Hypophosphatasia is a rare inherited disease due to deficiency of tissue non-specific alkaline phosphatase, an enzyme essential for the proper formation of bones. Hypophosphatasia appears in various forms largely depending upon the age of the patient. The most severe form is diagnosed before birth and is invariably lethal. If diagnosed after birth or later in life, the survival rate improves. Even though the genetic defect is known, presently there is no effective treatment for this disease. Enobia Pharma has developed ENB-0040, a fusion protein composed of human recombinant tissue non-specific alkaline phosphatase, for the treatment of hypophosphatasia. The objective of the present clinical study is to test the long-term safety and effectiveness of ENB-0040 to treat infant stage hypophosphatasia. All of the patients in this extension study must have completed a prior clinical study of ENB-0040. The duration of treatment with ENB-0040 in the extension study will be one year. During that year, eligible infants with hypophosphatasia will receive the drug three times per week by injection under the skin. Small quantities of blood and urine will be taken at intervals to follow the progress of the treatment and to monitor for any problems. X-rays will also be used at various times to assess the progress of bone formation.
Research &Related Other Project Information Item 7: Project Narrative Study Title: Protocol ENB-003-08: Extension of Protocol ENB-002-08: ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Severely Affected Patients with Infantile Hypophosphatasia (HPP) (Submitted to IND 100619 Dec. 31, 2008, and subsequently amended Jul. 13, 2009, copy of protocol can be found attached to item 18 of PHS 398 Research Plan Form of this application) 1 Treatment Rationale ENB-0040 is a fusion protein composed of human recombinant tissue non-specific alkaline phosphates (TNSALP), human IgG1 Fc and a poly-aspartate sequence which targets the compound to hydroxyapatite crystal. In vitro, ENB-0040 binds 32-fold more efficiently to reconstituted hydroxyapatite than does natural TNSALP [Mill?n 2008]. In a relevant mouse model of severe HPP, SC treatment with ENB-0040 significantly improves survival and preserves bone development. The planned enrollment for ENB-003-08 is up to 10 patients. Each patient will receive ENB-0040 drug for one year. 2 Purpose of the Study The purpose of Study ENB-003-08 is to evaluate the longer-term safety and efficacy of ENB-0040 when given SC thrice weekly in patients who completed Study ENB-002-08. The primary efficacy parameter will be the radiographic change in rickets. In addition, the study will assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of ENB-0040, its effect on putative HPP biomarkers, its ability to improve growth and prolong survival, and its possible effects on respiratory function and motor and neurological development. 3 Evaluations Safety and tolerability of ENB-0040 will be determined by assessing clinical and laboratory changes from baseline as well as any infection or inflammation at the injection site. More specifically, safety assessment will include adverse events (any change from baseline in physical examination, or vital signs), concomitant medication or therapy, laboratory assessments (routine chemistry, hematology, urinalysis, vitamin D), antibody formation to ENB-0040, and injection-site reactions. The efficacy of ENB-0040 will be determined by assessing radiographic changes in rickets. Standard images are obtained every 3 months and read centrally by a single reader blinded to the clinical history and chronological order using a 7-point Clinical Global Impression of Change and a Rickets Severity Index. 4 Significance of the Study The clinical study of ENB-0040 is very challenging, yet this new drug, with strong preclinical safety and efficacy data, must be evaluated in the clinic in a safe and rational manner to justify a future pivotal Phase III study for the long term treatment of hypophosphatasia, a life-threatening disease with no known effective treatment. The ENB-003-08 Phase II Extension Study represents a significant opportunity to advance the orderly accumulation of longer term safety and efficacy data for ENB-0040
