Ireland-based biopharmaceutical firm Alkermes has started a Phase I clinical trial of ALKS 8700, a novel monomethyl fumarate (MMF) molecule being developed for the treatment of multiple sclerosis (MS).
The trial will assess the safety, tolerability and pharmacokinetics of several oral formulations of ALKS 8700 compared to both placebo and active control groups in approximately 125 healthy volunteers.
ALKS 8700 is designed to rapidly and efficiently convert to MMF in the body and provide differentiated features compared to the currently marketed dimethyl fumarate, Tecfidera.
Alkermes chief medical officer Elliot Ehrich said: "We expect the results of this study to be highly informative and determine the therapeutic utility and differentiating features of ALKS 8700.
"ALKS 8700 leverages Alkermes' expertise in prodrug chemistry and oral controlled-release formulations to offer potential differentiated tolerability and dosing for patients with MS."
The randomized, double-blind trial will investigate the pharmacokinetics and pharmacodynamics of multiple formulations and doses of ALKS 8700 and is designed to determine those suitable to progress into advanced clinical testing.
The start of the Phase I trial follows the company's filing of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA), and the issuance of a composition of matter patent for ALKS 8700 from the US Patent and Trademark Office (USPTO) in March 2014, which is expected to provide patent protection into 2033.
Source: PBR Contract Research & Services © PBR 2010. Part of Progressive Digital Media Group Plc (21/07/14)
A common cold treatment and seven other drugs already approved for other conditions could help restore a protective coating eroded around neurons in multiple sclerosis patients, according to researchers led by a team at the University of California, San Francisco.
UCSF is spearheading a 50-patient clinical trial of the most promising drug — an over-the-counter antihistamine branded by Novartis as Tavist — that is expected to be completed by the end of the year.
Researchers warn MS patients not to rush out to buy Tavist, which also is sold generically as clemastine fumarate, because its safety and effectiveness is unknown in MS patients. What’s more, they don’t know what the proper dosage or treatment regimen of the drug might be for multiple sclerosis.
Still, the emergence of Tavist and the seven other drugs is a huge potential win for MS patients and researchers who only 14 months ago launched a new method for quickly screening 1,000 drugs already approved by the Food and Drug Administration for other conditions.
“A major unmet need in the development of therapeutics for repair in MS has been the ability to screen compounds in a high-throughput manner,” Jonah Chan, a neurology professor and senior author of a paper that appeared Sunday in the Journal Nature, said in a press release.
The research group includes scientists from Third Military Medical University in Chongqing, China, the University of Cambridge in the United Kingdom, and Trianja Technologies, north of Dallas.
Multiple sclerosis is a central nervous system disease in which the immune system attacks healthy nerve tissue, destroying the fatty myelin sheaths that are meant to protect the cells. By disrupting the electrical signals from the central nervous system to the body, MS leads to muscle weakness, worsening vision, poor balance or coordination, memory problems and other symptoms.
About 2.3 million worldwide have MS, according to the Multiple Sclerosis International Federation.
Researchers for years have focused potential treatments on soothing the inflammation caused by the intermittent and progressively worsening immune system attacks. Over the past decade, however, they have focused much of their work on stopping the erosion of myelin and, potentially, restoring myelin and protecting neurons.
Only last month drug maker Roche, the parent company of South San Francisco-based Genentech Inc., and Menlo Park-based venture capital firm Versant Ventures formed a company focused on regrowing myelin in MS patients. The basis for that company is a screening technology developed by Chan and his colleagues at UCSF.
The new automated system crafted by Chan’s research group, supported by donations to UCSF's MS Research Group, UCSF's Clinical and Translational Science Institute and the National Multiple Sclerosis Society, quickly tested if 1,000 FDA-approved drugs had any effect on oligodendrocyte precursor cells. So-called OPCs are the cells from which oligodendrocytes are derived in the brain and spinal cord, and it is those specialized oligodendrocytes that myelinate extensions of neurons that transmit signals to the brain. All eight drugs identified by the research team have a common mechanism of action — blocking a specific receptor — but clemastine was the most effective, according to UCSF. But there are five types of that receptor expressed in the nervous system and researchers want to know if clemastine blocks a single receptor of a combination.
In the ongoing Phase II trial — the second of the typically three-stage FDA drug-approval process — researchers mainly want to see if clemastine has an effect on MS patients’ vision at one, three and five months of treatment.
Patients in the trial will receive one four-milligram tablet of clemastine or a placebo twice a day for three months.
Source: San Francisco Business Times © 2014 American City Business Journals (07/07/14)
A casual conversation in a hockey locker room prompted a business partnership that may eventually help people suffering from multiple sclerosis and other neuro-degenerative diseases.
Joseph S. Erlichman, a biology professor at St. Lawrence University, and Mark L. Brackett, president of the Kinney Drug Inc. Foundation, are working with others to develop a drug to treat diseases such as MS and Amyotrophic Lateral Sclerosis, also known as Lou Gehrig’s Disease.
After playing hockey one evening, the two men discussed research that Mr. Erlichman and a few of his colleagues were conducting on live brain slices from mice.
The study focuses on observing how the compound cerium oxide affects neuro-damage that’s taken place in the mice. The rodents are observed after they’re placed on a motor-skill apparatus like a treadmill or balance beam to see if they show improvement after taking the cerium oxide.
For the past several years, students from SLU have been involved in that part of the research.
Mr. Erlichman said the results have been promising so far.
“We’ve been accruing an enormous amount of data,” he said. “We’ve found this has the potential to mitigate or decrease tissue damage or disease progression in a wide variety of pathologies.”
Essentially, the compound is effective at neutralizing free radicals that are associated with many pathological diseases, Mr. Erlichman said.
For multiple sclerosis, the compound appears to be as effective as Gilenya, a drug now used to treat the disease in humans, he said.
“We have also used the nanoparticles in the treatment of a mouse model of ALS with promising results,” he said.
