A clinical study to learn whether a new drug, TPN-101, is safe when given to AGS patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Transposon Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

27 Jan 2023 → 28 Feb 2025

Decision date (initial)

2024-09-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Transponson Therapeutics, Inc, United States

External identifiers

EU CT number

2024-511176-32-00

EudraCT number

2022-000064-21

ClinicalTrials.gov

NCT05613868

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Pharmacodynamic, Safety, Others

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 objectives 4

1. To assess PK of TPN-101 in plasma and CSF
2. To assess the PD effects of TPN-101 in blood and CSF
3. To assess effect of TPN-101 on cerebral blood flow
4. To assess clinical and functional status

Conditions and MedDRA coding

Aicardi-Goutières Syndrome (AGS)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003075-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

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 1 to < 5 years of age and >= 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. Mean of 3 IFN scores in peripheral blood (measured on 3 occasions, approximately 2 weeks apart, beginning at the first screening visit, during the 8-week Screening Period) > 2 standard deviations above the mean score of healthy controls. 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; fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required) 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; abstinence should only be used as a contraceptive method if it is in line with the subject's usual and preferred lifestyle. Periodic abstinence, e.g., calendar, symptothermal, postovulation methods, is not an acceptable method of contraception), 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. If male, with a partner who is not postmenopausal (for at least 2 years) or surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), the subject must agree to use a condom and that his partner will 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; vasectomy (provided that he 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; abstinence should only be used as a contraceptive method if it is in line with the subject's usual and preferred lifestyle. Periodic abstinence, e.g., calendar, symptothermal, postovulation methods, is not an acceptable method of contraception), from Screening through 3 months after the last dose of the study medication. Please see the protocol for the full list of inclusion criteria

Exclusion criteria 18

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 history of psychiatric disorders including, but not limited to, depression and/or suicidal behavior/ideation) 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 < 2 × upper limit of normal (ULN) are allowed
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. Initiation of treatment with, or change in the dose of, an immunomodulator within 30 days of 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
13. Any major surgery within 30 days of Screening or any planned major surgery during the study
14. For patients who agree to the optional lumbar puncture (LP), any contraindication to undergoing an LP including, but not limited to: inability to tolerate an appropriately flexed position for the time necessary to perform an LP; international normalized ratio (INR) > 1.4 or other coagulopathy; platelet count of < 120,000/μL; infection at the desired LP site; taking anti-platelet or anti-coagulant medication within 30 days of Screening (Note: low dose aspirin is permitted but should be stopped 5 days prior to the LP); severe deformity or abnormality of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma
15. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
16. Persons hospitalized without consent, or persons deprived of liberty by a judicial or administrative decision
17. Known hypersensitivity to any component of the study drug (Note: study drug excipients are microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate)
18. Physical and laboratory test findings, including the following: a. Evidence of organ dysfunction or any clinically significant deviation from normal physical examination or vital signs that are not specific to AGS and that could interfere with the conduct of the study, the interpretation of the data, or increase patient risk, in the opinion of the investigator b. Clinically significant abnormality on 12-lead ECG prior to study drug administration, confirmed by repeat testing c. Total alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2× ULN, confirmed by repeat testing d. Total bilirubin > 1.2 × the ULN (unless due to Gilbert's syndrome e. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 as calculated using the CKD-EPI Creatinine Equation (Levey 2009) for adults (>= 18 years) or the creatinine-based "Bedside Schwartz" equation (Schwartz 2009) for children f. Hemoglobin less than 8 g/dL, absolute neutrophil cell count of < 1500/μL, or platelet levels below the lower limit of normality (LLN) g. Positive blood screen for HIV or hepatitis B surface antigen h. Positive urine drug screen

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Reduction in innate immune signaling, as assessed by the expression of 24 ISG, used to calculate an IFN score in whole blood.
2. Incidence and severity of treatment-emergent adverse events (TEAEs) with TPN-101 administered for up to 48 weeks in patients with AGS.

Secondary endpoints 7

1. Concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF)
2. L1 expression including L1 RNA
3. IFN levels in blood and CSF, including IFN-alpha and IFN-gamma, and genome-wide RNA-Seq expression analysis in whole blood
4. Other inflammatory biomarkers in blood and CSF (e.g., neopterin)
5. Neurodegeneration biomarkers, including NfL, UCHL-1, tau, and GFAP in blood and CSF
6. Brain magnetic resonance imaging (MRI) including arterial spin labeling for measurement of cerebral blood flow
7. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Transposon Therapeutics Inc.

Sponsor organisation

Transposon Therapeutics Inc.

Address

2765 Sand Hill Road

City

Menlo Park

Postcode

94025-7098

Country

United States

Scientific contact point

Organisation

Transposon Therapeutics Inc.

Contact name

Andrew Satlin

Public contact point

Organisation

Transposon Therapeutics Inc.

Contact name

Andrew Satlin

Third parties 5

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications