Bmn 110 ph12 results
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  • 1. A Phase 1/2, Multicenter, Open-Label, Dose-EscalationStudy to Evaluate the Safety, Tolerability, and Efficacy of BMN 110 i S bj t with M in Subjects ith Mucopolysaccharidosis IVA l h id i (Morquio A Syndrome)Christian Hendriksz, MBChB, MSc, FRCPCH, MRCP, Consultant in Metabolic Disorders, Birmingham Childrens Hospital, UK
  • 2. Survey Studies: MPS IVA and MPS VI HaveS St di d HComparable Endurance •Average 6MWD i A in MorCAP 6 MWD Data Morquio Clinical Assessment Program (MorCAP) = 237 m Other Studies •Average 6MWD in MPS VI survey (non-drug study) = 273 m* *Swiedler et al 2005
  • 3. BMN110 RECOMBINANT HUMANGALACTOSAMINE 6-SULFATASE (GALNS)An Enzyme Replacement Therapy For Morquio Type IVA (MPS IVA) Enzyme E N-acetyl-galactosamine 6 sulfate sulfatase N t l l t i lf t lf t (GALNS): No changes Characteristics High specific activity naturally bone/cartilage activity, targeted and optimized for high uptake Intended Indication Intravenous ERT for MPS IVA Mechanism Reduce the accumulation of keratan sulfate (KS) in affected tissues Manufacturing Specially modified CHO cell line to produce high uptake and properly activated enzyme
  • 4. Phase 1/2 St d D iPh Study Design: O Open-Label, Withi P ti t D L b l Within Patient DoseEscalation 0.1 mg/kg/week 1.0 mg/kg/week 2.0 mg/kg/week 12 Weeks 12 Weeks 12 Weeks 20* Patients (age 5-18 y) ( 18 ) Key efficacy measurements 6 Minute Walk Test (6MWT) 3 Minute Stair Climb (3MSC) Respiratory Function Tests: •Forced Vital Capacity •Maximum Voluntary Ventilation Urine KS *20 enrolled, 2 withdrawn approx. Week 12; 2 unable to perform endurance tests
  • 5. Phase 1/2 St d BPh Study: Baseline D li Demographics hi Age at Enrollment, y g years•Mean age 8 years n 20 Mean (SD) 8.0 (2.9)•Mean height approx. g pp Min Max Mi , M 4 , 16102 cm, large variation Sex(74 to 155 cm) Male 12 (60%) Female 8 (40%)•Most patients below Height, cm3rd percentile for n 19height Mean (SD) 102.3 (19.8)•80% use wheelchairs 80% ee c a s Min , Max 74.3 , 154.9 Use of Wheelchairs 16 (80%)•Average baseline Use of Walking Aids 2 (10%)6MWD = 267 m
  • 6. Summary of Endurance Data in Subjects WithEvaluable Results Through Study Week 36 Statistic Week 24 Week 36 Change in 3 Minute Stair Climb from N 15 15 Baseline Mean ( M (p-value) l ) 6.9 (p=0.01) 6 9 ( 0 01) 8.9 (p=0.03) 8 9 ( 0 03) (stairs per minute) Median (p-value) 7.3 (p=0.01) 10.3 (p=0.06) Change in 6 Minute N 16 16 Walk Test from Mean 17 (p=0.36) 15 (p=0.38) Baseline Median 38 (p=0.09) 19 (p=0.35) (meters) T-test for mean comparison; Wilcoxon signed-rank test for median comparison • Median/mean improvement in 6MWT of 38 m/17 m at Week 24 and 19 m/15 m at Week 36 • Median/mean improvement in 3MSC of 7.3 /6.9 stairs/min at 7 3 /6 9 Week 24 and 10.3 /8.9 stairs/min at Week 36
  • 7. Summary of Respiratory Data in Subjects WithEvaluable Results Through Study Week 36 Statistic St ti ti Week W k 24 Week W k 36 Percent Increase in N 16 16 FVC(1) Mean <1% (p=0.98) 11% (p=0.06) Median <1% (p=0.85) 11% (p=0.01) Percent Increase in N 13 14 MVV(2) Mean 11% (p=0.09) ( ) 11% (p=0.04) ( ) Median 6.4% (p=0.15) 10% (p=0.06)(1) forced vital capacity; (2) maximum voluntary ventilation T-test for mean comparison; Wilcoxon signed-rank test for median comparison • MVV shows approximate 11 % mean increase from baseline at Week 24 (10% change at Week 12) • FEV1, FVC and MVV are increased from baseline at Week 36
