NIH Advances First-Ever Clinical Trial for Promising Jansen’s Disease Therapy

A major milestone has been reached in the journey to develop a treatment for Jansen’s metaphyseal chondrodysplasia (JMC) thanks to a decade of collaborative research and drug development led by investigators at the National Institutes of Health (NIH) and key scientific partners at NCATS.

From Mutation Discovery to Drug Development

The scientific team, including Dr. Harald Jüppner was the first to identify the H223R mutation in the PTHR1 gene, the most common and well-characterized cause of JMC. This discovery allowed researchers to develop a transgenic mouse model (C1HR) that closely mirrors the human disease, providing a critical platform for studying disease mechanisms and testing potential treatments.

Through extensive in vitro and in vivo work, researchers identified and optimized a class of molecules called PTH receptor inverse agonists (PTH-IA). These compounds are designed to suppress the abnormally high, ligand-independent activity of the mutated PTH receptor that causes JMC.

One particular PTH-IA compound showed significant therapeutic potential in the C1HR mouse model, leading to notable improvements in bone health and mineral ion balance, key clinical hallmarks of JMC.

TRND and NCATS Move Toward Clinical Trials

With support from the NIH’s Therapeutics for Rare and Neglected Diseases (TRND) program, an initiative of the National Center for Advancing Translational Sciences (NCATS), a full preclinical development campaign was launched to bring this potential therapy from the lab bench to human trials.

Key achievements include:

• Development of a clinical-grade, GMP-manufactured PTH-IA formulation

• Completion of GLP toxicology studies in adult and juvenile animals

• Comprehensive stability and safety testing

• Pharmacokinetics and bioanalytical method development

• Submission and approval of an Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA)

In a significant regulatory win, Orphan Drug Designation and Rare Pediatric Disease Designation were granted by the FDA for PTH-IA as a treatment for JMC, critical steps that recognize both the drug’s potential and the urgent unmet needs of this rare disease population.

First-in-Human Trial on the Horizon

Preparations are now underway to launch a first-in-human Phase 1 clinical trial in adults with JMC. A Phase 2 pediatric trial is also on the horizon, backed by extensive juvenile safety data and ongoing support from NIH.

In parallel, a natural history study of JMC is actively enrolling at the NIH Clinical Center to better understand disease progression and establish clinical endpoints that will inform future therapeutic studies.

This marks the first-ever targeted therapy developed specifically for Jansen’s Disease—and represents hope for patients who have long gone without treatment options. It also underscores the power of rare disease research partnerships, uniting molecular discovery, translational science, and regulatory innovation.

As the Jansen’s community eagerly anticipates the launch of the clinical trial, this work stands as a shining example of what's possible when patients, scientists, and public agencies work together toward a shared goal: a future with better treatments and brighter outcomes.