Miglustat: a first-in-class enzyme stabilizer for late-onset Pompe disease

Topic:

Clinical Trials

Poster Number: O332

Author(s):

Jon Brudvig, PhD, Amicus Therapeutics, Inc., Princeton, NJ, USA, Robert J. Hopkin, MD, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA, Barry Byrne, MD, PhD, University of Florida, Mazen M. Dimachkie, MD, University of Kansas Medical Center, Kansas City, KS, USA, Priya S. Kishnani, MD, Duke University Medical Center, Durham, NC, USA, Tahseen Mozaffar, MD, University of California, Irvine, CA, USA, Mark Roberts, MD, PhD, Salford Royal NHS Foundation Trust, Salford, UK, Benedikt Schoser, MD, Department of Neurology, LMU University Hospital, LMU Munich, Germany, Ans T. van der Ploeg, MD, PhD, Erasmus MC University Medical Center, Rotterdam, Netherlands, Brian Fox, PhD, Amicus Therapeutics, Inc., Princeton, NJ, USA, Fred Holdbrook, PhD, Amicus Therapeutics, Inc., Princeton, NJ, USA, Vipul Jain, MS, MBA, Amicus Therapeutics, Inc., Princeton, NJ, USA, Franklin Johnson, BA, MS, Amicus Therapeutics, Inc., Princeton, NJ, USA, Jennifer Zhang, MD, Amicus Therapeutics, Inc., Princeton, NJ, USA, Giancarlo Parenti, MD, PhD, University of Naples Federico II, Telethon Institute of Genetics and Medicine, Naples, Italy

In late-onset Pompe disease (LOPD), deficiency of the lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA) causes progressive loss of muscle and respiratory function. Cipaglucosidase alfa (cipa) is a recombinant human GAA (rhGAA) enriched with natural bis-mannose-6-phosphate to improve uptake into muscle. A key challenge with rhGAA therapy is inactivation at the near-neutral pH of blood. To address this challenge, intravenous cipa is delivered as a two-component therapy with oral miglustat (mig), an enzyme stabilizer that competitively and reversibly binds to cipa in blood. We present pre-clinical and clinical data to further clarify the efficacy and safety benefits of using cipa+mig in patients with LOPD as a two-component therapy. In dose-finding studies with Gaa knockout mice, muscle glycogen levels and grip strength were evaluated for cipa (20 mg/kg) with and without mig (10 mg/kg; equivalent human dose 260 mg). Glycogen reduction in quadriceps muscle was greater for cipa+mig than cipa alone. Grip strength improved at a greater rate for cipa+mig than cipa alone and approached levels that were not statistically different from wild-type mice after 5 months of treatment. In human patients with LOPD (n=11), mig (260 mg) increased cipa area under the curve in plasma by 28.5% versus cipa (20 mg/kg) alone. Patients treated with cipa alone showed dose-dependent decreases in urine hexose tetrasaccharide (Hex4) levels (surrogate glycogen storage marker) by up to ~15% from baseline that decreased by a further ~10% when mig (260 mg) was added. In a head-to-head study, cipa+mig had a similar safety profile to alglucosidase alfa. Of 151 patients treated with cipa+mig in three clinical trials, 21 (13.9%) had 68 adverse events related to mig only, none of which were serious. Stabilization of cipa by mig in circulation improved cipa exposure, further reduced Hex4 levels and was well tolerated in clinical studies in patients with LOPD. Supported by Amicus Therapeutics, Inc.