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Daclizumab

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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:
Placebo
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
Methods:
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
Endpoints:
Results:
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
QoL
Tertiary endpoint = EDSS score difference
Endpoints:
Significance:
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
Methods:
Results:
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
Significance:
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)
SELECTION (2014):
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"
Methods:
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
Endpoints:
Results:
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)
Significance:
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.
References:
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
Results:
Results:
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