Tianasen (ASO-GNAO1) for GNAO1-Encephalopathy With Epilepsy and Movement Disorders.

Official title

An Open-Label, Non-Randomized Study to Evaluate the Efficacy and Safety of ASO-GNAO1 (Tianasen) in Patients With GNAO1-Encephalopathy With Epilepsy and Movement Disorders Following Repeated Intrathecal Dose Escalation.

Overview

The goal of this clinical trial is to evaluate the efficacy and safety of the investigational drug ASO-GNAO1 (Tianasen) in pediatric patients with c.607G\>A mutation in the GNAO1 gene associated with epilepsy and neurodevelopmental disorder. The main questions it aims to answer are: 1. Does intrathecal administration of ASO-GNAO1 slow or halt the progression of motor and cognitive symptoms? 2. Is ASO-GNAO1 safe and well-tolerated in this patient population? 3. What is the appropriate therapeutic dose? This is an open-label study without a placebo control group due to the rare and severe nature of the disease. All participants will receive the active drug. Participants will: Receive escalating doses of ASO-GNAO1 via intrathecal injection over a 12-month period. Undergo frequent neurological assessments, biomarker testing, and safety monitoring.

Detailed description

The variant c.607G\>A in the GNAO1 gene is a gain-of-function (GOF) mutation associated with epilepsy and neurodevelopmental disorder.

ASO-GNAO1 (Tianasen) is an investigational antisense oligonucleotide (ASO) therapy designed for the treatment of GNAO1-encephalopathy. Its mechanism of action is allele-specific suppression of the mutant GNAO1 protein expression at the mRNA level. The compound mediates the degradation of mutant mRNA or inhibits its translation, thereby halting the synthesis of the pathogenic protein implicated in disease progression. This targeted suppression is anticipated to mitigate neurodegenerative processes and facilitate partial or complete restoration of neuronal function.

The drug candidate was identified through a screening platform analogous to that used for the development of Milasen, an FDA-authorized personalized ASO therapy for Batten disease. In vitro studies have demonstrated that ASO-GNAO1 (Tianasen) achieves approximately 85% suppression of the mutant GNAO1 allele activity (c.607G\>A mutation) while showing no significant effect on the wild-type allele, confirming its allele-specificity.

Background and Rationale. GNAO1 encephalopathy is a severe, debilitating monogenic neurodevelopmental disorder of childhood onset, characterized by progressive motor dysfunction and drug-resistant epilepsy and hyperkinesis. Currently, there are no approved disease-modifying therapies, and management is limited to palliative and symptomatic care. The disease course is progressive, leading to severe developmental delay, profound disability, and premature mortality.

The rationale for this first-in-human study is to evaluate the potential of ASO-GNAO1 (Tianasen) to alter the natural history of the disease in a population with no alternative effective treatment options.

Study Design and Preclinical Rationale. This study constitutes the first human administration of ASO-GNAO1 (Tianasen). It is initiated as an investigational personalized therapeutic development effort for children with a rare monogenic mutation.

The preclinical toxicology program supporting this trial included single- and repeat-dose toxicity studies in rats. Doses were administered at three levels (0.2 mg/kg, 0.5 mg/kg, and 1.0 mg/kg) via intrathecal bolus injection five times over a 12-week period. The maximum observation period in the repeat-dose toxicity study was 141 days (20 weeks). The established No Observed Adverse Effect Level (NOAEL) and the overall design of the abbreviated preclinical package are consistent with the regulatory precedent set by other personalized ASOs, such as Milasen, which was authorized for a single-patient Investigational New Drug (IND) application.

Rationale for Dose Selection. The starting dose and escalation regimen for this study are based on an integrated analysis of the preclinical toxicology data, including the determination of the NOAEL and the estimated maximum tolerated dose. Further justification is derived from the known pharmacokinetic and pharmacodynamic profiles of structurally and mechanistically similar ASO compounds approved for intrathecal administration in neurological diseases, notably nusinersen and the personalized therapy milasen. Dosing is designed to remain within the established safety margins while targeting concentrations anticipated to be therapeutic based on preclinical efficacy models

Interventions

• Biological Antisense oligonucleotide treatment (ASO)
  Intrathecal escalating doses from 0.3 mg/kg to 1.5 mg/kg (single administration per dose level)

Primary outcome measures

• Change in monthly seizure frequency [Time frame: Baseline to Week 50]
• Change in total monthly duration of seizures [Time frame: Baseline to Week 50]
• Change in frequency of non-epileptic hyperkinetic and dystonic episodes [Time frame: Baseline to Week 50]
• Change in duration of non-epileptic hyperkinetic and dystonic episodes [Time frame: Baseline to Week 50]

Secondary outcome measures (6)

• Change in epileptiform activity index on EEG [Time frame: Baseline, Week 46]
• Change in Barry-Albright Dystonia Scale score [Time frame: Baseline, Week 46]
• Change in concomitant medication dosages [Time frame: Baseline, Week 46]
• Change in Gross Motor Function Measure-88 total score [Time frame: Baseline, Week 46]
• Change in Denver Developmental Screening Test developmental age [Time frame: baseline and week 46]
• Change in Leiter-3 nonverbal IQ score [Time frame: Baseline and week 46]

Eligibility criteria

Inclusion criteria

• Informed Consent: Written informed consent from the parent(s) or legal guardian(s) of the patient and the child's assent (where applicable based on age and cognitive ability), obtained prior to the initiation of any study-related procedures.
• Age: Male or female children aged 1 year and older (≥1 year) until 14 years at the time of informed consent signing.
• Diagnosis: A confirmed a c.607G>A variant in of GNAO1 gene based on genetic testing, and a clinical presentation that includes both epilepsy and movement disorders.
• Treatment Resistance:

• For seizures: Documented resistance to antiseizure medications prior to screening, defined as the persistence of seizures despite adequate trials of at least two appropriately dosed antiseizure medications.
• For non-epileptic hyperkinesias/dystonia: Documented resistance to anti-hyperkinetic medications prior to screening, defined as the persistence of debilitating hyperkinesias or dystonic attacks despite adequate trials of at least two appropriately dosed anti-hyperkinetic medications.
• Contraception (for females of reproductive potential): For post- menarche female adolescents, a negative serum or urine pregnancy test at screening and agreement to use highly effective methods of contraception (e.g., hormonal implants, combined oral contraceptives, intrauterine device) throughout the study participation period.

Exclusion criteria

• Unacceptable Risk: Any concurrent severe medical, neurological, or psychiatric condition, or any other significant circumstance (e.g., unstable clinical status) that, in the judgment of the Investigator, could significantly increase the risk associated with study participation or the administration of the investigational product, or could interfere with the interpretation of study results.
• Impossibility of Intervention: Any anatomical abnormality, coagulation disorder, active infection, or other condition that constitutes a contraindication to or precludes the safe performance of repeated lumbar punctures for intrathecal administration of the study drug.
• Pregnancy or Lactation: Pregnancy, lactation, or intention to become pregnant during the study period.
• Concurrent Experimental Therapy: Receipt of any other investigational drug, device, or biological product within 1 month prior to screening or within a period of at least 5 half-lives of that product (whichever is longer).
• Protocol Compliance: Any other disease, condition, or behavioral factor that, in the opinion of the Investigator, could compromise the patient's safety, preclude adherence to the protocol schedule, or interfere with the study conduct and endpoint assessments. Age: 14 years and older

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Russia · 1 center

• Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pir — Moscow

Identifiers

NCT: NCT07363603 · ASO-GNAO1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