TABLE 2. IN SUBJECTS IN THE 20 MG/KG COHORT THERE WAS A SUBSTANTIAL INCREASE IN MEASURES OF RESPIRATORY MUSCLE STRENGTH: MIP INCREASED BY A 27% RELATIVE CHANGE FROM BASELINE; MEP INCREASED BY AN 14.1% RELATIVE CHANGE FROM BASELINE. ENDURANCE, AS MEASURED BY THE 6MWT, IMPROVED BY A 6.3% RELATIVE CHANGE FROM BASELINE (22.3 METERS), AND 3/16 SUBJECTS (18.8%) INCREASED THEIR WALK DISTANCE BY 75 METERS OR MORE. ONE PATIENT DISCONTINUED THE STUDY DURING THE INITIAL 24 WEEKS OF TREATMENT DUE TO A HYPERSENSITIVITY REACTION. SUBSEQUENT TO THE END OF POM-001 DURING THE FOLLOW UP EXTENSION PHASE STUDY A SECOND PATIENT DISCONTINUED THE STUDY DUE TO MILD TO MODERATE INFUSION RELATED REACTIONS. TWO ADDITIONAL PATIENTS ARE BEING TREATED AT REDUCED DOSES IN A DESENSITIZATION PROTOCOL FOLLOWING INFUSION REACTIONS OF URTICARIA. FIG 2. BMN 701 CLEARS GLYCOGEN MORE EFFICIENTLY THAN rhGAA IN POMPE MICE POM-001 SERIOUS ADVERSE EVENTS Age Gender Study ID Patient ID BMN 701 dose Event (PT) Causality/ Relatedness Outcome 58 Years Male POM-001 1118-1018 20 mg/kg Hypersensitivity Possible Recovered/ Resolved 44 Years Female POM-001 1099-1017 20 mg/kg Hypoglycaemia Related Recovered/ Resolved 50 Years Male POM-001 0121-1013 20 mg/kg Aggression Not Related Recovered/ Resolved 50 Years Male POM-001 1216-1020 20 mg/kg Hypertensive crisis Not Related Recovered/ Resolved SUBJECTS WITH ADVERSE EVENTS RESULTING IN INFUSION MODIFICATION a Adverse events N (%) b Multi-system adverse events c 5 (22.7%) d Hypoglycemia 2 (0.9%) Venous access difficulty 2 (0.9%) Psychiatric 1 (0.5%) Rash 1 (0.5%) a Infusion interruption, infusion rate change, dose reduction, drug withdrawn B N = number of subjects experiencing adverse events C including cardiac, gastrointestinal, nervous system, respiratory and skin disorders D One patient discontinued from study participation due to hypersensitivity reaction TABLE 3. THE MOST FREQUENT ADVERSE EVENTS INCLUDED HYPOGLYCAEMIA, HEADACHE, NAUSEA, DIZZINESS, AND CHEST DISCOMFORT. TABLE 1. THE SUBJECTS IN POM-001 HAD MILD TO MODERATE IMPAIRMENT OF ENDURANCE, AS MEASURED BY 6MWT AND OF RESPIRATORY FUNCTION AS MEASURED BY FVC UPRIGHT. *Maga et al, JBC. 288:1428–1438 (2013) STUDY OBJECTIVES AND DESIGN • Phase 1/2 Multiple Dose, Dose Escalation • 3 patients each at 5 mg/kg and 10 mg/kg; 4 at 20 mg/kg - every other week • Expansion phase of additional 12 patients at 20 mg/kg • Patient Population • Late onset Pompe disease • Naïve to prior rhGAA therapy • Ambulatory with mild to moderate pulmonary dysfunction • Safety Endpoints • Anti-BMN 701, -GAA,-IgE, -IGF1, -IGF2 • Adverse Events - IARs, SAEs, AEs • Blood glucose, vital signs • Exploratory Endpoints • FVC, Maximum Inspiratory and Expiratory Pressure (MIP and MEP), Maximum Ventilatory Volume (MVV); 6 Minute Walk Test (6MWT) • Urinary tetrasaccharide • MRI, MRS, Muscle biopsy (optional) • Pharmacokinetics SAFETY CTCAE Grade 3 and 4 adverse events were reported in 5 patients: Grade 3 and Grade 4 hypoglycemia in one patient each; and Grade 3 events of hypersensitivity, rash pruritic and venous thrombosis. Hypoglycemia, the most frequently reported adverse