PTH-IA treatment for Jansen's Metaphyseal Chondrodysplasia

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)

This study will test whether twice-daily subcutaneous injections of PTH-IA are safe and can reduce abnormal PTH signaling in children and adults with Jansen's Metaphyseal Chondrodysplasia.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 3 Years to 100 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (nih)
• Drugs / interventions: denosumab
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT07541209 on ClinicalTrials.gov

What this trial studies

This is a Phase 1/2, open-label, single-arm study of multiple ascending doses of PTH-IA given subcutaneously twice daily at the NIH Clinical Center. The trial enrolls adults and children (ages 3 and up) who have genetically confirmed activating PTH1R mutations and meet minimum weight requirements, with staged dose escalation to define tolerability. Primary outcomes focus on safety, dose-limiting toxicities, and pharmacokinetics, plus effects on serum PTH; secondary and exploratory outcomes include selecting an optimal dose range and measuring physical function, pain, quality of life, immunogenicity, and bone histology. The study is conducted under close clinical monitoring with frequent visits for dosing, labs, and safety assessments.

Who should consider this trial

Good fit: Ideal candidates are people with a confirmed activating germline PTH1R mutation (e.g., H223R, I458K/R, T410P/R), aged 3 years or older, meeting the study weight thresholds and able to provide consent and travel to the NIH Clinical Center.

Not a fit: Patients without activating PTH1R mutations, those younger than 3 years or below the study weight limits, or those with medical conditions that prevent study participation are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, PTH-IA could counteract the overactive PTH1R, reduce hypercalcemia and bone complications, and meaningfully improve growth, mobility, and quality of life for people with JMC.

How similar studies have performed: This inverse-agonist approach is novel for JMC and has limited preclinical data, with no established clinical successes in this disease to date.

Eligibility criteria

* 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.

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (RECRUITING)

Study contacts

• Principal investigator: Alison M Boyce, M.D. — National Institute of Dental and Craniofacial Research (NIDCR)
• Study coordinator: Olivia J de Jong, C.R.N.P.

Conditions: Jansen's Metaphyseal Chondrodysplasia, Jansen Type Metaphyseal Chondrodysplasia, Parathyroid Hormone 1 Receptor, PTH1R Mutations, Parathyroid Hormone-Related Peptide, Parathyroid Hormone Inverse Agonist