Approved ERT and those under investigation
Asfotase alfa (tradename Strensiq™ developed by Alexion Pharma) is a first-in-class tissue nonspecific alkaline phosphatase bone-targeted enzyme replacement therapy produced by in a Chinese hamster ovary cell line, designed to address the underlying cause of hypophosphatasia (HPP). TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa, is a soluble composed of two identical polypeptide chains. Each chain contains 726 with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartate peptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds. Treatment with asfotase alfa aims to improve the elevated enzyme substrate levels and improve the body’s ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death.
AM-Pharma has discovered that a key function of Alkaline Phosphatase (AP) is to protect organs against inflammation and tissue damage. While AP is found in many extracellular tissues of the human body, it is present at reduced levels in certain conditions including Acute Kidney Injury (AKI), Ulcerative Colitis (UC) and Hypophosphatasia (HPP). The Company’s proprietary therapeutics are disease modifying therapies with the potential to be “first-in-class” medicines.
Clinical proof-of-concept in two indications was confirmed by the positive results from Phase II clinical studies using native bovine AP, which demonstrated efficacy in patients with AKI and in patients with Moderate-to-Severe UC (a form of Inflammatory Bowel Disease).
AM-Pharma is now fully focusing on the development of the proprietary recombinant human form of this enzyme (recAP) for treatment of patients with AKI, UC or HPP. The company’s lead product, an intravenous formulation of recAP, is currently being investigated in a large Phase II clinical study in patients with sepsis-associated AKI.
The incidence and prevalence of all forms of HPP are thought to be less than 1:100,000. The European Medicines Agency (EMA) recently granted an orphan designation to recAP for the treatment of HPP.
recAP was tested in a knockout (Alpl−/−) mice model for life-threatening HPP. Mice received daily subcutaneous injections of recAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days.
It was shown that the administration of recAP improved the manifestations of HPP in these mice. Lifespan and body weight of these mice were normalized, and vitamin B6-associated seizures were absent with recAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of recAP-treated mice. There was no evidence of craniosynostosis in the highest dose of recAP-treated mice and ectopic calcification was not detected by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest recAP dose, including enamel, dentin, and tooth morphology.
Background information on the HPP model and recAP’s study results: Gasque et al, Bone 2015
Bone marrow transplantation, specifically hematopoietic stem cell transplantation, was used to treat two unrelated infant girls with life-threatening HPP. They improved. One was also treated with bone fragments and cultured osteoblasts, which are bone-forming cells. ‘Cultured cells’ refers to cells that are grown under specific conditions outside of their natural environment (the body) and instead within a laboratory. According to the medical literature, both of these patients demonstrated significant sustained, but incomplete improvement, although no more formal studies have been conducted on these procedures.
The drug teriparatide (parathyroid hormone 1-34) has been given “off-label” to several adults with HPP with metatarsal stress fractures or femoral pseudofractures, resulting in healing of the fractures. The drug is not permitted for use in children. More research is necessary to determine the long-term safety and effectiveness of teriparatide in the treatment of HPP.
Preliminary short-term results have also been reported from the use for HPP of an anti-sclerostin antibody. Sclerostin is a protein found in the star-shaped bone cells known as osteocytes. Sclerostin helps to reduce or suppress (downregulate) bone-forming cells called osteoblasts. Antibodies that act against sclerostin have been shown to increase bone mass in osteoporosis.