Adalimumab is a TNF-blocker which has recently received FDA approval in September 2014 for treatment of Pediatric with Crohn's Disease

1. Humira (adalimumab)
in Pediatric Crohn’s Disease
By Payam Javanmardi
Academy of Applied Pharmaceutical Sciences
Canada, Toronto, October 2014
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2. Table contents
Introduction
Clinical Pharmacology
Pharmacodynamics
Pharmacokinetics
Warning and Precautions
Drug Interactions
Use in specific populations
New approved indication
Clinical trial design and conduct
References
2

3. Humira has already received several FDA approvals
for treatment:
Rhematoid Arthritis Dec. 31, 2002
Psoriatic Arthritis Oct. 2005
Ankylosing Spondylitis July 31, 2006
Crohn’s Disease Feb. 27, 2006
Plaque Psoriasis Jan. 22, 2008
Polyarticular Juvenile Idiopathic Arthritis
Feb. 22, 2008
Ulcerative Colitis Sep. 28, 2012
3

4. Adalimumab (Humira) is a recombinant human IgG1
monoclonal antibody specific for human Tumor
Necrosis Factor (TNF-α). It consists of 1330 amino acids
and has a molecular weight of approximately 148KDa.
4

5. Adalimumab (Humira) is supplied as either a single
use, prefilled pen/prefilled glass syringe or a single
use institutional use vial.
The solution of Humira is clear and colorless, with a
pH of 5.2 .
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6. Clinical Pharmacology
Mechanism of action
TNF-α is a naturally occurring cytokine that
is involved in normal inflammatory and
immune responses.
Adalimumab (Humira) binds specifically to
TNF-α and block cell surface TNF receptors.
6

7. Adalimumab (Humira) modulates biological
responses that are induced or regulated by TNF-α,
inducing changes in the levels of adhesion
molecules responsible for Leukocyte migration
(ELAM-1, VCAM-1, and ICAM-1).
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8. 8

9. Clinical Pharmacology
Pharmacodynamics
After treatment with Adalimumab (Humira), a decrease in
levels of CRP, ESR, and Il-6 was observed comparing to
baseline in patients with RA.
A decrease in CRP levels was also observed in patients with
Crohn’s disease and Ulcerative Colitis.
Serum levels of MMP-1 and MMP-3 that produce tissue
remodeling responsible for cartilage destruction were also
decreased after Humira administration.
9

10. Clinical Pharmacology
Pharmacokinetics
The maximum serum concentration (Cmax)
and the time to reach the maximum
concentration (Tmax) were 4.7± 1.6 μg/ml
and 131± 56 hours respectively, following a
single 40mg subcutaneous administration of
Humira to healthy adult subjects.
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11. Clinical Pharmacology
Pharmacokinetics
The average absolute bioavailability of
adalimumab estimated from 3 studies
following a single 40mg subcutaneous dose
was 64%.
The Pharmacokinetics of adalimumab were
linear over the dose range of 0.5 to 10mg/kg
following a single IV dose.
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12. Clinical Pharmacology
Warning And Precautions
Patients treated with Humira are at
increased risk for developing serious
infections involving organ systems and sites
that may lead to hospitalization or death.
Aspergilosis, Blastomycosis, candidiasis,
Coccidomycosis, Histoplasmosis, Legionellosis,
Lysteriosis, Pneumocytosis, and Tuberculosis
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13. Clinical Pharmacology
Warning And Precautions
The risks and benefits of TNF-blocker
treatment including Humira should be
considered prior to initiating therapy in
patients with a known malignancy.
13

14. Clinical Pharmacology
Warning And Precautions
Anaphylaxis and Angioneurotic edema have
been reported following Humira
administration.
Use of TNF blockers including Humira, may
increase the risk of reactivation of hepatitis
B Virus in patients who are chronic carriers
of this virus.
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15. Clinical Pharmacology
Warning And Precautions
Some cases of neurologic and
hematological reactions have been found
being associated with TNF blocking agents
including Humira.
Cases of worsening congestive heart failure
and new onset of CHF has been reported
with TNF blockers.
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16. Clinical Pharmacology
Warning And Precautions
Treatment with Humira may result in the
formation of autoantibodies and, rarely, in
the development of a lupus-like syndrome.
There have been reports of severe hepatic
reactions including liver failure in patients
receiving TNF-blockers.
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17. Clinical Pharmacology
Drug Interactions
Concomitant administration of Humira with
other biologic DMARDS (e.g., anakinra and
abatacept) or other TNF blockers is not
recommended based upon the possible
increased risk for infections and other
potential pharmacological interactions.
The use of live vaccines with Humira must
be avoided.
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18. Clinical Pharmacology
Use in specific populations
Pregnancy
Adequate and well controlled studies with
Humira have not been conducted in
pregnant women.
Adalimumab is an IgG1 Mab and IgG1 is
actively transferred across the placenta
during the third trimester of pregnancy.
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19. Clinical Pharmacology
Use in specific populations
Pregnancy
No fetal harm was observed in reproductive
studies performed in cynomolgus monkeys.
Because reproductive studies are not
always predictive of human response, this
drug should be used during pregnancy only
if clearly needed.
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20. Clinical Pharmacology
Use in specific populations
Nursing Mothers
Limited data from published literature
indicate that adalimumab is present in low
levels in human milk and is not likely to be
absorbed by a breastfed infant.
However, caution should be exercised when
Humira is administered to a nursing woman.
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21. Clinical Pharmacology
Use in specific populations
Pediatrics
Humira administered during pregnancy
could affect immune response in the in
utero- exposed newborn and infant.
The clinical significance of elevated
adalimumab levels in infants is unknown.
21

