BG-12

BG-12 (BG00012, dimethyl fumarate) is an investigational oral therapy in Phase III clinical development as a monotherapy for the treatment of relapsing-remitting multiple sclerosis (RRMS), the most common form of MS, and in Phase II clinical development for rheumatoid arthritis (RA).

BG-12 received Fast Track designation in MS from the U.S. Food and Drug Administration (FDA), which may expedite U.S. regulatory review. Biogen Idec retains full worldwide commercial rights to BG-12.

Both U.S. and European regulators have accepted for review Biogen Idec's application for experimental multiple sclerosis drug BG-12, the company said on Wednesday.

The pill is seen by some Wall Street analysis as having the potential to become the world's leading treatment for the chronic, disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision.

Biogen already makes multiple sclerosis drugs Avonex and Tysabri, which are given by injection.

The company said the U.S. Food and Drug Administration granted a standard 10-month review for BG-12 and the European regulatory agency has validated its application. Both applications were submitted in the first quarter of this year.

Source: Reuters © 2012 Thomson Reuters (09/05/12)

The latest data on Biogen Idec Inc.'s (BIIB) experimental multiple-sclerosis pill BG-12 show "favorable safety and tolerability" that support the drug's use as a front-line treatment for MS patients, the biotechnology company said.

Details from the "Confirm" study on BG-12 were set for presentation at an American Academy of Neurology conference Tuesday. The drug is currently under review with U.S. and European regulators and could be approved early next year.
Positive data and high expectations for the MS treatment have helped drive Biogen shares to around all-time high levels recently. Most treatments for the chronic, inflammatory and potentially disabling disease are delivered by needle, but BG-12 is an oral drug that will likely be taken twice daily.

The Biogen-funded Confirm study of about 1,400 MS patients showed the most common side effects for BG-12 patients at two years were flushing, or reddening of the skin, and gastrointestinal issues such as diarrhoea and nausea. These problems were more common with BG-12 than they were with a placebo, but the side effects "decreased substantially" for BG-12 patients after the first month of treatment, the company said.

Meantime, BG-12 had a lower rate than placebo when it came to serious adverse events, which were mainly relapses of MS attacks. Also, the incidence of serious infections "was low and balanced across the study groups," and there were no malignancies among BG-12 patients, Biogen said.

The overall incidence of adverse events for patients on placebo was 92%. The rate was 94% for patients on two daily BG-12 doses and 92% for patients on three daily doses. The rate of serious events was 22% for placebo, 17% for two daily BG-12 treatments and 16% for three daily treatments.

"The safety profile has continued to hold up nicely from one study to the next," said Doug Williams, Biogen's executive vice president of research and development, in an interview.

Williams also said that Biogen believes BG-12 "should be front-line therapy for patients" based on the risk-benefit profile seen in BG-12 studies.

Biogen first released results from the Confirm study in October. The study met its main treatment goal by showing a reduced annualised relapse rate--which takes into account the total number of relapses among all patients--for BG-12 patients compared with those on placebo. The study measured patients for two years and also included patients treated with Teva Pharmaceutical Industries Ltd.'s injectable MS drug Copaxone.

Biogen hasn't disclosed how much BG-12 is expected to cost, but has said the price will likely be comparable to other MS agents. Patients in the Confirm study had the relapse, remitting form of MS, which involves flare-ups rather than constant disease progression. This is the most common form of the disease.

Source: Fox Business News ©2012 FOX News Network, LLC (24/04/12)

Biogen Idec Inc., a Weston-based biotechnology company known for its multiple sclerosis drugs, said it has submitted a New Drug Application to federal regulators to get approval to market a potential new MS treatment known as BG-12.

In December, Biogen Idec shares hit their high for 2011 after the company released promising results from a clinical trial of BG-12.

BG-12, the company’s designation for dimethyl fumarate, would be taken twice a day in pill form, and it is designed to treat of relapsing-remitting multiple sclerosis, sometimes called RRMS, the most common form of MS, Biogen Idec said in a press release.

Two other Biogen Idec MS drugs are delivered differently. Tysabri is administered in a once-a-month infusion, and Avonex is injected once a week, the company said.

Biogen Idec, which said today that it had submitted a New Drug Application to the US Food and Drug Administration, added that it plans to submit a similar request to European regulators within the next few days.

Biogen Idec said it anticipates hearing from regulatory authorities regarding the status and acceptance of its BG-12 submissions “within the next couple of months.”

In a separate press release this morning, the company said the FDA has approved two separate dosing innovations designed to improve the treatment experience for patients receiving Avonex. Currently, Avonex is delivered by syringe. What the FDA has approved is an “auto-injector” device for delivering a dose of Avonex. Because the auto-injector’s needle is thinner and shorter than that of a syringe, the hope is that the auto-injector will make things easier for patients.

Source: boston.com © 2012 NY Times Co (28/02/12)

Biogen Idec Inc's says its experimental multiple sclerosis drug BG-12 met the main goal of a closely watched clinical trial.

The Weston, Massachusetts-based biotechnology company said that a late-stage trial known as CONFIRM showed that BG-12, when given twice a day, cut the annualized relapse rate in patients with multiple sclerosis by 44 percent at two years versus placebo, and by 51 percent when given three times a day.

Investors had been waiting to see if the results would be comparable to an earlier trial known as DEFINE, which posted unexpectedly strong results showing BG-12 cut the annualized relapse rate by 53 percent when given twice a day. The results of the two trials were sufficiently similar to send the stock soaring.

If approved, BG-12 could significantly strengthen Biogen's position in the increasingly competitive market for multiple sclerosis drugs. It already sells Avonex, which is injected, and Tysabri, which is infused. BG-12 is a pill that would compete with Gilenya, a recently launched pill made by Novartis AG.

The CONFIRM study, unlike DEFINE, also tested BG-12 against Copaxone, a drug made by Teva Pharmaceutical Industries Ltd. Copaxone cut the annualized relapse rate by 29 percent.