In 2009 Mr. Brackett and Mr. Erlichman created the company Neuroredox, with Mr. Brackett serving as its chief executive officer.
Later they teamed up with Cerion Enterprises, a Rochester-based company, to create a new joint venture company, erion NRx, which will continue the necessary steps involved with developing the drug.
Other SLU professors have also been involved in the research, including William DeCouteau, Ana Y. Estevez, Karin Heckman and Matthew C. Skeels.
Upcoming steps include receiving approval from the Food and Drug Administration to test the drug’s effectiveness on humans. Determining whether the drug is toxic to humans will be a main factor in determining if it can be marketed to a pharmaceutical company and then sold to the public, Mr. Brackett said.
Finding a pharmaceutical company to invest in the product and applying for federal funding are other hurdles.
“You have to get all the ducks in a row,” Mr. Brackett said. “We have hired a consultant who has taken other drugs to market.”
Mr. Brackett, a former pharmacist, said he has been interested in neurological diseases for many years.
“These diseases cause a great deal of devastation and pain to families. We think we can help that,” he said.
Source: Watertown Daily Times (27/02/14)
Potential 'cure' for multiple sclerosis to be tested The National Center of Neurology and Psychiatry has developed a drug that it says might provide a cure to multiple sclerosis.
The center announced Monday that it will start a three-month clinical trial from March on nine patients. If the drug’s efficacy is confirmed, it will move on to a large-scale trial.
“We are hopeful as preliminary studies have produced very good results,” said Takashi Yamamura, head of the immunology department responsible for the drug’s development. About 2.5 million people around the world are estimated to suffer from the disease, which causes symptoms such as numbness, motion problems and vision loss. In Japan, there are an estimated 15,000 sufferers, including many young women, and the number is growing.
The autoimmune disease occurs when lymphocyte immune cells misidentify the body’s own cells as foreign. They attack nerve cells, causing inflammation and destroying them.
The drug developed by Yamamura stimulates a type of immune cell that softens the attacks by lymphocytes and creates a protein that suppresses inflammation. In the clinical trial, the drug will be drunk in powder form dissolved in water, according to the center.
Source: THE JAPAN TIMES © THE JAPAN TIMES LTD (26/02/14)
Quite often, the development of novel therapies for one disease indication later gives rise to its application for other diseases as well. In the case of Multiple Sclerosis treatment, the non-profit Myelin Repair Foundation (MRF) may have identified a proven drug for hypertension that could be used to stimulate repair and protect the brain in MS patients.
The discovery will be further explored in a new clinical trial that will be facilitated through a Cooperative Research and Development Agreement (CRADA) between the MRF and the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) at the NIH Clinical Center, which will seek to assess the use of hypertension drug MRF-008 as a potential neuroprotective therapeutic for Multiple Sclerosis.
The collaboration between the MRF and NIH is a unique one, since the Myelin Repair Foundation is a true non-profit research group that directs its research goals from a completely practical, patient-driven perspective, seeking to develop tangible Multiple Sclerosis treatments that can be realistically developed and commercialized. The Foundation’s commitment to publishing provable, reproducible results, together with the vast talent and resources at the NIH, bode well for fully exploring the efficacy of MRF-008 patients.
Scott Johnson, CEO, President and Founder of the Myelin Repair Foundation and himself a Secondary Progressive MS patient seeking viable, effective treatments in the near future, commented on the Foundation’s new collaboration with the NIH and what it could mean to future MS treatment options, stating, “As a non-profit organization beholden to patients, not profits, we are uniquely positioned to advance MRF-008, a generic drug identified by the MRF academic consortium, forward as a novel therapeutic candidate to stimulate repair for multiple sclerosis,” adding that, “With the NIH’s eminent expertise in MS clinical trials, we have found an exemplary partner to conduct the research necessary to assess MRF-008. With world-class advisors, academic scientists, industry partners and this opportunity to collaborate with NIH scientists, we remain on track to develop and deliver the next generation of MS therapeutics for patients.”
The MRF delivers substantial results from its research through the Foundation’s Accelerated Research Collaboration™(ARC™) model, which is designed to accelerate promising therapeutics to market through streamlining the research and development of promising compounds from the lab to the clinic, and ultimately to Multiple Sclerosis patients. MRF leveraged its ARC model to forge its new relationship with the NIH on studying the viability of MRF-008, and will continue to utilize the platform to facilitate partnerships between top academic scientists, pharmaceutical partners, and other key biotech and life sciences influencers.
The Myelin Repair Foundation will work closely with the NIH to assess MRF-008 as a therapeutic candidate in an MS clinical trial. MRF-008 is a generic FDA-approved compound for the treatment of hypertension identified by the Myelin Repair Foundation’s academic research consortium as a novel drug repurposing candidate for neuroprotection to stimulate MS repair. Dr. Irene Cortese, M.D. and Dr. Daniel Reich, M.D., Ph.D. will lead the research study at the NIH.
Visit the Myelin Repair Foundation to learn more about MRF-008.
Source: Bionews Texas (28/01/14)
A new clinical trial is underway for individuals who have secondary progressive multiple sclerosis (SPMS). Patients with SPMS generally have had relapsing-remitting MS, but now are having attacks that are less frequent and less well defined. Patients don’t generally recuperate from these attacks and disabilities begin set in. It is reported that 80% of patients with relapsing-remitting MS eventually develop secondary progressive Multiple Sclerosis, and this process tends to begin 15 or so years after being diagnosed with MS.
A Phase 3 trial will be held worldwide and is recruiting 1,530 individuals who have secondary progressive multiple sclerosis (SPMS) to test the safety and effectiveness of an experimental oral therapy siponimod (BAF312) manufactured by Novartis Pharmaceuticals AG versus an inactive placebo.
