Multiple Sclerosis Resource Centre
  • Home
  • About MS
  • MSRC Services
  • Get Involved
  • MS Research News
  • MSRC Groups
  • Useful Resources
  • Welcome To Josephs Court, MS Centre Of Excellence
  • Advertising
  • E-Newsletter
  • Contact Us
  • Cookie Policy
  • Investor in People
    You are here : Home » MS Research News » Drugs » Zenapax (daclizumab)

    Zenapax (daclizumab)

    A A A
    [Print this page]

    Share |


    Daclizumab is a humanized monoclonal antibody that binds to the CD25 alpha subunit of the high affinity IL-2 receptor. CD25 is expressed at low levels on resting T-cells (immune cells) and at high levels on T-cells that can become activated in response to autoimmune conditions such as MS.

    Daclizumab is believed to work by selectively binding to and inhibiting this receptor on activated T-cells without causing T-cell depletion.

    Daclizumab is an investigational agent in clinical development for the treatment of MS under a collaboration between Facet Biotech, acquired by Abbott in April 2010, and Biogen Idec.

    Safety issue puts daclizumab in doubt for MS

    ZenapaxDaclizumab, a biologic drug targeting the interleukin-2 pathway, showed sustained efficacy in the second year of a phase II trial in multiple sclerosis, but serious autoimmune issues also emerged, researchers said here.

    In a randomized extension study of high-yield process daclizumab called SELECTION, efficacy according to most measures was maintained or even increased in relapsing-remitting MS patients who had participated in the one-year SELECT trial, according to Gavin Giovannoni, MD, of Queen Mary University in London.

    But one patient died from autoimmune hepatitis and two others developed autoimmune conditions affecting vital organs, he reported at a late-breaking abstract session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.

    Hepatic monitoring in the daclizumab clinical program was stepped up after the potential for such effects was recognized, Giovannoni said. Nevertheless, other researchers suggested that the problem was serious enough to jeopardize the drug's future in MS.

    Daclizumab binds to the CD25 receptor protein, thereby preventing T cells from taking in IL-2. The resulting change in immune system activity is believed to decrease the autoimmune attack on nerve tissues that characterises MS.

    In the original randomized SELECT trial, annualized relapse rates after one year of treatment were cut by 50% with either of two doses of daclizumab versus placebo, and other outcome measures such as MRI lesion burden and disability progression were also significantly better with the drug.

    At the end of SELECT, patients were offered participation in the one-year extension study, in which those originally taking placebo were re-randomized to the same two doses used in the original trial (150 or 300 mg, by subcutaneous injection every 4 weeks).

    Patients in the SELECT active drug arms were also re-randomized to receive either continuous treatment with the same dose as in the original trial, or to a 24-week washout period followed by resumption of the original dose for 24 weeks.

    The purpose, Giovannoni explained, was threefold: to confirm the drug's efficacy in the original placebo group, to examine the durability of its effects with continuous treatment, and to see whether it would retain its efficacy when restarted after treatment interruption.

    Of 621 patients completing SELECT, 517 chose to participate in SELECTION, with 92% remaining through the full year.

    Patients in the initial placebo group had shown a mean annualized relapse rate of 0.434 in SELECT. When they switched to daclizumab, relapse rates fell to 0.179 (95% CI 1.23 to 0.261) in pooled data on both dosages, a decline of 59%.

    Disability progression in those patients was also reduced. A total of 17 patients in the placebo group during SELECT developed 3-month progression; in the extension phase, only seven of the former placebo patients showed such progression (P=0.033).

    New or enlarging T2 MRI lesions declined by 74% after switching to active treatment, and new gadolinium-enhancing T1 lesions decreased 86%, Giovannoni said (P not reported).

    In patients continuously treated with daclizumab, annualised relapse rates and the slowing of disability progression seen in SELECT was maintained in SELECTION, on the basis of pooled data in both dosage groups.

    Rates of new/enlarging T2 lesions in these study arms declined modestly but significantly (P=0.032) during SELECTION, Giovannoni reported.

    In the patients randomized to the 24-week daclizumab washout, gadolinium-enhancing lesion numbers rebounded to about triple the level seen at the end of SELECT, although they remained lower than at baseline.

    But at the end of SELECTION, when these patients had resumed daclizumab treatment for 6 months, mean lesion counts fell back to levels similar to those at the end of SELECT.

    Giovannoni also reported that CD56bright natural killer cell counts, a laboratory measure of daclizumab treatment, had risen roughly 10-fold from baseline during SELECT but leveled off in continuously treated patients in the extension.

    He said that was an indication that maximal drug effect may not be achieved until the second year of treatment.

    As in most MS drug trials, adverse events were common. But serious adverse events excluding relapses were not, with rates ranging from 5% to 8% in each treatment arm.

    Among the 517 patients treated in SELECTION, these included 13 serious infections, six skin events, eight cases of liver enzyme elevations beyond five times the upper limit of normal, one cancer, and the three cases of autoimmune attacks.

    Mark Freedman, MD, of the University of Ottawa, who was not involved in SELECT or SELECTION, told MedPage Today that the autoimmune issue could make the drug unapprovable, despite what he said was "a very potent [efficacy] signal without too much worrisome problems" in the initial phase.

    He noted that the SELECT-SELECTION program had alleviated one safety concern for the drug, arising from its mechanism of action.

    Because the drug targets the IL-2 pathway, he explained, some researchers worried that it might actually exacerbate rather than relieve MS. "A lot of cells use IL-2 to move, including regulatory T cells," Freedman said. The strong efficacy benefit clearly indicates that those concerns were groundless.

    But, he added, "I'm a little discouraged by the emerging autoimmune abnormalities -- and they're not single organ."

    He acknowledged that the developers of another investigational MS drug, alemtuzumab (Lemtrada), have not been discouraged by its propensity to induce autoimmune thyroid disease.

    But that's a less serious condition than the hepatic and renal autoimmune conditions seen in the daclizumab study, said Freedman, who is an investigator in an ongoing phase III trial of the drug.

    "This might not be a sustainable therapy," he said.

    The trial was funded by Abbott and Biogen Idec.

    Giovannoni reported research grant support from Bayer Schering Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and sanofi-aventis and personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer Schering Healthcare, Biogen Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. Other co-authors also reported extensive relationships with industry. Several co-authors were Biogen Idec employees.

    Freedman reported consultancy fees from Bayer, Biogen Idec, Teva, Merck Serono, Novartis, sanofi-aventis, and Celgene; payment for lectures from Bayer, Merck Serono, Novartis, and sanofi-aventis; and payment for development of educational presentations from Novartis, Lansdowne DIME, and Medscape. Freedman's institution received grants from Bayer and Genzyme.