Biogen said BG-12 cut the rate of disability progression by 21 percent when given twice a day and by 24 percent given three times a day. That result was not statistically significant and compares negatively with the DEFINE trial, which showed a cut in the rate of disability progression of 38 percent.

Biogen said the lack of statistical significance may be attributable to an unexpectedly low rate of disease progression in the placebo group. It said it is studying the data closely to better understand the figures.

Copaxone cut the rate of disability progression by 7 percent.

Analysts said the data, which will be presented in more detail at a future medical meeting, look promising.

"We believe these data generally 'confirm' BG-12's efficacy and clearly show that it's likely a more effective drug than Teva's Copaxone," said Mark Schoenebaum, an analyst at ISI Group, in a research note.

Multiple sclerosis is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision. BG-12 is designed to treat relapsing-remitting MS, in which flare-ups are followed by periods of remission. About 85 percent of people with MS are initially diagnosed with this form of the disease.

The most common side effects with BG-12 were flushing and gastrointestinal symptoms such as nausea.

Doug Williams, Biogen's head of research and development, said on a conference call that he does not see the difference in the twice a day and three times a day arms of the trial as meaningful, and that twice a day dosing will be "appropriate."

"I think the risk-benefit profile of BG-12 is quite attractive," he said. "It looks like a first-line therapy to me."

Williams said the company expects to file for approval of the drug in the first half of next year.

Source: Reuters (c) Copyright Thomson Reuters 2011 (27/10/11)

Biogen Idec BIIB today announced positive data from the Phase 3 DEFINE clinical trial of oral BG-12 (dimethyl fumarate) in people with relapsing-remitting multiple sclerosis (RRMS).

Results showed that 240 mg of BG-12, administered either twice a day (BID) or three times a day (TID), significantly reduced the proportion of patients who relapsed by 49 percent and 50 percent, respectively, at two years compared with placebo.

Detailed data from DEFINE will be presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) in Amsterdam, including a platform presentation on Friday, October 21, 2011 at 9:30 a.m. CEST.

"The significant clinical and radiological responses in DEFINE are further evidence that BG-12 may become an oral therapy of choice for MS patients," said Doug Williams, Ph.D., Biogen Idec's Executive Vice President of Research and Development. "Results from our second Phase 3 trial, CONFIRM, will provide additional insight into BG-12's profile, as well as a comprehensive data set to further discussions with regulatory authorities. We anticipate releasing top-line data from CONFIRM later this year."

DEFINE was the first of two Phase 3 clinical trials designed to determine the efficacy and safety of BG-12 in people with RRMS. Both BG-12 BID and TID met the primary and all secondary endpoints in the study. In addition to demonstrating a significant reduction in the proportion of patients who relapsed, BG-12 significantly reduced the annualized relapse rate (ARR) and the risk of disability progression as measured by the Expanded Disability Status Scale (EDSS) at two years compared to patients on placebo.

-- BG-12 reduced the risk of relapse by 49 percent in the BID group (HR 0.51; 95% confidence interval [CI] 0.40, 0.66; p<0.0001) and by 50 percent in the TID group (HR 0.50; 95% CI 0.39, 0.65; p<0.0001).

-- BG-12 BID reduced the ARR by 53 percent, while BG-12 TID reduced the ARR by 48 percent (p<0.0001 for both).

-- BG-12 BID reduced the risk of disability progression by 38 percent (HR 0.62; 95% CI 0.44, 0.87; p=0.0050), while BG-12 TID reduced this risk by 34 percent (HR 0.66; 95% CI 0.48, 0.92; p=0.0128).

"BG-12 may be a valuable treatment option for MS patients, combining strong efficacy, a favourable safety profile and oral administration," said Ralf Gold, M.D., Professor and Chair, Department of Neurology, St. Josef-Hospital/Ruhr-University, Bochum, Germany. "Preclinical research has shown that BG-12 has anti-inflammatory and neuroprotective effects. If the clinical responses seen in DEFINE are replicated in its second Phase 3 trial, BG-12 has the potential to provide a new approach to treating MS and be an important step forward for patients."

Magnetic resonance imaging (MRI) scans were performed at baseline, 24 weeks, one year and two years to determine the number of T2 hyperintense lesions, gadolinium-enhancing (Gd+) lesions and T1 hypointense lesions (a tertiary endpoint). At two years, results demonstrated that RRMS patients receiving BG-12 experienced significant reductions in the number of brain lesions compared to patients on placebo.

-- BG-12 BID and TID reduced the mean number of new or newly enlarging T2 hyperintense lesions by 85 percent and 74 percent (p<0.0001), respectively.

-- BG-12 BID and TID reduced the mean number of Gd+ lesions by 90 percent and 73 percent (p<0.0001), respectively.

-- BG-12 BID and TID reduced the mean number of new T1 hypointense lesions by 72 percent and 63 percent (p<0.0001), respectively.

"The BG-12 program further demonstrates Biogen Idec's commitment to developing innovative therapies to address unmet needs in the MS community," continued Dr. Williams. "BG-12's distinct mechanism of action, combined with strong efficacy and safety data, position it as a potentially valuable option for MS patients and a further growth driver for Biogen Idec."

In DEFINE, the safety profile for the two BG-12 treatment groups was similar. The overall incidence of adverse events (AEs), serious adverse events (SAEs) and AEs leading to study discontinuation was similar among the BG-12 and placebo groups. AEs were reported by 95 to 96 percent of patients, irrespective of study group. The most frequently reported AEs across the three study groups were flushing, MS relapse, nasopharyngitis, headache, diarrhea and fatigue. Flushing (35% BG-12; 5% placebo), gastrointestinal AEs such as diarrhea (17% BG-12; 13% placebo), nausea (13% BG-12; 9% placebo), upper abdominal pain (11% BG-12; 7% placebo) and abdominal pain (10% BG-12; 5% placebo) were higher in the BG-12-combined group than the placebo group, with the highest incidence in the first month of treatment, which decreased thereafter.