The drug, siponimod, is an immune system-modulating treatment designed to be a more selective sphingosine 1-phosphate receptor modulator than Gilenya (fingolimod, Novartis). Gilenya was approved in 2010 for adults with relapsing forms of MS to decrease the frequency of relapses to delay accumulation of physical disabilities.
In a Phase 2 trial, siponimod demonstrated safety and efficacy on MRI scans in individuals with relapsing-remitting MS. Information on this trial is available in The Lancet Neurology, Early Online Publication, June 11, 2013 . Siponimod is believed to act by retaining specific white blood cells in lymph nodes keeping then out of circulation and from getting into the central nervous system. This oral drug can also enter the central nervous system where it may have a direct anti-inflammatory or neurobiological effect. The secondary progressive multiple sclerosis (SPMS) study is currently recruiting participants and is sponsored by Novartis Pharmaceuticals under clinical trial identifier NCT01665144. The purpose of this phase 3 trial is to evaluate the safety and efficacy of Siponimod (BAF312) versus placebo in a variable treatment duration in patients with SPMS.
Patients will be randomized to receive Siponimod (BAF312) for a duration of 23 to 42 months with a maximum of 60 months. Patients who meet all inclusion and none of the exclusion criteria will be treated with BAF312 daily. Eligibility age runs 18 to 60 years and will include both sexes.
Inclusion criteria includes a prior history of relapsing remitting MS, SPMS defined as progressive increase of disability over a least 6 months, EDSS score of 3.0 to 6.5 and relapse of corticosteroid treatment within 3 months.
Of the 1,530 participants, 1,050 will take siponimod and 510 will take the placebo every day for up to 60 months. The primary outcome will look at the delay in to confirmed disability progression as measured by the EDSS scale. This scale has been in MS studies for more than 4 decades and is based on the presence of certain symptoms in a typical neurological exam. Secondary outcomes include disease activity as observed on MRI scans, scales that measure mobility, relapse rates, adverse events and abnormalities on lab tests.
Source: Bionews Texas (27/01/14)
An antioxidant designed by scientists more than 12 years ago to fight damage within human cells can treat symptoms in mice that have a multiple sclerosis-like disease, a new study led by an Indian-origin researcher has found.
The antioxidant - called MitoQ - has shown some promise in fighting neurodegenerative diseases. But this is the first time it has been shown to significantly reverse an MS-like disease in an animal.
The discovery by Oregon Health & Science University could lead to a new way to treat multiple sclerosis, which affects more than 2.5 million people worldwide.
Multiple sclerosis occurs when the body's immune system attacks the myelin, or the protective sheath, surrounding nerve fibres of the central nervous system. Some underlying nerve fibres are destroyed.
Resulting symptoms can include blurred vision and blindness, loss of balance, slurred speech, tremors, numbness and problems with memory and concentration.
The antioxidant research, published in the journal Biochimica et Biophysica Acta Molecular Basis of Disease, was led by P Hemachandra Reddy, an associate scientist in the Division of Neuroscience at OHSU's Oregon National Primate Research Center.
In the study, researchers induced mice to contract a disease called experimental autoimmune encephalomyelitis, or EAE, which is very similar to MS in humans.
They separated mice into four groups: a group with EAE only; a group that was given the EAE, then treated with the MitoQ; a third group that was given the MitoQ first, then given the EAE; and a fourth "control" group of mice without EAE and without any other treatment.
After 14 days, the EAE mice that had been treated with the MitoQ exhibited reduced inflammatory markers and increased neuronal activity in the spinal cord - an affected brain region in MS - that showed their EAE symptoms were being improved by the treatment.
The mice showed reduced loss of axons, or nerve fibres and reduced neurological disabilities associated with the EAE.
The mice that had been pre-treated with the MitoQ showed the least problems. The mice that had been treated with MitoQ after EAE also showed many fewer problems than mice who were just induced to get the EAE and then given no treatment.
"The MitoQ also significantly reduced inflammation of the neurons and reduced demyelination. These results are really exciting. This could be a new front in the fight against MS," Reddy said.
"It appears that MitoQ enters neuronal mitochondria quickly, scavenges free radicals, reduces oxidative insults produced by elevated inflammation, and maintains or even boosts neuronal energy in affected cells," said Reddy.
The hope has been that MitoQ might help treat neurodegenerative diseases like Alzheimer's and Parkinson's. Studies evaluating its helpfulness in treating those diseases are ongoing.
Source: Business Standard Copyrights © 2014 Business Standard Ltd (02/01/14)
Revalesio Corporation has announced a new collaboration with noted neurologist Dr. Roland Martin, Head of Neuroimmunology and MS Research at the Department of Neurology, University Hospital Zurich. Dr. Martin will be conducting a Phase IIa clinical trial of RNS60 in patients with relapsing-remitting multiple sclerosis (RRMS or MS). With 30 years experience, Dr. Martin is a recognized leader in the field of neuroimmunology and multiple sclerosis research.
The study will compare measurements of disease activity and progression in patients with RRMS during 6-months treatment with RNS60. The open label study will enroll 15 patients and evaluate the use of RNS60 by intravenous administration compared to patient's pre-treatment disease activity. The main outcome of the study will be the reduction of inflammatory activity in the brain as measured by Gd contrast-enhacing MRI lesions. Additional measures include progression of disability and biomarkers for RNS60 and general inflammation. The study will be conducted at the University Hospital Zurich in Switzerland and at Innsbruck Medical University in Innsbruck, Austria.
"Our MS development work with RNS60 has been an extraordinary process of discovery and pioneering research," said Dr. Richard Watson, Revalesio's Chief Science Officer. "We have published much of our data regarding RNS60's mechanisms in the pre-clinical models and are pleased to have Dr. Martin as a collaborator and to see RNS60 advance into the clinic for MS. We are hopeful this study will provide an efficacy signal that demonstrates RNS60's therapeutic potential and informs future clinical research."
