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Rebecca Hu

on 25 March 2015

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Transcript of Daclizumab

Humanized monoclonal antibody
Targets å subunit (CD25) of interleukin-2
Interleukin-2 signaling plays major role in initiating T cell activation -> autoimmunity
CD25 antagonism selectively inhibits activated T cells through CD56 natural killer cell-mediated lysis of autologous activated T cells
What is Dacluzimab?
Daclizumab: The Next Avonex?
Dacluzimab subcutaneous add-on to patients currently taking Avonex (CHOICE)
Dacluzimab high-yield process as monotherapy for 1 year (SELECT)
Dacluzimab high-yield process as extension monotherapy to second year (SELECTION)
Past studies
EDSS (scale of 1 - 10)
Annualized relapse rate
MRI measures (Gd+ contrast-enhancing T1-weighted & T2-weighted lesions)
Development of CIS & CDMS
Major Outcome Measures
First-line of treatment for > 15 years
Most common adverse reaction are flu-like symptoms
Intramuscular administration (subcutaneous not yet approved)
What about Avonex?
Test whether add-on Daclizumab decreases disease activity despite treatment with Avonex
Phase II: randomized, double-blind, placebo-controlled, add-on trial
CHOICE (2010):
n = 230 patients in 51 centers (214 completed)
Eligible patients = active relapsing MS who were on Avonex treatment
Randomly assigned 1:1:1 for 24 wks:
High-dose SC D 2mg/kg @ 2wk intervals for 11 doses
Low-dose SC D 1mg/kg @ 4 wk intervals for 6 doses alternating with placebo
Primary endpoint = total # of new or enlarged Gd+ lesions in MRI scans (every 4 wks for wks 8-24)
Secondary endpoints (wk 24):
Changes in # & volume of T1- and T2-weighted lesions on MRI scans
Annualized relapse rate
Changes in EDSS & MSFC-3 scores
Pharmacokinetic/pharmacodynamic assessments
Adverse events
Test the effect of Daclizumab as monotherapy
Used for patients with relapsing-remitting MS
Randomized, double-blind, placebo-controlled
Use of Daclizumab high-yield process versus standard Daclizumab treatment
SELECT (2013):
Primary endpoint = annualized relapse rate @ week 52
Secondary endpoints
Cumulative # of new Gd+ enhancing lesions on MRI scans
Proportion of relapsing patients
# of new or enlarging T2 lesions
Tertiary endpoint = EDSS score difference
Sample size n = 621
Eligible patients had at least one confirmed MS relapse in last 12 mo
Excluded patients with other MS types
Random assignment 1:1:1 (52 weeks):
Placebo (every 4 wks)
SC D HYP 150 mg (every 4 wks)
SC D HYP 300 mg (every 4 wks)
All personnel + patients masked to treatment
Efficacy results similar for both Daclizumab groups (150mg slightly more favored)
Showed importance of interleukin-2 in mediating effector + regulatory T cells
Adverse events seen in Daclizumab groups
Safety data show increase in risk of infection and of cutaneous & hepatic events
Extension of 2013 SELECT study
Multicenter, randomized, double-blind, 52-week extension trial (74 centers total)
Aim to assess the safety and immunogenicity of extended treatment with Daclizumab (2 year treatment period in total)
517 of 567 patients who completed SELECT
SELECT placebo patients randomly assigned 1:1
150mg SC D HYP every 4 wks
300mg SC D HYP every 4 wks
SELECT D HYP patients randomly assigned 1:1
Continue present dose
Continue present dose after 20-wk "washout period"
Primary endpoint = assess safety + immunogenicity of D HYP
Secondary endpoint = durability of D HYP on disease activity
Annualized relapse rate
MRI endpoints
Total volume of T2 hyperintense lesions/T1 hypointense lesions
CD56 = pharmacodynamic endpoint to assess effect of treatment washout
Whole brain volume decreased yr 2 (but could be associated with inflammation effects)
Reversal of CD56 increase began ~12 wks after last dose of D HYP in SELECT
Began before desaturation of CD25 on peripheral blood mononuclear cells -> site of action could be external to cells?
Effects of D HYP reversible in timeframe consistent with half-life of the antibody (24 wks)
More studies testing safety (both over longer course of time as well as with more patients)
Better characterize Daclizumab-induced AEs in various organs and their relationship to CD67 NK-cell mechanism of action
Yet to be fully established as a viable form of monotherapy
More effective than Avonex but need to be tested for hepatotoxicity
What's next?
Wynn D et al. "Dacluzimab in active relapsing MS CHOICE study." Lancet Neurol 2010.
Gold et al. "Dacluzimab high-yield process in relapsing-remitting MS SELECT study." Lancet 2013.
Giovannoni G et al. "Dacluzimab high-yield process in relapsing-remitting MS SELECTION study." Lancet Neurol 2014.
Foley et al. "Evidence for LT use of intramuscular interferon beta-1a." J Manag Care Pharm 2013.
Oh et al. "Dacluzimab-induced adverse events in multiple organ systems in MS." American Academy of Neurology 2014.
Primary endpoints showed efficacy of Daclizumab in ameliorating inflammation (higher dose --> higher efficacy)
Adverse events: slightly higher in Daclizumab groups (but only grade 3 events)
Treatment didn't affect T or B cell count, but apparent correlation between increase in CD56 and decrease in new Gd+ lesions
Clinical + pharmacodynamic effects reversible within 2-3 months of termination
Limitation of study: short treatment period
Full transcript