Alimentary Pharmacology and Therapeutics

Adalimumab maintains remission of Crohn’s disease after up

to 4 years of treatment: data from CHARM and ADHERE
R. Panaccione*, J.-F. Colombel†, W. J. Sandborn‡, G. D’Haens§,¶, Q. Zhou**, P. F. Pollack**, R. B. Thakkar** &
A. M. Robinson**

*Inflammatory Bowel Disease Clinic, SUMMARY

Division of Gastroenterology,
Department of Medicine, University of
Calgary, Calgary, AB, Canada. Background
†
Icahn School of Medicine at Mount Therapies that maintain remission for patients with Crohn’s disease are
Sinai, New York, NY, USA. essential. Stable remission rates have been demonstrated for up to 2 years
‡
University of California San Diego, La in adalimumab-treated patients with moderately to severely active Crohn’s
Jolla, CA, USA. disease enrolled in the CHARM and ADHERE clinical trials.
§
Academic Medical Center,
Amsterdam, The Netherlands.
¶ Aim
Department of Internal Medicine,
Imelda GI Clinical Research Center,
To present the long-term efficacy and safety of adalimumab therapy
Bonheiden, Belgium. through 4 years of treatment.
**AbbVie Inc, North Chicago, IL, USA.
Methods
Remission (CDAI <150), response (CR-100) and corticosteroid-free remis-
Correspondence to: sion over 4 years, and maintenance of these endpoints beyond 1 year were
Dr R. Panaccione, Division of assessed in CHARM early responders randomised to adalimumab. Cortico-
Gastroenterology, Department of steroid-free remission was also assessed in all adalimumab-randomised
Medicine, University of Calgary, Room patients using corticosteroids at baseline. Fistula healing was assessed in
6D28, TRW Building, 3280 Hospital
adalimumab-randomised patients with fistula at baseline. As observed, last
Drive NW, Calgary, AB T2N1N4
observation carried forward and a hybrid nonresponder imputation analysis
Canada.
E-mail: rpanacci@ucalgary.ca
for year 4 (hNRI) were used to report efficacy. Adverse events were
reported for any patient receiving at least one dose of adalimumab.

Publication data Results

Submitted 15 May 2013 Of 329 early responders randomised to adalimumab induction therapy, at
First decision 2 June 2013 least 30% achieved remission (99/329) or CR-100 (116/329) at year 4 of
Resubmitted 28 August 2013 treatment (hNRI). The majority of patients (54%) with remission at year 1
Accepted 30 August 2013 maintained this endpoint at year 4 (hNRI). At year 4, 16% of patients tak-
EV Pub Online 22 September 2013 ing corticosteroids at baseline were in corticosteroid-free remission and
24% of patients with fistulae at baseline had healed fistulae. The incidence
rates of adverse events remained stable over time.

Conclusions
Prolonged adalimumab therapy maintained clinical remission and response
in patients with moderately to severely active Crohn’s disease for up to
4 years. No increased risk of adverse events or new safety signals were
identified with long-term maintenance therapy. (clinicaltrials.gov number:
NCT00077779).

