A Study Investigating the Safety, Absorption, Elimination, and the Effect on the Immune System of ACI-19764 in Healthy Participants

A Single-Center, Double-Blind, Randomized, Placebo-Controlled Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single- and Multiple-Ascending Doses of ACI-19764 in Healthy Participants

The main purposes of this study are:

• to investigate the safety and tolerability of ACI-19764 when it is administered to healthy participants
• to determine how quickly and to what extent ACI-19764 is absorbed, transported, metabolized, and excreted by the body (fasted and after a meal)
• to determine the effect of ACI-19764 on specific markers in the blood that are part of the immune system

The effects of ACI-19764 will be compared with the effects of a placebo. ACI-19764 is a brain-penetrant NLRP3 inhibitor.

The study consists of 2 parts, Part A (SAD, single ascending dose) and Part B (MAD, multiple ascending doses). Participants in Part A will receive the study compound once and participants in Part B will receive the study compound multiple times (daily over 14 days). Each of these 2 study parts will be divided into different groups of participants to test different doses of ACI-19764.

In study Part A (SAD part), up to 6 dose levels with 8 male participants in each are planned (6 participants on ACI-19764 and 2 on placebo). Each cohort has a screening period followed by admission to the site for administration of ACI-19764. Participants remain onsite for observation for 3 days. Participants may need to return for additional visits for 2 days after discharge to check the blood levels of the drug. A safety follow up call is planned approximately 3 weeks after discharge. In one of the higher dose cohorts, the effect of food on drug levels in the blood will also be explored with an additional admission. There may be fewer than 6 cohorts.

In study Part B (MAD part), up to 3 dose levels with 10 participants (8 on active and 2 on placebo) in each are planned. Each dose level will be investigated in a separate cohort of 10 healthy male and female participants (with 4 participants of each sex on active treatment and 1 of each sex on placebo). Each cohort has a screening period followed by admission to the site for 17 days (14-day treatment and 3 days observation). Depending on the blood levels of the drug, participants may have to return to the site for additional blood tests for the 2 days following discharge. A safety phone call is planned approximately 3 weeks after discharge.

Inclusion Criteria:

1. Signed informed consent in a language understandable to the participant prior to any study-mandated procedure.

2. Healthy male (Parts A and B) or female (Part B) aged between 18 and 65 years (inclusive) at screening.

3. Body mass index of 18.0 to 29.9 kg/m2 (inclusive) at screening.

4. Ability to communicate well with the investigator, and to understand and comply with the study requirements.

5. Systolic blood pressure (SBP) 90-140 mmHg, diastolic blood pressure (DBP) 45-90 mmHg, and pulse rate 40 to 100 beats per minute (bpm) (all inclusive), measured on either arm (same arm used for both screening and admission), after 5 min in the supine position at screening and admission.

6. 12-lead safety ECG: QT interval corrected for HR using Fridericia's formula (QTcF) <450 ms for male participants and <470 ms for female participants, QRS interval <120 ms, PR interval <220 ms, and HR 40 to 100 bpm (inclusive), and without clinically relevant abnormalities, measured after 5 min in the supine position at screening and admission.

7. Fertile male participants (defined as physiologically capable of conceiving a child according to the investigator's judgment) must agree to refrain from fathering a child and:

   • Be sexually abstinent with women of childbearing potential (WoCBP) or use condoms during sexual intercourse with WoCBP from (first) study treatment administration up to at least 90 days after (last) study treatment administration. Male participants must advise their WoCBP partners consistently to use a highly effective method of contraception with a failure rate of <1% per year.
   • Do not donate sperm from (first) study treatment administration up to at least 90 days after (last) study treatment administration.

8. Part B only: Female participants must have a negative serum pregnancy test at screening and a negative urine pregnancy test at admission and a follicle-stimulating hormone (FSH) test must be performed at screening. WoCBP must agree to consistently and correctly use (from screening, during the entire study, and for at least 30 days after the last study treatment administration) a highly effective method of contraception with a failure rate of <1% per year, be sexually inactive, or have a vasectomized partner with a post-vasectomy semen analysis negative for sperm at least 6 months before screening. If a hormonal contraceptive is used, it must be initiated at least 1 month before the first study treatment administration and should be used in conjunction with barrier methods. WoCBP must agree to not donate eggs from screening until at least 30 days after the last study treatment administration.

9. Part B only: WoNCBP must be postmenopausal or have documented previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, or with premature ovarian failure (confirmed by a specialist), XY genotype, uterine agenesis.

