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    You are here : Home » MS Research News » Drugs » Laquinimod

    Laquinimod

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    Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration.

    Teva to test oral MS drug Laquinimod in combination therapy

    Oral MS DrugsTeva Pharmaceutical Industries Ltd. will test its experimental multiple-sclerosis pill in combination therapies as the company mounts a response to oral competitors to its best-selling injection Copaxone.

    The Israeli company is likely to start two clinical trials next year combining laquinimod with other drugs, President of Global Research and Development and Chief Scientific Officer Michael Hayden said in an interview at an MS conference in Lyon, France. One of the trials may seek to combine laquinimod with Copaxone, Hayden said.

    “We haven’t pulled the trigger on it but we are getting very close,” Hayden said, referring to the possible combination with Copaxone. In multiple sclerosis, “nobody uses combination therapy. It’s really strange.” Combining another treatment to laquinimod would mean a “paradigm change” in the the care of multiple sclerosis, Hayden said.

    “With the dual mechanisms, we have a chance to do that,” he said.

    Teva is searching for a new approach to MS treatments as Copaxone’s dominance begins to be threatened by pills such as Novartis AG’s Gilenya and Biogen Idec Inc’s BG-12, which is awaiting a decision from U.S. regulators. Teva also said today that it’s submitting its three-times weekly version of Copaxone for approval in the beginning of 2013.

    Slowing Deterioration
    While laquinimod failed to beat competing products in clinical trials on reducing the rates at which patients experience relapses, Teva is continuing development because studies suggest it slows the deterioration in physical ability caused by the disease. Teva is separately testing the pill in a final round of human trials at a higher dose as it seeks to verify that the drug effectively delays loss of muscle control and balance.

    A U.S. federal judge in New York handed Teva a ruling in June that may keep generic versions of Copaxone off the market until 2015. The victory may give Teva more time to switch patients to a new, higher-dose version of the drug. Teva said yesterday that a late-stage trial of a longer-acting formulation reduced MS relapses more than a placebo and showed a ‘‘favourable” safety profile.

    With a three times a week dose, patients on Copaxone “can focus on having the week-end without it,” Hayden said. “Weekends are times for different things, to be able to put your medication away, have a weekend without having to worry about it. For me, that would be an advantage.”

    Source: Bloomberg Business Week @ 2012 BLOOMBERG L.P (11/10/12)

    Third Phase III trial of oral MS drug Laquinimod initiated

    Oral MS Drugs Teva Pharmaceutical Industries Ltd. and Active Biotech have provided an update on the clinical development program of once-daily oral laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS). The companies are to initiate a third Phase III study of laquinimod, following the written agreement reached with the U.S. Food and Drug Administration (FDA) on the Special Protocol Assessment (SPA).

    The third Phase III laquinimod trial CONCERTO will evaluate two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS).

    "The results achieved in the previous Phase III trials of laquinimod support the clinical utility of this compound as a unique treatment option for multiple sclerosis," said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer, Teva Pharmaceutical Industries Ltd. "We are encouraged by the FDA's agreement on the trial design and planned analysis, and look forward to further developing laquinimod as a potential treatment option for RRMS patients."

    About Laquinimod

    Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.

    In addition to the MS clinical studies, laquinimod is currently in Phase II of development for Crohn's disease and Lupus.


    About Special Protocol Assessment (SPA)

    A SPA is a written agreement between the FDA (Food and Drug Administration) and a drug sponsor intended to confirm that the clinical trial protocol is adequate to meet current scientific and regulatory requirements for a potential new drug application.

    Source: Reuters (c) Thomson Reuters 2012 (09/08/12)

    EMA starts scientific review of Laquinimod in relapsing-remitting Multiple Sclerosis

    Oral MS DrugsActive Biotech announced that the European Medicines Agency (EMA) has completed the validation process for the marketing authorization application (MAA) of the medicinal product laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS).

    The completion of the MAA validation process and acceptance for review now leads to the formal scientific review process by EMA's Committee for Medicinal Products for Human Use.

    This acceptance of the EMA filing for review triggers a milestone payment of USD 5 million to Active Biotech from Teva.

    The MAA submission is supported by a pooled analysis of data from the two global Phase III clinical trials in RRMS involving more than 2,400 patients treated for two years, the ALLEGRO and BRAVO trials. This analysis further strengthens the positive results achieved in the studies.

    Additionally, Active Biotech and Teva continue to work with the Food and Drug Administration to determine the regulatory path forward for laquinimod in the U.S.

    ABOUT LAQUINIMOD

    Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.

    In addition to the MS clinical studies, laquinimod is currently in Phase II of development for Crohn's disease and Lupus.

    Source: Market Watch Copyright © 2012 MarketWatch, Inc (19/07/12)

    Oral Laqunimod may ease Multiple Sclerosis disability

    Laquinimod Yet another orally taken medication shows some promise in preventing relapse and disability for people with relapsing-remitting multiple sclerosis, a new report suggests.

    In the new study, laquinimod reduced the annual relapse rate by 23 percent, and disability progression by 36 percent.

    "We found that laquinimod, as compared with placebo, reduced the rate of relapse and slowed the progression of disability in patients with relapsing-remitting multiple sclerosis," the European researchers, led by Dr. Giancarlo Comi of the Institute of Experimental Neurology in Milan, wrote.

    The study, which was funded by the drug's manufacturer, Teva Pharmaceutical Industries, was published in the March 15 issue of the New England Journal of Medicine.

    Multiple sclerosis (MS) is a disease that damages the outside of nerve fibers in the central nervous system, according to the National Multiple Sclerosis Society. The brain, spine and optic nerves make up the central nervous system. Symptoms of the disease can include fatigue, numbness in the limbs, balance and coordination problems, bladder or bowel dysfunction, vision problems, pain and even paralysis, according to the society.

    Most patients -- about 85 percent -- have a form of MS that's called relapsing-remitting, the society has reported. That means that people have periods where the disease is very active, and at other times the disease remits. During these periods of remission, there may be complete or partial recovery of function, and the disease doesn't progress during remission, according to the society.

    All of the more than 1,100 people included in the current study had relapsing-remitting MS; the volunteers came from 139 sites in 24 countries. They were randomly assigned to receive a laquinimod pill or an inactive placebo once daily for 24 months.

    The annual relapse rate for those on the active drug was 0.30 compared to 0.39 for those on a placebo, a reduction in relapse of 23 percent for those on the medication. During the study, 63 percent of those on the drug remained relapse-free compared to 52 percent of those on placebo.

    Just over 11 percent of those taking laquinimod had confirmed disability progression compared to 15.7 percent of those on placebo, the researchers found.

    The drug was generally well-tolerated. The most significant side effects appeared to be urinary tract infections and a temporary abnormality in liver function tests.

    This isn't the first pill developed for MS. The first was Gilenya, which was approved in 2010 for the treatment of relapsing-remitting MS. This drug is currently under increased scrutiny in the United States and Europe because there have been 11 unexpected deaths in people taking the drug. Several other oral medications are in development. One is called teriflunomide, and it's also for the treatment of relapsing-remitting MS; its manufacturer recently filed for approval in the United States and Europe. Before Gilenya was approved, MS medications had to be given by injection.

    "This is meaningful because it's a more convenient way of taking medication. I don't think it will differ significantly in efficacy from other agents. The safety data looks good now, but many low-frequency side effects only become apparent [after a drug has been approved] in post-marketing trials," said Dr. Malcolm Gottesman, chief of the division of neurology, co-director of neuroscience and director of the Winthrop Comprehensive MS Care Center at Winthrop University Hospital in Mineola, N.Y.

    "Right now, it looks good. It looks like it works and is easy to take," Gottesman said, adding that it's not going to be a groundbreaking change in treatment.

    Timothy Coetzee, chief research officer for the MS society, said laquinimod works differently than the other pills and looks as if it might have some protective effects that other drugs don't offer, though more research is needed into that potential aspect.

    He said it's not clear if laquinimod's modest effect on relapse rates is "clinically meaningful," which means, does it make a difference to someone living with MS? He said that if the manufacturer files for U.S. Food and Drug Administration approval, "regulators are looking for a clinically meaningful impact."

    But, Coetzee added, "This study illustrates that there are oral agents becoming available for people with MS. And, it brings hope that we will have a next generation of agents, and that we can hopefully stop the progression of MS."

    Source: U.S.News & World Report Copyright © 2012 U.S.News & World Report LP (15/03/12)

    Study shows Laquinimod targets immune cells to increase neuroprotection

    Oral MS TreatmentsLaquinimod is an orally available synthetic compound that has been successfully evaluated in phase II/III clinical studies for the treatment of relapsing-remitting multiple sclerosis (RRMS).

    The mechanism of action of laquinimod has not been fully elucidated, but a study published in the January 2012 issue of The American Journal of Pathology suggests that laquinimod triggers immune cells within the central nervous system to produce and release brain-derived neurotrophic factor (BDNF), contributing to the repair or survival of neurons and thus limiting brain damage.

    "Our data are indicative of a direct and sustained effect of laquinimod on the up-regulation of bioactive BDNF in patients with RRMS. Additionally, we demonstrate that laquinimod targets monocytes and skews the phagocyte population towards a regulatory phenotype, which in turn mediates immune modulation in vivo," explained Jan Thöne, MD, of the Department of Neurology at St. Josef-Hospital Bochum and Ruhr-University Bochum, Germany.

