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MS TREATMENTS: TECFIDERA (dimethyl fumarate)

 
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PostPosted: Wed Mar 27, 2013 11:04 pm    Post subject: MS TREATMENTS: TECFIDERA (dimethyl fumarate) Reply with quote

From the New York Times, March 28, 2013:

Quote:
3rd Oral Drug to Treat MS Is Approved by the F.D.A.

By ANDREW POLLACK
A chemical once used to treat sofas — until it was found to cause rashes and blisters in people who sat on them — is now poised to become a major therapy for multiple sclerosis.

The Food and Drug Administration on Wednesday approved the chemical, dimethyl fumarate, which will be sold by Biogen Idec under the name Tecfidera, the third of a spate of oral drugs that are transforming the treatment of multiple sclerosis.

Despite the drug’s seemingly odd history, Wall Street analysts, doctors and patients expect Tecfidera to become a blockbuster because of its combination of efficacy and relative safety and the convenience of being a pill. Doctors and analysts say some patients have been putting off starting treatment until Tecfidera is available.

Feedback from doctors was “highly positive, with a strong consensus that Tecfidera offers a more favorable clinical profile than other oral or injectable first-line options,” Thomas Wei, an analyst at Jefferies, wrote on Monday.

...

While self-injected medicines like Avonex from Biogen and Copaxone from Teva that entered the market in the 1990s are still used by the majority of treated patients, newer oral drugs are making inroads. In addition to Tecfidera, the other two oral drugs are Gilenya from Novartis, approved in 2010, and Aubagio from Sanofi, approved in September.

The approvals will solidify Biogen’s position as a leader in multiple sclerosis drugs. In addition to Tecfidera and Avonex, the company also sells Tysabri, a highly effective intravenous drug but one that can cause a potentially fatal brain infection.

Biogen shares have more than doubled in the last two years, largely because of anticipation about Tecfidera. The shares closed on Wednesday at $182.68, up about 3 percent.

Biogen, which is based in Weston, Mass., did not immediately announce the price of Tecfidera, which was known as BG-12 during its development.

Stock fund portfolio managers polled by the research firm the ISI Group on Wednesday predicted a price of about $51,000 a year, which would be roughly in line with prices of the injectable drugs, but less than the $60,000 a year list price of Gilenya.

The effectiveness of multiple sclerosis drugs is often judged by how much they reduce the frequency of relapses, which are severe flare-ups of symptoms, compared to a placebo in clinical trials.

The injectable drugs reduced the frequency about 30 percent, as did the new oral drug Aubagio. Gilenya cut the rate about 54 percent.

Tecfidera cut the relapse rate 44 percent in one trial and 53 percent in another, which might put it a bit behind Gilenya. Tecfidera is also taken twice a day, while Gilenya is taken only once daily.

But Gilenya has side effects that make it off limits for some patients and require careful testing and monitoring for heart, liver and eye problems. Patients are supposed to remain in a medical facility for at least six hours after taking their first dose to make sure their heart does not slow down too much.

Tecfidera will have fewer restrictions and testing requirements. The prescribing information does recommend that blood cell levels be tested before a patient starts on the drug and annually thereafter. That is because Tecfidera can reduce white blood cell levels, leaving patients potentially vulnerable to infections. And some studies in animals suggest that the drug might cause fetal harm, making it a questionable choice for pregnant women, the label says.

Tecfidera’s most common side effect is flushing, which occurs in about 40 percent of patients. The drug can also cause nausea and diarrhea.

Dimethyl fumarate and some closely related compounds are simple molecules that have been used as food additives. The compound was also used to protect upholstery and shoes from mold during storage. But people in Europe developed skin irritation and other problems, causing its use in consumer goods to be banned there.

The first use of it in medicine was in 1959, when a German chemist treated his own psoriasis. A drug called Fumaderm, which is similar to Tecfidera, was approved to treat psoriasis in Germany in 1994.

It is not quite clear how Tecfidera works. It is thought that one way is to activate a pathway known as Nrf2, which helps protect the body from oxidative stress.

