Friday, 18 November 2011

Research: Effects of Dacluzimab in the CNS

Bielekova et al. Intrathecal effects of daclizumab treatment of multiple sclerosis.Neurology. 2011 Nov [Epub]

OBJECTIVES
We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS), who were suboptimal responders to interferon-β and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab reduces CEL in MSers with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system (within the cerebrospinal fluid in the brain).

METHODS: Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and cerebrospinal fluid (CSF).

RESULTS: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in MS Scripps Neurologic Rating Scale, and Expanded Disability Status Scale outcomes. There was significant expansion of CD56(bright) Natural Killer cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios . Surprisingly, CD25 epitope was equally blocked on the immune cells in the CSF and in peripheral blood.

CONCLUSIONS: Daclizumab therapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment.

Daclizumab is in late stage development for MS, These studies suggest either that the antibody penetrates the brain and down regulates the immune response. Alternatively it is possible that it inhibits NK activity in the blood and these then traffic into the brain. However this study indicates that this molecule can inhibit brain immune responses.

6 comments:

  1. This looks as good if not better than alemtuzumab- am I reading this right? It's got phase 3 trials yet so I presume its still about 4 years away from the market

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  2. Re: "This looks as good if not better than alemtuzumab- am I reading this right? It's got phase 3 trials yet so I presume its still about 4 years away from the market."

    The latest Daclizumab study was a 52 week study against placebo and the Alemtuzumab trials 2 years against an active comparator. So we can't compare them. However, the Daclizumab phase 3 is against and active comparator and may yet prove to be as good as Alemtuzumab. Regarding safety it is too early to call.

    4 years; that is correct. It is a relatively long way off.

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  3. I wonder why so much attention is being paid on the percentage of reduction of CEL. Professor Kappos once said:

    "Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability"

    http://www.ncbi.nlm.nih.gov/pubmed/10459905

    Ms is all about disability, isn't it?

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  4. Contrast-enhancing lesions (CEL) are 10 times more sensitive than clinical relapses. The measurement of CEL using monthly MRI scanning allows for shorter clinical trials with as few as 10-12 patients, when a baseline vs treatment crossover trial design is used.

    Of course control of progression of disability is of central importance, but your are onto this
    relapse frequency and disability data. Well that data indicates early relapsing frequncy has importance.

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  5. Is Hodgkins lymphoma linked to daclizumab? my friend has been treated for MS with daclizumab and she has been diagnosed with the Hodgkins lymphoma.
    is this drug safe if it is causing a cancer?

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  6. Re: "Is Hodgkins lymphoma linked to daclizumab?"

    Too soon to tell; Hodgkin's lymphoma may be more commoner in MS'ers and in family members of MS'ers. So it is difficult to blame Daclizumab if there has only been one case. This is why we need more data.

    J Natl Cancer Inst. 2004 May 19;96(10):780-4.
    Familial clustering of Hodgkin lymphoma and multiple sclerosis.
    Hjalgrim H, Rasmussen S, Rostgaard K, Nielsen NM, Koch-Henriksen N, Munksgaard L, Storm HH, Melbye M.
    Source
    Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark. hhj@ssi.dk
    Abstract
    BACKGROUND:
    Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies. Previous investigations have not supported this hypothesis, but the negative results could have been caused by methodologic problems. We therefore assessed the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and for their families and the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and for their families.
    METHODS: We identified 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives in Danish population-based registers and followed them for the occurrence of Hodgkin lymphoma. Analogously, we identified 4381 patients with Hodgkin lymphoma and 7388 of their first-degree relatives and followed them for the occurrence of multiple sclerosis. The relative risks (RRs) of Hodgkin lymphoma and multiple sclerosis were expressed as standardized incidence ratios (i.e., the ratio between observed and expected numbers of outcomes based on age, sex, and period-specific incidence rates). All statistical tests were two-sided.
    RESULTS: Overall, six cases of Hodgkin lymphoma were identified in patients with multiple sclerosis (RR for Hodgkin lymphoma = 1.40, 95% confidence interval [CI] = 0.63 to 3.12), two of which occurred in young adults (RR = 1.59, 95% CI = 0.40 to 6.37). The risk of young-adult-onset Hodgkin lymphoma was statistically significantly increased in the first-degree relatives of patients with multiple sclerosis (RR = 1.93, 95% CI = 1.01 to 3.71; n = 9 such lymphomas). Two cases of multiple sclerosis were identified among young adult patients with Hodgkin lymphoma (RR for multiple sclerosis = 0.82, 95% CI = 0.20 to 3.27), and the risk for multiple sclerosis was statistically significantly increased in their first-degree relatives (RR = 2.76, 95% CI = 1.44 to 5.31; n = 9 such multiple sclerosis cases).
    CONCLUSION: The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.

    ReplyDelete

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