fda advisory committee january 13, 2003 genzyme marketing application stn 103979 / 0 recombinant...

FDA Advisory CommitteeFDA Advisory CommitteeJanuary 13, 2003January 13, 2003

Genzyme Marketing ApplicationSTN 103979 / 0

Recombinant human -Galactosidase

For Treatment ofFabry Disease

Agalsidase beta: Proposed Agalsidase beta: Proposed indication and doseindication and dose

Proposed indication:“..indicated for use as a long-term enzyme

replacement..”

Proposed dose:1 mg/kg IV every other week

Approval requested under Accelerated Approval framework

Order of topicsOrder of topics

Fabry Disease overview Overview of clinical development of

agalsidase beta Highlights of notable study results Overview of accelerated approval Description of proposal for modification of

verification trial Review of historical data set and proposed

analysis

Fabry DiseaseFabry Disease X-linked deficiency of alpha-Galactosidase

Mostly males affected

Pathophysiology: accumulation of substrate

Many cell types involved

Early manifestations pain and paresthesias, angiokeratomas, hypohydrosis, ocular opacities

Primary morbidity and mortality vascular: renal, cardiac, neurologic

No approved treatment; only palliation

Orphan disease population

Overview of clinical trialsOverview of clinical trialsTrial Country Design n

FB9702 USA Sequential, open-label, dose-level escalation

15

AGAL-006

USA Extended administration for FB9702

15

AGAL-002

Multi-nat’l

Randomized 1:1, double-blind, placebo-controlled

58

AGAL-005

Multi-nat’l

Noncontrolled, extension for AGAL-002

58

AGAL-007

Japan Open-label, noncontrolled 13

AGAL-008

Multi-nat’l

Randomized 2:1, double-blind, placebo-controlled [Ongoing]

76

FB9702: DesignFB9702: Design

15 males with Fabry Disease

0.3-3.0 mg/kg, given q2 or q14 days for 5 doses

Histological scores on biopsies of liver, skin, heart, and kidney

PK, safety outcomes

FB9702: ResultsFB9702: Results Liver histology: insufficient data Skin, heart, and kidney histology

Reductions in capillary endothelial GL-3 for available paired biopsies

Reductions not seen in all cell types examined

Total GL-3 levels reduced in most organ biopsies

Plasma GL-3 levels fell in all groups PK Clinical efficacy not observed Infusion reactions occurred

AGAL-002: DesignAGAL-002: Design Double-blind 58 subjects randomized 1:1 to placebo or

agalsidase beta for 5 months Dose of product: 1 mg/kg every other week Objectives: activity and safety Subjects

No renal insufficiency (serum creatinine 2.2)

EvaluationsBaseline and end-of-trial biopsies

Kidney, skin, and heartClinical laboratory and antibodies

AGAL-002: EndpointsAGAL-002: Endpoints

Primary endpoint: Renal capillary endothelium histologyBlinded evaluations; pathologists trainedInitial readingSubsequent re-reading of low-score slidesEndpoint analysis: comparison of number of

subjects with a score of 0 at the end of the trial Secondary endpoints:

PainGL-3 histology composite

Kidney, skin, and heart capillary endotheliumTotal GL-3 levels in urine and kidney

AGAL-002: ConductAGAL-002: Conduct

Protocol changes Site enrollment

8 sites (Mt. Sinai with 20 subjects) No discontinuations Treatment assignment errors

4 reversals of treatment at one site2 subjects at another site with reversal

of treatment after 3rd dose Adherence to dosing excellent

AGAL-002: Demographics and AGAL-002: Demographics and baseline characteristicsbaseline characteristics

Well balanced for age, weight, height, plasma alpha-Gal and GL-3, years of symptoms, blood type (B, non-B)