Aliment Pharmacol Ther 2013; 38: 1236–1247

1236 ª 2013 John Wiley & Sons Ltd

doi:10.1111/apt.12499
 Four years of adalimumab for Crohn’s disease

INTRODUCTION METHODS
Crohn’s disease (CD) is a relapsing and remitting
intestinal inflammatory disorder. The pathogenesis of CHARM and ADHERE trials
CD is not well characterised, although environmental, Detailed methods and patient demographics of the
genetic and microbial factors leading to a dysregulated CHARM and ADHERE trials have been published
immune response are all thought to play key roles. previously.5, 10 Briefly, CHARM was a 56-week, multi-
Elevated levels of tumour necrosis factor alpha (TNFa) centre, phase III, double-blind, randomised, pla-
may be observed both at disease onset and during cebo-controlled trial to assess the efficacy and safety of
times of flare.1–3 Evolving treatment goals for CD adalimumab for the treatment of patients with moder-
include inducing and maintaining clinical and endo- ately to severely active CD. Adult patients with a diag-
scopic remission (also termed ‘deep remission’),4 avoid- nosis of CD for at least 4 months and a Crohn’s
ing prolonged exposure to corticosteroids, improving Disease Activity Index (CDAI) between 220 and 450
patient quality of life, and reducing hospitalisations received open-label induction with adalimumab (80 mg
and surgeries. at week 0, 40 mg at week 2). Patients enrolled in
The use of agents directed against TNFa has made a CHARM could have received previous treatment with
significant impact on the management of patients with another anti-TNF antagonist. CD-related medications
CD. However, most efficacy data with these agents are were to remain stable during CHARM, with the excep-
limited to that collected during relatively short-term (up tion of corticosteroids, which could be tapered at the
to 1 year) clinical trials. Due to the chronic relapsing investigator’s discretion beginning at week 8. Patients
and progressive nature of CD, clinical trial data over who experienced a flare after they tapered their dosages
longer durations of treatment (i.e. several years) are of steroids could have their corticosteroid dosages
desirable to demonstrate both long-term efficacy and increased to the dosage prior to the start of the taper.
safety of these agents. Adjustments (increases or decreases) in other CD-re-
Adalimumab, a fully human monoclonal antibody lated concomitant treatments, including initiation of a
against TNFa, has been shown in randomised, pla- treatment a patient was not taking previously, were
cebo-controlled clinical trials to be effective for the allowed in ADHERE following at least 3 months of
induction and maintenance of remission and to open-label adalimumab exposure. At week 4, patients
achieve mucosal healing in patients with moderately to were randomised to receive placebo, either 40 mg ada-
severely active CD.5–9 The Phase III adalimumab limumab weekly or 40 mg every other week. After week
maintenance trial CHARM (Crohn’s Trial of the Fully 12, patients who experienced a disease flare or nonre-
Human Antibody Adalimumab for Remission Mainte- sponse could move to open-label treatment with 40 mg
nance) was followed by a long-term, open-label exten- every other week, and then to 40 mg weekly for contin-
sion, ADHERE (Additional Long-Term Dosing With ued flare or nonresponse. At the end of CHARM,
HUMIRA to Evaluate Sustained Remission and Efficacy patients could enter the open-label extension ADHERE
in CD), which collected efficacy and safety data for up trial. Enrolment in ADHERE was conducted on a roll-
to 4 years of treatment with adalimumab. Previous ing basis as subjects completed CHARM, so the dura-
reports from ADHERE demonstrated that 2 years of tion of participation in ADHERE varied. Patients still
treatment with adalimumab was associated with main- on blinded therapy at the end of CHARM received
tenance of stable rates of clinical remission, fistula adalimumab 40 mg every other week upon entry to
healing, decreased hospitalisations and improved ADHERE. Patients on open-label adalimumab every
patient quality of life.10, 11 A later analysis of patients other week or weekly continued on the same regimen.
receiving corticosteroids at the start of adalimumab During ADHERE, patients on every other week ada-
therapy in CHARM demonstrated stable rates of corti- limumab could move to weekly dosing for disease flare
costeroid-free remission for up to 3 years.12 In this or for nonresponse. Termination of the ADHERE study
current report, we present the extended long-term effi- occurred at each study site upon country and local (if
cacy (including maintenance of clinical response and applicable) regulatory and reimbursement approval of
remission, fistula healing and corticosteroid-free remis- adalimumab for CD, and opening of the adalimumab
sion) and safety of adalimumab through 4 years of long-term registry (PYRAMID) for enrolment. All sites
therapy. were terminated in December 2008.

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R. Panaccione et al.

