A Phase 1/2 Open-label First-in-Human Dose-Escalating Safety and Efficacy Study Evaluating Subcutaneous Administration of PTH-IA in Adults and Children With Jansen s Metaphyseal Chondrodysplasia (JMC)

Summary

Jansen s Metaphyseal Chondrodysplasia (JMC) is a very rare disorder with only approximately 30 people known to have the disease worldwide. It is caused by parathyroid hormone 1 receptor (PTH1R) variants leading to constitutive activation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP). PTH1R is predominantly expressed in the kidneys and bone and growth-plate chondrocytes. Individuals with JMC develop severe growth impairment resulting in significant short stature, scoliosis, frequent fractures, bone pain, mineral-ion abnormalities (typically hypercalcemia and hypercalciuria), hypertension, and chronic kidney disease due to nephrocalcinosis and nephrolithiasis. Children often undergo multiple surgeries for skeletal fractures and deformities; mobility is commonly impaired, usually requiring assistive devices for ambulation. Other complications may include premature closure of cranial sutures and cranial nerve compressions with the potential for vision and/or hearing loss \[1-3\]. Physical function impairment and the need for complication-related operations have profound deleterious effects on quality of life in individuals with JMC. There are currently no approved therapies for JMC, and novel therapies are critically needed to prevent irreversible disease complications and improve patient quality of life. The inventors of the drug, parathyroid hormone inverse agonist (PTH-IA), have considerable expertise in both the basic and clinical aspects of PTH/PTHrP receptor molecular biology and pharmacology. They reported the first PTH1R JMC mutations (including the H223R mutation) over 20 years ago and identified certain PTH antagonist ligands that function as inverse agonists on the PTH1R JMC mutant receptors \[2, 4\]. These ligands suppress the mutant receptor s elevated basal rates of cAMP signalling, as assessed in cultured cells and animal models. In vivo studies confirm that inverse agonist ligands may be effective in treating JMC. This study involves the use of PTH-IA, a 30-amino acid PTH inverse agonist ligand with the amino acid sequence \[Leu11,dTrp12,Trp23,Tyr36\]-PTHrP(7-36)NH2. We hypothesize that PTH-IA will be a safe and effective treatment for individuals with JMC.

Description

Eligibility

Age range

3–100 years

Sex

All

Healthy volunteers

No

Interventions

• Drug
  PTH-IA

  PTH-IA is a 30-amino acid peptide expected to act as an inverse agonist, decreasing the proportion of mutant PTH1R receptors in the active-state conformation and leading to a reduction in basal cAMP signaling. This hypothesis is based on results from PTH-IA treatment of cells and animal models expressing the different PTH1R mutations seen in JMC individuals. In-vitro studies of HEK293 cells stably transfected with a Glosensor cAMP reporter and plasmids expressing the different PTH1R constitutively active mutant JMC alleles (H223R, I458K, I458R, T410P, and T410R) showed that the cells displayed agonist-independent cAMP generation. Treatment of cells expressing the different PTH1R mutations with PTH-IA resulted in a rapid and persistent reduction in basal cAMP signaling, indicating that the peptide can act as an inverse agonist and thus decreases the proportion of mutant receptors in the active-state conformation.

Location