tpn-101 in aicardi-goutières syndrome (ags)

Conditions: Aicardi-Goutières Syndrome (AGS)

Summary: a phase 2a multi-center, open-label single dose level study of tpn-101 in patients with aicardi-goutières syndrome (ags)

the study is planned in pediatric and adult patients with ags that are greater than 1 year and weigh at least 10 kg. the tpn-101 dose will be adjusted from 100 mg to 400 mg based on weight to achieve similar drug exposures in all subjects. the study plans to enroll 10 - 16 subjects. this study includes a 6-8 week screening period, a 48-week open label treatment period, and a 12-week follow-up period.

Eligibility criteria:
patients must meet all of the following criteria: inclusion 1. male or female participants of the following ages: 1. cohort 1: adults (≥ 18 years of age) 2. cohort 2: adolescents (12 to 17 years of age) 3. cohort 3: children 5 to 11 years of age 4. cohort 4: children 1 to \ = 10 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. 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): 1. early onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, and microcephaly, the latter appearing in the first year of life 2. calcifications particularly visible at basal ganglia level (putamen, pallidus, and thalamus), but also extending to the periventricular white matter 3. cerebral white matter abnormalities 4. cerebral atrophy 5. 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. 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 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, physical or laboratory abnormality 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 7. history of cancer within 5 years of screening, with the exception of fully treated non-melanoma skin cancers 8. receipt of an experimental agent within 30 days or 5 half-lives prior to screening, whichever is longer 9. prior treatment with an immunomodulator other than a jak inhibitor within 6 months of screening; patients taking jak inhibitors for ags must have been on a stable dose for one month prior to screening 10. current treatment with a nucleoside reverse transcriptase inhibitor (nrti) or other antiviral drug 11. receipt of systemic corticosteroids within 30 days prior to screening 12. any vaccination within 30 days prior to screening

Keywords: ags tpn-101 censavudine