A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)

Thiogenesis Therapeutics

Status and phase

Begins enrollment in 3 months

Phase 2

Conditions

MELAS Syndrome

Treatments

Drug: TTI-0102: cysteamine-pantetheine disulfide

Drug: D-Mannitol

Study type

Interventional

Funder types

Industry

Identifiers

NCT06990984

TTI-LSS-001

Details and patient eligibility

About

The goal of this clinical trial is to investigate oral TTI-0102 to evaluate its pharmacokinetics, safety, and preliminary efficacy in patients with Leigh syndrome spectrum, in three sequences. First sequence will be placebo-controlled and include 12 adolescents and adults weighing more than 40 kg. Second sequence will be open-label and include 3 adults and 3 children weighing 25-40 kg. Third sequence will also be open-label and will include 3 children weighing 20-25 kg. The main questions clinical trial aims to answer are:

Characterize the relationship between TTI-0102 drug levels by measuring
1. cysteamine pharmacokinetic (PK) parameters
2. pharmacodynamic (PD) efficacy measures
Generate a population PK model and determine dose level for later dosing groups
collect data to inform the design of a subsequent phase 2b/3 study of TTI-0102 in this patient population

Participants will be asked to:

Take the study drug twice daily for 12 weeks
Visit the clinic for checkups and testing 7 times in total: once prior to study drug dosing, then 5 times over the 12-week treatment period and one more time a month after the last study drug dose.

Enrollment

18 estimated patients

Sex

All

Ages

5 to 55 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Individuals aged 5 years to 55 years (inclusive) and weight-eligible, at the time of informed consent / assent and enrollment
Confirmed diagnosis of Leigh syndrome or Leigh-like disorder (Leigh syndrome spectrum [LSS]) with neurodevelopmental manifestations, which include documented developmental delay, developmental regression, or abnormal neurologic exam findings
Willing and able to comply with required study schedule and procedures, including daily TTI-0102 study drug dosing requirements, i.e., able to ingest solution orally
Adequate liver function as evidenced by total bilirubin < 1.5x upper limit of normal (ULN) and liver function tests < 3x ULN
Normal hematologic parameters defined as:

Absolute neutrophil count ≥ 1.0 x 109/L Platelet count ≥ 100,000/mm3 (100 x 109/L) Hemoglobin ≥ 9 g/dL

Non-fasting serum triglycerides < 300 mg/dL and non-fasting serum cholesterol < 300 mg/dL
Serum amylase and lipase < 2x ULN
Adequate immunoglobulin levels as outlined below that, in the opinion of the investigator, will not place the patient at increased risk of infection:

IgG ≥ 200 mg/dL IgM ≥ 30 mg/dL IgA ≥ 10 mg/dL

All sexually-active participants must agree to use effective contraception during study participation:
1. Females of reproductive potential must agree to use effective contraception without interruption from 28 days prior to starting TTI-0102 through 30 days after last dose of TTI-0102; have a negative serum pregnancy test result at screening; and agree to ongoing urine pregnancy testing during the subsequent study period.
2. Male patients must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of reproductive potential while participating in the study and through 30 days after the last dose of TTI-0102
  
  Exclusion Criteria:
Documented diagnosis of concurrent inborn errors of metabolism
Non-elective hospitalization related to their Leigh syndrome or mitochondrial disease within 60 days prior to screening
Treatment with taurine during the previous 30 days of screening, and not willing to discontinue for the duration of the study
Severe gastrointestinal disease including gastroparesis
Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
In the opinion of the investigator, clinically-significant or severe cardiac conditions, at the time of screening
History of drug or alcohol abuse
History of pancreatitis
Known or suspected hypersensitivity to cysteamine
Allergy to any medicine containing mercaptamine, penicillamine, or known hypersensitivity to any of the study drug ingredients
Exposure to any live vaccinations within 30 days prior to the first dose of TTI-0102, except for the influenza and / or COVID-19 vaccines
Planned surgical procedure during the study period
Clinically-significant proteinuria that requires ongoing medical therapy
Patients who are breastfeeding and / or are pregnant
History of solid organ transplant or bone marrow transplant
Treatment with any investigational drug, including an investigational drug for mitochondrial disease, within 30 days prior to receiving the first dose of TTI-0102
Patients with confirmed or suspected increased intracranial pressure, pseudotumor cerebri / idiopathic intracranial hypertension, and or papilledema
Currently active malignancy (other than adequately treated non-melanoma skin cancers, carcinoma in situ of the cervix, or other adequately treated carcinoma in situ) and / or ongoing treatment for malignancy are ineligible. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for at least one year
Recent infection requiring systemic anti-infective treatment that was completed ≤ 14 days prior to screening
Uncontrolled diabetes mellitus, as defined by HbA1c > 8%, despite adequate therapy
History of interstitial lung disease and / or pneumonitis
Known human immunodeficiency virus, active hepatitis B and / or hepatitis C infection(s)
Any uncontrolled psychiatric or medical condition which, in the opinion of the investigator, would interfere with the patient's safe participation in the study
Any other condition or prior therapy that in the opinion of the investigator would render the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol and / or likelihood of non-compliance with any study requirements