fda advisory committee january 13, 2003 genzyme marketing application stn 103979 / 0 recombinant...
TRANSCRIPT
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
AGAL-002: ResultsAGAL-002: Results
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
AGAL-002: ResultsAGAL-002: Results
Antibody development Occurred in 24/29 treated subjects
PharmacokineticsSmall amount of data suggests decrease
in enzyme exposure with highest antibody titers
AGAL-002: ResultsAGAL-002: Results
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
Requests & responses to first review Requests & responses to first review cyclecycle
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
Requests & responses to first review Requests & responses to first review cyclecycle
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)
Extension trial histology: 6 monthsExtension trial histology: 6 months
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
Extension trial histology: 18 monthsExtension trial histology: 18 months
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.
Accelerated ApprovalAccelerated Approval
§ 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
Accelerated ApprovalAccelerated Approval
§ 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.
Accelerated ApprovalAccelerated Approval
§ 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)
Historical creatinine data: Examples Historical creatinine data: Examples (continued)(continued)
0 1 2 3 4
1.5
2
3
4
5
6
78S
erum
Cre
atin
ine
Time (yrs)
Historical creatinine data: Examples Historical creatinine data: Examples (continued)(continued)
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