SAEs were reported in 21 percent of patients receiving placebo and 17 percent of patients receiving BG-12. The most frequently reported SAE across all treatment groups was MS relapse (15% placebo; 9% BG-12). There were no deaths related to study treatment. There was no increase in infections, serious infections, opportunistic infections or malignancies.

These data will be presented in two posters and a platform presentation at ECTRIMS/ACTRIMS:

-- Clinical Efficacy of BG-12, An Oral Therapy, In Relapsing-Remitting Multiple Sclerosis: Data from the Phase 3 DEFINE Trial (#95) will be presented by Professor Ralf Gold on Friday, October 21, 2011 from 9:30 to 9:45 a.m. CEST.

-- Efficacy on MRI Endpoints of BG-12, An Oral Therapy, In Relapsing-Remitting Multiple Sclerosis: Data from the Phase 3 DEFINE Trial (P#831) will be available for viewing on Friday, October 21, 2011 from 3:30 to 5:00 p.m. CEST.

-- Safety and Tolerability of BG-12 in the Phase 3 DEFINE Trial in Patients with Relapsing-Remitting Multiple Sclerosis (P#994) will be available for viewing on Friday, October 21, 2011 from 3:30 to 5:00 p.m. CEST.

About DEFINE

DEFINE (Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS) was a global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the efficacy and safety of BG-12 in people with RRMS. The primary objective was to determine if BG-12 is effective in reducing the proportion of relapsing patients at two years. Secondary endpoints included ARR, disability progression as measured by EDSS, and, in a cohort of sites, the number of new or newly enlarging T2 hyperintense lesions and the number of Gd+ lesions as measured by brain MRI. Additional endpoints included the safety and tolerability of BG-12.

DEFINE enrolled 1,237 patients, 18 to 55 years of age, at 198 sites in 28 countries. Patients participating in the study were required to have RRMS per McDonald criteria 1-4, a baseline EDSS score between 0.0 and 5.0 (inclusive), and at least one MS relapse in the 12 months prior to randomization or a Gd+ lesion on brain MRI scans within six weeks of randomization. Patients were randomized in a ratio of 1:1:1 to: 240 mg of BG-12 BID, 240 mg of BG-12 TID or placebo. All patients underwent clinical assessments at screening, baseline and every four weeks for up to two years.

About BG-12

BG-12 (dimethyl fumarate) is an investigational oral therapy in late-stage clinical development for the treatment of RRMS, the most common form of MS. BG-12 is the only compound in clinical trials for the treatment of MS known to activate the Nrf-2 pathway. Research suggests that BG-12 has the potential to reduce the activity and impact of inflammatory cells on the Central Nervous System (CNS) and induce direct cytoprotective responses in CNS cells. These effects may enhance the CNS cells' ability to mitigate the toxic inflammatory and oxidative stress that plays a role in MS pathophysiology.

Top-line data from the second Phase 3 trial of BG-12, CONFIRM, is anticipated in the second half of 2011.

Source: Biogen Idec (21/10/11)

Detailed data from a key trial of Biogen Idec Inc's experimental multiple sclerosis drug BG-12 revealed no new safety concerns, and showed similar efficacy when given twice or three times a day, according to a summary of results to be presented at an upcoming conference.

Initial results from the trial, known as DEFINE, were released in April and showed the drug, when given twice a day, cut the annualized relapse rate by 53 percent at two years compared with placebo, and cut the rate of disability progression by 38 percent.

Biogen said at the time that the side effects were similar to those seen in an earlier, mid-stage trial, but did not elaborate.

Multiple sclerosis is a chronic, often disabling disease that attacks the central nervous system and can lead to numbness, paralysis and loss of vision. BG-12 is designed to treat relapsing-remitting MS, in which flare-ups are followed by periods of remission. About 85 percent of people with MS are initially diagnosed with this form of the disease.

A summary of detailed data to be presented at a meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) later this month, and posted on the group's website late on Tuesday, did not show a meaningful difference in safety or efficacy than that seen in the initial data.

Moreover, the ECTRIMS summary showed a 48 percent reduction in annual relapse rate with three times a day dosing and a reduction in disability progression of 34 percent, in line with the results seen with twice a day dosing.

"These data confirm that the efficacy of the twice a day and three times a day arms were numerically very similar in DEFINE, and increase our confidence in the data," said Thomas Wei, an analyst at Jefferies and Company, in a research note. "We are particularly encouraged that there is no material difference in discontinuations due to adverse events."

About 16 percent of patients dropped out of the twice a day and three times a day group, compared to a rate of 13 percent for the group treated with a placebo.

Side effects included flushing of the face, which affected 38 percent of patients in the twice a day group and 32 percent in the three times a day group, compared to a rate of 5 percent in the placebo group. The incidence of serious adverse events was similar to the placebo, as was the incidence of infection.

"We view the safety profile as largely manageable," said Geoff Meacham, an analyst at J.P. Morgan, in a research note. "As of right now, BG-12's overall clinical profile does appear to be shaping up nicely."

However, Meacham noted that investors' expectations of BG-12 are relatively high, leaving Biogen little room for error.

Biogen is due to release data from a second late-stage trial of BG-12, known as CONFIRM, by the end of the year. If data from CONFIRM are positive, Biogen's shares could rise as much as 10 percent, according to some analysts, and have the potential to fall as much as 20 percent if the data disappoints.

Unlike most MS drugs, which are given by injection or infusion, BG-12 is taken orally. Oral drugs are expected to eventually become the most popular option for patients. So far the only oral drug to be approved in Gilenya, a drug made by Novartis AG that is given once a day.

Gilenya has shown a reduction in annualized relapse rates of about 54 percent.

Some analysts expect BG-12, if approved, to generate more than $1 billion in annual sales. Weston, Massachusetts-based Biogen already makes the MS drugs Avonex and Tysabri. It shares sales of Tysabri with its partner Elan Corp Plc.

Source: Reuters © 2011 Thomson Reuters (05/10/11)

Can Biogen Idec keep the hits coming? The biotech giant's stock has been at the top of the charts among its peers over the past year, helped considerably by its experimental multiple sclerosis drug BG-12's performance in late-stage development.

