Studies provide positive results for new MS drug (30/06/15)
Genentech has announced positive results from two studies evaluating ocrelizumab for people with relapsing multiple sclerosis (MS).
The studies (called OPERA I and OPERA II) met their primary and major secondary endpoints.
Treatment with ocrelizumab significantly reduced the annualised relapse rate (ARR) over a two-year period compared with interferon beta-1a. Ocrelizumab also significantly reduced the progression of clinical disability compared with interferon beta-1a, as measured by the Expanded Disability Status Scale (EDSS).
Treatment with ocrelizumab also led to a significant reduction in the number of lesions in the brain compared with interferon beta-1a, as measured by MRI, say researchers.
The number of recorded “adverse events”, or side effects, associated with ocrelizumab was similar to interferon beta-1a in both studies, the most common of which were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to interferon beta-1a.
Sandra Horning, MD, chief medical officer and head of Global Product Development, said: “Ocrelizumab has the potential to make a meaningful difference for people with MS. Based on these compelling results, we plan to submit the data for review to U.S. and EU regulatory authorities in the first quarter of 2016.”
Further analyses of the OPERA studies are ongoing and results from a Phase III study of ocrelizumab in people with primary progressive MS (PPMS) are expected later this year.
Source: Business Wire ©2015 Business Wire (30/06/15)
Gilenya ‘found to have long-term positive effects’ (30/06/15)
A new study published in the Journal of Neurology, Neurosurgery and Psychiatry has found long-term Gilenya therapy can maintain a low disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). The study, Long-Term (up to 4.5 years) Treatment With Fingolimod (Gilenya) In Multiple Sclerosis: Results From The Extension Of The Randomised TRANSFORMS Study, was conducted by an international team of researchers.
Gilenya is an immunomodulating drug and an effective therapy for RRMS. The safety, tolerability and efficacy of two oral doses (0.5 or 1.25 mg once daily) were assessed in the 12-month, randomised, double-blind phase three clinical trial called TRANSFORMS (NCT00340834) in relapsing remitting MS (RRMS) patients in comparison to treatment with interferon (IFN) beta-1a. The study revealed Gilenya at both doses significantly improved clinical and magnetic resonance imaging (MRI) outcomes with patients experiencing a reduction in the frequency of relapses in comparison to IFN beta-1a treatment.
Researchers conducted an extension study (up to 4.5 years) of the TRANSFORMS trial in which RRMS patients previously receiving Gilenya continued the same treatment and those under IFN beta-1a therapy received either 0.5 or 1.25 mg of the drug. The team analysed the patient’s annualised relapse rate, disability progression and MRI measures. In total, 1027 RRMS patients entered this extension study and only 772 completed it.
Researchers found the annualised relapse rate was significantly lower in patients under continuous Gilenya treatment than in patients who switched over from IFN beta-1a. Nevertheless, patients who switched from IFN to Gilenya exhibited a 50 per cent reduction in annualised relapse rate and a reduced MRI disease activity. Among the patients who switched therapies, there was an increase of around 50 per cent in the proportion of patients with no evidence of disease activity in the first year after Gilenya treatment. After 4.5 years of Gilenya therapy, both disability progression and MRI outcomes were not significantly different between the groups.
The research team concluded that switching from IFN beta-1a to Gilenya improved treatment efficacy, and that Gilenya therapy has a continuous long-term effect in maintaining a low disease activity in RRMS patients.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (30/06/15)
Link with antibodies offers new insight into MS diagnosis (26/06/15)
Researchers at Immco Diagnostics and the State University of New York have reported in the journal PLoS One that the frequency of specific auto reactive antibodies does not differ between patients with multiple sclerosis (MS) and people without the condition — a finding that could lead to improvements in diagnosis. The study is entitled “Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis.”
Patients with the progressive form of MS usually have a poor response to treatment, say researchers, as all approved therapies are currently indicated for the relapsing-remitting form. The progressive forms can be either primary progressive MS, where patients develop this form from the time of diagnosis, or secondary progressive MS, where patients initially experience a relapsing-remitting phase of neurological dysfunction that later evolves into a secondary progressive disease.
Immune auto reactive B cells and their antibody response have been reported previously by researchers to play a key role in MS development. In this study, the goal was to assess auto reactive antibodies’ frequency in patients with different MS forms, and see if they match up with clinical and magnetic resonance imaging (MRI) measures of MS disease progression. Possible co-morbidities were also evaluated, including infection by the Epstein-Barr virus (EBV), a common human herpes virus that targets B cells and which has been linked to an increased risk of MS.
Researchers analysed serum samples from patients and healthy controls for autoantibodies against three known antigens related to MS [CSF114(Glc), KIR4.1a and KIR4.1b] and against 26 different antigens linked to other autoimmune disorders, including systemic sclerosis, lupus, rheumatoid arthritis, among others.
Researchers found the frequencies of auto reactive antibodies against CSF114(Glc), KIR4.1a and KIRK4.1b were similar between healthy controls and RRMS, PPMS and SPMS patients, suggesting that these antibodies are not associated with MS or disease progression. In fact, none of the several autoreactive antibodies analysed, including anti-EBV antibodies, were found to differ in terms of frequency between MS patients and healthy controls.
The research team concluded that the frequency of the autoantibodies analysed in MS patients is similar to the ones in healthy controls, and that the presence of autoreactive antibodies was not associated with clinical and MRI measures of MS disease progression. Researchers expressed their concern that CSF114 and anti-KIR 4.1a and KIR 4.1b peptide antibodies might not have the diagnostic MS properties that were previously thought to have. These new insights could help physicians improve the diagnosis of MS in the future — a key advancement, since diagnosing and treating MS as early as possible is critically important to mitigating the disease.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (26/06/15)
'High prevalence of pain' highlighted in study (25/06/15)
Pain in multiple sclerosis (MS) patients is independently predicted by anxiety, according to a study published in Pain Medicine.
Jelena Drulovic, MD, PhD, from the Clinical Centre of Serbia in Belgrade, and colleagues conducted an international, cross-sectional survey to examine the prevalence, intensity, and associations of pain in MS. A total of 650 consecutive patients, diagnosed according to the Revised McDonald Diagnostic Criteria, were recruited from seven MS centres. During face-to-face interviews with neurologists, a semi-structured questionnaire was administered.
The researchers found the lifetime prevalence of pain was 66.5 per cent (point prevalence, 44.3 per cent). Comorbidity of pain and depression exhibited a prevalence of 29.1 per cent. There were significant associations between pain and older age, primary-progressive MS, higher Expanded Disability Status Scale score, and higher scores of Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety. Anxiety was found to be an independent predictor of pain in multivariate linear regression analysis.
"We confirmed high prevalence of pain, affecting approximately more than half of patients during the course of MS," the authors wrote.
"Pain in MS is associated with disability, depression, and especially with anxiety, which has significant implications for treatment."
Reference: Drulovic J et al. Pain Medicine. 2015; doi:10.1111/pme.12731.
Source: Neurology Advisor Copyright © 2015 Haymarket Media, Inc (25/06/15)
Herbicide detector could help with multiple sclerosis diagnosis (24/06/15)
The early diagnosis of certain types of cancer, multiple sclerosis and neuromyelitis optica, may soon be facilitated by the use of a nanometric sensor capable of identifying key biomarkers.
The nanobiosensor was developed at the Federal University of São Carlos (UFSCar), Sorocaba, in partnership with the São Paulo Federal Institute of Education, Science & Technology (IFSP), Itapetininga, São Paulo State, Brazil and was originally designed to detect herbicides, heavy metals and other pollutants.
"It's a highly sensitive device, which we developed in collaboration with Alberto Luís Dario Moreau, a professor at IFSP," said physicist Fábio de Lima Leite, a professor at UFSCar and the coordinator of the research group.
