, , - , 23 2015
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F . , - Krieckaert L, et al. Curr Opin Rheumatol 2012,
24:306311
-ximab-zumab-umab-cept-cept-umab-ximab-zumab
Fabs
- , *Maneiro JR, et al. JAMA Intern. Med. 2013; 1-13* - ** - , ,
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NB: , eMC website: www.medicines.org.uk/emc/ Accessed
02/11/11Remicade SPCEnbrel SPCHumira SPC Cimzia SPCSimponi SPC7ABTA
2015 | Company Confidential 2015
?
?Hetland ML et al. Direct comparison of treatment responses,
remission rates, and drug adherence in patients with rheumatoid
arthritis treated with adalimumab, etanercept, or infliximab:
results from eight years of surveillance of clinical practice in
the nationwide Danish DANBIO registry. Arthritis & Rheumatism
2010;62(1):2232 ABTA 2015 | Company Confidential 2015 2326 8 , -
EULAR 6 12 29 21% , , 15 12%, .
1814 , (63%) (37%). EULAR 6 12 29 21% , , 15 12%, . , , .
9
? 10
Kreickart et al. A&R , v64, No. 12, Dec 2012, pp 38503855 ,
(P=0.42).
ABTA 2015 | Company Confidential 2015
Guidelines on the Clinical Investigations of the
Pharmacokinetics of the Therapeutic Proteins of 31 July 2007
12 ?
JAMA.2011 Apr 13;305(14):1460-8
, . .12
(AAA) : 272 , ; 3
28% AAA. 18% 28 . AAA- (AAA+) , AAA- (AAA-) . AAA+ (DAS28100
AU/ml0
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AU/mLWithout AAAAAA titre >100 AU/mL
Bartelds GM, et al. JAMA. 2011;305:14601468. 14
14
:
, 3- , .
: 196 AAA- (72% )76 AAA+ (28% )28 (14% AAA-)29 - (38% AAA+)
3 Bartelds et al., JAMA, 2011; 305(14): 1460-146816ABTA 2015 |
Company Confidential 2015272
This one is not to be shown but here for information.
28 - AAA-29 - AAA+57
3 21% 10.3% -49% , ADA 10.7% -51% , ADA
17Bartelds et al., JAMA, 2011; 305(14): 1460-1468 : 272
This is another way to look at their data which I think is more
useful from a HCP perspective.
In the article they are saying (you can find the data on pages
1462-64 and also summed up on slide 20):
272 total patients in studyBy end of study (3 years later):76
pts are AAA+ (i.e. 28% of total)196 pts are AAA- (72% of total)Then
instead of looking at the number of people who discontinued
treatment because of Loss of Efficacy in relation to the overall
number of pts who started therapy, they carry out a sub-analysis on
AAA+ and AAA- subsets. So their message is: 29 pts discontinued
treatment because of LOE i.e. 38% (29/76) of the AAA+
sub-population28 pts discontinued treatment because of LOE i.e. 14%
(28/196) of the AAA- sub-population
I think that by presenting the data the way they do, they
emphasise data which are not relevant to the HCPs (unless the HCPs
are going to do regular blood tests to assess AAAs and try to use
these results as a (poor) indicator of potential outcomes - which
we know they won't).
I would argue that the way to look at the pts who dropped out
because of treatment failures is in relation to the total patient
population (which is ultimately the only thing that would matter to
the HCPs i.e. 'if I put 272 patients on ADA, how many of those will
discontinue because of treatment failure?) In that case the data
would look like (as presented on slide 19):
272 patients in studywithin 3 years:57 discontinued treatment
because of LOE (21% of total pts)of those:29 were AAA+ (10.7% of
total patients and 51% of pts who discontinued for LOE)28 were AAA-
(10.3% of total patients and 49% of pts who discontinued for
LOE)
The message becomes clearer:- only a small proportion of pts
will stop treatment because of treatment failure (21% - this is
probably in line with clinical trials and registries)- of those
roughly half are AAA+ and half are AAA- (so doesn't seem to be a
differentiator)- of the total pts population observed, only 10.7%
discontinued treatment for treatment failure and were AAA+
- () ? , ( ) .