    Neurotrophins, such as BDNF, are essential for the development and maintenance of neurons and axons in the central nervous system. Although BDNF is mainly produced by neurons, several types of immune cells also secrete BDNF, suggesting a role in neuroprotection.

    To elucidate the mechanism of action of laquinimod, and to explore its potential neuroprotective capacity, the researchers evaluated levels of BDNF in the serum of RRMS patients treated with laquinimod in phase II clinical trials. A significant and robust BDNF increase occurred in 76% of the laquinimod-treated patients, with up to an 11-fold increase in BDNF serum levels observed in individual patients. BDNF elevation in individual patients was independent of relapse rate, and there was no correlation between BDNF levels and age, gender, or baseline disability. Yet, the source of serum BDNF subsequent to treatment remained questionable.

    Experiments with animal models corroborated the findings in human patients. Experimental autoimmune encephalomyelitis (EAE; a model of MS) was induced in mice with a conditional BDNF deficiency in immune cells (LLF mice) and in wild-type (WT) control mice. Treatment with laquinimod resulted in a significant reduction in EAE incidence and disease severity in the WT mice. The effect of laquinimod was significantly reduced in the LLF-mice.

    Further studies showed that WT mice treated with a suboptimal dose of laquinimod demonstrated a significant reduction in the inflammatory area and level of demyelination. These mice also displayed a reduction of macrophage infiltration and a significant preservation of axonal densities in comparison with laquinimod-treated LLF mice and controls. The data suggest a BDNF-dependent mechanism of action for laquinimod in autoimmune demyelination.

    To investigate whether laquinimod-treated monocytes mediate immune modulation in vivo, laquinimod-stimulated monocytes were injected into WT mice at an early EAE disease stage. The mice showed less severe disease course than controls. Transfer of laquinimod-treated cells derived from LLF mice into WT mice with ongoing EAE did not influence disease course. The cells also secrete significantly less IL-10, an immunomodulatory cytokine that is associated with the generation of regulatory monocytes.

    "Consistent with immunomodulatory properties, laquinimod skewed monocytes towards a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients," said Dr. Thöne. "To date, selective targeting of monocytes has not been described for any other MS pipeline drug, highlighting an innovative mechanism of action of laquinimod."

    The article is "Modulation of Autoimmune Demyelination by Laquinimod via Induction of Brain Derived Neurotrophic Factor," by J. Thöne, G. Ellrichmann, S. Seubert, I. Peruga, D-H. Lee, R. Conrad, L. Hayardeny, G. Comi, S. Wiese, R.A. Linker, R. Gold (doi: 10.1016/j.ajpath.2011.09.037). It will appear in The American Journal of Pathology, Volume 10, Issue 1 (January 2012) published by Elsevier.

    Source: EurekAlert! (06/12/11)

    Oral MS drug Laquinimod submission put on hold

    LaquinimodTeva Pharmaceutical Industries has revealed that it will not be filing for US approval of its multiple sclerosis drug laquinimod in the near future.

    Teva chief executive Shlomo Yanai noted that the company met with the US Food and Drug Administration last week to discuss the New Drug Application for the late-stage oral MS drug and following the meeting, he said "we now believe that it would be premature to file the NDA at this time". Mr Yanai added that "the FDA has offered to work with us to determine the best design for conducting an additional trial".

    Mr Clark told PharmaTimes World News that the decision to put the submission on hold was "prudent". In August, initial results from the Phase III BRAVO study, the second of two late-stage trials on laquinimod, showed that the drug failed to meet its primary endpoint of reducing the annualised relapse rate when compared with placebo.

    However, at the time, Teva noted that the placebo and treatment study groups showed dissimilarity "in two baseline magnetic resonance imaging" characteristics and following a "pre-specified sensitivity analysis", when this imbalance was corrected, laquinimod demonstrated a significant reduction in the annualised relapse rate (21.3%) in the risk of disability progression and in brain volume loss (27.5%).

    In the summer, the company still felt confident that an adjustment of the data would be enough to support a filing but Mr Clark said "this was not something upon which we expected the FDA would look favourably". That, "in conjunction with the lack of overwhelmingly positive data previously", led the analyst to "remove estimates for laquinimod from our model some time ago". Mr Clark concluded by praising Teva management's decision "to deploy their resources in the most sensible way possible and, for now, that means holding off on laquinimod".

    Source: Pharmatimes Online Copyright PharmaTimes 2011 (03/11/11)

    Novel MS drug likely to survive missed endpoint

    LaquinimodWith one exception, the investigational oral drug laquinimod was more effective than placebo, and possibly better than interferon-beta-1a (Avonex), in reducing clinically relevant aspects of multiple sclerosis (MS), a researcher said here.

    But that exception was a doozy: on the phase III BRAVO trial's primary efficacy endpoint, annualized relapse rate, laquinimod failed to show significantly better efficacy than placebo, reported Timothy Vollmer, MD, of the University of Colorado in Denver.

    According to the two-year trial's prespecified method for measuring annualized relapse rates in the primary analysis, laquinomid produced a rate of 0.28 relapses, versus 0.34 for placebo (risk ratio 0.82, 95% CI 0.66 to 1.02, P=0.075).

    On the other hand, when the data were adjusted for baseline clinical factors associated with relapse rate that were imbalanced between treatment groups in the randomized trial -- also planned in the BRAVO protocol -- annualized relapse rates rose enough in the placebo group to give laquinimod a statistically significant advantage (0.37 placebo, 0.29 laquinimod, P=0.03).

    The raw and adjusted relapse rates in the trial's interferon arm were 0.26 and 0.27, respectively, both P<0.01 relative to placebo.

    More important, according to Vollmer, was that the drug was clearly helpful in reducing the progression of disability and brain atrophy, which are arguably the issues that matter most to patients.

    News of the missed primary endpoint had been announced in August by the trial's sponsor, Teva Pharmaceuticals. Vollmer's presentation Saturday at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis was the first full scientific report from the BRAVO trial.

    An unusual study

    BRAVO had an unusual three-arm design. Its 1,331 patients were randomized to receive oral laquinimod (0.6 mg/day), interferon by intramuscular injection (30 mcg once weekly), or an oral placebo. Thus, for patients, the laquinimod and placebo groups were blinded whereas the interferon was open label. Clinical and MRI evaluations were fully blinded for all three groups.

    Patients had active relapsing-remitting MS with a baseline EDSS disability score of no more than 5.5. Previous treatment with interferon products was an exclusion.

    Vollmer said the baseline factors that turned out to predict relapse rates and that differed between treatment groups were the hyperintense T2-lesion volumes and gadolinium-enhancing T1-lesion counts from MRI scans.

    Mean T2-lesion volumes were 9.6 mL (SD 10.3) in the laquinimod group versus 7.9 mL (SD 8.9) in the placebo group. Similarly, 39.6% of patients assigned to laquinimod had at least one gadolinium-enhancing T1 lesion compared with 33.4% of the placebo group.

    This higher lesion burden put the laquinimod patients at greater risk for relapse, Vollmer said, making the original primary endpoint comparison somewhat unfair.

    When the data were adjusted for baseline lesion burden, laquinimod not only reduced the relapse significantly compared with placebo, it also significantly cut the risk for three- and six-month confirmed disability progression.

    Vollmer told MedPage Today that this latter finding was the more clinically significant, arguing that patients' chief concern is always disability.

    He also pointed out that laquinimod appeared to outperform interferon in this respect, although he was careful to note that the trial was not designed to yield head-to-head comparisons of the two agents.

    The adjusted results for reduction of disability progression risk were as follows:

    Laquinimod versus placebo: 33.5% for three-month progression (P=0.04), 40.6% for six-month progression (P=0.04)
    Interferon versus placebo: 28.7% for three-month progression (P=0.09), 28.3% for six-month progression (P=0.14)
    Approximately 12% of the placebo group showed confirmed six-month disability progression after two years, compared with approximately 7% of patients taking laquinimod and 8% of the interferon group.

    Also, interferon appeared to have no effect on brain atrophy: mean brain volume loss from baseline was measured with MRI at 1.25% with interferon and 1.14% with placebo, whereas the loss was significantly lower in the laquinimod group, at 0.83% from baseline (P<0.0001 relative to placebo).

    All major adverse events and most minor ones were similar in the three treatment groups. The chief exception was back pain, seen in 10% of patients compared with 7% of those taking placebo and 3% of the interferon group. Back pain had also been associated with laquinimod in previous trials, with no clear answer yet as to the reason.

    Rates of alanine aminotransferase (ALT) elevation were somewhat higher with laquinimod than the other treatments, particularly in the mild to moderate range, according to Vollmer. Elevations above five times the upper limit of normal, though, were equally distributed across the three groups.

    All patients with ALT elevations who continued taking laquinimod eventually had the enzyme fall back into the normal range, Vollmer added.

    Overall, about 20% of each treatment group dropped out before completion, with adverse events listed as a reason in 5% of those assigned to laquinimod versus 4% of the placebo group and 6% of the interferon group.

    Vollmer said laquinimod appears to act primarily within the central nervous system to inhibit astrocyte activity and thereby reduce demyelination and neuronal loss there, rather than by targeting peripheral immune cells as many other MS treatments do.