    Primary source: European Committee for Treatment and Research in Multiple Sclerosis
    Source reference:
    Giovannoni G, et al "Primary results of the SELECTION trial of daclizumab HYP in relapsing multiple sclerosis" ECTRIMS 2012; Abstract 169.

    Source: Medpage Today © 2012 MedPage Today, LLC (15/10/12)

    Unique cell type found in Multiple Sclerosis

    Lymphoid Tissue Inducer CellsResearchers at NIH found evidence that a unique type of immune cell, lymphoid tissue inducer (LTi) cells, contributes to multiple sclerosis (MS). Their discovery helps define the effects of one of the newest drugs under investigation for treating MS, daclizumab. The scientists believe that their work could lead to a new class of drugs for treating this and other autoimmune disorders.

    Ongoing clinical trials have shown that daclizumab appears to help quiet the autoimmune response in MS patients, but its precise effects on the legions of cells that make up the immune system are not fully understood. The new study, published in Science Translational Medicine, shows that one effect of daclizumab is to thin the ranks of LTi cells. These cells are known to promote the development of lymph nodes and related tissues during fetal life, but their role during adulthood has been unclear. The new study marks the first time that LTi cells have been implicated in any human autoimmune disorder.

    Bibiana Bielekova, M.D., an investigator at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), and her team found that among MS patients participating in clinical trials of daclizumab, the number of LTi cells was elevated in patients not receiving daclizumab compared to those on the drug. Patients receiving daclizumab also had reduced signs of inflammation in the cerebrospinal fluid (CSF) that surrounds the brain. The researchers also found that daclizumab appears to steer the body away from producing LTi cells, in favour of another cell type that counteracts autoimmunity.

    Daclizumab is a mAb that alters signaling by interleukin-2 (IL-2), a key factor that mobilizes T cells. The drug was designed to suppress T-cell responses to IL-2, and it does so—but Dr. Bielekova had found previously that this suppression is indirect and depends on other immune cells. In their new study, Dr. Bielekova and her team discovered that daclizumab’s stimulatory effect on natural killer cells is paired with an inhibitory effect on LTi cells. They found evidence that the drug, via its effects on IL-2 signaling, acts on a type of stem cell. The drug appears to decrease the likelihood that this stem cell will develop into LTi cells, and sway it toward becoming natural killer cells.

    “This helps explain why natural killer cells are activated and their numbers are expanded by daclizumab therapy,” Dr. Bielekova said. Meanwhile, she notes, the drop in LTi cells was “intriguing” in itself, given the cells’ role in lymph node development.

    Inside lymph nodes, T cells and B cells are found in clusters called lymphoid follicles, where they wait for a signal that the body is under siege from infection. In autoimmune disorders, abnormal lymphoid follicles can develop and contribute to the autoimmune response. Secondary progressive MS, in particular, is associated with abnormal lymphoid follicles in the connective tissues (or meninges) surrounding the brain. These are believed to contribute to chronic brain inflammation in MS, eventually leading to shrinkage of the brain.

    Dr. Bielekova and her team reasoned that daclizumab, by suppressing LTi cells, should reduce the growth of lymphoid follicles. Since it is not possible to visualize these follicles in the live brain, the researchers measured the effects of daclizumab on markers of inflammation in the CSF. They found that CXCL13, a protein linked to lymphoid growth, and the IgG index, a measure of antibody production, decreased by an average of 50.4% and 13.5%, respectively, in trial participants who took the drug for 6.5 months.

    “To our knowledge, no other MS therapy reduces IgG index,” Dr. Bielekova said.

    She cautioned that this data provides only an indirect link between LTi cells and brain inflammation in MS. If further research confirms that the cells play an important role in MS or other autoimmune disorders, “pursuing the development of new drugs to selectively inhibit LTi cells could be a useful therapeutic strategy,” she remarks.

    Source: GEN © 2012 Genetic Engineering & Biotechnology News (06/08/12)

    Monoclonal antibody daclizumab (Zenapax) cuts MRI lesions in MS

    ZenapaxTreatment with the monoclonal antibody daclizumab (Zenapax) resulted in significant decreases in contrast-enhancing lesions on MRI in patients with multiple sclerosis (MS), a small, open-label study found.

    After 54 weeks of treatment, the number of new contrast-enhancing lesions decreased from a pretreatment median of 2.042 to 0.250, which represented an 87.6% reduction (P<0.001), according to Bibiana Bielekova, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., and colleagues.

    The total volume of these lesions also fell, from 0.328 mm2 to 0.034 mm2, which was an inhibition of 89.7% (P<0.001), the researchers reported in the November 22 issue of Neurology.

    These decreases persisted throughout therapy, they noted.
    Bielekova and colleagues previously demonstrated that MS patients who continued to have disease activity despite treatment with interferon-β showed improvements when daclizumab, which targets the α-chain of the interleukin-2 receptor CD25, was added to the regimen.

    They also found that patient response was accompanied by an increase in the number of CD56bright natural killer (NK) cells, which are immunoregulatory cells that can eliminate pathogenic activated T-cells.

    The potential benefits of daclizumab as add-on therapy with interferon-β in multiple sclerosis also were demonstrated in a phase II multicenter clinical trial known as CHOICE.

    To see if daclizumab could be used as monotherapy in multiple sclerosis and to explore the effects of the treatment on CD56bright NK cells and other inflammatory and immune markers, Bielekova's group enrolled 16 patients with relapsing-remitting multiple sclerosis.

    Participants received intravenous daclizumab in doses of 1 mg/kg at baseline and two weeks later, and then every month for one year.

    Two patients withdrew, one for lack of response and the other because of the development of palindromic rheumatism.

    Along with inhibition of contrast-enhancing lesions, the treatment also showed improvements on these secondary outcomes:

    Multiple Sclerosis Functional Composite, −0.165 to 0.175 (P=0.015)
    Scripps Neurologic Rating Scale, 93.5 to 97.5 (P=0.001)
    Expanded Disability Status Scale, 1.688 to 1.125 (P=0.001)
    The rate of relapses fell to 0.12 per patient-year from a baseline rate of 0.54 per patient-year for a 77.8% inhibition that was not deemed nonsignificant, according to the researchers.

    The improvements seen on MRI and clinical measures "suggest that the suppression of brain inflammation may allow endogenous repair mechanisms to partially restore function in early-stage [multiple sclerosis]," they explained.

    In general, the treatment was well tolerated, with a nonsignificant increase in the rate of infections and only temporary changes in laboratory values.

    Immunologic findings included increased proportions of NK cells in cerebrospinal fluid and blood, accompanied by decreases in the ratios of CD4/NK and CD8/NK cells.

