Assessment of Adalimumab Dose Selection for Adult Ulcerative Colitis
Using Exposure-Response Analyses
Michael Bewernitz1, Christine Garnett2,4, Klaus Gottlieb3, Kevin Krudys4, Andrew E. Mulberg3, Aisha P. Johnson3, Anil
Rajpal3, Yow-Ming Wang5, Lin Zhou5, Kevin Bugin3, Nitin Mehrotra4
(1) Division of Clinical Pharmacology 1, Office of Clinical Pharmacology (OCP), U.S. Food and Drug Administration (FDA) (2) Current address: Certara L.P., Saint Louis, Missouri, United
States (3) Division of Gastroenterology and Inborn Errors Products, Office of New Drugs, FDA (4) Division of Pharmacometrics, OCP, FDA (5) Division of Clinical Pharmacology 3, OCP, FDA
RESULTS
OBJECTIVES
Figure 1: Panel A: Probability of Remission at Week 8 Increases with Increasing Week 8 Adalimumab
Trough Concentration. Panel B: Inadequate Response Occurred Earlier in Patients with Lower Week 8
Concentrations.
 On September 28 2012, FDA approved adalimumab (Humira™) for
inducing and sustaining clinical remission in adult patients with
moderately to severely active ulcerative colitis (UC).
 Approved Dosing Regimen for UC: 160 mg on Day 1 followed by 80 mg
two weeks later (Day 15). This was followed by a maintenance dose of
40 mg every other week starting two weeks later (Day 29).
 Phase 2 dose ranging trials were not conducted. However, in one of the
two registration trials in UC patients (UC-I), the sponsor studied two
induction doses 80/40 (80 mg, followed two weeks later by a dose of 40
mg) and 160/80 (160 mg, followed two weeks later by a dose of 80 mg).
There was no difference in remission rate for induction observed
between adalimumab 80/40 and placebo.
Induction Phase
(A)
23/246
15/53
11/54
P=0.0002
8/53
5/53
Observed Conc. Range
Four quartiles
Q4
of week 8
Q3
trough
Q2
concentration
Q1
Placebo
}
(B)
Q4
Q3
Q2
Placebo
Q1
Hazard Ratio: 0.93 (P=0.0008)
+
censored observation
Time Until Inadequate Response (Weeks)
Week 8 Adalimumab Trough Concentration (μg/mL)
Table 3: Logistic Regression Analysis. Association Between Trough Concentration and
Week 8 Remission Remains Significant After Adjusting for Confounding Factors.
 Co-primary efficacy endpoints in Study UC-II:
• clinical remission at week 8 (induction of clinical remission)
• clinical remission at week 52 (maintenance of clinical remission)
Clinical remission is defined as the proportion of patients with a total Mayo score ≤ 2 and with
no individual subscore > 1
Table 1: Efficacy Results for Phase 3 Study UC-II
Proportion of Patients that have not Switched due to
Inadequate Response
BACKGROUND
The results of the logistic regression and Kaplan-Meier analyses are presented in
the figure and Tables 3 and 4 below:
Probability of Remission Per Mayo Score at Week 8
To determine if a higher dose could lead to improved
remission rates than the dose chosen for the registration trial
for patients with moderately to severely active UC.
•
Factor
Estimate
Univariate P-value
Multivariate Analysis P-value
Adalimumab concentration at 8 weeks
0.084
0.0002
0.0003
Baseline Mayo score
-0.4
---
<0.0001
Previous treatment with anti-TNF medication
-0.7
---
0.0253
Patients with higher week 8 trough concentrations have a higher probability of induction of clinical
remission (Figure 1A).
Patients with higher baseline Mayo scores have a lower probability of induction of clinical
remission.
Patients with prior exposure to anti-TNF agents have a lower probability of induction of clinical
remission consistent with the observed clinical data.
•
•
Table 4: Cox Proportional Hazards Analysis. Association Between Week 8 Trough
Concentrations and Time to Inadequate Response Remains Significant After Adjusting
for Confounding Factors.
In view of the relatively modest effect size seen in the trial we hypothesized
that a higher dose could have been more effective.
METHODS
Table 2: Trial Information for Study UC-II.
•
•
 Logistic Regression: Logistic regression analysis was conducted to
assess the relationship between the week 8 trough adalimumab
concentration and the probability of achieving clinical remission at week
8.
 Kaplan-Meier Analysis: Beginning at week 12, patients who
demonstrated an inadequate response switched to open-label 40 mg
adalimumab every other week. Kaplan-Meier plots were generated to
visualize the relationship between week 8 trough adalimumab
concentration and the time until inadequate response.
 Cox Proportional Hazards Model: The relationship between week 8
trough adalimumab concentration and time until inadequate response
was assessed with a Cox proportional hazards model.
 Numerous baseline risk factors (such as age, baseline Mayo score, prior
exposure to anti-TNF therapy, weight, etc.) were evaluated in the logistic
regression and Cox proportional hazards analyses.
REFERENCES
[1] FDA Slides for Gastrointestinal Disease Advisory Committee Meeting on August 28th, 2012
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Gastrointestin
alDrugsAdvisoryCommittee/UCM318077.pdf)
[2] Meeting minutes for Gastrointestinal Disease Advisory Committee Meeting on August 28th, 2012
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Gastrointestin
alDrugsAdvisoryCommittee/UCM319690.pdf)
[3] FDA briefing document for Gastrointestinal Disease Advisory Committee Meeting on August 28th,
2012
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Gastrointestin
alDrugsAdvisoryCommittee/UCM316786.pdf)
[4] Humira approval letter for UC
(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125057Orig1s232ltr.pdf)
[5] FDA approved package insert for Humira
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125057s232lbl.pdf)
Patients with higher week 8 trough adalimumab concentrations sustained their response (i.e. did
not exhibit inadequate response) over a longer period of time compared to patients with lower
week 8 trough adalimumab concentrations who demonstrate inadequate response earlier (Figure
1B).
Proportion of patients who did not demonstrate an inadequate response increased with increasing
concentration (32% for placebo, 29% for Q1, 40% for Q2, 53% for Q3, and 57% for Q4).
Maintenance Phase: A robust exposure-response relationship for clinical remission
at week 52 could not be established due to the large number of patient drop outs
during the course of the trial and the resulting missing PK data.
Safety:
• No new safety signals compared to Crohn’s disease indication
• Main AEs of interest were infections
• Infection rates similar to placebo
• Exposure not related to relevant safety endpoints in Crohn’s Disease indication
• Higher week 8 trough adalimumab concentrations are associated with:
1. Greater proportion of patients achieving clinical remission at week 8.
2. Greater time to inadequate response.
• Modest effect size (16.5% remission induction rate for adalimumab 160/80/40
versus 9.3% for placebo)
• Remission rate does not plateau over the observed concentration range
CONCLUSIONS AND IMPACT
 A higher dose for the induction of remission may provide greater benefit to UC
patients.
 These analyses were presented by the FDA review team at the Gastrointestinal
Drugs Advisory Committee (GIDAC) Meeting on August 28th 2012. A majority (14 of
17) of the GIDAC members voted that the optimal adalimumab dose for UC has not
been established, although the dosage studied demonstrated clinical efficacy.
 Exposure-response analyses were pivotal in enhancing our understanding the
adequacy of the proposed adalimumab induction dosing regimen. Based on the
results of these analyses along with the observed clinical data, FDA required the
Sponsor to conduct a post marketing clinical trial to evaluate the efficacy and safety
of adalimumab induction dosing regimens utilizing doses higher than those
previously studied.