    As a result, a greater effect against neurodegeneration and disability, as opposed to acute attacks, is is not surprising with the drug, he suggested.

    That also means laquinimod is shaping up as a drug that might best be used in combination with other agents that target immune elements more directly.

    "I think the future of MS therapy probably will be in combinations, as it has in other fields," he said. Because laquinimod "is not a primary immunosuppressant," he added, it might produce "an additive and possibly a synergistic effect" with other drugs.

    'What we care about is disability'

    Daniel Kantor, MD, medical director of the Neurologique Foundation in Ponte Vedra, Fla., agreed that laquinimod looks to be a drug to prevent or delay disability, so therefore its apparently smaller effect against relapses is less of a problem.

    "Patients and doctors have been saying for years that relapses are fine [as a treatment target], but what we care about is disability. So if it becomes true that what we're really talking about is a disability drug, then you're less interested in [the effect against] relapses," he told MedPage Today.

    "The safety profile looks extremely good," said Kantor, who was not involved with the BRAVO study. "If we can have a drug especially in combination, that would be very useful for us."

    BRAVO is the second phase III trial of laquinimod to be completed. The other was ALLEGRO, main results of which were presented earlier this year.

    The BRAVO study was sponsored by Teva Pharmaceuticals.

    Vollmer reported consulting or other relationships with Teva, Acorda, Biogen Idec, Hoffman LaRoche, Novartis, Xenoport, Guidepoint Global, PRIME Education, Global Prairie, Daiichi Sankyo, Projects in Knowledge, Lilly, Medical Logix, MSDx, Esai Pharma, and Schering-Plough Biopharma. He also has grants, or pending grants payable to his institution, from Teva Neuroscience, Biogen Idec, Lilly Research Laboratories, Genzyme, Ono Pharmaceuticals, Elan Pharmaceuticals, Acorda Therapeutics, Novartis, Sanofi Aventis, Pfizer, NIH, PDL Biopharma, Biosite, EMD Serono, Genentech, and Daiichi Sankyo.

    Kantor has had relationships with Biogen Idec, ONO Pharmaceuticals, Questcor, Teva, Acorda Therapeutics, Bayer HealthCare, EMD Serono, Forest Laboratories, Pfizer, and Merck.

    Primary source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Vollmer T, et al "A placebo-controlled and active comparator phase III trial (BRAVO) for relapsingremitting multiple sclerosis" ECTRIMS/ACTRIMS 2011; Abstract 148.

    Source: MedPage Today © 2011 Everyday Health, Inc. (24/10/11)

    Laquinimod demonstrates its potential as a new oral MS treatment (ECTRIMS and ACTRIMS)

    LaquinimodTeva Pharmaceutical Industries Ltd. and Active Biotech today announced the presentation of Phase III clinical and pre-clinical data, which collectively demonstrate that once-daily oral laquinimod modulates the pathological processes of multiple sclerosis to impact disease activity, disability progression and brain volume loss.

    The data will be featured in more than 20 scientific posters and presentations this week at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) in Amsterdam, The Netherlands.

    Findings from the second Phase III study, BRAVO, being highlighted as late-breaking research, showed that at 24-months, the primary endpoint of reduction in annualized relapse rates (ARR) did not reach statistical significance (0 = 0.075); however, after applying a pre-specified sensitivity analysis to correct for meaningful imbalances in baseline characteristics (MRI) between treatment groups, laquinimod significantly reduced ARR (21.3%, p = 0.026). Laquinimod also demonstrated a significant reduction in the risk of disability progression as measured by the Expanded Disability Status Scale (EDSS) (33.5%, p = 0.044) and in MRI-measured brain volume loss (27.5%, p =< 0.0001). The safety and tolerability profile of laquinimod was favorable.

    New exploratory analyses from ALLEGRO, the first Phase III study in the laquinimod clinical development program, demonstrated that laquinimod had an effect on the rate of severe relapses, showing a 38 percent reduction in the annualized rate of relapses requiring hospitalization and a 27 percent reduction in those requiring intravenous steroids. Treatment with laquinimod was also associated with a 36 percent reduction in the risk for three month confirmed EDSS progression (p=0.0122) and a 48 percent reduction in the risk for six month confirmed EDSS progression (p= 0.0023). Additionally, laquinimod had a positive impact on patient-reported fatigue and cognitive functioning, as assessed by the Modified Fatigue Impact Scale (MFIS) and the short-form (SF)-36 general health survey.

    "The life-long, debilitating nature of multiple sclerosis and well-recognized clinical variability, underscore the need for therapies that can slow disease progression and improve patient treatment experience," said Professor Giancarlo Comi, Director of the Department of Neurology and Institute of Experimental Neurology at the San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Italy. "Both Allegro and Bravo studies provide consistent evidence of a clear impact of Laquinimod on progression of disability and brain atrophy, measures of the neurodegenerative process of MS. These effects on disease burden together with the effects on relapse management, the convenience of oral administration and the excellent safety and tolerability profile represent a unique approach to the treatment of MS.

    "Several supportive pre-clinical studies being presented further elucidate the potential novel mechanisms of action of laquinimod, which target both neurodegeneration occurring directly in the CNS and peripheral inflammation," said Wolfgang Brück, M.D., Director of Neuropathology at Georg-August-University in Goettingen, Germany. "The cuprizone and EAE mouse model studies showed that laquinimod reduced demyelination, axonal damage and resulted in dose-dependent decreases in pro-inflammatory cytokines, further demonstrating that the compound acts directly on resident CNS cells to decrease neurodegeneration and brain tissue loss."

    "The data presented at ECTRIMS contribute to the growing body of scientific evidence supporting the novel clinical profile of laquinimod," said Jon Congleton, Senior Vice President and General Manager, Teva Neuroscience. "We are excited by the prospect of laquinimod providing a treatment option that addresses important attributes of RRMS therapy, namely reduction of disability progression and irreversible tissue loss, without compromising convenience, safety or tolerability."

    Source: Teva Pharmaceutical Industries Ltd. and Active Biotech (19/10/11)

    Laquinimod for MS misses primary endpoint in BRAVO trial

    LaquinimodTeva Pharmaceutical Industries Ltd. and Active Biotech announced today initial results from the Phase III BRAVO study, which was designed to evaluate the efficacy, safety and tolerability of oral laquinimod compared to placebo and to provide a benefit-risk assessment comparing oral laquinimod and a reference arm of injectable Interferon B-1a (Avonex(R)).

    BRAVO is the second of two pivotal Phase III studies in the clinical development program for laquinimod, an investigational, oral, once-daily therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). Results showed that the BRAVO study did not achieve its primary endpoint of reducing the annualized relapse rate (p=0.075).

    The randomization process for BRAVO was adequately performed; however, placebo and treatment study groups showed dissimilarity in two baseline magnetic resonance imaging (MRI) characteristics. According to a standard and pre-specified sensitivity analysis included within the original statistical analysis plan, when this imbalance was corrected laquinimod demonstrated a significant reduction in the annualized relapse rate (21.3%, p=0.026), in the risk of disability progression as measured by Expanded Disability Status Scale (EDSS) (33.5%, p=0.044) and in brain volume loss (27.5%, p<0.0001).

    The BRAVO findings support the direct effect of laquinimod within the central nervous system (CNS) and are in line with the results of the first laquinimod Phase III trial, ALLEGRO. Additionally, as in ALLEGRO, the BRAVO study found that laquinimod demonstrated a favorable safety and tolerability profile compared to placebo.

    Compared to placebo, treatment with Interferon B-1a reduced annualized relapse rates; however, a reduction in brain tissue loss was not demonstrated and a reduction in the progression of disability did not yield a supportive p value.

    The BRAVO study was not designed to provide direct statistical comparisons of efficacy endpoints between the two active arms.

    "We are encouraged by the overall outcomes achieved in the laquinimod Phase III clinical development program, and plan to submit applications to regulatory authorities in the U.S. and EU," said Professor Yitzhak Peterburg, Teva's Group Vice President, Global Branded Products. "Teva remains committed to the clinical development of laquinimod and is confident that the drug could provide a unique option for the treatment of multiple sclerosis."

    "Data from the ALLEGRO and BRAVO studies demonstrated that laquinimod reduced disability and brain tissue loss, two of the most important goals in the treatment of relapsing forms of multiple sclerosis," said Professor Per Soelberg Sorensen, MD, Head of MS Research Unit, Copenhagen University Hospital, Rigshospitalet, Co-principal investigator of the BRAVO study. "These effects, coupled with a favorable safety profile and a once-daily dosing regimen create a promising potential treatment for the disease."

    Additional analyses of the BRAVO study data are ongoing, and results will be submitted for presentation at a scientific congress later in the year.

    Source: Market Watch Copyright Business Wire 2011 (01/08/11)

    Top-line data for Laquinimod in MS released

    Teva-Active Biotech LogoSummary
    Top-line data from the ALLEGRO study of laquinimod for the treatment of relapsing remitting MS was released today with more details expected later this week.    The study randomized 1106 patients to either 0.6 mg laquinimod or placebo and followed them for 2 years. Compared to placebo, laquinimod reduced the annualized relapse rate by 23%,  the progression of disability by 36%, and the progression of atrophy by 33%.   Gadolinium enhancing lesions and new T2 weighted lesions were reduced.

