Glatiramer acetate and interferon beta-1a for intramuscular administration: a study of outcomes among multiple sclerosis intent-to-treat and persistent-use cohorts.

Abstract
Objective: To study outcomes of multiple sclerosis (MS) patients treated with either glatiramer acetate (Copaxone * ) or interferon beta-1a for once-weekly, intramuscular administration (Avonex dagger ).

Methods: An 'intent-to-treat' (ITT) cohort (n = 1282) was established, consisting of patients diagnosed with MS who began therapy on either glatiramer acetate (GA) or intramuscular interferon beta-1a (IFN beta-1a-IM) and had continuous insurance coverage from 6 months before to 24 months after the date when they began taking the medication.

A 'persistent use' (PU) cohort (n = 639) was also constructed, consisting of individuals who, in addition to the criteria listed above, had a claim for GA or IFN beta-1a-IM within 28 days of the end of the 2-year post-period.

Data were obtained from the i3 InVision Data Mart Database from July 2001 to June 2006. Multivariate regressions were used to examine both the 2-year total direct medical costs and the likelihood of relapse associated with the use of each of these alternative MS medications.

A relapse was defined as either being hospitalized with a principal diagnosis of MS or having an outpatient visit with a MS diagnosis followed within 7 days by a claim for a corticosteroid. All regressions controlled a wide range of factors that may potentially affect outcomes.

Results: In the ITT cohort, patients who started therapy on GA had a significantly lower 2-year risk of relapse (10.01 vs. 5.18%; p = 0.0034) as well as significantly lower 2-year total medical costs ($44,201 vs. $41,121; p = 0.0294). In the PU cohort, patients who used GA also had a significantly lower 2-year risk of relapse (7.25 vs. 2.16%; p = 0.0048) as well as significantly lower total medical costs ($67,744 vs. 63,714; p = 0.0445).

Limitations: The analyses relies on an administrative claims database of an insured population and hence, may not be generalizeable to other populations. In addition, such a database precludes measurement of lost work time, unemployment, caregiver burden or other costs associated with MS.

Conclusions: Results from this study indicate that the use of GA is associated with significantly lower probability of relapse as well as significantly lower 2-year total direct medical costs than IFN beta-1a-IM.

Castelli-Haley J, Oleen-Burkey MA, Lage MJ, Johnson K.

Teva Neuroscience, Kansas City, MO, USA.

Source: Pubmed PMID: 20662760 (30/07/10)

Biogen Idec and Elan Corporation, plc today announced enrollment of the first patient in a global Phase IIIb, randomized, rater-blinded, active-controlled study designed to evaluate switching to Tysabri(R) (natalizumab) from Copaxone(R) (glatiramer acetate) or Rebif(R) (interferon beta-1a) in patients with relapsing-remitting multiple sclerosis (RRMS).

The study, called SURPASS, is expected to enroll 1,800 patients in 27 countries and provide direct comparative data of different treatment options for RRMS patients who experience breakthrough disease activity.

"Despite being on therapy, many MS patients still experience disease progression, resulting in loss of physical abilities and permanent damage to the central nervous system," said Richard Rudick, M.D., chair of the SURPASS trial advisory committee and director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. "Currently, there is limited data to inform decisions about how to switch in patients who have disease activity while on therapy. The goal of the SURPASS study is to provide that data so physicians can improve treatment decisions and outcomes for their MS patients."

A significant number of MS patients continue to experience clinical relapses and disease progression despite treatment with disease-modifying therapies such as Copaxone and Rebif. The SURPASS study, a large, well-controlled comparative trial of MS treatments, will evaluate switching to TYSABRI versus staying on or switching between Copaxone and Rebif and determine whether early use of Tysabri in the treatment algorithm ultimately leads to better outcomes.

"Tysabri is a compelling treatment option that is bringing hope to many MS patients," said Alfred Sandrock, M.D., M.P.H., senior vice president of neurology research and development at Biogen Idec. "By evaluating Tysabri against other MS treatments, our goal is to provide the data needed to make better treatment decisions and improve patients' lives."

"We believe the SURPASS study has the potential to improve the way MS is treated," said Carlos Paya, M.D., Ph.D., president at Elan. "Despite significant advances in treatment, the unmet medical need for many MS patients remains great and this study supports our commitment to continuing to advance the standard of care in MS."

About SURPASS

SURPASS is a global, Phase IIIb, multicenter, randomized, rater-blinded, parallel-group, active-controlled trial designed to provide direct comparative data to inform patients and physicians of the relative benefits of different treatment options when faced with breakthrough disease activity. The large, well-controlled comparative study assessing Tysabri, Copaxone and Rebif is expected to enroll 1,800 patients with RRMS, ages 18 to 60 years old, with a baseline Expanded Disability Status Scale (EDSS) score from 0.0 to 5.5. Patients must have been treated with a stable regimen of either Copaxone or Rebif as their principal first therapy for MS for six to 18 months prior to randomization. Patients must also have had disease activity within 12 months prior to screening defined as one or more clinical relapses or two or more new MRI lesions (Gd+ and/or T2 hyperintense lesions).

The primary endpoint of the study is the annualized relapse rate. Secondary endpoints include the change from baseline to 48 weeks in T2 lesion volume and the proportion of subjects who remain free of disease activity -- defined as no clinical relapses, no new Gd+ lesions, no new or newly-enlarging T2 lesions, and no sustained progression on EDSS. Additional study objectives will evaluate the safety and tolerability of switching to Tysabri.

Participants will be randomized in a 2:1:1 ratio to one of the following groups:

-- Group 1: 900 patients will receive Tysabri 300 mg intravenous (IV) every four weeks;

-- Group 2: 450 patients will receive interferon beta-1a 44 mcg subcutaneous (SC) three times per week; and

-- Group 3: 450 patients will receive glatiramer acetate 20 mg SC once daily.

Source: Biogen Idec and Elan Corporation, plc (25/03/10)

OBJECTIVES: To confirm that neutralizing antibodies (NAb) to interferon beta can persist after therapy withdrawal and to evaluate whether persisting NAb are associated with a worse clinical disease course in multiple sclerosis (MS).

DESIGN: Retrospective study. SETTING: Tertiary referral center in the Netherlands. Patients A total of 71 patients with relapsing-remitting multiple sclerosis treated with interferon beta in the past.

MAIN OUTCOME MEASURES: Persisting NAb after therapy withdrawal were tested using the cytopathic effect assay. Patients with and without persisting NAb were compared on several outcomes: the change in annualized relapse rate from prior to interferon beta treatment initiation to after cessation of treatment, time to sustained disability on the Kurtzke Expanded Disability Status Scale, and the use of disease-modifying treatments after cessation of treatment with interferon beta.

RESULTS: Seventeen of 71 patients (24%) tested NAb positive after a median interval of 25 months (interquartile range, 10-51 months) after interferon beta treatment cessation. Eleven of these 17 patients (15%) were high-titer NAb positive (>150 10-fold reduction units per mL). Persisting NAb were associated with an increase in the annualized relapse rate (P = .04) and a reduction in time to reach a sustained Expanded Disability Status Scale score of 6.0, ie, the need for unilateral assistance to walk 100 m (P = .02). Moreover, NAb-positive patients were treated with second-line therapy significantly more often, especially mitoxantrone (P = .006).

CONCLUSION: Anti-interferon beta NAb can persist after interferon beta treatment withdrawal and are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and is supported by the observed need for more aggressive therapy after interferon beta treatment cessation. Prospective studies are warranted to confirm these results.

Source: Pubmed PMID: 20142519 (22/02/10)

PROLOR Biotech, Inc., today reported positive results from a comparative study in primates of its longer-acting version of the multiple sclerosis drug interferon beta (IFN-beta-1a-CTP, referred to as IFN-beta-CTP). 

The study was designed to measure the potential increase in durability (half-life), overall drug exposure (AUC) and biological potency of PROLOR's long-acting CTP-modified human interferon beta when compared with commercially available interferon beta. 

Interferon-beta-1a (referred to as IFN-beta), which is indicated for the treatment of multiple sclerosis (MS), is currently marketed by Merck Serono as Rebif® and by Biogen Idec as Avonex®, with combined annual sales estimated at more than $3 billion worldwide.

The study results show that PROLOR's CTP-modified IFN-beta, when compared with commercially available recombinant IFN-beta, showed 13 times prolonged durability (half-life), and 55 times prolonged overall drug exposure (AUC) in primates.  IFN-beta-CTP also demonstrated strong biological potency as measured by several well-validated biomarkers including anti-viral activity and changes in neopterin, and 2'-5' oligo A synthesase.

The expanded biological potency seen in this new study is consistent with the results of a previous study in mice conducted by PROLOR, which compared the anti-tumor activity of IFN-beta-CTP to commercially available IFN-beta in a model of human cancer.  In that study, IFN-beta-CTP showed 100% inhibition of human melanoma tumors implanted in nude mice after eight days and 87.5% inhibition after 10 days, versus 50% inhibition with commercially available IFN-beta after eight days and just 12.5% inhibition after 10 days.

"The results of this new primate study, together with the strong biological activity seen in our melanoma tumor growth model, further confirm the clinical potential for IFN-beta-CTP as a long-acting version for the treatment of multiple sclerosis, with the potential  to provide important benefits to MS patients," said Dr. Abraham Havron, CEO of PROLOR Biotech.  "Many MS patients currently rely on IFN-beta to keep their disease in check, but to do so they must inject the drug frequently, with the attendant risk of adverse reactions that often accompany these injections.  By potentially allowing these patients to dramatically reduce the required injection frequency, we believe our IFN-beta-CTP could significantly enhance their quality of life."

Source: PROLOR Biotech, Inc. (25/01/10)

Data from an observational phase IV study of 499 patients entitled The Swiss MS Skin Project show that multiple sclerosis (MS) patients taking Avonex (interferon beta-1a IM) reported significantly fewer injection site reactions (ISRs) compared to patients on Betaferon® (interferon beta-1b), Copaxone® (glatiramer Acetate) or Rebif ®(interferon beta-1a).

The study also showed Avonex patients were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies. These data were presented as a poster at the 25th Annual European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Düsseldorf, Germany.

"This study showed that treatment with Avonex leads to fewer injection site reactions which is an important factor in improving compliance. As the only once-weekly injection treatment, Avonex offers people with relapsing MS an easy-to-use and highly effective treatment option," said Dr. Karsten Beer, lead investigator for the study and private neurologist in Wil, Switzerland. "Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives."

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking Avonex, Betaferon, Copaxone, or Rebif (ABCRs). These data are important as ISRs are thought to reduce treatment compliance among patients. The study enrolled nearly 500 patients on ABCRs for a minimum of two years (mean treatment duration of 5.9 years) and followed patients for a total of one year. Study findings include:

At the first assessment, significantly fewer Avonex patients experienced ISRs (13.4% vs 57.7% for Betaferon [p < .0001], 30.4% for Copaxone [p = 0.056], 67.9% for Rebif [p < 0.001]), necrosis (0.0% vs 5.7% for Betaferon [p = 0.0279], 0.0% for Copaxone [p = NS], 6.0% for Rebif [p = 0.0201]) and lipoatrophy (1.2 % vs 8.9% for Betaferon [p = 0.0210], 13.0% for Copaxone [p = 0.0322], 10.3% for Rebif [p = 0.0093]);

No Avonex patients missed a dose in the four weeks prior to first assessment due to ISRs (vs 5.7% for Betaferon [p = 0.44], 4.3% for Copaxone [p = NS], and 7.1% for Rebif [p = 0.011]). These percentages were statistically significant versus Betaferon and Rebif; and

Significantly more patients remained on Avonex over the one year trial (86.6% vs 79.7% for Betaferon, 60.9% for Copaxone, and 83.2% for Rebif [overall p = 0.0364]) than any other treatment.

Source: Medical News Today © 2009 MediLexicon International Ltd (14/09/09)

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced the results of the complete 40-week IMPROVE (Investigating MRI Parameters with Rebif(R) imprOVEd formulation) study. These data show a significant 69% reduction in the number of combined unique brain MRI lesions in patients with relapsing-remitting multiple sclerosis (RRMS) at 16 weeks after initiation of treatment with Rebif(R) (44 micrograms three times a week) compared to placebo (3.0 versus 0.9 in the placebo and Rebif(R) groups respectively, p < 0.001) (primary end point).

A post-hoc analysis showed that this positive effect can be detected as early as 4 weeks after treatment initiation. The decreased number of brain lesions was sustained over the 40-week trial period in patients treated with Rebif(R). The 16-week results also show a 58% reduction in relapse rate versus placebo (p = 0.0104).

“The IMPROVE study confirms the consistency of the safety profile of Rebif(R), while showing further evidence of the early onset of action of Rebif(R) on MRI outcomes in patients suffering from multiple sclerosis,” said Dr. Nicola De Stefano, Professor of Neurology, Department of Neurological and Behavioural Sciences, University of Siena, Italy, and the Principal Investigator of the IMPROVE trial.

The 40-week analysis shows that patients originally randomized to placebo and switched to Rebif(R) at week 16 had a statistically significant decrease in combined unique active (CUA) lesions (mean number of CUA lesions/patient/scan decreased from 2.31 while on placebo (up to week 16) to 0.65 while on Rebif(R) (weeks 17-40), p < 0.001) (secondary end point).

The safety profile of Rebif(R) reported in this study is consistent with the known safety profile of Rebif(R). No unexpected safety concerns were identified in this study.

About the IMPROVE Study

The IMPROVE study was a two-arm, randomized, double-blind, controlled, multicenter, international Phase IIIb study to evaluate the efficacy, safety and tolerability of a reformulated version of Rebif(R) in patients with relapsing-remitting MS (according to the revised McDonald criteria) and evidence of active disease. A total of 180 patients were randomized in a 2:1 ratio to receive either 44 micrograms of Rebif(R) three times a week, subcutaneously, or placebo for an initial period of 16 weeks.