"We were able to increase sensitivity dramatically by going down to the nanometric scale,"
The nanobiosensor consists of a silicon nitride (Si3N4) or silicon (Si) nanoprobe with a molecular-scale elastic constant and a nanotip coupled to an enzyme, protein or other molecule.
When this molecule touches a target of interest, such as an antibody or antigen, the probe bends as the two molecules adhere. The deflection is detected and measured by the device, enabling scientists to identify the target.
"We started by detecting herbicides and heavy metals. Now we're testing the device for use in detecting target molecules typical of nervous system diseases, in partnership with colleagues at leading centres of research on demyelinating diseases of the central nervous system"
The migration from herbicide detection to antibody detection was motivated mainly by the difficulty of diagnosing demyelinating diseases, cancer and other chronic conditions before they have advanced beyond an initial stage.
The criteria for establishing a diagnosis of multiple sclerosis or neuromyelitis optica are clinical (supplemented by MRI scans), and patients do not always present with a characteristic clinical picture. More precise diagnosis entails ruling out several other options first.
The development of nanodevices will be of assistance in identifying these diseases and reducing the chances of false diagnosis.
The procedure can be as simple as placing a drop of the patient's cerebrospinal fluid on a glass slide and observing its interaction with the nanobiosensor.
"If the interaction is low, we'll be able to rule out multiple sclerosis with great confidence," Leite said.
"High interaction will indicate that the person is very likely to have the disease." In this case, further testing would be required to exclude the possibility of a false positive.
"Different nervous system diseases have highly similar symptoms. Multiple sclerosis and neuromyelitis optica are just two examples. Even specialists experience difficulties or take a long time to diagnose them. Our technique would provide a differential diagnostic tool," Leite said.
The next step for the group is to research biomarkers for these diseases that have not been completely mapped, including antibodies and antigens, among others. The group has begun tests for the detection of head and neck cancer.
Source: Phys.org © Phys.org 2003 - 2015, Science X network (24/06/15)
New technology looks into the eye and brings cells into focus (23/06/15)
Eye doctors could soon be using computing power to help them see individual cells in the back of a patient's eye, thanks to imaging technology developed by engineers at the University of Illinois.
Such detailed pictures of the cells, blood vessels and nerves at the back of the eye could enable earlier diagnosis and better treatment for degenerative eye and neurological conditions.
The technique applies adaptive optics – the method astronomers use to correct telescope images so they can more clearly see stars beyond the twinkling – to the instruments that scan the retina at the back of the eye. However, the Illinois team does the correction computationally, instead of using complex hardware. Led by electrical and computer engineering professor Stephen Boppart, the research team published its work in the journal Nature Photonics.
"The eye has always been a bit of a challenge to image. It's a very complicated organ," said Dr Boppart.
"There are many microscopic structures that are hard to see. Many diseases that affect vision also start at the microscopic level, so being able to see those early changes is going to lead to better, earlier treatment."
The prevailing imaging technique in ophthalmology, known as optical coherence tomography or OCT, is useful for general imaging of the eye but cannot focus down to the scale of individual rods and cones, the light-sensitive cells lining the retina that make sight possible. In addition, OCT images are often blurred by the eye's imperfections and constant motion.
Computational adaptive optics applies complex algorithms to OCT data correcting for eye aberrations and motion, yielding high-resolution, real-time images that show individual cells and nerves.
Hardware-based adaptive optics systems have been developed to enhance OCT imaging with elaborate setups of lenses, mirrors and lasers, but such systems are so costly and unwieldy that they are impractical for clinical use, Boppart said. However, the new computational approach could be applied to existing OCT systems, with minor hardware updates to older systems for compatibility.
Computational adaptive optics also hold an advantage over hardware setups in that they can tailor themselves to a patient's unique eye structures and shape, and doctors can take one quick scan and afterward focus in on different parts of the eye.
"I think computational adaptive optics can be really helpful to the clinical community," said Fredrick South, a graduate student and a co-author of the paper.
"It could give ophthalmologists information that, currently, they have to infer from other measurements. They can't directly look at the photoreceptors and watch them die off during macular degeneration, for example. They just have to guess what's going on. It could be possible to use computational adaptive optics in these real-world applications both for diagnosis of disease and tracking of treatments."
The researchers are initially focusing on using computational adaptive optics to track age-related macular degeneration, a progressive eye disease, and multiple sclerosis. Since nerve fibres make up the top layer of the retina, the eye could be a unique window into nerve health for multiple sclerosis patients, Boppart said. The researchers hope the detailed pictures gleaned from applying computational adaptive optics can illuminate how changes in the retina correspond to disease severity and track how cells and nerves respond to treatments.
"The eye is so important, because we rely on sight more than any of our other senses," Boppart said. "Here's a technology that was developed basically to remove the twinkle from stars, and now we want to use it to correct imperfections left by Mother Nature, allowing us to see patients' eyes better and to help them more."
Source: Phys.org © Phys.org 2003 - 2015, Science X network (23/06/15)
Study offers insights into energy metabolism in multiple sclerosis (23/06/15)
Researchers at the United Arab Emirates University in Abu Dhabi have published in the journal BMC Neuroscience new insights into the involvement of mitochondria and energy metabolism in the pathology of multiple sclerosis (MS) in rats.
The study is entitled Bioenergetics Of The Spinal Cord In Experimental Autoimmune Encephalitis Of Rats.
Mitochondria are small cellular organelles responsible for the production of energy (in the form of ATP) in the body through the process of respiration. Mitochondrial dysregulation has been linked to axonal damage and demyelination in MS human patients and the corresponding experimental autoimmune encephalomyelitis (EAE) model in mice.
Curiously, rodents have been reported to apparently recover from EAE with minimal neurological deficits. This recovery is thought to be linked to a downregulation of pro-inflammatory factors and clearance of infiltrating immune cells (T cells).
The cellular bioenergetics (energy metabolism) of the central nervous system (CNS) during the early development and clinical course of EAE has, however, been poorly investigated. In this study, the team hypothesized that the CNS bioenergetics may be used as a prognosis predictor of the disease and that it may explain disease remission in rodents, a recovery time where animals experience few or no symptoms. EAE susceptible and resistant rats were used and their oxygen consumption and ATP concentration in the spinal cord tissue were determined. Cell death (or apoptosis) was also assessed.
Researchers observed that in terms of cellular respiration in the CNS, no difference was found between diseased and healthy rats. Significant inflammation and apoptosis events were, however, observed in EAE susceptible animals, suggesting that both processes play a relevant role in the development of clinical disease, having little effect on mitochondrial function. These animals exhibited smaller mitochondria in the spinal cord regions with immune infiltrates. Demyelination events were also found in these specific regions at the initial stage of the disease.
The research team concluded that EAE at an early stage does not seem to significantly affect the CNS cellular respiration and ATP content, suggesting that the role played by mitochondria in demyelination and EAE development is minimal. The team hypothesizes that the recovery of rats with EAE might be due to the presence of a large population of functional mitochondria in regions of the spinal cord that have not been affected by the disease (no immune infiltrates). Based on the findings, the research team suggests that any intervention based on preserving the energy metabolism in EAE animals will likely improve disease outcome. Further studies are required to determine how these findings can be translated into the human context.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (23/06/15)
Study suggests benefits of vitamin D (23/06/15)
A team of researchers from the Isfahan University of Medical Sciences in Iran, led by Dr Masoud Etemadifar, have conducted a randomised controlled clinical study in 15 pregnant women with low vitamin D levels and multiple sclerosis.
Women treated with 50,000 IU/week (International Units) of vitamin D3 showed significantly higher vitamin D levels and fewer symptoms related to MS six months after delivery of their babies, as measured by the expanded disability status scale.
