Pharmacokinetics, pharmacodynamics, and safety of moss‐aGalactosidase A in patients with Fabry disease

Abstract

Moss-aGalactosidase A (moss-aGal) is a moss-derived version of human α-galactosidase developed for enzyme replacement therapy in patients with Fabry disease. It exhibits a homogenous N-glycosylation profile with >90% mannoseterminated glycans. In contrast to mammalian cell produced α-galactosidase, moss-aGal does not rely on mannose-6-phosphate receptor mediated endocytosis but targets the mannose receptor for tissue uptake. We conducted a phase 1 clinical trial with moss-aGal in six patients with confirmed diagnosis of Fabry disease during a 28-day schedule. All patients received a single dose of 0.2 mg/kg moss-aGal by i.v.-infusion. Primary endpoints of the trial were safety and pharmacokinetics; secondary endpoints were pharmacodynamics by analyzing urine and plasma Gb3 and lyso-Gb3 concentrations. In all patients, the administered single dose was well tolerated. No safety issues were observed. Pharmacokinetic data revealed a stable nonlinear profile with a short plasma half-life of moss-aGal of 14 minutes. After one single dose of moss-aGal, urinary Gb3 concentrations decreased up to 23% 7 days and up to 60% 28 days post-dose. Plasma concentrations of lyso-Gb3 decreased by 3.8% and of Gb3 by 11% 28 days post-dose. These data reveal that a single dose of moss-aGal was safe, well tolerated, and led to a prolonged reduction of Gb3 excretion. As previously shown, moss-aGal is taken up via the mannose receptor, which is expressed on macrophages but also on endothelial and kidney cells. Thus, these data indicate that moss-aGal may target kidney cells. After these promising results, phase 2/3 clinical trials are in preparation. K E Y W O R D SAgalsidase, alpha-galactosidase, Fabry disease, mannose receptor, moss, Physcomitrella

Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease

“…Therefore, plant-made lysosomal enzymes were considered inadequate for treatments relying predominantly on ERT trafficking via M6P-receptors until recently. However, we and others could show uptake of plant-made enzymes with mannose-and N-acetylglucosamine-terminated glycans into lysosomes for example of alpha-galactosidase, which is being deployed in treatment of another LSD-Fabry disease [6,15,19].…”

Developments in the treatment of Fabry disease

“…No serious adverse events were reported and pharmacokinetic evaluation shows a half-life of 14 minutes in plasma after a single infusion. 73…”

Stable Protein Sialylation in Physcomitrella

“…β-glucocerebrosidase, an enzyme for replacement therapy in Morbus Gaucher treatment, is obtained from carrot-cell suspensions (van Dussen et al, 2013) or ZMapp, a combination of antibodies for treatment of Ebola infections, is produced in N. benthamiana lacking plant-typical N- glycan modifications (Margolin et al, 2018). Besides these approved plant-made biopharmaceuticals there are further promising candidates in clinical trials, such as virus-like particles bearing influenza hemagglutinin proteins as Medicago sativa -derived vaccine against influenza (D’Aoust et al, 2010) or the moss-produced α-galactosidase for enzyme replacement therapy in Morbus Fabry treatment (Shen et al, 2016; Hennermann et al, 2019). The majority of pharmaceutically interesting glycoproteins are terminally sialylated in their native form.…”

“…Preclinical trials of moss-derived recombinant human complement factor H were recently effectively accomplished (Häffner et al, 2017; Michelfelder et al, 2017), along with the moss-GAA (acid alpha-1,4-glucosidase) against Pompe disease (Hintze et al, 2020). Furthermore, the clinical phase I study of the recombinantly produced candidate biopharmaceutical moss-aGal against Fabry disease was successfully completed (Reski et al, 2018; Hennermann et al, 2019). Moss-GAA and moss-aGal proved to have better overall performance compared to their variants produced in mammalian cell cultures (Hennermann et al, 2019; Hintze et al, 2020), demonstrating the potential of P. patens to produce biobetters.…”

“…Furthermore, the clinical phase I study of the recombinantly produced candidate biopharmaceutical moss-aGal against Fabry disease was successfully completed (Reski et al, 2018; Hennermann et al, 2019). Moss-GAA and moss-aGal proved to have better overall performance compared to their variants produced in mammalian cell cultures (Hennermann et al, 2019; Hintze et al, 2020), demonstrating the potential of P. patens to produce biobetters. However, the last step in humanizing N- glycans, protein sialylation, still has to be accomplished.…”