At the end of the initial 16-week treatment period, patients from the placebo group were switched in a single-blinded fashion to treatment with Rebif(R) 44 micrograms three times a week subcutaneously for a further period of 24 weeks (the physician assessing treatment response and side effects was blinded). Patients who were initially assigned to the Rebif(R) group continued to receive active treatment for an additional period of 24 weeks. The duration of the whole treatment period was 40 weeks.

The primary end point was the number of combined unique active (CUA) MRI brain lesions at Week 16 in the Rebif(R) group compared with the placebo group, using the baseline MRI scan as a reference. The secondary end point was the number of CUA lesions/patient/scan during the double-blind phase (Weeks 1-16) versus the rater-blind phase (Weeks 17-40) in patients originally randomized to placebo.

Source: Merck Serono (13/09/09)

Biogen Idec today announced data results from the CHAMPIONS (Controlled High-Risk AVONEX® (interferon beta-1a) Multiple Sclerosis (MS) Prevention Study In Ongoing Neurologic Surveillance) study, an open label follow-up to CHAMPS (Controlled High Risk Subjects AVONEX MS Prevention Study).

Based on the CHAMPS study, AVONEX was granted approval for use in patients who experienced their first clinical MS episode with MRI findings. The CHAMPIONS ten-year follow up showed that patients treated immediately after their first episode had significantly less chance of experiencing a second attack versus those patients with delayed treatment. These results at ten years also indicate that 80 percent of patients taking AVONEX were below an Expanded Disability Status Scale (EDSS) score of three. These data were presented as a poster at the Annual American Academy of Neurology (AAN) meeting.

"There is a consensus among physicians that early initiation of effective therapy beginning shortly after symptom onset may be required to alter the long term course of MS, but until now there has been little evidence to support this hypothesis," said Dr. R. Philip Kinkel, director of the multiple sclerosis center, Beth Israel Deaconess Medical Center in Boston, MA and lead investigator of CHAMPIONS. "This data confirms that treatment of high risk patients beginning shortly after symptom-onset reduces relapse rates and may reduce disease progression for up to 10 years. This may translate into an ability to remain active and enjoy daily activities that otherwise might be lost without treatment."

The CHAMPIONS open label follow-up study was designed to determine long-term clinical outcomes and the ten-year follow up included 155 patients from 24 of the 50 Phase III CHAMPS study sites. Key findings include:

-- 40 percent reduction in conversion to CDMS in patients treated immediately upon diagnosis of CIS versus those that were delayed by a median of 30 months (original placebo randomization arm)

-- 91 percent of patients had an EDSS less than 4.0 after 10 years;

-- 80 percent of patients on AVONEX had an EDSS of less than 3; and

-- the annualized relapse rate for patients with up to 10 years of care was only 0.25, suggesting a relapse rate of only one relapse every four years

"The CHAMPIONS study adds to the long-term follow-up data available and supports the benefits of starting early and staying on treatment with AVONEX," said Thorsten Eickenhorst, M.D., vice president of global medical affairs, Biogen Idec. "This follow-up study conducted in MS patients who received early treatment reinforces the clinical effectiveness of AVONEX in patients who experience their first clinical MS episode."

Source: Medical News Today © 2009 MediLexicon International Ltd (08/09/09)

Background:  Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta-1a is responsible for disease amelioration. The impact of interferon beta-1a on the chemoattraction of immune cells has not been fully addressed.

Objective:  To address the influence of interferon beta-1a on the expression of chemokines and their receptors in a standardized setting.

Design:  The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples.

Setting:  Outpatient units in Germany.

Patients:  Seventeen RRMS patients given interferon beta-1a (Avonex; Biogen Idec, Research Triangle Park, North Carolina) intramuscularly once weekly, 9 age-matched untreated RRMS patients, and 8 age-matched healthy control donor individuals were enrolled in the initial study from August 24, 2006, through December 15, 2006. These patients were from the outpatient units of the MS Practice Study Group in Ulm, Germany.  For the validation study, an additional group of interferon beta–treated (interferon beta-1a; Avonex) RRMS patients was recruited from March 12, 2007, through April 2, 2007. This second cohort of patients comprised 4 MS patients who developed neutralizing antibodies (NABs) during the treatment compared with 7 MS patients who did not. The study was approved by the ethics committee of the University of Düsseldorf and the Technical University of München.

Main Outcome Measures:  Gene expression and serum chemokine protein levels.

Results:  CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta-1a–treated, NAB-negative MS patients. In contrast, gene expression in interferon beta-1a–treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta–treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta-1a–treated, NAB-positive MS patients.

Conclusions:  We demonstrate that interferon beta-1a strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta.

Sabine Cepok, PhD; Herbert Schreiber, MD; Steve Hoffmann, MD; Dun Zhou, MD; Oliver Neuhaus, MD; Gloria von Geldern, MD; Sonja Hochgesand; Stefan Nessler, MD; Veith Rothhammer, MD; Michael Lang, MD; Hans-Peter Hartung, MD; Bernhard Hemmer, MD

Source: Arch Neurol. 2009;66(10)(doi:10.1001/archneurol.2009.138).  (11/08/09)

Patients with relapsing-remitting multiple sclerosis (RRMS) show early benefit from a new formulation of subcutaneous interferon (IFN) beta-1a as measured by magnetic resonance imaging (MRI), according to a study presented at the 19th Meeting of the European Neurological Society (ENS).

Nicola De Stefano, MD, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy, spoke on behalf of the researchers from the Study to Evaluate Rebif New Formulation (IFN-Beta-1a) in Relapsing Remitting Multiple Sclerosis (IMPROVE).

The phase 3b double-blind, placebo-controlled, multicentre study evaluated the efficacy, safety, and tolerability of a new formulation of IFN beta-1a compared with placebo in patients with active RRMS. This new formulation is free from serum-derived products and has been developed with the aim of improving injection tolerability and reducing immunogenicity.

In the double-blind phase, 180 patients were randomised to receive either the new formulation of IFN beta-1a 44 mcg 3 times weekly or placebo for 16 weeks.

The primary endpoint was the number of combined unique active (CUA) brain lesions at week 16. Secondary endpoints included changes in T2 load and cumulative number of new gadolinium-enhancing and T2 lesions.

"Every single MRI endpoint was significantly in favour of the active treatment," Dr. De Stefano summarised.

At week 16, the number of CUA lesions was significantly lower with IFN beta-1a (0.9 vs 3.0 in the placebo group, P < .001).

More than half of the patients (53.3 %) in the active-treatment group had no CUA lesions at week 16, compared with 16.7% in the placebo group.

"A beneficial effect of the treatment can be seen even in a short period," Dr. De Stefano noted. "Post hoc analyses showed a significant effect already at 4 weeks."

From week 4 on, the mean cumulative number of CUA lesions was significantly lower in the IFN beta-1a group, with a 41% reduction compared with the placebo group.

The cumulative number of new gadolinium-enhancing and new T2 lesions was significantly reduced at 16 weeks (P <.001).

At week 16, the change in T2 burden of disease was significantly lower with IFN beta-1a than placebo (P < .001).

The most commonly reported adverse event was flulike illness (50% and 17% in the IFN and placebo groups, respectively).

As Dr. De Stefano mentioned, a 24-week, single-arm, rater-blind treatment phase was initiated after the double-blind phase and has been completed recently, and the results will be presented soon.

[Presentation title: Beneficial Effects of a New Formulation of Subcutaneous Interferon Beta-1a on Magnetic Resonance Imaging Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis: Results at 16 Weeks From a Double-Blind, Placebo-Controlled Study. Abstract P348]

Source: Doctor's Guide (c) 1995-2009 Doctor's Guide Publishing Limited (24/06/09)

Patients with multiple sclerosis (MS) who adhere to their treatment with interferon (IFN) beta-1a without interruption have lower relapse and progression rates than patients who do not adhere to their medication as regularly, said researchers at the 19th Meeting of the European Neurological Society (ENS).

In the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study, IFN beta-1a 22 or 44 mcg administered subcutaneously 3 times weekly proved effective in reducing relapses and delaying disability progression in patients with relapsing-remitting multiple sclerosis (RRMS) compared with placebo.

After the initial 2-year double-blind phase, patients originally randomised to placebo were re-randomised to IFN beta-1a 22 or 44 mcg 3 times weekly for an additional 2 years.

On study completion, all patients were offered the choice of continuing to receive blinded or open-label treatment during years 5 to 6. Beyond year 6, patients could continue on any or no disease-modifying drug.

Data from the long-term follow-up (LTFU, up to 8 years) supported the efficacy of the treatment.

Bernard M.J. Uitdehaag, MD, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands, presented the results of a post hoc exploratory analysis of the LTFU cohort on June 22.

The analysis evaluated only the long-term clinical efficacy outcomes in the group of patients who were originally randomised to IFN beta-1a 44 mcg, focussing on continuity of treatment. Clinical outcomes of patients who were treated continuously (n = 45) were compared with those who had had some medication interruptions (n = 91).

"Patients in the continuous group had a lower mean annualised relapse rate than those in the noncontinuous group," Dr. Uitdehaag explained. From baseline to LTFU, the annualised relapse rates were 0.51 and 0.61 in the continuous and noncontinuous groups, respectively.

The proportion of patients who were free from relapses was similar between groups (13.3% and 16.5% in the continuous and noncontinuous groups, respectively).

Confirmed Expanded Disability Status Scale progression rates at 3 months were higher in patients with noncontinuous treatment (64.8% vs 46.7%).

In addition, a lower proportion of patients in the continuous group converted to secondary progressive MS compared with the noncontinuous group (11.1% vs 25.3%).

Although the potential effect of other factors must be considered and confounding cannot be excluded, these data suggest that better outcomes may be expected in patients who adhere to treatment and who avoid treatment interruptions over the long term.

"Of course these are only retrospective data, and we cannot prove the causality," Dr. Uitdehaag emphasised.

The researchers plan to assess whether the outcomes have been reached before or after stopping the medication on an individual level because it is difficult to determine on a group level, according to Dr. Uitdehaag.

Source: Doctors Guide (c) 1995-2009 Doctor's Guide Publishing Limited (24/06/09)

In patients with relapsing-remitting multiple sclerosis (MS), progression of disability and higher relapse rates are early markers of long-term disease severity, while initiation of treatment with intramuscular interferon (IFN) beta-1a can delay this progression when initiated in patients with low disease burden, new findings suggest.

Richard Rudick, MD, director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic Foundation, in Ohio, presented the results here at the Consortium of Multiple Sclerosis Centers (CMSC) 23rd Annual Meeting in a poster session.

Previous data from the National Institutes of Health–funded Multiple Sclerosis Collaborative Research Group (MSCRG) indicated that intramuscular IFN beta-1a decreased relapse frequency and slowed disability over 2 years, the researchers note. The current study assessed data from a 15-year follow-up of that study to identify early markers of long-term response to therapy in the MSCRG study population.

A strong relationship between magnetic resonance imaging (MRI) activity during the first 2 years of the MSCRG study and long-term Expanded Disability Status Scale (EDSS) progression at 15 years was evident in patients who received intramuscular IFN beta-1a, but this association was not observed with patients who received placebo.

Specifically, 87.5% of IFN-beta-1a–treated patients who had 2 or more gadolinium-enhanced lesions at 2 years progressed to EDSS scores of 6.0 or greater at 15 years compared with only 35.3% of IFN-treated patients with fewer than 2 lesions (P = .0003).

In addition, 61.5% of IFN-treated patients who had at least 3 new or enlarging T2 lesions at year 2 progressed to EDSS scores 6.0 or greater at 15 years, whereas only 38.1% of patients with less than 3 new or enlarging T2 lesions reached that disability level at year 15.

"We previously reported that IFN beta-1a recipients who developed 3 or more new T2 lesions during 2 years had greater disability progression and more brain atrophy compared with IFN recipients with less MRI activity," Dr. Rudick told Medscape Neurology. "We did not see this same relationship in the placebo recipients. The current study confirmed those results but with much longer follow-up and using clear-cut markers of clinically significant disability," he said.

According to Dr. Rudick, the findings have clinical implications in that they suggest that MRI may provide a method to identify patients who respond poorly to IFN beta-1a. "This would have major implications, because patients could be continued on IFN beta-1a if their MRI is stable and switched to other treatments if it is not," he said. "It also would provide a possible outcome measure (MRI change while on IFN beta-1a) to develop biological markers of treatment response," he added.

Further Support

According to Mark S. Freedman, MD, professor of neurology at the University of Ottawa, in Ontario, and director of the Multiple Sclerosis Research Clinic, the findings from this study support evidence from other studies showing that early activity in patients receiving treatment is an indicator of poor prognosis.

However, he points out that about half of the patients in the initial study did not continue on to the 15-year follow-up phase, making it difficult to make conclusions regarding the long-term efficacy as it relates to early response.

"I am an advocate of treating clinically isolated syndrome (CIS), or the first event of MS," Dr. Freedman told Medscape Neurology. "For patients who clearly have CIS, all current treatments are likely to translate into better long-term protection," he said, although he added that not all agents should be used for initial treatment.

"We have now several treatments and are soon to have several more choices," he added.

Source: Medscape Today  © 2009 Medscape, LLC (16/06/09)

Adding steroid to multiple sclerosis treatment shows promise in study.

Using a steroid drug in combination with a multiple sclerosis (MS) drug may give patients more relief from symptoms than using the MS drug alone, suggests a new study.

In the study, which included 341 people with relapsing-remitting MS, some patients were randomly selected to receive the steroid drug methylprednisolone in three doses over three days once a month, in addition to regular treatment with the MS drug interferon beta-1a. Others received the interferon drug and a placebo.

During the three-year study, the patients were assessed every three months. Those who took the steroid/interferon drug combination had 38 percent fewer relapses (episodes when the disease is active) than those who took the placebo and interferon, the study found. The patients in the steroid/interferon group also showed slight improvement on a test of MS disability, while those in the placebo/interferon group showed a slight decline.