Although not statistically significant, the relapse number among the study participants also appeared to be lower in women supplemented with vitamin D.
The study did have limitations in that it was only exploratory in nature and featured a small sample size.
However, the findings revealed that, compared to routine care, the supplementation of pregnant women with MS with standard high-dose supplementation of vitamin D had a significantly positive effect on the disease.
These results are promising and warrant the need for further studies with larger sample sizes and longer follow-ups to ascertain the true safety and efficacy of supplementation in this subgroup of patients.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (23/06/15)
Drug firm turns to ancient Chinese medicine (22/06/15)
A company that specialises in turning University research into marketable drugs is licensing Harvard research related to the blue evergreen hydrangea root, a part of the plant that has been used in traditional Chinese medicine for centuries.
Allied-Bristol Life Sciences, a joint venture between university commercialisation specialist Allied Minds and US pharmaceuticals giant Bristol-Myers Squibb, is licensing research carried out by Professor Malcolm Whitman and Dr Tracy Keller at Harvard from 2002 onwards.
The pair found that the active ingredient in blue evergreen hydrangea root, called halofuginone, can block a type of rogue T-cell and also identified how it blocks these cells.
T-cells are the part of the immune system that tackles viruses, but rogue T-cells attack healthy cells and can cause inflammation and damage. This occurs in autoimmune conditions such as multiple sclerosis, type 1 diabetes and lupus.
Allied-Bristol Life Sciences is hoping to use the Harvard research, based on a synthetic form of halofuginone, to develop drugs to treat these types of conditions.
Whitman and Keller’s findings were published in 2012 and reported on the effects of halofuginone on a mouse with a model of multiple sclerosis. But this is the first time a company has explicitly stated they want to make a drug based on the research.
Blue hydrangea root has been used for at least 2,000 years in Chinese medicine and its efficacy was first noticed in the 1940s in the West, according to Harvard Magazine’s report of Whitman and Keller’s research.
But until the Harvard pair studied the root nobody knew exactly how it worked, meaning it was impossible to replicate its effects in a drug.
Allied-Bristol Life Sciences CEO Satish Jindal said: “The work done by Whitman and Keller is a terrific example of a promising early-stage therapeutic application that has the potential to make a significant difference to patients.
“We are pleased to support this project through the next phase of drug discovery to identify a candidate for clinical development. This is a great example of the type of university research that ABLS looks for, where our expertise and experience can accelerate bringing new therapies to patients that need them.”
Dr Whitman said: “Our research is at the right stage for an infusion of resources and expertise to accelerate its progression. We look forward to seeing the development of lead compounds from our laboratories into novel therapeutics for the treatment of fibrotic disease, and potentially other indications.”
Source: Business Insider Australia © 2007-2015 Allure Media (22/06/15)
3-D study of receptors throws up "surprises" (19/06/15)
Scientists at The Scripps Research Institute (TSRI) have teamed up with several other institutions and pharmaceutical companies, including the University of Southern California (USC), San Diego's Receptos Inc. and Japanese company Ono Pharmaceutical Co., Ltd., to publish the first 3D structures of a receptor implicated in many diseases of the brain and in normal physiology throughout the body.
Surprisingly, the structures revealed a new understanding of the body's use of cannabinoids—a naturally produced substance chemically related to marijuana.
The new research, published June 18, 2015, in the journal Cell, sheds light on the molecular architecture of receptors for a family of small fat molecules known as lysophosphatidic acid (LPA), part of a larger class of fat molecules (lysophospholipids) linked to conditions including hydrocephalus, pain, hypoxic brain damage, psychiatric disorders, multiple sclerosis, fibrosis and cancer.
"The study has particular relevance to understanding and possibly treating the brain," said TSRI Professor Jerold Chun. "This structure is the first for an LPA receptor—and it revealed a couple of surprises."
Chun is co-senior author of the study with Michael A. Hanson, president of GPCR Consortium and former director of structural biology at Receptos, and Raymond Stevens, director of the Bridge Institute at USC and founding director of iHuman Institute of ShanghaiTech University.
Chun and his colleagues first identified the protein, called lysophosphatidic acid receptor 1 (LPA1), in studies of the brain nearly 20 years ago. The LPA1 receptor sits within and spans membranes of cells to bind with LPA in the body. When bound, LPA1 sends a signal into the cell to influence a range of functions, such as cell migration, shape, survival and proliferation.
While the scientists knew the importance of LPA1, the Chun lab's studies into the biology of the molecule indicated that it was a kind of G protein-coupled receptor (GPCR), known to be difficult to image.
To overcome this challenge, in this study the team used techniques developed by Stevens and colleagues to stabilise the receptor in the presence of drug-like molecules synthesised by researchers at Ono Pharmaceutical. Stevens noted the work by Ono and the chemistry it did to enable the structural biology (with a focus on lung fibrosis) was a big breakthrough.
This collaboration enabled the formation of crystals that were used for x-ray crystallography, a high-resolution imaging technique.
The resulting data revealed two important features of LPA1.
One was the discovery that LPA1 lacks any sort of "cap" on top of it. Instead, it has an opening where ligands (binding partners, rather like keys to locks) can slip from the outside of the cell into the binding pocket. This allows ligands from aqueous sources to avoid the water-repelling lipids surrounding the receptor, solving the long-standing mystery of how LPA bound to proteins in blood and other fluids could easily activate LPA1.
Importantly, the researchers found LPA1 has a "baggy" binding pocket, suggesting that other molecules could bind within it. This route of entry contrasts with that of S1P1, a previously crystalised receptor for a distinct lysophospholipid (called sphingosine 1-phosphate or S1P), which possesses a more linear, rigid binding pocket.
This structural detail enabled the identification of new ligands capable of activating LPA1. Prior studies from the Chun lab had identified protein sequence similarities between LPA1 and cannabinoid receptors, but the commonly known ligands for these receptors did not activate LPA1. The structural data led the researchers to examine modified versions of cannabinoid ligands that might activate LPA1.
The new publication proved this prediction true, providing the first evidence of "cross-talk" between the two systems via a common receptor and establishing a new relationship between two, distinct families of fats—LPAs and the cannabinoids—offering new strategies for understanding and therapeutically accessing these distinct lipid signals.
"This series of structures further illuminates the field of lipid receptors enhancing our understanding of how closely related GPCRs distinguish between very similar endogenous ligands not only through binding interactions but also through route of entry," said Hansen.
"This is a new way of understanding a fundamental interaction between signalling lipids and their receptors," said Chun.
Chun calls the new study the "end of one chapter" his lab started 20 years ago with the identification of LPA1 "and the start of another" through the newly established links to cannabinoid signalling. "This feels good, and I'm happy to have been a part of it," said Chun.
Source: Phys.org © Phys.org 2003 - 2015, Science X network (19/06/15)
More positive data reported by MedDay (19/06/15)
MedDay, a biotechnology company focused on the treatment of nervous system disorders is reporting additional positive data from its pivotal Phase III clinical trial, MS-SPI, with MD1003, a highly-concentrated pharmaceutical grade biotin, in patients with progressive multiple sclerosis.
The data shows an improvement of the Clinical Global Impression of change observed after 12 months of treatment with MD1003 and confirms the positive results presented at the American Academy of Neurology in April 2015.
Frederic Sedel, Chief Executive Officer of MedDay, said: "We are pleased to announce further positive findings which confirm the promising MD1003 Phase III data announced earlier this year. MD1003 remains the only drug to date that has demonstrated an ability to decrease the rate of disease progression and improve a significant proportion of patients with progressive MS.
"A second phase III placebo-controlled trial is underway looking at the effect of MD1003 in MS patients with permanent visual loss following optic neuritis and we look forward to announcing data from this trial later this year and potentially investigating a drug filing thereafter."