Data analysis one dose of adalimumab (n = 854) (including open-label

The long-term effect of adalimumab treatment (CDAI induction therapy in CHARM) through 4 years of treat-
over time, clinical remission and clinical response ment (or up to 70 days after the last dose of ada-
through week 212 of adalimumab treatment) was limumab, if treatment was prematurely discontinued) to
assessed in the all-adalimumab mITT population from assess long-term safety.
CHARM, which consisted of patients who achieved at
least a 70 point reduction in CDAI from baseline with Statistical methods
open-label induction therapy and were randomised to The CDAI over time was analysed using a nonlinear
any adalimumab every other week or weekly (rando- model using four-parameter log-logistic function. Cate-
mised responders; n = 329). Patients who responded to gorical endpoints were analysed using three methods,
open-label induction therapy who were randomised to as-observed, last observation carried forward (LOCF)
40 mg every other week (n = 172) were also analysed and a hybrid nonresponder imputation (hNRI). The time
separately. Efficacy endpoints evaluated in CHARM and patients spent in ADHERE varied because of the rolling
ADHERE (which initiated study enrolment in 2003) enrolment from CHARM, different timing of study site
were primarily based on CDAI (i.e. clinical remission or closure and movement of patients to commercial drug.
clinical response). Reflective of the standard of care for As not all patients who completed CHARM participated
CD at the time, mucosal healing was not assessed in in the study for the full 4 years, NRI was used to analyse
either study. Clinical remission was defined as CDAI results for the all-adalimumab mITT population through
<150, whereas clinical response was defined as a decrease year 3, whereby patients with missing data (for any rea-
in CDAI of ≥100 points from baseline (CR-100). Mainte- son, including study termination) were assumed not to
nance of clinical remission and clinical response beyond have achieved the endpoint. After year 3, missing data
1 year was assessed in patients who enrolled in for patients who were documented to have moved to
ADHERE and who were in clinical remission (n = 145) commercial adalimumab were analysed using the LOCF
or CR-100 (n = 172) at week 56 of CHARM. Fistula method, and patients with data missing for any other
healing (defined as complete healing of draining fistulae, reason were assumed to not have efficacy. An additional
assessed using gentle compression during physical exam- analysis of clinical remission was conducted on the
ination) through 4 years was assessed for all ada- patients randomised to adalimumab every other week
limumab-randomised patients (regardless of response to using three imputation methods: one as described above;
induction therapy) with fistula(e) at the baseline of one using the same imputation rules, except that patients
CHARM (n = 70). Corticosteroid-free remission (CDAI who received dose escalation were also assumed to not
<150 without concomitant corticosteroids) was assessed have achieved remission from that point forward; and an
in randomised responders regardless of baseline cortico- as-observed analysis for patients who remained on every
steroid use (n = 329) and also for randomised patients other week dosing throughout the study. NRI was used
taking corticosteroids at the baseline of CHARM, regard- to assess corticosteroid-free remission through year 4
less of response to induction therapy (n = 206). Mainte- and maintenance of corticosteroid-free remission from
nance of corticosteroid-free remission beyond 1 year was week 56 of CHARM. LOCF was not used to analyse cor-
determined for two groups of patients who were in corti- ticosteroid-free remission because it was possible for sub-
costeroid-free remission at week 56 of CHARM: rando- jects to initiate corticosteroids between study visits when
mised responders (n = 147) and all randomised patients remission was assessed.
who used corticosteroids at CHARM baseline (n = 53).
Initiation of corticosteroids or immunosuppressants RESULTS
(defined as azathioprine, 6-mercatopurine or methotrex-
ate) in the randomised responder population (n = 329) Patient disposition
was also analysed throughout the study period. Detailed patient demographics from CHARM and dispo-
sition data from CHARM and ADHERE have been
Clinical assessment reported previously5, 10 Briefly, patients were representa-
CDAI was collected at baseline and at weeks 2, 4, 6, 8, tive of patients with long-standing moderately to severely
followed by every 4 weeks through week 56 of CHARM5 active CD, with a mean baseline CDAI of 313. Nearly
and at 12-week intervals during ADHERE.10 Adverse 50% of enrolled patients had previously been treated
events were recorded for any patient receiving at least with another anti-TNF antagonist. As of the December

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 Four years of adalimumab for Crohn’s disease

2008 termination date, at least 50% of subjects who moved to weekly dosing in years 2 to 4 of treatment
enrolled from CHARM remained in ADHERE through (Figure 1).
Week 156 (212 weeks from CHARM baseline). A dia-
gram of the patient flow during CHARM and ADHERE Maintenance of clinical remission and response
is shown in Figure 1. Of the patients randomised to ada- CDAI over time from baseline to week 212 for the
limumab every other week during CHARM, 16.5% CHARM mITT population is shown in Figure 2a. The

854 patients enrolled in CHARM

CHARM
(weeks 0-56)
778 randomized in CHARM

PBO N = 261 ADA 40 mg eow N = 260 ADA 40 mg ew N = 257

70 with fistulae at BL:

N = 30 (ADA eow); N = 40 (ADA ew)
206 on corticosteroids at BL:
N = 99 (ADA eow); N = 107 (ADA ew)

ADHERE
(weeks 56-212)

139 entered ADHERE 144 entered ADHERE 184 entered ADHERE

N = 50 N = 28 N = 40
N = 89 N = 116 N = 144
Entered on Entered on Entered on
Entered on Entered on Entered on
OL ADA OL ADA OL ADA
40 mg eow 40 mg eow 40 mg eow
40 mg ew 40 mg ew 40 mg ew

N = 28 N = 61 N = 43 N = 73 N = 47 N = 97
moved to cotinued moved to cotinued moved to cotinued
40 mg on 40 mg 40 mg on 40 mg 40 mg on 40 mg
ew eow ew eow ew eow

188 discontinued during ADHERE

60 adverse event
37 lack of efficacy
15 lost to follow-up
30 withdrew consent

46 other reasons

Figure 1 | Disposition of CHARM patients entering ADHERE. The primary reason for discontinuation during ADHERE is
also shown for all patients. ADA, adalimumab; PBO, placebo; eow, every other week; ew, weekly; OL, open-label.

