Early treatment with a four times higher dose of Myozyme (alglucosidase alpha) was safe and enabled normal motor development and normalization of markers of muscle damage and disease progression in a boy with classic infantile-onset Pompe disease, according to a study.
The study, “Early higher dosage of alglucosidase alpha in classic Pompe disease,” appeared in the Journal of Pediatric Endocrinology and Metabolism.
Classic infantile-onset Pompe disease is characterized by a complete or near-complete deficiency in the activity of the acid alpha-glucosidase (GAA) enzyme, leading to a pronounced accumulation of glycogen in the cardiac, skeletal, and smooth muscles. This is typically associated with cardiomyopathy (heart muscle disease), profound hypotonia (low muscle tone), and progressive respiratory failure.
Enzyme replacement therapy (ERT) has been associated with clinical benefits in Pompe disease, but its effectiveness in the classic infantile-onset form is often limited. Sanofi Genzyme‘s Myozome is one such ERT. Of note, this therapy is no longer available in the U.S. — Sanofi Genzyme’s indicated product is now Lumizyme.
Factors such as later age at diagnosis, more clinical complications at the start of treatment, and development of an immune response have been proposed to explain the lack of effectiveness of Myozyme.
Recent studies suggested that higher doses of ERT could be beneficial in extending ventilator-free breathing and improve motor outcomes in classic infantile-onset Pompe disease patients who are cross-reactive immunologic material (CRIM)-positive.
CRIM-positive patients produce detectable amounts of GAA, are typically immunologically tolerant (no immune response) to recombinant (made in the lab) human GAA, such as Myozyme/Lumizyme, and tend to respond well to ERT. Similar benefits were found upon early treatment with a standard dose in patients diagnosed at newborn screening.
Investigators from the University of Torino in Italy described six patients (three boys and three girls) with classic infantile-onset Pompe disease — defined as clinical onset within six months after birth — who were treated with different therapeutic regimens.
Myozyme doses used ranged from 20 mg/kg every other week to 40 mg/kg per week. The patients were also given rituximab (375 mg/m2/ week for four weeks) and methotrexate (0.4 mg/kg three times weekly for four weeks) for immune tolerance induction. Rituximab is marketed under the brand name Rituxan — by Genentech and Biogen — in the U.S. and Mabthera (by Roche, which owns Genentech) in Europe.
The first five patients started treatment with a standard dose of Myozyme (20 mg/kg every other week) at a mean age of 3.2 months. One patient was treated within the first month of life.
Two CRIM-negative patients — who lack GAA and develop high levels of antibodies against therapy with rhGAA, lowering ERT efficacy — developed an immune response against Myozyme. In contrast, CRIM-positive patients did not develop this antibody response.
Left ventricular mass index, which may reflect adverse cardiac outcomes, was significantly improved or normalized by the standard Myozyme dose. Three of these five patients were able to sit at a mean age of 9.6 months. All required ventilator support from 10.1 months, and three died at a mean age of 22.2 months. The fifth patient was still alive at study completion at 5 years old, but required a tracheostomy for breathing and a gastrostomy tube for feeding.
The sixth patient, a boy, received a higher Myozyme dose (40 mg/kg/week). His clinical onset was before birth, showing bradycardia — a slower-than-normal heart rate — from 29 weeks of gestation, which is a newly described clinical presentation, the team noted.
At birth, he experienced bradycardia, hypotonia, and respiratory distress, which was rapidly corrected via oxygen supplementation. Then, he began having multiple episodes of supraventricular tachycardia — an abnormally fast heartbeat.
Pompe disease diagnosis was established on his fifth day of life, by evidence of near-complete GAA deficiency on dried blood. He showed hypertrophic (enlargement) cardiomyopathy on echocardiography and excess level of creatine kinase (CK), a marker of muscle damage.
Treatment with a high dose of Myozyme was started at 14 days of age, which enabled early and stable normalization of cardiac morphology; CHOP-INTEND score, an assessment of motor skills; and CK level. Concentrations of the enzymes lactate dehydrogenase, aldolase, and aspartate aminotransferase, which are indicators of tissue/liver damage, were normal. The boy was also receiving treatment for his abnormal heart rate, simplified to just amiodarone at 2 months old.
He achieved regular neuromotor milestones during the first year, which included unassisted sitting at 7 months and walking at 13 months. Up to the study completion, the patient showed normal neurological development, except for a delay in speech. Myozyme, administered at a normal rate, led to no infusion-related reactions or adverse effects despite the higher dose.
“In conclusion, we suggest that early higher dosage of [Myozyme] (40 mg/kg/week) may further improve clinical prognosis in patients with classic Pompe disease,” the scientists wrote. “Studies on more patients treated by this approach are needed.”