Adalimumab in Pediatric Crohn's Disease

Humira (adalimumab)in Pediatric Crohn’s Disease

By Payam Javanmardi

Academy of Applied Pharmaceutical Sciences

Canada, Toronto, October 2014

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Table contentsIntroduction

Clinical Pharmacology

Pharmacodynamics

Pharmacokinetics

Warning and Precautions

Drug Interactions

Use in specific populations

New approved indication

Clinical trial design and conduct

References2

Humira has already received several FDA approvalsfor treatment:

Rhematoid Arthritis Dec. 31, 2002Psoriatic Arthritis Oct. 2005Ankylosing Spondylitis July 31, 2006Crohn’s Disease Feb. 27, 2006Plaque Psoriasis Jan. 22, 2008Polyarticular Juvenile Idiopathic Arthritis

Feb. 22, 2008Ulcerative Colitis Sep. 28, 2012

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Adalimumab (Humira) is a recombinant human IgG1monoclonal antibody specific for human TumorNecrosis Factor (TNF-α). It consists of 1330 amino acidsand has a molecular weight of approximately 148KDa.

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Adalimumab (Humira) is supplied as either a singleuse, prefilled pen/prefilled glass syringe or a singleuse institutional use vial.

The solution of Humira is clear and colorless, with apH of 5.2 .

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Clinical PharmacologyMechanism of action

TNF-α is a naturally occurring cytokine thatis involved in normal inflammatory andimmune responses.

Adalimumab (Humira) binds specifically toTNF-α and block cell surface TNF receptors.

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Adalimumab (Humira) modulates biologicalresponses that are induced or regulated by TNF-α,inducing changes in the levels of adhesionmolecules responsible for Leukocyte migration(ELAM-1, VCAM-1, and ICAM-1).

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Clinical PharmacologyPharmacodynamics

After treatment with Adalimumab (Humira), a decrease inlevels of CRP, ESR, and Il-6 was observed comparing tobaseline in patients with RA.

A decrease in CRP levels was also observed in patients withCrohn’s disease and Ulcerative Colitis.

Serum levels of MMP-1 and MMP-3 that produce tissueremodeling responsible for cartilage destruction were alsodecreased after Humira administration.

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Clinical PharmacologyPharmacokinetics

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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Clinical PharmacologyPharmacokinetics

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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Clinical PharmacologyWarning 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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The risks and benefits of TNF-blocker

treatment including Humira should be

considered prior to initiating therapy in

patients with a known malignancy.

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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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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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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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Clinical PharmacologyDrug 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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Clinical PharmacologyUse 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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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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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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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.

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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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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.

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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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In 2012, the European Commission approvedHumira for the treatment of Pediatric 6-17 years ofage with severe active Crohn’s disease who failed,are intolerant to, or have contraindications toconventional therapy.

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In September 25, 2014 FDA approved Humira forthe treatment of Pediatric patients with moderatelyto severely active Crohn’s disease for whom certainother treatments have not worked well enough.

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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.

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Enrolled patients had over the previous two yearperiod an inadequate response to corticosteroidsor an immunomodulator (e.g., azathioprine, 6-mercaptopurine, or methotrexate).

Patients who had previously received a TNFblocker were allowed to enroll if they hadpreviously had loss of response or intolerance tothat TNF blocker.

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192 pediatric patients (6 t0 17 years of age) withPCDAI >30 were planned to to be entered into thestudy at approximately 55 sites in the US, Canada,and Europe.

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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 thateither terminated early from the study or did notrollover into extension study.

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Patients received open-label induction therapy at a dosebased 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 mg31

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

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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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Out of total 192 patients:

188 completed 4-week Induction Period

At week 4, 28% (52/188) of patients were in clinicalremission.

152 completed 26-week Treatment

At week 26, 33.5% (63/188) of patients were in clinicalremission.

52 completed 52-week Treatment

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At both weeks 26 and 52, the proportion of patientsin clinical remission and clinical response wasnumerically higher in the high dose groupcompared 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

Dailymed.nim.nih.govabbvie.mediaroom.comwww.drugs.comClinicaltrials.govncbi.nim.nih.gov

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