Showing posts sorted by relevance for query Dimethyl fumarate. Sort by date Show all posts
Showing posts sorted by relevance for query Dimethyl fumarate. Sort by date Show all posts

Thursday, March 28, 2019

Alkermes and Biogen Announce U.S. Food and Drug Administration Acceptance of Diroximel Fumarate New Drug Application for Multiple Sclerosis

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Alkermes plc (Nasdaq: ALKS) and Biogen Inc. (Nasdaq: BIIB)  announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for diroximel fumarate (BIIB098), a novel oral fumarate in development for the treatment of relapsing forms of multiple sclerosis (MS). The NDA has been assigned a PDUFA (Prescription Drug User Fee Act) target action date in the fourth quarter of 2019. If approved, Biogen intends to market diroximel fumarate under the brand name VUMERITY™, which has been conditionally accepted by the FDA and will be confirmed upon approval.
“The NDA filing acceptance for diroximel fumarate further demonstrates the productive collaboration between Alkermes and Biogen and brings us closer to our shared goal of offering a new therapeutic option for people with MS,” said Craig Hopkinson, M.D., chief medical officer and senior vice president, medicines development and medical affairs at Alkermes. “We believe diroximel fumarate has the potential to be a meaningful new offering for patients with MS, and we look forward to continued engagement with the FDA throughout the review process.”
“For more than two decades Biogen has been at the forefront of delivering new medicines to MS patients,” said Michael Ehlers, M.D., Ph.D., executive vice president, research and development at Biogen. “We are encouraged by the FDA’s acceptance of the NDA for diroximel fumarate, which we believe could help elevate the treatment of this complex and often debilitating disease.”
Alkermes is seeking approval of diroximel fumarate under the 505(b)(2) regulatory pathway, referencing Biogen’s dimethyl fumarate data. The NDA submission includes data from EVOLVE-MS-1, a Phase 3, open-label, two-year safety study in relapsing-remitting MS (RRMS) patients. It is hypothesized that the distinct chemical structure of diroximel fumarate may impact its gastrointestinal (GI) tolerability. Alkermes is conducting EVOLVE-MS-2, a head-to-head GI tolerability study versus dimethyl fumarate, with results expected later this year.

About the Diroximel Fumarate Clinical Development Program

The key components of the clinical development program of diroximel fumarate include the EVOLVE-MS-1 study, a Phase 3, open-label, two-year safety study in relapsing-remitting MS (RRMS) patients, along with pharmacokinetic bridging studies comparing diroximel fumarate and dimethyl fumarate. In addition, Alkermes is conducting the EVOLVE-MS-2 study in patients with RRMS, a five-week, head-to-head gastrointestinal (GI) tolerability study versus dimethyl fumarate.

About Diroximel Fumarate

Diroximel fumarate (BIIB098) is a novel oral fumarate candidate in development for the treatment of relapsing forms of MS. Diroximel fumarate is designed to rapidly convert to monomethyl fumarate in the body and may have the potential to offer differentiated GI tolerability due to its chemical structure as compared to dimethyl fumarate.





Thursday, November 12, 2015

Interim data from long-term extension Tecfidera® (dimethyl fumarate) study



Dimethyl fumarate


In continuation of my update on Dimethyl Fumarate


Biogen (NASDAQ: BIIB) will, this week, present data at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain, demonstrating the efficacy and safety of TECFIDERA® (dimethyl fumarate) across a broad range of people with relapsing-remitting multiple sclerosis (RRMS). The data includes important findings for people in the early stages of the disease (as determined by cognitive testing using paced auditory serial addition test 3), and coincides with recent recommendations on the importance of early treatment highlighted by the MS Society.(1)

A post-hoc analysis of the Phase 3 DEFINE and CONFIRM studies showed that dimethyl fumarate had significant effects on clinical outcomes in RRMS patients who initiated treatment early in their disease course, defined as those patients with a baseline Expanded Disability Status Scale (EDSS) score of ≤2.0 (indicating minimal to no disability). Compared to patients treated with placebo, dimethyl fumarate reduced the adjusted relapse rate (ARR) [95% confidence interval, CI]: 0.132 [0.102, 0.170] vs 0.357 [0.291, 0.438]; 63% reduction; p<.0001) and risk of 12-week confirmed disability progression (0.14 vs 0.24; 40% reduction; p=.0066) over a period of two years.(2)

In an interim analysis of newly diagnosed patients in the ENDORSE long-term extension study (two years in DEFINE or CONFIRM followed by four years in ENDORSE), the ARR for newly-diagnosed patients (diagnosis of multiple sclerosis within 1 year prior to study entry or previously treated with cortico-steroids alone) who started dimethyl fumarate treatment at the beginning of the study (n=144) remained low at 0.14 (0.10–0.19). In those patients who switched from placebo to dimethyl fumarate, the ARR was reduced from 0.26 (0.18–0.37) from the placebo period (years zero to two) to 0.10 (0.06–0.16) when dimethyl fumarate treatment was received (years three to six), representing a 61% reduction of risk; p<0.0001.3



Tuesday, March 17, 2020

FDA Approves Vumerity (diroximel fumarate) for Multiple Sclerosis



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 Biogen Inc. (Nasdaq: BIIB) and Alkermes plc (Nasdaq: ALKS),  announced  the U.S. Food and Drug Administration (FDA) approval of Vumerity (diroximel fumarate), a novel oral fumarate with a distinct chemical structure, for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Biogen holds the exclusive, worldwide license to commercialize Vumerity and intends to make it available in the United States in the near future.

