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| ■ Hematology & Endocrinology |
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Recombinant Human Parathyroid Hormone
PTH is a peptide of 84 amino acid residues that is synthesized in and secreted from the
parathyroid gland. It is a major regulator of calcium and skeletal homeostasis, acting primarily through its
receptor on target cells in bone and kidney. Unlike its physiological role as a catabolic molecule, the
intermittent administration of PTH mediates anabolic increase of bone mass as has been demonstrated in numerous
animal and human studies. This unusual property of PTH is being exploited by several drug companies, including
Eli Lilly and NPS Pharmaceuticals, to develop it as a therapeutic drug for the metabolic disease, osteoporosis.
Forteo, a short version of hPTH, has been launched by E. Lilly in the US and European markets. PTH, as a
therapy for osteoporosis, is unique in that it is anabolic in bone, as compared to currently available therapies
such as estrogen, calcitonin and bisphosphonates which are all antiresorptives.
We have developed an efficient and novel process for the large-scale production of recombinant hPTH using an
inducible expression system of E. coli. A proprietary fusion expression system and a site-specific proteolytic
cleavage method have also been developed. Preclinical studies with recombinant hPTH using ovariectomized, and
thus osteopenic, rats demonstrated that it was effective in the restoration of bone in terms of both amount and
strength. Preclinical toxicity studies using mice, rats and cynomolgus monkeys were carried out to determine
the maximum tolerable dose and the no toxic effect dose, which subsequently proved the safety of recombinant
hPTH for clinical use. Both preclinical studies were carried out in the UK.
 An IND was filed
with the US FDA and two phase I clinical studies were conducted in the UK and USA. A phase IA clinical
study (UK) with healthy volunteers was completed in a single-blind and dose escalation mode, demonstrating
tolerability of the drug in human. The phase IB study (USA) was a randomized, double-blind, multidose (daily
dosing for 7 days) study evaluating the safety and tolerability of recombinant hPTH in healthy postmenopausal
women. The drug was well tolerated and showed expected physiological activities, demonstrating its suitability
for further development. A phase II randomized and double-blind study (Germany) is now under way to investigate
the efficacy and safety of hPTH on postmenopausal osteoporosis patients. A total of 200 patients are included
in this study and treated daily for a period of 1 year. |
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