    However, a decrease in the B cell/NK cell ratio was seen only in cerebrospinal fluid.

    An additional observation was that daclizumab bound T-cells and NK cells, which led to full blockade of the CD25-Tac epitope needed for binding of interleukin-2.

    However, there were no changes in the expression of CD122 on T-cells, or of the chemokine receptors CXCR3 or CCR5 in cerebrospinal fluid.

    Changes in immune cells in cerebrospinal fluid suggested that daclizumab works through different mechanisms than other monoclonal antibodies currently used for MS, such as rituximab (Rituxan) and natalizumab (Tysabri).

    "While other [monoclonal antibodies] decrease immune cells in the intrathecal compartment by decreasing migration or by depletion, daclizumab exerts true immunomodulatory effects," the researchers observed.

    These immunologic findings supported the researchers' conclusion that daclizumab treatment does not interfere with the migration of immune cells to the intrathecal compartment of the central nervous system. This is important because immune cells perform vital surveillance and repair functions in the central nervous system, they noted.

    Their findings, which they termed "reassuring," also demonstrated that CD56bright NK cells are able to destroy pathogenic T-cells directly in affected tissue.

    "The ability of daclizumab to induce effective immunoregulation without limiting access of the immune cells to the intrathecal compartment may have long-term advantage over therapies that cause indiscriminate depletion of the immune cells from the CNS," they wrote.

    They concluded that large studies will be needed to evaluate the long-term efficacy and safety of this treatment and to compare the effects of different disease-modifying drugs in MS.

    Several of the authors are coinventors holding NIH patents relating to daclizumab and receive royalty payments.

    In addition, some authors reported serving as consultants to companies such as Biogen Idec, Merck Serono, Teva, and sanofi-aventis, as well as to organizations such as the Weatherall Institute for Molecular Studies and the Myelin Repair Foundation.

    Primary source: Neurology
    Source reference: Bielekova B, et al "Intrathecal effects of daclizumab treatment of multiple sclerosis" Neurology 2011: 77: 1877-1886.

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

    Daclizumab (Zenapax) shows promise in MS

    ZenapaxTreatment with daclizumab (Zenapax), an investigational monoclonal antibody drug, cut annualized relapse rates in half among patients with early relapsing-remitting multiple sclerosis (MS) in a placebo-controlled trial, a researcher said here.

    Annualized relapse rates averaged 0.21 and 0.23 with two different dosage levels of daclizumab, compared with 0.46 for patients put on placebo in the one-year, 600-patient trial known as SELECT (both P<0.001), reported Gavin Giovannoni, MD, of Queen Mary University in London.

    The drug also showed significant efficacy in a host of secondary outcomes, including physical function, disability progression, and MRI lesion burden, he said at the joint meeting of the European and American Committees for Treatment and Research in Multiple Sclerosis.

    But there was one worrisome note in the trial: A patient's death from a psoas abscess that developed following a skin wound. "We think daclizumab may be related to this complication," Giovannoni said at a late-breaking abstract session where he presented the findings.

    Daclizumab targets the CD25 molecule on CD4-positive T cells, which prevents them from interacting with interleukin-2. The result is a reduction in activated T cells and an increase in CD56-rich natural killer cell proliferation, Giovannoni explained.

    That, in turn, is believed to alter the balance of immune activity in patients with MS to reduce disease activity.

    The SELECT trial, conducted in Europe and India, randomized the 600 participants in roughly equal numbers to subcutaneous injections of placebo or daclizumab, at 150 or 300 mg, given every four weeks for one year. Annualized relapse rate was the primary outcome measure.

    Patients had the relapsing-remitting form of MS with Expanded Disability Status Scale (EDSS) scores of no more than 5. To confirm active disease, they also had to have had an MRI-confirmed relapse within the previous year.

    Median time since diagnosis was two years in the placebo group and three years in the two active-drug groups.

    One impressive finding was that fewer than 10% of patients dropped out of the study prematurely, and only 1% to 2% quit because of adverse events.

    Key findings on secondary outcomes were as follows:

    Proportion of patients relapse-free at one year: About 63% of the placebo group versus 80% for both daclizumab dosage groups (P<0.001)
    Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical score: +3.0 points for placebo, -1.1 points for 150 mg daclizumab (P=0.0001), +1.4 points for 300 mg daclizumab (P=0.12)

    Confirmed three-month disability progression: 14% of the placebo group, 6% of the 150 mg daclizumab group (P=0.02), 8% of the 300 mg daclizumab group (P=0.09)

    Adjusted mean new or enlarged gadolinium-enhancing lesion counts from weeks eight to 24: 4.8 for placebo, 1.5 for 150 mg daclizumab, 1.0 for 300 mg daclizumab (both P<0.0001 versus placebo)

    Adjusted mean new or enlarging T2 lesions at week 52: 8.1 for placebo, 2.4 for 150 mg daclizumab, 1.7 for 300 mg daclizumab (both P<0.0001)
    Except for the death from abscess, serious adverse events were more common in the placebo group than either of the daclizumab groups, the difference being in relapses.

    Most other adverse events showed no signs of increase in the study's daclizumab arms. Even injection-site reactions were equally common in the placebo group as with the active drug.

    One exception was elevation in alanine or aspartate aminotransferase enzymes, which was above five times the upper limit of normal. These were seen in 4% of both daclizumab dosage groups (eight patients each) versus just one patient in the placebo group.

    However, the liver enzyme levels returned to normal in 15 of these daclizumab patients, with seven staying on the drug without interruption.

    Other trials are still ongoing with daclizumab, including a phase III study called DECIDE. These trials have instituted monitoring and treatment algorithms to minimize the safety risks, Giovannoni said.

    Session co-moderator Reinhard Hohlfeld, MD, of Ludwig-Maximillian University in Munich, said the SELECT results were surprisingly good given the drug's apparent mechanism of action.

    The "very complex tinkering with the immune system" that daclizumab treatment represents would not necessarily be expected to be beneficial, he said.

    Giovannoni said that the drug's stimulation of CD56-rich natural killer cells also appears in response to other disease-modifying therapies in MS. But he also noted that it still hasn't been confirmed that this action is responsible for its clinical efficacy, as opposed to serving merely as a biomarker of reduced autoimmune activity.

    He said a study of CD56-rich natural killer cells in relation to MS and daclizumab treatment was currently in the works.

    The study was funded by Biogen Idec and Abbott Therapeutics.

    Giovannoni reported research grant support from Bayer Schering Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and sanofi-aventis, and personal payments for advisory board service from Bayer Schering Healthcare, Biogen Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals.

    Hohlfeld reported past compensation from Bayer Schering, Teva, Merck Serono, Biogen Idec, and Novartis.