... European regulators recommended last week that Tecfidera be approved as well.



The entire article can be seen here.


Last edited by agate on Tue May 07, 2013 8:57 am; edited 2 times in total
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PostPosted: Thu Mar 28, 2013 8:39 am    Post subject: MSAA announcement Reply with quote

From the MSAA, March 28, 2013:

Quote:
Tecfidera Approved for the Long-Term Treatment of MS

The United States Food and Drug Administration (FDA) announced on March 27, 2013 that it has approved Tecfidera™ (dimethyl fumarate or DMF, formerly known as BG-12) as a first-line therapy for the long-term treatment of relapsing forms of multiple sclerosis (MS). Tecfidera’s parent company, Biogen Idec, submitted a New Drug Application (NDA) to the FDA for the approval of this drug in February 2012. ...

Tecfidera is the 10th drug to be approved as a disease-modifying therapy (DMT) for the long-term treatment of MS. Tecfidera is administered in pill form orally (by mouth) and is the third oral DMT approved for MS. The approved dosage is 240 mg to be taken two-times daily. The previous oral medications were approved in 2010 (Gilenya®) and in 2012 (Aubagio®). Five other DMTs for MS are taken via self-injection – the first of which was approved in 1993; the remaining two DMTs are administered via intravenous injection. While none of these treatments can cure MS, they all have been shown to be effective in reducing the number and severity of relapses (disease flare-ups), slow disease activity (in terms of fewer and less-active lesions in the brain), and in some instances, slow disease progression.

MSAA Chief Medical Officer Dr. Jack Burks explains, "With the FDA approval of Tecfidera, a pill taken twice daily, another first-line oral treatment option for people with relapsing forms of MS becomes available. The combination of robust effectiveness data with only transient side effects consisting mainly of flushing and gastrointestinal symptoms adds another valuable treatment option for patients and doctors to discuss. The future for individuals with MS is brighter than ever, and this is true not only for those with relapsing forms of MS, but for others also. Encouraging drug trials are currently underway in an effort to provide treatment options for the entire MS community, including those with non-relapsing, progressive forms of the disease."

Mechanisms of Action – How Tecfidera Works

Tecfidera is related to a medication called Fumaderm®, which was previously shown to be effective in patients with psoriasis and used for this indication in Germany for many years. The mechanism of action in MS is still under investigation; however, Tecfidera may have a distinct dual mechanism of action.

First, it is an immunomodulator, modulating or affecting how the immune system functions. It exhibits anti-inflammatory properties, which is an important component in the effective treatment of relapsing forms of MS. This induces anti-inflammatory cytokines (small proteins that may stimulate or inhibit the function of other cells) and appears to suppress damaging macrophage cell activity. Macrophages are a type of white blood cell that can damage both the protective covering (myelin) to the nerves of the central nervous system (those of the brain, spinal cord, and optic nerves) and can also damage the nerves themselves.

Second, Tecfidera may have neuroprotective effects, potentially protecting the nerves and their myelin covering from damage. This is due to its activation of a substance that is critical for resistance to cellular damage (from what is termed "oxidative stress"), and is also critical for normal immune function.

Completed Studies with Tecfidera

Two large Phase III trials were conducted with Tecfidera; both showed positive outcomes. The Phase III DEFINE study, which compared two doses of Tecfidera against placebo in 1,200 patients, was completed in February 2011. The Phase III CONFIRM study, which enrolled 1,232 patients, tested two dose levels against placebo, and also compared Copaxone against the same placebo group; the study was completed in September 2011.

The Phase III DEFINE study was a multicenter, double-blind trial of Tecfidera. In this study, 240 mg of Tecfidera was given either twice or three times daily versus placebo for two years. The study met its primary endpoint with a 49 to 50-percent reduction in the proportion of patients who relapsed during the study period. One of the secondary clinical endpoints was confirmed disability progression. Each of the two Tecfidera doses reduced the risk of sustained disability progression (for at least 12 weeks) by 34 to 38 percent.