Only 2 females, both in agalsidase beta group

About 90% “White” in both groups

AGAL-002: ResultsAGAL-002: Results Primary endpoint: kidney histology score

Comparison of number of 0-scoresp < 0.001

Score

Placebo

n=29

Agalsidase beta

n=29

Baseline End Baseline End

0 0 0 1 20

1 4 7 7 8

2 15 11 14 0

3 10 11 7 1*

AGAL-002: ResultsAGAL-002: Results

Important supportive analyses by Genzyme Consistency of pathologists in scoringTrial siteAge; ethnicity and genderCapillary scoring criterion on individual

slides CBER analyses

Quartiles of baseline plasma and kidney GL-3

Summary : primary endpoint result robust

AGAL-002: ResultsAGAL-002: Results Secondary endpoints

McGill pain questionnaire—no effectSkin and heart capillary endothelium –

number with scores of 0

Organ

Placebo

N=29

Agalsidase beta

N=29

Baseline End Baseline End

Heart 5 1 5 21

Skin 2 1 2 29


Secondary endpoints (cont’d)Urinary GL-3

Results inconclusiveKidney GL-3 (median reduction):

34% agalsidase beta6% placebo

GFRNo difference between groups

Serum creatinine: No change from baseline for either

group


Antibody development Occurred in 24/29 treated subjects

PharmacokineticsSmall amount of data suggests decrease

in enzyme exposure with highest antibody titers


SafetyNo deathsSerious adverse events show no patternInfusion-related events chief concern

16/29 agalsidase treated, 0 placebo 12/16 with suspected hypersensitivityNo factors predict susceptibility

Nonserious adverse events show no concerning pattern

AGAL-002: ConclusionsAGAL-002: Conclusions

AGAL-002 is the largest controlled experience of agalsidase beta to date

Primary endpoint showed robust effect on renal endothelium histology

No differences between groups on clinical efficacy outcomes

Infusion reactions common, sometimes severe

Antibody reactivity common

AGAL-005: Single arm, open-label AGAL-005: Single arm, open-label treatment extension to AGAL-002treatment extension to AGAL-002

1 mg/kg every other week All subjects from AGAL-002 Procedures

Kidney, heart, and skin biopsy at 6 months

Additional skin biopsy at 12 and 18 months and yearly thereafter

Principal effect measurement: kidney histologically determined GL-3

Serum and urine labs, antibodies, clinical status, safety determined

Open-label extension treatment: Open-label extension treatment: ResultsResults

Numbers of subjects with scores of 0 in capillary endothelium at 6 months of the

extension

Placebo-agal Agal-agal

Kidney interstitial 24/24 23/24

Skin superficial 21/23 23/24

Heart 13/18 19/22

Requests & responses to first review Requests & responses to first review cyclecycle

Initial FDA Review Letter (Dec. 2000) Acknowledged evidence of effect on endothelial

cells Raised concern if surrogate was likely to predict

clinical benefitRenal function not affected during study;

possibility of years of treatment needed before benefit seen

Histologic findings not uniform across cell types; certain cell types in kidney, skin, and heart did not show reduction in accumulation


Infusion reaction information limitedSome reactions severePossibility of increase in frequency or

severity with duration of useInsufficient basis to predict susceptibility

Development of antibodies widespreadPotential for diminution of histological

effect Possibly prior to clinical benefit

Potential ongoing safety risk 6 month data from extension study do not

alleviate concern for long-term use


Concerns regarding Verification Study Adequacy of poweringFeasibility to complete

Complete response to CR letter received from Genzyme (April, 2001)

Extension trial histology: 6 monthsExtension trial histology: 6 months

Cell Type Placebo-Agal Agal-Agal

Glomerular endothelial

21/21 17/17

Interstitial 19/24 23/23

Noncapillary endothelial

19/22 19/20

Mesangial 19/21 17/17

Histology on additional cell types

Number of subjects with scores of 0(only among those with non-0

baseline score)


Podocytes and mesangial cell matrix: no notable effect

Noncapillary smooth muscle cellsNo subjects with scores of 0, but >77%

had a decrease in score from baseline Distal convoluted tubules/collecting ducts

From 67% (placebo crossovers) to 50% (agal beta continuers) of subjects had a decrease in score


