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FDA Review of Clinical Data Laronidase for the treatment of Mucopolysaccharidosis I

FDA Review of Clinical Data Laronidase for the treatment of Mucopolysaccharidosis I BioMarin Pharmaceuticals, Inc. FDA/Center for Biologics Evaluation and Research. Introduction. BioMarin proposes the use of laronidase for the treatment of patients with MPS I

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FDA Review of Clinical Data Laronidase for the treatment of Mucopolysaccharidosis I

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  1. FDA Review of Clinical Data Laronidase for the treatment of Mucopolysaccharidosis I BioMarin Pharmaceuticals, Inc. FDA/Center for Biologics Evaluation and Research

  2. Introduction • BioMarin proposes the use of laronidase for the treatment of patients with MPS I • Proposed dose: 0.58 mg / kg(100 U / kg) IV administered once weekly

  3. MPS I • MPS I: lysosomal storage disease due to a genetic deficiency of a-L-iduronidase (IDU) • Progressive accumulation of glycosaminoglycans or GAG (Heparan sulfate and Dermatan sulfate) • MPS I affects multiple tissues and organs, leading to death during childhood in the most severe form • Morbidity and mortality usually from airway / pulmonary or cardiomyopathy / valvular disorders • 3 broad clinical categories (MPS I H, H-S, S) by severity, are arbitrary definitions in a continuum spectrum

  4. MPS I: Clinical Background • Diagnosis: IDU assay: serum, WBC’s, skin fibroblasts • Treatment: Supportive care only, for complications • Allogeneic BMT restricted to most severe MPS I Hurler: can be effective but usually limited to patients younger than 2 years. • Significant morbidity and mortality with this treatment, and without benefits to treat/ prevent neurologic decline

  5. Clinical Studies In all studies same Laronidase dose used

  6. BIO7500 • Non-controlled, open label • Initial study period: 26 weeks, extended and ongoing • 10 subjects • Male / female, age: older than 5 years • Enzymatic deficiency • Hepatosplenomegaly, ­GAG • Dose: 0.58 mg / kg IV over 3-4 hours, weekly

  7. BIO 7500 Notable evaluations • Liver / spleen volume by MRI • Urinary GAG per mg creatinine • Shoulder, knee, elbow ROM • Cardiac assessments • Airway assessments (Sleep study, MRI of airway index) • CNS: brain, cervical cord MRI

  8. BIO7500 Results • Liver volume: all reduced ≥ 20% by 1 year • Urinary GAG: all reduced ≥ 50% by week 6 • Most subjects had improvements in: • joint ROM (particularly shoulder flexion) • NYHA scores • Sleep apnea • Echo, visual acuity, CNS abnormalities, bone evaluations showed no change • Non-controlled, open label nature of this study precludes any conclusions about clinical efficacy

  9. BIO7500 Safety Results • Safety: • 8 / 10 subjects: SAE’s (allergic reactions, pneumonia, cervical cord compression, hydrocephalus) • 2 of these: death • Subject 008 (age 7) died after wk 103: • Respiratory distress and arrest • Viral lymphocytic myocarditis, bronchiolitis • High anti-laronidase IgG throughout study • Complement activation weeks 6-12 • Subject 002 (age 13) died after wk 137: • After surgical procedure

  10. BIO7500 Safety Results (Cont.) • Immunogenicity • 10 / 10 (+) by ELISA, 4 / 10 (+) by Western Blot (more specific). • Titers generally peak at 8-20 weeks and decline over time.