The Phase III CONFIRM study was also a multicenter, double-blind trial. For two years, it compared the same two doses of Tecfidera with placebo (as done in the DEFINE study) and also compared the same placebo group to a group receiving daily subcutaneous injections of Copaxone. (Please note that the study was not designed to compare the effectiveness of Tecfidera to Copaxone.) The study met its primary endpoint with a reduction in relapse rates of 44 to 51 percent for Tecfidera compared to placebo. No statistically significant difference was observed in the remaining clinical endpoint of confirmed disability progression, possibly due to the unexpectedly low rate of progression in the placebo group.


In both studies, compared to placebo, individuals given Tecfidera had significantly reduced disease activity as shown on magnetic resonance imaging (MRI) scans. These included significant reductions in the number and size of new and enhancing brain lesions (areas of disease activity, inflammation, and potential damage to the myelin and nerves).

Continuation Studies

A continuation study of 1,736 patients who participated in the DEFINE and CONFIRM studies called ENDORSE is evaluating the long-term safety profile of Tecfidera as well as its long-term efficacy on clinical outcomes, MRI scans, and quality-of-life. The study will continue through 2013, although initial data were presented in fall 2012. No new safety concerns were identified, and no deaths were thought to be related to the medication. There were 14 malignancies observed (less than 1 percent) in this patient population, though it was not apparent that these were directly caused by Tecfidera.

The Phase II EXPLORE trial is evaluating oral Tecfidera as a combination therapy with an injectable medication. It will determine the safety and tolerability of Tecfidera when administered in combination with interferons or Copaxone to 100 people (who continue to have evidence of disease activity despite receiving consistent treatment for at least one year). Efficacy endpoints (determining the effectiveness) will also be assessed in a subset of participants. The study concluded in 2012 and the results are expected in 2013.

Side Effects and Adverse Events

In the large studies leading up to the approval of Tecfidera, flushing and gastrointestinal events, such as diarrhea, nausea and vomiting, and abdominal pain, were the most commonly reported side effects. Flushing and gastrointestinal events occurred in approximately 30 to 40 percent of patients and occurred more often at the beginning of treatment, decreasing in frequency after the first one to two months on this medication.

Other adverse events, which were mild or moderate in severity, included upper respiratory infection, pruritus (chronic itching), and erythema (skin redness or rash). The only serious adverse events (aside from MS relapses) to occur in two or more patients taking Tecfidera during these large studies was gastroenteritis (an inflammation of the lining of the intestines) and gastritis (an inflammation of the stomach lining).

In terms of long-term health risks, reduced white-blood cell (lymphocyte) counts were seen during the first year of treatment (lymphocytes are disease-fighting cells). However, the incidence of infection did not differ between the treated and placebo groups during the studies. Because of the reduced white-blood cell counts, the FDA recommends that prior to starting Tecfidera, and annually thereafter while still on the treatment, patients be given a complete blood count to monitor their ability to fight infection.

The occurrence of malignancies were low and did not differ between treatment groups in the DEFINE trial. No malignancies were reported with the CONFIRM trial.

During the first six months of therapy in the DEFINE study, liver enzymes were elevated in 6 percent of individuals taking Tecfidera, compared to 3 percent of the placebo group. No cases of liver failure were reported in either study. Excess protein in the urine (proteinuria) was observed slightly more often in the treated groups versus the placebo group of the DEFINE study. No cases of kidney failure were reported in either study.

For More Information

Additional information on Tecfidera may be found by visiting http://www.tecfidera.com. Individuals may also learn more through Biogen Idec’s patient assistance program’s website at http://www.msactivesource.com or by calling (800) 456-2255. In addition to MSAA’s website (at http://mymsaa.org), individuals may call MSAA at (800) 532-7667 for more information about MS and its treatments. Questions to MSAA’s Client Services Department may be emailed to MSquestions@mymsaa.org.