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R. Panaccione et al.
(a) 400

350

300

250

CDAI
200

150

100

50

0
8 26 56 80 104 164 212
Weeks from CHARM baseline

hNRI
(b) 100
LOCF
As-observed
77.6 79.3
Patients in remission (%)

80
70.6 73.7
69.7
61.7 61.1 60.2
60 58.7 59.9 57.4 56.5
52.0 50.5
44.1 45.3
40 39.5
30.1

20
171 193 171 166 197 166 145 189 145 149 201 149 130 198 130 99 186 73
329 329 277 329 329 235 329 329 208 329 329 192 329 329 164 329 329 99
0
26 56 80 104 164 212
Weeks from CHARM baseline

hNRI
LOCF
(c)
100 As-observed
91.5
88.5
85.5 84.1 84.8
81.6
Patients achieving CR100 (%)

80 76.6
73.9 72.9 72.9
68.7 71.1 69.9
61.1
60
53.2 51.7
45.6
40 35.3

20

226 252 226 201 243 201 175 234 175 170 240 170 150 240 150 116 230 84
329 329 277 329 329 235 329 329 208 329 329 192 329 329 164 329 329 99
0
26 56 80 104 164 212
Weeks from CHARM baseline

Figure 2 | Maintenance of clinical remission and response in patients responding to adalimumab induction therapy
and receiving any dose of ADA: mITT (n = 329). (a) Crohn’s disease activity index (CDAI) over time: Nonlinear
model using four-parameter log-logistic function. Dotted line represents the threshold for clinical remission (CDAI
<150). (b) Percentage of patients in remission (CDAI <150) over time. (c) Percentage of patients achieving clinical
response (CR-100) over time. Green bars, hNRI analysis; orange bars, LOCF analysis; blue bars, as-observed.

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 Four years of adalimumab for Crohn’s disease

CDAI was at the threshold for clinical remission (150) by Initiation of concomitant medications
week 8, and decreased steadily through 4 years During CHARM and ADHERE, corticosteroid and
from CHARM baseline. The proportions of the all- immunomodulator use was initiated by 17.8% (35/197)
adalimumab mITT population achieving clinical remis- and 2.3% (4/173), respectively, of randomised responders
sion during CHARM and ADHERE are shown in who were na€ıve to these therapies at the baseline of
Figure 2b. Ongoing adalimumab treatment was associ- CHARM.
ated with maintained efficacy through 4 years, using
as-observed, LOCF or the more conservative hNRI impu- Maintenance of corticosteroid-free remission
tation method. Similar results were observed for patients The rates of corticosteroid-free remission for randomised
achieving clinical response (CR-100) (Figure 2c). Remis- responders (regardless of baseline corticosteroid use) and
sion rates were also stable over 4 years in the subset of in patients randomised to adalimumab receiving corti-
the mITT population randomised to adalimumab every costeroids at CHARM baseline are shown in Figures 6A,
other week (Figure 3). B. Corticosteroid-free clinical remission rates remained
The proportions of patients maintaining clinical remis- stable through the 4-year treatment period, and greater
sion and response to adalimumab therapy beyond week 56 than half of patients using corticosteroids at baseline and
of CHARM are shown in Figures 4a,b respectively. Ongo- in corticosteroid-free remission at the end of CHARM
ing adalimumab therapy maintained response and remis- maintained corticosteroid-free clinical remission
sion in greater than half of patients at year 4, even with throughout ADHERE.
the conservative hNRI imputation method.
Safety
Maintenance of fistula healing An overview of rates of treatment-emergent adverse
The data for fistula healing in patients randomised to events of interest during adalimumab exposure, up to
adalimumab who had draining fistulas at baseline are 212 weeks, in the safety population, which includes any
shown in Figure 5. Rates of fistula healing were main- patient exposed to adalimumab including the patients
tained throughout the 4-year period of follow-up. who did not respond to induction therapy, is outlined in

All, hNRI
No dose escalation, hNRI
100 No dose escalation, observed 95.2
92.7
89.4
86.5
83.0
80
72.1
Patients in remission (%)

60
47.7 45.9
43.6
40 39.5 36.6 38.4
34.9
29.1 29.7
27.3
23.3
20 17.4

82 75 49 79 68 45 63 50 39 66 51 42 60 40 38 47 30 20
172 172 68 172 172 52 172 172 47 172 172 47 172 172 41 172 172 21
0
26 56 80 104 164 212
Weeks from CHARM baseline

Figure 3 | Long-term maintenance of remission in patients randomised to adalimumab 40 mg eow: mITT (n = 172).
Percentage of patients in remission (CDAI <150) over time. Green bars, all patients randomised to adalimumab every
other week (all, hNRI analysis); orange bars, patients randomised to adalimumab every other week excluding patients
that escalated to weekly dosing (no dose escalation, hNRI analysis); blue bars, patients randomised to adalimumab
every other week excluding patients that escalated to weekly dosing (no dose escalation, as-observed analysis).