    Analysis
    Laquinimod is an immunomodulator discovered by Active Biotech and being developed with Teva as a treatment for MS, Crohn’s disease and lupus nephritis. In February 2009, the FDA granted Fast Track designation to laquinimod in MS.  A second phase III, BRAVO, comparing laquinimod to placebo and Avonex (Biogen) will be complete later this year and submission to the FDA could occur in early 2012.
     
    Laquinimod has several proposed mechanisms of actions. Animal studies show it causes a TH1 to Th2 shift with an anti-inflammatory profile. It also down regulates MHC class II, chemokines and adhesion related molecules important to inflammation. It crosses the blood brain barrier and may also play a neuroprotective role by increasing BDNF.
     
    Though comparison of efficacy across studies is difficult, the ALLEGRO data generally shows relapse rate efficacy inferior to the injectable interferons and glatiramer but reduction in disability progression may be more similar or superior.   Other medicines, such as Tysabri (Biogen) and Gilenya (Novartis) had more effect on relapse rate.   Disability progression data for laquinimod was similar to Gilenya, but inferior to Tysabri. Tysabri and Gilenya have more potential safety concerns. We await BRAVO to better determine if laquinimod is superior or similar to one of the interferons.
     
    Laquinimod is not being developed in a vacuum and two other oral agents, BG-12 (Biogen) and teriflunimide (Sanofi) could also submit to the FDA by the end of 2012.  Top-line teriflunomide data was released in late 2010 with a 31% reduction in relapse rate and a 30% reduction in disability progression for the higher 14 mg dose. A BG-12 press release was released today stating all primary and secondary endpoints were met using either the bid or tid dose. However, values were not included in the release. Both of these agents also appear to be safe. Without further details, efficacy comparisons are difficult.
     
    The advantage of a safe pill appeals to many MS patients and neurologists, especially if they are more concerned about safety than efficacy. A paradigm shift to first line use of the safer but less effective oral agents may occur by 2015 to the detriment of the current self-injectable agents with similar efficacy.  Due to modest efficacy, these newer oral agents are less likely to be used much for breakthrough disease, very common over time in MS.

    Source: Gerson Lehrman Group © 2011 Gerson Lehrman Group. (12/04/11)

    Successful results for phase III study with oral Laquinimod for Multiple Sclerosis

    Teva & Active Biotech LogosTeva Pharmaceutical Industries Ltd. and Active Biotech announced today initial results from the two-year Phase III ALLEGRO study, which demonstrated that relapsing-remitting multiple sclerosis (MS) patients treated with 0.6 mg daily oral laquinimod experienced a statistically significant reduction in annualized relapse rate compared to placebo.

    Additional clinical endpoints, including significant reduction in disability progression, as measured by Expanded Disability Severity Scale (EDSS), were also achieved.

    Laquinimod was safe and well-tolerated. The overall frequencies of adverse events were comparable to those observed in the placebo group. No deaths were reported in laquinimod-treated patients. Overall incidence of infections was similar between the two arms of the trial.

    "This pivotal study met its primary endpoint while maintaining a very good safety profile," says Principal Investigator, Professor Giancarlo Comi, Director of the Department of Neurology and Institute of Experimental Neurology at the University Vite Salute, San Raffaele, Italy. "Laquinimod demonstrated a significant reduction in the progression of disability which may be explained by its unique mechanism of action that includes neuroprotective properties. Laquinimod may therefore be a promising therapeutic option for the MS community."

    "We are very pleased to have achieved this major milestone in the development of oral laquinimod, a novel therapy that can potentially improve the lives of many MS patients in a safe way," said Shlomo Yanai, Teva's President and Chief Executive Officer.

    Additional analyses of the ALLEGRO study data are ongoing, and detailed results will be submitted for presentation at a leading scientific conference during the first half of 2011.

    Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. The second phase III study, BRAVO is still ongoing with results anticipated in the third quarter of 2011. Regulatory submissions in the U.S. and the EU will then follow.

    In addition to the ongoing MS clinical studies, laquinimod is currently in Phase II development for Crohn’s disease and Lupus, and is being studied in other autoimmune diseases.

    Following the successful study results, Teva filed a patent application covering the use of laquinimod in slowing the progression of disability in MS patients.

    ABOUT LAQUINIMOD

    Laquinimod is a novel once-daily, oral immunomodulatory compound being developed as a disease-modifying treatment for MS. The global Phase III clinical development program evaluating oral laquinimod in MS consists of two pivotal studies, ALLEGRO and BRAVO:

    The first clinical study, ALLEGRO, was a two-year multi-national, multi-center randomized, double blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of laquinimod in MS patients. The study was conducted at 139 sites in 24 countries and enrolled 1,106 MS patients. Patients were randomized to receive a once-daily oral dose of 0.6 mg laquinimod or matching placebo. The primary outcome measure was the number of confirmed relapses; secondary measures included confirmed disability progression and changes in MRI active lesions,. Patients who completed the ALLEGRO study are offered to join an open-label extension phase, in which they will be treated with laquinimod 0.6mg daily until the drug is commercially available.

    The second clinical study, BRAVO, is a two-year, multi-national, multi-center, randomized, double-blind, parallel-group, placebo-controlled study designed to compare the safety, efficacy and tolerability of a once-daily oral dose of 0.6 mg laquinimod over placebo and to perform a comparative risk-benefit assessment between laquinimod and interferon beta-1a. Enrollment of 1,332 patients at 154 sites in the U.S, Europe, Israel and South Africa was completed in June 2009. BRAVO study results are expected in the third quarter of 2011.

    In addition to the ongoing MS clinical studies, laquinimod is currently in Phase II development for Crohn’s disease and Lupus, and is being studied in other autoimmune diseases.

    Source: Business Wire (c) 2010 Business Wire (09/12/10)

    Laquinimod data demonstrates MS treatment has neuroprotective properties

    Teva & Active BiotechTeva Pharmaceutical Industries Ltd. and Active Biotech announced that data providing further evidence of the neuroprotective properties of laquinimod in animal studies were presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Gothenburg, Sweden. Laquinimod is an investigational, once-daily oral immunomodulator for the treatment of relapsing remitting multiple sclerosis (RRMS).

    These results, generated from several pre-clinical studies evaluating the mechanism of action (MOA) of oral laquinimod, demonstrated that:

    * Laquinimod reverts the disruption of neurogenic processes that can occur with chronic inflammation in the central nervous system (CNS), and is associated with a significant reduction in the percentage of demyelination and axonal damage. 

    * Laquinimod differentially influenced the activity of select immune cells, reducing their pro-inflammatory characteristics while increasing the production of neurotrophic factors known to be involved in neuroprotection and repair mechanisms.

    * Laquinimod treatment is associated with an increase in brain-derived neurotrophic factor (BDNF), a pivotal factor in the development and maintenance of the CNS.

    "These results add to the accumulating body of data establishing the novel MOA of laquinimod. These MOA studies suggest that laquinimod has the potential to prevent demyelination, which is associated with multiple sclerosis, and therefore may provide neuroprotection in the treatment of RRMS," said Prof. Ralf Gold, Department of Neurology, St. Josef-Spital, Ruhr University Bochum, Germany. "Research is ongoing to further evaluate laquinimod, and we look forward to additional data, including the forthcoming results from the Phase III clinical development program."

    Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. Two global Phase III clinical studies, ALLEGRO and BRAVO, have completed enrollment and are currently ongoing, with results anticipated in 2011.

    ABOUT THE STUDIES

    * [P885] Laquinimod prevents the inflammation-induced derangement of neurogenic niches in experimental autoimmune encephalomyelitis mice.

    Poster Session: Neuroprotection 2, October 15, 3:30pm-5:00pm CET (F. Ruffini, A. Bergamaschi, C. Marinaro, R. De Ceglia, L. Muzio, R. Furlan, L. Hayardeny, G. Comi, G.Martino)

    * To determine if laquinimod is capable of reverting non-cell autonomous dysfunction of endogenous neural stem cells following chronic inflammation within the central nervous system (CNS), C57Bl/6 mice were immunized with myelin oligodendrocytes glycoprotein (MOG) peptide 35-55 and treated subcutaneously (s.c.) with increasing doses of laquinimod (1, 5, 10 or 25 mg/kg laquinimod). At the end of the study (day 25 p.i.), CNS of EAE mice was collected for pathological and molecular studies. Pathological and molecular study results in mice with EAE suggest that treatment with 25 mg/kg of laquinimod administered after EAE onset resulted in a significant reduction in the percentage of demyelination and axonal damage as well in the number of inflammatory responses.   An in vivo increase in cell proliferation was also observed.

    [P881] Laquinimod ameliorates experimental autoimmune encephalomyelitis via BDNF-dependent mechanisms.