The Biogen Idec-supported study also found that MS-related brain lesions stayed the same size or shrank in the steroid/interferon group but grew larger in the placebo/interferon group. The findings were presented this week at the annual meeting of the American Academy of Neurology, in Seattle.

"These results indicate that these two drugs may have a synergy when taken together and provide a more beneficial effect on the disease activity," study author Dr. Mads Ravnborg, of the Danish Multiple Sclerosis Research Center at Copenhagen University Hospital in Denmark, said in an American Academy of Neurology news release. "This is a promising finding, as the benefit from interferon is only moderate, and not everyone responds fully to the treatment, so anything we can do to boost those results is positive."

Source: Bio-Medicine © 2003-2009 Bio-Medicine (01/05/09)

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy.

METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center.

RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers.

CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Source: Pubmed PMID: 19204263 (19/02/09)

Merck Serono announced that the ongoing IMPROVE (Investigating MRI Parameters with Rebif imprOVEd formulation) study met its primary endpoint. The primary objective of the study was to evaluate the efficacy of the new formulation of Rebif^®, compared to placebo, in patients with relapsing-remitting multiple sclerosis (RRMS) and active disease by means of magnetic resonance imaging (MRI) at the end of 16 weeks of treatment.

The 16-week study results show that the mean number of combined unique active brain MRI lesions per patient was reduced by 69% in patients treated with the new formulation of Rebif® compared with those receiving placebo, a statistically significant result (p<0.001).

"Patients who received Rebif® experienced far fewer new active brain MRI lesions than the placebo group after 16 weeks of treatment," said Dr. Mark Freedman, Professor of Neurology at the University of Ottawa, Director of the MS Research Clinic at the Ottawa Hospital, and an investigator of the IMPROVE trial. "These data demonstrate a significant effect of the new formulation of Rebif® on disease activity and provide further evidence of its benefit in treating patients with relapsing-remitting multiple sclerosis."

The IMPROVE study is a two-arm, randomized, double-blind, controlled, multicenter, international Phase IIIb study to evaluate the efficacy, safety and tolerability of the new formulation of Rebif® in patients with RRMS according to the revised McDonald criteria and evidence of active disease.

A total of 180 patients were randomized in a 2:1 ratio to receive either the new formulation of Rebif® 44 micrograms three times a week subcutaneously, or placebo for an initial period of 16 weeks. At the end of this initial 16-week treatment period, patients from the placebo group have been switched in a single-blinded fashion to treatment with the new formulation of Rebif® 44 micrograms three times a week subcutaneously for a period of 24 weeks (the physician assessing treatment response and side effects is blinded).

Patients who were initially assigned to the new formulation of Rebif® group continue to receive active treatment for an additional period of 24 weeks. The duration of the whole treatment period is 40 weeks.

The primary endpoint of the study is the difference between the number of combined unique active MRI lesions at week 16 in the group treated with the new formulation of Rebif® versus the placebo group. Combined unique active MRI lesions are defined as an active lesion on T1 sequence with gadolinium or T2 sequence, or both, avoiding double counting. The primary endpoint mainly reflects inflammatory activity (gadolinium-enhancing T1 lesions), but also reflects disease progression (T2 lesions).

The primary efficacy analysis showed that, at week 16, the number of combined unique active brain lesions was significantly lower in patients treated with the new formulation of Rebif® than in patients who received a placebo (p<0.001). The mean number of combined unique active brain lesions per patient was reduced by 69% in patients treated with the new formulation of Rebif® compared with those receiving placebo (0.7 versus 2.2). The median number of combined unique active brain lesions at week 16 was 0.0 in the group treated with the new formulation of Rebif® and 1.0 in the placebo group.

Over half (53%) of patients treated with the new formulation of Rebif® had zero combined unique active brain lesions at week 16, compared to only 16.7% in the placebo group.

Results for the secondary and tertiary endpoints of the IMPROVE study will be available at the end of the 40-week treatment period.

The safety profile of the new formulation of Rebif® reported in this study is consistent with the known safety profile of Rebif®. No unexpected safety concerns were identified in this study. The new formulation of Rebif® was approved in the European Union in August 2007 and in Canada in September 2007. It is now marketed in all EU countries and in Canada. The new formulation of Rebif® is not available in the United States.

Source: Merck Serono (24/09/08)

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today that patient enrollment has been completed in the REFLEX trial (REbif FLEXible dosing in early multiple sclerosis). This randomized, double-blind, placebo-controlled, international Phase III trial is designed to evaluate the therapeutic benefit of Rebif(R) (interferon beta-1a) on the time to conversion to multiple sclerosis (MS) in people with a first clinical event suggestive of the disease.

"It has been demonstrated that treatment with interferon beta can reduce the risk of developing multiple sclerosis," said Anton Hoos, Executive Vice President, Global Development, Merck Serono. "However, additional research still needs to be conducted in this area and we believe the REFLEX study will provide valuable insights."

A total of 517 patients considered at risk of developing MS due to a recently experienced isolated demyelinating event (e.g. optic neuritis, myelopathy or brainstem syndrome) and having magnetic resonance imaging (MRI) brain scans consistent with early signs of MS have been enrolled in the REFLEX trial. Study participants were randomized in a 1:1:1 ratio to receive either Rebif(R) 44 micrograms three times a week, Rebif(R) 44 micrograms once a week, or placebo as a subcutaneous injection.

Patients will be treated for a period of 24 months, or up to the time when they experience a second attack leading to a diagnosis of clinically definite MS. At this point, patients are offered open-label treatment with Rebif(R) 44 micrograms three times a week.

The primary endpoint of the REFLEX trial is time to conversion to MS, according to the McDonald criteria. Further endpoints include time to conversion to clinically definite MS (the main secondary endpoint), assessments of MRI brain scans, clinical relapses and disability progression.
Rebif(R) is currently approved for the treatment of relapsing forms of MS. It has been proven effective in all three key measures of treatment effectiveness: MRI lesion area and activity*, relapse rates and disability progression. The safety profile of Rebif(R) is supported by a robust, ongoing clinical development and post-marketing program and a 10-year record of use by MS patients.

The REFLEX trial is being conducted with the new formulation of Rebif(R). The new formulation of Rebif(R) was approved in the European Union in August 2007 and in Canada in September 2007 and is now marketed in all EU countries and in Canada. The new formulation of Rebif(R) is not available in the United States.

* The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

Source: ITnews © 1999-2008 NICE Srl. Riproduzione riservata (17/09/08)

Biogen Idec announced that enrollment is complete in the ASSURANCE trial, a long-term follow-up study which will assess up to 15 years of Avonex(R) (interferon beta-1a) treatment in an effort to provide detailed data on the long term efficacy of the drug. ASSURANCE is a multi-center, open-label follow-up study of patients with relapsing remitting multiple sclerosis (MS) treated with Avonex or placebo for at least two years in the phase III pivotal trial. In the trial, 136 of a possible 172 patients were identified for this study at four major MS centers including: Cleveland Clinic Foundation, The State University of New York at Buffalo, Oregon Health and Science University and Georgetown University Medical Center.

The 15-year follow-up study is designed to determine the effect of long term Avonex treatment on disability progression and quality of life. Additionally, the study will assess the impact of treatment on patients' independent living ability. Outcomes of this study will potentially provide further evidence of the benefits of initial and continued treatment with Avonex.

"We are conducting this study to show further evidence that patients who stay on treatment achieve long-term clinical benefits even after 15 years," said Dr. Bianca Weinstock-Guttman, associate professor of neurology and director Baird MS and Pediatric MS Center, Jacobs Neurological Institute at SUNY University at Buffalo. "Because of the chronic nature of MS, it is important for patients to start on an effective therapy as soon as possible to help reduce relapses, delay physical disability progression and protect to help prevent future disability. It is equally important that it is a therapy that they can stay on for the long run."

The 15-year follow-up study targeted the 172 patients who completed at least two years of treatment in the original Avonex phase III pivotal trial. The pivotal trial showed that treatment with Avonex significantly slowed the accumulation of physical disability, and time to sustained progression in EDSS score was significantly lengthened in patients treated with Avonex as compared to placebo.

Final results of the ASSURANCE 15-year follow-up study are expected to be released in Q3 2008.

Source: Biogen Idec (28/08/08)

A combination treatment with interferon beta 1a and atorvastatin in people with MS was investigated. Surprisinglyit was found that people who took both medications had more relapses and more activity on MRI......

OBJECTIVE: To explore whether high dose atorvastatin can be administered safely to persons with relapsing remitting multiple sclerosis (MS) taking thrice weekly, 44 mcg dose subcutaneous interferon beta-1a.

METHODS: Persons with clinically stable, relapsing remitting MS, on standard high dose subcutaneous interferon beta-1a, were randomized in a double blinded fashion to receive either placebo or atorvastatin at dosages of 40 mg or 80 mg per day for 6 months. Blinded neurologic examinations and brain MRI readings were obtained at months 0, 3, 6, and 9. Laboratory blood testing was performed monthly. Main outcome measures were the determination of drug toxicity using blood tests and ECG and determination of MS-related disease activity, either clinical relapses, or new or contrast enhancing lesions on MRI.

RESULTS: Twenty-six subjects received at least one dose of study drug. Ten of 17 subjects on either 80 mg or 40 mg of atorvastatin per day had either new or enhancing T2 lesions on MRI or clinical relapses. One of the nine subjects on placebo had a relapse with active lesions on MRI. The subjects receiving atorvastatin were at greater risk for either clinical or MRI disease activity compared to placebo (p = 0.019). Significant changes in blood tests were noted only for lower cholesterol levels in subjects receiving atorvastatin.

CONCLUSION: The combination of 40 or 80 mg atorvastatin with thrice weekly, 44 mcg interferon beta-1a in persons with multiple sclerosis resulted in increased MRI and clinical disease activity. Caution is suggested in administering this combination.

Source: PubMed PMID: 18525027 (18/06/08)

"It is clear that a key priority in the treatment of MS is for patients to maintain a sense of normalcy," said Richard Brook, Head, Retrospective Analysis, JeSTARx Group and a study author. "Data from this study show that patients taking AVONEX miss less work due to sick leave compared to patients taking Copaxone, helping to maintain their lifestyle. Also, patients taking AVONEX saved sick leave costs and short-term disability costs for their employers and healthcare insurers compared to Copaxone."

The study analyzed an integrated employer dataset of U.S. employees from 2001-2007 to gather HBCs and lost work time from the Human Capital Management Services (HCMS) Research Reference database. HCMS receives information on all employees' short- and long-term-disability claims, workers' compensation claims, and sick-leave claims (both time and salary replacement costs). The database also contains employee-specific information on demographics, company type, job type, employment status, salary, co-pays, deductibles, and health plan. The HCMS database is representative of the general U.S. workforce in terms of age and gender; however the salaries tended to be higher than the general U.S. workforce. This study included only MS patients that were employed at the time of analysis.

The HBC portion of the study data involved a total of 311 employees and showed that among the four DMTs:

AVONEX patients reported low total sick leave (SL) and short-term disability (STD) costs;

Copaxone patients had significantly higher SL ($969 vs. $523) (P<0.05) and STD ($1056 vs. $87) (P<0.05) costs than AVONEX

The absentee portion of the study data involved a total of 273 employees and showed that among the four DMTs:

AVONEX patients reported 42 percent less sick leave than Copaxone (2.98 days/year vs. 7.18 days/year; P≤0.01)

About the Study

Records of 785 patients with MS were extracted from the database. Available data was obtained from the 311 patients on a DMT: (IFN -1a IM (AVONEX) n = 156, IFNβ-1b (Betaseron) n = 55, glatiramer acetate (Copaxone) n = 87, or IFN -1a SC (Rebif) n =13), and were followed for one year after their initial prescription. Two-part regression modeling was used to determine the annual cost differences (in 2007 USD) and annual lost time (in days) between cohorts while controlling for demographics, job-related information, geography, and Charlson Comorbidity Index.

"Such reductions in sick leave days, sick leave costs and short-term disability related costs reinforce the real-life benefits and proven clinical efficacy of AVONEX," said Dr. Kitty Rajagopalan, director of Global Health Economics, Biogen Idec. "We pride ourselves on providing a treatment that is not only efficacious, but allows our patients to live a normal life that includes the ability to consistently attend work. Therefore this is an important addition to the body of evidence that demonstrates the impact of MS on patients and the importance of treating appropriately."

Source: Biogen Idec. (02/06/08)

Led by Dr. Norman Putzki at the University of Duisburg-Essen, in Essen, Germany, and Professor Hans-Peter Hartung at Heinrich-Heine University in Dusseldorf, Germany, the prospective, observational, open label, multicenter study, analyzed 1,157 patients with RRMS, who had received no immunomodulatory therapy within the preceding 12 months before beginning the study. Upon commencement of the study, patients received 30 mcg AVONEX once-weekly and were examined at five data-points over a period of 12 months (at study initiation, after three, six, nine and 12 months). Apart from relapse rate and EDSS scores, QoL was measured by means of EQ-5D, as well as the participation in training for injection, the influence of injection training on the therapeutic behavior and further parameters.

The study demonstrates the importance of treatment with AVONEX in patients with relapsing remitting multiple sclerosis (RRMS), showing the ability to slow disability progression, reduce relapses, and improve QoL. The study results also indicated that:

• Over 90 percent of patients felt an improvement or noticed no reduction in their general health while on AVONEX.
• Mean EDSS score remained practically unchanged over the 12-month treatment period (2.06 at baseline and 2.14 at the 12-month visit; p=0.233).
• Injection training and care through a nurse service was found to improve handling of side effects in nearly 60 percent of patients.

“These data reinforce that AVONEX provides patients with the ability to delay disability progression and shows that effective treatment with AVONEX may enhance QoL,” said Dr. Norman Putzki, primary study author, Department of Neurology, University of Duisburg-Essen, Germany.

“As a company, we are committed to providing efficacious treatment options such as AVONEX in an effort to help improve the quality of life of MS patients,” said Thorsten Eickenhorst, MD, Vice President of Medical Affairs at Biogen Idec.

AVONEX is the number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is proven after the first attack. AVONEX is also proven to slow the progression of physical disability (as shown by 37 percent reduction over two years) and reduce the number of relapses. Nearly nine out of 10 patients remained fully functional after five years. AVONEX has been proven effective in clinical trials for up to three years.

Source: Biogen Idec. (17/04/08)

A preliminary study suggests that combining a medication currently used to treat multiple sclerosis with an antibiotic may slow the progress of the disease, according to an article posted online today that will appear in the February 2008 print issue of Archives of Neurology, one of the JAMA/Archives journals.

“Multiple sclerosis (MS) is an immune-mediated disorder that affects genetically susceptible individuals after exposure to certain, as yet unidentified environmental antigens,” or disease-causing agents, the authors write as background information in the article. The development of MS involves inflammation that destroys parts of the brain along with progressive degeneration of brain tissue. The most common type is relapsing remitting MS, in which patients experience attacks of symptoms such as muscle weakness and spasms followed by periods of symptom-free remission. Many patients with relapsing-remitting MS who take interferon, a medication that boosts the immune system and fights viruses, still experience relapses and may continue to develop new areas of damaged brain tissue (lesions) visible on magnetic resonance imaging (MRI).

Alireza Minagar, M.D., of Louisiana State University Health Sciences Center, Shreveport, and colleagues conducted a single-center trial involving 15 patients (average age 44.5) with relapsing-remitting MS who had been taking interferon for at least six months and were experiencing symptoms and developing new brain lesions. For four months, participants took 100 milligrams daily of the antibiotic doxycycline in addition to continuing interferon therapy. They underwent monthly neurological examinations, MRI to detect brain lesions and blood work to monitor safety.

After four months, the combination treatment resulted in fewer lesions visible on MRI—60 percent of the patients had more than a one-fourth reduction in the number of lesions from the beginning of the study. The patients also had reduced average scores on a scale designed to assess disability levels. Only one patient relapsed; adverse effects were mild and included only known effects of the two drugs individually rather than new effects associated with combining the medications.

Antibiotics in the tetracycline family, including doxycycline, may be effective against MS and other inflammatory diseases by inhibiting the action of enzymes that destroy certain nervous system cells, protecting the brain and increasing the effectiveness of the immune system, the authors note.

“There is growing interest in combination therapy in patients with MS to stabilize the clinical course, reduce the rate of clinical relapses and decelerate the progressive course of the underlying pathologic mechanism,” they write. “Overall, data from this cohort suggest that the treatment combination of oral doxycycline and interferon beta-1a may be safe and effective in some patients with MS; however, further controlled clinical trials are warranted to demonstrate safety and efficacy in a larger patient population.”

Abstract

Objective: To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing remitting multiple sclerosis (RRMS) having breakthrough disease activity.

Design: Open-label, 7-month trial.

Setting: Louisiana State University Health Sciences Center, Shreveport.

Patients: Fifteen patients with RRMS taking interferon beta-1a with breakthrough disease activity took doxycycline for 4 months. Patients underwent monthly neurologic examination,magnetic resonance imaging of the brain using triple-dose gadolinium, and safety blood work.

Interventions: Ongoing treatment with intramuscular interferon beta-1a plus oral doxycycline, 100 mg daily, for 4 months.

Main Outcome Measures: The primary end point was gadolinium-enhancing lesion number change, and the secondary end points were relapse rates, safety and tolerability of the combination of interferon beta-1a and doxycycline in patients with MS, Expanded Disability Status Scale score, serum matrix metalloproteinase-9 levels, and transendothelial migration of monocytes exposed to serum from patients with RRMS.

Results: Combination of doxycycline and interferon beta-1a treatment resulted in reductions in contrastenhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P
.001 for both).Only 1 patient relapsed. Multivariate analyses indicated correlations between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. Transendothelial migration of monocytes incubated with serum from patients with RRMS undergoing combination therapy was suppressed. Adverse effects were mild; no adverse synergistic effects of combination therapy or unexpected adverse events were reported.

Conclusions: Combination of intramuscular interferon beta-1a and oral doxycycline treatment was effective, safe, and well tolerated. Controlled clinical trials in larger cohorts of patients with MS are needed to evaluate the efficacy and tolerability of this combination.

Source: Arch Neurol. 2008;65(2):(doi:10.1001/archneurol.2007.41) ©2008 American Medical Association. All rights reserved.(10/12/07)

Patients with relapsing-remitting multiple sclerosis (MS) treated with 250 mcg Betaseron (interferon beta-1b) experienced less injection site pain and fewer injection site reactions than those treated with 44 mcg Rebif. Moreover, among those who experienced injection site pain, significantly more patients on Rebif versus Betaseron said that pain negatively influences their satisfaction with treatment. These results from the BRIGHT (Betaseron(R) versus Rebif(R) Investigating Higher Tolerability) study were published in this month's issue of Multiple Sclerosis.

"BRIGHT is the first large-scale study to compare injection site reactions and pain with two high-dose interferons," said Dr. Karl Baum, an author of the study, and Chief of Neurology, Hennigsdorf Clinic, Hennigsdorf, Germany. "Injection site reactions and pain occur in many patients using injection interferon therapies, and these results show that reducing pain helps to improve their satisfaction with treatment. This is important because greater patient satisfaction may improve patient adherence to therapy and consequently, its effectiveness."

"MS is a chronic disease that requires long-term treatment. An effective therapy with high tolerability and comprehensive patient support programs, like Betaseron, can greatly aid patients in achieving better outcomes," said Ludger Heeck, Ph.D., vice president and general manager, Specialized Therapeutics, Bayer HealthCare Pharmaceuticals. "The results of the BRIGHT study confirm the importance of good tolerability in achieving high patient satisfaction."

The prospective, non-randomized, observational study compared Betaseron (interferon beta-1b) 250 mcg (subcutaneous, every other day) with Rebif (interferon beta-1a) 44 mcg (subcutaneous, three times weekly). The valid case population of the study included 445 patients who were treated with 15 consecutive injections of either Betaseron or Rebif for an observation period of four to five weeks.

Significantly more Betaseron than Rebif patients were pain-free at all time points measured (immediately after injection, 30 minutes after injection, and 60 minutes after injection) over the course of 15 injections. Specifically, at 30 minutes after injection, 42.6 percent of Betaseron patients were pain-free, versus 19.7 percent of Rebif patients. At the conclusion of the study, more than half of the patients treated with Betaseron reported that they experienced no injection site reactions (51.8 percent) versus only one-third of the patients treated with Rebif (33.8 percent). The proportion of pain-free injections per patient was also greater with Betaseron than with Rebif at all time points. This was regardless of the needle size used for either product.

Among participants who used autoinjectors (92 percent), there were significantly more pain-free patients in the Betaseron group versus the Rebif group at all time points (e.g., at 30 minutes after injection, 40.2 percent versus 16.2 percent). Additionally, more patients treated with Betaseron either had no pain or stated that their injection-site pain had no influence on their satisfaction with treatment, compared to those treated with Rebif (76.9 percent versus 64.1 percent).

About the BRIGHT Study

BRIGHT is a multicenter, international, non-randomized, prospective, observational study comparing the tolerability of Betaseron (250mcg) with Rebif (44mcg). The study included 454 patients (306 patients on Betaseron and 148 patients on Rebif) from 76 centers in 13 countries. Patients started treatment within three months prior to recruitment and were on the full dose of therapy. Nine of the patients were excluded because they did not take the full dose of either study drug. Although this was a non-randomized trial, patients were well matched for demographic and clinical characteristics.

Patients self-injected and self-assessed injection site pain for 15 consecutive injections using a 0-100 mm visual analogue scale (VAS) diary immediately after injection, and 30 minutes and 60 minutes post-injection. Injection site reactions were professionally assessed and confirmed. To qualify for a "pain-free" status, a patient must have had an assessment of "no pain" (VAS=0) at all 15 injections.

At the 15th injection, patients also were asked to assess how much injection site pain influenced their overall satisfaction with treatment. Patients who used an autoinjector were asked to assess its ease of use. The use of autoinjectors was recommended in the study.

Source: Bayer HealthCare (09/11/07)

A retrospective study comparing outcomes of relapsing-remitting multiple sclerosis (RRMS) patients treated either with COPAXONE^® (glatiramer acetate injection) or high-dose interferon beta-1a (Rebif^®) demonstrated that patients continuously treated with COPAXONE^® had a significantly lower risk of relapse (p=0.0049) and experienced significantly lower two-year total medical costs (p<0.0001) than those continuously treated with interferon beta-1a (Rebif^®).

The results of the study, “A Comparison of Outcomes Among Multiple Sclerosis Patients Treated with Glatiramer Acetate Injection or High-Dose Interferon Beta-1a,” were presented at the 10^th European International Society for Pharmacoeconomics and Outcomes Research (E-ISPOR) meeting, in Dublin, Ireland. The study analyzed medical claims of patients (n=845) from United Healthcare to examine the association between use of a drug and two-year direct medical costs and risk of relapse.

“Medical costs are an increasingly important factor in treating a chronic disease such as multiple sclerosis,” said MerriKay Oleen-Burkey, PhD, director of Outcomes Research at Teva Neuroscience and study investigator. “Findings of this study not only indicated that COPAXONE^® provided patients with a significant treatment benefit by lowering risk of relapse, but lowered the financial burden associated with the disease, in terms of medical costs,” Oleen-Burkey added.

About the Study

In the retrospective database analyses of United Healthcare medical claims for the time period from September, 2001 to June, 2006, multivariate regressions were used to examine the association between the use of COPAXONE^® and interferon beta-1a (Rebif^®) and two-year direct medical costs and relapses. The study analyzed both intent-to-treat (ITT) (n=845) and continuous use (CU) (n=410) patient cohorts. The ITT cohort included patients with an RRMS diagnosis who initiated therapy on either COPAXONE^® or interferon beta-1a (Rebif^®), and had continuous insurance overage from 6 months prior to drug initiation through 24 months after drug initiation.

The CU cohort consisted of patients who used the medication of interest within 28 days of the end of the two-year period. Patients who initiated treatment with COPAXONE^® (glatiramer acetate injection) in the ITT cohort experienced a significantly lower risk of relapse (odds ratio = 0.543, p=0.0305) and lower two-year direct medical costs ($7,244, p=0.0002) compared to those who began treatment with interferon beta-1a (Rebif^®). Patients who were treated with COPAXONE^® in the CU cohort experienced a significantly lower risk of relapse (odds ratio=0.213, p=0.0049) and significantly lower two-year total medical costs ($12,098, p<0.0001).

Source: Teva Neuroscience, Inc.(26/10/07)

The analysis suggests that patients taking AVONEX for two years were less likely to experience disability progression over time (eight years) when compared to placebo. These data were announced today at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) conference in Prague, Czech Republic.

The analysis involved 160 patients with RRMS who received at least two years of treatment (81 placebo, 79 interferon beta-1a), in the AVONEX Phase III trial and who were re-examined eight years post-randomization. 45 patients met the criteria for two-year disability progression sustained for six months (n=18 AVONEX, 27 placebo).

The analysis revealed:

• Patients initially treated with AVONEX were less likely than patients initially receiving placebo to progress to EDSS scores of greater than or equal to 4.0 at eight years
• Six month sustained EDSS progression during the pivotal two-year trial was a significant predictor of disability progression eight years later
• Almost twice as many patients who had sustained progression in EDSS during the two-year trial progressed to an EDSS of greater than or equal to 4.0 than patients who did not progress (84% sustained, versus 44% unsustained)
• Almost three times as many progressed to an EDSS of greater than or equal to 6.0 (67% sustained, versus 24% unsustained)   

"This new analysis presents further evidence that patients who are treated for two years achieve long-term, clinically significant disability
benefits," said Dr. Richard Rudick, vice-chairman of Neurological Institute at the Cleveland Clinic Foundation. "For a person with RRMS, starting and staying with treatment slows disability progression, as measured by EDSS."

EDSS is a common disability outcome measure that is used in multiple sclerosis clinical trials. EDSS greater than or equal to 4.0 signifies
relatively severe disability, such as impacting physical coordination or the ability to walk without assistance.

AVONEX is the number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is effective after the first attack. AVONEX is also proven to slow the progression of physical disability (as shown by 37% reduction over two years) and reduce the number of relapses. AVONEX has been proven effective in clinical trials for up to three years.

This study was funded by Biogen Idec.

Source: Biogen Idec. (15/10/07)

Merck Serono, a division of Merck KGaA, announced today new results of a two year (96 week) Phase IIIb study in 260 patients which has shown that the new formulation of Rebif® (interferon beta-1a) offers a near three-fold improvement in injection tolerability for patients with relapsing remitting multiple sclerosis (RRMS). These results are compared with historical data for the previous formulation of Rebif® (30.8% versus 85.8%) (1).

These study results will be presented today at a satellite symposium and tomorrow at a poster session at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague, Czech Republic.

"Rebif is an established first-line disease modifying treatment for relapsing types of MS" said Professor Gavin Giovannoni from The Royal London Hospital. "Injection site reactions can lead to withdrawal from treatment. The reduction in these reactions with the new formulation should improve treatment benefit to patients."

Rebif® has a favourable benefit-to-risk profile (2) and has a proven efficacy and safety profile, which has been demonstrated consistently across numerous phase III clinical trials and clinical practice (1, 3-5). The new study results have also confirmed consistent efficacy of the new formulation of Rebif® compared with previous experience (1). At 96 weeks, 53.3% of patients remained relapse-free and overall the expanded disability status scale (EDSS) score remained stable throughout the study.

The new formulation of Rebif® was approved on August 10, 2007, by the European Commission and is due to be launched in the UK in early 2008. The new formulation of Rebif® is the first and only therapy for multiple sclerosis that is serum free, both from animal and human-derived components (HSA-free and FBS-free) and is the latest product development from Merck Serono. Other recent enhancements have included the launch of a new initiation pack designed to make starting Rebif® therapy easier and more convenient.