The Clinical Global Impression of change is a seven point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as:
One - very much improved;
Two - much improved;
three - minimally improved;
Four - no change;
Five - minimally worse;
Six - much worse;
Seven - very much worse.
During the MS-SPI trial, the Clinical Global Impression of change has been assessed by the clinician (clinician global impression, CGI) as well as by the patient (subject global impression, SGI) after 12 months of treatment. Mean CGI and SGI scores assessed at month 12 were statistically significantly better in the intervention group compared with the placebo group.
These results confirm the previously reported data of MS-SPI where the primary endpoint was defined as the proportion of patients who improved either on EDSS or on timed 25-foot walk (TW25) at M9, with a confirmation of the improvement at 12 months (M12) was met.
The mean change of EDSS between M0 and M12 decreased in the MD1003 group compared to progression in the placebo group. In the MD1003 arm, only four per cent of patients treated with MD1003 exhibited EDSS progression at M9 confirmed at M12 vs 13 per cent in the placebo group (p=0.07), which equates to a 67 per cent decreased risk of progression in the active arm within the studied period.
Source: Copyright PR Newswire © 2015 PR Newswire Association LLC (19/06/15)
Copaxone patent invalidated again (19/06/15)
A U.S. appeals court has again invalidated a patent held by Teva Pharmaceutical Industries on its top-selling multiple sclerosis drug Copaxone, clearing the way for the launch of a cheaper, generic version.
The 2-1 decision by the U.S. Court of Appeals for the Federal Circuit, the nation's top patent tribunal, was a blow to Teva in its seven-year fight against two generic drugmakers over the patent protections for Copaxone.
It is the second time the appeals court has reviewed Teva's patent. In January, the U.S. Supreme Court said the appeals court took the wrong approach in its original decision to cancel the patent.
The extended litigation has benefited Teva, which has been able to continue to sell Copaxone without competition from other manufacturers that would offer steep discounts for their generic versions.
A Teva spokesman said the company is "committed to pursuing all legal pathways, including seeking further appellate review."
Two teams have been developing generic forms of Copaxone: one involving Novartis AG's Sandoz unit and Momenta Pharmaceuticals Inc and another involving Mylan Inc and Natco Pharma Ltd.
Momenta president and CEO Craig Wheeler said in a statement the company was pleased with the decision.
"We look forward to providing patients with a more affordable generic alternative for the treatment of multiple sclerosis," he said.
Teva's patent covered a method of manufacturing the drug. The Federal Circuit said that under the high court's latest standards for determining when a patent is too vague to deserve legal protection, the Teva patent is indefinite.
Teva "has failed to inform with reasonable certainty those skilled in the art about the scope of the invention," the court said.
Teva had sued Sandoz and Mylan in 2008 and 2009 in federal court in New York for patent infringement over their Copaxone copycat versions.
Central to the case was how the district judge interpreted a specific term in a key patent for the drug. The appeals court did not accept that interpretation and invalidated the patent.
The Supreme Court said the Federal Circuit should have deferred to the district judge unless there is evidence of "clear error," sending the case back down.
Source: Reuters © Thomson Reuters 2015 (19/06/15)
Biomarker identified to measure MS severity (19/06/15)
In a study published in the journal Nature Communications, researchers have clarified the lifespan of antibody-producing cells and have also identified a novel biomarker that could be used to monitor autoimmune conditions such as multiple sclerosis and lupus erythematous.
The humoral immune response is mediated by cells in plasma and is responsible for fighting infections. Plasma cells secrete antibodies, proteins that are able to identify pathogens and destroy them. However, antibodies with specific characteristics sometimes attack their host tissues causing autoimmune conditions like multiple sclerosis (MS) or lupus erythematosus(SLE).
“Balanced regulation of the production and activity of plasma cells is therefore vital,” Professor Edgar Meinl of the LMU Medical Centre said.
The researchers were able to identify a mechanism of action involved in the regulation of these antibody producing cells’ lifespan. Specifically, the researchers found a cell-surface receptor, called BCMA, can be a useful biomarker for monitoring the severity of autoimmune diseases.
The cells in the plasma are produced by B-cells, which carry certain membrane-bound receptors that are able to identify antigens. When B-cells recognize an antigen, they are able to differentiate it into a clone of plasma cells that secrete the antigen-binding protein in soluble form as antibody. But the life-span of these antibodies is dependent on the BCMA receptor survival.
The extension of the lifespan of the plasma cells is activated by the BAFF and APRIL survival factors, BCMA ligands.. “However, the lifetime of plasma cells cannot be prolonged indefinitely. Otherwise the organism would become swamped with antibodies, increasing the risk of an autoimmune reaction,” Meinl explained.
“We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane-bound enzyme gamma-secretase acts as a brake on immune reactions by fragmenting BCMA.”
BCMA extended the cell’s membrane and is projected in the extracellular medium. Gamma-secretase removes the exposed portion by cutting the protein inside of the plasma membrane. That this enzyme cleaves the receptor directly was a surprise: “Up to now, it was only known to be involved in the degradation of membrane proteins that had already been cleaved by other enzymes.
“BCMA is the first natural substrate of gamma-secretase to be identified that is directly cleaved by the enzyme,” said Meinl, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”
The cleaved fragment is constant, and can be detected in fluid of the body as soluble BCMA (sBCMA). The evidence from this new study showed that in patients with Lupus, the sBCMA levels in the blood are high and associated correlated with the disease severity.
“In MS patients sBCMA levels were increased specifically in the cerebrospinal fluid, which bathes the brain and the spinal cord,” said Meinl. “So, sBCMA is an indicator of the intensity of ongoing immune reactions. sBCMA is therefore well suited to serve as an informative clinical parameter for the assessment of the therapeutic effects of different treatment regimes on plasma cells.”
Results from this study could trigger the development of treatments, with both B cells and the BCMA/BAFF/APRIL mechanism being targets for lupus and multiple sclerosis, treatment.
Soure: Multiple Sclerosis News Today © BioNews Services 2015 (19/06/15)
Gene that "triggers" multiple sclerosis identified (18/06/15)
New research identifies a pivotal gene in multiple sclerosis, linking it to the most important genetic factor that drives the condition.
The human leukocyte antigen class II proteins (HLA-II) is the strongest genetic factor that influences multiple sclerosis. It helps the immune system distinguish the body’s own proteins from foreign proteins, and disturbing this system increases the chances of auto-immune disease. Researchers from The Netherlands and Qatar have discovered how mutation of a single base in the CLEC16A gene interferes with the normal function of HLA-II.
The mutation in CLEC16A results in a faulty HLA-II system, generating blind immune cells that are unable to differentiate pathogen-derived proteins (also known as antigens) from the body’s own proteins. When such blind immune cells escape to the brain, they destroy nerve-insulating myelin, resulting in multiple sclerosis.
The scientists found that silencing the activity of the CLEC16A gene in specific antigen-presenting cells disrupted the ability of HLA-II to display antigens on the cell membrane. Next, they identified that the levels of inactive CLEC16A protein in peripheral blood mononuclear cells of multiple sclerosis patients were two times higher than those of healthy individuals, indicating that CLEC16A has a role in the disease.
“In the future, immunology will continue to unravel what all the risk genes such as CLEC16A really do in the complex adaptive immune system, hopefully aiding the development of new drugs that could interfere with relevant disease-causing pathways,” says lead author Rogier Hintzen from the University Medical Centre, Rotterdam.
Source: Nature Middle East © 2015 Nature Publishing Group (18/06/15)
Researchers suggest short transition period between RRMS therapies (18/06/15)
A team led by researchers at the University Hospital Basel in Switzerland say they have found a short period of eight to 12 weeks is the optimal timing to be considered when patients with relapsing-remitting multiple sclerosis (RRMS) are switched from Tysabri (natalizumab) to Gilenya (fingolimod) therapy.
The study was recently published in the journal Neurology.
In this study, researchers conducted a randomised, multicentre, double-blind, placebo-controlled trial (TOFINGO) to determine the optimal timing for initiating Tysabri after discontinuing Gilenya in 142 RRMS patients. The goal was to maintain disease control and avoid potentially harmful additive effects on immune surveillance. The team tested the intervals of eight, 12 and 16 weeks between the last Tysabri infusion and the first Gilenya treatment over 32 weeks. Brain MRI recurrence and clinical disease activity were evaluated.
Researchers found in total, 78.9% (112) of the patients completed the study. The number of active MRI lesions was found to increase according with the duration of the interval between the two therapies. More patients were found to be relapse-free in the eight-week (88%) and 12-week (91%) periods in comparison to the 16-week period (84%). Of the cohort, 68% of the patients experienced mild or moderate adverse events with no major differences between the groups. No unusually severe relapses or opportunistic infections were reported.
The team concluded that patients with RRMS switching from Tysabri to Gilenya therapy should undergo a short period of eight to 12 weeks between therapies, as this time interval is associated with less MRI disease activity than longer periods. The authors suggest that additional studies should be performed to determine whether an interval shorter than eight weeks would further improve disease control with reasonable risks.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (18/06/15)
Researcher improves methodology for predicting genetic ‘mutations’ (16/06/15)
Researchers around the world have sequenced the genomes of patients living with from common, multi-gene diseases, looking for common mutations in their control regions. However these studies produce hundreds of mutations, many of which prove to be benign.
Now a research team led by associate professor of biomedical engineering, Michael Beer, have generated a new computational formula for predicting which mutations in control regions will wreak the most havoc. Their research has been published in Nature Genetics.
Their focus was on finding genetic control regions in stretches of DNA positioned near most genes. These regions act like dimmer switches which control the amount of each protein produced. Mutations in control regions generally have more subtle effects than mutations in genes themselves, but they can contribute to common, genetically complex, chronic diseases such as diabetes.
Beer’s team first “trained” their computer program to recognise and measure DNase sensitivity in susceptible genetic control regions. DNase is an enzyme that cuts DNA wherever it is not tightly wound. The openness of particular sequences of DNA varies among different types of cells and only control regions with open DNA can be active. How vulnerable certain stretches of DNA are to DNase is therefore an indication of which control regions are important in a given cell type.
They then computationally simulated “mutating” every DNA letter in turn and recalculated each section’s contribution to DNAse sensitivity. The larger the change in sensitivity after a given mutation, the more likely it is that that mutation will effect gene activity levels in the cell, Beer says.
The team compared these computer predictions to the known effects of some mutations, and to the predictions made by alternative programs. When the programs’ “rules” were set to be equally thorough in their searches, Beer’s program was 56 percent accurate — 10 times more accurate than the next best program.
Beer worked with Andrew McCallion, PhD an associate professor at the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine to further test the computational formula to predict the impact of mutations in the control regions for two pigment-related genes in mouse skin cells. They found that there was a strong correlation between the program’s prediction and the actual change experienced by the cells.
Dr. Beer and his team also tested their formula in mouse and human liver cells, and in human leukemia cells, and got similar results. They also tested their formula on three control region mutations already known to affect cholesterol levels, hemoglobin levels and prostate cancer. Again they found that these mutations drew higher computer scores than other mutations in the same control regions.
Finally, the team examined the control regions for T helper cells, a type of immune cell that can contribute to autoimmune diseases. Their calculations identified 15 different control region mutations associated with nine different immune system disorders from allergies to multiple sclerosis and Crohn’s disease. The research honed in on the exact genetic mutation that mattered. Beer says, “The next step is to test gene activity levels in patients and find out if our predictions were right. If so, it should help us determine how the activity is being perturbed and how we can fix it.”
This computational analysis can be repeated on many other diseases to provide timesaving insights for each.
Other authors of the report include Dongwon Lee, David Gorkin, and Maggie Baker, of the Johns Hopkins University School of Medicine, and Benjamin Strober and Alessandro Asoni who contributed to the project while undergraduates in the Department of Biomedical Engineering.
Source: Johns Hopkins Biomedical Engineering © 2015 Johns Hopkins Department of Biomedical Engineering (16/06/15)
Lifetime of antibody-producing cells is investigated (16/06/15)
Clinicians at Ludwig-Maximilians-Universitaet (LMU) in Munich have elucidated a mechanism involved in determining the lifespan of antibody-producing cells, and identified a promising new biomarker for monitoring autoimmune diseases like multiple sclerosis and lupus erythematosus.
The so-called humoral immune response is mediated by plasma cells and plays a central role in combating infections. Plasma cells secrete antibodies - a class of proteins that specifically recognise infectious pathogens and facilitate their destruction. Individual plasma cells make only a single species of antibody that normally recognizes a single structure. Nevertheless, antibodies with certain specificities may erroneously attack the tissues of their host, causing autoimmune diseases such as multiple sclerosis (MS) or lupus erythematosus (SLE).
“Balanced regulation of the production and activity of plasma cells is therefore vital,” says Professor Edgar Meinl (LMU Medical Centre).
Long-term antibody-mediated immunity is provided by so-called long-lived plasma cells, and Meinl and his research team have now identified a novel mechanism involved in regulating the lifespan of these antibody producing cells. This involves the shedding of a particular cell-surface receptor, named BCMA, which is known to bind factors that promote plasma-cell survival. The released segment that is cut off the receptor can be detected in the circulation, and the LMU group has shown that it provides a useful biomarker for monitoring the severity of autoimmune conditions.
Plasma cells develop from progenitors called B-cells that carry specific membrane-bound receptors which recognize foreign proteins termed antigens. When a B cell encounters its cognate antigen, it differentiates into a clone of plasma cells that secrete the antigen-binding protein in soluble form as antibody. How long an antibody-producing plasma cell survives in the body depends largely on the survival receptor BCMA.
When the BCMA binds its ligands, the survival factors BAFF and APRIL, a genetic program is activated which effectively extends the lifespan of the plasma cell.
“However, the lifetime of plasma cells cannot be prolonged indefinitely. Otherwise the organism would become swamped with antibodies, increasing the risk of an autoimmune reaction,” Meinl explained. “We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane-bound enzyme gamma-secretase acts as a brake on immune reactions by fragmenting BCMA.”
As a so-called transmembrane receptor, BCMA extends through the cell membrane and projects into the extracellular medium. Gamma-secretase removes the exposed portion by cutting the protein inside of the plasma membrane. That this enzyme cleaves the receptor directly was a surprise:
“Up to now, it was only known to be involved in the degradation of membrane proteins that had already been cleaved by other enzymes. BCMA is the first natural substrate of gamma-secretase to be identified that is directly cleaved by the enzyme,” said Meinl, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”
The cleaved fragment is stable, and can be detected in body fluids as soluble BCMA (sBCMA). Analysis of clinical samples from patients with multiple sclerosis or lupus erythematosus has indicated that the molecule could provide a useful biomarker for autoimmune disease. Lupus is a systemic condition which affects the whole organism. In lupus patients, levels of sBCMA in the blood were found to be abnormally high - and were correlated with the severity of the disease. Multiple sclerosis is an organ-specific disease, which targets the central nervous system.
“Correspondingly, in MS patients sBCMA levels were increased specifically in the cerebrospinal fluid, which bathes the brain and the spinal cord,” said Meinl.
“So, sBCMA is an indicator of the intensity of ongoing immune reactions. sBCMA is therefore well suited to serve as an informative clinical parameter for the assessment of the therapeutic effects of different treatment regimens on plasma cells.”