“The FDA’s approval of Vumerity delivers on Biogen’s commitment to pursue new therapies that may provide meaningful impact for people living with relapsing MS, and we look forward to bringing it to the MS community as an additional treatment option,” said Alfred Sandrock, Jr., M.D., Ph.D., executive vice president, research and development, and chief medical officer at Biogen. “Vumerity is a novel fumarate that offers the well-characterized efficacy of Tecfidera® (dimethyl fumarate) and has been studied for improved patient-reported gastrointestinal tolerability.”
“The approval of Vumerity for relapsing MS marks the culmination of a multi-year development program and is the latest milestone in our mission to develop new treatments for patients living with chronic central nervous system disorders,” said Craig Hopkinson, M.D., chief medical officer and senior vice president of medicines development and medical affairs at Alkermes. “We are grateful to the patients and study investigators who have participated in our Vumerity clinical trials and we look forward to working with our collaboration partners at Biogen to make this new treatment available to patients.”
The FDA approval of Vumerity was based on a New Drug Application (NDA) submitted under the 505(b)(2) filing pathway. It included data from pharmacokinetic bridging studies comparing Vumerity and Tecfidera to establish bioequivalence, and relied, in part, on the FDA’s findings of safety and efficacy for Tecfidera.
The NDA submission also included interim exposure and safety findings from EVOLVE-MS-1, an ongoing, Phase 3, single-arm, open-label, two-year safety study evaluating Vumerity in patients with relapsing-remitting MS. Interim results from EVOLVE-MS-1 at the time of NDA submission included a low overall rate of Vumerity treatment discontinuation due to adverse events (6.3 percent), and a rate of less than one percent of patients who discontinued Vumerity treatment due to gastrointestinal (GI) adverse events. Additional exploratory efficacy endpoints in the ongoing EVOLVE-MS-1 study showed changes in clinical and radiological measures compared to baseline.
“MS is a heterogeneous disease, and real-world patient circumstances can vary, reinforcing the benefits of having therapeutic choices to support the diverse range of treatment considerations,” said Robert Naismith, M.D., professor of neurology, Washington University School of Medicine in St. Louis. “Throughout its clinical development program, Vumerity has demonstrated a desirable therapeutic profile, making it a compelling new option for patients.”
“MS is a lifelong disease that has a significant impact on the people affected and their caregivers. We are encouraged by the progress being made in the treatment of MS, and pleased that another treatment option will soon be available,” said Bruce Bebo, Ph.D., executive vice president, research, National MS Society. “It’s important for people with MS to have treatments that are both efficacious and tolerable to help manage their disease.”
Under the terms of the license and collaboration agreement between Biogen and Alkermes, Biogen will pay Alkermes $150 million in connection with the FDA’s approval of Vumerity. Biogen plans to account for this milestone payment as an asset that will be amortized over the expected useful life of the product. Alkermes is also entitled to receive a mid-teens percentage royalty on worldwide net commercial sales of Vumerity, subject, under certain circumstances, to minimum annual payments for the first five years following FDA approval and customary reductions as set forth in the agreement.
https://www.drugbank.ca/drugs/DB14783

Tuesday, July 4, 2017

TSRI scientists shed light on molecular workings of MS drug

Image result for dimethyl fumarate
In continuation of my update on Tecfidera

A study by scientists at The Scripps Research Institute (TSRI) has helped to de-mystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera®. The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism remains mysterious.

Using a new TSRI technology that can quickly reveal a drug's protein targets, the scientists showed that Tecfidera® interacts with multiple T cell proteins, in some cases inhibiting their activity, and helping to suppress the T cell activation that is a key feature of MS flare-ups.

"This new technology has given us insights into the therapeutic modulation of the immune system that we could not have obtained with standard approaches," said co-senior author John R. Teijaro, an assistant professor at TSRI.

The study was reported recently in Science Signaling.
Treatment for an Autoimmune Disease

MS is an autoimmune disease of the brain featuring damage to nerve fibers and producing a range of symptoms, including tingling in the extremities, muscle weakness, muscle spasms, visual problems and mood instability. About 400,000 people in the United States and about 2.5 million worldwide have MS, mostly in a form with intermittent flare-ups of symptoms—which can start to worsen inexorably.