RNS60 has been tested in numerous pre-clinical models of MS and has shown the ability to halt disease progression by limiting glial infiltration (inflammation in the brain), protecting myelin and enriching the regulatory T-cell (TREG) populations in animals treated with RNS60. Data from these pre-clinical models can be found in the academic journal PLOS ONE.
About RNS60 Revalesio has pioneered the use of RNS60 as a therapeutic that alters whole cell conductance through effects on voltage-sensing membrane-bound proteins, thereby modulating the activity of G protein-coupled receptors and the secretion of cytokines, chemokines resulting in decreased inflammation and cell death. RNS60 contains charge-stabilized nanostructures (CSN) that are created by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow. RNS60 has demonstrated a reduction in inflammatory responses that are linked to numerous diseases, including neurodegenerative, respiratory and cardiovascular diseases.
Source: The Sacramento Bee Copyright © The Sacramento Bee 2013 (11/11/13)
GeNeuro announced today that its GNbAC1 humanized monoclonal antibody was found to have a very good safety profile when administered to patients with relapsing and progressive forms of Multiple Sclerosis as part of a Phase 2a study. GNbaC1 is a first-in-class monoclonal antibody targeting a toxic protein of endogenous retroviral origin that has been identified as a potential key factor in the onset and development of multiple sclerosis. Enrollment of patients into a multinational Phase 2b study is expected to begin during the first half 2014.
“The safety data achieved in this Phase IIa study is excellent and supports the future development of GNbaC1 in both relapsing remitting and progressive MS,” commented François Curtin, CEO of GeNeuro. “While presenting at the recent ECTRIMS1 congress in Copenhagen last month, GeNeuro’s approach was highlighted as one of the most innovative and promising new treatments in clinical development against MS as it specifically targets a potential causal factor of the disease.”
In the completed Phase 2a clinical study including a six-month extension, conducted to establish safety and pharmacokinetics, GNbAC1 demonstrated very good safety following repeated administration at 2 mg/kg and 6 mg/kg. The repeated administrations did not affect the immune system, the TLR4 function was preserved and no signs of induction of immunogenicity were observed.
About the ENV toxic Protein and its role in Multiple Sclerosis and other pathologies
The sequencing of the human genome revealed human endogenous retroviruses (HERV) represent more than 8% of the human genome and result from the integration of exogenous retroviruses DNA during the primate evolution.
The Multiple Sclerosis associated retrovirus (MSRV) is a member of the HERV-W family and was initially isolated in cell cultures from patients affected with Multiple Sclerosis in the 90’s. MSRV is normally latent in the genome of individuals, but it can be re-activated by certain co-factors to expresses a pathogenic protein, MSRV-Env. Recent evidence has demonstrated that this ENV-protein is expressed in MS lesions from an early stage, is pro-inflammatory and inhibits remyelination.
Source: Rock Hill Herald Online Copywrite Rock Hill Herald 2013 (04/11/13)
Financial support given for development of NRP2945 as potential therapy for MS progression(14/10/13)
CuroNZ, an Auckland biotechnology start-up company developing treatments for progressive multiple sclerosis, has been awarded funding of US$ 540,000 from the National Multiple Sclerosis Society through Fast Forward to support preclinical studies needed to develop CuroNZ’s NRP2945 candidate as a potential therapy to protect the nervous system from MS damage.
Current therapies available for treating multiple sclerosis do not adequately treat progressive stages of the disease or directly protect the nervous system from that damage that leads to progression.
The funding will enable CuroNZ to undertake pre-clinical proof of concept, pharmacokinetic and toxicity studies to bring the drug candidate lead NRP2945 closer to an investigational new drug (IND) application. As part of the project, CuroNZ will collaborate with leading research organisations including the University of Auckland and Monash University in Melbourne. With its unique mechanism of action and a pristine safety profile to date, NRP2945 has the potential to act as a neuroprotective agent which might eventually be developed into a product that can help patients with progressive MS, worldwide.
Finding ways to stop MS progression is a strategic priority of the National MS Society’s research program. A key aspect of the Society’s comprehensive approach to driving research progress is the support of promising research discoveries – such as NRP2945 - toward commercial drug development.
About CuroNZ: CuroNZ was founded in 2009 by Dr. Frank Sieg who discovered the drug candidate portfolio called Neural Regeneration Peptides (NRPs) in Germany. He subsequently brought them to New Zealand with the hope of being able to eventually develop products that could benefit patients suffering from the debilitating effects of progressive MS.
Source: Scoop Health News © Scoop Media 2013 (14/10/13)
Genmab A/S announced top-line results from a Phase II study of the subcutaneous formulation of ofatumumab in relapsing-remitting multiple sclerosis (RRMS).
A total of 232 subjects with RRMS were randomized in the study. There was a clear separation from placebo on the cumulative number of new gadolinium enhancing lesions (active brain lesions) over a period of 12 weeks in subjects treated with all doses of ofatumumab compared to subjects treated with placebo [p < 0.001]. For the primary endpoint, analysis of data from weeks 0-12 estimated a 65% reduction in the cumulative number of new T1 gadolinium enhancing lesions for all doses [p < 0.001]. In weeks 4-12, analyses of data estimated a >= 90% reduction in the cumulative number of new T1 gadolinium enhancing lesions for all cumulative doses of ofatumumab >= 30 mg [p < 0.001].
There were no unexpected safety findings in the study. From weeks 0-12, injection related reactions were the most common adverse reaction and were observed in 52% of subjects receiving ofatumumab compared to 15% of subjects receiving placebo. There were five serious adverse events (SAEs) reported, all subjects received a 60 mg dose of ofatumumab and none of these subjects withdrew from the study. Twelve subjects withdrew during this time period; 10 of these subjects were receiving ofatumumab. To date, no cases of progressive multifocal leukoencephalopathy (PML) or opportunistic infections have been observed.