Skin superficial and deep capillary endothelial cell scores at 18 months

Endothelial cell location

Placebo-Agal Agal-Agal

Zero Non-Zero

Zero Non-Zero

Superficial

Capillary

20 2 21 3

Deep vessel

capillary

17 4 16 6

Long-term skin histology-skin Long-term skin histology-skin superficial capillary endotheliumsuperficial capillary endothelium

5-month controlled

phaseSingle-arm treatment phase

Pt # Treatment BL End 6 mo 12 mo

18 mo

30 mo

1 Pbo-Agal 2 2 0 0 1 0

2 Agal-Agal 2 0 0 0 1 0

3 Pbo-Agal 3 2 0 0 1 0

4 Agal-Agal 2 0 0 1 2 0*

5 Agal-Agal 2 0 0 0 1 n.d.

Five subjects with non-0 month 18 scores

Open-label extension: Additional Open-label extension: Additional resultsresults Renal endpoints

GFR and serum creatinine (18 months)no change in either group

Urinary GL-3 (6 months): inconclusive

Plasma GL-3 (12-months) Decreased in crossover group (15.3 to 0.6 ng/l)Remained low in continuer group (2.3 to 1.4

ng/l)

Antibody development (18 months)25/28 crossovers seroconverted3 continuers seroconverted during the extension

Open-label extension: Safety resultsOpen-label extension: Safety results

1 death Serious adverse events

Biopsy, miscellaneous, infusional, and cardiac/neurological

Other adverse eventsInfusional

34/58 subjects in the 1st 6 monthsDecrease in frequency with time3 withdrawals for the development of IgE

No pattern of other toxicities

Open-label extension: ConclusionsOpen-label extension: Conclusions

Biopsy data in placebo crossovers confirm the short-term results from AGAL-002

Despite widespread antibody development, histological effects, GFR, and serum creatinine appear to be stable

Infusion reactions wane in frequency, do not disappear with time

AGAL-007AGAL-007

Open-label trial of 13 males with Fabry Disease; same duration and dose of treatment as AGAL-002

Bioactivity data resultsEndothelial cell score 0 in nearly all subjects Podocytes, mesangial cell matrix no changeOther cell types

Reductions consistent with AGAL-002No change in renal functionNo change in sweating, abdominal pain

Antibody: 11/13 seroconversions

Additional safety dataAdditional safety data

Data baseAGAL-006 (15 subjects)AGAL-007 (13 subjects)AGAL-008 : ongoing, double-blind, placebo-

controlled trial (deaths, SAE only available) Events

5 deaths consistent with vasculopathy; 1 sepsis

Serious adverse events cardiac/neurologic, infusional, and other

Summary of safety and efficacySummary of safety and efficacy Histology results are robust, not isolated, but not

uniform; stable to antibody formation

No treatment effect observed on clinical efficacy assessments including pain or on renal function

Antibody development nearly universal

Severe infusion reactions may occur; no predictive factor; IgE development occurs, some diminution in frequency of infusion reactions

Accelerated ApprovalAccelerated Approval

§ 601.40 Scope

Applies to biological products studied for safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments.


§ 601.41 Approval based on a surrogate endpoint.

FDA may grant marketing approval on the basis of:Adequate and well-controlled clinical trialsEstablishing an effect on a surrogate

endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit


§ 601.41 Approval based on a surrogate endpoint.

Approval carries requirement to study product further To verify and describe its clinical benefitPostmarketing studies would usually be

studies already underway. Such studies must also be adequate and

well-controlled.Such studies shall be carried out with due

diligence.


§ 601.43 Withdrawal procedures. (a) For biological products approved under

§ 601.40, FDA may withdraw approval, following a hearing … if: (1) A postmarketing clinical study fails

to verify clinical benefit(2) The applicant fails to perform the

required postmarketing study with due diligence

Verification trial AGAL-008Verification trial AGAL-008 Currently fully enrolled Design

Double-blind, placebo-controlledSubjects must have renal impairmentEndpoint composite of 1st occurrence any of

Serum creatinine 33% rise or need for dialysis

MI, new symptomatic arrhythmia, unstable angina, new or worsening heart failure

New stroke, TIAPrimary endpoint: comparison of rate of

composite event

Proposal for conversion of Proposal for conversion of verification trialverification trial