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R. Panaccione et al.

hNRI
LOCF
(a) 100
As-observed
86.2 86.8 84.7
82.1 83.0 82.8 83.8
80.0
80 77.2 77.2

Patients in remission (%)

64.8
60
53.8

40

20

112/ 119/ 112/ 112/ 125/ 112/ 94/ 120/ 94/ 78/ 116/ 62/
145 145 135 145 145 129 145 145 111 145 145 74
0
80 104 164 212
Weeks from CHARM baseline

hNRI
LOCF
As-observed
(b) 100
90.1 91.8 88.4
90.9 91.5 90.1
87.2
84.9 83.7
81.4
80
Patients achieving CR100 (%)

69.2

60
54.7

40

20

146/ 155/ 146/ 140/ 152/ 140/ 119/ 150/ 119/ 94/ 144/ 73/
172 172 159 172 172 154 172 172 130 172 172 81
0
80 104 164 212
Weeks from CHARM baseline

Figure 4 | Long-term maintenance of clinical remission and response for patients in remission or response at week 56
of CHARM. (a) Percentage of patients who were in remission at the end of CHARM (CDAI <150) (n = 145) that
maintained remission over time. (b) Percentage of patients who had a clinical response at the end of CHARM (CR-
100) (n = 172) that maintained a response over time. Green bars, hNRI analysis; orange bars, LOCF analysis; blue
bars, as-observed.

Table 1. The safety database of 854 patients comprised Abdominal and anal abscess were the most common
1669.7 patient-years of exposure to adalimumab. The serious infections reported, with incidence rates of 0.7
exposure-adjusted rates of all categories of adverse events and 1.0 events/100PY respectively. Almost all opportu-
were consistent with the 2-year exposure report.10 The nistic infections were candidiasis, with oral candidiasis
most common category of adverse events was infection. occurring most frequently (0.9 events/100PY), and no

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 Four years of adalimumab for Crohn’s disease

hNRI
100
LOCF
As-observed

Patients with healed fistulae (%)

80
67.7
65.2
60.4 60.0 62.2
60 58.6 57.1
55.2 55.7
50.0 51.4 52.9
45.7
41.4
40
34.3 32.9
30.0
24.3
20

32/ 35/ 32/ 29/ 36/ 29/ 24/ 37/ 24/ 23/ 39/ 23/ 21/ 41/ 21/ 17/ 40/ 15/
70 70 58 70 70 48 70 70 40 70 70 37 70 70 31 70 70 23
0
26 56 80 104 164 212
Weeks from CHARM baseline

Figure 5 | Long-term efficacy of fistula healing in patients randomised to adalimumab with fistulas at baseline (ITT,
n = 70). Green bars, hNRI analysis; orange bars, LOCF analysis; blue bars, as-observed.

new cases of tuberculosis were observed since the 2-year any anti-TNF agent. Long-term maintenance of clinical
report. After 4 years of adalimumab treatment, the rate remission (including corticosteroid-free remission) and
of demyelinating disease was 0.2 events/100PY, with no response was achieved in clinically meaningful propor-
new events reported since the 2-year exposure report. tions of adalimumab-treated patients with CD. In addi-
No events of heart failure were observed. There were 53 tion, for patients presenting with draining fistulas or
liver-related AEs reported, the majority (n = 48) of those using corticosteroids at baseline of the CHARM
which were abnormalities or increases in liver function trial, long-term fistula healing and corticosteroid-free
tests. No cases of hepatic failure were observed. The remission were maintained through 4 years of treatment.
overall incidence rate through year 4 of any malignancy Taken together, these results underscore the long-term
was low and remained stable since the 2-year exposure efficacy of adalimumab maintenance therapy.
report (1.6 events/100PY). The most commonly reported One important observation is that three different
malignancy was basal cell carcinoma (0.4 events/ analysis methods, as-observed, LOCF and the more
100PYs). Additional malignancies observed since the stringent hybrid NRI, were used to measure various cate-
2-year report included one case each of colon cancer, gorical endpoints, with each analysis method producing
hepatocellular carcinoma, lung adenocarcinoma, renal distinct results. Larger differences between LOCF and
cell carcinoma and vulval cancer. Two treatment-emer- hNRI were observed at later time points. The lower per-
gent deaths occurred during the entire follow-up period, centages observed with hNRI analysis at later time points
one during CHARM and one during ADHERE; the can be explained by classifying those patients who left
details of these have been previously reported.5, 10 No the study for any reason (except those who were docu-
cases of hepatosplenic T-cell lymphoma were observed. mented to move from study drug to commercially avail-
able adalimumab after week 156 of follow-up) as
DISCUSSION nonresponders. However, as noted in Figure 1, it is
Data regarding the long-term efficacy and safety of important to mention that not all of these patients left
anti-TNF therapy are largely limited to observational or the trial due to loss of response to adalimumab. The true
retrospective reports of patient cohorts from single cen- estimate of potential efficacy at each time point is likely
tres.13 This report extends the safety and efficacy data of to lie somewhere between the values determined by the
adalimumab for the treatment of CD for up to 4 years least conservative (as-observed) and the most conserva-
of therapy, from the previously reported results in tive (hNRI) analyses.
CHARM and ADHERE,10–12 and provides data from the Maintenance of remission was also evident in the subset
longest duration of follow-up in a clinical trial for CD of of patients randomised to the approved 40 mg every other

