Long-Acting Parathyroid Hormone Analog for Treatment of Hypoparathyroidism
Hypoparathyroidism is a life-long disease of orphan-drug status that is characterized by an inadequate production of parathyroid hormone (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 renal damage (and nephrocalcinosis and nephrolithiasis), even if blood calcium levels increase to only the lower end of the normal range. Clinical tests with subcutaneous 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 that oral calcium/vitamin D supplementation is continued, and urinary calcium excretion may not be reduced over the entire day with either PTH peptide.
We have developed a novel class of long-acting PTH analogs that were selected due to their unique biological properties at the PTH/PTHrP receptor (PTHR1). A single injection of these long-acting PTH peptides leads to a sustained (24-48 hours) calcemic response in rodents and monkeys, which is accompanied by a sustained reduction in urinary calcium excretion, as well as a sustained reduction 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, we have selected one, called LA-PTH, based on its superior potency in vitro and in vivo, for further development through the RAID program. Our current data predict that LA-PTH can be more effective as a treatment of 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/vitamin D therapy.
Massachusetts General Hospital (General Hospital Corp.)
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 insufficient parathyroid gland activity (hypoparathyroidism) can suffer from multiple symptoms caused by low blood calcium levels; these can include minor problems like muscle twitching or severe, possibly life-threatening complications such as tetany and seizures. We now have developed a long-acting PTH analog that is likely to provide major improvements over current medical therapy for this group of patients.
Approved studies are ongoing.
- Synthesis of GMP and non-GMP material
- Formulation development
- PK/ADME studies
- IND-directed toxicology