With new Phase III data on the potential blockbuster expected within weeks, analysts told Reuters about some of the key factors that could play a role in the success of oral drug in the MS market.

Biogen, the world's largest provider of MS therapies, is banking on BG-12 to enter the new market for oral drugs against relapses of the nerve-damaging disease, which is most often treated with injected meds. The company's Phase III trial--dubbed DEFINE--impressed earlier this year, showing the drug could reduce annualized relapse rates 53% compared with placebo, Reuters reports. And drug has the potential to offer better safety than Gilenya, Novartis' oral MS pill that gained FDA approval last year.

For BG-12 to keep its positive momentum, the drug has to repeat the success of the DEFINE study with upcoming results from the Phase III trial appropriately named CONFIRM. Analysts will be watching closely for any safety issues in the 1,400-patient study that, even if the drug eventually gets a market green light, could deter doctors from prescribing it and hurt its chances of reaching blockbuster status. Unlike the previous late-stage study, there's also an arm of the newer trial that includes patients on long-approved MS treatment Copaxone.

While some stock pickers have been bullish about Biogen's chances with BG-12, others sound much more skeptical about the drug's prospects ahead of the big data event. BMO Capital Markets analyst Jim Birchenough has nudged clients to sell shares of Biogen before the data arrive. "We believe commercial expectations for Biogen Idec's multiple sclerosis franchise, in particular for BG-12, have been overestimated and that risk to upcoming CONFIRM data has been underestimated," he said, as quoted by Reuters.

Yet with Biogen's stock price up about 10% over the past week, lots of investors appear to be betting on the company's new BG-12 data to keep its streak alive.

Source: FierceBiotech © 2011 FierceMarkets. (19/09/11)

A Phase 3 trial of Biogen Idec Inc.'s multiple sclerosis treatment BG- 12 met the primary endpoint of reducing the number of patients who relapsed at two years when compared with a placebo.

The investigational oral compound, dimethyl fumarate, also met secondary targets, including lower annual relapse rates and disability progression rates at two years, as well as a favorable safety and tolerability profile. The study included more than 1,200 patients and evaluated two dosing levels.

The compound, which is aimed at relapsing-remitting multiple sclerosis, received fast-track designation in 2008 from the U.S. Food and Drug Administration. The fast-track designation is intended to expedite the review of drugs to treat serious diseases and meet an unmet medical need.

Results from a separate Phase 3 trial comparing dimethyl fumarate and glatiramer acetate against a placebo are expected in the second half of the year.

The company in February reported its fourth-quarter earnings dropped 21% on restructuring charges while its multiple sclerosis treatments continued to show sales growth. The results were the first from the company since it unveiled a restructuring in November that cuts costs, and focused the company around developing neurology treatments and its current franchise of multiple sclerosis drugs.

Source: Dow Jones Newswires Copyright (c) 2011 Dow Jones & Company, Inc. (11/04/11)

Fumarates: Unique position amongst the active MS drugs due to neuroprotective potential

Fumaric acid salts have been in use against severe psoriasis for a long time. About ten years ago, researchers in Bochum speculated that they may also have a favourable effect on Multiple Sclerosis (MS) as a result of their TH2 polarizing mechanisms.

In parallel to phase III studies, research is actively searching for the precise effective mechanisms. This has now been achieved by a neuroimmunological group at Bochum: fumaric acid salts detoxify radicals released during the inflammation process. In this way, they protect nerve and glial cells. Neurologists at the Ruhr University Hospital, St. Josef Hospital, working with Prof. Dr. Ralf Gold report early online in the leading neurology journal BRAIN.

Previous history. inspiration from dermatology

Like Multiple Sclerosis, psoriasis is an auto-immune disease, in which the immune system attack the body's own cells. In MS, the "insulating myelin layer" of the axons is destroyed in this way. About ten years ago, the RUB dermatologist Prof. Peter Altmeyer informed his colleague, the neurologist Prof. Horst Przuntek, that the mixture of fumaric acid salts registered for treatment of psoriasis under the trade name FUMADERM could possibly exert favourable effects in MS as well. In turn, the Swiss manufacturer Fumapharm sponsored a small study in Bochum. Ten patients were examined for a period of 48 weeks (Schimrigk et al European Journal of Neurology 2006, 13: 604). In Parallel to this, Fumapharm supported basic research which Prof. Gold then performed at his MS Institute in Göttingen (Schilling et al. Clin Exp Immunology 2006; 145: 101-107).

Fumaric acid salts detoxify radicals and protect nerve cells

After that, the scenario moved rapidly: the US pharmaceutical company BiogenIdec with its focus in MS research took over Fumapharm AG and initiated a successful Phase II study (Kappos, Gold, Lancet 2008; 372: 1463). Parallel to this, the group around Prof. Gold, who had moved to Bochum in the meantime, intensively studied the effective mechanisms. It was seen that the effect of the fumaric acid salts, unlike that of "standard medications" against MS, is not merely based on the suppression or the modulation of the immune system, but detoxifies damaging "oxidative radicals" released during the inflammation processes and thus supports the survival of nerve cells. The Nrf2 transcription factor plays a central role in this context. "In this way, fumaric acid assumes a special position in the MS world as a "neuro-protective/antioxidant substance", Prof. Gold explains.

Results of new study are being expected in summer 2011

An international, placebo-controlled, blind study (DEFINE, Sponsor: BiogenIdec) with 1,200 MS patients and the fumaric acid salt BG12 has just been completed under the leadership of Prof. Gold. Evaluation is being expected for summer 2011. "If the study is successful, one could easily imagine that the antioxidant effect of the fumaric acid also synergizes with established MS medication such as interferon-ß thus forming an ideal combination therapy", Prof. Gold speculates. "This is significant insofar as both fumarates as well as interferon do not contain any long-term risks according to the current state of knowledge – unlike many modern strong MS therapies."

