M. Whyte, C. Greenberg, T. Edgar, B. Van Sickle, M. Hamdan, N. Salman, M. Bober, W. McAlister, D. Wenkert, H. Landy

Hypophosphatasia (HPP) features low serum alkaline phosphatase (ALP) due to deactivating mutation(s) within the gene that encodes the "tissue nonspecific" isoenzyme of ALP (TNSALP). Consequently, inorganic pyrophosphate, a natural substrate for this ectoenzyme, accumulates extracellularly and blocks skeletal mineralization. HPP severity spans stillbirth from profound skeletal hypomineralization to osteomalacia presenting in adult life. There is no established medical treatment.

ENB-0040 is a bone-targeted, human recombinant, TNSALP fusion protein that preserved skeletal mineralization and survival and prevented vitamin B6-responsive seizures and dental defects in a TNSALP knockout mouse model of infantile HPP (JBMR 23:777, '08).  Patient trials began in the summer '08. In a phase 1, month-long, multi-center, open-label protocol, 6 adults received 1 IV infusion of 3 mg/kg ENB-0040 followed by weekly SC injections of 1 or 2 mg/kg (Endocrine Soc, abstract, in press).

Here, we report findings from our 6-mo, open-label protocol involving 5 patients with life-threatening HPP (ages 3 wk - 36 mo at baseline), with up to 6 mo of ENB-0040 treatment.  Previously, each had shown worsening skeletal disease and respiratory symptoms predicting a lethal outcome.

At age 7 mo, patient 1 with infantile HPP received a single IV infusion of 2 mg/kg of ENB-0040 followed by 1 and then 3 mg/kg SC 3X/wk. During therapy, there was substantial remineralization of the skeleton, weaning from ventilatory support, and improved growth and motor development.  After receiving only 3 wk of treatment, Patient 2, also with infantile HPP, showed skeletal remineralization (Figure), and then improved ventilation. Both patients 1 & 2 have been released from hospital to continue ENB-0040.  The remaining 3 patients, including one with perinatal HPP, have varying degrees of skeletal disease and have each been treated for at least 1 mo. The infant with perinatal disease shows correction of hypercalcemia and remineralization of ribs after 9 wk of SC treatment.

There have been no drug-related serious adverse events, or development of anti-ENB-0040 antibodies. Bioavailability of ENB-0040 has ranged from 50–90%. SC dosing has resulted in ENB-0040 activity in the therapeutic target range.

Substantial skeletal remineralization and improved clinical status has been demonstrated in association with ENB-0040 bone-targeted enzyme replacement therapy in 3 severely affected infants with HPP in this short term study.

Disclosures: M. Whyte, Enobia Pharma, Montreal, Canada: Research Grants. C. Greenberg, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. D. Wenkert, Enobia Pharma, Montreal, Canada: Research Grants. T. Edgar, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. H. Landy, Enobia Pharma, Montreal, Canada: Employment (full or part-time). N. Salman, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. M. Hamdan, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. B. Van Sickle, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. M. Whyte, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration. M. Bober, Enobia Pharma, Montreal, Canada: Consulting Fees or Other Remuneration.

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