    Primary source: ECTRIMS/ACTRIMS Triennial Meeting
    Source reference:
    Giovannoni G, et al. "A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis: primary results of the SELECT trial," ECTRIMS/ACTRIMS 2011; abstract 149.

    Source: Med Page Today © 2011 Everyday Health, Inc (24/10/11)

    Positive results from first registrational trial for Daclizumab HYP in RRMS

    DaclizumabBiogen Idec and Abbott today announced positive top-line results from SELECT, a global, registrational Phase 2b clinical trial designed to evaluate the investigational compound daclizumab high-yield process (DAC HYP) in people with relapsing-remitting multiple sclerosis (RRMS) over one year.

    Results showed that DAC HYP, administered subcutaneously once every four weeks, significantly reduced annualized relapse rate by 54 percent in the 150 mg dose arm (p< 0.0001) and 50 percent in the 300 mg dose arm (p=0.0002) compared to the placebo arm at one year. DAC HYP met key secondary endpoints for the 150 mg and 300 mg arms, respectively, providing a highly statistically significant reduction in the cumulative number of new gadolinium-enhancing (Gd+) lesions between weeks eight and 24 (69%; 78%); in the number of new or newly enlarging T2 hyperintense lesions at one year (70%; 79%); and in the reduction in the proportion of patients who relapsed (55%; 51%). DAC HYP also showed a trend toward improvement in quality of life measures at one year.

    The SELECT trial also investigated DAC HYP’s effect on disability progression as measured by the expanded disability status scale (EDSS) as a tertiary endpoint. Findings showed that DAC HYP reduced the risk of sustained disability progression at one year by 57 percent in the 150 mg dose arm and by 43 percent in the 300 mg dose arm compared to placebo. Additional analyses are ongoing and the companies anticipate presenting detailed data at an upcoming medical meeting.

    “The exciting results for DAC HYP, along with previous clinical data, support our continued investigation of this candidate as a promising new approach to treating multiple sclerosis,” said Doug Williams, Ph.D., Biogen Idec’s Executive Vice President of Research and Development. “DAC HYP’s convenient once-monthly, subcutaneous administration, combined with a strong efficacy profile, suggest that it may provide an attractive option for MS patients. We hope to confirm the results of SELECT in our second registrational trial, DECIDE.”

    “These results bring us one step closer in the development of a potential new treatment option for multiple sclerosis, an area of medicine where there continues to be a significant need for novel approaches for patients," said Eugene Sun, M.D., Vice President, Global Pharmaceutical Clinical Development, Abbott. "We look forward to continued analysis of the SELECT data and the opportunity to present these results in full context at an upcoming scientific forum."

    In the SELECT trial, the overall incidence of adverse events and treatment discontinuations were similar in all study arms. Serious infections (2% versus 0%), serious cutaneous events (1% versus 0%) and liver function test abnormalities greater than five times the upper limit of normal (4% versus <1%) occurred more frequently in DAC HYP-treated patients than in the placebo group. There was one death in SELECT due to a complication of a psoas muscle abscess in a patient recovering from a serious skin adverse event and one in the ongoing dose blinded extension study (SELECTION) due to possible autoimmune hepatitis; a contributory role for DAC HYP in these events could not be excluded.

    In addition to SELECT, DAC HYP is being studied in a Phase 3 registrational clinical trial called DECIDE, which is currently enrolling patients. DECIDE is evaluating the efficacy and safety of once-monthly subcutaneous DAC HYP as a monotherapy compared to interferon beta 1-a therapy over two to three years of treatment.

    About SELECT

    SELECT was a global, randomized, double-blind, placebo-controlled, one-year, dose-ranging study to determine the safety and efficacy of DAC HYP in 600 patients with RRMS. The study evaluated two doses of DAC HYP (150 mg or 300 mg every four weeks) and had a greater than 90 percent study completion rate in all treatment groups. The primary endpoint was the reduction in annualized relapse rate in patients with RRMS at one year. Secondary endpoints included the reduction in the cumulative number of new gadolinium-enhancing (Gd+) lesions between weeks eight and 24, in the number of new or newly enlarging T2 hyperintense lesions at one year, and in the proportion of patients with RRMS who relapsed, as well as improvement in quality of life measures in patients with RRMS at one year. Additional endpoints assessed the safety and tolerability of DAC HYP.

    About DAC HYP

    Daclizumab high-yield process (DAC HYP) is a subcutaneous formulation of daclizumab and an investigational therapy for the treatment of RRMS, the most common form of MS. DAC HYP is a humanized monoclonal antibody that binds to CD25, a receptor subunit that is expressed at high levels on T cells that are thought to become abnormally activated in autoimmune conditions, such as MS. Data from previous clinical trials showed that DAC HYP increases CD56bright NK cells, which target the activated immune cells that can play a key role in MS without causing general immune cell depletion.

    Sources: National Post © 2011 National Post (09/08/11)

    Daclizumab trial for relapsing-remitting MS begins

    ZenapaxActive Comparator Study Designed to Examine the Safety and Efficacy of Daclizumab Formulated for Monthly Subcutaneous Dosing.

    Biogen Idec and Abbott  today announced enrollment of the first patient in a global Phase III study evaluating the efficacy and safety of daclizumab compared to interferon beta-1a (Avonex(R)) in patients with relapsing-remitting multiple sclerosis (RRMS), the most common form of multiple sclerosis (MS).

    The trial, called DECIDE, will investigate a subcutaneous formulation of daclizumab intended for monthly administration, which has the potential to provide a new immunomodulatory approach for treating MS. Under the terms of the collaboration agreement, Biogen Idec will make a $30 million milestone payment to Abbott. This payment is due upon enrollment of the first patient in the DECIDE trial.

    "Despite significant advances in MS therapy, many patients continue to experience disease activity. The MS community is eager for new treatment approaches," said Ludwig Kappos, M.D., Head, MS-Research Group, University Hospital, Basel, Switzerland, and lead investigator for the study. "As shown in previous studies, daclizumab appears to selectively target immune cells that are thought to become activated in MS and cause damage to the central nervous system."

    DECIDE is a global Phase III, randomized, double-blind, active-comparator study expected to enroll approximately 1,500 RRMS patients in 28 countries. The trial will investigate a subcutaneous formulation of daclizumab intended for once-monthly administration as a monotherapy compared to treatment with interferon beta 1-a, one of the most common treatments for MS. Daclizumab is also being investigated in the ongoing Phase IIb registration-enabling SELECT trial, which is evaluating the efficacy and safety of monthly subcutaneous doses of either 150 mg or 300 mg of daclizumab monotherapy.