event in POM-001, is an expected pharmacologic effect of BMN 701 due to the activity of the GILT tag. In 12/14 subjects hypoglycemia was mild to moderate. In all patients hypoglycemia was transient, and resolved with caloric supplementation (oral in most, IV in the minority) and without sequelae. IMMUNOGENICITY * All 22 treated subjects became positive for anti-GAA, anti-701, and anti-IGF2, the predominant Ab response detected against GAA/701. There was no apparent relationship between anti-GAA or anti-BMN 701 Ab titer and safety or efficacy. Ninety percent (20/22) of subjects demonstrated a low titer and possibly transient response against IGF1 and IGF2. INSULIN LIKE GROWTH FACTORS 1 AND 2 In the presence of low titer anti-IGF1 and 2 Ab, there was no apparent trend in increasing or decreasing IGF1 and IGF2 levels over time. * The BioAnalytical Science Group at BioMarin developed the immunogenicity assays and tested the clinical samples. CONCLUSIONS BMN 701 resulted in marked improvement in respiratory endpoints in late onset Pompe disease patients • In the 20 mg/kg cohort MIP, MEP and FVC improved by 27%, 14%, and 2%, respectively,relative to baseline BMN 701 improved endurance measures • In the 20 mg/kg cohort a mean improvement in 6MWT of 22 m was observed relative to baseline • Three patients experienced a greater than 75 m improvement relative to baseline BMN 701 was generally well tolerated in the study • Infusion associated reactions (IARs) were consistent with those observed with other ERT • Infusion associated hypoglycemia, an expected pharmacologic effect of BMN 701, was transient and readily manageable with caloric supplementation • The predominant Ab response detected is against GAA and BMN 701, however there is no apparent relationship between Ab response safety or efficacy • There is a low-titer, possibly transient response against IGF1 and IGF2; there is no apparent trend in increasing or decreasing IGF1 and IGF2 levels over time. BMN 701 is a promising new treatment for late onset Pompe disease A Phase 3 trial with BMN 701 is anticipated to start late 2013/early 2014 (see clinicaltrials.gov for details) INTRODUCTION BMN 701 is a novel chimeric fusion protein of portions of human IGF2 and acid alpha-gluco- sidase (GAA). In rat myoblasts, BMN 701 is more efficiently taken up by cells than rhGAA. In Pompe mouse models, BMN 701 is more effective at reducing glycogen deposits in heart, dia- phragm, and other skeletal muscles than rhGAA and it does so at lower doses. FIG 1. BMN 701 (GILT TAGGED rhGAA) IS MORE EFFICIENTLY TAKEN UP BY CELLS. POM-001 MIP: CHANGE FROM BASELINE TO WEEK 24* MIP (% Predicted) 0 5 10 15 20 25 30 Baseline Week 24 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 *n = 16 (20 mg/kg cohort) POM-001 MEP: CHANGE FROM BASELINE TO WEEK 24* MEP (% Predicted) -10 -5 0 5 10 15 20 25 Baseline Week 24 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 *n = 16 (20 mg/kg cohort) Exposure The mean duration of exposure for study subjects in the 5 mg/kg, 10 mg/kg and 20 mg/kg cohorts was 26, 24 and 23.25 weeks respectively. 