  11. BIO7500 Conclusion • Demonstration of bioactivity in liver GAG accumulation and urinary GAG excretion • No apparent correlation between IgG titers and reduction in liver / spleen size or urinary GAG • Open label, non-controlled study design does not allow conclusion of efficacy

  12. Study 003 • Randomized, Double-blind, Placebo-controlled, Multinational study • Duration: 26 weeks of treatment • Eligibility: • Male / female, age older than 5 years • IDU Enzyme activity < 10 % LLN • Signs and symptoms of MPS I • Baseline predicted FVC ≤ 80% • Dose: 0.58 mg / kg IV weekly

  13. Study 003 Notable evaluations • Pulmonary function tests • 6 minute walk distance (6MWD) • Sleep study • Liver volume • Urinary GAG • Joint ROM • EKG / echo

  14. Study 003 Endpoints • Primary: • Mean change from baseline to week 26 in % FVC based on current height • Mean absolute change from baseline to week 26 in 6MWD • Analysis method: Wilcoxon Rank Sum (ITT subjects) • Statistically significant only if both p < 0.05

  15. Study 003 Endpoints • Secondary: • AHI • Liver volume • Shoulder flexion • Disability index from CHAQ / HAQ • Multiple tertiary endpoints

  16. Study 003 Results • 45 subjects were randomized • 22 laronidase and 23 placebo • 5 centers

  17. Study 003 Results Demographic & Baseline characteristics

  18. Study 003 ResultsBaseline Characteristics (Cont.) • Both groups similar regarding: • Time from onset of symptoms • Time from diagnosis • Enzyme activity (± 1.5 %) • Weight and height • Baseline % FVC and 6MWD were lower in laronidase group, compared to placebo

  19. Study 003 Results % FVC

  20. Study 003: % FVC by study visit

  21. Study 003 FVC • FVC in absolute volume change from baseline to week 26: • Laronidase: 0.11 ± 0.14 L • Placebo: - 0.02 ± 0.13 L • p < 0.01

  22. Study 003: % FVC by gender and study visit(baseline height)

  23. 7-12 13-18 19-65 Laronidase 0 Placebo 0 Laronidase 26 Placebo 26 Study 003 Results % FVC by age category

  24. Study 003 Impairment % FVC at baseline Least Most

  25. Study 003 Results% FVC by impairment versus gender • Distribution of subjects: • Most laronidase males in the 2 most impaired %FVC categories at baseline • Most laronidase females in the 2 least impaired %FVC categories at baseline • Therefore, the effect of gender cannot be distinguished from the effect of impairment at baseline for laronidase subjects

  26. Study 003 6 Minute Walk Distance D wk 0 - 26 Placebo: -18 meters Dwk 0- 26 Laronidase: 20 meters p=0.07

  27. Study 003 6 MWD

  28. Study 003: 6 MWD by gender & study visit

  29. Study 003 6 MWD by impairment at baseline Quartiles of baseline distance walked (m)

  30. 7-12 13-18 19-65 Laronidase 0 Placebo 0 Laronidase 26 Placebo 26 Study 003 6 MWD by age category

  31. Study 003 2nd EP: Apnea Hypopnea IndexChange in AHI from baseline to week 26

  32. Study 003 Secondary endpoints (Cont.) • Liver volume: • Laronidase: -19 % (n=22) • Placebo: +1 % (n=22) • P = 0.001 • Similar to Phase 1 data • Disability Index: no difference between groups • Shoulder flexion: no difference between groups

  33. Study 003 Tertiary Endpoints • Urinary GAG: • Substantial decrease as early as week 4 among laronidase subjects • Change from baseline to week 26: • Laronidase: - 108 mcg / g creatinine • Placebo: + 67 mcg / g creatinine • P < 0.001 • Other endpoints: no difference between groups

  34. Study 003 Pharmacokinetic studies • 12 laronidase subjects assessed at infusion 1, 12 and 26 • Cmax :slight ­ (0.2 to 0.3 U/mL) over study period • Volume of distribution (Vz): ¯ wk 1 - 12 (0.6 to 0.3 L/Kg) • Decrease in Vz may be affected by antibody formation • Inverse correlation between antibody titers and Vz • Unknown if distribution of antibody bound-laronidase is different than unbound enzyme • Unknown if antibody formation affects differential lysosomal uptake among organs and tissues

  35. Study 003 Safety • AE’s mostly related to infusions of the assigned study agent • Prevalence in treatment groups • 11/ 23 placebo had 82 IAR’s • 7 / 22 laronidase had 66 IAR’s • Most common: headache, flushing and rash • Severe AE’s were most likely related to MPS I • SAE’s: • Hospital admission for abdominal pain (constipation) • Cardiac valvular disease worse requiring surgery. Complicated by cardiac arrest, sepsis, renal failure • Partial obstruction of ventricular shunt.