    "The DECIDE study builds on the positive results we saw in the CHOICE trial, which showed that daclizumab, when added to interferon beta, significantly reduced MS lesions compared to interferon beta therapy alone," said Alfred Sandrock, M.D., Ph.D., Senior Vice President of Neurology Research and Development at Biogen Idec. "Initiating this trial demonstrates our commitment to developing new treatment options for patients who suffer from this terrible disease."

    "Initiating the Phase III DECIDE trial is a tremendous milestone for the collaboration as it brings daclizumab one step closer to becoming a potential new treatment option for patients with MS," said Eugene Sun, M.D., Vice President, Global Pharmaceutical Clinical Development, Abbott. "Extensive preclinical and clinical experience with daclizumab suggest this drug holds promise as a new approach for the treatment of MS, and we look forward to expanding our knowledge further with the DECIDE trial."

    Multiple sclerosis, one of the most common neurological disorders, affects more than 2.5 million people worldwide. In MS, certain immune cells, called T-cells, become activated and are believed to migrate to the central nervous system (CNS), releasing cytokines that injure nerve fibers in the CNS and cause the symptoms of MS.

    Daclizumab is a humanized monoclonal antibody that binds to CD25, a receptor subunit that is expressed at low levels on resting T-cells and at high levels on T-cells that are thought to become activated in response to MS. Daclizumab is believed to work by selectively targeting these activated T-cells without causing general T-cell depletion.

    Data from the Phase II CHOICE trial demonstrated that daclizumab 2mg/kg administered subcutaneously every two weeks in combination with interferon beta (IFNB) therapy led to a 72 percent reduction in the number of new or enlarged MS lesions when compared to IFNB therapy alone in patients with active, relapsing forms of MS. Additional analysis from the study revealed that daclizumab led to an increase of a subset of natural killer cells (CD56bright NK cells) that help regulate the immune system. This increase was associated with a significant reduction in MS lesion formation. The incidence of common adverse events was similar in all treatment groups. Some serious adverse events occurred in daclizumab treated patients, which were most commonly infections that resolved with standard interventions.

    About DECIDE

    DECIDE (Daclizumab HYP Efficacy Compared to Interferon Beta 1-a Study for Multiple Sclerosis) is a two- to three-year, Phase III, muliticenter, double-blind, randomized, parallel-group, monotherapy, active-control study designed to determine the efficacy and safety of daclizumab versus interferon beta 1-a, one of the most common MS treatments, in patients with RRMS. The trial is expected to enroll approximately 1,500 RRMS patients in 28 countries. The study will include patients between the ages of 18 to 55 years with an Expanded Disability Status Scale (EDSS) score ranging from 0.0 to 5.0.

    The primary objective of the study is to determine the efficacy of daclizumab compared to interferon beta 1-a in preventing MS relapse, with annualized relapse rate as the primary endpoint. The study will also examine the efficacy of daclizumab compared to interferon beta 1-a in slowing functional decline and disability progression and in maintaining quality of life.

    During the 96- to 144-week treatment period, all study participants will receive either a subcutaneous injection of daclizumab 150 mg once every four weeks or weekly injections of interferon beta 1-a.

    About Daclizumab

    Daclizumab is a humanized monoclonal antibody that binds to the CD25 alpha subunit of the high affinity IL-2 receptor. CD25 is expressed at low levels on resting T-cells (immune cells) and at high levels on T-cells that can become activated in response to autoimmune conditions such as MS. Daclizumab is believed to work by selectively binding to and inhibiting this receptor on activated T-cells without causing T-cell depletion. Daclizumab is an investigational agent in clinical development for the treatment of MS under a collaboration between Facet Biotech, acquired by Abbott in April 2010, and Biogen Idec. Daclizumab is currently being studied in two registrational clinical trials in patients with MS.

    Source: Biogen Idec (24/05/10)

    Add-On Daclizumab (Zenapax) may reduce MS disease activity more than Interferon Beta alone

    ZenapaxAdd-on daclizumab treatment might reduce multiple sclerosis disease activity more than standard interferon beta treatment alone, according to a study published online first and appearing in the April edition of The Lancet Neurology.

    Daclizumab has reduced multiple sclerosis disease activity in previous non-randomised studies. In the current study, John W. Rose, MD, Neurovirology Research Laboratory, VA Medical Center, Salt Lake City, Utah and colleagues aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving standard interferon beta treatment.

    The international, multicentre, phase 2 study randomised 230 patients with active relapsing multiple sclerosis who were taking interferon beta to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group; n = 75), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group; n = 78), or interferon beta and placebo for 24 weeks (n = 77).

    The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain magnetic resonance imaging (MRI) scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of immune system cells and immune system response were assessed in an exploratory substudy.

    The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta/placebo group compared with 1.32 in the interferon beta plus high-dose daclizumab group and 3.58 in the interferon beta plus low-dose daclizumab group.

    In the substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells or T-cell proliferative response compared with interferon beta alone. The number of CD56bright natural killer cells was 7 to 8 times higher in both daclizumab groups than in the interferon beta/placebo group. Common adverse events were equally distributed across groups.

    "This study provides confirmatory data that daclizumab treatment causes an expansion of CD56bright natural killer cells and adds support to the theory that expansion of CD56bright natural killer cells might mediate some of the effects of daclizumab on reducing multiple sclerosis lesion activity," the authors wrote. "In addition to the results of previous trials of daclizumab in multiple sclerosis, several lines of evidence have suggested a potential immunoregulatory function for CD56bright natural killer cells: they are expanded during conditions of natural immune tolerance -- for example, pregnancy."

    "This randomised controlled trial indicates that daclizumab can reduce new lesion formation in relapsing multiple sclerosis compared with interferon beta alone...Multiple sclerosis treatments that have the potential to improve in risk-benefit ratios when compared with available treatments are needed; thus, additional studies to define the long-term clinical risks and benefits of daclizumab are warranted."

    In an accompanying comment, Olaf Stüve, MD, and Benjamin M. Greenberg, MD, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, said: "All clinical and paraclinical evidence suggests that daclizumab mediates its beneficial effects at least partly through expanding regulatory CD56bright natural killer cells. It might now be time to explore further how these cells can be expanded in patients by other means... Identifying the physiological mechanism or mechanisms that lead to the expansion of these cells during disease remission might prove crucial in further understanding disease mechanisms and in developing novel therapeutics."

    Source: Doctors Guide Channels (c) 1995-2010 Doctor's Guide Publishing Limited. (16/02/10)

    Facet Biotech announces Daclizumab program in Multiple Sclerosis to advance

    Daclizumab (Zenapax)

    Facet Biotech Corporation announced its decision, along with its partner Biogen Idec, to continue planning for the phase 3 trial of daclizumab high-yield process (DAC HYP) in multiple sclerosis (MS). The company plans to request a Special Protocol Assessment from the U.S. Food and Drug Administration (FDA) prior to the initiation of this study. The companies expect to start the phase 3 trial during the first half of 2010.

