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.

Study Description:

This is a Phase 1/2 open-label, single-arm study to evaluate the safety of multiple ascending doses of PTH-IA administered subcutaneously twice a day in individuals with JMC conducted at the National Institutes of Health Clinical Center.

Objectives Primary Objectives

Period 1 - Adult

1. Evaluate the safety and tolerability of PTH-IA in adults with JMC (>=18 years)
2. Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in adults (>= 18 y/o) years old with JMC

Period 2 Adult and Pediatrics

1. Evaluate the safety and tolerability of PTH-IA in adults and children aged 3-17 years old with JMC
2. Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in children aged 3-17 years old with JMC
3. Evaluate the effect of PTH-IA on serum PTH levels on children and adults with JMC

Secondary Objectives

Periods 1 and 2

1. Identify the optimal dose range of PTH-IA
2. Evaluate potential measures of efficacy of PTH-IA in JMC

Exploratory Objectives

Periods 1 and 2

1. Evaluate the effect of PTH-IA on physical function
2. Evaluate the effect of PTH-IA on pain and health-related quality of life (QOL)
3. Evaluate the immunogenicity of PTH-IA
4. Describe the baseline and response to treatment histological characteristics of bone lesions in JMC

Endpoints Primary Endpoints

Period 1

1. Dose limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs)
2. PK parameters after multiple ascending doses of PTH-IA

Period 2

1. Dose limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs)
2. PK parameters after multiple ascending doses of PTH-IA
3. Change in serum PTH from baseline to end of treatment

Secondary Endpoints

Periods 1 and 2

1. Absolute levels and percentage change from baseline in serum corrected calcium pre- and post-intervention at end of treatment
2. Absolute levels and change in ratio of serum corrected calcium to PTH ([mg/dl]/[pg/ml]) pre- and post-intervention at end of study
3. Absolute levels and percentage change from baseline in fractional excretion of calcium at end of treatment
4. Change in tubular reabsorption of phosphate and ratio of tubular maximum reabsorption of phosphate to GFR between pre- and post-intervention at end of treatment
5. Absolute levels and percentage change from baseline in urine nephrogenous cAMP at end of treatment
6. Absolute levels and percentage change from baseline in serum phosphate at end of treatment
7. Change in bone turnover markers (P1NP, BSALP, CTX, osteocalcin) between pre- and post-intervention at end of treatment
8. Absolute levels and percentage change from baseline in markers of mineral homeostasis: 1,25(OH)2 vitamin D and ratio of 1,25(OH)2 vitamin D to PTH at end of treatment
9. Change in pre-defined sentinel skeletal lesion metabolic activity representing region of most intense pathology as measured by 18F- NaF PET/CT (<= 5 lesions) between pre- and post-intervention at end of treatment
10. Change in pre-defined target skeletal lesion mineral density representing region of most intense pathology as measured by 18F- NaF PET/CT (<= 5 lesions) between pre- and postintervention at end of treatment
11. Change in nephrocalcinosis scores on ultrasound from baseline to end of treatment (0-no nephrocalcinosis and 3- severe nephrocalcinosis)
12. Change in HR-pQCT parameters of the radius and tibia: total BMD, cortical and trabecular BMD; cortical thickness, cortical porosity, BV/TV, trabecular number, thickness, and separation; stiffness and failure load of the peripheral skeleton
13. Minimally effective dose defined by dose at which the mean of two highest PTH levels increases to 30-40 pg/mL (in individuals with baseline PTH <= 20 pg/mL) in the absence of DLTs. In individuals with baseline PTH >20 pg/mL, the optimal dose will be the dose at which the mean of two highest PTH obtained increases to 55-65 pg/mL in the absence ofDLTs.

Exploratory Endpoints

Periods 1 and 2

1. Change from baseline in range of motion of upper and lower extremities
2. Change from baseline in manual muscle strength testing of bilateral upper and lower extremities
3. Change from baseline in gait assessment
4. Change from baseline in assessment of skeletal bowing
5. Change from baseline in walking speed
6. Change from baseline in PROMIS pain intensity, pain interference, mobility, and fatigue scores
7. Development and characterization of anti-drug antibodies (ADAs)
8. JMC lesion histology as assessed by bone biopsies

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Willingness of participant and/or guardian to sign a written informed consent form, which must be obtained prior to initiation of study procedures.

2. Period 1: Adults >=18 years of age

   Period 2: Adults and children 3-17 years of age

3. Minimum body weight of 35 kg for participation in Period 1 and 18 kg for participation in Period 2.

4. Have an activating germline mutation of PTHIR (H223R, I458K, I458R, T410P, or T410R)

5. 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.

6. For males of reproductive potential: use of condoms or other methods described above to ensure effective contraception with partner.

7. 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.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Pregnancy or lactation
2. 25-hydroxyvitamin D <=20 ng/mL. Patients will be eligible for rescreening after a repletion period lasting up to 6 months.
3. Clinically significant renal disease with estimated glomerular filtration rate (eGFR) <=45 mL/ min/1.73 m2.
4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal. If transaminitis is present, patients will be eligible for rescreening for a period of up to 6 months.
5. Hgb <12 gm/dL for women and girls >=16 years, <=13 gm/dL for men and boys >=16 years, and <=11.5 gm/dL in children <=15 years. If reduced hemoglobin levels are related to iron, B12, or folate deficiency, patients will be eligible for rescreening after a repletion period lasting up to 6 months.
6. Hypersensitivity or intolerance to any active substance or excipient of PTH-IA
7. History of surgical removal of all parathyroid glands.
8. Treatment with bisphosphonate use within 6 months of screening
9. Treatment with denosumab within 3 months of screening
10. Treatment with thiazides within 4 weeks of screening
11. Any other significant medical conditions that, in the opinion of the study team, may present a concern for participant safety or difficulty with data interpretation.

This study will comply with the NIH Data Sharing Policy and the Clinical Trials Registration and Results Information Submission rule.

Results from this trial will be made available 12 months after the primary study completion date.

PI will consider reasonable requests from qualified researchers for access to clinical data.