References

1. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology 2002; 59: 1496-506.
2. Francis GS. Importance of benefit-to-risk assessment for disease-modifying drugs used to treat MS. J Neurol 2004; 251 (Suppl 5): v42-9.
3. Li D, Paty D, UBC MS/MRI Analysis Research Group, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo controlled study of interferon-b1a in relapsing-remintting multiple sclerosis. Ann Neurol 1999; 46: 197-206
4. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcultaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498-504, Erratum inLancet 1999; 353; 678.
5. PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: Long-term efficacy of interferon-β-1a in relapsing MS. Neurology 2001; 56: 1628-36.

About the Study

The study was a two-year (96 weeks) Phase IIIb, international, multicenter, single-arm, open-label study with historical controls, evaluating the safety and immunogenicity of the new formulation of Rebif® (interferon beta-1a) 44 micrograms (mcg) subcutaneously (sc) three times weekly (tiw) in 260 patients with relapsing forms of multiple sclerosis (MS).

No unexpected adverse events were reported with the new formulation of Rebif®. Safety outcomes were consistent with the known profile of Rebif®. The majority of adverse events were mild or moderate in severity. The most frequent side effect was flu-like symptoms (71.5%), which is typical of interferon therapy; most were mild in severity. Flu-like symptoms are transient. Prophylactic antipyretic treatment is recommended.

Source: Merck Serono (11/10/07)

"The number of events (relapses) was insufficient to establish a statistically significant difference between the two products, despite a trend advantage for Rebif," the report said.

The 96-week Phase IV study involving almost 800 patients will be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague.

Merck inherited Rebif through its recent 10.2 billion-euro ($14 billion) acquisition of Swiss biotech company Serono.

Serono had hoped to gain market share from Copaxone in the case of a positive outcome from the head-to-head study.

Source: Reuters (C) Reuters 2007. All rights reserved (10/10/07)

"Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen," wrote E. Schott and colleagues, University of Berlin, Department of Medicine.

The researchers concluded: "Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD."

Schott and colleagues published their study in World Journal of Gastroenterology (Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferon beta 1a. World Journal of Gastroenterology, 2007;13(26):3638-40).

Source: NewsRx.com Copyright © 2007 NewsRx (05/09/07)

"The EVIDENCE study was a head-to-head comparison of two important Interferon beta-1a products for MS, and it determined that there is a significant early and sustained benefit, both for clinical and MRI outcomes, from using a higher frequency and higher dose of interferon," said lead investigator Anthony Traboulsee, MD, clinical assistant professor, department of neurology, University of British Columbia Hospital, Vancouver, British Columbia, Canada. "The data presented here is an extension of the MRI results, specifically looking at T 2 burden of disease," Dr. Traboulsee added. "T 2 burden of disease represents the chronic accumulation of new and old MS lesions, and it was the first MRI measure approved by regulatory agencies for clinical trials."

The EVIDENCE trial compared T 2 burden of disease (BOD) between two groups of patients: subjects in one group (n=279) were given 44 mcg of Interferon beta-1a (IFN beta-1a) subcutaneously (sc) three times a week, while subjects in the other group (n=274) received 30 mcg of IFN beta-1a intramuscularly (im) once a week. The primary endpoint was percentage change in BOD over 48 weeks, and all patients with evaluable T 2 MRI scans at baseline and at week 48 were included in the analysis.

The investigators found that median percentage reduction in BOD from baseline to week 48 was greater in the 44 mcg sc treatment group than in the 30 mcg im group (–6.7 % [range –65, 431] versus –0.6 % [range –61, 197]). Median absolute reduction in BOD was also greater in the 44 mcg sc group (–189.5 mm3; range –23454, 56869) than the 30 mcg im group (–19.0 mm3; range –13337, 10161).

Based on these data, the investigators concluded that patients treated with 44 mcg of subcutaneous Interferon beta-1a three times per week had significantly greater reductions in T 2 burden of disease than those receiving 30 mcg intramuscular injections once a week. According to Dr. Traboulsee, "this study demonstrates the benefits of high dose, high frequency dosing on suppression T 2 BOD, and is consistent with previous results showing similar benefits on relapse rates."

Financial support for the EVIDENCE trial was provided by Merck Serono, the makers of Interferon beta-1a.

[Presentation title: Reduction in T2 Burden of Disease Is Greater With Interferon beta-1 a 44 mcg Administered Subcutaneously Three Times Weekly Than 30 mcg Administered Intramuscularly Once Weekly: 1-Year Analysis of the EVIDENCE Study Data. Abstract P539]

Source: Doctor's Guide Channels (c) 1995-2007 Doctor's Guide Publishing Limited. All rights reserved. (21/06/07)

Treatment with interferon beta in MS patients can be associated with the development of neutralising antibodies (NAbs), which have been shown to reduce the therapeutic effect of interferon at high titres, said lead investigator James P. Simsarian, MD, director, Multiple Sclerosis Program, Neurology Center of Fairfax, Ltd., Fairfax, Virginia, and neurologist, Inova Fairfax Hospital, Falls Church, Virginia, United States.

The new human serum albumin-free formulation of Rebif was created to minimise the incidence of NAbs and to optimise the potential benefits of treatment with interferon.

A 96-week multicentre, single-arm, open-label study of RNF enrolled 260 adults with an Expanded Disability Status Scale score <6.0 and a diagnosis of relapsing MS according to the McDonald criteria. Patients in the study self-injected RNF 44 mcg/0.5 mL subcutaneously, 3 times weekly.

Blood samples were examined at weeks 12, 24 and 48, and the proportion of RNF-treated Nab-positive patients was compared with historical Rebif data from similar patients treated with 44 mcg Rebif, 3 times weekly in the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) study.

At 48 weeks, 227 (87.3%) of patients were still on treatment. Patients treated with RNF were nearly 6 times less likely to become Nab-positive (titre >/= 20 NU/mL) at both 24 weeks and 48 weeks compared with patients in the EVIDENCE study.

Incidence of prespecified adverse events was markedly lower for injection-site reaction in RNF (30%) versus historical data (84%), which represented a threefold reduction. Similar reductions were noted for cytopenia (10% vs 12%), depression and suicidal ideation (6% vs 20%), hepatic disorders (13% vs 17%), skin rashes (5% vs 12%), thyroid disorders (2% vs 5%) and hypersensitivity reactions (5% vs 3%).

According to the authors, these changes constitute notable improvements to the typical safety profile of injectable Rebif.

As expected with an HSA-free formulation, incidence of flu-like symptoms was higher with RNF (71% vs 48%), although most events were mild/moderate in severity.

This study was sponsored by Merck Serono International SA.

[Presentation titles: Safety and Immunogenicity of Rebif New Formulation (RNF) a New Subcutaneous Formulation of Interferon beta-1a 44 mcg Three Times Weekly: 1-Year Results of a Phase IIIb Study in Patients With Relapsing Multiple Sclerosis. Abstract P06.077. Safety and Immunogenicity of Rebif New Formulation (RNF) a New Subcutaneous Formulation of Interferon beta-1a 44 mcg Three Times Weekly: 1-Year Results of a Phase IIIb Study in Patients with Relapsing Multiple Sclerosis. Abstract P06.077]

Source: Doctors Guide Channel All contents Copyright (c) 1995-2007 Doctor's Guide Publishing Limited. All rights reserved. (09/05/07)

Researchers analysed 10,622 patients over one year to assess how demographic, administrative and clinical variables affect MS costs and utilisation patterns and to examine the economic impact of treating MS. The independent data contained in Multiple Sclerosis Benchmarks(TM) ⁽¹⁾, the retrospective, claims-based, observational study, showed that patients treated with AVONEX had the lowest average one-year cost compared to patients receiving other interferon beta treatments. It has been estimated that the total annual economic burden of MS in the United States exceeds $6.8 billion with a lifetime cost of $2.2 million per patient. ⁽²⁾

"MS is a disease that can have an impact beyond its debilitating effect on patients," said Michael Pollock, Vice President, Global Health Economics, Biogen Idec. "Cost-effectiveness is an increasingly important factor in treating chronic diseases like MS. This study shows that in addition to its clinical impact, AVONEX can also help to substantially reduce the cost of care for patients living with this disease, when compared to other interferon beta treatments."

The MS Benchmarks analysis showed the total costs over one-year to MS patients on interferon beta therapy were: AVONEX, $19,896.15; Rebif(R) (Interferon beta-1a) sc, $22,207.85; and Betaseron(R) (Interferon beta-1b), $21,073.33.

In addition, AVONEX patients were more likely to refill their prescriptions (avg.9.6/yr vs. 8.1 and 8.2/yr for other interferon beta therapies) and were less likely to use certain concomitant medications. Over the one-year period, use of disease-modifying therapies (interferon beta and glatiramer acetate) was almost always observed as monotherapy, reflecting little evidence of combination use or switching between products.

Additionally, according to data from the Quality Assessment of Multiple Sclerosis Therapy (QUASIMS) study presented at the AMCP Conference, patients do not derive additional clinical benefit from switching among interferon beta therapies. QUASIMS, an open-label, retrospective, observational study conducted in 14 countries, analysed 7,156 MS patients who had received two years of uninterrupted therapy with interferon beta as initial therapy or follow-up therapy.

⁽¹⁾ "Multiple Sclerosis Benchmarks" is a trademark of Managed Care Measures, LLC.

⁽²⁾ Coyle PK, Hartung HP. Use of interferon beta in multiple sclerosis: rationale for early treatment and evidence for dose-and frequency-dependent effects on clinical response. Multiple Sclerosis. 2002: 8:2-9.

Source: Biogen Idec Inc (13/04/07)

"We've received questions from the FDA that require our response,'' said Benedicte Bogh, a spokeswoman at the company's Merck Serono unit in Geneva, in a telephone interview today. ``We continue to work very closely with the FDA to address these requests.''

Merck needs Rebif to beef up sales from branded pharmaceuticals, which are growing slower than at competitors, as the German company rebuilds the unit to focus on cancer, diabetes and central nervous diseases. Merck Serono plans to use the new formulation to increase its share of the $5 billion global market and surpass its larger rival, Biogen Idec Inc.'s Avonex for MS.

The company applied for approval of the treatment, which has fewer side effects than the current version, last April. The Food and Drug Administration, which usually gives its decision within 10 months, was due to rule on the application by Feb. 4. Bogh declined to comment on how long the regulator may take to complete its review.

The new version, which isn't made from human or animal-based materials although it is produced in mammalian cells, reduces reactions at the injection site and results in fewer antibodies forming compared with older versions of the medicine.

Biogen Idec's Tysabri

``The new formulation is intended to replace the current formulation,'' Bogh said. ``It will support our objective to reach global market leadership for Rebif.''

Source: Bloomberg.com Copywrite Bloomberg L.P. 2007 (06/02/07)

Merck Serono announced today that it has begun the ONWARD (Oral Cladribine Added ON To Rebif New Formulation in Patients With Active Relapsing Disease) Phase II study. The ONWARD study will evaluate the safety, tolerability and efficacy of two dose regimens of Merck Serono's proprietary oral formulation of cladribine when added to the new formulation of Rebif(R) (interferon beta-1a) in multiple sclerosis (MS) patients with active disease despite treatment with Rebif(R). Oral cladribine is currently also evaluated as a monotherapy in a fully enrolled Phase III pivotal trial (the CLARITY study) for first-line treatment of relapsing forms of MS. The new formulation of Rebif(R) is under regulatory review by the European Medicines Agency, the US Food and Drug Administration and other healthcare authorities.

"Multiple sclerosis patients with signs of active disease while on treatment with a disease modifying drug may benefit from adding another agent with a different mechanism of action, to complement and increase the overall efficacy while maintaining an acceptable safety and tolerability profile," said Bruno Musch, Merck Serono's Head of Neurology Clinical Development. "The different mechanism of action and the oral intermittent administration of oral cladribine make it a potentially useful add-on therapy to Rebif(R) at a critical time of disease progression."

"Oral cladribine is currently being evaluated as a monotherapy in the CLARITY Phase III pivotal study and is on track to become the first oral therapy for first-line treatment of multiple sclerosis", said Franck Latrille, Merck Serono's Head of Product Development. "We are now initiating the ONWARD study as we believe that oral cladribine also has a great potential as an add-on therapy, for patients who have signs of active relapsing disease while on a treatment."

The ONWARD study is a two-year (96 weeks), randomised, double-blind, placebo-controlled, international trial. The trial will be conducted in 40 sites located in the United States and in Europe. It will involve 260 MS patients who have experienced at least one relapse while taking Rebif(R) during the year prior to study enrollment. Study participants will be randomised in one of the three arms of the study to receive one of two different dose regimens of oral cladribine or matching placebo tablets, in addition to the new formulation of Rebif(R) 44 micrograms subcutaneous three times a week. In the study, oral cladribine is given in two or four treatment cycles in the first year, with each cycle consisting of daily administration for four or five consecutive days, which means study patients take oral cladribine therapy for only 8 to 20 days during that year. In the second year, two treatment cycles are administered in all dose regimens.

The primary safety endpoints of the ONWARD study consist of a wide range of safety and tolerability parameters measured during 96 weeks of treatment. The primary efficacy endpoint is the mean change in the number of new T1 gadolinium-enhanced lesions per subject per magnetic resonance imaging (MRI) scan from baseline to 96 weeks.

About oral cladribine

Merck Serono's proprietary oral formulation of cladribine is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that interferes with the behaviour and the proliferation of certain white blood cells, particularly lymphocytes, which are involved in the pathological process of MS. Through its differentiated mechanism of action, oral cladribine may offer a safe and effective new option to patients with MS.

SOURCE Serono International S A (24/01/07)

Serono announced today the initiation of a Phase III clinical trial to evaluate the effect of two dosage regimens of the new formulation of Rebif(R) (interferon beta-1a 44 mcg, three times a week or once a week) on the time to conversion to multiple sclerosis (MS) in people with first clinical symptoms suggestive of the disease. The trial, called the REFLEX study (REbif FLEXible dosing in early MS), will involve 480 patients considered at risk of developing MS because of a recently experienced isolated demyelinating event and of typical magnetic resonance imaging (MRI) brain scans.