After 28 weeks of treatment, response to etanercept did not
differ between patients who were anti-TNF naive and switchers with
anti-drug antibodies (DAS28=2.11.3 vs DAS28=2.01.3; p=0.743). In
contrast, switchers without anti-drug antibodies had a diminished
response to etanercept treatment compared to patients who were TNF
naive (DAS28=1.21.3 vs DAS28=2.11.3; p=0.001) and switchers with
antibodies (DAS28=1.21.3 vs DAS28=2.01.3; p=0.017).
Patients with RA with an immunogenic response against a first
TNF-blocking agent had a better clinical response to a subsequent
TNF blocker compared to patients with RA without anti-drug
antibodies. Hence, determining immunogenicity can be helpful in
deciding in which patient switching could be beneficial and can be
part of a personalised treatment regimen.19
Jamnitski A, Bartelds GM, Nurmohamed MT, et al. The presence or
absence of antibodies to infliximab or adalimumab determines the
outcome of switching to etanercept. Ann Rheum Dis2011;70:284-288 -
() ?P=0.743P=0.001P=0.017
After 28 weeks of treatment, response to etanercept did not
differ between patients who were anti-TNF naive and switchers with
anti-drug antibodies (DAS28=2.11.3 vs DAS28=2.01.3; p=0.743). In
contrast, switchers without anti-drug antibodies had a diminished
response to etanercept treatment compared to patients who were TNF
naive (DAS28=1.21.3 vs DAS28=2.11.3; p=0.001) and switchers with
antibodies (DAS28=1.21.3 vs DAS28=2.01.3; p=0.017).20
21
ABTA 2015 | Company Confidential 2015 - () ?Jamnitski A,
Bartelds GM, Nurmohamed MT, et al. The presence or absence of
antibodies to infliximab or adalimumab determines the outcome of
switching to etanercept. Ann Rheum Dis2011;70:284-288: (anti-drug
antibodies ADA). , , .
Patients with RA with an immunogenic response against a first
TNF-blocking agent had a better clinical response to a subsequent
TNF blocker compared to patients with RA without anti-drug
antibodies. Hence, determining immunogenicity can be helpful in
deciding in which patient switching could be beneficial and can be
part of a personalised treatment regimen.21
3 65
3 , , ( EULAR 6 ) 3.1 / 3 ( DAS28 6 )Daien CI, et al. J
Rheumatol. 2012;39:15331538.
p=0.0202ETN 3.146ETN < 3.1DAS28 at 6 months
p=0.0302NR at 6 months486R at 6 monthsETN at 3 months (g/ml)
NR = Non Responder R= Responder22 . .
22Between 2009 and 2010, we included 19 women with active RA who
were candidates for ETN therapy. Response criteria were evaluated
at 3 and 6 months. Serum concentrations of ETN and anti-ETN
antibodies were measured by ELISA at baseline and at 3 and 6
months.Results. Eighteen patients completed followup. Three-month
ETN concentrations were lower for 6-month nonresponders than
responders (p = 0.03). Three-month ETN levels correlated
significantly with change in DAS28 between baseline and 6 months (r
= 0.62, p = 0.006). The best predictor of response at 6 months was
observed with an ETN threshold of 3.1 g/ml at 3 months. No anti-ETN
antibodies were found.
, : ? , - (-) , , . - . . .
: . , . , .2. , . . . 1.3. , . , () , , . , () , , .
4. , . - . (, ).
23
B . . - . , . , . , , , .
, , , , , , , Krieckaert CL, et al. Ann Rheum Dis.
