Tahseen Mozaffar1, Barry J. Byrne2, Mazen Dimachkie3, Robert J. Hopkin4, Priya Kishnani5, Mark Roberts6, Benedikt Schoser7, Ans Van Der Ploeg8, Jon Brudvig9, Brian Fox9, Frederick Holdbrook9, Vipul Jain9, Franklin Johnson9, Jennifer Zhang9, Giancarlo Parenti10
1Department of Neurology, University of California, Irvine, 2University of Florida, Gainesville, 3Department of Neurology, University of Kansas Medical Center, 4Department of Human Genetics, Cincinnati Children's Hospital Medical Center, 5Duke University Medical Center, 6Salford Royal NHS Foundation Trust, 7Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, LMU Munich, 8Erasmus MC University Medical Center, 9Amicus Therapeutics, Inc., 10Metabolic Unit, Department of Translational Medical Sciences, University of Naples Federico II
Objective:
To demonstrate the benefits of the two-component therapy cipaglucosidase alfa (cipa) plus oral miglustat (mig) in patients with late-onset Pompe disease (LOPD).
Background:
In LOPD, deficiency of the lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA) causes progressive loss of muscle and respiratory function. 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 mig, an enzyme stabilizer that competitively and reversibly binds to cipa in blood.
Design/Methods:
We analyzed clinical and preclinical data, including dose-finding studies with GAA knockout mice treated with cipa (20mg/kg) with and without mig (10mg/kg).
Results:
In mice, glycogen reduction in quadriceps muscle was greater for cipa+mig than cipa alone. Grip strength improved more with 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 (260mg) increased cipa area under the curve in plasma by 28.5% versus cipa (20mg/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 (260mg) 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 3 clinical trials, 21 (13.9%) had 68 adverse events related to mig only, none of which were serious.
Conclusions:
The two-component therapy combining cipa with mig achieved better stabilization of cipa 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.
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