TREATMENTS FOR POMPE DISEASE what’s in the toolbox now, and what is still under construction SCOTT A. HELLER, MD 1 LET’S FIRST GO OVER SOME BASIC POMPE DISEASE CONCEPTS: GENETICS 2 CELL 23 PAIRS OF CHROMOSOMES PER CELL 3 WITHIN THESE CHROMOSOMES, WE HAVE GENES 4 GENES: INSTRUCTION MANUAL (BLUEPRINT) FOR OUR BODY PROVIDE INSTRUCTIONS FOR BUILDING ALL THE PROTEINS AND CHEMICALS THAT MAKE OUR BODIES FUNCTION 5 DNA: THE LETTERS MAKING UP THE INSTRUCTION MANUAL 6 ONE TYPE OF CHEMICAL THAT OUR GENES ARE IN CHARGE OF MAKING ARE ENZYMES 7 WHAT DOES AN ENZYME DO? ENZYMES HELP FACILITATE CHEMICAL REACTIONS THROUGHOUT THE BODY ESPECIALLY BREAKING THINGS DOWN 8 WHAT DOES THIS HAVE TO DO WITH POMPE DISEASE?? 9 POMPE DISEASE GENE MUTATION: RESULTS WHEN THE SPECIFIC SEQUENCE OF LETTERS MAKING UP A GENE CHANGES 10 DEFECTIVE GAA GENE PREVENTS THE CELLS FROM MAKING ENOUGH OF AN ENZYME CALLED ACID ALPHA GLUCOSIDASE 11 WHY IS ALPHA GLUCOSIDASE SUCH A BIG DEAL? 12 13 LYSOSOMES: THE RECYCLING CENTERS OF THE CELL 14 GLYCOGEN ONE OF THEIR JOBS IS TO BREAK DOWN GLYCOGEN, WHICH IS A STORAGE FORM OF GLUCOSE IN THE BODY. TO DO THIS, THEY USE A TOOL CALLED ACID ALPHA GLUCOSIDASE. 15 16 17 Glycogen Lysosome IF THE CELLS DO NOT MAKE ENOUGH ACID ALPHA GLUCOSIDASE AND ARE NOT ABLE TO BREAK DOWN THE GLYCOGEN, THEN GLYCOGEN BUILDS UP IN THE LYSOSOME AND IT STARTS TO SWELL. 18 THE BUILDUP OF GLYCOGEN DAMAGES THE MUSCLES, CAUSING WEAKNESS19 HOW CAN WE FIX THIS? 20 ENZYME REPLACEMENT THERAPY (ERT) 21 WHAT’S ALREADY IN THE TOOLBOX: ENZYME REPLACEMENT THERAPY (ERT), 1.0 22 A SYNTHETIC VERSION OF ACID ALPHA GLUCOSIDASE ENZYME. 23 LUMIZYME Delivered by slow intravenous infusion (IV), 20 mg/kg, every two weeks. 24 HOW DOES ERT WORK? 25 GOAL: REPLACE THE MISSING ENZYME, ACID ALPHA GLUCOSIDASE 26 27 28 29 LUMIZYME: SUCCESSES AND SHORTCOMINGS 30 LUMIZYME SUCCESSES • In Infant Onset Pompe (IOPD), it has been shown to significantly improve survival. • In Late Onset Pompe (LOPD), it has been shown to have a statistically significant, albeit modest, effect on motor function (measured by the 6-Minute Walk Test) and respiratory (forced vital capacity) function. 31 LUMIZYME SHORTCOMINGS • The majority of patients either remain stable or continue to decline while on this treatment. • Effect of treatment is less clear for patients who are already nonambulatory or receiving ventilatory support. 32 POTENTIAL TREATMENTS CURRENTLY UNDER INVESTIGATION 33 ERT 2.0 34 neoGAA 35 Phase 3 randomized, multicenter, multinational, double-blinded study comparing the efficacy and safety of repeated biweekly infusions of neoGAA (GZ402666) and alglucosidase alfa in treatment-naïve patients with late onset Pompe disease 36 STUDY OVERVIEW • Phase 3, multicenter, multinational, randomized, double-blind, 12-month study comparing the efficacy and safety of neoGAA and alglucosidase alfa (both at 20 mg/kg qow) in treatment-naïve patients with LOPD ages 3 and above (ambulatory, not on invasive ventilation). • The study includes an open-label neoGAA long term follow-up phase for all patients, in which patients in the alglucosidase alfa arm will be switched to neoGAA treatment after 12 months (total duration of ~3 years). • Will assess