These findings could facilitate the development of optimized and personalized modes of therapy. Both B cells and the BCMA/BAFF/APRIL system constitute promising targets for the treatment of lupus and multiple sclerosis, as blocking their activity could inhibit the production of the autoimmune antibodies. In the case of lupus, an agent directed against BAFF has already been approved for clinical use. Unfortunately, for unknown reasons, it is effective in only a subset of patients. Further clinical studies on agents that target BAFF, APRIL and their receptors are currently underway. In future, sBCMA could be used to measure and optimize the impact not only of these new therapies but also of already proven treatments, since it enables one to monitor the levels of plasma cells.
Source: News-Medical.net Copyright 2000-2015 AZoM.com Limited (16/06/15)
MediciNova announces update on phase 2b trial (16/06/15)
MediciNova has announced that the ongoing clinical trial of MN-166 (ibudilast) in patients with progressive multiple sclerosis (PMS) has finished the randomisation of 255 patients, exceeding the initial goal of 250 patients.
The National Institute of Neurological Disorders and Stroke (NINDS) aims to conduct an interim analysis of the drug efficacy in the third quarter of 2016, once half of the patients have completed the treatment over 96 weeks.
Yuichi Iwaki, MD, PhD, president and CEO of MediciNova, said: “We are very pleased to have exceeded the enrolment target in this important study. The unmet medical need for progressive MS patients is extremely high as there is no treatment approved for long-term use for these patients. We look forward to providing further updates as the study progresses.”
MN-166 is a first-in-class, orally bioavailable, small molecule glial attenuator that suppresses pro-inflammatory cytokines IL-1ß, TNF-a, and IL-6, and may upregulate the anti-inflammatory cytokine IL-10.
The SPRINT-MS is a Phase 2 Secondary and Primary Progressive Ibudilast NeuroNEXT trial in patients with Multiple Sclerosis designed to evaluate the tolerability, safety, and efficacy of MN-166 (ibudilast) given twice per day to patients with primary or secondary progressive multiple sclerosis (PPMS or SPMS). It involves 28 clinical sites across the United States.
Patients were randomised to receive an inactive control (placebo) or MN-166 (ibudilast) 100 mg/day (50 mg twice daily). For the remainder of the study, patients may be either untreated with long-term disease modifying therapy (DMT) or may continue either glatiramer acetate (GA) or interferon beta (IFNβ-1a or IFNβ-1b) treatment.
The trial involves a controlled randomisation therapy status (IFN/GA verus. no DMT) and disease status (PPMS versus SPMS).
The study primary endpoints are to evaluate the activity of the drug in comparison to the placebo over a period of time of 96 weeks. This will be assessed with magnetic resonance imaging (MRI) using brain parenchymal fraction (BPF). The other primary endpoint involves the assessment of the drug safety and tolerability versus the placebo in with PPMS or SPMS patients. The study secondary endpoints involve imaging analyses of brain and retinal tissue integrity, cortical atrophy disability, cognitive impairment, neuropathic pain and quality-of-life. The study will also include an exploratory analysis of pharmacokinetic and biomarker.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (16/06/15)
‘Positive impact’ of Mediterranean diet (16/06/15)
Several studies have reported that the Mediterranean diet slows cognitive decline and lowers risk of neurodegenerative conditions. While most of the research has been conducted in Mediterranean countries, consumption of the Mediterranean diet by other population groups have provided similar results.
A study on 2,000 New Yorkers who consumed the Mediterranean diet reported lower risk of Alzheimer’s disease; and another study on 1,410 elderly French individuals found slower cognitive decline with higher adherence to the Mediterranean diet. Last year, a review article called the Mediterranean diet a “model” diet for the prevention of Alzheimer’s disease.
While high intakes of cereals, vegetables, legumes, fruits and olive oil that make up the typical Mediterranean diet are recognised to be beneficial, a recent study found long-term consumption of a Mediterranean diet supplemented with extra virgin olive oil or nuts had a positive impact on cognitive function in an older Spanish population. Phenolic compounds present in extra virgin olive oil and nuts may be the components responsible for this positive effect on cognition, according to the investigators of the study.
In an article published in the March, 2015 issue of the journal Molecules, researchers specifically reviewed literature to explain how phenols present in extra virgin olive oil prevent neurodegenerative diseases.
According to the paper, olive oil contains about 230 chemical compounds of which carotenes and phenolic compounds are the main antioxidants. Of the phenols, hydroxytyrosol is the key phenolic compound present mainly in olives and olive products that are, in turn, the chief source of hydroxytyrosol in the Mediterranean diet.
Scientific evidence suggests that, as a potent antioxidant, hydroxytyrosol is not only effective in removing reactive oxygen species produced during oxidative stress, but it may also improve an organism’s defense against oxidative stress.
Oxidative stress, which produces more reactive oxygen species than the body can detoxify, may cause damage to the DNA and body proteins, and may be the origin of neurodegenerative conditions such as Alzheimer’s and Parkinson’s, as well as cancer, atherosclerosis, and diabetes.
Extensive research has identified hydroxytyrosol from olive oil to possess antioxidant, antimicrobial, and antidiabetic abilities. Additionally, hydroxytyrosol may provide protection against heart diseases and play a role in preventing or slowing the growth of tumors.
Research carried out in vitro and ex vivo to determine hydroxytyrosol’s role as a neuroprotective agent shows that hydroxytyrosol from olive oil protects cells from oxidative stress, improves resistance to oxidative stress, lowers incidence of brain cell death, and reduces neurotoxicity and DNA damage.
Furthermore, in some in vitro studies, hydroxytyrosol has been associated with the nuclear factor E2-related factor 2 (Nrf2) and Antioxidant Responsive Elements (ARE) neuroprotective pathways. The Nrf2 plays a positive role in regulating antioxidant response elements, which in turn regulate gene expression of several phase II detoxifying enzymes.
Supplementing the diet of mice with extra virgin olive oil and hydroxytyrosol enhanced cognitive function, and reversed oxidation, learning and memory damage. In another study, EVOO and hydroxtyrosol acted as brain antioxidants and provided protection against oxidative damage in mice with Huntington disease.
While in vitro and in vivo studies on animal models have linked hydroxytyrosol to improved health and cognition, there are very few studies on the effect of hydroxytyrosol in humans. So far, only three clinical trials on the role of hydroxytyrosol on breast cancer prevention; the effect of hydroxytyrosol supplements on multiple sclerosis; and its influence on phase II enzymes are underway.
Although more research is needed to establish the role of EVOO hydroxytyrosol in preventing neurodegenerative diseases, there is ample evidence that suggests that consuming a Mediterranean diet is beneficial for cognitive health.
Source: Olive Oil Times © 2015 Olive Oil Times (16/06/15)
Test could find complete virus history (05/06/15)
A new blood test can find just about every virus you ever caught — in a single drop of blood.
Doctors are hoping the test might be used to find out whether viruses might cause a range of chronic diseases such as diabetes or heart disease, and to see whether infections early in life can affect your immunity later.
"VirScan is a little like looking back in time. Using this method, we can take a tiny drop of blood and determine what viruses a person has been infected with over the course of many years," said Stephen Elledge, a Howard Hughes Medical Institute researcher at Brigham and Women's Hospital in Boston, who led the study.
"Right now, a physician needs to guess what virus might be at play and individually test for it. With VirScan, we can look for virtually all viruses, even rare ones, with a single test."
The test looks for the body's immune response to viruses. It finds antibodies that keep the viruses from coming back, which can stay circulating in the blood for years.
Elledge thinks the test will cost about $25 (£16) to run.