    Poster Session: Neuroprotection 2, October 15, 3:30pm-5:00pm CET (J. Thöne, D. Lee, S. Seubert, L. Hayardeny, R. Linker, R. Gold)

    * To further elucidate the mechanism of action of laquinimod and to examine its potential neuroprotective capacity via modulation of BDNF secretion, laquinimod was tested in myelin oligodendrocyte glycoprotein (MOG) induced EAE experiments using mice at 6-8 weeks of age on C57Bl/6J background, and with a conditional deficiency for BDNF in T cells and monocytes (LLF mice). Histological analyses reveal that mice with BDNF deficiency, treated with laquinimod, had more severe experimental autoimmune encephalomyelitis (EAE), or animal model of MS progression, than mice not BDNF deficient, and actually experience an increase in BDNF levels. This suggests that the mechanism of action of laquinimod is BDNF dependent and may contribute to neuroprotection. [P882] Differential activity of laquinimod on production of inflammatory molecules and neurotrophic factors by human microglia and macrophages.

    Poster Session: Neuroprotection 2, October 15th, 3:30pm-5:00pm CET (C. Silva, J. Wang, M. Mishra, V.W. Yong)

    * To determine whether laquinimod modulates the production of inflammatory molecules and growth factors by microglia and macrophages, the cells were isolated from the peripheral blood of healthy adult human volunteers and cultured from the brains of human fetal samples or from adult human surgical brain resections.  Cytokines and matrix metalloproteinase-9 (MMP-9) were measured by ELISA of cell-conditioned media and growth factor transcripts were determined using PCR of cellular extracts. Treatment with laquinimod reduces the expression of inflammatory responses by autoimmune microglia and in healthy human cells and increases production of the neuroprotective BDNF by threefold.

    [P251] Laquinimod rescue therapy in mice with experimental autoimmune  encephalomyelitis.

    Poster Session: Experimental Models 1, October 14th, 2010, 3:30pm-5:00pm CET (C. Wegner, R. Pförtner, W. Brück)

    * To test whether laquinimod could improve EAE symptoms as a late-stage rescue therapy. The next goal was to assess if this late-stage treatment alters the extent of demyelination and inflammation in MOG induced EAE. Laquinimod rescue therapy given from days 30 to 60 improved clinical disease scores in the majority of animals in comparison to the control group. Findings indicate that late stage therapy with laquinimod is effective in ameliorating the disease severity. Results indicate that laquinimod may have a role in future treatment of MS.

    Source: Teva Pharmaceutical Industries Ltd. and Active Biotech (16/10/10)

    Positive benefit-risk profile for MS candidate Laquinimod

    Teva & Active BiotechTeva Pharmaceutical Industries Ltd. and Active Biotech reported Monday that a 36-week phase IIb extension study of Laquinimod in the treatment of relapsing remitting multiple sclerosis or RRMS demonstrated sustained positive benefit-risk profile.

    Laquinimod is an investigational, once-daily oral immunomodulator being developed as a disease-modifying treatment for RRMS. Laquinimod is currently in Phase II development for Crohn's disease and Lupus, and is being studied in other autoimmune diseases. The investigational Laquinimod has received Fast Track designation from the U.S. Food and Drug Administration or FDA in February 2009.

    In the extension study, patients originally randomized to placebo in the LAQ/5062 phase II study were re-randomized to either 0.3 mg or 0.6 mg, while patients originally randomized to active treatment continued with the same treatment assignment for an additional 36 weeks.

    Teva reported that the patients who switched from placebo to Laquinimod showed a 52% reduction in the mean number of gadolinium-enhancing-GdE T1 lesions, a marker of disease activity. Patients initially randomized to 0.6 mg laquinimod showed a maintenance of reduced MRI activity.

    Two hundred thirty-nine or 93% patients completed the extension phase of the multinational double-blind study and 222 or 87.1% had a final scan.

    The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase. No new adverse events emerged during the extension study. Further, incidence rate of liver enzymes elevation observed in the core study decreased in the extension phase.

    Teva said treatment with laquinimod was associated with a sustained reduction in relapse rate, no evidence of immunosuppression and good safety and tolerability profile.

    Further, the company said, it looks forward to the results of the Phase III Allegro and Bravo studies on multiple sclerosis patients in 2011.

    Active Biotech developed laquinimod and licensed it to Teva in June 2004. A Phase IIb study in 306 patients demonstrated significantly reduced MRI disease activity, by 60% versus placebo in relapsing remitting multiple sclerosis or RRMS patients.

    Source: RTT News © 2010 RTTNews (20/09/10)

    Laquinimod immunomodulatory action confers both neuroprotective and anti-inflammatory properties

    Teva, Active Biotech LogosTeva Pharmaceutical Industries Ltd. and Active Biotech presented data further illuminating the novel, dual mechanism of action (MOA) of investigational oral, once-daily, laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS), conferring neuroprotective and anti-inflammatory properties. Results from several preclinical studies suggest that laquinimod elicits a protective therapeutic effect by reducing demyelination and inducing axonal protection.

    These studies expand upon a growing body of data suggesting the mechanism of oral laquinimod in RRMS patients is targeted immunomodulation, and may help contribute to the favourable benefit-to-risk profile associated with this compound.

    “MS patients, and the physicians who treat them, await the availability of an oral agent with an efficacy and safety profile required to address the chronic, lifelong nature of the disease,” explains Prof. Wolfgang Brück, head of the Neuropathology Dept., the Georg-August-Universität, Göttingen, Germany. “The seemingly targeted immunomodulation that appears to be associated with the dual MOA of laquinimod and the favourable benefit-to-risk profile seen in patients studied for up to 3.5 years, make the drug a potential candidate to address this unmet need for an oral therapy.”

    Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. Two global Phase III clinical trials, BRAVO and ALLEGRO, have completed enrollment and are currently ongoing.

    ABOUT THE STUDIES

    The studies evaluating the properties of laquinimod presented at ECTRIMS include:

    * Laquinimod induces up-regulation of neurotrophins in serum of patients with relapsing-remitting multiple sclerosis (P 783, 15:30 – 17:00 Immunomodulation – 2, September 11, 2009)
    R. Linker, J. Thöne, G. Comi, R. Gold (Bochum, DE; Rome, IT)

    596 serum samples from RRMS patients participating in the LAQ/5062 trial were tested for the presence of neurotrophic factors, including neurotrophin (NT)-3, NT-4 and brain derived neurotrophic factor (BDNF). Data on the expression of neurotrophic factors were correlated with their functional activity in a neuronal survival assay. Treatment with 0.6 mg of laquinimod resulted in a significant and specific, up to 11-fold increase in BDNF serum levels as compared to baseline, as well as to placebo treatment after 3 months. Besides an immunomodulatory mechanism of action, laquinimod has the ability to increase levels of neurotrophic factors in vivo possibly contributing to neuroprotection in MS patients.

    * Anti-inflammatory pathways activated by laquinimod in CD4+, CD8+, CD14+, CD19+ and NK peripheral blood cells subtypes of relapsing-remitting multiple sclerosis patients (P 264, 15:30-17:00 Immunomodulation – 2, September 10, 2009)
    M. Gurevich, B. Timan, L. Hayardeny, A. Achiron (Ramat Gan, Netanya, IL)

    High throughout gene expression analysis of in-vitro incubation of peripheral blood mononuclear cells from RRMS patients with laquinimod demonstrated that laquinimod induced in-vitro immunomodulatory effects that are characterized by activation of anti-inflammatory IL-4 pathway in CD4+ cells, promotion of apoptosis in CD8+ and B cells and suppression of metabolic activity of CD14+ and NK cells.

    * Reduced inflammation, demyelination and axonal damage after therapeutic laquinimod treatment in experimental autoimmune encephalomyelitis (P 441, 15:30 – 17:30 Immunomodulation – 1, September 11, 2009)
    C. Wegner, C. Stadelmann, W. Brück (Gottingen, DE)

    In animal models of MS, laquinimod inhibits the development of acute and chronic experimental autoimmune encephalomyelitis (EAE). Laquinimod modulates the cytokine balance in favour of anti-inflammatory Th2/Th3 cytokines. Therapeutic treatment with laquinimod is effective in ameliorating the extent of macrophage and T cell infiltration, demyelination and axonal damage. Findings indicate that laquinimod might have an axon-protective effect in addition to its anti-inflammatory properties.

    * The effect of laquinimod on the distribution of monocyte subsets (P 808, 15:30 – 17:00 Immunomodulation – 2, September 11, 2009)
    T. Birnberg, S. Jung (Rehovot, IL)

    Monocytes are circulating blood leukocytes that play important roles in inflammatory responses. In mice, monocytes originate in the bone-marrow from Macrophages and Dendritic cells precursor. Murine blood monocytes encompass two main Ly6Chi and Ly6Clow subsets. Recent evidence suggests that the ratio of the two monocyte subsets can have effects on the susceptibility of the organism to various disorders, including experimental autoimmune encephalomyelitis (EAE) lesions. These cells are accumulating in the blood and CNS immediately prior to EAE clinical episodes. The results indicate that the effect by which laquinimod exerts its clinical efficacy in autoimmune diseases may be due to its impact on the myeloid precursor cells.

    Source: Zikkir © 2009 ZIKKIR WORLD (16/09/09)

    Enrollment complete in second Phase III laquinimod multiple sclerosis trial

    Teva and Active Logos

    Teva Pharmaceutical Industries and Active Biotech have completed patient enrollment for the second pivotal Phase III clinical trial, Bravo, evaluating the novel, oral once-daily immunomodulating compound, laquinimod, for the treatment of relapsing-remitting multiple sclerosis.

    Bravo is a global clinical trial designed to evaluate the efficacy, safety and tolerability of laquinimod compared to placebo, and to provide risk-benefit data for laquinimod compared to a currently available injectable treatment, Avonex.