_________________________________

Written by Susan Courtney
Reviewed by Jack Burks, MD

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PostPosted: Wed Apr 24, 2013 10:56 pm    Post subject: PML found in patients taking dimethyl fumarate Reply with quote

In every ointment, one is apt to find a fly....

Some patients taking a very similar drug have developed PML. US News and World Report (April 24) has an article about it.
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PostPosted: Mon May 06, 2013 10:16 pm    Post subject: New England Jrl. of Med. article on Phase 3 trial of BG-12 Reply with quote

The September 20, 2012, issue of the New England Journal of Medicine contains this article by Ralf Gold et al., "Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis".
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PostPosted: Wed May 08, 2013 6:32 pm    Post subject: Neurology Now article--end of the injectable ABCRs? Reply with quote

This article is in Neurology Today, May 2, 2013:

Quote:
With New Oral Ms Drug, New Therapeutic Options

Valeo, Tom


A new oral multiple sclerosis (MS) drug reported to be safer, more effective, and less expensive than most alternatives could emerge as a front-line agent for relapsing-remitting multiple sclerosis (MS), according to some neurologists and industry analysts.

The US Food and Drug Administration approved dimethyl fumarate, tested as BG-12 and marketed as Tecfidera, on Mar. 27. Developed by Biogen Idec, the agent will have a wholesale annual cost of about $54,900, according to the company — about 8 percent less than the Novartis agent, fingolimod (Gilenya), which sells for about $59,595 annually.

By not establishing a new price peak among the notoriously expensive MS drugs, dimethyl fumarate could emerge as a first-line agent instead of being held in reserve until less expensive drugs have failed, experts told Neurology Today.

In two phase 3 trials, both published in the Sept. 20, 2012 issue of the New England Journal of Medicine, BG-12 cut the number of relapses in half compared with placebo. In DEFINE (Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS), a two-year study involving more than 1,200 patients with relapsing-remitting MS, BG-12 reduced relapses by 53 percent among those taking the oral medication twice daily, and by 48 percent among those taking it three times daily (p<0.001 for the comparison of each BG-12 regimen with placebo). The study also showed a reduction in disability progression of 38 percent (hazard ratio, 0.62; 95% CI, 0.44 to 0.87; p=0.005) among those taking the pill twice a day, and 34 percent for among those taking three per day (hazard ratio, 0.66; 95% CI, 0.48 to 0.92; p=0.01).

The two-year CONFIRM (COmparator and aN oral Fumarate In Relapsing-remitting MS) study, which also involved more than 1,200 MS patients, compared BG-12 with glatiramer acetate (Copaxone) and a placebo, and found that BG-12 reduced relapses by 44 percent among those who took it twice a day (0.18-0.28, 95% CI, p<0.001), and by 51 percent among those taking it three times daily (0.16-0.25, 95% CI, p<0.001). However, the trial did not find evidence that the drug reduced disability progression.

Glatiramer acetate, in contrast, reduced relapses by only 29 percent (0.23-0.35, 95% CI, p=0.01) compared with placebo, and did not slow the progression of disability.

The results, which have excited neurologists and MS patients alike, followed a lackluster phase 2 trial involving 257 patients, in which BG-12 reduced relapses by only 32 percent.

“The phase 2 trial that led to phase 3 was a lot smaller,” said Michael Kaufman, MD, director of the Multiple Sclerosis Center at the Carolinas Medical Center in Charlotte, NC. “You probably should believe the phase 3 trial results, because those trials were larger and longer, so chance played less of a role. But it's a little confusing why phase 2 wasn't as good as phase 3.

”Dimethyl fumarate, a methyl ester of fumaric acid, modulates the immune system and reduces neuroinflammation apparently by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway, which encodes proteins that increase antioxidant and detoxification enzymes, according to a 2011 article in Brain. The authors of that paper found evidence of Nrf2 upregulation in the spinal cord of autopsy specimens taken from MS patients and in mouse models of MS.