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R. Panaccione et al.

(a) 100
BL steroid use, ITT
Randomized responders, mlTT
80

corticosteroid-free remission (%)

60
Patients in
45.9 44.7
39.5 40.1
40 36.5

25.7 25.7 26.2

21.8 23.2
20.1
20 15.5

53/ 151/ 53/ 147/ 45/ 130/ 54/ 132/ 48/ 120/ 32/ 66/
206 329 206 329 206 329 206 329 206 329 206 329
0
26 56 80 104 164 212
Weeks from CHARM baseline

BL steroid use, ITT

(b) 100
Randomized responders, mlTT

84.9
80 76.9 76.2 77.4
corticosteroid-free remission (%)

71.7
66.7

60
Patients in

50.9

40 38.1

20

38/ 113/ 45/ 112/ 41/ 98/ 27/ 56/

53 147 53 147 53 147 53 147
0
80 104 164 212
Weeks from CHARM baseline

Figure 6 | Maintenance of corticosteroid-free clinical remission in patients who were taking corticosteroids at CHARM
baseline (ITT, n = 206) and in randomised responders, regardless of baseline corticosteroid use (mITT, n = 329). (a)
Percentage of patients who discontinued corticosteroid use and achieved clinical remission (CDAI <150) over time
(NRI analysis). (b) Percentage of patients who achieved corticosteroid-free clinical remission at the end of CHARM
(n = 53 for the ITT population taking corticosteroids at baseline of CHARM and n = 147 for the randomised
responder population) and maintained corticosteroid-free clinical remission over time (NRI analysis). Green bars,
patients taking corticosteroids at baseline; orange bars, all randomised responders, regardless of baseline
corticosteroid use.

week maintenance dose of adalimumab, with slightly escalated were able to regain efficacy.14 A recently pub-
higher rates of remission observed when patients who lished analysis from CHARM suggested that weekly dos-
escalated to weekly dosing were included in the analysis. ing may be associated with greater efficacy than every
This finding is consistent with a previously published other week dosing in patients with elevated CRP who have
report from CHARM that showed that patients who dose lost response to treatment with a prior anti-TNF agent.15

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 Four years of adalimumab for Crohn’s disease