    The Bravo study completed patient enrollment in June 2009, recruiting more than 1,200 patients at 156 sites in the US, Europe, Israel and South Africa.

    Allegro, the first global Phase III trial of laquinimod, completed enrollment in November 2008, after recruiting more than 1,000 patients at 152 sites in North America, Europe and Asia, said Teva. The trial is currently ongoing.

    Moshe Manor, Teva's group vice president of global branded products, said: "Teva and Active Biotech are encouraged by the potential of laquinimod to address patients' unmet need for an oral immunomodulating multiple sclerosis therapy that provides efficacy while maintaining safety. We look forward to continuing our clinical Phase III program of laquinimod, and hope it will offer enhanced quality of health for relapsing-remitting multiple sclerosis patients."

    Source: Teva Pharmaceutical Industries and Active Biotech (29/06/09)

    New data demonstrates immunomodulatory effects of Laquinimod on Multiple Sclerosis disease activity

    Teva and Active Biotech Logos

    Teva Pharmaceutical Industries Ltd. and Active Biotech announced results from several new clinical and preclinical studies providing further insight on the immunomodulatory mechanism of action (MOA) of laquinimod, a novel oral once-daily compound being developed for the treatment of relapsing-remitting multiple sclerosis (RRMS).

    Four sets of data being presented at the 61st Annual American Academy of Neurology Meeting (AAN) in Seattle stand to increase the understanding of how laquinimod may reduce multiple sclerosis activity and affect mechanisms related to disease pathology.

    Research looking at the mechanism by which the compound exerts its clinical effect is ongoing; Current available data indicate that laquinimod impacts RRMS by modulating key processes of the immune system, and suggest an immunomodulating effect within the central nervous system (CNS).

    “As we continue to study how laquinimod impacts multiple sclerosis, we remain encouraged by the potential of this oral candidate,” explains Scott Zamvil, M.D., Associate Professor, Department of Neurology University of California, San Francisco, “Laquinimod, with a balanced safety and efficacy profile, may address a currently unmet medical need for patients seeking effective oral therapy for multiple sclerosis that is also well tolerated and safe."

    Laquinimod recently received Fast Track designation from the US Food and Drug Administration (FDA) which may allow the drug to enter the market as soon as late 2011. Teva completed enrollment for the first of its two Phase III clinical trials for laquinimod (ALLEGRO) in November 2008, and the second global Phase III study (BRAVO) is on schedule to complete patient enrollment in the first half of 2009.

    ABOUT THE STUDIES
    The studies evaluating the MOA of laquinimod being presented at AAN include:
    • The effect of laquinimod on lymphocyte VLA-4 properties under shear flow conditions (Scientific session, April 30 from 1:30 PM – 3:30 PM, Room 605/610)
    Liat Hayardeny, Sara Feigelson, Valentin Grabovsky, Joel Kaye, Rotem Keshet, Guy Cinamon, Ronen Alon, Netanya, Israel, Rehovot, Israel
    o New data from this evaluation of a murine model suggest laquinimod selectively inhibits the chemokine-induced activation of T cell VLA-4 binding to VCAM-1, an endothelial cell adhesion molecule involved in T cell migration into the CNS. These data suggest a novel MOA of laquinimod.

    • Down regulation of antigen presentation and inflammatory pathways by laquinimod in cultured peripheral blood mononuclear cells of untreated multiple sclerosis patients and healthy subjects (Poster session I, April 28 from 7:00 AM – 10:00 AM, Room 6E)
    Rotem Or-Bach, Polina Sonis, Michael Gurevich, Anat Achiron, Ramat-Gan, Israel
    o Data demonstrate laquinimod is intricately involved in the inflammatory response. Specifically, the early molecular events induced by laquinimod in RRMS patients were shown to potentially be the down regulation of MHC-class II gene transcription factors, the suppression of pro-inflammatory and cytokine related genes and the activation of an anti-inflammatory gene.

    • Laquinimod Inhibits MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) in CD4+CD25+ Regulatory T-cell Depleted Mice (Poster session VIII, April 30 from 11:30 AM – 2:30 PM, Room 6E)
    Nora Tarcic, Emanuel Raymond, Joel Kaye, Netanya, Israel
    o Results show laquinimod is effective in inhibiting disease severity with or without the presence of CD4+CD25+ cells, indicating the compound does not require this specific regulatory pathway. These findings further define its immunomodulatory effect.

    • Effect of laquinimod on the Dendritic Cell compartment (Poster session I, April 28 from 7:00 AM – 10:00 AM, Room 6E)
    Tal Birnberg, Steffen Jung, Rehovot, Israel
    o Results from this additional murine study demonstrate that the effect of laquinimod on autoimmune deviation may also be due, in part, to its impact on the dendritic cell compartment, which is critical for the initiation and perpetuation of T cell-driven autoimmune disorders.

    Source: Teva Pharmaceutical Industries Ltd.(29/04/09)

    Oral laquinimod for multiple sclerosis granted fast track status by FDA

    Laquinomid

    Teva Pharmaceutical Industries Ltd. and Active Biotech announced that oral laquinimod, an investigational treatment for relapsing-remitting multiple sclerosis (RRMS), has received a Fast Track designation from the U.S. Food and Drug Administration (FDA). Teva completed enrollment for the first of its two Phase III clinical trials for laquinimod (ALLEGRO) in November 2008 and is currently enrolling RRMS patients globally for the second Phase III study (BRAVO).

    Drugs designated for Fast Track are intended for the treatment of a serious or life-threatening condition and have demonstrated the potential to address unmet medical needs. Fast Track designation can potentially facilitate development and expedite the review process. This may allow the drug to enter the market as soon as late 2011.

    “As global leaders in the treatment of multiple sclerosis, Teva is committed to bringing additional safe, effective and convenient therapies to MS patients,” said Moshe Manor, Vice President, Global Innovative Resources Group at Teva Pharmaceutical Industries. “We are pleased that the FDA has awarded laquinimod with a Fast Track designation, and are hopeful it will be part of our growing portfolio of innovative therapies.”

    “We're encouraged by the reports we've seen from the Phase II clinical trial of laquinimod, and if this agent continues to prove safe and effective, it would be a welcome new treatment option available to people with multiple sclerosis,” said Dr. John Richert, Executive Vice President, Research and Clinical Programs, National MS Society.

    About Laquinimod

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. Results from a Phase IIb study in 306 patients were published in June 2008 in The Lancet and reported that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent (51 percent mean reduction) versus placebo in RRMS patients. In addition, the study showed a favorable trend toward reducing annual relapse rates and in the number of relapse-free patients compared with placebo. Treatment was well tolerated, with some transient and dose-dependent increases in liver enzymes reported, without clinically-evident liver damage.

    In addition to the efficacy that laquinimod has shown in Phase II RRMS clinical trials, laquinimod has demonstrated potent therapeutic efficacy in preclinical models of other autoimmune diseases such as Crohn’s disease, rheumatoid arthritis, insulin-dependent diabetes mellitus, Guillain Barré Syndrome, and Lupus. The broad profile of efficacy in animal models of inflammatory diseases suggests that laquinimod affects a pivotal pathway of inflammation and autoimmunity. Teva has also initiated a clinical study to evaluate laquinimod for Crohn’s disease and expects to initiate the clinical development of laquinimod for Lupus Nephritis in the near future.

    About the Phase III Program

    Allegro (assessment of oral laquinimod in preventing progression of MS), a pivotal, global, 24/30-month, randomized, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of laquinimod versus placebo in the treatment of RRMS, completed recruitment of more than 1,000 patient at 152 sites throughout North America, Europe and Asia in November 2008.

    Bravo (benefit-risk assessment of Avonex® and laquinimod), a pivotal, global, 24 month, randomized, double-blind, parallel-group, placebo-controlled Phase III study designed to compare the safety and efficacy of laquinimod with placebo and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, is currently enrolling patients at centers throughout the United States, as well as Canada, Europe and Israel. The enrollment goal is approximately 1,200 patients with RRMS.

    Source: Teva Pharmaceutical Industries Ltd.and Active Biotech (13/02/09)

    Enrollment in Laquinimod phase III relapsing-remitting Multiple Sclerosis clinical trial completed

    Teva Pharmaceutical Industries Ltd. and Active Biotech  announced completion of patient enrollment for the Phase III clinical trial, Allegro, in relapsing-remitting multiple sclerosis (RRMS). The pivotal Allegro study is designed to evaluate the efficacy, safety and tolerability of the oral investigational compound, laquinimod, versus placebo in the treatment of RRMS.

    The Allegro study completed patient screening at the end of the third quarter. Recruitment of over 1,000 patients at 152 sites throughout North America, Europe and Asia was finalized in November. The completion of recruitment triggers a milestone payment of $5 million to Active Biotech from Teva Pharmaceutical Industries Ltd.

    A second pivotal Phase III clinical trial evaluating laquinimod, called Bravo, is currently enrolling patients globally. The Bravo trial aims to provide risk-benefit data for laquinimod versus Avonex®, an available injectable treatment.

    Previous data from the phase IIb core study and its 36-week extension period (presented at the World Congress on Treatment and Research in MS in September) demonstrated the rapid onset and sustained efficacy of laquinimod in reducing disease activity, as well as the favourable safety profile of the compound.

