Good news for patients with Hypophosphatasia (HPP). Data presented at American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting in Houston, TX indicate that treatment with Alexion’s investigative orphan drug asfotase alfa can significantly reduce risk of death over a 5-year period and can improve many measures including bone growth and healing in young children affected with this devasting disease.
The results were presented in 3 abstracts at the ASMBR meeting.
HPP is a genetic, chronic and progressive ultra-rare metabolic disease that can lead to progressive damage to multiple vital organs, destruction and deformity of bones and premature death. HPP is caused by mutations in the gene encoding an enzyme known as tissue non-specific alkaline phosphatase (TNSALP). Asfotase alfa is an investigational enzyme replacement therapy for the treatment of HPP.
Five-year survival data
Whyte et al (abstract 1097)  reported that treatment with asfotase alfa significantly improved survival in pediatric patients (ages ≤5 years at enrollment) with severe HPP. Over the 5-year analysis period, 89% (33/37) of patients treated with asfotase alfa survived compared with 27% (13/48) of untreated historical control patients. Invasive ventilator-free survival was also significantly improved in treated patients (p
<0.0001); 83% (21/25) of treated patients required no invasive ventilation and survived, compared with 25% (12/48) of historical control patients.
Martin Mackay, PhD, executive vice president and global head of R&D at Alexion Pharmaceuticals stated, “Survival was significantly improved among severely affected infants and children with HPP treated with asfotase alfa compared with a historical control of untreated patients, which is an important finding for the HPP community who currently has no approved treatment options.”
In a press release
, lead presenter Michael P. Whyte, MD, Medical-Scientific Director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis, MO said, “Improved survival in treated patients likely reflects better mineralization of the rib cage, which then had a positive effect on respiratory function. We were also pleased to report that the majority of treated patients who had Vitamin B6
–responsive seizures survived, whereas historically these seizures had always been a fatal complication.”
Extension study in young children
Whyte and colleagues  presented data from an extension study in which children with HPP who started the study at the age of 3 or less (N=11) and were treated with asfotase alfa for up to three years experienced sustained improvement in growth and physical function.
Whyte et al stated that patients (N=11) had early (3 months, p
=0.03) and sustained (3 years, p
=0.008) bone healing as measured by the radiographic global impression of change (RGI-C) scale and the rickets severity scale (RSS). Interestingly, at the beginning of the study, 10 or the 13 patients required respiratory support at or soon after entry into the study but at the last assessment, only one patient continued to require respiratory support. The 3-year survival rate of approximately 90%.
Other measures reported in the study include:
For patients treated with asfotase alfa, improvement in growth as measured by height/length Z-score was observed. Median height/length Z-score was -3.7 at baseline, indicating marked delay relative to peers; over the course of treatment, median change from baseline in Z-score steadily increased from -0.3 at three months to +2.3 at three years.
In asfotase alfa treated patients, improvement in functional development was observed as measured by the Bailey’s Scales of Infant and Toddler Development 3rd Edition (BSID-3), with all evaluable patients (N=9) demonstrating increases in age-equivalent scores, indicating acquisition of new gross motor, fine motor and cognitive skills during treatment.
The most common adverse events (AEs) were pyrexia (7/10), mild or moderate injection-site reactions (6/10) and upper respiratory tract infection (6/10).
Extenstion study in children 5 - 12 years
Madson et al  presented data from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in HPP patients aged 5-12 at study entry.
Madson et al found that:
In patients treated with asfotase alfa, a significant and clinically meaningful decrease in disability was observed, as measured by the Child Health Assessment Questionnaire (CHAQ), from a median of 1 at baseline to 0.25 at six months to 0 at 24 months and last assessment (p≤0.007).
A significant reduction in pain was observed in treated patients, as measured by the Pediatric Outcomes Data Collection Instrument (PODCI), from a median baseline score of 78 to a median score of 100 at last assessment (p=0.0389). The PODCI is a comfort/pain rating scale, with 100 representing best possible outcome or best health.
Improvements in strength and agility were observed for treated patients as measured by the shuttle run, one-legged hop test and standing long jump, three components of the BOT-2. Median time to complete a 50 foot shuttle run improved from 22 seconds at baseline to 9 seconds at last assessment (p<0.0001). The median number of one-legged stationary hops completed in 15 seconds improved from 0 at baseline to 21 hops at last assessment (p=0.0001). The median distance jumped via a standing long jump improved from 11 inches at baseline to 46 inches at 36 months (p<0.0001).
Improvement in growth, as measured by height Z-score, was observed in treated patients, from a median of -1.26 at baseline to a median of -0.72 at last assessment (p=0.0027).
The most common AEs were mild or moderate injection site reactions. No deaths, serious AEs or withdrawals due to AEs over the three years of treatment were observed in this study.
Katherine L. Madson, MD, PhD, from the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis , MO stated, “In the data presented at ASBMR, we observed rapid and sustained healing of bones, increased physical function, reduced disability, reduced pain and improvements in growth in children with HPP who were treated with asfotase alfa for up to three years,” adding, “These new physical function data, which include an improved ability to run, jump and hop, reflect better strength and agility for these children who were previously faced with significant skeletal and muscular challenges.”
About Asfotase Alfa
Asfotase alfa is a targeted enzyme replacement therapy that is designed to address the underlying cause of HPP by aiming to restore the genetically defective metabolic process. In 2013, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for asfotase alfa. In April 2014, Alexion initiated the rolling submission of a Biologics License Application (BLA) for asfotase alfa as a treatment for patients with HPP with the FDA.