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)