"We are encouraged by the results from this study, which we believe underline the potential of subcutaneous ofatumumab for treatment of relapsing-remitting multiple sclerosis," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
About the study
This multi-center, randomized, double-blind, placebo controlled Phase II study, conducted by GlaxoSmithKline (GSK), included subjects who had RRMS. The primary objective of the study was to determine whether 3, 30 or 60 mg of ofatumumab given subcutaneously reduces the number of new T1-weighted gadolinium-enhancing brain lesions (active brain lesions) over a period of 12 weeks, as compared with placebo, in subjects with RRMS.
Subjects in the study were randomized to one of the following treatment arms: 3 mg, 30 mg, or 60 mg of subcutaneous ofatumumab every 12 weeks or 60 mg of subcutaneous ofatumumab every 4 weeks, or placebo followed by 3 mg of subcutaneous ofatumumab at week 12. The treatment period for all subjects was 24 weeks; subjects were then followed until B-cell repletion for at least an additional 24 weeks. Currently, all subjects have completed the 24-week treatment period; some subjects continue to be followed as per protocol.
Ofatumumab is a human monoclonal antibody which targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loopsi. Ofatumumab is being developed under a co-development and collaboration agreement between Genmab and GSK. Under the companies' agreement, GSK is solely responsible for development of ofatumumab in autoimmune indications and all related costs.
Source: The Wall Street Journal Copyright ©2013 Dow Jones & Company, Inc (11/10/13)
Scientists at The Scripps Research Institute (TSRI) have identified a set of compounds that may be used to treat multiple sclerosis (MS) in a new way. Unlike existing MS therapies that suppress the immune system, the compounds boost a population of progenitor cells that can in turn repair MS-damaged nerve fibres.
One of the newly identified compounds, a Parkinson's disease drug called benztropine, was highly effective in treating a standard model of MS in mice, both alone and in combination with existing MS therapies.
"We're excited about these results, and are now considering how to design an initial clinical trial," said Luke L. Lairson, an assistant professor of Chemistry at TSRI and senior author of the study, which is reported online in Nature on October 9, 2013.
Lairson cautioned that benztropine is a drug with dose-related adverse side effects, and has yet to be proven effective at a safe dose in human MS patients. "People shouldn't start using it off-label for MS," he said.
A New Approach
An autoimmune disease of the brain and spinal cord, MS currently affects more than half a million people in North America and Europe, and more than two million worldwide. Its precise triggers are unknown, but certain infections and a lack of vitamin D are thought to be risk factors. The disease is much more common among those of Northern European heritage, and occurs about twice as often in women as in men.
In MS, immune cells known as T cells infiltrate the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating called myelin on some nerve fibers. As nerve fibers lose this myelin coating, they lose their ability to transmit signals efficiently, and in time may begin to degenerate. The resulting symptoms, which commonly occur in a stop-start, "relapsing-remitting" pattern, may include limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression, among other problems.
Current therapies, such as interferon beta, aim to suppress the immune attack that de-myelinates nerve fibers. But they are only partially effective and are apt to have significant adverse side effects.
In the new study, Lairson and his colleagues decided to try a complementary approach, aimed at restoring a population of progenitor cells called oligodendrocytes. These cells normally keep the myelin sheaths of nerve fibers in good repair and in principle could fix these coatings after MS damages them. But oligodendrocyte numbers decline sharply in MS, due to a still-mysterious problem with the stem-like precursor cells that produce them. "Oligodendrocyte precursor cells (OPCs) are present during progressive phases of MS, but for unknown reasons don't mature into functional oligodendrocytes," Lairson said.
A 100,000-Molecule Screen
Using a sophisticated small-molecule screening laboratory that TSRI manages in conjunction with the California Institute of Regenerative Medicine and in collaboration with the California Institute for Biomedical Research (Calibr), Lairson and his team screened a library of about 100,000 diverse compounds for any that could potently induce OPCs to mature or "differentiate."
Several compounds scored well as OPC differentiation-inducers. Most were compounds of unknown activity —but one, benztropine, had been well characterized and indeed was already FDA-approved for treating Parkinson's disease. "That was a surprise, and it meant that we could move forward relatively quickly in testing it," said graduate student Vishal A. Deshmukh, first author of the paper who performed most of these experiments.
With the help of Brian R. Lawson, a senior author of the paper and assistant professor of immunology at TSRI, and his colleague Research Associate Virginie Tardif, Deshmukh set up tests of benztropine in mice with an induced MS-like autoimmune disease—a model commonly used for testing prospective MS drugs.
In these tests, benztropine showed a powerful ability to prevent autoimmune disease and also was effective in treating it after symptoms had arisen—virtually eliminating the disease's ability to relapse. Although benztropine on its own worked about as well as existing treatments, it also showed a remarkable ability to complement these existing treatments, in particular two first-line immune-suppressant therapies, interferon-beta and fingolimod.
"Adding even a suboptimal level of benztropine effectively allowed us, for example, to cut the dose of fingolimod by 90%—and achieve the same disease-modifying effect as a normal dose of fingolimod," said Lawson. "In a clinical setting that dose-lowering could translate into a big reduction in fingolimod's potentially serious side effects." In further analyses, the researchers confirmed that benztropine works against disease in this mouse model by boosting the population of mature oligodendrocytes, which in turn restore the myelin sheaths of damaged nerves—even as the immune attack continues. "The benztropine-treated mice showed no change in the usual signs of inflammation, yet their myelin was mostly intact, suggesting that it was probably being repaired as rapidly as it was being destroyed," said Lawson.
Benztropine is known to have multiple specific effects on brain cells, including the blocking of activity at acetylcholine and histamine receptors and a boosting of activity at dopamine receptors. But Lairson and his colleagues found evidence that the drug stimulates OPCs to differentiate mainly by blocking M1 or M3 acetylcholine receptors on these cells.