The active metabolite of dimethyl fumarate — monomethyl fumaric acid — is already licensed in Germany and sold under the trade name Fumaderm as an oral treatment for psoriasis. After two physicians noticed that two patients with MS stabilized after treatment with Fumaderm, a 2006 study was conducted and found that seven relapsing-remitting MS patients showed a reduction in the number and volume of lesions after 18 weeks of treatment with Fumaderm — results that encouraged Biogen to develop the drug.

Dimethyl fumarate, once used to combat moisture and mildew in couches, shoes, and other consumer products, was blamed for an outbreak of severe dermatitis among people exposed to the compound. After a Dutch researcher established the link in a 2008 paper, dimethyl fumarate was banned for such uses in Europe.

Dimethyl fumarate is the third FDA-approved oral drug for MS following fingolimod, which reduces relapses by about 54 percent, and teriflunomide (Aubagio), which reduces them by about 30 percent — the same as older injectable drugs.

However, dimethyl fumarate produces far milder side effects than other MS medications. Around 40 percent of patients experience some gastrointestinal distress and skin flushing, which usually disappear after a few weeks of treatment.

“I'd say we have 150 to 200 patients who have been waiting for this drug to come out,” said John Corboy, MD, professor and director of neurology faculty affairs at the University of Colorado School of Medicine, who also serves on the editorial advisory board for Neurology Today. “That's not due to promotion on our part — we generally tell people if you're doing well on a drug there's no reason to stop it — but there's a high level of expectation among patients for this medication, which was not the case when the first or second oral drug came on the market.”

BG-12 requires very little monitoring, unlike fingolimod, teriflunomide, and Biogen's natalizumab (Tysabri), which is administered through an IV drip.

“When I saw the package insert I was impressed by the brevity of it,” said Dr. Corboy. “We're used to black box warnings and long discussions of side effects and lab tests. This requires almost no monitoring, and there's no risk mitigation strategy.”

An oral drug is especially welcome to long-term MS patients who have been injecting themselves with an interferon for so long they have developed induration, and have trouble finding new injection sites. “This is a drug that will be potentially attractive for new starts too because it doesn't have any significant side effects,” said Bruce A. Cohen, MD, a professor in the Davee department of neurology and clinical neurosciences at Northwestern University's Feinberg School of Medicine in Chicago. “Of course, as with any new drug, we don't know what we don't know, and problems may emerge over time, so we'll have to be vigilant, but I would say that this drug offers excellent efficacy and with modest tolerability issues.”

How does the newest MS drug compared with other MS drugs approved by the FDA in the last few years? Although natalizumab reduces relapse rates by about 68 percent, and appears to produce a 50 percent reduction in the probability of sustained disability, the drug brings with it a 1 in 3,000 chance of causing progressive multifocal leukoencephalopathy (PML), which usually causes death or severe disability. The risk of PML is increased in people who carry antibodies for the common John Cunningham, or JC virus, which typically lies dormant in the gastrointestinal tract, but can cross the blood-brain barrier and infect oligodendrocytes and astrocytes.

“We stratify the MS world into two populations — those that are JC antibody negative and those that are JC antibody positive,” said Timothy L. Vollmer, MD, professor and director of clinical research in the University of Colorado School of Medicine's department of neurology. “In JC-negative patients, natalizumab remains a very attractive therapy, but in patients who are infected with the JC virus, the cumulative risk of PML approaches 1 in 400. If chemotherapy or immunosuppressants are involved, the risk approaches 1 in 80.”

Patients who take fingolimod face a small risk of serious side effects, including skin cancer, viral infections, and potentially fatal heart rhythm disturbances.

Teriflunomide can have negative effects on blood pressure, bone marrow, liver, kidneys, skin, peripheral nerves, among other areas.

“I don't see any reason to put patients on first-line injectables now that dimethyl fumarate and fingolimod are available,” said Dr. Vollmer. “I don't know if one is superior to the other — that's still an open question — but we do know that both are superior to the current first-line agents.”

