Hypoparathyroidism is a disorder in which the parathyroid glands in the neck do not make enough parathyroid hormone (PTH). PTH controls levels of calcium, phosphorus and vitamin D in the blood and in bones. Too little PTH leads to deficiencies in these vitamins and minerals, causing symptoms such as muscle twitching and seizures. Hypoparathyroidism can run in families, but a more common cause is injury to the parathyroid glands during surgery. No treatment currently exists to correct PTH deficiency; instead, patients are given large amounts of calcium and vitamin D, which can damage the kidneys. In previous clinical trials, patients were given PTH replacement therapy, but the version of PTH used was short-acting and had to be given by injection frequently. The investigators have developed a longer-lasting version of therapeutic PTH, the effects of which last 24 to 48 hours. They will continue to prepare the compound for testing in human clinical trials.
Hypoparathyroidism is a life-long disease of orphan-drug status that is characterized by an inadequate production of PTH, resulting in hypocalcemia and hyperphosphatemia. Instead of having their missing PTH replaced, affected individuals currently are given large amounts of oral calcium and active vitamin D analogs, treatments that increase considerably the risk of kidney damage (nephrocalcinosis and nephrolithiasis), even if blood calcium levels increase to only the lower end of the normal range. Clinical tests with subcutaneously administered PTH(1-34) and PTH(1-84) peptides of native sequence have demonstrated some efficacy; however, because of its short duration of action, at least two daily injections of PTH(1-34) are needed, and even then, serum calcium levels can fluctuate widely. Moreover, PTH(1-34) therapy often requires continued oral calcium and vitamin D supplementation, and urinary calcium excretion may not be reduced over the entire day with either PTH peptide.
The key investigators have developed a novel class of long-acting PTH analogs that were selected for their unique biological properties at the PTH/PTHrP receptor (PTHR1). A single injection of these long-acting PTH peptides leads to a 24- to 48-hour sustained calcemic response in rodents and monkeys, which is accompanied by a sustained reduction in urinary calcium excretion and in blood phosphorus levels. Injection of either PTH(1-34) or PTH(1-84) failed to induce similarly prolonged effects. Among several of the long-acting PTH analogs identified, the investigators have selected LA-PTH, based on its superior potency in vitro and in vivo, for further development through BrIDGs. The team’s current data predict that LA-PTH can be more effective as a treatment for hypoparathyroidism than current modalities and that the new analog may be especially valuable for individuals with activating calcium-sensing receptor mutations, a particularly difficult-to-treat patient group who have an even higher risk of nephrocalcinosis and nephrolithiasis under conventional calcium and vitamin D therapy.
Massachusetts General Hospital (General Hospital Corp.), Boston
Michael Mannstadt, M.D.
Thomas Gardella, Ph.D.
Harald Jueppner, M.D.
Robert Neer, M.D.
John Potts, M.D.
Public Health Impact
Patients with hypoparathyroidism can suffer from multiple symptoms caused by low blood calcium levels. Symptoms can include minor problems like muscle twitching or severe, possibly life-threatening complications, such as seizures. The investigators have developed a long-acting PTH analog that is likely to provide major improvements over current medical therapy for this group of patients.
BrIDGs program scientists collaborated on the completion of formulation development, manufacture of Good Manufacturing Practice (GMP) and non-GMP material, including drug supply for clinical trials, and pharmacokinetic and IND-directed toxicology studies.