arthritis advisory committee july 29, 2008 actemra (tocilizumab) for rheumatoid arthritis fda...

Arthritis Advisory Committee Arthritis Advisory Committee July 29, 2008July 29, 2008

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Actemra (tocilizumab)Actemra (tocilizumab)for Rheumatoid Arthritisfor Rheumatoid Arthritis

FDA PerspectiveFDA Perspective

Actemra (tocilizumab)Actemra (tocilizumab)for Rheumatoid Arthritisfor Rheumatoid Arthritis

FDA PerspectiveFDA Perspective

Sarah Okada, M.D.Division of Anesthesia, Analgesia, and

Rheumatology Products

Sarah Okada, M.D.Division of Anesthesia, Analgesia, and

Rheumatology Products


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OverviewOverview

• Brief background on RA clinical development programs and claims

• Overview of tocilizumab (TCZ) pivotal trials– Very brief recap of efficacy– Summary of safety

• Brief background on RA clinical development programs and claims

• Overview of tocilizumab (TCZ) pivotal trials– Very brief recap of efficacy– Summary of safety


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“Typical” Drug Development for RA“Typical” Drug Development for RA

• Phase 1, phase 2– Including initial study of safety in combination with MTX– 3 mo RCT for proof of concept using ACR 20

• Phase 3– Large RCTs at least 3 mo in duration– Characterize monotherapy and combination w other DMARD’s,

especially MTX – May include large “clinical practice” trial – assess safety of add-on

therapy w prevalent DMARD regimens• Phase 4

– Early RA, 1st line treatment– Juvenile Idiopathic Arthritis (JIA)– Comparative studies– Long-term (e.g. 5 year) safety studies– Study of impact of treatment on immunization response

• Phase 1, phase 2– Including initial study of safety in combination with MTX– 3 mo RCT for proof of concept using ACR 20

• Phase 3– Large RCTs at least 3 mo in duration– Characterize monotherapy and combination w other DMARD’s,

especially MTX – May include large “clinical practice” trial – assess safety of add-on

therapy w prevalent DMARD regimens• Phase 4

– Early RA, 1st line treatment– Juvenile Idiopathic Arthritis (JIA)– Comparative studies– Long-term (e.g. 5 year) safety studies– Study of impact of treatment on immunization response


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Currently Recognized ClaimsCurrently Recognized Claims• Signs & symptoms

– ACR20, primary endpoint >3 mos• Inhibition of progression of structural damage

– Change from baseline in radiographic score, e.g. Total Sharp Score

– Controlled period >6 mos, total >1yr• Improvement in physical function

– Improvement in HAQ-DI >0.22 units at end of controlled period, >3 mos; maintained in open-label

• Major clinical response– ACR70 for >6 continuous months

• Complete clinical response/remission– ACR remission + radiographic arrest >6 months

• Signs & symptoms– ACR20, primary endpoint >3 mos

• Inhibition of progression of structural damage– Change from baseline in radiographic score, e.g. Total

Sharp Score– Controlled period >6 mos, total >1yr

• Improvement in physical function– Improvement in HAQ-DI >0.22 units at end of controlled

period, >3 mos; maintained in open-label• Major clinical response

– ACR70 for >6 continuous months• Complete clinical response/remission

– ACR remission + radiographic arrest >6 months


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Tocilizumab Biologics License Tocilizumab Biologics License Application (BLA)Application (BLA)

Tocilizumab Biologics License Tocilizumab Biologics License Application (BLA)Application (BLA)

• Intended to seek initial claim of reducing signs and symptoms of moderately to severely active RA

• 24 week data from 5 pivotal studies– Covers the range of RA patients, from early RA to more

refractory – Includes data for monotherapy, concomitant MTX and other

non-biologic DMARDs• Open-label Long-Term Extensions (LTE)

– Patients completing the core studies were allowed to enroll into LTE upon completion

– Planned for total of 5 years– Interim data submitted; close to 1500 patients have received

tocilizumab for up to 18 months

• Intended to seek initial claim of reducing signs and symptoms of moderately to severely active RA

• 24 week data from 5 pivotal studies– Covers the range of RA patients, from early RA to more

refractory – Includes data for monotherapy, concomitant MTX and other

non-biologic DMARDs• Open-label Long-Term Extensions (LTE)

– Patients completing the core studies were allowed to enroll into LTE upon completion

– Planned for total of 5 years– Interim data submitted; close to 1500 patients have received

tocilizumab for up to 18 months


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EfficacyEfficacyEfficacyEfficacy


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Summary of ACR Responders at Week 24Summary of ACR Responders at Week 24Summary of ACR Responders at Week 24Summary of ACR Responders at Week 24