Dimethyl fumarate is likely to take the largest bite out of the market for glatiramer acetate, according to Dr. Corboy. “The main attraction for glatiramer acetate has been safety, and it is a safe drug,” he said, “but if dimethyl fumarate is perceived to be equally safe and oral and better, why would anyone take glatiramer acetate?”
-----------------------------------
LINK UP FOR FURTHER READING:

•. Gold R, Kappos L, Dawson KT, et al.for DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098–1107.
View Full Text | PubMed | CrossRef

•. Fox RJ, Miller DH, Dawson KT, et al.for CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087–1097.
View Full Text | PubMed

•. Linker RA, Lee DH, Gold R, et al.Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134 (Pt. 3):678–692.
•. Rantanen T.The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer. Br J Dermatol 2008;159:218–21.
•. Schimrigk S, Brune N, Przuntek H, et al.Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006;13(6):604–10.


The article can be seen here.
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PostPosted: Wed May 15, 2013 5:49 pm    Post subject: NEJM letter on PML case related to dimethyl fumarate Reply with quote

The April 25, 2013, issue of the New England Journal of Medicine contains a letter about a PML case in someone with possible MS who had been prescribed a psoriasis drug, Psorinovo, in which the active agent is dimethyl fumarate:

Quote:
To the Editor:

Preparations containing various mixtures of fumaric acid esters are prescribed for psoriasis in several countries, in many cases for off-label use, and are regarded as safe.1 One such preparation is enteric-coated, slow-release Psorinovo (compounding pharmacy, Mierlo-Hout), in which the active agent is dimethyl fumarate and in which copper gluconate was used as an additive until 2010....

On November 5, 2012, a 42-year-old woman who reported having progressive right-sided hemiparesis since May consulted us for a second opinion. She had been given a diagnosis of possible multiple sclerosis in September and at that time received 3000 mg of intravenous methylprednisolone over 3 days, without effect. Her medical history was notable for psoriasis, for which she had been taking 420 mg of Psorinovo per day since 2007, supplemented by 1000 mg of calcium ascorbate per day and EPA-1000 fish oil capsules (EPA denotes the omega-3 fatty acid eicosapentaenoic acid).
Sequential magnetic resonance imaging (MRI) scans of the brain ... showed small, deep white-matter lesions and one large progressive lesion, which was suggestive of progressive multifocal encephalopathy (PML), as described in a study of imaging findings in relation to PML resulting from treatment with monoclonal antibodies.2

Hematologic studies revealed lymphopenia, with a count of 200 lymphocytes per cubic millimeter (normal range, 600 to 2900). We realized in retrospect that the lymphopenia had developed after the initiation of treatment with Psorinovo.... The patient was seronegative for HIV, but a semiquantitative, real-time polymerase-chain-reaction (PCR) assay of a specimen of the cerebrospinal fluid was positive for the JC virus.

We made a diagnosis of PML, stopped treatment with Psorinovo on November 7, and then started treatment for PML with mefloquine and mirtazapine.

Initially, the hemiparesis remained progressive, even though the lymphopenia began to abate.... On December 7, we noticed signs of an immune reconstitution inflammatory syndrome (IRIS) on MRI, with indications becoming more evident on December 13.... We initiated treatment with intravenous methylprednisolone. Her clinical condition stabilized in early January 2013, and we observed the first signs of recovery on January 31.

We believe that treatment with Psorinovo contributed to the development of PML in our patient. First, lymphopenia developed during treatment with Psorinovo and is a well known side effect.1 Second, our patient had used no immunosuppressive medication before the onset of PML, and she was seronegative for HIV. Finally, the occurrence of IRIS after the discontinuation of Psorinovo argues in favor of a causal link.