In addition to setting up initial clinical trials, Lairson and his team hope to learn more about how benztropine induces OPC maturation, and how its molecular structure might be optimized for this purpose. "We're also looking at some of the other, relatively unknown molecules that we identified in our initial screen, to see if any of those has better clinical potential than benztropine," he said.
"This work, like our previous studies with hematopoietic and mesenchymal stem cells, illustrates the power of small molecules to control stem and precursor cells in ways that may ultimately lead to a new generation of drugs for regenerative medicine," said Peter G. Schultz, the Scripps Family Chair Professor in the Department of Chemistry at TSRI and one of the study's senior authors.
Source: News-Medical.Net (10/10/13)
Karo Bio receives funding from the National MS Society to develop ERbeta Agonists for treatment of progressive MS(13/09/13)
Karo Bio AB has been awarded $0,5 million from the National Multiple Sclerosis Society through Fast Forward to develop a novel treatment – ERbeta agonists -- for progressive forms of Multiple Sclerosis (MS). The funds will finance the further preclinical development of Karo Bio’s advanced compounds.
Karo Bio’s ERbeta agonist has the potential to slow disease progression in multiple sclerosis as preclinical models show that it protects neurons and restores myelin. Damaged myelin leads to symptoms of illness and disability in MS patients. This intended profile differs dramatically from currently approved MS therapies, which are used for the treatment of relapsing MS and reduce inflammation, but do not restore myelin or directly protect neurons.
“We are very pleased to have received this funding from the National MS Society to support our efforts to address important unmet medical needs among MS patients” says Per Bengtsson, CEO of Karo Bio. “Our aim is to achieve a significant breakthrough in the treatment of MS.”
This investment by the National MS Society is a continuation of a strategic research focus on gender differences in MS. That effort helped drive basic research into the role of sex hormones, and estrogen in particular. Karo Bio’s development of ERbeta agonists reflects the potential of this approach, and fits the Society’s comprehensive strategy to stop the progression of disability in MS and to restore function.
About Karo Bio
Karo Bio is a pharmaceutical company focused on the research and development of innovative drugs for large medical needs. The world-leading knowledge of nuclear receptors as target proteins for the development of pharmaceuticals and the related mechanisms of action, are utilized as a foundation for developing novel, more effective and safer pharmaceuticals. The company runs drug development projects mainly within the therapeutic areas neuropsychiatry, inflammation, autoimmune diseases and cancer. The company has a number of strategic agreements and collaborations with international pharmaceutical companies. Karo Bio is based in Huddinge, Sweden, has 42 employees.
Source: PipelineReview.com © by La Merie Publishing (13/09/13)
Trophos SA announced today that they have completed enrollment in the Translate MS-Repair Phase Ib multiple sclerosis (MS) trial.
The trial is a randomized, placebo controlled, Phase Ib study in multiple sclerosis (MS) patients treated with Trophos' olesoxime as an add-on therapy to Interferon beta. In three months, 44 patients have been recruited in three investigational sites in France. The first subject was enrolled on April 2 and the last subject on July 11, 2013.
Though many disease-modifying treatments effectively address the inflammatory episodes in relapsing remitting MS, they have almost no effect on the long term disability associated with MS resulting from progressive neurodegeneration. Promoting remyelination and providing neuroprotection are new concepts for the treatment of MS. Trophos' olesoxime is the most advanced oral small molecule to demonstrate these activities in relevant preclinical models.
The Phase Ib study will evaluate safety, tolerability and PK data of a six month treatment with olesoxime in MS patients stably treated with interferon beta. In addition, the study is also planned to analyze multi-center feasibility of potential imaging biomarkers as surrogate outcome measures.
The 24 month Translate MS-Repair project is funded by the French Agence Nationale de Recherche (ANR) through their Recherches Partenariales et Innovation Biomedicale 2012 program. The Translate MS-Repair consortium is led by Trophos and includes Assistance Publique Hopitaux de Marseille, Centre Hospitalier Universitaire de Rennes, Centre Hospitalier Universitaire de Reims, Centre National de la Recherche Scientifique, Institut national de recherche en informatique et en automatique.
"Completing recruitment in this clinical study so rapidly is a great achievement and a major step in the development of olesoxime as a potential treatment for neurodegeneration and myelin repair in MS," said professor Jean Pelletier, Assistance Publique Hopitaux de Marseille, the principal investigator for this study. "All the partners involved, Trophos, clinical research teams and MRI centers are highly motivated and have worked hard to initiate this study. We can now anticipate that the top line results will be available in the first half of 2014 and that will pave the way for the further clinical development of olesoxime in MS patients."
This randomized, double-blind, placebo-controlled, six month study will assess safety, tolerability and pharmacokinetics of six months treatment with 495 mg/day olesoxime in relapsing remitting MS patients who are stably treated with any form of Interferon beta (Avonex(R), Rebif(R), Extavia(R), Betaseron(R)).
An additional objective of the Translate MS-Repair project is to survey a number of non-conventional MRI techniques for the use in future multicenter trials as biomarkers of neuroprotection and/or myelin repair. Use of such techniques as Magnetization Transfer Ratio (MTR), Diffusion Tensor Imaging (DTI) or 23Na-MRI in combination with conventional MRI techniques such as gadolinium-enhanced T1- and T2-weighted MRI may provide new tools to assess neuroprotective and/or restorative treatments in MS or other neurodegenerative diseases. Exploratory analysis of preliminary efficacy data with olesoxime will provide some results to be used for planning the Phase II and III program.
"This trial is funded by a second EUR 1 million grant we received from the ANR to support the development of olesoxime for the treatment of MS. The Translate MS-Repair project follows the results generated by the first Trophos' led consortium project, MS-Repair. These results showed convincing evidence that olesoxime promotes myelin repair in multiple preclinical demyelinating disease models," said Rebecca Pruss, chief scientific officer, Trophos. "The Phase Ib study is a prerequisite to a future Phase II study to evaluate if olesoxime could activate remyelination and consequently prevent long term disability in MS patients."
