Safety and Efficacy of PTH-IA
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age3-100
SponsorNational Institute of Dental and Craniofacial Research (NIDCR)
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
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)
Disqualifiers
Pregnancy or lactation
25-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.
Trial design
Design model
Single group
Treatments tested in this trial
PTH-IA
DrugPTH-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 groups
12 Participants
are divided into 1 treatment groupGroup A: Treatment with PTH-IAExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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).
Time frame
104 +/- 10 days2
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.
Time frame
104 +/- 10 days3
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).
Time frame
28 weeks +/- 10 days4
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.
Time frame
28 weeks +/- 10 daysSecondary outcomes
1
Periods 1 and 2 - Identify the optimal dose range of PTH-IA.
To measure the absolute levels and percentage change: - From baseline in serum-corrected calcium pre- and post-intervention at the end of treatment.- In the ratio of serum-corrected calcium to PTH (\[mg/dl\]/\[pg/ml\]) pre- and post-intervention at the end of the study.- From baseline in fractional excretion of calcium at the end of treatment.- From baseline in urine nephrogenous cAMP at the end of treatment.- From baseline in serum phosphate at the end of treatment.- 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 the end of treatment.- To define the minimally effective dose defined by the dose at which the mean of the two highest PTH levels increases to 30-40 pg/mL (in individuals with baseline PTH \<= 20 pg/mL) in the absence of DLTs.
Time frame
Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.2
Periods 1 and 2 - Evaluate potential measures of efficacy of PTH-IA in JMC.
To measure the change in: - Tubular reabsorption of phosphate and the ratio of tubular maximum reabsorption of phosphate to GFR between pre- \& post-intervention at the end of treatment.- Bone turnover markers (P1NP, BSALP, CTX, osteocalcin) between pre- \& post-intervention.- Pre-defined sentinel skeletal lesion metabolic activity representing region of most intense pathology as measured by 18F- NaF PET/CT (\<= 5 lesions) between pre- \& post-intervention.- Pre-defined target skeletal lesion mineral density representing region of most intense pathology as measured by 18F- NaF PET/CT (\<= 5 lesions) between pre- \& post-intervention. - Nephrocalcinosis scores on ultrasound from baseline to end of treatment (0-no nephrocalcinosis to 3-severe).- 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.
Time frame
Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.Sponsors and contacts
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Source ClinicalTrials.gov