Title

R. Linker, R. Gold et. al.: Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. In: Brain 2011: 134; 678, doi:10.1093/brain/awq386

Source: Eureka Alert (08/03/11)

BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis

BG-12, an immunomodulatory agent, reduces frequency of new gadolinium-enhancing (Gd+) lesions in relapsing multiple sclerosis (MS). This study reports the effect of 240 mg BG-12 orally three times daily (tid) for 24 weeks on the evolution of new Gd+ lesions to T1-hypointense lesions.

Brain magnetic resonance imaging (MRI) scans from patients in placebo and 240 mg BG-12 tid arms of a phase 2b study were examined retrospectively.

Included patients had at least one new Gd+ lesion from weeks 4 to 12. Week 24 scans were analyzed for number and proportion of new Gd+ lesions that evolved to T1-hypointense lesions.

Eighteen patients receiving BG-12 and 38 patients receiving placebo were included in the analysis. The analysis tracked 147 new Gd+ lesions in patients from the BG-12 group and 221 Gd+ lesions in patients from the placebo group. The percentage of Gd+ lesions that evolved to T1-hypointense lesions was 34% lower with BG-12 treatment versus placebo (29%, BG-12; 44%, placebo; odds ratio 0.51; 95% confidence interval 0.43, 0.61; p < 0.0001).

In addition to reducing frequency of new Gd+ lesions, BG-12 significantly reduced probability of their evolution to T1-hypointense lesions in patients with MS compared with placebo.

Macmanus DG, Miller DH, Kappos L, Gold R, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, Meluzinova E, Dufek M, Yang M, O'Neill GN, Dawson K.

NMR Research Unit, University College London Institute of Neurology, Queen Square, London, WCIN 3BG, UK.

Source: J Neurol. 2010 Oct 21 & Pubmed PMID: 20963434 (05/11/10)

Biogen Idec today announced enrollment of the first patient in a multicenter Phase II clinical trial designed to evaluate its investigational oral therapy BG-12 (dimethyl fumarate) in combination with commonly used first-line treatments in patients with relapsing-remitting multiple sclerosis (RRMS).

The trial, called EXPLORE, will evaluate the safety and tolerability of BG-12 when administered with beta interferons (IFNB) or glatiramer acetate (GA) to patients who continue to have evidence of disease activity despite receiving consistent monotherapy for at least a year. Efficacy endpoints will also be assessed in a subset of patients.

"An ongoing treatment challenge in MS is that many patients continue to experience disease activity despite being on therapy," said Alfred Sandrock, M.D., Ph.D., Senior Vice President of Neurology Research and Development at Biogen Idec. "The goal of the EXPLORE trial is to evaluate whether BG-12 may be a safe and effective agent to use in combination with other MS therapies, an important consideration for patients for whom new treatment strategies are needed."

BG-12 is the first compound in trials for the treatment of MS that has been shown to activate the Nrf2 transcriptional pathway.

Experimentally, the Nrf2 pathway has demonstrated neuroprotective and anti-inflammatory properties. Activation of this pathway in MS patients may potentially prevent further cell damage and tissue loss caused by the disease.

Preclinical studies have shown that activation of the Nrf2 pathway defends against oxidative-stress induced neuronal death, protects the blood-brain barrier and supports maintenance of myelin integrity in the central nervous system. Central nervous system inflammation and damage may trigger the symptoms common in RRMS such as fatigue, cognitive deterioration and physical disability.

Data from the Phase IIb study in RRMS, combined with experimental data showing BG-12's ability to activate the Nrf2 pathway, continue to support its evaluation as a monotherapy in two extensive ongoing Phase III MS studies, DEFINE and CONFIRM, which are fully enrolled. These data also support its further investigation as a combination therapy in EXPLORE.

"The MS community is eager for new treatment options for this debilitating disease," said Robert Fox, M.D., Staff Neurologist and Medical Director at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. "BG-12 may offer patients an additional treatment strategy. Its potential to both reduce inflammation and promote neuroprotection, its safety data to date, as well as its oral administration, support this study of BG-12 as a possible combination therapy for MS."

"The EXPLORE trial is another demonstration of Biogen Idec's commitment to MS," said Dr. Sandrock. "We have one of the most extensive MS pipelines in the industry, with multiple programs that target pathways thought to be critical in treating MS. This pipeline includes late-stage programs such as BG-12, PEGylated interferon beta 1a, and daclizumab, earlier-stage programs such as anti-LINGO, and several preclinical programs."

About EXPLORE

EXPLORE is an open-label, multicenter Phase II clinical trial that will enroll approximately 100 RRMS patients in the United States currently receiving IFNB or GA as monotherapy.

Patients in the trial must have received consistent therapy with IFNB or GA for at least one year prior to enrolling in the trial and have evidence of disease activity. EXPLORE will primarily evaluate the tolerability and safety of BG-12 as a combination therapy by the incidence and type of adverse events (AEs), serious AEs and AEs leading to discontinuation of study treatment, as well as the incidence and type of laboratory abnormalities and MS disease activity in all study patients.

In a subset of patients, the study will also investigate the efficacy of BG-12 in combination with IFNB or GA by evaluating the mean number of new and total gadolinium-enhancing (Gd+) lesions on brain MRI scans.

Patients enrolled in EXPLORE will have monthly MRIs. They will continue on their prescribed treatments (IFNB or GA) for two months, at which point they will receive 240 mg of BG-12 three times daily in combination with their existing treatment for an additional six months.

About BG-12

BG-12 (BG00012, dimethyl fumarate) is an investigational oral therapy in Phase III clinical development as a monotherapy for the treatment of relapsing-remitting multiple sclerosis (RRMS), the most common form of MS, and in Phase II clinical development for rheumatoid arthritis (RA). BG-12 received Fast Track designation in MS from the U.S. Food and Drug Administration (FDA), which may expedite U.S. regulatory review. Biogen Idec retains full worldwide commercial rights to BG-12.

The Phase IIb study of BG-12, which was published in The Lancet, showed that BG-12 as a monotherapy reduced the number of new gadolinium enhancing (Gd+) lesions by 69 percent in patients with RRMS when compared to treatment with placebo (p<0.0001). The presence of Gd+ lesions is thought to indicate continuing inflammatory activity within the central nervous system. Results from this study stimulated further evaluation of BG-12's potential for neuroprotection.