Convert placebo-controlled trial to an open-label trial

Each subject continues for 3 years or to endpoint event

Historical data as comparator

Historical control data collectionHistorical control data collection

Protocol AGAL-014: Historical data collectionObjective: generate event rate for the

historical populationSites asked to enroll, patients consentedData collection focused upon renal

function and adverse events, cardiac adverse events, neurologic adverse events

Collection of demographics and characteristics

Historical control: “Qualified” data Historical control: “Qualified” data setset Establishment of “qualified” data set

For each patient, determine if there is a date at which the patient would qualify as a subject for AGAL-008

Use data starting at the time of qualification

Data for “qualified” set stop when patient receives agalsidase or has renal, cardiac or neurologic adverse event (endpoint event)

“Qualified” data will often not include all collected creatinine values for each patient

Historical control: “Qualified” data Historical control: “Qualified” data setset 27 / 51 sites agreed to participate

Patient participation

Based on interim review of screening logs

58% of patients agreed to participate

Complete study included 447 subjects

103 patients included in “qualified” data

Historical control: Failure to Historical control: Failure to “qualify”“qualify” Reasons for patients to fail to provide data to

“qualified” data set (447 total patients)

Disqualification Reason

Number of patients Patients with missing data

Serum creatinine

186 (normal)

12

(high)

38

Alpha-Gal activity

76 leukocyte

62

plasma

64

Age 24 38

Any criterion 332

Adverse event 12

Historical control: demographics and Historical control: demographics and characteristicscharacteristics

Qualifiers

N=104

AGAL-008

N=61

Age (years) Mean ± sd 38 ± 10 46 ± 10

Serum creatinine

(mg/dl) Mean ± sd 1.5 ± 0.5 1.7 ± 0.5

GFR*

(ml/min/1.73 m2) Mean ± sd 62 ± 19 52 ± 17

Gender (Male) N (%) 98 (94) 54 (89)

Ethnicity (Caucasian) N (%) 88 (85) 55 (90)

*estimated

Characteristics of “qualified” datasetCharacteristics of “qualified” dataset

Among 103 “qualified” patients:

Number of creatinine values per patient18 patients with only 1 creatinine value22 patients with only 2 creatinine values63 patients with 3 or more creatinine

values

Duration of followupMedian period of followup 1.4 years41 patients with 1 month or less

Historical creatinine data: ExamplesHistorical creatinine data: Examples

0.0 0.5 1.0 1.5 2.0 2.5 3.0

1.5

2

2.5

3

3.5

4

4.55

Ser

um C

reat

inin

e

Time (years)

Historical creatinine data: Examples Historical creatinine data: Examples (continued)(continued)

0 2 4 6 8 10

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.8

1.9

2.0S

erum

Cre

atin

ine

Time (yrs)


0 1 2 3 4

1.5

2

3

4

5

6

78S

erum

Cre

atin

ine

Time (yrs)


0 1 2 3 4 5

1.5

2

2.5

3

3.5

4

4.5S

erum

Cre

atin

ine

Time (yrs)

Historical datasetHistorical dataset

Proposed use of historical dataObjective: provide quantitative

comparison to data from revised-design Study 008

Define new primary endpoint for revised Study 008:

Comparison of percentage of patients with 50% or higher rise in creatinine within 3 years of starting enzyme treatment

Historical DatasetHistorical Dataset

Proposed use of historical data (cont’d)Use historical dataset to derive estimate

of percent of patients showing 50% rise in creatinine within 3 years of “qualification” date

Analyze Study 008 by comparing Study 008 observed rate of renal dysfunction progression (50% creatinine rise) to historical estimate

Issues in use of historical controlIssues in use of historical control

Comparability of populations in historical and new trial datasets

Comparability of patient-external factors that influence disease course

Accuracy of analytic/modeling method for prediction

Robustness of historical dataset under application of selected analytic method

Comparability of historical to trial Comparability of historical to trial populationpopulation Patient ascertainment process very different Self-selection process may be different

