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Recombinant Human Beta-Glucuronidase Associated With Highly Significant and Sustained Reduction in Dermatan Sulfate in Patients with MPS VII

Paul Harmatz - Speaker World Symposium 2017Paul Harmatz, MD

February 18, 2017—San Diego, California—Recombinant human beta-glucuronidase has been associated with a highly significant and sustained reduction in dermatan sulfate in patients with mucopolysaccharidosis type VII.

This outcome of a phase III, multicentre, randomised, placebo-controlled, blind-start, single-crossover study was reported at the 13th Annual WORLDSymposium, from February 13–18.

Paul Harmatz, MD, of the University of California, San Francisco, Benioff Children’s Hospital, Oakland, explained that mucopolysaccharidosis type VII (MPS VII) is an ultra-rare autosomal recessive disease with no approved therapy.

MPS VII, Sly syndrome, is one of the least common forms of the mucopolysaccharidoses. MPS VII is estimated to occur in fewer than one in 250,000 births. The defective gene responsible for Sly syndrome is located on chromosome 7.

The disorder is caused by deficiency of the enzyme beta-glucuronidase. In its rarest form, Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body. Survival is usually a few months or less. Most children with Sly syndrome are less severely affected.

Neurological symptoms may include mild to moderate intellectual disability by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision.

Other symptoms include short stature, some skeletal irregularities, joint stiffness, restricted movement, and umbilical and/or inguinal hernias. Some patients may suffer repeated bouts of pneumonia during their first years of life. Most children with Sly syndrome live into the teenage or young adult years. Growth and motor skills are affected, and mental retardation also occurs.

Dr. Harmatz and colleagues reported results of a phase III trial of recombinant human beta-glucuronidase, an investigational therapy for MPSVII.

Twelve subjects were randomised 1:1:1:1 to treatment sequence groups A, B, C or D (Group A = recombinant human beta-glucuronidase; Groups B, C or D = placebo). Placebo groups crossed over to recombinant human beta-glucuronidase at weeks 8 (group B), 16 (group C), or 24 (group D). All subjects received ≥24 weeks of recombinant human beta-glucuronidase 4 mg per kilogram of body weight via IV infusion.

Endpoints included urinary glycosaminoglycans levels and clinical assessments including a multidomain responder index that included six clinical measures (walking, pulmonary function, shoulder flexion, visual acuity, and fine and gross motor skills) and fatigue and physician/caregiver assessments of change. Minimally important differences were prespecified for multidomain responder index scoring (+1, 0, or –1 minimally important difference changes).

Baseline urinary glycosaminoglycans levels (dermatan sulfate) were approximately 28-fold above the upper limit of normal. After 24 weeks of treatment, dermatan sulfate showed a least-squares mean decrease from baseline of -64.8% (±2.46%; P < .0001). The multidomain responder index mean score improved by +0.5 domains (±0.8; P = .0527) at 24 weeks.

The ratio of total positive to negative domains was 3:1, showing a trend of overall improvement. A post hoc multidomain responder index analysis including fatigue showed a mean improvement of +0.8 domains (±1.14; P = .0433). Clinically important changes were also seen on an individual-subject basis.

The safety profile was acceptable with two hypersensitivity infusion-associated reactions and no recurring hypersensitivity reactions, with no deaths or treatment discontinuations. Seven subjects developed anti-recombinant human beta-glucuronidase antibodies (not associated with hypersensitivity adverse events).

Dr. Harmatz concluded that human recombinant human beta-glucuronidase treatment was associated with a highly significant and sustained reduction in dermatan sulfate (P < .0001). Multidomain responder index data support the clinical benefit provided by recombinant human beta-glucuronidase.

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.

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