    About Laquinimod

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. Results from a Phase IIb study in 306 patients were published in June 2008 in The Lancet and reported that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent (51 percent mean reduction) versus placebo in RRMS patients. In addition, the study showed a favorable trend toward reducing annual relapse rates and in the number of relapse-free patients compared with placebo. Treatment was well tolerated, with some transient and dose-dependent increases in liver enzymes reported, without clinically-evident liver damage.

    In addition to the efficacy that laquinimod has shown in Phase II RRMS clinical trials, laquinimod has demonstrated potent therapeutic efficacy in preclinical models of other autoimmune diseases such as Crohn's disease, rheumatoid arthritis, insulin-dependent diabetes mellitus, Guillain Barré Syndrome, lupus and Inflammatory Bowel Disease. The broad profile of efficacy in animal models of inflammatory diseases suggests that laquinimod affects a pivotal pathway of inflammation and autoimmunity. Teva expects to initiate the clinical development of laquinimod for Crohn's disease and Lupus Nephritis in the near future.

    About the Phase III Program

    Allegro (assessment of oral laquinimod in preventing progression of MS) is a pivotal, global, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of laquinimod versus placebo in the treatment of RRMS.

    Bravo (benefit-risk assessment of Avonex® and laquinimod) is a pivotal, multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study designed to compare the safety and efficacy of laquinimod with placebo and to provide risk-benefit data for laquinimod versus a currently available injectable treatment. The enrollment goal is approximately 1,200 patients with RRMS.

    The global clinical program will include centers throughout the United States as well as centers in Canada, Europe, and Israel.

    Source: Teva Pharmaceutical Industries Ltd. and Active Biotech. (19/11/08)

    Laquinimod shows significant and sustained impact on Multiple Sclerosis disease activity

    Teva Logo

    Teva Pharmaceutical Industries Ltd. said new data from the extension phase of oral laquinimod in relapsing-remitting multiple sclerosis, or RRMS, demonstrated a significant reduction in the mean number of gadolinium-enhancing lesions in both patients who switched from placebo to laquinimod and patients who continued with their initial laquinimod dose.

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS by Active Biotech, Sweden. Laquinimod is licensed to Teva Pharmaceutical.

    The reduction was significant for both patients switching to high-dose and low-dose laquinimod. In addition, the proportion of patients who switched to active treatment from placebo, and remained enhancing lesion-free, increased from 31% to 47%, further reinforcing the efficacy of laquinimod on Magnetic Resonance Imaging measured disease activity.

    Giancarlo Comi, University Vita-Salute San Raffaele, Italy, principal investigator of the study said, "With increased number of patients exposed to laquinimod, we found no new risks or safety issues. This reinforces earlier results demonstrating the laquinimod safety profile. The MS community looks forward to future data as we continue enrolling patients in the laquinimod Phase III clinical program."

    Teva is currently enrolling patients for Allegro and Bravo, two pivotal Phase III clinical trials of laquinimod. The enrollment goal is approximately 1,000 patients with RRMS.

    Source: RTT News © 2008 RTTNews (19/09/08)

    Second large global phase III trial of oral laquinimod for Multiple Sclerosis starts enrollment
    Teva Pharmaceutical Industries Ltd. and Active Biotech AB announced today that patients are being enrolled for the BRAVO Phase III pivotal trial.

    BRAVO is a global, 24-month, double-blind study designed to evaluate the efficacy, safety and tolerability of the oral compound laquinimod versus placebo, and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex® .

    The BRAVO trial, which was initiated in April this year, aims to enroll approximately 1,200 patients with relapsing-remitting multiple sclerosis (RRMS). A second global Phase III trial of laquinimod including 1,000 patients, ALLEGRO, is also ongoing and recruiting patients globally. "All currently approved multiple sclerosis (MS) treatments are administered via injection or infusion. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS,” said Dr. Timothy Vollmer, Medical Director, Rocky Mountain MS Center, Denver, Colorado, and principal investigator of the BRAVO study. "Additionally, the mode of action for laquinimod is unlike any other MS compound, existing or experimental. We are hopeful that this research will expand our abilities to combat the disease through novel targeting.”

    Data recently published in The Lancet demonstrated that oral dose of laquinimod significantly reduced the median magnetic resonance imaging (MRI) disease activity by 60 percent, compared to placebo and was well tolerated in RRMS patients. The majority of patients from the study are still receiving treatment with laquinimod in an open-label extension trial.

    "The safety profiles of oral therapies are of increasing interest to the MS community; We are hopeful that laquinimod will be both efficacious and safe thus providing patients with an optimal risk-benefit profile,” said Dr. Per Soelberg Sorensen, Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, and principal investigator of the BRAVO study.

    Source: Die Welt © Die Welt (16/07/08)

    Laquinimod shows great promise in Multiple Sclerosis trial
    Laquinimod, a new type of immumodulatory agent for relapsing-remitting multiple sclerosis, led to a 40% reduction in lesions, according to results of a multicenter, placebo-controlled phase IIb trial.

    Patients treated with laquinimod at a dose of 0.6 mg a day averaged 2.6 gadolinium-enhancing lesions on MRI compared with 4.2 for the placebo group (P=0.0048) as reported by Giancarlo Comi, M.D., of the University Vita-Salute and colleagues in the June issue of The Lancet.

    The between-group difference emerged early in the trial, and follow-up beyond the primary study period demonstrated even larger reductions in MRI-detected lesions with laquinimod versus placebo.

    Additionally, the number of new lesions was reduced by 50% in the laquinimod group.

    "The decrease of MRI activity during the last part of the study was evidence for both gadolinium-enhancing and new T2 lesions, indicating that laquinimod reduces not only the extent of blood-brain barrier opening, but also the accrual of fixed lesions," the authors said.

    Available therapies for multiple sclerosis all target inflammatory aspects of the disease. In addition, all of the approved therapies require injection, creating a potential advantage for any oral agent.

    Laquinimod is structurally related to linomide, a drug that reduced disease activity in MS but had unacceptable toxicity, the authors said. Preclinical and phase I clinical studies suggested laquinimod had greater activity and a more favourable safety profile compared with linomide.

    In a previous 24-week, randomized phase II study, laquinimod 0.3 mg/d suppressed formation of new MS lesions and was well tolerated. Those results led to the current evaluation of two different doses of the drug.

    The study involved 306 patients relapsing-remitting multiple sclerosis with who had had one or more relapses in the previous year and at least one gadolinium-enhancing lesion on screening MRI. Investigators at 51 centers in nine countries randomized the patients to placebo or to laquinimod 0.3 mg/d or 0.6 mg/d.

    The trial lasted 36 weeks, and the primary outcome was the cumulative total of gadolinium-enhancing lesions from the final four MRI scans at weeks 24, 28, 32, and 36.

    Compared with placebo, laquinimod 0.6 mg reduced the average number of lesions per scan on the final four MRI scans by 40.4%.

    The 0.3 mg dose did not significantly reduce the number of lesions compared with placebo (3.9 versus 2.6).

    Comparison of the median cumulative number of lesions from the last four MRI scans resulted in a 55% reduction in the number of lesions with laquinimod 0.6 mg versus placebo (4.0 versus 9.0).

    The number of new T2 lesions on the last four scans was 44% lower with laquinimod 0.6 mg (P=0.0013), and the number of new T1-hypointense lesions was 51% lower in the laquinimod 0.6 mg group (P=0.0064).

    Examination of MRI scans from weeks 12 through 36 demonstrated a 51% reduction in the mean number of gadolinium-enhancing lesions with laquinimod 0.6 mg (2.7 versus 4.4) and a 60% decrease in the median number of lesions (6.0 versus 15.0).

    Patients in the laquinimod 0.6 mg group had an annualized relapse rate of 0.52 compared with 0.77 for those on placebo which was not statistically significant (P=0.0978). Additionally, 70.8% of laquinimod 0.6 mg patients were relapse-free compared with 62.7% of the placebo group.

    Both doses of laquinimod were well tolerated.  The primary treatment-related effect was a transient, dose-related increase in liver enzymes, the authors said.

    Source: The Lancet - Comi G, et al "Effect of laquinimod on MRI-monitored disease activity in aptients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, placebo-controlled phase IIb study" Lancet 2008; 371: 2085-2092. (20/06/08)

    Initiation of Enrollment in Pivotal Phase III Clinical Study of Oral Laquinimod for Relapsing-Remitting Multiple Sclerosis
    Teva Pharmaceutical Industries Ltd. and Active Biotech AB announced today the initiation of enrollment in the Allegro trial (assessment of oral laquinimod in preventing progression of multiple sclerosis). Allegro is a global pivotal, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of the oral investigational compound laquinimod versus placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS). The Allegro trial aims to enroll approximately 1,000 patients with RRMS.

    "Currently there are several RRMS treatments available; however, they are all administered via injection or infusion. An orally administered therapy brings us one step closer to offering patients and physicians a highly effective, new, convenient and less invasive method of drug delivery," said Doug Jeffery, M.D., Ph.D., Associate Professor, Wake Forest University Baptist Medical Center. "Previous Phase II studies have demonstrated positive results for laquinimod, and we hope that results from this pivotal Phase III trial will further reinforce these findings."