We think this case report is of special relevance since preparations of fumaric acid esters, including dimethyl fumarate, are emerging drugs that may have a broader range of therapeutic indications in the near future.3-5

Bob W. van Oosten, M.D., Ph.D.
Joep Killestein, M.D., Ph.D.
Frederik Barkhof, M.D., Ph.D.
Chris H. Polman, M.D., Ph.D.
Mike P. Wattjes, M.D.
VU University Medical Center, Amsterdam, the Netherlands
bw.vanoosten@vumc.nl
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PostPosted: Wed Jun 19, 2013 11:15 am    Post subject: ACTRIMS: GI tolerability events w/Tecfidera in MS Reply with quote

Presented at the ACTRIMS/CMSC conference in Florida, May 31, 2013:

Quote:
Gastrointestinal Tolerability Events with BG-12 (Dimethyl Fumarate) in MS


Krzysztof Selmaj, MD, PhD , Medical University of Lodz, Lodz, Poland, Lodz, Poland
Ralf Gold, MD , St Josef Hospital, Ruhr University, Bochum, Germany, Bochum, Germany
Robert J. Fox, MD, FAAN , Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH
Eva Havrdova, MD, PhD , Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, Prague, Czech Republic
Gavin Giovannoni, PhD , Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK, London, United Kingdom
Amy Pace, ScD , Biogen Idec Inc., Weston, MA, USA, Weston, MA
Mark Novas, MD , Biogen Idec Inc., Weston, MA, USA, Cambridge, MA
Leslie Meltzer, PhD , Biogen Idec Inc., Weston, MA, USA, Weston, MA
Christophe Hotermans, MD, PhD , Biogen Idec Inc., Weston, MA, USA, Weston, MA
Katherine T. Dawson, MD , Biogen Idec Inc., Weston, MA, USA, Cambridge, MA
J. Theodore Phillips, MD PhD FAAN , Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA, Dallas, TX


Background:

BG-12 (dimethyl fumarate) demonstrated an acceptable safety profile in Phase 3 studies. Common adverse events (AEs) associated with BG-12 included flushing and gastrointestinal (GI) events. Most patients reported GI events that were mild/moderate in severity and decreased substantially in incidence after the first month of treatment.
Objectives: To characterize GI AEs in relapsing–remitting MS patients treated with BG-12 twice daily (BID) in a post-hoc analysis of integrated data from the Phase 3 DEFINE and CONFIRM studies.

Methods:

Incidence, nature, severity, and management of GI AEs (by manual review of indications of concomitant medications and timing vs AEs) were summarized for patients treated with BG-12 240 mg BID versus placebo in DEFINE and CONFIRM, focusing on Months 0–3 (when GI AE incidence was highest).

Results:

A total of 769 patients received BG-12 and 771 received placebo with 70% and 65% completing 2 years of treatment, respectively. GI AEs were reported by 40% versus 31% patients overall, and 41% versus 34% patients who completed 2-year treatment (sensitivity analysis) in BG-12 and placebo groups, respectively. In Months 0–3, the incidence of GI AEs was 27% versus 17% in BG-12 and placebo groups, respectively. 3% versus <1% patients discontinued treatment due to GI AEs, and 11% versus 4% had GI AEs that required symptomatic therapy, respectively. Within the first 3 months of BG-12 treatment, the most common (≥5% patients) events were nausea, diarrhea, abdominal pain (upper or unspecified), and vomiting.

Of the abdominal/upper abdominal pain, nausea/vomiting, and diarrhea events, 91%, 95%, 96% were mild/moderate, 7%, 12%, 6% resulted in treatment discontinuation, 93%, 95%, 96% resolved (median duration 9.5 days, 8 days, 8 days), and 38%, 33%, 26% utilized symptomatic therapy, respectively. Common symptomatic therapies for abdominal/upper abdominal pain were omeprazole, paracetamol, ranitidine; nausea/vomiting were metoclopramide, domperidone; and diarrhea was loperamide (efficacy not assessed).