There are thousands of viruses, from rhinoviruses and adenoviruses that cause the common cold, to the human immunodeficiency virus that causes AIDS. A total of 206 different species of viruses are known to infect people, and each species has various strains.
Most blood tests are designed to look for one particular virus at a time. Elledge and his colleagues wanted to design a test that would find all the viruses — a collection called the virome.
They developed the test using bacteriophages, which are viruses that attack bacteria. They engineered different bacteriophage to make a little piece of protein from more than 1,000 known viruses.
The test goes into a drop of blood, which is enough to carry all the antibodies trained to recognize a virus that's infected someone — or those activated by a vaccine.
Writing in the journal Science, the team said they tested blood samples from 569 people from the United States, Peru, South Africa and Thailand.
On average, people had antibodies against 10 species of virus. There were a few people who'd been infected with many different viruses — five people had antibodies against 62 species, and two had been infected with 84 different species.
It's well known that viruses can cause disease. The human papilloma virus (HPV), for instance, causes cervical cancer, as well as head and neck cancer and cancers of the genitals. Epstein-Barr virus, which infected 88 percent of the volunteers, is linked to lymphoma and is suspected of causing some cases of stomach cancer. It's also been linked with multiple sclerosis.
Enterovirus D-68, a distant relative of polio, concerned doctors when it made an unusual resurgence last year and appeared to cause a mysterious polio-like syndrome in a few children.
Having a test that can look for all sorts of viral infections at once can help researchers tighten up these links, and also help them find possible other links between viruses and long term health.
It's not perfect, however, and Elledge said some viruses didn't turn up as often as they expected.
"For example, the frequency at which we detect influenza (53.4 per cent) and poliovirus (33.7 per cent) is lower than expected given that the majority of the population has been exposed to or vaccinated against these viruses," they wrote.
It also only found that about 24 percent of the people tested had antibodies to chickenpox, also called varicella, which is far fewer than expected.
But when they tried the test against people who knew they had HIV and hepatitis C, the test was 95 to 100 percent accurate. "We didn't falsely identify people who were negative," Elledge added. "That gave us confidence that we could detect other viruses, and when we did see them we would know they were real.
"Although we detected antibody responses to rare and highly virulent viruses such as Marburg and bat lyssavirus, they were found in less than 0.4 percent of the population.”
Elledge's team says the test could easily be expanded to include other human pathogens such as bacteria, fungi, and protozoa. The test might also be used to find out if there are consequences of being infected with two or more particular viruses.
Source: NBC © NBCNews.Com (05/06/15)
Oral MS medications ‘don't improve treatment adherence’ (04/06/15)
Caitlin Dionne, RN, of Lahey Outpatient Centre in Massachusetts, and colleagues developed the MS Treatment Adherence Questionnaire in order to draw more honest answers about treatment compliance out of MS patients, noting that patient response to direct physician inquiry is often questionable.
The questionnaire included six questions related to DMT use: number of missed doses in four weeks; reason dose was missed; perceived side effects; ease of administration; and medication satisfaction. In the study, medication types were divided into subcutaneous or intramuscular (SC/IM), monthly IV injections, or oral DMTs.
Between October and November 2014, Dionne and colleagues collected data from 209 patients. Eighty nine patients (42.5 per cent) were on oral medication, 90 (43 per cent) on SC/IM, and 30 (14.5 per cent) on IV infusion. Among patients on oral DMTs, 45 per cent reported no missed doses, compared to 70.8 per cent of SC/IM and 93.3 per cent of IV infusion patients. Ease of taking the medication did not seem to affect treatment compliance, as 77 per cent, 60 per cent, and 33 per cent of patients on oral, IV, and SC/IM injections reported ease of use, respectively. Among patients taking oral and SC/IM injections, forgetfulness was among the top reasons for missing a dose.
As for how side effects may affect compliance, the majority of patients on IV infusion did not experience side effects, while 18.6 per cent of orals and 20.2 per cent of SC/IM patients reported them.
The authors speculated that side effect profiles related to oral DMTs may be at the centre of the reason for the poor compliance rates among oral users, despite oral DMTs' association with ease of use.
In another study, researchers from Washington, D.C.'s Veterans Affairs Medical Centre evaluated the effects of using a telehealth program on DMT compliance. The preliminary study, which followed 30 patients for six months, compared compliance rates with use of a MS-specific home automated telehealth system (MS HAT) to treatment as usual.
Patients — all who used SC/IM injections — who were assigned to the MS HAT group received text or email reminders to administer their medication through the system, which supports patient self-management, patient-provider communication, and patient education.
Although the MS HAT administration reminders was negatively correlated with syringe counts, the authors noted that as self-report adherence improved, the number of syringes collected increased. Overall, the results suggest that monitoring self-reported adherence through an automated teleheath system is a reliable method of assessing DMT adherence.
Source: Neurology Advisor © 2015 Haymarket Media, Inc. (04/06/15)
Effects of Lemtrada ‘long lasting’ study finds (04/06/15)
Longer-term data indicate the effects of Lemtrada are long-lasting in patients with relapsing-remitting multiple sclerosis (RRMS).
An extension study showed patients treated with the drug remained free of new MRI disease activity for up to four years, even though most of them had not had a treatment for 3 years.
The rate of brain atrophy also remained low in these patients at the end of four years.
The drug, which targets the CD52 antigen found in abundance on B cells and T cells, received US Food and Drug Administration approval in November to treat patients with MS in whom two other therapies had failed. The drug depletes these B and T cells, which are thought to cause the damaging inflammatory process in MS, before these cells "come back and repopulate," said MS expert Ann Bass, MD, Neurology Center of San Antonio, Texas.
It's believed this distinctive pattern of B and T cell repopulation may rebalance the immune system.
But the drug carries risks for significant adverse effects, which can include infusion-associated reactions such as itchiness, gastrointestinal adverse effects, kidney disease, infections, and thyroid disorders, that require "heavy" laboratory monitoring, said Dr Bass.
For this reason, Lemtrada is typically used only in patients with highly active disease. "Candidates for this treatment include those who have already had a relapse on their current therapy, those who have MRI activity that's breaking through on the current therapy, and those who have disability progression that's worsening even on current therapy," said Dr Bass.
The two-year multicenter, rater-blinded study, CARE-MS II, one of two pivotal trials for the drug, showed that compared with patients with RRMS taking subcutaneous interferon β-1a, 44 μg, those who had received a baseline Lemtrada treatment (12 mg) and another treatment at 12 months had a 49 per cent decreased annualised relapse rate and a 42 per cent decrease in six-month sustained accumulation of disability.
The drug seems to have "this nice control of the disease in the absence of ongoing treatment, which is quite novel," commented Anthony Traboulsee, MD, University of British Columbia, Canada.
"One of the important questions is how long will this last before there is some breakthrough disease activity."
That, he said, was the point of the open-label extension study.
At the end of the original two-year trial, patients who were receiving interferon could opt to begin taking the drug, and those who were already taking it could receive additional treatments — a third and fourth cycle — as needed.
For this analysis, MRI outcomes included gadolinium (Gd)-enhancing, new or enlarging T2 hyperintense and new T1 hypointense lesion activity; freedom from MRI activity (absence of Gd-enhancing and new or enlarging T2 lesions); and brain volume loss measured by change in brain parenchymal fraction (BPF).
Of the original study cohort, 393 (92.9 per cent) patients entered the extension phase. At four years, 67.7 per cent of these patients had received only the initial two courses of treatment, 24.2 per cent had needed one additional course, and 7.4 per cent had received two additional courses.
The proportions of patients free of Gd-enhancing lesions were 86.5 per cent and 89.1 per cent at years three and four respectively. The numbers of new or enlarging T2 (69.0 per cent and 70.3 per cent) or new T1 lesions (87.5 per cent and 86.3 per cent) remained stable.
