NEW YORK — The investigational bone-targeting enzyme replacement therapy ENB-0040 was associated with significant bone mineralization and clinical improvements at 6 months in five infants with life-threatening hypophosphatasia who were given the compound in a phase II open-label trial.
The 24-week study initially enrolled six patients (five girls) aged 6–36 months at baseline who were all symptomatic early in life, with severe rickets, respiratory insufficiency, hypercalcemia, and nephrocalcinosis. All had a high likelihood of death or significant morbidity. Dosing was 2 mg/kg given once intravenously, followed by subcutaneous doses of 1 mg/kg thrice weekly for 23 months, with the possibility of dose adjustment depending on clinical response.
Marked improvements were seen in the radiographic appearance of rickets in three infants, with increased mineralization, resolution of radiolucencies, physeal narrowing, and less flaring. There were no new fractures. Another infant showed substantial improvement that was not quite as dramatic as the other three. The fifth infant, with profound hypomineralization, had no radiographic improvement, Dr. Michael P. Whyte said at a joint meeting of the Lawson Wilkins Pediatric Endocrine Society/European Society for Pediatric Endocrinology.
Radiographic evidence of skeletal mineralization was associated with reduced plasma levels of pyridoxal 5′-phosphate and increased levels of parathyroid hormone, which was initially suppressed in all patients. There was a concurrent decline in the calcium to creatinine ratio, “as though bone and mineral were moving into the skeleton, a sign of hungry bones,” accompanied by a need to increase dietary calcium, said Dr. Whyte, medical/scientific director of the center for metabolic bone disease and molecular research at Shriners Hospitals for Children, St. Louis.
Evidence of improved growth, including linear growth, head circumference, and growth catch-up appearing in later assessments, was seen in all five patients. Respiratory problems, present in four of the five infants at baseline, improved in three infants after 6 months of therapy. One patient, who had been on continuous positive airway pressure and bilevel positive airway pressure and was on the verge of endotracheal intubation, was able to be treated with just nighttime nasal oxygen after 6 months of ENB-0040. Motor function, assessed by Bayley scores, also improved in all five patients.
There were no drug-related serious adverse events and the subcutaneous doses were well tolerated, with only mild redness and swelling seen at the injection site. There were no clinical signs or symptoms of hypocalcemia or of increased intracranial pressure. No anti–ENB-0040 antibodies developed. One infant was withdrawn after showing signs of distress during treatment, leaving five for subsequent analysis.
There is currently no established treatment for hypophosphatasia (HPP), an inborn error of metabolism resulting from a mutation within a gene that codes for tissue-nonspecific alkaline phosphatase (TNSALP). Mortality among infants less than 6 months of age with the perinatal form of the disease is around 50%, he said.
Manufactured by Montreal-based Enobia Pharma Inc., ENB-0040 is a subcutaneously administered recombinant compound of TNSALP fused to a patented bone-targeting peptide, designed to replace the missing enzyme in HPP patients. It was given an orphan drug designation in the United States and the European Union in 2008 and was granted fast-track status for HPP treatment by the Food and Drug Administration in May 2009, according to the company Web site. Dr. Whyte is a consultant for Enobia Pharma and received grant support for this study.
X-rays above show response to treatment using a recombinant compound of TNSALP fused to a bone-targeting peptide.
Source Courtesy Enobia Pharma Inc.