Source: Biogen Idec (15/06/10)

Biogen Idec announced that its oral compound BG-12 (dimethyl fumarate) achieved key milestones in clinical trials for multiple sclerosis (MS) and rheumatoid arthritis (RA). In recent months, the last patient was enrolled in the CONFIRM trial, the second of two Phase III trials designed to evaluate the efficacy and safety of BG-12 as a monotherapy in patients with relapsing-remitting multiple sclerosis (RRMS). Both the DEFINE and CONFIRM Phase III trials are now fully enrolled and will evaluate the effect of BG-12 on clinical relapse, disability progression, various MRI measures of disease activity, and safety.

The last patient was also enrolled in a Phase II study to evaluate the safety, tolerability and efficacy of BG-12 in combination with methotrexate in subjects with active RA who had an inadequate response to conventional disease-modifying antirheumatic drug (DMARD) therapy.

"There is significant unmet need in both the MS and RA communities for additional treatment options," said Kate Dawson, M.D., senior director, Medical Research, Biogen Idec. "The Phase IIb study of oral BG-12 in patients with MS showed promising MRI results regarding the compound's ability to reduce inflammation and its potential for neuroprotection. We look forward to results from the DEFINE and CONFIRM Phase III MS studies, as well as the proof-of-concept trial in RA."

BG-12 has been shown to activate the Nrf2 transcriptional pathway, which pre-clinical studies have shown defends against oxidative-stress induced neuronal death, protects the blood-brain barrier and supports maintenance of myelin integrity in the central nervous system. Central nervous system inflammation and damage may trigger the symptoms common in RRMS such as fatigue, cognitive deterioration and physical disability. Because of BG-12's unique effect on the Nrf2 pathway and its oral delivery, BG-12 is also being considered for future MS combination therapy studies.

Additionally, as an oral compound, BG-12 holds promise for patients with RA. Its combination of anti-inflammatory and potential cytoprotective properties support the compound's evaluation in RA.

BG-12 is an oral formulation of dimethyl fumarate. Fumaderm®, a therapeutic for the treatment of psoriasis in Germany, includes dimethyl fumarate as one of the active ingredients. Fumaderm has more than 14 years of post-marketing experience and approximately 100,000 patient years of use.

About DEFINE and CONFIRM

DEFINE (Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS) is a two-year, randomized, double-blind, placebo-controlled, dose-comparison study of 240 mg BID or TID of BG-12 orally compared to placebo in 1,200 patients with RRMS.

CONFIRM (COmparator and aN oral Fumarate In Relapsing-remitting MS) is a two-year, randomized, placebo-controlled and active reference comparison study in more than 1,400 patients with RRMS. In the three-arm study, patients are randomized to 240 mg BID or TID of BG-12 orally, placebo capsules orally, or 20 mg of Copaxone® (glatiramer acetate) via subcutaneous injection.

These Phase III, global, multi-center trials are being conducted in more than 300 centers in N. America, Europe and throughout the world.

Source: Medical News Today © 2009 MediLexicon International Ltd (09/12/09)

Owing to its infrequent dosing and positive efficacy, nearly 90 percent of surveyed neurologists indicate they will prescribe Merck Serono/EMD Serono's oral cladribine for the treatment of multiple sclerosis.

The new Physician & Payer Forum report entitled Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? finds that the percentage of surveyed neurologists willing to prescribe oral cladribine is higher than the percentage willing to prescribe the emerging oral therapies Biogen Idec's BG-12 and Novartis/Mitsubishi Tanabe's FTY-720 (fingolimod).

The report also finds that emerging oral therapies will likely be prescribed most often to patients with relapsing-remitting multiple sclerosis and as second-line therapies.

"Neurologists we surveyed indicate that oral cladribine, FTY-720, and BG-12 will each be prescribed to patients with any disease subtype but that these therapies will be preferentially prescribed to approximately one-quarter of patients with relapsing-remitting disease," said Decision Resources Analyst Bethany Kiernan, Ph.D. "This is likely due to these agents' ongoing clinical trials involving relapsing-remitting multiple sclerosis patients. Additionally, surveyed neurologists will prescribe emerging oral therapies to about one-fifth of secondary progressive multiple sclerosis patients. Yet despite the similarities in projected prescribing patterns among these therapies, our findings indicate that oral cladribine will be favoured over FTY-720 as well as BG-12, suggesting that clinicians have begun to differentiate these oral agents from one another."

The report also finds that the majority of surveyed MCO pharmacy directors will give emerging oral therapies non-preferred tier status on their commercial plans. More than half of surveyed MCOs expect to place oral cladribine, FTY-720 and BG-12 on tier 3 of their commercial plans' formularies. Surveyed pharmacy directors cite the high cost of these agents as the main reason for their non-preferred status. However, about one-quarter of surveyed pharmacy directors expect to place these therapies on tier 2 of their formularies, which is likely due to their perceived advantages in efficacy, safety, and/or convenience compared with current drugs.

Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? is based on a U.S. survey of 102 neurologists and 20 MCO pharmacy directors. Their responses were compared to assess similarities and differences of opinion regarding clinical, economic and scientific factors.

Source: Decision Resources (10/09/09)

Biogen Idec announced the publication of Phase IIb data showing that a 240 mg three-times-daily dose of the company's novel oral compound, BG-12 (BG00012, dimethyl fumarate), reduced the number of new gadolinium enhancing (Gd+) lesions by 69 percent in patients with relapsing-remitting multiple sclerosis (MS) when in comparison to therapy with placebo (p<0.0001).

The data also showed a 53 percent reduction in the mean number of T1-hypointense lesions and a 44 percent reduction in cumulative new Gd+ lesions in patients treated with BG-12 in comparison to therapy with placebo. The presence of Gd+ lesions is thought to indicate continuing inflammatory activity within the central nervous system. T1-hypointense lesions are linked to significant breakdown and loss of brain tissue. An ad hoc analysis conducted during the study showed a decrease in the likelihood of Gd+ lesions evolving into T1-hypointense lesions (black holes), warranting further clinical study into the potential neuroprotective and anti-inflammatory effects of BG-12. These results have been reported in the October 25th issue of The Lancet.