21 patients continued treatment in an extenstion phase study. POM-001: DEMOGRAPHICS AND BASELINE CHARACTERISTICS POM-001 (All: N=22) POM-001 (20 mg/kg: N=16) Age - yrs (range) 49.3 (28– 58) 50.1 (42 – 58) Sex 64% M/ 36% F 63% M/ 37% F Weight - kg (range) 89.0 (49.2 – 144.5) 88.9 (49.2- 144.5) Time since initial diagnosis – years (range) 2.7 (0.1 – 11.3) 3.0 (0.1 – 11.3) GAA activity - % (range) 9.6 (1.7 – 23.7) 10.8 (1.7 – 23.7) 6MWD - meters (range) 352.5 (SD:151.1) (60 – 555) 354.5 (SD:156.9) (60 – 555) FVC Upright - % predicted (range) 60.9 (SD: 19.2) (31 - 95) 58.1 (SD: 18.4) (31 – 84) MOST FREQUENT ADVERSE EVENTS (IN > 3 SUBJECTS) Preferred Term N (%) Preferred Term N (%) Hypoglycaemia 14 (63.6) Chills 3 (18.2) Headache 9 (40.9) Cough 3 (18.2) Nausea 8 (36.4) Oedema peripheral 3 (18.2) Dizziness 7 (31.8) Oropharyngeal pain 3 (18.2) Fall 7 (31.8) Palpitations 3 (18.2) Chest discomfort 6 (27.3) Rash 3 (18.2) Vomiting 6 (27.3) Felling hot 3 (18.2) Contusion 5 (22.7) Hypertension 3 (13.6) Diarrhea 5 (22.7) Nasopharyngitis 3 (13.6) Dyspnoea 5 (22.7) Pain in extremity 3 (13.6) Tachycardia 5 (22.7) Tremor 3 (13.6) Back pain 3 (18.2) TABLE 5. SERIOUS ADVERSE EVENTS IN POM-001. FIG 3. ALL SUBJECTS IN THE 20 MG/KG DOSE COHORT INCREASED MIP (WITH THE EXCEPTION OF 1 PATIENT WHO REMAINED STABLE). FIG 4. MOST SUBJECTS IN THE 20 MG/KG DOSE COHORT EITHER INCREASED MEP OR REMAINED STABLE. TABLE 4. INFUSION RELATED ADVERSE EVENTS IN POM-001. BMN 701 and GILT Technology The potential advantages of "Glycosylation Independent Lysosomal Targeting (“GILT”) include: – Patented peptide tag derived from human IGF2 targets lysosome by binding the cation independent mannose 6 phosphate receptor • High-affinity ligand is on every GAA molecule – Applicable to other LSDs GAA GILT Baseline Week 24 Absolute change from Baseline % Change from baseline Pulmonary (mean) FVC (% predicted) 58.1% 59.3% 1.2% 2.0% MVV (L/min) 67.6 70.6 2.9 4.3% MEP (% predicted) 36.4% 41.6% 5.1% 14.1% MIP (% predicted) 40.6% 51.6% 11.0% 27.0% Endurance (mean) 6MWT (meters) 354.5 376.8 22.3 6.3% High responders 3/16 subjects with>75 m increase in 6MWD 18.8% EFFICACY POM-001 Phase 1/2 Study of BMN 701, GILT-tagged Recombinant Human (rh) GAA in Late-Onset Pompe Disease: Preliminary Report Barry Byrne 1 , Richard Barohn 2 , Bruce Barshop 3 , Drago Bratkovic 4 , Claude Desnuelle 5 , Tarekegn Hiwot 6 , Derralynn Hughes 7 , Pascal Laforet 8 , Eugen Mengel 9 , Mark Roberts 10 , Becky Schweighardt 11 , Troy Tompkins 11 , William Lang 11 , Jonathan LeBowitz 11 1 University of Florida, School of Medicine, Gainesville, FL, USA, 2 Kansas University Medical Center, Kansas City, KS, USA, 3 University of California San Diego Health System, San Diego, CA, USA, 4 IMVS Pathology, Adelaide, SA, Australia, 5 Le Centre Hospitalier de Nice, Nice, France, 6 University Hospital Birmingham, Birmingham, UK, 7 Royal Free & University College Medical School, London, UK, 8 Hôpital Pitié-Salpêtrière, Paris, France, 9 Johannes-Gutenberg-University Mainz, Mainz, Germany, 10 Salford Royal NHS Foundation Trust, Salford, UK, 11 BioMarin Pharmaceutical, Novato, Ca, USA View publication stats View publication stats