    "We look forward to working with Biogen Idec to advance the DAC HYP program," said Faheem Hasnain, president and CEO of Facet Biotech. "We believe that DAC HYP could be an important treatment option for MS. Despite advances in MS treatment, there remains a significant need for additional therapies in this patient population."

    The companies continue to enroll patients in the SELECT phase 2b monotherapy study of DAC HYP in MS as they plan for the phase 3 study. The independent Safety Monitoring Committee (SMC) for the SELECT study conducted a planned interim futility analysis of a subset of the data and, based on that analysis, the SMC recommended the continuation of the SELECT trial. SELECT remains a blinded study.

    Additional details about the phase 3 study will be available prior to the start of the trial. Upon enrollment of the first patient into the phase 3 study, Facet would receive a $30 million milestone payment from Biogen Idec.

    SELECT is a phase 2b, randomized, placebo-controlled, dose-ranging study of DAC HYP as a monotherapy treatment in patients with relapsing-remitting MS. Approximately 600 patients will be randomized to receive 150 mg DAC HYP, 300 mg DAC HYP or placebo every four weeks as a subcutaneous injection. The primary endpoint is reduction in the annualized relapse rate. Secondary endpoints include reductions of new or enlarged gadolinium-enhanced magnetic resonance imaging lesions. SELECT is considered to be the first of two registration-enabling trials required by regulatory authorities.

    Under the terms of the collaboration agreement between Facet and Biogen Idec, in the U.S. and Europe, the two companies equally share the costs of all development activities and, if any of the products are commercialized, all operating profits. Each party will have co-promotion rights in the U.S. and Europe, based upon sales capabilities of each party at the time. Outside the U.S. and Europe, Biogen Idec will fund all incremental development and commercialization costs and pay a royalty to Facet. Facet also is eligible for future development and regulatory milestones based on the further successful development of daclizumab.

    About Daclizumab

    Daclizumab is a humanized monoclonal antibody that binds to the high affinity IL-2 receptor and selectively inhibits this receptor on activated T cells. Hoffmann-La Roche, Inc. currently markets daclizumab under the name Zenapax® under a license from Facet Biotech. Zenapax is indicated for intravenous use for the prophylaxis of acute organ rejection in patients receiving renal transplants. For clinical development in chronic diseases, Facet has developed a high-yield manufacturing process for daclizumab (DAC HYP), which includes a high concentration, liquid formulation for subcutaneous delivery. DAC HYP is an investigational agent in clinical development for the treatment of MS under a collaboration between Facet and Biogen Idec. Daclizumab is not approved for the treatment of MS.

    Source: Facet Biotech (04/08/09)

    Phase 2 Data Show Daclizumab Significantly Reduced Multiple Sclerosis Lesions in Patients Receiving Interferon Beta Therapy
    Biogen Idec Inc. and PDL BioPharma, Inc. (PDL) announced today that Phase 2 data demonstrated a significant reduction in new or enlarged gadolinium-enhancing lesions when daclizumab is added to interferon beta therapy in patients with active relapsing multiple sclerosis (MS). These data will be presented tomorrow at the 23rd Congress of the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS) in Prague, Czech Republic.

    The ongoing Phase 2, randomized, double blind, placebo-controlled clinical study, known as the CHOICE trial, studies MS patients who continue to have active MS disease while receiving interferon beta therapy. The study patients who received daclizumab 2 mg/kg subcutaneously every two weeks showed a statistically significant 72% reduction in the number of new or enlarged gadolinium-enhancing lesions (Gd+) at week 24, compared to patients on interferon beta therapy alone. Patients from the CHOICE study were followed for an additional 48 weeks after the daclizumab treatment period to further assess safety and efficacy.

    "Patients who received daclizumab every two weeks experienced far fewer new or enlarged gadolinium-enhancing lesions than the control group, which indicates that the antibody may be a promising option for patients with MS," said Dr. Xavier Montalban, Director of the Unit of Clinical Neuroimmunology at the Hospital Val D'Hebron in Barcelona, Spain. "In addition, we were encouraged to see a trend in the reduction of the number of relapses, or exacerbations, that these MS patients experienced. Further study is warranted."

    Daclizumab is a humanized monoclonal antibody that targets the IL-2 receptor on activated T cells. Biogen Idec and PDL plan to initiate the SELECT study, a Phase 2 trial of daclizumab alone in the same relapsing patient population, by the end of 2007.

    "We are very pleased to see positive results from the CHOICE study, the first randomized trial of daclizumab in patients with relapsing MS," said Mark A. McCamish, M.D., Ph.D., chief medical officer, PDL BioPharma. "We recognize how monoclonal antibodies have changed modern medicine and see great potential in their ability to treat serious diseases, including cancer and select immunological diseases such as MS. We're very excited to move development of daclizumab forward with our partner Biogen Idec, the acknowledged leader in the MS field."

    "Daclizumab represents an exciting opportunity within our growing MS portfolio," said Alfred Sandrock, M.D., Ph.D., senior vice president, neurology research and development, Biogen Idec. "MS is a complex disease that requires an arsenal of treatment options for patients. We look forward to advancing the daclizumab development program and initiating the SELECT trial by the end of the year."

    Study Results

    The CHOICE trial is evaluating the efficacy and safety of daclizumab or placebo added to interferon beta therapy in 230 patients with active MS who were enrolled at study centers in the U.S. and Europe. Patients were randomized to receive daclizumab 2 mg/kg every two weeks, daclizumab 1 mg/kg every four weeks, or placebo added to ongoing interferon beta treatment.

    The primary efficacy analysis showed that at 24 weeks, the 75 patients in the 2 mg/kg group experienced 72% fewer new or enlarged Gd+ on average compared to the 77 patients who received a placebo (p=0.004). The 78 patients in the 1 mg/kg group experienced a 25% reduction in new or enlarged lesions compared with placebo but that measurement did not achieve statistical significance.

    Based on data up to week 24, analysis of the relapse rate, which was a secondary endpoint, indicates that both daclizumab regimens revealed a trend in reducing the annualized relapse rate compared to placebo (an approximately 35% reduction), but these observations did not reach statistical significance.

    Preliminary safety data showed similar rates of infection across all treatment groups with an overall greater incidence of serious infections in the daclizumab treated groups. (4.6% versus 1.3% placebo). Urinary tract infections were slightly higher with the 2 mg/kg dose (17% vs 13% placebo). The incidence of cutaneous events was higher in the combined daclizumab groups (34% daclizumab vs. 27% placebo) but was mild to moderate and most resolved with little or no treatment.