    Recently, Teva concluded a 36-week extension of the 36-week Phase IIb core trial, which demonstrated that laquinimod 0.6 mg met its primary endpoint. The data from this extension trial further confirmed and strengthened the results from the initial 36-week Phase IIb trial. The majority of the patients that have participated in the trial are now receiving treatment with laquinimod in a continued open-label extension trial.

    The initiation of Phase III clinical trial is a critical milestone for Teva in our commitment to the MS community, said Moshe Manor, Group Vice President - Global Innovative Resources, of Teva Pharmaceutical Industries Ltd. We are excited about the development of Laquinimod, which together with Copaxone, will broaden our MS platform and position Teva as a leading company in the MS field.

    Additional new data, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on October 13, 2007 in Prague, demonstrated that laquinimod reduced inflammation, demyelination and axonal damage in an animal model experimental autoimmune encephalomyelitis (EAE), indicating that the compound may have both anti-inflammatory and neuroprotective properties.

    Based on encouraging results from various animal models, laquinimod is now being investigated for other autoimmune diseases.

    We are very pleased to see how Teva has successfully advanced the laquinimod clinical trial program in order to bring a novel, first-in-class product to the market for the treatment of MS, said Sven Andréasson, President and CEO of Active Biotech AB.

    The efficacy, safety, and tolerability of laquinimod will also be studied in an additional Phase III pivotal trial in RRMS (BRAVO), which is expected to begin enrollment in the first quarter of 2008. This trial is a multinational, multi-center, randomized, parallel-group, placebo-controlled study which will compare the effects of laquinimod to those of placebo, and provide risk-benefit data comparing once-daily orally administered laquinimod to a product presently used for treatment of RRMS (an active comparator). This study plans to enroll approximately 1,200 participants who will be followed for 24 months.

    About Allegro

    Allegro is a multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study, currently enrolling approximately 1,000 patients with RRMS. The globally conducted study will include centers in the United States as well as centers throughout Canada, Europe, and Israel.

    About Laquinimod

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A recent Phase IIb study in 306 patients was presented at the 2007 Annual Meeting of the American Academy of Neurology (AAN).

    The data demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced magnetic resonance imaging (MRI) disease activity by 40 percent versus placebo (p=0.0048) in RRMS patients, and was well tolerated. Looking into the median data of the primary end point laquinimod 0.6mg reduces disease activity (MRI) by 55% compared to placebo.

    Laquinimod showed consistent and robust effect (statistical significant) on all secondary MRI end points. In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment with both 0.3 and 0.6 mg doses were well tolerated with only some transient and dose-dependent increases in liver enzymes reported. To date 460 MS patients have received laquinimod in various clinical trials.

    Source: Teva Pharmaceutical Industries Ltd.(07/11/07)

    Teva and Active Biotech to Initiate Pivotal Phase III Trial Program of Oral Laquinimod for Relapsing Multiple Sclerosis
    Teva Pharmaceutical Industries Ltd. and Active Biotech AB today announced that the companies are initiating a clinical Phase III program for laquinimod, a novel once-daily, orally administered immunomodulatory compound for the treatment of relapsing multiple sclerosis (RMS). The studies will now begin following the successful conclusion of a second phase II study and the outcome of discussions with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA).

    The companies are to commence two global Phase III trials of laquinimod during this year. The Phase III trials will take place in centers in the United States, Europe, and other locations worldwide, to further confirm the results of the Phase II trials.

    “We are extremely excited about initiating the Phase III clinical program for oral laquinimod, as we believe laquinimod is a potential new and convenient treatment option for MS patients,” said Shlomo Yanai, President and CEO of Teva Pharmaceutical Industries Ltd. “The accelerated development of oral laquinimod is part of our commitment to MS patients to develop additional improved therapies that combine superior efficacy and excellent safety.”

    “Laquinimod has the potential to be a novel, orally-administered disease modifying treatment for people suffering from multiple sclerosis,” said Sven Andréasson, President and CEO of Active Biotech. “Laquinimod would represent a milestone for patients as it would provide them with an efficacious and safe treatment, as well as a new drug delivery option that is suitable for long-term treatment.”

    About Phase II Laquinimod Trials

    Results from a 36-week, randomised, double-blind, placebo-controlled Phase IIb trial evaluating the effect of oral daily 0.3 and 0.6 mg doses of laquinimod on magnetic resonance imaging (MRI) -monitored disease activity in patients with RRMS were recently presented at the American Academy of Neurology (AAN) Annual Meeting in May, 2007. Data from the trial demonstrated that an oral 0.6 mg dose of laquinimod given daily significantly reduced MRI disease activity by 40 percent in RRMS patients and was well tolerated. In addition, there was a favorable trend towards reducing annual relapse rates, the number of relapse-free patients and time to first relapse compared with placebo. Treatment with both 0.3 and 0.6 mg doses of laquinimod were well tolerated with only some transient and dose-dependent increases in liver enzymes.

    A previous 24-week Phase IIa trial conducted by Active Biotech demonstrated that oral 0.3 mg laquinimod given daily was well tolerated and reduced the formation of active lesions in RRMS.

    About Laquinimod

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. To date, 460 MS patients have received laquinimod in various clinical trials.

    Source: Teva and Active Biotech (08/06/07)

    Laquinimod cuts multiple sclerosis relapse
    Teva Pharmaceutical Industries Ltd. and Active Biotech AB has announced that data from a 36-week, randomised, doubleblind, placebo-controlled phase IIb study demonstrated that an oral 0.6 mg dose of laquinimod given daily significantly reduced magnetic resonance imaging (MRI) disease activity by 38 per cent in RRMS patients and was well tolerated. In addition, there was a favourable trend towards reducing annual relapse rates, the number of relapse-free patients and time to first relapse compared with placebo.

    Treatment with a 0.3 mg dose showed no statistical significant difference compared with placebo. "Current RRMS options are effective for the treatment of the disease, but an oral therapy such as laquinimod would represent a milestone for patients as it would provide them with a completely unique, non-invasive method of drug delivery," said Giancarlo Comi, MD, director of department of neurology and institute of experimental neurology, Universita Vita-Salute, San Raffaele, Milan, Italy.

    "Preliminary studies have already demonstrated the positive effect of laquinimod versus placebo, but these new data confirmed that a higher dose was even more effective and remained well tolerated." The 36-week study evaluated the effect of oral daily 0.3 and 0.6 mg doses of laquinimod on MRI-monitored disease activity in patients with RRMS. The majority of the patients who participated in the study continued treatment with laquinimod in an ongoing, blinded 9 month extension study. This extension study is followed by an open label study where patients will receive 0.6 mg laquinimod for an additional 24 months.

    "The results of this study, which once again demonstrate the efficacy and tolerability of once-daily oral laquinimod, are very exciting for the MS community both patients and researchers," said Shlomo Yanai, president and CEO of Teva Pharmaceutical Industries Ltd. "Teva will soon initiate phase III studies to confirm oral laquinimod's therapeutic benefits, and we expect to begin enrolment of the trial later this year."

    Source: Pharmabiz.com Copyright © Saffron Media Pvt. Ltd.(05/05/07)

    Laquinimod Phase IIb Trial Confirms Efficacy and Favorable Safety Profile and Shows Significant Reduction in the Rate of Inflammatory Disease Activity

    Teva Pharmaceutical Industries Ltd and Active Biotech AB today announced that a Phase IIb study designed to evaluate the safety and efficacy of laquinimod, a once-daily novel oral agent, in relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.

    Laquinimod treatment significantly reduced the rate of inflammatory disease activity, as measured by the cumulative number of Gadolinium enhancing lesions on brain MRI scans after 36 weeks of treatment. Laquinimod treatment also demonstrated a considerable reduction in the number of clinical relapses compared to placebo. This Phase IIb multi-center, randomized, double-blind, placebo-controlled study enrolled approximately 300 patients in 8 European countries and in Israel.

    The evaluation of the safety and side-effect data confirmed the favourable safety profile that was seen in earlier phase II clinical trials. The majority of the patients who participated in the study are currently continuing treatment with laquinimod in an ongoing, blinded extension study.

    "The study results with once daily oral laquinimod are very encouraging and further demonstrate our ongoing commitment to developing new classes of therapies for MS, including oral therapies, to treat the disease, as well as to improve the patients' quality of life", said Israel Makov, President and CEO of Teva Pharmaceutical Industries Ltd.

    "As of today, nearly 400 patients have received laquinimod in various clinical trials over the last years. The data from the completed studies together with preclinical documentation, confirm laquinimod's efficacy and favorable safety profile in MS patients," said Sven Andreasson, President and CEO of Active Biotech AB.

    The positive result of the clinical trial triggers a milestone payment to Active Biotech.

    Further details about the study will be given at Teva's Innovative R&D Day in New York City on September 26th, 2006. A complete presentation of the Phase IIb data will be given at upcoming relevant scientific meetings.

    Teva is discussing laquinimod's development plan with regulatory authorities in order to accelerate the clinical program into Phase III.

    About Laquinimod

    Laquinimod is a novel once-daily, orally administered immunomodulatory compound developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries Ltd. in June 2004.

    Source: Teva Pharmaceutical Industries Ltd

    © Multiple Sclerosis Resource Centre

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