ITT =

Intent to

Treat


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Subgroup Analyses: By Demographics and Geographic Subgroup Analyses: By Demographics and Geographic RegionRegion

Subgroup Analyses: By Demographics and Geographic Subgroup Analyses: By Demographics and Geographic RegionRegion

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Subgroup Analyses: By Disease CharacteristicsSubgroup Analyses: By Disease CharacteristicsSubgroup Analyses: By Disease CharacteristicsSubgroup Analyses: By Disease Characteristics

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Sensitivity AnalysesSensitivity AnalysesSensitivity AnalysesSensitivity Analyses


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SafetySafetySafetySafety


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ExposureExposureExposureExposure


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Overview of Adverse Events and DeathsOverview of Adverse Events and DeathsOverview of Adverse Events and DeathsOverview of Adverse Events and Deaths


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Exposure-Adjusted Incidence RatesExposure-Adjusted Incidence RatesExposure-Adjusted Incidence RatesExposure-Adjusted Incidence Rates

Background rates for RA patients: 2.4-2.5 deaths/100 pt-yrs

Background rates for RA patients: 1.3-1.4 malignancies/100 pt-yrs

Background rates for RA patients: 5-6 SIE/100 pt-yrs for TNF inhibitors, 2-4 SIE/100 pt-yrs for non-biologic DMARDs


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DeathsDeaths• 5 patients died of cardiac etiologies (4 MI and 1

cardiac failure)• 4 patients died of infectious etiologies

• 5 patients died of cardiac etiologies (4 MI and 1 cardiac failure)

• 4 patients died of infectious etiologies


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Neoplasms/MalignanciesNeoplasms/Malignancies


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Serious infectionsSerious infections

•No protocol-mandated TB screening or prophylaxis

•68 (52 in TCZ-groups) patients had a history of TB and/or positive PPD at baseline (but patients with active or history of recurrent TB were excluded)

•No patients developed reactivation or dissemination of TB

•2 cases of extrapulmonary mycobacterial infection in LTE (1 patient PPD neg, the other without history of risk factors or exposure)


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Serious Adverse EventsSerious Adverse Events

• Exposure adjusted rates – Were similar for placebo/DMARD and

TCZ/DMARD treatment arms (16 & 17/100 pt-yrs, respectively)

– Were lower for TCZ 8 mg/kg and MTX monotherapy groups (10 & 12/100 pt-yrs, respectively)

– Did not rise in LTE (13/100 pt-yrs)

• Most common SAEs– Infections (2% in controlled period, 5% in LTE)– GI and Injury SOCs (1% in controlled period, 2%

in LTE)

• Exposure adjusted rates – Were similar for placebo/DMARD and

TCZ/DMARD treatment arms (16 & 17/100 pt-yrs, respectively)

– Were lower for TCZ 8 mg/kg and MTX monotherapy groups (10 & 12/100 pt-yrs, respectively)

– Did not rise in LTE (13/100 pt-yrs)

• Most common SAEs– Infections (2% in controlled period, 5% in LTE)– GI and Injury SOCs (1% in controlled period, 2%

in LTE)

LTE=Long-term extension


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Serious Adverse EventsSerious Adverse Events• Myocardial infarction

– 15 events/4158 pt-yrs = 0.35/100 pt-yrs– Published rates in RA patients

• 0.47/100 pt-yrs, ARAMIS database• 0.76/100 pt-yrs, NDBRD

• Cerebrovascular accidents– 9 events/4158 pt-yrs = 0.22/100 pt-yrs– Published rates in RA patients

• 0.11/100 pt-yrs in female RA pts within Nurse’s Health Study

• 0.76/100 pt-yrs in UK General Practice Research database

• Myocardial infarction– 15 events/4158 pt-yrs = 0.35/100 pt-yrs– Published rates in RA patients

• 0.47/100 pt-yrs, ARAMIS database• 0.76/100 pt-yrs, NDBRD

• Cerebrovascular accidents– 9 events/4158 pt-yrs = 0.22/100 pt-yrs– Published rates in RA patients

• 0.11/100 pt-yrs in female RA pts within Nurse’s Health Study

• 0.76/100 pt-yrs in UK General Practice Research database

ARAMIS=Arthritis, Rheumatism and Aging Medical Information System

NDBRD=National Data Bank for Rheumatic Diseases


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AE Causing DiscontinuationAE Causing Discontinuation


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Other AE of Interest: GI PerforationsOther AE of Interest: GI Perforations• 11 events in the 5 RA pivotal studies/LTE• 5 events in the Chugai RA studies• Patients were receiving TCZ 8 mg/kg at time of event

