# Presentation: 534303

## FDA Advisory CommitteeJanuary 13, 2003

- Genzyme Marketing Application
- STN  103979 / 0
- Recombinant human -Galactosidase
- For Treatment of
- Fabry Disease

## Agalsidase beta:  Proposed indication 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 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 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 trials

| Trial | 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: 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: 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: 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)
- Evaluations
- Baseline and end-of-trial biopsies
- Kidney, skin, and heart
- Clinical laboratory and antibodies

## AGAL-002: Endpoints

- Primary endpoint: Renal capillary endothelium histology
- Blinded evaluations; pathologists trained
- Initial reading
- Subsequent re-reading of low-score slides
- Endpoint analysis: comparison of number of subjects with a score of 0 at the end of the trial
- Secondary  endpoints:
- Pain
- GL-3 histology composite
- Kidney, skin, and heart capillary endothelium
- Total GL-3 levels in urine and kidney

## AGAL-002: Conduct

- Protocol changes
- Site enrollment
- 8 sites (Mt. Sinai with 20 subjects)
- No discontinuations
- Treatment assignment errors
- 4 reversals of treatment at one site
- 2 subjects at another site with reversal of  treatment after 3rd dose
- Adherence to dosing excellent

## AGAL-002: Demographics and baseline 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: Results

- Primary endpoint: kidney histology score
- Comparison of number of 0-scores
- p < 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: Results

- Important supportive analyses by Genzyme
- Consistency of pathologists in scoring
- Trial site
- Age; ethnicity and gender
- Capillary scoring criterion on individual slides
- CBER analyses
- Quartiles of baseline plasma and kidney GL-3
- Summary : primary endpoint result robust

## AGAL-002: Results

- Secondary endpoints
- McGill pain questionnaire—no effect
- Skin 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: Results

- Secondary endpoints (cont’d)
- Urinary GL-3
- Results inconclusive
- Kidney GL-3  (median reduction):
- 34% agalsidase beta
- 6%  placebo
- GFR
- No difference between groups
- Serum creatinine:
- No change from baseline for either group

## AGAL-002: Results

- Antibody development
- Occurred in 24/29 treated subjects
- Pharmacokinetics
- Small amount of data suggests decrease in enzyme exposure with highest antibody titers

## AGAL-002: Results

- Safety
- No deaths
- Serious adverse events show no pattern
- Infusion-related events chief concern
- 16/29 agalsidase treated,  0 placebo
- 12/16 with suspected hypersensitivity
- No factors predict susceptibility
- Nonserious adverse events show no concerning pattern

## AGAL-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 treatment 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: Results

- 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 cycle

- Initial FDA Review Letter (Dec. 2000)
- Acknowledged evidence of effect on endothelial cells
- Raised concern if surrogate was likely to predict clinical benefit
- Renal 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 cycle

- Infusion reaction information limited
- Some reactions severe
- Possibility of increase in frequency or severity with duration of use
- Insufficient basis to predict susceptibility
- Development of antibodies widespread
- Potential 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 cycle

- Concerns regarding Verification Study
- Adequacy of powering
- Feasibility to complete
- Complete response to CR letter received from Genzyme (April, 2001)

## Extension 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 months

- Podocytes and mesangial cell matrix: no notable effect
- Noncapillary smooth muscle cells
- No 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 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 superficial capillary endothelium

|  |  | 5-month controlled phase |  | 
Single-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 results

- 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 seroconverted
- 3 continuers seroconverted during the extension

## Open-label extension: Safety results

- 1 death
- Serious adverse events
- Biopsy, miscellaneous, infusional, and cardiac/neurological
- Other adverse events
- Infusional
- 34/58 subjects in the 1st 6 months
- Decrease in frequency with time
- 3 withdrawals for the development of IgE
- No pattern of other toxicities

## Open-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-007

- Open-label trial of 13 males with Fabry Disease; same duration and dose of treatment as AGAL-002
- Bioactivity data results
- Endothelial cell score 0 in nearly all subjects
- Podocytes, mesangial cell matrix no change
- Other cell types
- Reductions consistent with AGAL-002
- No change in renal function
- No change in sweating, abdominal pain
- Antibody: 11/13 seroconversions

## Additional safety data

- Data base
- AGAL-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 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 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 Approval

**§ 601.41 Approval based on a surrogate endpoint.**
- FDA may grant marketing approval on the basis of:
- Adequate and well-controlled clinical trials
- Establishing an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit

## Accelerated Approval

**§ 601.41 Approval based on a surrogate endpoint.**
- Approval carries requirement to study product further
- To verify and describe its clinical benefit
- Postmarketing 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 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-008

- Currently fully enrolled
- Design
- Double-blind, placebo-controlled
- Subjects must have renal impairment
- Endpoint 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, TIA
- Primary endpoint: comparison of rate of composite event

## Proposal for conversion of verification 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 collection

- Protocol AGAL-014:  Historical data collection
- Objective: generate event rate for the historical population
- Sites asked to enroll, patients consented
- Data collection focused upon renal function and adverse events, cardiac adverse events, neurologic adverse events
- Collection of demographics and characteristics

## Historical control: “Qualified” data set

- 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 set

- 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 “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 characteristics

|  |  | 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” dataset

- Among 103 “qualified” patients:
- Number of creatinine values per patient
- 18 patients with only 1 creatinine value
- 22 patients with only 2 creatinine values
- 63 patients with 3 or more creatinine values
- Duration of followup
- Median period of followup 1.4 years
- 41 patients with 1 month or less

## Historical creatinine data: Examples

## Historical creatinine data: Examples (continued)

## Historical creatinine data: Examples (continued)

## Historical creatinine data: Examples (continued)

## Historical dataset

- Proposed use of historical data
- Objective:  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 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 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 population

- 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 factors

- May influence disease course
- Medical management changes over time
- Disease specific treatments
- Symptom/sign-specific treatments with impact on disease-related impairment of  organ system

## Accuracy of historical control analytic method

- Accuracy of analytic/modeling method for prediction
- Modeling may or may not be used
- If model used, adequacy of factors included to account for disease natural course
- If model used, validity of model’s assumptions

## Robustness of historical data

- Robustness of historical dataset with selected analytic method
- Provision of similar estimates from similar datasets
- Number of patients
- Number of observations per patient
- Frequency, uniformity of intervals of observation
- Frequency 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 time
Assume ln(creatinine) is linear over time
Apply model to calculate a slope of renal progression for 103 individual patients
Empirical 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

- Based on modeling of creatinine rise over time
- Assume ln(creatinine) is linear over time
- Apply model to calculate a slope of renal progression for 103 individual patients
- Empirical 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 method*

## 
Adequacy of model
Assumes 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

- Adequacy of model
- Assumes 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 method*

## Adequacy of the prior proposed modeling
32% progression rate as method proposed
23% 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 method
40% progression rate in 43 early patients
27% progression rate in 60 later patients
32% progression rate in total 103
Illustrates that data are unstable to additions or removal of patients

- 32% progression rate as method proposed
- 23% 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 method
- 40% progression rate in 43 early patients
- 27% progression rate in 60 later patients
- 32% progression rate in total 103
- Illustrates that data are unstable to additions or removal of patients

*Assessment of prior proposed method*

## Robustness of dataset to analytic method
Include data only up to doubling of creatinine
Only 50% rise actually of interest
87% of data values retained
Yields progression rate of 21%
Empirical assessment 
Free of modeling assumptions
Examine dataset for all patients with approx 3 yrs of data, calculate fraction who show renal progression
41% rate observed; but only 17 patients available

- Include data only up to doubling of creatinine
- Only 50% rise actually of interest
- 87% of data values retained
- Yields progression rate of 21%
- Empirical assessment
- Free of modeling assumptions
- Examine 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 control*

## Conclusions about prior proposal
Prior proposal modeling method dependent upon validity of assumptions
Difficult to test validity
Result sensitive to change in assumptions
Empirical method may have advantages
Assumption-free
Present dataset too limited to apply
Increasing the available dataset may substantially improve the soundness of the historical comparison

- Prior proposal modeling method dependent upon validity of assumptions
- Difficult to test validity
- Result sensitive to change in assumptions
- Empirical method may have advantages
- Assumption-free
- Present dataset too limited to apply
- Increasing the available dataset may substantially improve the soundness of the historical comparison

*Prior 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 patients
Using 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 

- Create historical data subset matched to Study 008 patients using “propensity score” based on specified covariates
- Add information from Study 008 placebo patients
- Using 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 data*

## Completeness of covariate selection in propensity score 
Missing covariate data for historical patients
Assess amount and missing-at-random approach to addressing
Not 1:1 matching of Hx to Study008 Agal patients
Permits multiple Hx to 1 Agal
Does 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

- Missing covariate data for historical patients
- Assess amount and missing-at-random approach to addressing
- Not 1:1 matching of Hx to Study008 Agal patients
- Permits multiple Hx to 1 Agal
- Does 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 method*