Norman W. Barton

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double‐blind, multinational, Phase 3 study

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment‐naïve, anemic patients with GD1 (4–62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 109/L (P=0.002); 45 U/kg: +66.4%; +40.9 × 109/L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: −50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: −39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug‐related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease‐specific parameters measured demonstrated clinically meaningful improvements after 12 months. Am. J. Hematol. 88:166–171, 2013.

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9‐month, global, randomized, double‐blind, non‐inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment‐naïve patients aged 3–73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent‐to‐treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per‐protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent‐to‐treat and per‐protocol populations, respectively. The lower bound of the 97.5% one‐sided confidence interval in both populations lay within the pre‐defined non‐inferiority margin of −1.0 g/dL, confirming that velaglucerase alfa is non‐inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross‐reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am. J. Hematol. 88:179–184, 2013.

Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy

Background: Late infantile metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder that causes severe demyelination of the nervous system. The neuronal metabolite N-acetylaspartate (NAA) serves as a source of acetyl groups for myelin lipid synthesis in oligodendrocytes and is known as a marker for neuronal and axonal loss. NAA and other metabolite levels measured by proton magnetic resonance spectroscopy (MRS) correlate with performance of the brain in normal children. There is a need for sensitive measures of disease progression in patients with MLD to enable development of future treatments. Methods: A cross-section of 13 children with late infantile MLD were examined by proton MRS. Signals from NAA, total choline, and total creatine in the deep white matter were measured and correlated with the results of cognitive and motor function tests. Results: The NAA signal decreased as the disease process advanced. Motor function, measured by the Gross Motor Function Measure–88, varied from 13 (only head movement in the supine position) to 180 (able to walk) across the study cohort, demonstrating a wide range in functional status. Similarly, varied decreases were observed in cognitive function. We report strong positive correlations between standardized measures of motor and cognitive function and NAA levels in the deep white matter. Conclusions: We suggest that NAA levels could serve as a sensitive biomarker in children with MLD. Proton MRS may provide a valuable tool for measuring the effects of treatment interventions in this disorder.

Gaucher disease: Progress and ongoing challenges

Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder due to deficient activity of arylsulfatase A (ASA) that causes accumulation of sulfatide and lysosulfatide. The disorder is associated with demyelination and axonal loss in the central and peripheral nervous systems. The late infantile form has an early‐onset, rapidly progressive course with severe sensorimotor dysfunction. The relationship between the degree of nerve damage and (lyso)sulfatide accumulation is, however, not established.

The Effects of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase (rhSOD) in Premature Infants with Respiratory Distress Syndrome (RDS)

The Effects of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase (rhSOD) in Premature Infants with Respiratory Distress Syndrome (RDS)

Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in preterm infants

Background:rhIGF-1/rhIGFBP-3 is being investigated for prevention of retinopathy of prematurity in extremely preterm infants.Methods:A population pharmacokinetic model was developed using data from phase I/II (Sections A–C) trials of rhIGF-1/rhIGFBP-3 and additional studies in preterm infants to predict optimal dosing to establish/maintain serum IGF-1 within physiological intrauterine levels. In Section D of the phase II study, infants (gestational age (GA) (wk+d) 23+0 to 27+6) were randomized to rhIGF-1/rhIGFBP-3, administered at the model-predicted dose of 250 µg/kg/d continuous i.v. infusion up to postmenstrual age (PMA) 29 wk+6 d or standard of care. An interim pharmacokinetic analysis was performed for the first 10 treated infants to verify dosing.Results:Serum IGF-1 data were reviewed for 10 treated/9 control infants. Duration of therapy in treated infants ranged 1–34.5 d. At baseline (before infusion and <24 h from birth), mean (SD) IGF-1 was 19.2 (8.0) μg/l (treated) and 15.4 (4.7) μg/l (controls). Mean (SD) IGF-1 increased to 45.9 (19.6) μg/l at 12 h in treated infants, and remained within target levels for all subsequent timepoints. For treated infants, 88.8% of the IGF-1 measurements were within target levels (controls, 11.1%).Conclusion:Through the reported work, we determined appropriate rhIGF-1/rhIGFBP-3 dosing to achieve physiological intrauterine serum IGF-1 levels in extremely preterm infants.

Roscoe Owen Brady, MD: Remembrances of co-investigators and colleagues

To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Bradys research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Bradys efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Bradys pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases.

Industry Perspectives on Orphan Drug Development

This chapter presents perspectives from the pharmaceutical industry concerning the development of orphan drugs. This includes outlining orphan drug development in biotechnology, the various factors necessary for commercializing orphan drug candidates, phases and trials of clinical development and factors which may affect commercialization of a product. The chapter concludes with implications for patients and families.