    PDL and Biogen Idec entered into a collaboration agreement in 2005 to co- develop and commercialize daclizumab in MS and indications other than transplant and respiratory diseases. Under the collaboration, the companies are also co-developing volociximab (also known as M200), an antibody in Phase 2 development for the treatment of various solid tumors. PDL and Biogen Idec share equally the costs of all development activities and all operating profits for both products within the U.S. and Europe. The companies jointly oversee development, manufacturing and commercialization plans for collaboration products and divide implementation responsibilities to leverage each company's capabilities and expertise. Each party will have co-promotion rights in the U.S. and Europe. Outside the U.S. and Europe, Biogen Idec will fund all incremental development and commercialization costs and pay a royalty to PDL on sales of collaboration products.

    Source: Biogen Idec Inc. and PDL BioPharma, Inc. (12/10/07)

    Daclizumab phase II trial in relapsing and remitting multiple sclerosis
    MRI and clinical results

    Objective: Daclizumab is an interleukin 2 receptor chain specific humanised monoclonal antibody that has shown promising therapeutic effects in multiple sclerosis (MS). Daclizumab treatment in patients with relapsing and remitting MS was administered to determine effects on MRI and clinical outcomes.

    Methods: Patients with MS on interferon (IFN) therapy but with continuing relapses and contrast enhancing lesions (CEL) were selected. Patients were evaluated with monthly MRI scans and clinical rating scales starting 3 months prior to treatment and then at 0.5 to 27.5 months during treatment. Daclizumab (1 mg/kg IV) was administered twice in the first month (initiated and administered again in 2 weeks), followed by treatments every 4 weeks. IFN was continued until 5.5 months after daclizumab was initiated. Patients were then placed on daclizumab monotherapy. Patients with recurrent CEL were restarted on IFN with daclizumab therapy at (1.5 mg/kg IV) every 28 days.

    Results: Nine patients qualified for inclusion and completed the trial. Efficacy measured by both total CEL and new CEL (p < 0.001), relapses, timed ambulation, Expanded Disability Status Scale, and Neurologic Rating Scale (p < 0.05 to p < 0.01) was observed.

    Conclusion: Daclizumab was effective in reducing contrast enhancing lesions and improving clinical scores in patients with relapsing and remitting multiple sclerosis with active disease not controlled by interferon therapy. These results provide evidence for long-term efficacy and support further clinical development of daclizumab.

    • J. W. Rose, MD, J. B. Burns, MD, J. Bjorklund, CCRC, J. Klein, APRN, H. E. Watt, BS and N. G. Carlson, PhD From the Neurovirology Research Laboratory (J.W.R., J.B.B., J.B., J.K., H.E.W., N.G.C.) and Geriatric Research Education Clinical Center (N.G.C.), Veterans Affairs Salt Lake City Health Care System, and Departments of Neurology (J.W.R, J.B.B., J.K., N.G.C.) and Neurobiology and Anatomy (N.G.C.) and Brain Institute (J.W.R., N.G.C.), University of Utah, Salt Lake City.

    Source: NEUROLOGY © 2007 American Academy of Neurology (21/08/07)

    PDL Biopharma Patent Claims Upheld
    PDL Biopharma Says European Patent Office Upheld Company's Patent Claim.

    Biotechnology company PDL Biopharma Inc. said Tuesday (24/04/07) the European Patent Office upheld the company's claims to a patent used in its antibody technology.

    The patent covers several of the company's products, including daclizumab which is currently in mid-stage studies as a multiple sclerosis treatment. The patent had been disputed by up to 18 other parties at one point, including Genentech Inc.

    Genentech and four others had already withdrawn their opposition by the time of the decision.

    Source: Yahoo! Finance Copyright © 2007 Yahoo! Inc. All rights reserved (25/04/07)

    Primary Endpoint Met in Phase 2 Trial of Daclizumab in Patients With Relapsing Multiple Sclerosis
    - Anti-IL-2 receptor antibody significantly reduced the number of new or enlarged lesions compared to placebo; data to be submitted for presentation at upcoming medical meeting.

    - Phase 2 monotherapy trial to be initiated.

    Biogen Idec, Inc. and PDL BioPharma, Inc. announced today that the ongoing CHOICE trial, a Phase 2, randomised, double-blind, placebo-controlled trial of daclizumab, met its primary endpoint in relapsing multiple sclerosis (MS) patients being treated with interferon beta. Patients receiving daclizumab 2 mg/kg subcutaneously every 2 weeks showed a significant reduction in the number of new or enlarged gadolinium-contrast-enhancing lesions (Gd-CELs) at week 24.

    Daclizumab is a humanised monoclonal antibody that targets the IL-2 receptor on activated T cells. Study results will be submitted for presentation at an upcoming medical meeting later this year. Based on a joint review of the 24-week data, the companies plan to initiate a Phase 2 monotherapy trial of daclizumab, and to advance the overall clinical development program in relapsing MS.

    "We are very pleased to see positive results from the first randomised trial of daclizumab in patients with relapsing MS, and we look forward to advancing the clinical development program with our partner and acknowledged leader in the MS field, Biogen Idec," said Mark A. McCamish, M.D., Ph.D., chief medical officer, PDL BioPharma. "While the week 24 data set will be presented later this year, we are planning to move forward with additional development activities, most notably the initiation of the SELECT trial, which will study daclizumab as a single agent in patients with relapsing MS."

    "We congratulate PDL on conducting a successful trial of daclizumab in MS," said Al Sandrock, M.D., Ph.D., senior vice president, neurology research and development, Biogen Idec. "Daclizumab represents an exciting opportunity within our growing MS portfolio. We look forward to initiating the SELECT trial and continuing to work closely with our partner, PDL, in advancing this important clinical program."

    The adverse event profile observed to date in this study is generally consistent with the safety profile described in the United States (U.S.) prescribing information for daclizumab. Patients are being followed for an additional 48 weeks after the daclizumab treatment period to further assess safety and efficacy.

    The CHOICE trial is evaluating the efficacy and safety of daclizumab or placebo added to interferon beta therapy in 230 patients with active MS who were enrolled at study centers in the U.S. and Europe. Patients were randomised to receive daclizumab 2 mg/kg every two weeks, daclizumab 1 mg/kg every four weeks or placebo added to ongoing interferon beta treatment.