"Trophos has a long history of building consortia from a network of scientists and clinical investigators to target a range of therapeutic targets. The Translate MS-Repair and MS Repair projects are the most recent examples of this consortia-based approach," said Christine Placet, CEO, Trophos. "Trophos' olesoxime has demonstrated great promise as a potential treatment for a variety of neurodegenerative diseases. In addition to this study in MS patients, olesoxime is being studied in SMA patients. Combined with the compound TRO40303 that is targeting cardiac ischemia-reperfusion injury, this generates a considerable market potential of nearly USD 2 billion for the conditions targeted by our pipeline."
About the Translate MS-Repair study (under ANR grant agreement ANR-12-RPIB-0005)
The Phase Ib study is a randomized, placebo-controlled, double blind study planned to evaluate tolerance, safety and PK data of olesoxime in relapsing remitting MS patients stably treated with any form of interferon beta. The study will evaluate conventional endpoints such as relapse rate and lesion load measured by MRI. The study will also assess the feasibility of performing non-conventional MRI including MTR, DTI and 23Na-MRI. The Translate MS-Repair project is a partnership between Trophos, three clinical research teams led by professor Jean Pelletier in Marseille (APHM, CHU La Timone), professor Gilles Edan, CHU Rennes and Dr. Ayman Tourbah, CHU Reims and two MRI teams in Marseille (professor Jean-Philippe Ranjeva, APHM/CNRS and CEMEREM-CRMBM) and Rennes (professor Christian Barillot, INRIA VISAGES). It will pave the way for future Phase II and Phase III clinical trials to assess the ability of olesoxime to promote repair and prevent neurodegeneration underlying progressive disability in MS patients.
Olesoxime (TRO19622) is a mitochondrial targeted, cholesterol-like compound that is currently undergoing clinical evaluation for the treatment of spinal muscular atrophy. Olesoxime's safety and tolerability has already been tested in 15 clinical trials involving 968 patients or healthy volunteers and proved to have an excellent safety profile. The mechanism of action of olesoxime involves prevention of mitochondrial dysfunction and improved microtubule dynamics, both implicated in neuroprotection and oligodendrocyte maturations. Studies in preclinical models showing that olesoxime favors myelination were reported by Trophos and colleagues in Annals of Neurology (Magalon et al, Ann Neurol. 2012 Feb; 71(2):213-26
Source: Pipeline Review.com © by La Merie Publishing 2013 (06/08/13)
Existing drugs for motor neurone disease, asthma and heart disease are being tested as possible treatments for advanced multiple sclerosis (MS).
About 500 people with late-stage MS are to enrol in clinical trials in England and Scotland to see if three common drugs can slow disease progression.
Research suggests the medicines may protect the brain from further damage.
There is currently no treatment for secondary progressive MS, a form of the disease marked by increased disability.
About 100,000 people are living with MS in the UK. Symptoms include problems with walking, balance, speech, vision and extreme fatigue.
Treatments are available to help with relapses and symptoms of MS during the early stages of the disease. However, despite clinical trials, scientists have so far failed to find a medicine that works in the late stages of MS.
Now, after reviewing published data on drug treatments that might help protect nerves in the brain, UK researchers are focusing on three drugs that are licensed for other conditions.
The three drugs are amiloride - currently licensed to treat heart disease and high blood pressure; ibudilast - an asthma drug used in Japan - ; and riluzole, the sole treatment for motor neurone disease.
All have shown some promise as a treatment for MS in small-scale trials.
Participants in the larger trials in London, Edinburgh and 13 other sites in the UK will be monitored for signs of progression of MS with scans and other clinical tests.
Dr Jeremy Chataway is consultant neurologist at University College London, which will carry out the London study.
He said the drugs selected are the most promising candidates for testing to see if they have an effect in slowing the progression of MS.
He told BBC News: "There is no treatment for secondary progressive MS. This is a really appropriate and scientific way of getting a pipeline of drugs so that we can one day get a treatment that works."
Patients entering the trial will be given brain scans at the beginning and end of the two-year study to see whether the drugs have an effect on slowing down brain tissue loss.
"We hope at least one of these drugs will show that it significantly reduces the rate of brain loss - we're hoping for 30% or 40% reduction," he added.
The MS-SMART trial, as it is known, will test the three drugs against a dummy treatment (placebo) in 440 people with secondary progressive MS.
Dr Susan Kohlhaas, head of biomedical research at the MS society, said: "People with MS have lived for years in hope that one day we will find an effective treatment for secondary progressive MS; this trial, although still early stage, takes us one step closer to make that hope a reality."
Commenting on the approach to the research, Prof Jayne Lawrence, chief science adviser for the Royal Pharmaceutical Society, said finding new medical uses for existing drugs offered hope to patients.
Aspirin, for example, had found many therapeutic uses - as a painkiller and in preventing strokes and heart disease, she said.
"It's becoming much more popular now because it costs so much to develop a [new] drug. At least you've got an idea of what the toxicity is so you can reduce the time it takes to develop the drug."
The research is funded by the Medical Research Council and the Multiple Sclerosis Society.
More information on the study can be found at MS-SMART Trial - Home
Source: BBC News © British Broadcasting Corporation 2013 (17/07/13)
Avanir Pharmaceuticals, Inc. announced completion of patient enrollment in the company's phase II, placebo controlled study testing three doses of AVP-923 for the treatment of central neuropathic pain in multiple sclerosis. Top-line results from this study are expected in the fourth calendar quarter of 2013.
"Final completion of enrollment in PRIME is an important milestone in the AVP-923 development pathway," said Joao Siffert, MD, chief scientific officer at Avanir. "We are looking forward to the results from this study to help guide design of our phase III studies in neuropathic pain."