"It has been demonstrated that early treatment with interferon-beta can reduce the risk of developing multiple sclerosis. Optimising the impact of such treatment on development of irreversible neurological damage and ascertainment of long term outcomes is still subject of active experimental and clinical research", said Professor Ludwig Kappos, from the Department of Neurology, University Hospital Basel, Switzerland, and a member of the Steering Committee of the REFLEX study. "The REFLEX study will determine the respective therapeutic benefit of two different dosage regimens of the new formulation of Rebif(R) for people at risk of developing multiple sclerosis."

The REFLEX study is a randomised, double-blind, placebo-controlled, multicenter trial. Study participants will receive either the new formulation of Rebif(R) 44 mcg three times a week (160 patients), or the new formulation of Rebif(R) 44 mcg once a week (160 patients), or placebo (160 patients) as a subcutaneous injection for a period of 24 months, unless they suffer from a second attack leading to a diagnosis of clinically definite MS. In this case, patients will be offered open label treatment with the new formulation of Rebif(R) 44 mcg three times a week. The primary endpoint of the study is time to conversion to MS, according to the McDonald criteria. Other endpoints will include assessments of MRI brain scans, clinical relapses and disability progression.

The REFLEX study will also evaluate the effect of the new formulation of Rebif(R) on cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT). Cognitive dysfunction can occur early in MS and impact memory, ability to process information and learning. A sub-study will assess retinal nerve fiber thickness (a marker of axonal loss) by means of optical coherence tomography (OCT). This sub-study will be conducted in selected centers, equipped with this leading edge technology. In addition, the REFLEX study will aim at identifying genetic/genomic profiles associated with disease and treatment outcomes.

The new formulation of Rebif(R) has been developed by an innovative approach, using state-of-the-art technologies. It is under regulatory review by the European Medicines Agency, the US Food and Drug Administration and other healthcare authorities, and is not currently approved.

Source: Serono International S A (12/12/06)

Biogen Idec announced today that AVONEX(R) (Interferon beta-1a), the most prescribed multiple sclerosis (MS) therapy worldwide, is now available in Japan. AVONEX is available in more than 90 countries, and its introduction in Japan extends Biogen Idec's leadership in the treatment of MS to an important and underserved market.

In July 2006, the Japanese Ministry of Health, Labour and Welfare approved AVONEX for the prevention of MS relapse. AVONEX is the first new MS treatment available in Japan in six years. It is the second disease-modifying therapy approved to treat MS in Japan and the only one that can be administered once a week. In international clinical trials, AVONEX has been proven to slow the progression of disability and reduce the frequency of clinical relapses, as well as delay the development of clinically definite MS.¹

"For more than a decade, Biogen Idec has been committed to advancing the treatment of MS, and we look forward to extending that dedication to serve patients and their families in Japan," said James C. Mullen, President and Chief Executive Officer, Biogen Idec. "The introduction of AVONEX to the Japanese MS community continues our mission of delivering important therapeutics to patients around the world."

There are approximately 12,000 people diagnosed with MS in Japan.² However, a number of patients are believed to be undiagnosed. In addition, many Japanese patients are treated with acute rather than long-term therapy, and there are a number of patients who have discontinued therapy due to perceived lack of efficacy or side effects. Initially, AVONEX will be introduced in Japan to hospitals with MS experts, and then Biogen Idec expects it will become more widely available.

"AVONEX is the leading choice for prescribing physicians and their MS patients because it offers proven efficacy and a convenient dosing regimen that patients can adhere to over the long term," said Toshio Nakata, President of Biogen Idec Japan. "MS is a debilitating disease that remains under-treated in Japan, and we believe patients can benefit greatly from the availability of a new treatment option."

¹ AVONEX(R) (Interferon beta-1a) prescribing information

² Japanese Intractable Diseases Information Center, 2006.

Source: Biogen Idec (08/11/06)

"As someone who is constantly on the go, being able to store my AVONEX at room temperature for up to 7 days is very convenient." said Cathy F. who has been taking AVONEX for 9 years.

AVONEX remains the only once-a-week disease modifying therapy to both slow the progression of physical disability and reduce the frequency of clinical relapses for people with MS.

"Biogen Idec is committed to the discovery and development of new therapeutic options for people living with MS as well as continuous improvement of existing ones ." said Michael Panzara MD, MPH, VP, Chief Medical Officer, Neurology Strategic Business Unit.

Source: Genetic Engineering News

Multiple sclerosis is thought to be an autoimmune disease, a disease that occurs when the body's own immune system attacks a  key protein covering on the nerves, resulting in serious movement problems and other symptoms.

With relapsing-remitting MS, the initial form of the disease in 85 percent of patients, MS attacks are separated by periods of relatively normal function.

"Long-term treatment with (interferon beta-1a) is feasible and tolerated by most patients with some evidence of sustained benefit regarding clinical disease progression and MRI related outcomes," said Dr. Ludwig Kappos from University Hospital Basel, Switzerland.

Kappos and colleagues report follow-up data for up to 8 years after entry of patients into the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study.

Early treatment with interferon beta-1a, particularly at a high dose, helped prevent disease relapses, the researchers note. Moreover, early treatment appeared to slow long-term disease progression based on MRI findings.

Treatment with interferon was generally well tolerated, the investigators say, with no new safety concerns.

"This trial represents another enormous expenditure of effort to determine whether we are helping our relapsing-remitting MS patients with existing therapies," writes Dr. John H. Noseworthy from the Mayo Clinic College of Medicine, Rochester, Minnesota in a related editorial.

"I respect this effort," Noseworthy concludes, "but am cautious about the authors' conclusions that 'patients with relapsing-remitting MS can experience sustained benefit over many years from early interferon beta-1a...three times weekly therapy.' Perhaps this is true (I hope it is), but the evidence is not yet fully convincing to me."

Kappos responded: "Noseworthy is correct in that this study did only provide indicative evidence for efficacy as it did not have an untreated (comparison) group from year 3 onwards and because at the end of the day we do not know what the impact of those patients who did not complete the follow-up would have been."

Nonetheless, he concluded, "Justification of early treatment with interefron-beta...is not only based on this observation but also on data from early treatment studies and from new insights in the neuropathology of early and late phases of MS."

SOURCE: Neurology, September 2006.

GAP is the largest study of its kind to evaluate patient adherence to long-term treatments for multiple sclerosis in a real-world setting with 176 sites across 22 countries participating. The cross-sectional observational study enrolled 2,566 patients with relapsing-remitting MS taking one of the DMTs. Neurologists completed a practice-related survey and patients completed a patient survey on their treatment adherence practices, plus the MS International Quality of Life Questionnaire and the MS Neuropsychological Screening Questionnaire. Non-adherence was defined as missing at least one injection or changing dose within four weeks prior to the survey. The World Health Organization (WHO) has defined treatment adherence as both compliance (taking a medication in the dose and according to the schedule prescribed) and persistency (maintenance of the drug regimen over the long-term), and suggests that non-adherence is one of the most important factors contributing to decreased multiple sclerosis treatment effectiveness.

The GAP study found that patients taking AVONEX had statistically significant higher adherence rates than the other DMTs. Results showed that 85% of patients taking AVONEX were adherent to therapy, compared to patients who were non-adherent on Rebif® (Interferon beta-1a) sc 22mcg (22%, p=0.006), Rebif® 44 mcg (27%), Betaferon/Betaseron® (Interferon beta-1b) (30%) and Copaxone® (glatiramer acetate) (34%), (all p<0.0001). In addition to the high adherence rate seen in the GAP study, AVONEX is the only available once-weekly MS treatment that has been proven to delay the risk of developing clinically definite MS for up to five years in patients who begin treatment immediately after their initial MS attack.

"Adherence is a critical component in chronic disease treatment, directly impacting long-term efficacy. The GAP study suggests that AVONEX leads to superior adherence which may contribute to long-term effectiveness," said Bernd Kieseier, MD, Professor of Neurology, Heinrich-Heine-Universitat, Dusseldorf, Germany, and a lead investigator in the project. "The study also demonstrated that therapeutic choice can directly affect a patient's adherence to multiple sclerosis treatment, with factors such as frequency of drug administration, how the therapy is administered, side effects, and how effective the patient perceives their treatment also playing a role."

The study showed that adherent patients reported better quality of life, less cognitive impairment and fewer problems with injection site reactions that non-adherent patients. Findings also demonstrated that the most common reason for non-adherence to multiple sclerosis treatment was forgetting to administer the injection (50%). Other factors affecting adherence included duration of current therapeutic treatment and duration of the disease.

"The GAP study aimed to characterise those factors that are associated with adherent versus less adherent MS disease-modifying agent injection-taking behavior. These results have substantial implications in terms of our ability to anticipate difficulties that patients may have with specific therapeutic regimens, and for disease-modifying injection therapies in general," said Eliot Frohman, MD, PhD, Professor of Neurology and Ophthalmology, and Director, Multiple Sclerosis Program and Vertigo and Eye Movement Clinics at University of Texas Southwestern Medical Center.

Source: Biogen (29/09/06)

Serono announced today data from an ongoing two-year (96 weeks) Phase IIIb trial show that the new formulation of Rebif® (interferon beta-1a) 44 mcg subcutaneously (sc) three times weekly (tiw) for the treatment of relapsing forms of multiple sclerosis (MS) offers substantial improvement in tolerability and reduction in antibody formation observed at one year (48 weeks), compared with historical data from patients. Historical data for the currently available formulation of Rebif® is the EVIDENCE study. These data are presented today at a satellite symposium at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid, Spain.

"These results are promising news for patients with multiple sclerosis," said Prof Per Soelberg Sorensen, from the Danish MS Research Center, Copenhagen University Hospital, Rigshospitalet and an investigator of the trial. "If approved the new formulation of Rebif® potentially represents an improvement in the treatment of patients with multiple sclerosis."

The incidence of injection site reactions with the new formulation of Rebif® at 48 weeks was nearly three-fold less than in the EVIDENCE study (29.6% versus 83.8%). Injection site reactions are one of the reasons why some patients discontinue MS treatment. Treatment enhancements resulting in a decrease of injection site reactions are usually associated with improved compliance and adherence to treatment.

The primary endpoint of the study is the proportion of neutralizing antibody positive patients at the last assessment. At 48 weeks, the data showed that 13.9% of patients treated with the new formulation of Rebif® were neutralizing antibody positive. In the EVIDENCE study at 48 weeks, 24.4% of the patients were positive. Persistent neutralizing antibodies were detected in 2.5% of the patients treated with the new formulation of Rebif® at 48 weeks. In the EVIDENCE study at 48 weeks, the rate of persistent neutralizing antibodies observed was 14.3%.

"The new formulation of Rebif® has been developed by an innovative approach, using state-of-the-art technologies, with a major focus on the molecule's structural and functional integrity," said Franck Latrille, Senior Executive Vice President Global Product Development at Serono. "Based on the improvements in tolerability and immunogenicity, the new formulation of Rebif® could lead to an improved benefit-to-risk profile."

The new formulation of Rebif® is the latest of many product developments from Serono to continually enhance the convenience and tolerability of Rebif®. Other enhancements have included the Rebiject II auto-injector to facilitate injections; a 29 gauge-5 bevel needle pre-filled syringe, the thinnest needle in a ready-to-use pre-filled syringe for the treatment of MS; and a titration pack designed to make starting on Rebif® therapy easier and more convenient. The new formulation of Rebif® is currently under regulatory review by the European Medicines Agency, the US Food and Drug Administration and other healthcare authorities.

The results presented today are the 48-week results from a 96-week, Phase IIIb, multicenter, single-arm, open-label study evaluating the safety and immunogenicity of the new formulation of Rebif® 44 mcg sc tiw in 260 patients with relapsing forms of MS. The primary objective of the study was to compare the antigenicity of new formulation Rebif to historical data.

Source: Serono International S A

Teva Neuroscience, Inc., announced today the initiation of the first-ever study designed to examine how the implementation of regularly scheduled interferon beta  (IFN-(beta) ) neutralizing antibody (NAb) tests in multiple sclerosis (MS) patients receiving high-dose IFN-(beta) therapy ultimately affects treatment patterns, versus the usual care of IFN-(beta) patients. The study, called the NAbs Count Study, began enrollment in approximately 130 centers across the United States with the first patient entering the trial on July 25, 2006.

Studies have shown that the presence of IFN-(beta) NAbs may negatively alter the therapeutic effectiveness of the commercially available IFN-(beta) class of disease modifying drugs commonly used to treat multiple sclerosis, which includes IFN-(beta)-1a SC (Rebif®), IFN-(beta)-1b SC (Betaseron®), and IFN-(beta)-1a IM (Avonex®), and that NAbs developed in five percent to 45 percent of all multiple sclerosis patients treated with these drugs (1, 2, 3). Despite the evidence that patients who develop NAbs are likely to become IFN-(beta) non-responders, and present an increased risk of relapses and disease progression, NAbs testing has not been a part of routine clinical practice (4).

"The initiation of the NAbs Count Study underscores Teva's long-standing commitment to the MS community," said Judy Abdalla, Senior Director Medical Affairs, Teva Neuroscience. "We are excited to be working with some of the top medical centers in the United States to gather information that could provide additional information on what guides multiple sclerosis treatment decisions."

The European Federation of Neurological Societies (EFNS) released guidelines recommending that IFN-(beta) NAbs testing be conducted in all IFN-(beta)-treated MS patients at 12 and 24 months of therapy. The EFNS guidelines also recommend that testing should be repeated in patients who test positive for NAbs and therapy with IFN-(beta) should be discontinued in patients with high titers of NAbs sustained at repeated measurements with 3- to 6-month intervals (5).

