A Phase I Randomised, Double Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Effect of Food on the Bioavailability of SKY-0515 in Healthy Volunteers and Patients with Huntington’s Disease

Exclusion Criteria46

• Part C (ii):
• Huntington’s Disease patients will be excluded from Part C (ii) of the study if there is evidence of any of the following:
• Any active infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
• Suffers from frequent or recurrent infections (defined as greater than or equal to 3 recurrent or separate occurrences in the 12 months preceding first study drug administration or 2 recurrent or separate occurrences in the 6 months preceding first study drug administration).
• Active malignancy and/or any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma or low grade cervical intraepithelial neoplasia).
• Evidence of clinically relevant immunosuppression, including (but not limited to), immunodeficiency conditions such as common variable hypogammaglobulinemia.
• History of hypersensitivity reaction, anaphylaxis or other clinically significant (CS) reactions or known allergy to the study drug or its ingredients.
• Presence or history of cardiovascular disease (including unstable angina, myocardial infarction, chronic heart failure).
• History of any CS disorder, including haematologic, pulmonary, hepatic, renal, GI, connective tissue disease, uncontrolled endocrine/metabolic, oncologic (within the last 5 years), neurologic (including seizures, strokes, brain tumours), and psychiatric diseases, or any disorder that may prevent the successful completion of the study or influence the absorption, distribution, metabolism, excretion, or action of the study drug.
• Note: Participants with history of resolved childhood asthma, history of migraine (if lesser than or equal to 1 monthly episode and not on preventative medication), or history of non-hospitalised depression (if not on any anti-depressant) will be allowed to participate in the study.
• Presence or having sequelae of GI, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs (prior gall bladder and/or appendix removal is not exclusionary if the procedure was undertaken greater than or equal to 3 months prior to study drug administration; if less than 3 months, history of such procedures may still be considered not exclusionary if it is deemed appropriate by the Investigator).
• History of surgery or hospitalisation within 12 weeks prior to screening, or surgery planned during the study.
• Are a suicide risk, as determined by meeting any of the following criteria:
• a. Suicide attempt within one year prior to screening
• b. Suicidal ideation as defined by a positive response to Question 5 on the C-SSRS (Baseline Visit Form) at screening
• c. Presence or previous history of uncontrolled major depression
• d. Significant suicide risk, per Investigator discretion.
• Have marked cognitive impairment defined as with a Montreal Cognitive Assessment (MoCA) score lesser than or equal to 18 and at the discretion of the investigator.
• Note: The above assessments may be repeated, if abnormal values were recorded in the first instance, at the discretion of the Investigator (or delegate).
• Presence of CS psychosis and/or confusional states, in the opinion of the Investigator.
• Lack of suitable veins for multiple venepunctures/cannulations as assessed by the Investigator or delegate at screening and Day 1 (pre-dose)
• Participant has donated blood/blood products or experienced significant blood loss within 3 months prior to the first dose administration.
• Laboratory results at screening that indicate inadequate renal function (estimated creatinine clearance of lesser than 30 mL/min calculated by the Cockcroft and Gault formula).
• Liver function test results elevated more than 1.5-fold above the ULN for GGT, ALP, AST or ALT. Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants.
• Liver function tests outside the normal range for bilirubin (more than 1.5-fold above the ULN for total bilirubin).
• Any clinically relevant laboratory finding or medical condition that could place the subject or patient at risk for participation in the study, in the opinion of the Investigator.
• Use of any vaccinations within 14 days (within 4 weeks for live virus vaccines) prior to the first study drug administration.
• Recently initiated use of any non-HD prescription medication or over-the-counter medication/ supplements/herbal medications less than 12 weeks prior to first dose of study drug. Exceptions include:
• a. Contraception;
• b. Antihistamines;
• c. Occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days) or ibuprofen (doses of 400 mg up to every 6 hours or 1.2 g per day maximum for no more than 3 consecutive days);
• d. Standard doses of multivitamins;
• e. Medications used for management for HD may be permitted (at the discretion of the Investigator), if patient commenced medication at least 12 weeks prior to first drug administration and are on a dose regimen that is not anticipated to change during the study;
• f. St. John’s Wort (hypericin) may not be taken within 30 days prior to first dose of study drug.
• Recently initiated therapy with or used antipsychotics, anti-depressant, or tetrabenazine less than 12 weeks prior to Day 1.
• Note: participants who have been on a stable dose of the aforementioned therapies for at least 12 weeks prior to screening and who are on a dose regimen that is not anticipated to change during the study may be included (at the discretion of the Investigator).
• Concurrent enrolment in another clinical study, or participation in another clinical study within 45 days prior to screening.
• Concurrent enrolment or previous participation at any time in any Huntingtin lowering antisense oligonucleotide, small molecule, gene therapy study.
• Regular consumption of greater than 10 standard alcoholic drinks/week where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], 30 mL spirit [40% Alc/Vol]).
• Positive alcohol breath test at screening and pre-dose on Day 1.
• Positive urine drugs of abuse test at screening and pre-dose on Day 1.
• Participant is unwilling to smoke less than 5 cigarettes or equivalent per week during study participation (screening to End of study).
• Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.
• Known substance abuse or medical, psychological, or social conditions that, in the opinion of the PI (or delegate), may interfere with the participants inclusion in the clinical study or evaluation of the clinical study results.
• Positive HBsAg, HepC virus antibody, or HIV antibody tests.
• Any other CS medical condition (other than HD) or prior therapy that in the opinion of the Investigator (or delegate) would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.