reported adverse event category over 4 years of ada-

Table 1 | Overview of treatment-emergent adverse
limumab exposure was infections. The incidence rates of
events of interest: all adalimumab patients from first
dose through year 4 any infections, opportunistic infections and serious infec-
tions were stable over time. Similarly, the incidence rate
Any adalimumab of any malignancies remained low and was stable over
n = 854,
PY = 1669.7
time, suggesting no cumulative risk associated with
Events (E/100PY) ongoing adalimumab exposure. Furthermore, prolonged
treatment with adalimumab for CD did not reveal any
Any adverse event (AE) 9736 (583.1)
Any AE at least possible 1933 (115.8) new safety signals. The overall safety data for 4 years of
drug related adalimumab therapy for CD were consistent with long--
Severe AE 730 (43.7) term safety data representing nearly 12 years of ada-
Serious AE 517 (31.0) limumab exposure across multiple indications.16
Any AE leading to 252 (15.1)
Patient selection for biological therapy is an important
discontinuation of study drug
Any infection 1966 (117.7) consideration to gain the greatest benefit of therapy over
Serious infection* 102 (6.1) a prolonged duration of time. The LOCF analysis found
Tuberculosis† 3 (0.2) that 80% of patients who achieved remission with
Malignancy‡ 26 (1.6)
adalimumab therapy at 1 year continued to be in remis-
Injection site pain 125 (7.5)
Opportunistic infection§ (excluding TB) 22 (1.3) sion over the next 3 years. A previous analysis found
Congestive heart failure 0 that patients with disease duration of less than 2 years
Demyelinating disorder 3 (0.2) had the greatest likelihood of achieving remission at
Liver event¶ 53 (3.2) 1 year in CHARM and the higher rate of remission
Deaths 2 (0.1)
persisted through the 3 years of data evaluated.17 These
AE, adverse event; PY, patient-years. patients also had a trend towards fewer adverse events.
* Serious infections since week 60 of ADHERE included Additional factors associated with a greater likelihood of
abdominal abscess (two events), anal abscess (nine events),
remission included elevated CRP at baseline and no
limb abscess (one event), gastroenteritis (three events), pyelo-
nephritis (three events), sepsis (one event), abscess intestinal prior treatment with an anti-TNF agent. Selection of
(one event), bronchitis (one event), lobar pneumonia (one patients with short disease duration and evidence of
event), lower respiratory tract infection (one event), sinusitis active inflammation for adalimumab treatment would
(one event), urinary tract infection (one event), cellulitis (four likely lead to greater rates of long-term efficacy than
events), cervicitis (one event), infectious peritonitis (one
event), muscle abscess (one event), perineal abscess (one those reported here.
event). The length of time that a clinician should continue
† No new cases of tuberculosis were reported since week 60 maintenance therapy with TNF antagonists for patients
of ADHERE. with CD remains a key point of discussion. Although
‡ Malignancies since week 60 of ADHERE included basal cell data from the STORI trial18 suggested that infliximab
carcinoma (four events), skin cancer (one event), breast can- withdrawal was successful in approximately half of
cer (one event), squamous cell carcinoma (one event), colon
patients with CD in stable remission, given the progres-
cancer (one event), renal cell carcinoma (one event), hepato-
cellular carcinoma (three events), lung adenocarcinoma (one sive and lifelong nature of CD, physicians should care-
event), vulval cancer (one event). fully consider the risks and benefits of different
§ Opportunistic infections included mostly candidiasis (21 approaches in the long-term use of biologics. It is possi-
events). One event of cytomegalovirus infection was reported. ble that patients in deep remission are at lower risk of
¶ Liver events included abnormal or increased liver function future relapse.4 Long-term treatment strategies, including
tests (48 events), hepatic steatosis (three events), hepatitis withdrawal of either an anti-TNF agent or concomitant
(one event) and hepatic neoplasm (one event).
immunomodulator therapy, need further evaluation.
The long-term follow-up of this study provides bene-
In addition to efficacy, it is important to examine ficial information about remission and response rates
safety of prolonged anti-TNF therapy to provide clini- over time. However, a few limitations of the study exist.
cians with information to aid determination of the bene- First, the analysis of the long-term efficacy of ada-
fits and risks of this strategy. Adverse events of special limumab was complicated by the varying duration of
interest with TNF antagonist therapy include serious follow-up, with not all patients reaching the week 212
infections and malignancies.16 The most commonly visit due to study termination. We attempted to over-

Aliment Pharmacol Ther 2013; 38: 1236-1247 1245

ª 2013 John Wiley & Sons Ltd
R. Panaccione et al.

