Study in Asymptomatic GRN-FTD Patients to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001

This is an open-label, multiple dosing study in asymptomatic GRN-FTD carriers to investigate the safety, tolerability, PK, and PD of VES001. The study follows a MAD design within a single cohort, investigating 2 distinct dose levels (Dose 1: 360 mg and Dose 2: 900 mg), consecutively over a 3-month period. A total of 6 participants will be recruited over a fixed enrolment period of 6 months.


Eligibility Criteria:
Inclusion Criteria:

* Has provided signed informed consent, prior to any study-mandated procedure.
* Has a BMI of ≥ 18 to ≤ 32 kg/m2, and with a minimum weight of 50 kg
* Is an asymptomatic carrier of the GRN mutation, previously confirmed via genetic testing AND historical records (as documented by FRS and FTLD-CDR-NACC-SB) available for review by the investigator

Note: Genetic testing for GRN mutation status will not be conducted as part of methodology or procedures in this study. The study relies on the previously confirmed GRN mutation data in medical history of the potentially eligible participants.

* In good physical health assessed by the investigator and medical history of the participant, physical examinations (PEs), laboratory tests, ECGs, and vital signs
* Is a FOCBP; as defined in CTFG 2020, must have a negative urine pregnancy test at screening and agree to heterosexual abstinence or the use at least 1 highly effective form of contraception (with a failure rate of \<1% per year when used consistently and correctly), from the start of the screening period through 90 days after the last dose of the study drug (Appendix 3). All females are considered of childbearing potential unless they are postmenopausal (at least 12 consecutive months of amenorrhea in the appropriate age group without other known or suspected cause) or have been sterilised surgically (e.g., hysterectomy, bilateral oophorectomy, bilateral salpingectomy).
* Is a male participant who has not had a vasectomy and is sexually active with FOCBP must agree to use a barrier method of birth control from the start of the screening period through 90 days after the last dose of the study drug
* Is a male participant who must agree not to donate sperm from the start of the screening period, through the study, and for at least 90 days after the last dose of the study drug
* Is a female participant who must agree not to donate ova from the start of the screening period, through the study, and for at least 90 days after the last dose of the study drug
* Has the ability to communicate well with the investigator in the Dutch language (at the Erasmus Medical Centre) or English language (at the UCL) and willing to comply with the study restrictions.

Exclusion Criteria:

* Has evidence of any active or chronic disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the participant in the opinion of the investigator (following a detailed medical history, physical examination, vital signs \[SBP, DBP, HR, respiratory rate, body temperature\], and 12-lead ECG). Minor deviations from the normal range may be accepted, if judged by the investigator to have no clinical relevance.
* Has a history of any known neurologic disease, cognitive impairment, diagnosed abnormal cognitive decline related to the participant's age, a history of seizure, or (significant) head trauma.
* Has a history of active malignancy within the last 5 years, with the exception of fully resected cell carcinoma of the skin.
* Has clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel, and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before dosing to confirm eligibility or judged to be clinically irrelevant for healthy participants
* Tests positive for HBsAg, HCV Ab, HIV1 Ab, or HIV2 Ab at screening.
* Has SBP greater than 140 (untreated hypertension) or less than 90 mm Hg, and DBP greater than 90 or less than 50 mm Hg at screening.
* Has abnormal findings in the resting ECG at screening defined as:

  1. QTcF \> 450 or \< 300 msec for males and QTcF \> 470 or \< 300 msec for females
  2. Notable resting bradycardia (HR \< 45 bpm) or tachycardia (HR \> 100 bpm)
  3. Personal or family history of congenital long QT syndrome or sudden death attributed to underlying heart disease
  4. ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement (e.g., neuromuscular artefact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T-wave, merged T- and U-waves, prominent U-waves)
* Has evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker
* Meets criteria that would preclude a LP, such as:

  1. a local infection at the site of the LP
  2. \< 50 × 10E3/μL platelet count at screening
  3. clinically significant coagulation abnormality
  4. significant active bleeding, treatment with an anticoagulant, or treatment with 2 or more antiplatelet agents
  5. history of clinically significant back pathology and/or back injury (e.g., degenerative disease, spinal deformity, or spinal surgery) that may predispose to complications or technical difficulty with LP
* Has any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable).
* Uses any medications (prescription or OTC), within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to 1.2 g/day).
* Uses any vitamin, mineral, herbal, and dietary supplements within 7 days of study drug administration, or less than 5 half-lives (whichever is longer).
* Participated in an investigational drug or device study (last dosing of previous study was within 90 days or less than 5 elimination half-lives of the investigational treatment, whichever is longer, before first dosing of this study).
* Has any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence, psychiatric disease, or usage of anti-psychotic medications.
* Has a history of abuse of addictive substances (alcohol, illegal substances, drug abuse, or regular user of sedatives, hypnotics, tranquillisers, or any other addictive agent) in the past 2 years.
* Tests positive for drugs of abuse at screening or Day 1.
* Is a smoker of more than 10 cigarettes per day prior to screening or who use tobacco products equivalent to more than 10 cigarettes per day and unable to abstain from smoking while in the unit.
* Is demonstrating excess in caffeine consumption (more than 8 cups of coffee or equivalent per day)
* Has had a loss or donation of blood over 500 mL within 3 months (males) or 4 months (females) prior to screening or intention to donate blood or blood products during the study.
* Is a female, who is pregnant, breast-feeding, or planning to become pregnant during the study.
* Has any surgical or medical condition possibly affecting drug absorption (e.g., gastrectomy).
* Is, in the judgment of the investigator, actively suicidal and therefore deemed to be at significant risk for suicide.
* Has answered "yes" to either Question 4 or Question 5 on the "Suicidal Ideation" portion of the C-SSRS and the ideation occurred within the past 6 months OR has answered "yes" to any of the suicide-related behaviours on the "Suicidal Behaviour" portion of the C-SSRS and the behaviour occurred within the past 1 year.