BG-12 is the first compound that has been shown to activate the Nrf2 transcriptional pathway, which prior studies have shown defends against oxidative-stress induced neuronal death, protects the blood-brain barrier, and supports maintenance of myelin integrity in the central nervous system.

"The effects of BG-12 on inflammatory brain lesions, together with the corresponding safety data, strongly support further research in Phase III clinical studies to define its place in the future of relapsing-remitting MS therapy," said the study's primary investigator, Professor Ludwig Kappos, acting Chair of Neurology and Research Group Leader, Department of Biomedicine, University Hospital Basel, Switzerland. "Because of BG-12's unique mechanism of action and its oral administration, it could be valuable as a treatment for a number of MS patients and not just those who prefer to not initiate injectable therapies".

"While further study is necessary, enhancing the body's normal cellular protection pathways while reducing inflammation would be a unique approach to this disease," said Michael Panzara, MD, MPH, Vice President, Chief Medical Officer of Neurology, Biogen Idec. "At Biogen Idec, we are continuing to invest and apply our expertise in MS with new research into novel compounds such as BG-12 to further improve the lives of people with this disease."

Phase IIb Data Demonstrate Positive Efficacy and Favorable Safety Profile for BG-12

In this study, patients treated with a 240 mg three-times-daily dose of BG-12 showed a reduction in the number of new Gd+ lesions by 69 percent at weeks 12 to 24, in comparison to therapy with placebo (p<0.0001). The data also showed a 53 percent reduction in T1-hypointense lesions and a 44 percent reduction in cumulative new Gd+ lesions in patients treated with BG-12 in comparison to therapy with placebo. An ad hoc analysis demonstrated a reduced probability of the conversion of Gd+ lesions into T1-hypointense lesions, suggesting the possibility of additional neuroprotective benefits as observed in an earlier pilot study of ten patients with MS receiving oral fumaric acid ester treatment.

BG-12 also significantly reduced the number of new or enlarging T2-hyperintense lesions by 48 percent versus placebo, and 63 percent of patients given BG-12 had no new T2-hyperinstense lesions, compared with 26 percent receiving placebo.

Though the study was not adequately powered to evaluate relapse endpoints, relapse rates in all BG-12 therapy groups decreased between the first and the second part of the study, which may indicate a delayed and increasing effect of BG-12 over time.

The most common, non-MS related adverse events that occurred more frequently in patients receiving BG-12 240 mg three times daily than those receiving placebo included flushing, headache, nausea, diarrhea, upper abdominal pain, hot flush, and abdominal pain. Flushing and gastrointestinal-related events decreased during the course of BG-12, particularly during the first one-to-two months of therapy. Frequency of infection was low in all therapy groups and did not differ from that of the placebo group.

Data from this Phase IIb study lead the company to further pursue the development of BG-12. Two Phase III trials, DEFINE and CONFIRM, are currently underway evaluating the effect of BG-12 on measurements of clinical relapse, the progression of disability, and various MRI measures. BG-12 was granted Fast Track designation by the U.S. Food and Drug Administration earlier this year.

About the Study Design
In this Phase IIb randomized, double-blind, placebo-controlled, dose-ranging study, patients (n= 257), aged 18-55 years, with relapsing-remitting MS were randomly assigned to receive one of the following therapy regimens for 24 weeks: 120 mg of BG-12 once daily, 120 mg three times daily, 240 mg three times daily or placebo. The initial therapy period was followed by an extension period of 24 weeks for safety assessment, during which patients in the placebo group received BG-12 at 240 mg three times daily. The primary endpoint for the study was the total number of Gd+ lesions on brain MRI scans at weeks 12, 16, 18 and 24. Additional endpoints included cumulative number of new Gd+ lesions, new or enlarging T2-hyperintense lesions, new T1-hypointense lesions and annualized relapse rate. Safety and tolerability were also assessed. Results show that BG-12 met all of the study endpoints when given at the dose of 240 mg three times daily.

Source: Biogen Idec (24/10/08)

The DEFINE (determination of the efficacy and safety of oral fumarate in relapsing-remitting MS) and CONFIRM (comparator and an oral fumarate in relapsing-remitting MS) studies will include more than 2,000 total patients in North America, Europe and rest of world. These studies have been initiated internationally, and Biogen Idec plans to initiate these studies in the U.S. later this year. DEFINE and CONFIRM are two-year, randomised, multi-center, double-blind, placebo-controlled, dose-comparison studies to determine the safety and efficacy of BG-12 in subjects with relapsing-remitting MS. CONFIRM will also include a glatiramer acetate (Copaxone®) reference comparator arm.

Endpoints of both studies include evaluating the effect of BG-12 on measurements of clinical relapse, the progression of disability, and various MRI measures.

“Earlier studies of BG-12 support its potential as an oral therapy for multiple sclerosis. The extensive Phase III clinical program of BG-12 will provide greater understanding of its promise in MS,” said DEFINE lead investigator Ralf Gold, MD, Professor and Chair of the Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum. “MS is a disease that continues to have an unmet need for safe and effective oral therapeutic options.”

“The development of BG-12 furthers Biogen Idec’s commitment to advancing the treatment of MS. We have a diverse portfolio of therapeutic candidates and are dedicated to the pursuit of innovative research that will yield multiple options for people living with this devastating disease,” said Alfred Sandrock, MD, PhD, Senior Vice President, Neurology Research and Development, Biogen Idec.

