According to a study published in the March 8 issue of the New England Journal of Medicine, a promising new treatment for hypophosphatasia (HHP) – a rare and occasionally fatal bone disorder that can affect infants and young children – has been identified by a team of doctors at Washington University School of Medicine in St. Louis, in collaboration with Shriners Hospital for Children and other institutions.

The condition is a rare, inherited disease that affects bones and teeth. It upsets bone metabolism by preventing vital minerals, such as calcium, from depositing in the skeleton.

In the study, the researchers reveal that young children with the most severe forms of the condition generally demonstrated significantly improved symptoms at one year of treatment, including:

  • improved motor development
  • increased bone strength
  • improved breathing
  • and some participants managed to walk

Lead author of the study, Michael P. Whyte, M.D., professor of medicine of pediatrics and of genetics, at Washington University School of Medicine in St. Louis, who treats patients at Shriners Hospital for Children in St. Louis, explained:

“This was a small trial, but we were thrilled to see these results. From our experience with studies in mice, we had high hopes. But I think the outcome thus far is beyond anything we had expected.”

The severity of the condition varies considerably. Mildest forms of HHP may not be observed until adulthood, some forms of the condition may only affect teeth, and the most severe forms of the condition can cause death by respiratory failure. However, in young children, especially infants, HHP can result in bone weakness, known as rickets.

The prevalence of severe forms of the disease is approximately 1 in 100,000, although this figure differs worldwide. HHP is most prevalent in the Mennonite community in Manitoba, Canada, where 1 in every 2,500 infants shows HHP.

Whyte who is also the medical and scientific director of the Center of Metabolic Bone Disease and Molecular Research at Shriners Hospital for Children in St. Louis, said:

“When the condition is extremely severe, a baby may be born with almost no visible bones in an X-ray. If an infant has fractured or very thin ribs, the thorax is not going to work properly as a bellows, and respiration is compromised. Together with the profound muscle weakness also seen in severe hypophosphatasia, respiratory lethality is a frequent consequence.”

The researchers enrolled 11 infants and young children, aged between 20 days to 3 years, who were diagnosed with severe HHP to participate in the study. As there is currently no approved medication therapy for the condition, all participants received the trial medication asfotase alfa, a compound called ENB-0040.

At the start of the study, the majority of the participants required respiratory support in order to help them breath, while 9 of the 11 patients had severe of extremely severe rickets; two were classified as moderate. In addition, the majority of participants were only able to turn their heads while lying on their backs, as a result of delayed motor development. Although two of the participants, aged between 2 and 3 years old, were able to sit unsupported, they were unable to crawl or pull to standing.

Out of the participants, 9 completed one year of treatment, 1 participant withdrew from the treatment, and 1 patient died as a result of sudden fever and sepsis that was not attributable to the medication.

The researchers found that the majority of patients demonstrated considerable healing of rickets after receiving treatment for 6 months. Furthermore, six patients were able to breath unaided after one year of treatment. All of the participants who completed 1 year of therapy made progress or significant progress in motor development:

  • 2 participants were able to crawl
  • 1 pulled to standing
  • 1 participant was able to sit unsupported
  • 1 participant could move on all limbs against gravity
  • Two began taking steps
  • and both the two older participants who could only sit, were able to walk after 1 year of treatment

Like several genetic disorders, HHP is the result of mutations that damage a vital protein. In HHP, the protein is an enzyme called alkaline phosphatase.

This damaged enzyme is unable to dissolve chemicals as it should, as a result chemicals build up. One of these chemicals is known to prevent mineralization, inhibiting phosphate crystals and calcium from growing and penetrating the skeleton to build normal bone.

ENB-0040, is a manufactured form of normal alkaline phosphatase, although it is enhanced so that it is targeted to bone.

According to Whyte, treating individuals with HHP by giving them normal phosphatase is not a new concept. Over 20 years ago, Whyte and his team tried to treat individuals with HHP by giving them blood plasma with excess alkaline phosphatase, although results from the study demonstrated that increasing alkaline phosphatase levels in the blood.

More recently, Whyte’s collaborators have found the missing link: adding a short protein chain that attaches to bone allowed the alkaline phosphatase to be targeted to the skeleton.

Whyte and his team then demonstrated that the targeting chain worked effectively in a mouse model of severe HHP. They found that as long as the mice received daily injections of ENB-0040 starting at birth, their life span returned to normal.

The 9 participants who completed 1 year of treatment in this study continue to receive treatment, and are currently taking part in an extension study.

For more information about clinical trials recruiting patients with HHP, visit clinicaltrials.gov.

Written by Grace Rattue