About the Study

The NAbs Count Study is a 12-month, randomised, controlled, open-label, parallel group study taking place in approximately 130 study sites in the United States. Patients 18 years of age and older with a diagnosis of MS who have been receiving high-dose IFN-(beta) therapy at approved doses - either Rebif® or Betaseron® - continuously for at least 12 months are eligible. The study is expected to enroll approximately 2,440 subjects.

Patients will be randomised to one of two study groups. One group of patients (Regularly Scheduled NAb Testing Arm) will be scheduled for multiple IFN-(beta) NAb tests (up to 3 NAb tests over a nine-month period) with a follow-up visit at 12 months. The other cohort of patients (Usual Care Arm) will be observed for 12 months under usual care conditions, which typically do not include regularly scheduled NAb tests. As the primary endpoint of the study, researchers will evaluate the differences between study arms in the proportion of subjects whose high-dose IFN-(beta) therapy was changed during a 12-month follow-up period. Patients and health care providers interested in learning more about the study can visit www.clinicaltrials.gov and enter the trial's identifier code of NCT00336557 for more information.

Please see enclosed additional important information.

(1)Avonex® Prescribing Information, www.avonex.com (2)Rebif® Prescribing Information, www.rebif.com (3)Betaseron ® Prescribing Information, www.betaseron.com (4)Giovannoni G, Goodman A. Neutralizing anti-IFN-{beta} antibodies: How much more evidence do we need to use them in practice? Neurology 2005; 65(1):6-8.

(5)P.S. Sorensen, et al. "Guidelines on use of anti-IFN-(beta) antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-(beta) antibodies in multiple sclerosis" European Journal of Neurology 2005, 12: 817-827

Source: Teva Neuroscience, Inc.

Serono announced today that the European Commission has approved an update of the Summary of Product Characteristics (SmPC) of Rebif® (interferon beta-1a), in order to align it with current medical practice. Throughout the European Union, Rebif® can now be prescribed after the diagnosis of multiple sclerosis (MS) has been confirmed based on one attack and subsequent positive magnetic resonance imaging (MRI) scans.

The 'therapeutic indication' section of the SmPC of Rebif® now takes into account the McDonald criteria, which are the current reference criteria for the diagnosis of MS. The SmPC of Rebif® was previously based on the Poser criteria, which were in use at the time of Rebif® approval in the European Union in 1998, and Rebif® was consequently indicated for MS patients who had experienced at least two attacks. Compared with the Poser criteria, the McDonald criteria utilise MRI evidence as an alternative to a second attack, and allow the same patients to be diagnosed with more sensitivity and specificity. Current understanding of the disease supports that it is critical to initiate treatment as soon as the diagnosis of MS is established to ensure the best possible outcome for the patients.

"We are delighted with the European Commission decision," said Roberto Gradnik, Senior Executive Vice President Europe at Serono. "MS has an initial stage when clinical manifestations are not pronounced but irreversible neurological damage is taking place. This neurological damage determines the relative risk of progression of the disease. People with MS living in Europe will be able to benefit from the proven efficacy of Rebif® as soon as MS is diagnosed, when it is needed most."

Rebif® is proven effective on the following three key measures of treatment effectiveness: MRI lesion area and activity, relapse rates, and disability progression. The safety and efficacy of Rebif® are supported by eight-year follow-up data and 12 years of patient experience from around the world.

The European Commission decision means that the updated SmPC of Rebif® is valid immediately in all 25 member states of the European Union. In most other regions of the world, the therapeutic indication of Rebif® already takes into account the McDonald criteria.

About Rebif®

Rebif® (interferon beta-1a) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis and is similar to the interferon beta protein produced by the human body. Interferon helps modulate the body's immune system, fight disease and reduce inflammation.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 80 countries worldwide. In the United States, Rebif® is co-marketed by Serono, Inc. and Pfizer Inc. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area[1]. Rebif® is available in a 22 mcg and 44 mcg ready-to-use pre-filled syringe and a titration pack, and can be stored at room temperature for up to 30 days if a refrigerator is not available.

Most commonly reported side effects are injection site disorders, flu-like symptoms, elevation of liver enzymes and blood cell abnormalities. Patients, especially those with depression, seizure disorders, or liver problems, should discuss treatment with Rebif® with their doctors.

Source: Serono International S.A.

AVONEX® (Interferon beta 1a), the most prescribed multiple sclerosis (MS) therapy worldwide may now be administered with a needle that is 20 percent shorter and thinner than the currently approved needle. People living with MS and taking or considering AVONEX may speak with their healthcare provider to see if the smaller needle is appropriate for them.

"Some of my patients have expressed a strong interest in administering AVONEX with a smaller needle," said Dr. Mitchell Freedman from the Triangle MS Center at Raleigh Neurology Associates who is also an Adjunct Professor of Neurology at the University of North Carolina. "The ability to administer AVONEX via a smaller needle may make the once-a-week injection more patient friendly."

Additionally, a supplemental application has been filed with the U.S. Food and Drug Administration (FDA) to provide a new needle attachment, which will lock onto the syringe to make it easier for patients to know that the needle is firmly attached as well as a proposed change in the room temperature storage recommendations for AVONEX. FDA action on this supplement is expected in the fall. These proposed enhancements for administering and storing AVONEX are being pursued in response to the requests of people with MS who are looking for convenient therapies.

Source: Biogen Idec

Israel-based Teva said the study of patients with relapsing-remitting MS found that Copaxone reduced their annual relapse rate by an additional 57 percent over Avonex, and that neurologic disability did not worsen in 86 percent of patients.

Officials at Biogen Idec, based in Cambridge, Massachusetts, could not be immediately reached for comment.

Both drugs are approved to treat relapsing-remitting MS, the most common form of the disease, which causes a progressive disability that can include blurred vision, weakness, poor muscle coordination and loss of memory and mental function as nerves lose their insulating sheath.

The study involved 85 patients who had been treated with Avonex for at least 18 months before relapsing or experiencing intolerable toxicity. They were then switched to Copaxone and followed for an additional 36 to 42 months.

The results were published in the June issue of the European Journal of Neurology.

Dr. Omar Khan, associate professor of neurology at Detroit's Wayne State University and senior author of the study, said the results suggest that observation of relapse rates, patient tolerability, and toxicity assessment are valuable for determining when therapy should be switched.

Source : Yahoo News Copyright © 2006 Reuters Limited. All rights reserved.

Biogen Idec today marks the 10th anniversary of AVONEX(R) (Interferon beta-1a), the most prescribed multiple sclerosis (MS) therapy worldwide, as the company's CEO James Mullen, rings the NASDAQ Stock Market Opening Bell. AVONEX, manufactured by Biogen Idec, was approved for relapsing forms of MS by the U.S. Food and Drug Administration (FDA) on May 17, 1996. Shortly after its introduction in the U.S., it became the number one prescribed therapy in MS. Today more than 130,000 patients worldwide choose AVONEX to treat their MS.

Biogen Idec is recognizing the AVONEX anniversary with the publication of a commemorative book, "Profiles of Inspiration" and a companion video. The book and video showcase extraordinary people with MS whose lives have been positively impacted by AVONEX. The book and video will soon be available on www.AVONEX.com. 

"Biogen Idec is proud to recognize the 10th anniversary of AVONEX, the number one prescribed MS therapy worldwide, and the impact it has made on the lives of patients around the world. People living with MS inspire and motivate us each and every day to redouble our efforts to advance the science and treatment of this disabling disease. The introduction of AVONEX was an important step forward in the treatment of MS, but we know a significant unmet need persists, and we will continue our unyielding commitment to offer patients hope in their fight against this disease," said Mullen.

The anniversary is being celebrated by MS patients, physicians and caregivers in a series of events around the US intended to raise awareness of MS and to celebrate the role AVONEX has played in transforming MS care.

"The mission of the National Multiple Sclerosis Society is to end the devastating effects of MS," said John Richert, MD, vice president, research and clinical programs of the National Multiple Sclerosis Society. "We support the efforts of companies such as Biogen Idec who are committed to research and development of breakthrough therapies that can offer help to people living with MS."

AVONEX remains the only once-a-week disease modifying therapy proven to both slow the progression of disability and reduce the frequency of clinical relapses for people with MS, a chronic disease of the central nervous system. In the pivotal trial that led to its approval in the U.S., AVONEX demonstrated a 37% reduction in progression to disability compared with placebo. Recently published data demonstrated that AVONEX reduced the risk of developing clinically definite MS for up to five years in patients who began treatment immediately after their initial MS attack compared to those who delayed the treatment.

Source: Biogen Idec

According to study chairman, Fred D. Lublin, M.D., Saunders Family Professor of Neurology at Mount Sinai School of Medicine-Corinne Goldsmith Dickinson Center for Multiple Sclerosis, "This is a very important trial because, if effective, combination therapy will allow us to take advantage of these agents that have different and complementary mechanisms of action to slow or halt progression of MS."

An estimated 400,000 Americans suffer from MS, a chronic neurological disease that affects the central nervous system. MS is most commonly diagnosed in young adults. Relapsing-remitting MS, the most common form of new cases of the disease, is characterized by episodes of attacks of neurologic dysfunction, which occur over many years.

Approximately 130,000 MS patients are receiving either FDA-approved interferon beta-1a weekly (Avonex®) or glatiramer acetate daily (Copaxone®) to treat relapsing forms of MS. However, because these agents provide only a partial amelioration of the risk for additional attacks and development of disability, there is a major and continuing need for better therapies. As yet, there is no cure for MS.

CombiRx will determine whether the combination of these treatments is more effective than either treatment alone. This trial is unique among placebo controlled studies, in that none of the participants will receive placebo alone. All participants will receive at least one active, FDA-approved treatment. Specifically, 50% will receive the combined investigational therapy, 25% will receive interferon beta 1-a weekly plus a daily placebo, and 25% will receive glatiramer acetate daily plus a weekly placebo.

In addition to CombiRx, participants will be offered the opportunity to volunteer for another study known as Biomarkers in MS. This study is designed to determine if there are specific genes and proteins that can predict the course and progression of MS. More importantly, this study may allow identification of markers that may be useful in distinguishing which MS patients may respond to specific treatments. According to Dr. Henry McFarland, Clinical Director, NINDS, "As with the data from the CombiRx Trial, the implications of the Biomarkers in MS Study could be enormous, both for the individual patient as well as for the costs associated with MS treatment and hence the health care providers and the general public."

One thousand patients are being recruited for these studies at approximately 80 sites across the US and Canada.

Men and women between 18 and 60 years of age who have been diagnosed with relapsing-remitting MS and who have not previously taken interferon beta-1a weekly (Avonex®) or glatiramer acetate daily (Copaxone®) may be eligible to participate in both studies. Participants will be randomly assigned to one of the three study groups and will receive treatment over 36 months. Clinic visits will be scheduled every three months throughout the treatment period to assess the impact of treatment.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Jeffrey I. Greenstein, MD, director, Multiple Sclerosis Institute, Philadelphia, Pennsylvania, and colleagues assessed the safety of the addition of azathioprine to intramuscular interferon beta 1-a in patients who were incompletely responsive to intramuscular interferon beta-1a and to determine if the combination would improve both clinical and magnetic resonance imaging (MRI) outcomes.

Dr. Greenstein presented the results of the 12-month, open-label safety study on April 4th.

The study enrolled 12 patients with relapsing-remitting MS who had experienced at least one relapse in the prior 12 months while on interferon beta-1a alone. None of the 12 subjects had interferon neutralizing antibodies. They received a combination of a 30-mcg intramuscular injection of interferon beta-1a plus 150 mg azathioprine orally each week.

"Although the currently approved therapies for the treatment of MS have proven efficacy in relapse reduction, and some of them slow disease progression, it is estimated that 50% to 70% of patients on monotherapy will experience ongoing disease activity," Dr. Greenstein observed. "Combination therapy, particularly the use of agents with different modes of action, may improve outcomes."

Interferon-beta therapy has pleiotropic immunomodulatory, anti-inflammatory, and antiviral effects. Potential effects in MS include reduction of matrix metalloproteinase activity, inhibition of proliferation, and enhanced secretion of interleukin-10, he said.

Azathioprine reduces cellular and humoral immunity by inducing T-cell apoptosis and inhibits T-cell/APC conjugation, producing immunosuppression.

Both agents have shown reductions in relapse rates in MS, he added.

In the trial, safety evaluations were performed at baseline and months 1, 2, 3, 6, 9, and 12.

Three subjects withdrew from the study because of nonadherence, limb fracture, and treatment-induced nausea. No significant hematologic or hepatic toxicity occurred.

At the 12-month evaluation, results showed that the annualized relapse rate was significantly decreased from baseline following treatment (1.4 to 0.3, P <.001). In addition, the number of gadolinium-positive lesions decreased from a mean of 3.3 to 0.5 (P <.0625).

Neither the Expanded Disability Status Score (EDSS) nor the Multiple Sclerosis Functional Composite or its components were significantly affected by combination therapy (P =.280; P =.190, respectively).

Dr. Greenstein said that larger trials of longer duration are needed to confirm the efficacy of the combination.

"Overall, the combination appears safe and well tolerated in patients with relapsing-remitting MS and potentially effective, with a significant effect on relapse rate and trends towards magnetic resonance imaging and disease improvement on both EDSS and MRI measures after treatment," Dr. Greenstein concluded.

The study was supported by Biogen Idec, Inc.

[Presentation title: A Safety Study of Interferon-Beta1a (Avonex) and Azathioprine in Breakthrough Disease in Relapsing-Remitting Multiple Sclerosis. Abstract P01.085]

Source: Doctor's Guide Channels Copyright (c) 1995-2006 Doctor's Guide Publishing Limited. All rights reserved

Serono announced today the submission of a supplemental Biologics Licence Application (sBLA) to the US Food and Drug Administration (FDA) and of a variation to the current Marketing Authorization to the European Medicines Agency (EMEA) for a new formulation of Rebif® (interferon beta-1a) as a treatment of multiple sclerosis (MS).