BG-12 Phase II Study Results

Data from a Phase II study designed to evaluate the efficacy and safety of BG-12 were presented at two European neurological medical meetings in 2006. The Phase II multi-center, double-blind, placebo-controlled, dose-ranging study enrolled 257 patients at sites in 10 countries in Europe. Patients were randomised to receive placebo or BG-12 at 120 mg, 360 mg, or 720 mg per day orally for six months. The patient group treated with 720 mg of BG-12 per day had a 69% reduction (p<0.001) in the mean number of new gadolinium-enhancing lesions versus placebo as measured monthly from weeks 12 to 24 of the study. The 720 mg dose group also had a 48% reduction (p<0.001) in new or newly enlarging T2-hyperintense lesions at six months compared to baseline. Although the study was not powered to achieve statistical significance for this endpoint, there was a 32% reduction (p=0.272) in relapse rate compared to placebo at the 720 mg dose. The results of the 120 mg and 360 mg BG-12-treated groups were not statistically significant versus placebo on any endpoints.

The most common adverse events were flushing, gastrointestinal disorders, headache, and nasopharyngitis. The incidence of liver enzyme elevation greater than or equal to three times the upper limit of normal at any time during the placebo controlled phase of the study was between 2% and 8% in the three active treatment groups, compared with 5% in the placebo group. Improvement in liver enzyme levels was seen after discontinuation of BG-12. The overall rate of infection was the same in the total BG-12-and placebo-treated groups, and no opportunistic infections occurred.

About BG-12

Data suggest that BG-12, an oral fumarate derivative, is an immunomodulator with a novel mechanism of action with a combination of cytoprotective and anti-inflammatory properties. Based on available clinical and scientific information with BG-12 and fumarates, there is strong technical rationale for development of BG-12 in a number of T-cell mediated autoimmune and/or inflammatory diseases.

Source: Biogen Idec (09/01/07)

Fumapharm AG, founded in Switzerland in 1983, develops therapeutics derived from fumaric acid esters for patients with high unmet medical need. The company has two products: FUMADERM(R), a commercial product available in Germany for the treatment of psoriasis, and BG-12, a clinical-stage product that has been jointly developed with Biogen Idec. BG-12, an oral fumarate, is being studied for the treatment of multiple sclerosis (MS) and psoriasis.

"This acquisition supports our goal of developing innovative therapeutic options for people living with MS," said James C. Mullen, Biogen Idec's President and Chief Executive Officer. "We look forward to continuing the development of BG-12, a promising oral compound in MS, as well as expanding our European operations by working with Fumapharm's existing partners to provide FUMADERM to psoriasis patients in Germany."

On May 30, 2006, Biogen Idec and Fumapharm announced positive results from a Phase II study designed to evaluate the efficacy and safety of BG-12 in patients with relapsing-remitting MS. The study achieved its primary endpoint, demonstrating that treatment with BG-12 led to a statistically significant reduction in the total number of gadolinium-enhancing brain lesions as measured by MRI with six months of treatment versus placebo.

"Biogen Idec is perfectly positioned to continue the development of BG-12 because of its global commercial and regulatory experience and unsurpassed expertise in MS. We are proud of the work that Fumapharm has accomplished in the last 20 years and are confident that Biogen Idec will continue our legacy of helping patients," said Dr. Hans Peter Strebel, Chairman and CEO of Fumapharm.

The transaction, which has been approved by the boards of directors of both companies and is subject to customary closing conditions, is expected to close within the next two months. Upon completion, Biogen Idec will acquire all of the issued and outstanding shares of the capital stock of Fumapharm and will take over manufacture and sale of FUMADERM for the treatment of psoriasis in Germany through Fumapharm's existing network. Financial terms of the transaction were not disclosed.

About BG-12

In October 2003, Biogen Idec licensed certain exclusive worldwide rights to develop and market BG-12, oral fumarate derivative with an immunomodulatory mechanism of action, from Fumapharm. Biogen Idec and Fumapharm are evaluating BG-12 in a range of diseases, including MS and psoriasis. In April 2005, the companies announced that the primary endpoint was met in a Phase III study designed to evaluate the efficacy and safety of BG-12 in the treatment of moderate to severe psoriasis.

In the Phase II MS study, the most commonly reported adverse events were flushing, gastrointestinal disorders, headache, and nasopharyngitis. Liver enzyme elevations were reported in 2% to 8% of the active treatment groups, compared to 5% in the placebo group. Infection rates were balanced.

Source: Biogen Idec (31/05/06)

"We are encouraged that these Phase II data demonstrate that BG-12 may be a promising oral therapy to treat MS. As part of our ongoing commitment to MS patients, we are working with regulatory authorities to determine the next steps in the development of this program," said Burt Adelman, MD, executive vice president, Development, Biogen Idec.

This Phase II multi-center, double-blind, placebo-controlled, dose-ranging study enrolled 257 patients at sites in 10 countries in Europe. Patients were randomized to receive placebo or BG-12 at 120 mg, 360 mg, or 720 mg per day for six months. The patient group treated with 720 mg of BG-12 per day had a 69% reduction in the mean number of gadolinium-enhancing lesions versus placebo as measured monthly from weeks 12 to 24 of the study. The 720 mg dose group also had a 48% reduction in newly enlarging T2-hyperintense lesions. BG-12 therapy was also associated with a trend towards reduction in relapse rate. The patient group treated with 720 mg of BG-12 per day had a 32% reduction in relapse rate compared to placebo, however, the study was not designed to achieve statistical significance for this endpoint.

The results of the 120 mg and 360 mg BG-12-treated groups were not statistically significant versus placebo. Patients were followed for an additional six months as part of a dose-blinded safety extension study.

The most common adverse events were flushing, gastrointestinal disorders, headache, and nasopharyngitis. The incidence of liver enzyme elevation greater than or equal to three times the upper limit of normal at any time during the placebo controlled phase of the study was between 2% and 8% in the three active treatment groups, compared with 5% in the placebo group. Improvement in liver enzyme levels was seen after discontinuation of BG-12. Infection rates were found to be balanced between the BG-12-and placebo-treated groups and no opportunistic infections occurred.

About Biogen Idec

Biogen Idec creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare.

About Fumapharm AG

Fumapharm has licensed exclusive worldwide rights to develop and market BG-12 to Biogen Idec. Fumapharm is a privately held pharmaceutical company headquartered in Lucerne, Switzerland.

Source: Biogen Idec(30/05/06)

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