22. Clinical Pharmacology
Use in specific populations
Pediatrics
Post-marketing cases of lymphoma,
including hepatosplenic T-cell lymphoma
and other malignancies, some fatal, have
been reported among children,
adolescents, and young adults who received
treatment with TNF blockers including
Humira.
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23. Clinical Pharmacology
Use in specific populations
Geriatrics
The frequency of serious infection and
malignancy among Humira treated patients
over 65 years of age was higher than for
those under 65 years of age in clinical
studies.
23

24. Humira a new indication for Pediatric
Crohn’s Disease
In the United States, there are an estimated
38.000 children and teens with Crohn’s
disease.
Since there is no known cure for Crohn’s
disease, one of the treatment goals of
Pediatric Crohn’s disease is to induce and
maintain clinical remission.
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25. In 2012, the European Commission approved
Humira for the treatment of Pediatric 6-17 years of
age with severe active Crohn’s disease who failed,
are intolerant to, or have contraindications to
conventional therapy.
25

26. In September 25, 2014 FDA approved Humira for
the treatment of Pediatric patients with moderately
to severely active Crohn’s disease for whom certain
other treatments have not worked well enough.
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27. IMAgINE 1 study (NCT00409682)
In April 2007, a multicenter, randomized,
double-blind, parallel group 52-week clinical
phase 3 study was launched:
To evaluate the safety, efficacy, and
pharmacokinetics of the Human ANTI-TNF
monoclonal Antibody Adalimumab in
pediatric subjects with moderate to severe
Crohn’s disease.
27

28. Enrolled patients had over the previous two year
period an inadequate response to corticosteroids
or an immunomodulator (e.g., azathioprine, 6-
mercaptopurine, or methotrexate).
Patients who had previously received a TNF
blocker were allowed to enroll if they had
previously had loss of response or intolerance to
that TNF blocker.
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29. 192 pediatric patients (6 t0 17 years of age) with
PCDAI >30 were planned to to be entered into the
study at approximately 55 sites in the US, Canada,
and Europe.
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30. The duration of the study was to be up to 65 weeks,
which included:
1-to-3-week screening period
An induction period
A maintenance period
and a 70-day follow-up call for all subjects that
either terminated early from the study or did not
rollover into extension study.
30

31. Patients received open-label induction therapy at a dose
based on their body weight (≥ 40 Kg and <
40 Kg).
Patients ≥ 40 Kg
Week 0
160 mg
Week 2
80 mg
Patients < 40 Kg
Week 0
80 mg
Week 2
40 mg
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32. Randomization phase (1:1) at week 4
Patients ≥ 40 Kg
HMD Regimen
40 mg, eow
LMD Regimen
20 mg, eow
Patients < 40 Kg
HMD Regimen
20 mg, eow
LMD Regimen
10 mg, eow
32

33. Dose escalation at week 12
Patients (Group) Dose-escalated
Low Maintenance Dose 51 % (48/95)
High Maintenance Dose 38% (35/93)
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34. Out of total 192 patients:
188 completed 4-week Induction Period
At week 4, 28% (52/188) of patients were in clinical
remission.
152 completed 26-week Treatment
At week 26, 33.5% (63/188) of patients were in clinical
remission.
52 completed 52-week Treatment
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35. At both weeks 26 and 52, the proportion of patients
in clinical remission and clinical response was
numerically higher in the high dose group
compared to the low dose group.
LMD, 20/10 mg
eow
N=95
HMD, 40/20 mg eow
N=93
Week 26
Clinical Remission 28% 39%
Clinical Response 48% 59%
Week 52
Clinical Remission 23% 33%
Clinical Response 28% 42% 35

36. Dailymed.nim.nih.gov
abbvie.mediaroom.com
www.drugs.com
Clinicaltrials.gov
ncbi.nim.nih.gov
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