  36. Study 003 Safety (Cont.) • Labs: positive anti-laronidase IgG by RIP: • 20 laronidase subjects from weeks 4 or 8 to week 26 • 1 placebo subject (one visit only) • (-) IgE and complement activation in 3 IAR’s

  37. Study 003 Conclusions • Effect of laronidase on primary endpoints: • % FVC • Small effect size (mean increase 110 mL or 5.3 % predicted) (p=0.02) • Time course: Abrupt ­ wk 20 – 26 in laronidase, abrupt ¯ wk 0 – 4 in placebo, unexplained • Non uniform across subsets:­ effect in female and milder pulmonary restriction at baseline • 6 Minute Walk Distance • 38 m absolute mean difference, (p=0.07) • Non uniform across subsets: ­ effect in younger, female, with larger distance walked at baseline

  38. Study 003 Conclusions (Cont.) • AHI some suggestion of benefit in more severely affected subjects only • Pharmacodynamic effects on liver volume and urinary GAG in all subjects • Frequent infusion reactions in both treatment groups, generally mild to moderate • Anti-laronidase IgG formation nearly universal • Pharmacokinetic data suggestive of changes over time. Unclear long term consequences

  39. Study 006 • Open label, non-controlled extension study to 003 • All 45 subjects enrolled • Ongoing study (data from first 24 weeks presented) • Laronidase administered at 0.58 mg / kg (100 U / kg) IV weekly • Infusions performed at the 5 original sites or at 13 regional sub-sites. • Most evaluations at study entry (week 26 of Study 003) and every 12 weeks

  40. Study 006 % FVC by study visit Controlled Noncontrolled

  41. Study 006ChangesFVC by GenderStudy 003 or 006

  42. Study 006 Changes FVC by Age in Study 003 or 006

  43. Study 006 % FVC changes • Changes in absolute lung volumes were very small and similar for both groups • Unlike Study 003 data showing greater effect in less impaired laronidase subjects, no pattern can be seen during 24 weeks of Study 006 between groups across the quartiles of baseline % FVC impairment. This finding is expected due to absence of overall treatment effect.

  44. Study 006 6MWD Noncontrolled Controlled

  45. Study 006 Results6MWD in subset analyses • Gender: similar changein males / females of both groups • Age category: similar changein the 3 age categories of both groups • Severity at baseline: similar change in all quartiles of severity at baseline of both groups

  46. 2nd EP: AHI Changes in Studies 003 and 006

  47. Study 006: Other Endpoints • Liver volume decreased by 12.6 % in the placebo/laronidase group • Compare to 19 % decrease in the laronidase group in Study 003 • Both groups had a mean 6 degrees improvement in shoulder flexion during Study 006 • Disability Index was unchanged in both treatment groups during Study 006 • Urinary GAG ¯ a mean 69 % in the placebo/laronidase group

  48. Study 006 Safety • AE’s reported similar to those in Study 003 • One death (placebo/laronidase) of complication of URI/bronchitis • One notable SAE: life-threatening infusion reaction (anaphylactic) requiring emergency tracheostomy

  49. Study 006 Safety • 40 / 45 subjects in Study 006 developed anti-laronidase IgG by RIP assay • 21/23 placebo/laronidase became (+) during Study 006 • 20/22 laronidase/laronidase were (+) at entry, and another subject became (+) during Study 006; 2 (+) subjects became (-) after being (+) during Study 003. • No correlation with AE’s or IAR’s

  50. Study 006 Conclusions • % FVC: No changes in either group during study • 6MWD: 20 meters mean increment for both groups • No clear trend in subsets (age, gender, impairment) • Liver volume and urinary GAG were substantially reduced • Data in other secondary and tertiary endpoints were inconclusive

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