Aicardi-Goutières Syndrome (AGS) MedDRA version: 22.1 Level: PT Classification code 10083189 Term: Aicardi-Goutieres syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: TPN-101
Product Code: TPN-101
Pharmaceutical Form: Oral powder in sachet
INN or Proposed INN: Censavudine
CAS Number: 634907-30-5
Current Sponsor code: TPN-101
Concentration unit: mg mil
Sponsors
Transposon Therapeutics, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female participants of the following ages: a. Cohort 1: Adults (= 18 years of age) b. Cohort 2: Adolescents (12 to 17 years of age) c. Cohort 3: Children 5 to 11 years of age d. Cohort 4: Children = 6 kg in weight 2. Molecular diagnosis of AGS due to biallelic mutations in 1 of the following 5 genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, or SAMHD1, or due to a recognized dominant mutation in TREX1. 3. IFN score in peripheral blood > 2 standard deviations above the mean score of healthy controls measured on 3 occasions, approximately 2 weeks apart, during the 6-week Screening Period. The IFN score, determined on a Nanostring panel, is the median fold change in expression of a panel of 24 interferon-stimulated genes (ISGs) compared with the median IFN score of healthy controls. 4. Clinical syndrome consistent with AGS diagnosis based on clinical, CSF, and radiological findings. The following are examples of such findings (none of these are required for inclusion): a. Early onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, and microcephaly, the latter appearing in the first year of life b. Calcifications particularly visible at basal ganglia level (putamen, pallidus, and thalamus), but also extending to the periventricular white matter c. Cerebral white matter abnormalities d. Cerebral atrophy e. Important systemic symptoms in the early stages of the disease including irritability, feeding and sleeping difficulties, unexplained fevers, and the appearance of chilblain-like skin lesions on the fingers, toes, and ears 5. Women of childbearing potential (WOCBP) must be surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or agree to use highly effective methods of contraception, e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success); or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), from Screening through 3 months after the last dose of the study medication. Women who are pregnant or breastfeeding are not eligible for enrollment. 6. Has a reliable caregiver to accompany the patient to all study visits. Caregiver must have frequent contact with patient and be willing to monitor the patient's health and concomitant medications throughout the study. Are the trial subjects under 18? yes Number of subjects for this age range: 12 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 4 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Mutation in IFIH1, ADAR1, LSM11, or RNU7-1. 2. Pre-/perinatal infections, in particular the TORCH complex (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus) 3. Presence of other significant neurological disorders; brain tumor or other space-occupying lesion; history of severe head injury 4. Clinically significant intercurrent illness, medical condition (e.g., hematological, endocrine, cardiovascular, renal, hepatic, or gastrointestinal disease) or medical history (including neurological or mental illness) that would jeopardize the safety of the patient, limit participation, or compromise the interpretation of the data derived from the patient 5. Autoimmune disease requiring treatment or management (quiescent rheumatoid arthritis, psoriasis, treated autoimmune thyroiditis, or controlled Type 1 diabetes are acceptable) 6. History of human immunodeficiency virus (HIV), hepatitis B, or any active infection during Screening, unless the patient will have been symptom-free for at least 30 days prior to study drug administration. Patients with treated hepatitis C with no laboratory evidence of active disease and liver enzymes 1.4 or other coagulopathy; platelet count of 2× ULN, confirmed by repeat testing d. Total bilirubin > 1.2 × the ULN (unless due to Gilbert’s syndrome) e. Serum creatinine > 168 µmol/L (1.9 mg/dL), confirmed by repeat testing f. Hemoglobin less than 7.5 g/dL or absolu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To demonstrate proof-of-mechanism for TPN-101 in AGS, as evidenced by reduction in interferon (IFN) score •To assess the safety and tolerability of TPN-101 in patients with (AGS);Secondary Objective: •To assess PK of TPN-101 in plasma and CSF •To assess the PD effects of TPN-101 in blood and CSF •To assess effect of TPN-101 on cerebral blood flow •To assess clinical and functional status;Primary end point(s): •Reduction in innate immune signaling, as assessed by the expression of 24 ISG, used to calculate an IFN score in whole blood. •Incidence and severity of treatment-emergent adverse events (TEAEs) with TPN-101 administered for up to 48 weeks in patients with AGS. ;Timepoint(s) of evaluation of this end point: 48 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF) • L1 expression including L1 RNA • INF status in blood and CSF, including IFN-alpha, IFN-gamma, as well as by measuring antiviral protective capacity (IFN activity) in patient serum and CSF, and genome-wide RNA-Seq expression analysis in whole blood • Other inflammatory biomarkers in blood and CSF, (e.g., neopterin) • Neurodegeneration biomarkers, including NfL, UCHL-1, tau, and GFAP in blood and CSF • Brain magnetic resonance imaging (MRI) including arterial spin labeling for measurement of cerebral blood flow • Clinical and functional status, as measured by Vineland-3, AGS Scale, Caregiver Diary Score, BSID III, WPPSI-IV, WISC-V, WAIS-IV, GMFM-88, and classification according to 5 systems: GMFCS, MACS, CFCS, EDACS, and VFCS ;Timepoint(s) of evaluation of this end point: Week 48 and monitored throughout the study | — |
Countries
France, Italy, United Kingdom
Contacts
Public ContactAndrew Satlin
Transposon Therapeutics, Inc
Outcome results
None listed