  • 8. UrineU i KS D Decreases i R in Response t ERT to 0.1 mg/kg/wk 1.0 mg/kg/wk 2.0 mg/kg/wk•Significant d Si ifi t decrease b t between B Baseline and W k 4 (0 1 mg/kg/wk d li d Week (0.1 /k / k dose), )further decrease between Week 28 and Week 32 (2 mg/kg/wk dose)•41% mean and 47% median decrease between Baseline and Week 36
  • 9. Antibody d Additional BiA tib d and Additi l Biomarkers k• All patients developed drug specific antibody response by Week 18 of treatment• Preliminary analysis shows no apparent relationship between total antibody level and safety or efficacy outcomes t• Changes in biomarkers of inflammation, matrix factors, metabolism, metabolism and growth were measured during ERT; data analysis is ongoing
  • 10. Safety 0.1 1.0 2.0 Continuation mg/kg/week mg/kg/week mg/kg/week Period Entire Study Category C (n=20) ( 20) (n=18) ( 18) (n=18) ( 18) (n=18) ( 18) (n=20) ( 20) AEs 18 (90.0%) 18 (100.0%) 17 (94.4%) 15 (83.3%) 20 (100.0%) Drug-Related AEs 12 (60.0%) 10 (55.6%) 7 (38.9%) 5 (27.8%) 14 (70.0%) SAEs 6 (30.0%) 2 (11.1%) 8 (44.4%) 3 (16.7%) 13 (65.0%) Drug-Related SAEs 2 (10.0%) 1 (5.6%) 2 (11.1%) 1 (5.6%) 4 (20.0%) AEs D i Infusion AE During I f i 15 (75 0%) (75.0%) 13 (72 2%) (72.2%) 10 (55 6%) (55.6%) 9 (50 0%) (50.0%) 17 (85 0%) (85.0%) SAEs During Infusion 5 (25.0%) 0 1 (5.6%) 1 (5.6%) 6 (30.0%) AEs Causing Study 1 (5.0%) 0 0 0 1 (5.0%) Discontinuation • Number of patients experiencing drug related AEs decreases over time • M Most SAE not d SAEs drug related l d • 2 patients withdrew, one due to severe type I hypersensitivity accompanied by drug specific IgE at low dose, other for personal reasons (sibling) • One patient suspended treatment after Week 45 due to recurrent infusion reactions but remains enrolled in study
  • 11. 6 Minute Walk Distance, M di Ch Mi t W lk Di t Median Change F From B Baseline, Ph li Phase1/2 Morquio ERT Trial Compared to Other MPS Trials Median Median Change at •Morquio Phase 1/2 trial Trial (Treatment Baseline End of Treament median change at Week 24 Period)) 6MWD Period Phase 1/2 Morquio (38 m) compares fa orabl favorably (24 Weeks) 258 m 38 m with median improvements Phase 1/2 Morquio in other Phase 3 MPS trials (36 Weeks) 258 m 19 m Phase 3 MPS VI treated (24 Weeks) 123 m 19 m • Other MPS trials showed Phase 3 MPS VI minimal increase or placebo (24 Weeks) 204 m 6m decrease in placebo group Phase 3 MPS I treated (26 Weeks) 349 m 28 m Phase 3 MPS I placebo (26 Weeks) 360 m - 11 mNotes:• Morquio data represent n = 16 subjects that had evaluable data at baseline through Week 36.• Naglazyme data represents average of 2 values at each point, 6 minute time point of 12 MWT.
  • 12. 3 Minute Stair Climb, Median Change From Baseline Phase 1/2 Climb Baseline,Morquio ERT Trial Compared to Other MPS Trials Median Baseline Median Change at Trial (Treatment 3MSC End of Treament Period) P i d) (stairs/min) ( t i / i ) Period ( t i / i ) P i d (stairs/min) • MMorquio Ph i Phase 1/2 Phase 1/2 Morquio (24 trial median Weeks) 32 7 improvements at Week Phase 1/2 Morquio (36 24 and at Week 36 Weeks) 32 10 greater than Phase 3 MPS VI treated (24 Weeks) 17 5 improvement in MPS VI Phase 3 MPS VI S trial placebo (24 Weeks) 25 4 Notes: • Morquio data represent n = 15 subjects that had evaluable data at baseline through Week 36. • MPS VI data represents average of 2 values at each point.
  • 13. Morquio PhM i Phase 1/2 T i l S Trial Summary• Morquio A patients have impaired endurance and respiratory function similar to other MPS disorders• Walk and stair climb improved (comparable to other ERTs)• Urine KS reduced, largest decrease occurs in 2 mg/kg dose interval• Respiratory function improved (comparable to other ERTs)• Overall safety profile is favorable• These data support conducting a Phase 3, randomized trial pp g