First in Human Adaptive Study to Investigate the Kinetic Properties of the Novel PET Radioligand [11C]CHDI-00491009 and Its Suitability for Quantification of Aggregated Mutant Huntingtin in the Brains of People With Huntington's Disease
This is a FIH (first-in-human) study to evaluate the clinical utility of the radioligand \[11C\]CHDI-00491009 as a PET tracer that binds specifically to mutant huntingtin (mHTT) aggregates in Huntington's disease (HD). The study is divided into three cohorts defined by the Huntington's Disease Integrated Staging System (HD-ISS): Cohort 1 - initial tracer validation (3 healthy controls (HCs)); Cohort 2 - target validation and test-retest variability (6 HD-ISS Stage 3 participants and 6 age and biological sex-matched HCs); Cohort 3 - target sensitivity (6 HD-ISS Stage 2 participants and 6 age and biological sex-matched HCs). An interim analysis (IA) will be conducted after the completion of each cohort, followed by a final analysis for the study. In addition to imaging, exploratory biomarkers, including somatic instability index, soluble mHTT and total huntingtin (HTT), will be assessed. All participants with HD (PwHD) will have an additional blood sample drawn at the screening visit to assess the somatic instability index and will also be invited to provide an optional cerebrospinal fluid (CSF) sample for measurement of soluble mHTT and total HTT.
⁃ PwHD HD-ISS Stages 2 and 3 and HC participants who:
• Are female or male adults, age 18-64 years old, inclusive.
• Have body mass index (BMI) between 19 and 35, inclusive.
• Have capacity to give full informed consent in writing and have read and signed the informed consent form (ICF).
• Are able to comply with study procedures, including fasting and blood sampling.
• Are able and willing to travel to the imaging center in Leuven, Belgium.
• Are willing to comply with the use of adequate contraceptive measures.
• HD-ISS Stage 2 participants who:
• Have a huntingtin gene CAG expansion between 40 and 50, inclusive; and
• Are classified within HD-ISS Stage 2 per the HD-ISS criteria using HD-ISS Modified Stage calculator.
• Have a PIN score of 0.47 to 1.84 \[prognostic index normed for HD (PIN) where PIN = (PIHD - 883)/1044 where PIHD = 51 x TMS + (-34) x SDMT + 7 x Age x (CAG - 34) (TMS is the UHDRS Total Motor Score, and SDMT is the UHDRS Symbol Digit Modalities Test)\].
⁃ HD-ISS Stage 2 participants who:
⁃ 7\. Have a huntingtin gene CAG expansion between 40 and 50, inclusive; and 8. Are classified within HD-ISS Stage 2 per the HD-ISS criteria using HD-ISS Modified Stage calculator.
⁃ 9\. Have a PIN score of 0.47 to 1.84 \[prognostic index normed for HD (PIN) where PIN = (PIHD - 883)/1044 where PIHD = 51 x TMS + (-34) x SDMT + 7 x Age x (CAG - 34) (TMS is the UHDRS Total Motor Score, and SDMT is the UHDRS Symbol Digit Modalities Test)\].
⁃ HC participants who:
⁃ 13\. Have no known family history of HD; or 14. Have a known family history of HD and have been tested for the huntingtin gene CAG expansion and are not at genetic risk for HD (CAG \< 36).
⁃ 15\. Age match (+/- 5 years) and biological sex match to each HD participant in Cohort 2 and Cohort 3 (except for Cohort 1, no matching).