(except one who remains on blinded treatment)• Most patients were receiving prednisone and/or NSAIDs

concomitantly

• 11 events in the 5 RA pivotal studies/LTE• 5 events in the Chugai RA studies• Patients were receiving TCZ 8 mg/kg at time of event

(except one who remains on blinded treatment)• Most patients were receiving prednisone and/or NSAIDs

concomitantly


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Other AE of Interest: Demyelinating AEOther AE of Interest: Demyelinating AE

• ~4700 patients have been exposed to TCZ for ~7961 pt-yrs exposure in the global RA program

• These 4 cases = 0.05 per 100 pt-yrs• Background rate of demyelinating disorders in RA patients

is not currently known

• ~4700 patients have been exposed to TCZ for ~7961 pt-yrs exposure in the global RA program

• These 4 cases = 0.05 per 100 pt-yrs• Background rate of demyelinating disorders in RA patients

is not currently known


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Lab Abnormalities: HematologyLab Abnormalities: HematologyLab Abnormalities: HematologyLab Abnormalities: Hematology

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Lab Abnormalities: LipidsLab Abnormalities: LipidsLab Abnormalities: LipidsLab Abnormalities: Lipids

•All lipid parameters, including HDL, increased; however the TC/HDL ratio was also increased


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Lab Abnormalities: Liver EnzymesLab Abnormalities: Liver EnzymesLab Abnormalities: Liver EnzymesLab Abnormalities: Liver Enzymes


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Lab Abnormalities: Liver EnzymesLab Abnormalities: Liver EnzymesLab Abnormalities: Liver EnzymesLab Abnormalities: Liver Enzymes


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Predicting Serious HepatotoxicityPredicting Serious Hepatotoxicity

• Hy’s law: based on the observation by the eponymous Dr. Hy Zimmerman that drug-induced jaundice caused by hepatocellular injury, without an obstructive component, has a high rate of bad outcomes (10-50% mortality)

• Hy’s law components:– Transaminase elevations >3 x ULN and– Total bilirubin >2 x ULN and– No evidence of biliary obstruction (elevated alkaline

phosphatase) or Gilbert’s syndrome• Based on original estimates of mortality, severe drug-induced

liver injury can be estimated to occur at a rate of at least 1/10th the rate of Hy’s law cases

• Hy’s law utilized by FDA to identify drugs likely to be capable of causing severe liver injury

• Hy’s law: based on the observation by the eponymous Dr. Hy Zimmerman that drug-induced jaundice caused by hepatocellular injury, without an obstructive component, has a high rate of bad outcomes (10-50% mortality)

• Hy’s law components:– Transaminase elevations >3 x ULN and– Total bilirubin >2 x ULN and– No evidence of biliary obstruction (elevated alkaline

phosphatase) or Gilbert’s syndrome• Based on original estimates of mortality, severe drug-induced

liver injury can be estimated to occur at a rate of at least 1/10th the rate of Hy’s law cases

• Hy’s law utilized by FDA to identify drugs likely to be capable of causing severe liver injury


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Single Hy’s Law Case Identified in Tocilizumab Global RA Program

Single Hy’s Law Case Identified in Tocilizumab Global RA Program

• Female, late 50’s, completed 6-months of TCZ 8 mg/kg monotherapy with only isolated increases in total bilirubin >1 x ULN and without simultaneous increase in transaminases or alkaline phosphatase

• Enrolled in LTE, began MTX at 20 mg weekly without dose titration, began treatment with open-label TCZ 8 mg/kg

• Week 5, noted to have ↑AST 2 x ULN, ↑ALT 4 x ULN and ↑T Bili < 2 x ULN

• Week 9, AST peaked at >10 x, ALT at >16 x, and T bili at >2 x; TCZ and MTX withheld, elevations normalized by week 12

• Week 11, MTX re-started at 10 mg/week• Week 12, TCZ re-started at 4 mg/kg• Week 15, transaminases and total bilirubin were above ULN• Week 16, study treatment discontinued and patient withdrawn• Week 20, transaminases and total bilirubin were normal• No clinical adverse events were associated

• Female, late 50’s, completed 6-months of TCZ 8 mg/kg monotherapy with only isolated increases in total bilirubin >1 x ULN and without simultaneous increase in transaminases or alkaline phosphatase

• Enrolled in LTE, began MTX at 20 mg weekly without dose titration, began treatment with open-label TCZ 8 mg/kg

• Week 5, noted to have ↑AST 2 x ULN, ↑ALT 4 x ULN and ↑T Bili < 2 x ULN

• Week 9, AST peaked at >10 x, ALT at >16 x, and T bili at >2 x; TCZ and MTX withheld, elevations normalized by week 12

