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FDA Advisory Committee January 13, 2003

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..”

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FDA Advisory Committee January 13, 2003

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  1. FDA Advisory CommitteeJanuary 13, 2003 Genzyme Marketing Application STN 103979 / 0 Recombinant human -Galactosidase For Treatment of Fabry Disease

  2. 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

  3. 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

  4. 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

  5. Overview of clinical trials

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. AGAL-002: Results • Primary endpoint: kidney histology score • Comparison of number of 0-scores • p < 0.001

  13. 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

  14. AGAL-002: Results • Secondary endpoints • McGill pain questionnaire—no effect • Skin and heart capillary endothelium – number with scores of 0

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Open-label extension treatment: Results Numbers of subjects with scores of 0 in capillary endothelium at 6 months of the extension

  21. 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

  22. 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

  23. 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)

  24. Extension trial histology: 6 months • Histology on additional cell types Number of subjects with scores of 0 (only among those with non-0 baseline score)

  25. 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

  26. Extension trial histology: 18 months Skin superficial and deep capillary endothelial cell scores at 18 months

  27. Long-term skin histology-skin superficial capillary endothelium Five subjects with non-0 month 18 scores

  28. 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/ml) • Remained low in continuer group (2.3 to 1.4 ng/ml) • Antibody development (18 months) • 25/28 crossovers seroconverted • 3 continuers seroconverted during the extension

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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.

  35. 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

  36. 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.

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. Historical control: Failure to “qualify” • Reasons for patients to fail to provide data to “qualified” data set (447 total patients)

  44. Historical control: demographics and characteristics *estimated

  45. 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

  46. Historical creatinine data: Examples

  47. Historical creatinine data: Examples (continued)

  48. Historical creatinine data: Examples (continued)

  49. Historical creatinine data: Examples (continued)

  50. 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

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