2012;71:19141915. Van Schouwenburg, et al. ARD. 2013;72:104109;
ARD. 2013;72:16801686.% () (12.520
mg/week)04010560208414014281128470431541263060 50
(510 mg/week) (22.5 mg/week)
26
No MTX (0 mg/week, n=70), low dose MTX (510 mg/week, n=40),
intermediate dose MTX (12.520 mg/week, n=54), or high dose MTX
(22.5 mg/week, n=108)
26
CONCERTO: 26 40 mg ADA + 2.5 mg MTX40 mg ADA + 5 mg MTX40 mg ADA
+ 10 mg MTX40 mg ADA + 20 mg MTXITT-NRIITT, intent to treat; NRI,
non-responder imputation Burmester G, et al. Ann Rheum Dis 2014;18
Feb [Epub ahead of print]100806040200 (%)
42.944.056.660.2
p=0.005 , DAS28(CRP)< 3.227 10 20
CONCERTO 26- III . - . . 40 ( ) 2,5 20 ( ).
2,5 , 5 , 10 , 20 . 12,5 20 . , . . , : 2,5 10 (. 9)15. 10 20
.27
- 4.5 7.0/1 10 10 20 . : 59 g/mL2ADA (/) ()28 Burmester G, et
al. Ann Rheum Dis 2014;18 Feb [Epub ahead of print]
. , : 2,5 10 . 10 20 . , .28
CONCERTO , CONCERTO , .
() () () () () - () () / Burmester, et al. Ann Rheum Dis
2013;72:517524
: () () , : ( .. ) ; U.S. Food and Drug Administration.Code of
federal regulations, Title 21.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32.
Accessed 3 July 2012.
: - COCHRANE 9 , /, 5 -:
: >16 , , (n=160) (n=45) Cohrane, MEDLINE EMBASE ( 2010)160
47676 46 11954
- ; ; ;
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
2011
: .
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstractVSVSVSVS
: ( 1.28, =0.00013) ( 1.47, =0.012) ( 1.37, P=0.015) ( 4.68,
=0.028)
; ;
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
: ( 1.09, =0.2) ( 0.53, =0.27) ( 0.69, P=0.6)
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
; ;
(vs. control) : ( 2.34) ( 1.55) * (vs. control) : ( 1.57) (
4.75) * (vs. control) : ( 4.05)
!
* - ;
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
, , :
: ( ) , ( 1.63)
; ;
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
, ( 2.00)* ( 1.92) ( 1.72) , ( 2.17)
* -
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
, ; ; : ( )
, - (9 ) :127 1000 ( ) vs. 118 1000 (), :137 1000 ( ) vs. 98
1000 () :35 1000 ( ) vs. 26 1000 ():20 10 000 ( ) vs. 4 10 000
()
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
, , , , , DMARDs , , DMARDs, DMARDs Disease Modifying
Antirheumatic
Drugshttp://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008794.pub2/abstract
,
, , , 95% -20,2-21,8 22,6-24,124,3-32
/100 -N. A. Accortt et al., A retrospective database analysis
describing recurrent infection risk among patients using
TNF-inhibitors, other biologic DMARDS , and non-biologic DMARDS,
presented at EULAR 2014, abs FRI0257
95% ETN1517,2ADA13,916,5INF16,419,9
N. A. Accortt et al., A retrospective database analysis
describing recurrent infection risk among patients using
TNF-inhibitors, other biologic DMARDS , and non-biologic DMARDS,
presented at EULAR 2014, abs FRI0257/100 -
ADA ADA 1,2,3
Burmester GR, et al. Ann Rheum Dis. 2009;68:1863-1869 Schiff MH,
et al. Ann Rheum Dis. 2006;65:889-894 Burmester GR et al. Ann Rheum
Dis 2012. Jul 6 [Epub] 71 ( , , )
/100 -4,870 -12,506 -
18,284 -
23,943 -
: - Gomez-Reino et al. A&R 2007;57:756-761 / 100,000 (
BIOBADASER, ; n=5198
* Favalli et al, Autoimmunity Reviews, Jan 2009, vol. 8, no. 3,
p. 266-273 : - - 3- - * / 100,000 ( LORHEN, ; n=1064)
, *: ( ),
* -
!