60% of patients agreed to participate Distribution of important demographics Distribution of important disease-specific

factors Adequacy of understanding of important factors

Distribution of important characteristics which are not yet known to be important

Genzyme’s approach: Use eligibility criteria to create “qualified” dataset

Comparability of patient-external Comparability of patient-external factorsfactors

May influence disease course Medical management changes over time

Disease specific treatmentsSymptom/sign-specific treatments with

impact on disease-related impairment of organ system

Accuracy of historical control Accuracy of historical control analytic methodanalytic method

Accuracy of analytic/modeling method for predictionModeling may or may not be usedIf model used, adequacy of factors

included to account for disease natural course

If model used, validity of model’s assumptions

Robustness of historical dataRobustness of historical data Robustness of historical dataset with

selected analytic method Provision of similar estimates from similar

datasetsNumber of patientsNumber of observations per patientFrequency, uniformity of intervals of

observationFrequency may be non-random

Possible over-representation of disease progression events

Cautionary note based on prior proposal

Genzyme prior proposal provides an example method to illustrate potential pitfalls

Based on modeling of creatinine rise over timeAssume ln(creatinine) is linear over timeApply model to calculate a slope of renal

progression for 103 individual patientsEmpirical Bayes method permits slope

value for patients with 1 or more data values

Determine proportion of patient slopes that predict at least a 50% rise in creatinine within 3 years

Prior historical data analytical Prior historical data analytical methodmethod

Adequacy of modelAssumes linear rise ln(creatinine)

Sample data figures illustrate some, but not all patients, show linear trend

Non-linear alternative models (e.g., quadratic) provided better fit to dataset

Attribution of slope to patient data of only 1 value is of uncertain and untestable accuracy

Assessment of prior proposed Assessment of prior proposed methodmethod

Adequacy of the prior proposed modeling32% progression rate as method proposed23% progression rate with 1/creatinine

instead of ln(creatinine)Illustrates that assumption of ln(cr) is

correct transform important; but remains unproven

Robustness of dataset to analytic method40% progression rate in 43 early patients27% progression rate in 60 later patients32% progression rate in total 103

Illustrates that data are unstable to additions or removal of patients

Assessment of prior proposed Assessment of prior proposed methodmethod

Robustness of dataset to analytic methodInclude data only up to doubling of creatinine

Only 50% rise actually of interest87% of data values retainedYields progression rate of 21%

Empirical assessment Free of modeling assumptionsExamine dataset for all patients with approx

3 yrs of data, calculate fraction who show renal progression

41% rate observed; but only 17 patients available

Issues in use of historical controlIssues in use of historical control

Conclusions about prior proposalPrior proposal modeling method dependent

upon validity of assumptionsDifficult to test validityResult sensitive to change in

assumptions Empirical method may have advantages

Assumption-freePresent dataset too limited to apply

Increasing the available dataset may substantially improve the soundness of the historical comparison

Prior historical analysis: ConclusionsPrior historical analysis: Conclusions

Use existing historical dataset Create historical data subset matched to Study

008 patients using “propensity score” based on specified covariates

Add information from Study 008 placebo patientsUsing an unspecified prediction model, impute

values into historical dataset based on Study 008 placebo-period data

Using unspecified outcome measure, calculate historically predicted outcome event rate for Study 008 enzyme-treated patients

Compare prediction to actual observed event rate

New proposed analysis of historical New proposed analysis of historical datadata

Completeness of covariate selection in propensity score

Missing covariate data for historical patientsAssess amount and missing-at-random

approach to addressing Not 1:1 matching of Hx to Study008 Agal patients

Permits multiple Hx to 1 AgalDoes not ensure all Agal with at least 1 Hx

match Unspecified prediction model; used in imputation Unspecified outcome measure evaluated Conclusion: Full details required prior to being

able to assess proposal comprehensively

Issues: New proposed analytical Issues: New proposed analytical methodmethod

fda advisory committee january 13, 2003 genzyme marketing application stn 103979 / 0 recombinant...

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