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)
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.
⁃ In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Willingness of participant and/or guardian to sign a written informed consent form, which must be obtained prior to initiation of study procedures.
• Period 1: Adults \>=18 years of age
• Period 2: Adults and children 3-17 years of age
• Minimum body weight of 35 kg for participation in Period 1 and 18 kg for participation in Period 2.
• Have an activating germline mutation of PTHIR (H223R, I458K, I458R, T410P, or T410R)
• Female participants of reproductive potential must agree to use one form of highly effective contraception. Highly effective contraception includes:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.
• Male sterilization (at least 6 months prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant for the study duration.
• Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormonal vaginal ring or transdermal hormone contraception
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Barrier methods of contraception used correctly by the male partner: condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
• For males of reproductive potential: use of condoms or other methods described above to ensure effective contraception with partner.
• Stated willingness to comply with all study procedures and availability for the duration of the study, including the ability and willingness to travel to the NIH Clinical Center.