Most patients were free of MRI activity at year three (68.4 per cent) and year four (69.9 per cent).
"What makes it novel is the fact you can go for years and years after your treatment without having new MRI activity," commented Dr Traboulsee.
The durable effects of the drug may be due to the distinct pattern of lymphocyte depletion and repopulation following treatment, said Dr Traboulsee.
Source: Medsape Multispeciality © 1994-2015 by WebMD LLC (04/06/15)
New MS drug shows good results (04/06/15)
Daclizumab HYP (Zinbryta) may have an advantage over interferon-beta-1a (Avonex) in terms of patient-centred functional outcomes in multiple sclerosis (MS), researchers claim.
In a post-hoc analysis from the DECIDE trial, patients on Daclizumab HYP had greater improvements in specified measured areas than those on the interferon-beta-1a, Michael Kaufman, MD, of Carolinas Health Care, and colleagues reported at the Consortium of Multiple Sclerosis Centers meeting.
The DECIDE trial previously found Daclizumab HYP cut relapse rates and disability progression to a greater extent than interferon-beta-1a.
For the post-hoc analysis, Kaufman and colleagues looked at data from a 1,841-patient trial that randomised relapsing-remitting patients on both drugs. They assessed outcomes on the Multiple Sclerosis Functional Composite (MSFC) test, which includes three standard MS ambulatory assessments -- the Timed 25-Foot Walk test (T25FW), the Nine-Hole Peg Test (9HP), and the Paced Auditory Serial Addition Test-3 (PASAT-3). They also assessed cognitive function using the Symbol Digit Modalities Test (SDMT).
They found that over the 96-week study period, the median z-score change from baseline in the MSFC was significantly greater in the daclizumab HYP group.
The authors also reported significantly greater improvements in cognition.
"Over two to three years, daclizumab HYP showed greater improvement than interferon-beta 1a in patient-centred measures of functional disability," Kaufman said. "This supports earlier findings that daclizumab HYP demonstrated superior efficacy to interferon beta-1a across key clinical and radiographic MS outcome measures. It has the potential to be a new therapeutic option for relapsing-remitting MS."
The HYP at the end of the drug's name stands for high yield process, which is intended to distinguish the drug from an earlier formulation sold as Zenapax. Biogen and AbbVie recently filed the biologics license application (BLA) for daclizumab HYP.
Source: MedPage Today © 2015 MedPage Today, LLC (04/06/15)
Missing link found between brain and immune system (02/06/15)
In a discovery that could overturn decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist.
That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.
"Instead of asking, 'How do we study the immune response of the brain?' 'Why do multiple sclerosis patients have the immune attacks?' now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG).
"It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can't be studied. But now we can ask mechanistic questions.
"We believe that for every neurological disease that has an immune component to it, these vessels may play a major role. Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component."
Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, described his reaction to the discovery by Kipnis' lab: "The first time these guys showed me the basic result, I just said one sentence: 'They'll have to change the textbooks.' There has never been a lymphatic system for the central nervous system, and it was very clear from that first singular observation - and they've done many studies since then to bolster the finding - that it will fundamentally change the way people look at the central nervous system's relationship with the immune system."
The discovery was made possible by the work of Antoine Louveau, PhD, a postdoctoral fellow in Kipnis' lab. The vessels were detected after Louveau developed a method to mount a mouse's meninges - the membranes covering the brain - on a single slide so that they could be examined as a whole. "It was fairly easy, actually," he said. "There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn't have worked."
After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: "I called Jony [Kipnis] to the microscope and I said, 'I think we have something.'" As to how the brain's lymphatic vessels managed to escape notice all this time, Kipnis described them as "very well hidden" and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. "It's so close to the blood vessel, you just miss it," he said. "If you don't know what you're after, you just miss it."
"Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris," Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the "phenomenal" surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.
The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.
Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (02/06/15)
Multiple sclerosis patients have less vascular comorbidities (02/06/15)
People with multiple sclerosis may have lower rates of vascular comorbidities, including hypertension, diabetes, and hyperlipidemia, results from a study indicate.
Elizabeth Triche, PhD, of St. Francis Hospital and Medical Center in Hartford, Connecticut, and colleagues looked at vascular complications in a single-center cohort of multiple sclerosis (MS) patients in the general population. The results were presented in a poster session at the Consortium of Multiple Sclerosis Centers 2015 Annual Meeting.
Among 200 MS patients (mean age 45 years) with a mean disease duration of eight years and mean body mass index (BMI) of 28 kg/m2, rates of vascular comorbidities were similar to the general population, however, upon further analyses, gender and age-specific differences emerged.
In women aged 20 to 44 with MS, 4.1% had hypertension compared to 8.7% of the general population, and in women aged 45 to 64, hypertension rates were 25% compared to 39.5% in the general population. A similar trend was seen for hyperlipidemia, with 23.5% of women with MS aged 45 to 64 with hyperlipidemia compared to 42.4% of the general population.
The opposite trend was seen for diabetes in women with MS, where compared to the general population, 4.1% of women with MS aged 44 and under had diabetes compared to 1.7% of the general population.
Among men with MS, rates of hypertension and hyperlipidemia were similar across age groups in both cohorts; however men with MS (all age groups) had lower rates of diabetes than the general population.
The mechanism of the relationship isn't fully understood, however some have suggested that the lower rates of vascular comorbidities among people with MS is related to MS patients having greater access to healthcare.
Triche EW et al. Poster EG08. Vascular Comorbidities Among Patients with Multiple Sclerosis at a Comprehensive Care Center. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27-30, 2015; Indianapolis, IN.
Source: Neurology Advisor © 2015 Haymarket Media, Inc (02/06/15)
Lemtrada ‘a permanent therapy’ claims doctor (01/06/15)
Speaking at the 2015 Annual Meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis, Indiana, Mr Samuel F. Hunter, MD, PhD, president of the Advanced Neurosciences Institute in Franklin, Tennessee, gave a presentation on outcomes in patients with relapsing multiple sclerosis (MS) treated with Lemtrada (alemtuzumab).
He said the first trial began 24 years ago, so primary care physicians may want to share this with their MS patients who are concerned about trying a “new” drug.
Hunter said Lemtrada is thought of as a “permanent” disease-modifying therapy.
“It cleans the immune system up, both the B and T cells. Transiently, it removes a lot of these cells and lets the immune system reconstitute. No one knows how it can make MS better yet, but the immune system is different,” he said.
At the same time, there is a risk of autoimmunity, infusion reactions, and malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders in patients who receive treatment.
He said Lemtrada was the first drug that was tested head-to-head with interferon beta-1a, which is the standard treatment. In the two trials that were done, he said it was clear Lemtrada was much more effective than interferon beta-1a.
“The longer it goes, the better it looks because you’re changing the immune system with Lemtrada,” he said.
Hunter added that Lemtrada is good in the short term and even better in the long term for relapsing-remitting MS.
“This is a big stick for treating relapsing MS,” he said. “It has a little more risk than other treatments, but you get something for it that any internist could manage.”
This includes monthly laboratory testing for kidney problems at the manufacturer’s expense to watch for blood, thyroid, or kidney problems.
Hunter conducted a phase I non-randomised open label study of 60 patients, using them as their own control. Most patients who switched to Lemtrada had been on the injectable drugs interferon beta-1a or Copaxone.
He said most patients stayed stable for up to two years after one treatment and then got even better with more treatments. “It’s clear Lemtrada works for a while, then it wears off and then we retreat those patients,” he said.
“MRI is really boring after treatment because it stays calm,” Hunter added. “At the same time, some will also get worse. You just have to find the treatment responders.”
Source: MD All Specialities Copyright MD Magazine 2006-2015 Intellisphere, LLC (01/06/15)