Exclusion Criteria:

1. Known hypersensitivity to any excipient of the ACI-19764 formulations.
2. Known clinically relevant hypersensitivity or allergy to any therapeutic treatment (including non-steroidal anti-inflammatory drugs [NSAIDs], or nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 [NLRP3] inhibitors), vaccines, cosmetics, natural rubber or latex and/or food.
3. Clinically relevant findings on the physical examination at screening or on Day -1.
4. Clinically relevant findings in clinical laboratory tests
5. Clinically relevant history or presence of rhythm disorders, congestive heart failure, or structural heart disease.
6. History or presence of clinically relevant surgical intervention which, in the opinion of the investigator, could potentially interfere with the safety/tolerability and/or absorption, distribution, metabolism, and excretion (ADME) of the study treatment.
7. History or presence of acute, ongoing, recurrent, or chronic clinically relevant diseases which, in the opinion of the investigator, could potentially interfere with the assessment of safety/tolerability and/or ADME of the study treatment.
8. History or current acute or chronic pulmonary pathology including but not limited to chronic obstructive pulmonary disease (COPD), asthma, and recurrent lung infections.
9. Lifetime history of suicide attempt (including active attempt, interrupted attempt or aborted attempt) or suicidal ideation in the past 6 months according to the C-SSRS at screening.
10. History of cancer within the past 5 years other than treated squamous cell carcinoma, basal cell carcinoma, and melanoma in situ, or in-situ prostate cancer, in-situ cervix carcinoma, or in-situ breast cancer which have been fully removed and are considered cured.
11. Previous unexplained history of recurrent pre-syncope or syncope with no clear provoking features or syncope in the context of medical investigations that is likely to complicate interpretation of the safety of the drug in the opinion of the Investigator.
12. Veins unsuitable for intravenous (i.v.) puncture on both arms.
13. Participation in a clinical study involving study treatment administration within 3 months (or within 5 half-lives before screening, whichever is longer) prior to (the first) study treatment administration or in more than 3 clinical studies within 1 year prior to (the first) study treatment administration.
14. History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
15. Consumption of >14 units of alcohol per week (females) or >21 units per week (males).
16. Excessive caffeine consumption.
17. Nicotine consumption from 3 months prior to (first) study treatment administration, checked at screening and on Day -1.
18. Loss (including donation) of 450 mL or more of blood or blood products within 2 months prior to (the first) study treatment administration.
19. Positive results from serum/urine drug or alcohol screen test at screening or on Day -1.
20. Positive hepatitis B and/or C serology results, except for vaccinated participants or those with past but resolved hepatitis, at screening.
21. Positive human immunodeficiency virus (HIV) serology results at screening.
22. Any circumstances or conditions which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
23. Legal incapacity or limited legal capacity at screening.
24. Treatment or intended treatment with any prescribed medications within 2 weeks prior to (first) study treatment administration, except for contraceptives (including hormonal contraceptive devices) in female participants (Part B only), and/or over-the-counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 1 week prior to (first) study treatment administration. Analgesia with paracetamol is acceptable (but not NSAIDs or aspirin >75 mg per day), unless for the short-term treatment of post lumbar puncture (LP) headache.
25. Any immunosuppressive therapies within 2 months prior to first study treatment administration.
26. Any biological compound for research or medical reasons within 12 months prior to (first) study treatment administration.
27. Any relevant bacterial, viral, fungal, or protozoal infection that manifested within the last 6 weeks prior to screening and/or an ongoing relevant bacterial, viral, fungal, or protozoal infection, as judged by the investigator, and/or evidence of immune dysfunction based on laboratory tests at screening. If mild infections occur during screening causing a rise in C-reactive protein (CRP), the participant should not be included until this has normalized.
28. Receipt of vaccine within 5 weeks prior to admission.
29. Any medical history of an active tuberculosis (TB) infection, positive test result for latent TB in the last 2 years, or any contact with TB-positive individuals in the last 4 weeks prior to screening.
30. Potential anticipated lack of compliance with study assessments and visit schedule.
31. Planned hospitalization (other than for study assessments) or surgery during the study.
32. Part A Food effect cohort only: Inability or unwillingness to completely consume the high-fat breakfast prior to study treatment administration.
33. Part B only: Pregnant or lactating women.
34. Part B (for those undergoing LP): Contraindications for LP including, but not limited to space-occupying lesions with mass effect or raised intracranial pressure, posterior fossa mass, anticoagulant or antiplatelet medications, coagulopathy, thrombocytopenia (<150×109/L), congenital spine abnormality, skin infection at the LP site or tattoo covering puncture site.
35. Part B (for those undergoing LP): Lower back pain at the time of the study or history of recurrent headaches in the last 6 months (more than 4 days a month of headaches that limit normal daily activity)