About the PRIME Study The objectives of the PRIME (Pain Research In Multiple sclErosis) study are to evaluate the safety, tolerability, and efficacy of AVP-923 for the treatment of central neuropathic pain in patients with multiple sclerosis. The trial is a multicenter, randomized, double-blind, placebo-controlled, 4-arm parallel group study. Eligible patients receive one of three dose levels of AVP-923 containing either 45mg DM/10 mg Q, 30mg DM/10mg Q, 20mg DM/10mg Q or placebo, daily for 12 weeks. The primary efficacy endpoint will be measured based on the Numeric Pain Rating Scale (PRS) as recorded in patient diaries. Primary analysis of this endpoint will correlate pain scores with dextromethorphan plasma concentrations. Secondary analysis will correlate pain scores with AVP-923 dose and also compare pain scores for those treated with placebo versus drug in each dose group. Secondary assessments include measures of fatigue, impact of MS on daily life, sleep quality, spasticity, cognition and depression. Standard safety assessments were also conducted.
About AVP-923 AVP-923 is a combination of two well-characterized compounds, the active CNS ingredient dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist) plus low-dose quinidine sulfate (a CYP2D6 enzyme inhibitor), which serves to increase the bioavailability of dextromethorphan. AVP-923 is being studied in several ongoing company sponsored Phase II clinical trials including agitation in Alzheimer's disease, neuropathic pain in Multiple Sclerosis, levodopa-induced dyskinesia in Parkinson's disease, and an investigator initiated study of behavioral symptoms of autism in adults. AVP-923 is an investigational drug not approved by the FDA.
Source: The Sacramento Bee Copyright © The Sacramento Bee (02/07/13)
Siponimod for patients with relapsing-remitting MS (BOLD): an adaptive, dose-ranging, randomised, phase 2 study(12/06/13)
Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis.
In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18—55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00879658.
Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17—57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29—69) for siponimod 0·5 mg (43 patients), 66% (48—80) for siponimod 1·25 mg (42 patients), 72% (57—84) for siponimod 2 mg (45 patients), and 82% (70—90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious).
Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial.
Novartis Pharma AG.
Prof Krzysztof Selmaj MD, Prof David KB Li MD, Prof Hans-Peter Hartung MD, Prof Bernhard Hemmer MD, Prof Ludwig Kappos MD, Prof Mark S Freedman MD, Olaf Stüve MD, Prof Peter Rieckmann MD, Prof Xavier Montalban MD, Tjalf Ziemssen MD, Lixin Zhang Auberson MD, Harald Pohlmann MSc, Francois Mercier PhD, Frank Dahlke MD, Erik Wallström MD
Source: The Lancet Neurology Copyright © 2013 Elsevier Limited (12/06/13)
Patient screening commences in phase IIa clinical trial with RHB-104 for multiple sclerosis(07/06/13)
RedHill Biopharma Ltd, an emerging Israeli biopharmaceutical company focused primarily on the development and acquisition of late clinical-stage, patent-protected, new formulations and combinations of existing drugs, announced that patient screening has commenced in the Phase IIa, proof of concept, clinical study (the "CEASE-MS Study"), to assess the efficacy and safety of fixed dose combination RHB-104, a patent protected combination therapy of three antibiotics in a single capsule, as an add-on therapy to interferon beta-1a in patients treated for Relapsing Remitting Multiple Sclerosis ("RRMS").
The phase IIa CEASE-MS Study follows the successful completion of four pre-clinical studies with RHB-104.
Sixteen patients with RRMS are expected to participate in the open label Phase IIa CEASE-MS Study, which will be conducted at two medical centers in Israel. The study is designed to assess the efficacy and safety of RHB-104 in RRMS patients after 24 weeks of treatment, with the primary endpoint being the number of combined unique active lesions after treatment as compared to baseline. Patients will be followed-up for an additional term of 24 weeks after completing treatment with RHB-104. Secondary endpoints will include changes in pro-inflammatory cytokine markers, Mycobacterium avium subsp. paratuberculosis (MAP) status, relapse rate, Expanded Disability Status Scale (EDSS) and safety and tolerability of RHB-104.
"We are very pleased that this important Phase IIa Multiple Sclerosis study is now underway," said Clara Fehrmann, RedHill's RHB-104 MS Product Manager. "There is an increasing awareness in the medical community to the possibility that a bacterial induced dysregulated immune system plays a critical role in the pathogenesis of MS. It is RedHill's hope that the CEASE-MS Study will demonstrate RHB-104's potential to become an effective treatment option for patients with MS."
Dr. Radi Shahien of Ziv Medical Center, Principal Investigator of the CEASE-MS Study added: "The MAP bacterium has been identified as a pathogen that may contribute to the development of MS. The CEASE-MS Study with RHB-104 aims to test this new hypothesis to the etiology of MS. RHB-104 has the potential to improve the lives of people with MS, and I am excited to be leading this important study."
Multiple Sclerosis is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system of uncertain etiology that exhibits characteristics of both infectious and autoimmune pathology. RHB-104 is a multifaceted drug that in addition to bactericidal properties against intracellular infections, has potentially distinct mechanisms of action that include both anti-inflammation and neuroprotection. The worldwide sales of MS therapies are estimated to have exceeded $14 billion USD in 20121. RHB-104 is also being evaluated for the treatment of Crohn's disease. The Company is planning to commence a first Phase III clinical trial (named "MAP US Study") for this indication by the third quarter of 2013, with recruitment of sites in the U.S., Canada and Israel underway.
The Company also plans to commence a Phase II/III clinical trial with RHB-105 (H. Pylori) in the third quarter of 2013.
RedHill has recently submitted its first U.S. New Drug Application ("NDA") for RHB-103 (migraine), and plans to submit a second U.S. NDA, for RHB-102 (oncology support anti-emetic), by the first half of 2014.
Source: NASDAQ © Thomson Reuters 2013 (07/06/13)