impact on respiratory muscle strength, limb muscle strength, endurance, and quality of life. 37 WHY NEO-GAA? • A proportion of patients with LOPD treated with alglucosidase alfa demonstrate suboptimal treatment response, especially in respiratory function, and may benefit from a potentially more potent treatment. • In nonclinical studies, it was more successful in reducing glycogen in muscle tissue compared with alglucosidase alfa. 38 WHAT IS NEO-GAA? a modification of alglucosidase alfa that results in the addition of multiple hexamannose structures containing two terminal mannose-6-phosphates (M6P), thereby increasing M6P levels on the compound M6P 39 Why is mannose 6-phosphate (M6P) content important? 40 M6P: a carbohydrate that binds the mannose 6-phosphate receptors at the cell surface for enzyme internalization and lysosome targeting. 41 MANNOSE 6-PHOSPHATE (M6P) alglucosidase alfa shows insufficient uptake in several disease-relevant muscles, which is likely due to an inadequate glycosylation of alglucosidase alfa with M6P 42 43 ALGLUCOSIDASE ALFA MR. ALGLUCOSIDASE ALFA 44 ALGLUCOSIDASE ALFA + M6P 45 OVERALL GOAL GET MORE ALGLUCOSIDASE ALFA INTO MORE CELLS FOR A MORE POWERFUL EFFECT 46 ERT 2.5 47 AN OPEN-LABEL, FIXED-SEQUENCE, ASCENDING-DOSE, FIRST-IN-HUMAN STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF INTRAVENOUS INFUSIONS OF ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT SUBJECTS WITH POMPE DISEASE 48 ATB200 next-generation rhGAA that is manufactured using a process of “optimized glycosylation” that yields significantly higher mannose 6-phosphate (M6P) content compared with alglucosidase alfa, providing more “efficient targeting” of cells 49 ATB200 • Studies show that ATB200 has optimized glycosylation for high-affinity binding to the mannose 6-phosphate receptors and targeting to the lysosome compared to alglucosidase alfa • Studies have also shown that significantly higher concentrations of traditional alglucosidase alfa are required for effective cellular uptake compared with ATB200 50 AT2221 • Active ingredient is Miglustat • Acts as a pharmacological chaperone to enhance the activity of ATB200. 51 HOW DOES AT221 (MIGLUSTAT) WORK? Recombinant human acid α-glucosidase enzymes, including ATB200, are not stable at neutral pH and can be irreversibly inactivated. AT2221 is able to bind to and physically stabilize ATB200 in the bloodstream, preventing this irreversible inactivation and thereby improving its effectiveness. 52 AT221 (MIGLUSTAT) SUCCESSES TO DATE Previous clinical trial (3 IOPD and 10 LOPD) demonstrated 6.8-fold increase in GAA activity when alglucosidase alfa was co-administered with miglustat vs alglucosidase alfa administered alone. 53 STUDY OBJECTIVE This study will assess the efficacy of ATB200 when co-administered with a chaperone (AT2221) 54 SUBJECTS WILL INCLUDE: • Men and women between 18 and 75 years of age • Both ERT-experienced and ERT-naïve • Ambulatory and nonambulatory 55 OVERALL HYPOTHESIS • Higher M6P content of ATB200 will enable better lysosomal targeting, which will translate into greater glycogen reduction. • This effect will be further improved by the co-administration of ATB200 with AT2221. 56 57.