Safety and Efficacy of PTH-IA

NCT07541209 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001653001653-D
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Jansen's Metaphyseal Chondrodysplasia

Keywords

Jansen Type Metaphyseal Chondrodysplasia; Parathyroid Hormone 1 Receptor (PTH1R); PTH1R Mutations; Parathyroid Hormone-Related Peptide (PTHrP); Parathyroid Hormone Inverse Agonist (PTH-IA)

Outcome Measures

Primary Outcomes (5)

• Period 1 - Adult: Evaluate the safety and tolerability of PTH-IA in adults with JMC (>= 18 years)

  To assess dose-limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs).

  104 +/- 10 days

• Period 1 - Adult: Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in adults (>= 18 y/o) years old with JMC

  To determine PK parameters after multiple ascending doses of PTH-IA.

  104 +/- 10 days

• Period 2 - Adult and Pediatrics: Evaluate the safety and tolerability of PTH-IA in adults and children aged 3-17 years old with JMC.

  To assess dose-limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs).

  28 weeks +/- 10 days

• Period 2 - Adult and Pediatrics: Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in children aged 3-17 years old with JMC.

  To determine PK parameters after multiple ascending doses of PTH-IA.

  28 weeks +/- 10 days

• Period 2 - Adult and Pediatrics: Evaluate the effect of PTH-IA on serum PTH levels in children and adults with JMC.

  To evaluate changes in serum PTH from baseline to the end of treatment.

  28 weeks +/- 10 days

Secondary Outcomes (2)

• Periods 1 and 2 - Identify the optimal dose range of PTH-IA.

  Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.

• Periods 1 and 2 - Evaluate potential measures of efficacy of PTH-IA in JMC.

  Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.

Study Arms (1)

Treatment with PTH-IA

EXPERIMENTAL

All participants will receive PTH-IA for up to 90+/-7 days in Period 1, and 24 weeks +/- 7 days in Period 2.

Drug: PTH-IA

Interventions

PTH-IA DRUG

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.

Treatment with PTH-IA

Eligibility Criteria

• Age: 3 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Pregnancy or lactation
• hydroxyvitamin D \<=20 ng/mL. Patients will be eligible for rescreening after a repletion period lasting up to 6 months.
• Clinically significant renal disease with estimated glomerular filtration rate (eGFR) \<=45 mL/ min/1.73 m2.
• 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.
• 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.
• Hypersensitivity or intolerance to any active substance or excipient of PTH-IA
• History of surgical removal of all parathyroid glands.
• Treatment with bisphosphonate use within 6 months of screening
• Treatment with denosumab within 3 months of screening
• Treatment with thiazides within 4 weeks of screening
• 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.

Sponsors & Collaborators

• National Institute of Dental and Craniofacial Research (NIDCR): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Jansen type metaphyseal chondrodysplasia

Study Officials

• Alison M Boyce, M.D.

  National Institute of Dental and Craniofacial Research (NIDCR)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Olivia J de Jong, C.R.N.P.

CONTACT

(240) 595-2764; olivia.dejong@nih.gov

Alison M Boyce, M.D.

CONTACT

(301) 827-4802; alison.boyce@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2026
• First Posted: April 21, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029
• Last Updated: April 29, 2026

Record last verified: 2026-04-15

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Results from this trial will be made available 12 months after the primary study completion date.
• Access Criteria: PI will consider reasonable requests from qualified researchers for access to clinical data.

Locations

US (1)