Conclusions:

The incidence of GI AEs was highest in the first 3 months of treatment. Most events were mild-to-moderate in severity and resolved after a median duration of less than 2 weeks while few GI events resulted in treatment discontinuation. Further studies are needed to evaluate the efficacy of individual management strategies.
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PostPosted: Thu Aug 01, 2013 6:42 pm    Post subject: Biogen says link to Tecfidera unlikely in woman's death Reply with quote

From the MS Foundation's MSFYi newsletter, August 1, 2013:

Quote:
Biogen Says Link to Tecfidera™ is Unlikely in Woman’s Death

A 59-year old woman with MS died due to bilateral pneumonia after discontinuing Tecfidera™, according to the drug’s distributor, Biogen Idec Inc. At the time of announcement Biogen said "a link to Tecfidera is unlikely" based on the circumstances of the case and cause of death.

The woman was not taking Tecfidera at the time of death, having discontinued the treatment 2.5 weeks earlier because of gastrointestinal problems, including nausea, vomiting, and diarrhea. Bilateral pneumonia, an infection of both lungs, is known to affect people with MS, the company said.

The woman, who had a history of irritable bowel disease and recurrent infections that included bronchitis, had been taking Tecfidera for 5.5 weeks before discontinuing treatment, according to Biogen. An investigation into her death is ongoing.

In clinical trials the drug's most common side effects were flushing as well as stomach problems, including vomiting and diarrhea, according to the U.S. Food and Drug Administration.
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PostPosted: Thu Oct 24, 2013 8:41 pm    Post subject: Tecfidera: Sidestepping the side effects Reply with quote

From the Rocky Mountain MS Center eMS News, October 24, 2013:

Quote:
Tecfidera: Sidestepping the Side Effects

Physicians prescribe, and we take, medications because they have a desired effect and produce a positive outcome. For example, with MS disease-modifying therapies the positive outcomes are a reduction in disease activity and disability progression. Sometimes a medication produces more than the desired effect and causes a problem. These worrisome outcomes can be adverse events or allergic reactions. Adverse events—undesired complications that are harmful and/or dangerous—are what most concern doctors. An example of an adverse event is PML. While it is unusual and infrequent, it is dangerous and medical providers carefully watch for it. Allergic reactions happen when the body's natural defense system overreacts. While they can be severe, more often they are resolved quickly—often by taking Benadryl.

Side effects—a phrase we often hear but may not fully understand—are different. Side effects are the undesired consequences that occur as a result of taking a medication, and while they can be annoying and troublesome, they are not generally dangerous and can be managed. Any change results in a side effect, or in other words, a consequence or outcome. Changing your diet has side effects: you may lose weight or have more energy. Having a child has side effects: you will sleep less and feel more tired, and likely experience a change in priorities and daily rhythms. Likewise, taking an MS medication has desired side effects: it can result in less or no new lesions (which demonstrate reduced disease activity) and fewer or no exacerbations. It can also result in everyday side effects that can be more challenging; for example, flu-like symptoms.

The good news is that these side effects are generally anticipated and can usually be well managed. Simply adhering to certain practices help. Tecfidera (BG-12), which was approved by the FDA in March 2013, is a good example. As you can read here, phase II and III studies demonstrated the drug’s efficacy and safety. Because of this and the fact that it is an oral medication, FDA approval of Tecfidera was highly anticipated and since its emergence it has been prescribed for many patients. However, as with most medications, Tecfidera can result in some challenging side effects. These few important reminders for patients on the therapy can help:

    ~Know about the two common side effects that patients on Tecfidera may encounter: flushing and stomach problems. Flushing can include redness, itching or rash, and stomach problems can include nausea, vomiting, diarrhea, stomach pain or indigestion. Both flushing and stomach problems generally decrease over time.

    ~If you have pre-existing stomach problems, talk to your medical provider before taking Tecfidera. There are pre-treatment strategies that often help reduce or eliminate these issues. There are pre-treatment strategies that can help manage flushing as well.

    ~Always take Tecfidera with morning and evening meals. Taking Tecfidera with food helps the body better absorb it. It is also recommended to take it at the same time daily.

    ~Tecfidera side effects can be worked through and it is critical not to give up on the medication. If side effects begin to interfere with daily activity, contact your medical provider to discuss how to manage them.


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