a less frequent dosing schedule among the interferon class of treatments for MS. The most common side effects include injection site erythema, influenza-like illness, pyrexia (fever), headache, myalgia (muscle pain), chills, injection site pain, asthenia (weakness), injection site pruritus (itching), and arthralgia (joint pain). Plegridy is being developed by Biogen Idec who also markets Tecfidera, Avonex, Tysabri, Fampyra, and Rituxan.
In the phase III ADVANCE study involving more than 1500 people with RRMS, Plegridy demonstrated a reduction in relapses, disability progression and the number of MS lesions when compared to placebo. Data from the first year of the study demonstrated that Plegridy significantly reduced annualized relapse rate (ARR) at one year by 36%, reduced the risk of 12-week confirmed disability progression by 38%, and significantly reduced the number of new or newly enlarging T2-hyperintense lesions when compared to placebo. The ADVANCE two-year data was consistent with the positive efficacy and safety results observed in year one.
In other research news:
A new study shows that diets that are lower in magnesium and folate are correlated with higher fatigue scores in multiple sclerosis patients.
Bitarafan S, Harirchian MH, Nafissi S, et al. Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients. Iran J Neurol. 2014;13(1):28-32.
Researchers studying stem cell rejection following transplantation discovered that mice infected with the neurotropic JHM strain of mouse hepatitis virus (JMHV) who were injected with human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) experienced improved motor skills and a reduction in neuroinflammation and demyelination about two weeks after the injections. Mice who had been paralyzed regained the ability to walk. Further studies are warranted.
Chen L, Coleman R, Leang R, et al. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis. Stem Cell Reports. 2014. doi:10.1016/j.stemcr.2014.04.005. Epub 2014 May 15.
While the controversy over venous disease in MS is new (i.e. the CCSVI hypothesis), the observation of perivenular MS plaques and venous theories about MS pathogenesis are as old as the history of MS research. Researchers conducted a thorough search of the literature dating from 1839 to 2012 to compose a concise history of vascular theories over the centuries.
Rae-Grant AD, Wong C, Bernatowicz R, Fox RJ. Observations on the brain vasculature in multiple sclerosis: A historical perspective. Multiple Sclerosis and Related Disorders (2013). doi:10.1016/j.msard.2013.08.005.
Researchers in California have identified a plausible biomarker that can be used to predict long-term MS progression. Using proton magnetic resonance spectroscopy (MRS), researchers measured metabolite abnormalities known to be associated with neurodegeneration. N-acetylaspartate (NAA) is an amino acid generated by mitochondria that is confined almost exclusively to neurons and axons in the CNS. A reduction of NAA will occur when there is loss of neurons and axons—thus reflecting neurodegeneration—but may also decrease when there is potentially reversible neuroaxonal dysfunction. Myo-inositol (mI) is generated by glial cells, in particular astrocytes. An increase of mI in white matter lesions and normal-appearing white matter (NAWM) in MS may reflect astrocyte proliferation.
Using MRS, researchers discovered that the ratio of N-acetylaspartate and mI had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor. The mI:NAA ratio was a predictor of brain-volume change in two cohorts of MS patients. Researchers established that the mI:NAA ratio predicted clinical disability in an initial cohort of patients (n=59) and predicted Multiple Sclerosis Functional Composite evolution, Expanded Disability Status Scale evolution, and Expanded Disability Status Scale sustained progression in an independent second cohort (n=220) of patients confirming the results of the initial study. Researchers found that myelin water fraction did not show predictive value. This study demonstrates that the mI:NAA ratio can predict appropriate clinical and imaging measures of MS progression over a substantial period of time (3.5 years).
Llufriu S, Kornak J, Ratiney H, et al. Magnetic Resonance Spectroscopy Markers of Disease Progression in Multiple Sclerosis. JAMA Neurol. 2014 May 19. doi:10.1001/jamaneurol.2014.895. [Epub ahead of print]
Miller DH. Magnetic Resonance Spectroscopy: A Possible In Vivo Marker of Disease Progression for Multiple Sclerosis? JAMA Neurol. 2014 May 19. doi:10.1001/jamaneurol.2014.896. [Epub ahead of print]