Data from a Phase III clinical trial in patients with relapsing forms of MS show that the new formulation of Rebif® results in a substantial improvement in overall tolerability, as measured by pre-specified parameters including injection site reactions, which are an important factor for patients when choosing an MS therapy. The trial data also show that the incidence of antibody formation with the new formulation of Rebif® is reduced. Serono expects data on the new formulation of Rebif® to be presented at a major medical conference in the second half of 2006.

"These results are promising news for patients with multiple sclerosis," said Prof Per Soelberg S0rensen, from the Danish MS Research Center, Copenhagen University Hospital, Rigshospitalet and an investigator of the trial. "While Rebif® is well established in the treatment of relapsing forms of multiple sclerosis, results from this clinical trial show that the new formulation offers promising improvements which could translate into additional benefits to the patient."

"Serono is focused upon providing multiple sclerosis patients with enhanced therapeutic solutions," said Franck Latrille, Senior Executive Vice President Global Product Development. "This is supported by innovative development and manufacturing technology platforms that we have implemented to deliver world-leading biotech therapies."

The new formulation of Rebif® is the latest of many product developments from Serono to continually enhance the convenience and tolerability of Rebif®. Other enhancements have included the new Rebiject II auto-injector to facilitate injections; a 29 gauge-needle pre-filled syringe, the thinnest needle in a ready-to-use pre-filled syringe for the treatment of MS; a titration pack designed to make starting on Rebif® therapy easier and more convenient.

About Rebif®

Rebif® (interferon beta-1a) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis and is similar to the interferon beta protein produced by the human body. Interferon helps modulate the body's immune system, fight disease and reduce inflammation.

Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more than 80 countries worldwide. In the United States, Rebif® is co-marketed by Serono, Inc. and Pfizer Inc. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area[1]. Rebif® is available in a 22 mcg and 44 mcg ready-to-use pre-filled syringe and a titration pack, and can be stored at room temperature for up to 30 days if a refrigerator is not available.

Most commonly reported side effects are injection site disorders, flu-like symptoms, elevation of liver enzymes and blood cell abnormalities. Patients, especially those with depression, seizure disorders, or liver problems, should discuss treatment with Rebif® with their doctors.

Source: Serono International S.A.

The study, known as CHAMPIONS (Controlled High Risk AVONEX Multiple Sclerosis Prevention Study In Ongoing Neurological Surveillance), was designed to determine whether the effect of early treatment with AVONEX in delaying relapses and reducing the accumulation of MS brain lesions could be sustained for up to five years.

"These CHAMPIONS data provide unique insight into the effect of AVONEX for up to 5 years when initiated early in the course of MS," said lead study investigator R. Philip Kinkel, M.D., Director of the Multiple Sclerosis Center at Beth Israel Deaconess Medical Center in Boston, MA and Associate Professor of Neurology at Harvard Medical School. "CHAMPIONS provides additional evidence that patients who start on AVONEX earlier have a sustained advantage over those patients who start therapy later."

The study followed patients who began treatment immediately after their initial MS attack and compared this to initiation of treatment more than two years after onset of symptoms. The patients studied were considered at risk of suffering additional MS attacks because of the presence of brain MRI scan abnormalities.

The 203 MS patients who enrolled in the CHAMPIONS study were followed for a total of five years after their initial attack. Patients who began treatment with AVONEX immediately after their first attack had a 43% decrease in the risk of developing a second attack compared to those who began treatment on placebo, after adjusting for the potential confounding effects of age, CHAMPS qualifying event, CHAMPS baseline brain MRI T2 lesion volume, and baseline number of gadolinium-enhancing lesions.

About the Study

CHAMPIONS is an open-label extension of CHAMPS, (Controlled High Risk Subjects AVONEX Multiple Sclerosis Prevention Study), a randomized, double-blind, placebo-controlled Phase III clinical trial involving 383 patients who had just experienced their first MS attack and who had brain MRI scan abnormalities characteristic of MS. In CHAMPS, AVONEX-treated patients experienced a 44% decrease in the rate of developing a second attack when compared to placebo over a three-year period. Based on the CHAMPS results, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) approved AVONEX to be used in patients who have experienced a first clinical episode if they have brain MRI scan abnormalities consistent with MS.

Source: Biogen Idec

Viragen and Roslin are conducting avian expression studies on various protein candidates including interferon beta-1a, which is currently marketed under two competing brand names for the treatment of MS. These MS products are Avonex®*, marketed by Biogen Idec, and Rebif®**, marketed by Serono, with combined annual global sales over $2.5 billion.

The Project's Scientific Leader, Dr. Helen Sang of Scotland's Roslin Institute, commented, "We are extremely pleased to report this key advance in our program to develop a preferred platform for the production of selected biopharmaceutical proteins, having now successfully developed transgenic hens that are synthesizing significant quantities of interferon-beta as a component of their egg white. This is the second protein candidate with which we have achieved promising results, as we previously reported expression and recovery of a functional humanized antibody. As we fully characterize the interferon- beta that is recovered, both biochemically and by functional tests, we expect such results will confirm our progress."

"This is a truly remarkable achievement for our team in Scotland and represents a major event towards our goal to definitively position the OVA(TM) System as a revolutionary transgenic bio-manufacturing alternative," stated Dr. Karen Jervis, Vice President and Managing Director of Viragen (Scotland) Ltd. "We will continue to collect eggs from these hens and subsequent generations to confirm quality and quantity of the protein. In addition, we will be analyzing the carbohydrate profile of the product, which may represent another key advantage to OVA(TM)-expressed proteins. Certain biotech drugs require post-translational modifications in order that the drug retains its full efficacy and is well tolerated when used as a human therapeutic. Although we must confirm the nature of the modifications conferred by the OVA(TM) System, we are hopeful that avian transgenic production may be able to retain these beneficial modifications, which may in turn translate to a lower cost of goods and a more economical process."

While more data are required to provide a precise economic model, Viragen's President & CEO, Charles A. Rice, stressed the significance of this achievement, "We are continuing to report historic scientific breakthroughs, as we achieve the essential prerequisites to develop a viable, cost-effective, transgenic bio-manufacturing system. To imagine the potential, based on the highest expression levels we have found, it is conceivable that a small flock of a couple of hundred hens could satisfy the entire U.S. market demand for interferon beta-1a. These figures are preliminary, but certainly suggest why this technology might be so desirable to a company seeking new benefits in the manufacturing of current and future products. We congratulate our Scotland teams at VSL and the Roslin Institute for their commitment, patience, perseverance and fine work on this important project, and we look forward to even more dramatic results throughout this year."

*Avonex® (interferon beta-1a) is a registered trademark of Biogen Idec, Inc.

** Rebif® (interferon beta-1a) is a registered trademark of Serono, Inc.

Viragen has no agreements with Biogen Idec or Serono and did not collaborate with either company in connection with these avian expression studies.

About the OVA(TM) System:

Viragen holds the worldwide exclusive license to commercialise the OVA(TM) System (Avian Transgenic Biomanufacturing) as granted by the Roslin Institute (Scotland). The project is designed to develop the chicken into a pharmaceutical bioreactor, one that can meet the growing need for protein-based human therapeutics. Based on the creation of lines of transgenic hens which have been engineered to produce a target protein in their eggs using the LentiVector® gene delivery system licensed from Oxford BioMedica plc, this technology is being developed as an efficient and economical alternative to standard bio-manufacturing techniques, having many apparent advantages in ease of scale-up, lower costs of production and quality of product produced.

This project has been funded in part from a grant awarded by the Scottish Executive's "SPUR Plus Program", designed to support significant technological advances being made in Scotland.

About Viragen, Inc.:

With global operations in the U.S., Scotland and Sweden, Viragen is a biotechnology company engaged in the research, development, manufacture and commercialization of pharmaceutical proteins for the treatment of viral diseases and cancers. Our product portfolio includes: Multiferon® (multi- subtype, natural human alpha interferon) targeting a broad range of infectious and malignant diseases; and humanized monoclonal antibodies targeting specific antigens over-expressed on many types of cancers. We are also pioneering the development of Avian Transgenic Technology, with the renowned Roslin Institute, as a revolutionary manufacturing platform for the large-scale, efficient and economical production of human therapeutic proteins and antibodies.

Source: Viragen, Inc.

More evidence shows neutralizing antibodies hamper effect of treatment

Should Canadian neurologists be testing their multiple sclerosis patients on interferon beta-1a or interferon beta-1b therapy for neutralizing antibodies? And if a patient tests positive, what then?

The questions have been brought up again by an editorial and three papers in a recent issue of Neurology.

Previous studies suggested the presence of neutralizing antibodies affected clinical outcomes and markers of disease progression seen with imaging, but the full implications of how they affect interferon therapy in MS was not clear. Neutralizing antibodies against interferon beta typically appear after six to 24 months of interferon treatment, so their impact on outcomes could not be properly assessed with some of the earlier, shorter trials.

The papers in Neurology provide more evidence that neutralizing antibodies interfere with clinical outcomes and show that if a patient repeatedly tests positive, the antibodies are bound to stay.

A two-year extension of the PRISMS (prevention of relapses and disability by interferon beta-1a subcutaneously in multiple sclerosis) trial allowed investigators to better examine the issue of neutralizing antibodies. In their report in Neurology, the investigators conclude relapses increased after patients developed neutralizing antibodies to the interferon beta-1a (Rebif). Patients who tested positive for neutralizing antibodies also did more poorly on disability outcome measures compared with those who tested negative.

A second study, this time from the four-year European interferon beta-1a (Avonex) intramuscular dose comparison study investigators, showed patients with neutralizing antibodies are significantly more likely to have higher relapse rates and worsening of expanded disability status scores from baseline compared with patients who are negative for neutralizing antibodies.

Results from the Danish Multiple Sclerosis Study group suggest if a patient has not developed neutralizing antibodies after two years of interferon treatment, the chances of them developing them are slim. Patients who remain positive for neutralizing antibodies for more than 18 months will probably remain positive, their findings show.

The proportion of patients who developed neutralizing antibodies ranged from 3.2% in the European study, to 14% to 22% in PRISMS (with more in the low-dose group) and 40% in the Danish study.

Canadian neurologists have the means to screen for neutralizing antibodies. All three pharmaceutical companies who manufacture interferon therapies for MS patients offer the test at their laboratories. Physicians must submit a request to have the test done for a specific patient.

But some say that is not enough. "I think everybody should be tested. That is just my feeling," said Dr. Stanley Hashimoto, a neurologist and clinical professor at the University of British Columbia when asked to comment by the Medical Post. Dr. Hashimoto tests his patients when they come in for routine visits. The cost of the test is covered by the pharmaceutical company.

Patients have to be tested numerous times because approximately 30% of those who initially test positive for neutralizing antibodies may later spontaneously become negative. This was reflected in the Danish study, which found 7% of the 455 patients treated fluctuated between positive and negative status over the two-year study.

Dr. Hashimoto said management should be changed if the patients have persistently high titres of neutralizing antibodies.

"I think that as long as the titres are high and persistent—by persistent I would say between six months to a year—I would stop the drug and wait for the titre to come down to zero," he said.

There are problems with testing Canadian MS patients for neutralizing antibodies. For one, the laboratory technique that produces the most reliable results has not been established. There are also no standardized cutoff points for "high" and "low" levels of neutralizing antibodies, and what titre is of clinical importance has not been established.

Then there remains the tricky question: If a patient seems to be doing well on interferon therapy yet tests positive for neutralizing antibodies, what then?

Dr. Hashimoto said he would stop interferon treatment in patients with persistently high titre of neutralizing antibodies even if the patient was doing well. Interferon beta therapy has a modest benefit, and if the patient is doing well it might not be due to the drug at all.

"Just because they are doing well certainly is no reason why I wouldn't stop the drug," he said. "Many people disagree with that."

Guidelines

In a paper published in the Canadian Journal of Neurological Sciences last year, the Canadian MS working group recommended treatment decisions be made based on clinical observations instead of on levels of neutralizing antibodies.

"Response to therapy should be weighed on a patient-to-patient basis and take into account the 'little things' we often ignore. If a patient appears to be doing well and objectively we see little change, then that's a good thing. On the other hand, if a patient reports continuing problems, inability to perform their activities of daily living or their job requirements and we find objective change, I would put more weight on those than any neutralizing antibody test," said Dr. Mark Freedman, lead authors of the CJNS paper and director of the multiple sclerosis research unit at the Ottawa Hospital Research Institute.

"The bottom line is, in very few situations would a neutralizing antibody titre either be helpful or useful in directing the therapy of MS," Dr. Freedman said.

© Copyright The Medical Post. All rights reserved

Males treated with interferon were found to have a bone mass density that was lower than that of those who had not been treated with the drug, according to Spanish research.

Women on interferon had the same bone mass density as those women treated only with corticosteroids.

Patients with multiple sclerosis are at greater risk of suffering from osteoporosis and pathological fractures, and the use of corticoids together with immobilisation and vitamin D deficiency is one of the causes of low bone mass.

Results are paradoxical because interferon plays a part in regulating bone metabolism and inhibits the development of osteoclasts, the cells responsible for bone resorption.

Ref: Rev Neurol 2003 May 16-31;36(10):901-3 Perez Castrillon JL, Cano Del Pozo M, Sanz lzquierdo S, Velayos Jimenez J, Dib Wobakin W. Hospital Rio Hortega, Valladolid, Espa a.

New findings presented at the American Academy of Neurology Annual Meeting in Honolulu, Hawaii revealed clinically relevant differences in disease activity after increasing the dose and frequency of beta interferon therapy in relapsing-remitting MS patients. The results also showed that reducing the dose and frequency of beta interferon is associated with increased disease activity.

Professor Luca Durelli, Chief of the MS Centre of University Department of Neurosciences, Turin, Italy, and principle investigator of the study, said, "These data confirm the benefits of high-dose, high-frequency beta interferon and demonstrate the risks of changing to a lower-dose regimen even in the absence of clinical or MRI disease activity. These findings will help guide prescribing choices for MS patients."

Ref: Prof. Luca Durelli - University MS Centre, University of Torino

© Multiple Sclerosis Resource Centre