Two large clinical trials published in 2012 found that Tecfidera® is almost twice as effective as an older standard MS drug at reducing the rate of flare-ups. It also appears to slow the disease's progression. But how the drug works has never been clear.

Despite its recent (2013) US Food and Drug Administration approval for MS, the drug is neither new nor high-tech. It is a relatively simple organic compound, dimethyl fumarate (DMF), that has been in the biomedical literature for decades. It was once used in Europe to prevent mold growth in sofas during storage and shipping, although the European Union banned it from consumer products in 2009 after it was linked to severe allergic skin reactions. It has proved more useful as a pharmaceutical: since the 1990s it has been an effective treatment—as the main ingredient in the drug Fumaderm®—for the autoimmune skin disease psoriasis. Success against psoriasis led to its investigation as a potential MS drug.

Until recently, the leading theory was that DMF works against MS primarily by unleashing the activity of a protein called Nrf2, which helps protect the brain from autoimmune damage by marshaling a powerful anti-oxidant response and which may also reduce immune system activation. Studies published in the past year have suggested, however, that DMF works principally by reducing immune system activity and does so independently of Nrf2. In recent years, there have also have been several reports among patients taking Fumaderm® or Tecfidera® of a potentially fatal viral brain infection called progressive multifocal leukoencephalopathy, which normally occurs only in people whose immune systems have been seriously weakened.

Wednesday, December 28, 2016

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

In continuation of my update on dimethylfumarate 

The metabolite of a drug that is helping patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, researchers say.

The oral drug, dimethylfumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, said Dr. Bobby Thomas, neuroscientist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University.

Dimethyl fumarate dimethylfumarate Monomethyl fumarate Structure monomethylfumarate, 


But the new study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas, corresponding author of the study in The Journal of Neuroscience.

Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience, said Dr. John Morgan, neurologist, neuroscientist and Parkinson's disease specialist in the MCG Department of Neurology. In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.

"Nrf2 is a natural protective mechanism we have for oxidative stress," Thomas said. The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.

DMF was approved for multiple sclerosis three years ago by the Food and Drug Administration. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.

In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years. By the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neurons, said Morgan, a study coauthor. "Presentation is after the disease is kind of out of the gate."

To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, the researchers first gave the mice either the drug or metabolite the day before they started the toxin.

Dopamine-producing neurons are located in a darker-pigmented central portion of the brain called the substantia nigra. Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress even in a healthy scenario, Morgan said. To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neurons, he said.

To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant, glutathione, and reduces the power of cell powerhouses, called mitochondria, by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells, Thomas said.

The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.

Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.

As a next step, they are working toward a clinical trial of MMF in patients with early Parkinson's disease. Although the metabolite could be easily formulated for humans, it has not yet been done, Thomas notes.

"If we can catch them early enough, maybe we can slow the disease," Morgan said. "If it can help give five to eight more years of improved quality of life that would be great for our patients."

Clinical studies of the drug in Parkinson's are being planned in the United Kingdom and additional analogues of its metabolite, which could be used clinically and which the researchers think ultimately will be the best option for patients, are under development.
Oxidative stress is a byproduct of the body's use of oxygen. Free radicals, generated by oxygen use, are unstable molecules that can interfere with usual cell function and are believed to contribute to a wide range of conditions from normal aging to Alzheimer's disease. Simply giving antioxidants, such as vitamin E, which work more like scavengers to scarf up free radicals, has not worked in combating neurodegenerative disease, Thomas said. He's optimistic that directly targeting Nrf2 will be effective in at least slowing the disease, but there remains a need for clinically safe Nrf2 activators.

Activity of the Nrf2 pathway tends to slowly decline with age. Exercise upregulates Nrf2, and Morgan regularly encourages his patients to be as active as possible. A small group of patients with Parkinson's in Europe has a concentrated activation of Nrf2 that at least delays their disease onset. Parkinson's tends to be diagnosed in the mid-to-late 50s and early 60s and is more common in men.

One concern with chronically elevating anti-oxidant and anti-inflammatory molecules with drugs like DMF and MMF is creating some of the same problems that immunosuppressive drugs given to organ transplant patients create. Chronic suppression of the immune response makes patients more susceptible to invaders like cancers and infections.

Ref : http://www.jneurosci.org/content/36/23/6332.short?sid=e7a934c5-6996-4fff-bfa9-f2c600507e1f

Wednesday, April 24, 2013

FDA Approves Tecfidera - a New Treatment for Multiple Sclerosis


We know that, Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF was initially recognized as a very effective hypoxic cellradiosensitizer. Later, DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (Fumaderm). Other diseases, such as necrobiosis lipoidica, granuloma annulare, and sarcoidosis were also found to respond to treatment with DMF in case reports or small patient series. Recently, phase III clinical trials found that DMF (BG-12) successfully reduced relapse rate and time to progression of disability in multiple sclerosis. DMF is thought to haveimmunomodulatory properties without significant immunosuppression.
In a non-medical use, DMF was applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF was also banned...

Now...