• Week 11, MTX re-started at 10 mg/week• Week 12, TCZ re-started at 4 mg/kg• Week 15, transaminases and total bilirubin were above ULN• Week 16, study treatment discontinued and patient withdrawn• Week 20, transaminases and total bilirubin were normal• No clinical adverse events were associated


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Implications of Hy’s Law CaseImplications of Hy’s Law Case

• Confounded by concomitant initiation of relatively high dose MTX, which has known hepatotoxicity, but with positive re-challenge to TCZ

• 1 case in approximately 4700 patients in the TCZ global RA program:– Using estimate of severe drug-induced liver injury

as occurring at 1/10th the rate of Hy’s Law cases, 1 case might be expected in 47,000 treated patients

• Confounded by concomitant initiation of relatively high dose MTX, which has known hepatotoxicity, but with positive re-challenge to TCZ

• 1 case in approximately 4700 patients in the TCZ global RA program:– Using estimate of severe drug-induced liver injury

as occurring at 1/10th the rate of Hy’s Law cases, 1 case might be expected in 47,000 treated patients


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Plausible Mechanisms?Plausible Mechanisms?

• IL6 appears to have a hepatoprotective effect on various forms of liver injury and promotes hepatocyte regeneration– Inhibition could lead to increased hepatocyte

susceptibility to hepatotoxic insults• Hepatocytes express high levels of IL6 receptor

– With ubiquitous anti-IL6R mAb binding in the liver, could even minimal complement-mediated cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC) result in some hepatic injury?

• IL6 appears to have a hepatoprotective effect on various forms of liver injury and promotes hepatocyte regeneration– Inhibition could lead to increased hepatocyte

susceptibility to hepatotoxic insults• Hepatocytes express high levels of IL6 receptor

– With ubiquitous anti-IL6R mAb binding in the liver, could even minimal complement-mediated cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC) result in some hepatic injury?


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ImmunogenicityImmunogenicityImmunogenicityImmunogenicity• 2% (46/2553) of patients tested were positive for anti-TCZ antibodies; 3%

(13/477) of patients tested in the LTE• 6% (10/159) of patients tested for events of potentially immunogenic origin

were positive; 3% (2/75) of patients tested in the LTE• In patients tested for loss of efficacy, 0/14 in the 6-month controlled period

and 1/50 in the LTE were positive

• 2% (46/2553) of patients tested were positive for anti-TCZ antibodies; 3% (13/477) of patients tested in the LTE

• 6% (10/159) of patients tested for events of potentially immunogenic origin were positive; 3% (2/75) of patients tested in the LTE

• In patients tested for loss of efficacy, 0/14 in the 6-month controlled period and 1/50 in the LTE were positive

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Infusion ReactionsInfusion ReactionsInfusion ReactionsInfusion Reactions• 7-9% of pts in TCZ tx groups experienced an acute infusion-related AE, compared to

5% of pts on placebo infusions, slightly higher (11%) in LTE• Discontinuations due to infusional AEs were uncommon• Of the 6 patients experiencing anaphylaxis, 3 were anti-TCZ antibody positive, 1 was

negative, 2 were not tested• Anaphylaxis events tended to occur at the 2nd to 4th infusions

• 7-9% of pts in TCZ tx groups experienced an acute infusion-related AE, compared to 5% of pts on placebo infusions, slightly higher (11%) in LTE

• Discontinuations due to infusional AEs were uncommon• Of the 6 patients experiencing anaphylaxis, 3 were anti-TCZ antibody positive, 1 was

negative, 2 were not tested• Anaphylaxis events tended to occur at the 2nd to 4th infusions

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Risk-Benefit OverviewRisk-Benefit OverviewRisk-Benefit OverviewRisk-Benefit Overview


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SummarySummary

• Efficacy– Treatment with tocilizumab resulted in statistically

significant increases in clinical responses• Safety

– Treatment with tocilizumab appears to be associated with increased risk of serious infection and significant liver enzyme elevation

– Malignancies, GI perforations and demyelinating adverse events were observed in the clinical trials but the relative risk and role of TCZ treatment for the development of these AEs is not well-defined

• Decision to approve and optimal patient population requires careful balancing of benefits and risks

• Efficacy– Treatment with tocilizumab resulted in statistically

significant increases in clinical responses• Safety

– Treatment with tocilizumab appears to be associated with increased risk of serious infection and significant liver enzyme elevation

– Malignancies, GI perforations and demyelinating adverse events were observed in the clinical trials but the relative risk and role of TCZ treatment for the development of these AEs is not well-defined

• Decision to approve and optimal patient population requires careful balancing of benefits and risks

arthritis advisory committee july 29, 2008 actemra (tocilizumab) for rheumatoid arthritis fda...

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