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.

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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