    PDL and Biogen Idec entered into a collaboration agreement in 2005 to co-develop and commercialise daclizumab in MS and indications other than transplant and respiratory diseases. Under the collaboration, the companies are also co-developing volociximab (also known as M200), an antibody in Phase 2 development for the treatment of various solid tumors. PDL and Biogen Idec share equally the costs of all development activities and all operating profits for both products within the U.S. and Europe. The companies jointly oversee development, manufacturing and commercialisation plans for collaboration products and divide implementation responsibilities to leverage each company's capabilities and expertise. Each party will have co-promotion rights in the U.S. and Europe. Outside the U.S. and Europe, Biogen Idec will fund all incremental development and commercialisation costs and pay a royalty to PDL on sales of collaboration products.

    About Daclizumab

    Daclizumab is a humanised monoclonal antibody that binds to the IL-2 receptor on activated T cells, inhibiting the binding of IL-2 and the cascade of pro-inflammatory events contributing to organ transplant rejection and autoimmune and related diseases. Daclizumab is in development for MS by PDL and Biogen Idec, and separately by PDL in asthma and transplant maintenance. Hoffman-La Roche, Inc. currently markets daclizumab under the name Zenapax® under a license from PDL. Zenapax antibody is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplants.

    Source: PDL BioPharma, Inc.(12/03/07)

    Hopes raised for effectiveness of multiple sclerosis drug
    A national research team led by the University of Cincinnati's Bibiana Bielekova, MD, report new insights into how anti-rejection drug helps MS patients.

    Discovery of the mechanism of a drug being tested for the treatment of multiple sclerosis (MS) has revealed that it's not only more effective than first thought, but might also help in the management of other autoimmune diseases, organ transplant rejection and even cancer.

    A research team led by the University of Cincinnati's Bibiana Bielekova, MD, report new insights into the role of the MS drug daclizumab (Zenapax) in the March 27 online version of the Proceedings of the National Academy of Sciences. The article will appear in print April 11.

    The exact cause of MS is unknown, but one theory is that it may it be triggered by exposure to a viral infection or environmental influences. The disease takes different courses in different people and can go into remission for many years, recurring occasionally or progressing quickly into degeneration of all motor functions that control muscles, strength, vision and balance. The very progressive form of the disease can end in death.

    Scientists have long thought that in MS the specific white cells (T-cells) that fight off infection actually turn on the body they are supposed to protect, attacking the myelin sheath that protects the nerves.

    "Without the insulating cover, the nerve axons short-circuit, much like a damaged electric cord might," says Dr. Bielekova, director of UC's Waddell Center for Multiple Sclerosis. "Also, many nerve cells (neurons) do not survive without myelin sheath."

    It was also believed that since activated T-cells need a growth factor called interleukin 2 for their function, drugs that can block the interaction of interleukin-2 and T-cells could be used to control MS.

    Daclizumab is being tested against MS because it has already proved useful in preventing rejection of transplanted organs, "and we thought it works by inhibiting T-cell activation," Bielekova says.

    Earlier research by Dr. Bielekova and her group showed that daclizumab benefits MS patients, especially those who have highly inflammatory MS. This latest study, sponsored by the National Institutes of Health (NIH), involved 22 MS patients.

    "We monitored T-cell function in patients who were injected with the drug, expecting to see that the drug inhibited T-cell function," says Dr. Bielekova.

    "We didn't see that at all. To our surprise the T-cells were functioning normally."

    But something unexpected was happening–the numbers of T-cells circulating in the blood of patients taking daclizumab were declining by about 10 percent. Simultaneously, the number of immune cells known as "regulatory natural killer cells," which are very rare in normal human blood, increased.

    Regulatory natural killer cells are known to proliferate in special conditions, such as pregnancy or bone marrow transplantation.

    "Not only did the number of regulatory natural killer cells increase in patients treated with daclizumab," says Dr. Bielekova, "but that expansion correlated with the treatment outcome--the more these cells expanded, the better the MS patients did during the trial. And the longer the patients were on the therapy, the more regulatory natural killer cells they had and the better they responded to treatment."

    "The best news is that natural killer cells are actually very efficient immune cells that fight viruses or cancers," says Dr. Bielekova, "so it appears that daclizumab doesn't damage the immune system. It only shifts the emphasis of the immune reaction from T-cells to natural killer cells. However, larger studies need to be performed to evaluate the safety of long-term daclizumab therapy."

    The current results, however, suggest that daclizumab might also help in the management of autoimmune diseases, organ transplant rejection and perhaps even cancer, she says.

    Having found one drug pathway that appears to be important for the treatment of MS, Dr. Bielekova says, "The hope is that we can learn how to enhance this pathway by drugs that can be taken orally, rather than injected." As a result of these findings by Dr. Bielekova's research team, daclizumab is now being tested as a possible MS treatment in a phase-2 trial across the United States, including UC, and Europe.

    Dr. Bielekova is a member of the Neuroscience Institute, a collaborative of nine academic departments at UC College of Medicine, University Hospital and independent physician practice groups. The institute is dedicated to patient care, research, education and the development of new medical technologies.

    The study was conducted at the Neuroimmunology Branch (NIB) of the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). Coauthors include Marta Catalfamo, PhD, of the National Cancer Institute (NCI); Susan Reichert-Scrivner, MS, Amy Packer and Magdalena Cerna, NINDS; Thomas Waldmann, MD, NCI; Henry McFarland, MD, NINDS, Pierre Henkart, PhD, NCI; and Roland Martin, MD, NINDS.

    The NIH applied for two patents related to this discovery that have been bought by drug companies. Dr. Bielekova and three coauthors. Dr. Waldmann, Dr. McFarland and Dr. Martin, are each receiving patent royalty payments from the NIH.

    Source: University of Cinncinati (29/03/06)

    © Multiple Sclerosis Resource Centre

    Related Items
    Ampyra (Fampyra)
    ATX-MS-1467
    Aubagio® (Teriflunomide)
    Avonex®
    AZ01
    Betaseron® (Betaferon®)
    BG-12
    Cannabis And Cannabinoid Research
    Copaxone®
    Cyclophosphamide
    Cyrevia
    Dextromethorphan
    Gilenya® (fingolimod)
    Laquinimod
    Lemtrada (alemtuzumab)
    Lisinopril
    Low Dose Naltrexone - Latest News
    Masitinib
    MIS416
    MN-166 (Ibudilast)
    NeuroVax
    Novantrone (Mitoxantrone)
    NT-KO-003
    Ocrelizumab
    ONO-4641
    PEGylated interferon beta
    PI-2301
    Rebif®
    RPC1063
    RPI-78M
    RTL-1000
    Sativex®
    SHK
    Statins
    Tcelna(TM)
    Trimesta (Oral Estriol)
    Tysabri®


    Did you find this information useful? Would you like to comment on this page? Let us know what you think! We welcome all comments and feedback on any aspect of our website - please click here to contact us.