come this by analysing the data using different imputa- Pharma (previously named Celltech Therapeutics, Ltd).
tion methods for missing data. A second limitation of W Sandborn has served as a consultant for AbbVie,
this long-term efficacy study is that assessment of ActoGeniX NV, AGI Therapeutics, Inc., Alba Therapeu-
mucosal appearance was not collected in CHARM and tics Corporation, Albireo, Alfa Wasserman, Amgen,
ADHERE. With the increasing interest in the concept AM-Pharma BV, Anaphore, Astellas, Athersys, Inc.,
of mucosal healing, data regarding the long-term effi- Atlantic Healthcare Limited, Aptalis, BioBalance Corpo-
cacy of adalimumab on mucosal healing or disease pro- ration, Boehringer-Ingelheim Inc, Bristol-Myers Squibb,
gression using a digestive damage score (such as the Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon
recently developed Lemann score)19 are of interest, but Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo
could not be analysed using this data set as endoscopic Technologies, Coronado Biosciences, Cytokine Pharma-
or radiographic imaging data were not collected in sciences, Eagle Pharmaceuticals, Eisai Medical Research
CHARM and ADHERE. Finally, there is increasing Inc, Elan Pharmaceuticals, EnGene, Inc., Eli Lilly, En-
interest in the correlation of serum drug levels of teromedics, Exagen Diagnostics, Inc., Ferring Pharma-
anti-TNF agents and antibodies against these agents and ceuticals, Flexion Therapeutics, Inc., Funxional
efficacy, but samples for assessment of pharmacokinetic Therapeutics Limited, Genzyme Corporation, Genentech,
parameters were not collected during CHARM or Gilead Sciences, Given Imaging, GlaxoSmithKline,
ADHERE. Human Genome Sciences, Ironwood Pharmaceuticals,
In summary, these data suggest a substantial clinical Janssen, KaloBios Pharmaceuticals, Inc., Lexicon Phar-
benefit with long-term adalimumab therapy for patients maceuticals, Lycera Corporation, Meda Pharmaceuticals,
with moderately to severely active CD. The rates of Merck Research Laboratories, MerckSerono, Merck &
adverse events were stable with long-term treatment up Co., Millennium, Nisshin Kyorin Pharmaceuticals Co.,
to 4 years. Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, Optimer
Pharmaceuticals, Orexigen Therapeutics, Inc., PDL Bio-
AUTHORSHIP pharma, Pfizer, Procter and Gamble, Prometheus Labo-
Guarantor of the article: Remo Panaccione. ratories, ProtAb Limited, Purgenesis Technologies, Inc.,
Author contributions: RP, JFC, WJS and GD collected Receptos, Relypsa, Inc., Salient Pharmaceuticals, Salix
data. QZ performed statistical analyses. RP, JFC, WJS, Pharmaceuticals, Inc., Santarus, Shire Pharmaceuticals,
GD, QZ, PFP, RBT and AMR contributed to the design Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc. (a
of the study, interpretation of data and analyses, and GSK company), S.L.A. Pharma (UK) Limited, Targacept,
writing and review of each draft of the publication. All Teva Pharmaceuticals, Therakos, Tillotts Pharma AG,
authors approved the final version of the manuscript. TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vas-
cular Biogenics Limited (VBL), Warner Chilcott UK
ACKNOWLEDGEMENTS Limited; has received speaker fees from AbbVie, Bris-
Declaration of personal interests: R Panaccione has tol-Myers Squibb and Janssen; and has received research
received consultant and/or lecture fees from AbbVie, funding from AbbVie, Bristol-Myers Squibb, Genentech,
Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Bio- GlaxoSmithKline, Janssen, Millennium, Novartis, Pfizer,
gen Idec, Bristol-Myers Squibb, Centocor, ChemoCen- Procter and Gamble Pharmaceuticals, Shire Pharmaceuti-
tryx, Eisai Medical Research Inc, Elan Pharmaceuticals, cals, and UCB Pharma. G D’Haens has served as a con-
Ferring, Genetech, GlaxoSmithKline, Janssen, Merck sultant for AbbVie, Actogenix, Amgen, Boehringer
Sharp and Dohme Corp, Millennium Pharmaceuticals Ingelheim, Janssen, Cosmo Technologies, Elan, Engene,
Inc. (now Takeda), Ocera Therapeutics Inc., Otsuka Ferring Pharmaceuticals, Giuliani, GlaxoSmithKline,
America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Merck, MSD, Neovacs, Novonordisk, Otsuka, PDL Bio-
Prometheus Laboratories, Schering-Plough, Synta Phar- pharma, Pfizer, Receptos, Salix Pharmaceuticals, SetPoint,
maceuticals Corp, Teva, UCB Pharma, and Warner Chil- Shire, Sigmoid Pharma, Takeda, Teva, Tillots, UCB; has
cott. J-F Colombel has served as consultant, advisory served as a speaker for AbbVie, Tillotts, Tramedico, Fer-
board member or speaker for AbbVie, Bristol Meyers ring, MSD, UCB, Norgine, Shire; and has received
Squibb, Ferring, Genentech, Giuliani SPA, Given Imag- research funding from AbbVie, Janssen Biologics, Given
ing, Merck & Co., Millenium Pharmaceuticals Inc., Pfizer Imaging, MSD, DrFalk Pharma, Photopill. Q Zhou, R
Inc. Prometheus Laboatories, Sanofi, Schering Plough Thakkar and A Robinson are employees of AbbVie Inc,
Corporation, Takeda, Teva Pharmaceuticals, UCB and own AbbVie stock and/or options. P Pollack is a

1246 Aliment Pharmacol Ther 2013; 38: 1236-1247

ª 2013 John Wiley & Sons Ltd
 Four years of adalimumab for Crohn’s disease

former Abbott employee, and owns stocks in AbbVie reviewed and approved the publication. The preparation
Inc, and Abbott. of this study was funded by AbbVie Inc. Writing support
Declaration of funding interests: AbbVie Inc funded the was provided by Kristina Kligys, PhD, of AbbVie Inc.
study and the analysis, provided writing support and and was funded by AbbVie Inc.

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