A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Adult Volunteers

INTERVENTION: Part 1: SAD. Participants will receive 1 dose of either SIR9900 or placebo as an oral tablet on Day 1. A total of approximately 88 healthy participants are planned to be enrolled. Approximately 48 healthy adult participants in 6 cohorts in Part 1 (8 participants per cohort), with 6 randomised to receive a single oral dose of SIR9900 and 2 to receive placebo. The following dose level cohorts are planned with all cohorts to be randomised to receive either SIR990 or placebo: • Cohort 1: 3 mg • Cohort 2: 10 mg • Cohort 3: 30 mg (SAD cohort 3 is also FE cohort period 1) • Cohort 4: 100 mg • Cohort 5: 200 mg • Cohort 6: 400 mg During the treatment period of Part 1 SAD study, participants will remain admitted to the Clinical Research Unit (CRU) from Day 1 until Day 5 . Participants enrolled in cohort 3 (30 mg cohort) will be readmitted to the CRU on Day 9 (+1) (period 2) to receive a second dose on Day 10 after a washout period of 9 days as part of the Food Effect study. Part 2: MAD. Approximately 40 healthy adult participants in 4 cohorts in Part 2 (10 participants per cohort) with 8 participants randomised to receive an oral dose of SIR9900 once daily (QD) for 10 consecutive days and 2 to receive an oral dose of placebo once daily for 10 consecutive days. The following dose level cohorts are planned: • Cohort 1 (healthy adults): 3 mg • Cohort 2 (healthy adults): 10 mg • Cohort 3 (healthy adults): 30 mg • Cohort 4 (healthy adults): 100 mg During the treatment period of Part 2 MAD study, participants will remain admitted to the Clinical Research Unit (CRU) from Day 1 until Day 14. SIR9900 will be supplied as tablets for oral administration at dosage strengths 3 mg, 10 mg, and 50 mg. Adherence t CONDITION: Inflammatory and Immune System ‐ Other inflammatory or immune system disorders Inflammatory diseases, particularly in central nervous system;Degenerative diseases, particularly in central nervous system.; ; Inflammatory diseases, particularly in central nervous system ; Degenerative diseases, particularly in central nervous system. Neurological ‐ Neurodegenerative diseases PRIMARY OUTCOME: PART 1 (SAD) ; To evaluate the safety and tolerability of ascending single oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12‐lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.[1. Adverse Event's (AE's) and Serious Adverse Events (SAE's) will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class (SOC) and preferred terms (PT). AE's and SAE's will be continuously assessed as they are reported or observed and reviewed daily from post dose of Investigational product (IP) on Day 1 until the follow up visit on Day 12. ; ; 2. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day ‐1 and Day 1 pre‐dose (within 60 minutes prior to dosing) then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post‐dose), Day 2 (24 & 36 hrs post‐dose), Day 3 (48 & 60 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose) and Day 12 (Follow up Visit), post‐commencement of intervention.; ‐ Blood pressure will be assessed pre dose using a sphygmomanometer (blood pressure cuff ). Blood pressure readings will be collected in triplicate and will be measured with 1‐3 min interval between readings at screening only. Blood pressure will be measured with participant in a sitting position for at least 5 minutes at screening, and participant in a supine position for at least 5 minutes at other visits; ‐ Heart Rate will be assessed pre dose and post dose by counting the number of heart beats.; ‐ Tympanic Temperature will be assessed pre dose and post dose using a tympanic thermometer.; ‐ Respiratory rate will be assessed pre dose and post dose by observing the number of breaths a participant takes.; ; 3. Single 12‐lead ECG will be performed at all scheduled time points after at least 10 minutes supine on Day 1 pre‐dose (within 60 minutes prior to dosing) and then Day 1 (0.5, 1, 2, 3, 4, 6 and 12 hours post‐dose), Day 2 (24hrs post‐dose), Day 3 (48hrs post‐dose), Day 4 (72hrs post‐dose), Day 5 (96 hrs post‐dose). The recommended order for assessments required at the same time point is ECG, vital signs, blood collection.; ; 4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted conditions will be collected via venepuncture at the Screening Visit, Day ‐1 (if required), Day 1 (2 hrs post‐dose), Day 2 (24 hrs post‐dose), Day 3 (48 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose) and at Day 12 (Follow Up Visit) post‐commencement of intervention.; ; 5. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the CRU. Urinalysis will be performed at Screening Visit, Day ‐1 (if required), Day 1 (2 hrs post‐dose), Day 2 (24 hrs post‐dose), Day 3 (48 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose) and at Day 12 (Follow Up Visit) post‐commencement of intervention.] PART 1 SAD Cohort 3 ‐ Food Effect (FE); To evaluate the safety and tolerability of ascending single oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12‐lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.[1. AE's and Serious Adverse Events (SAE's) will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class (SOC) and preferred terms (PT). AE's and SAE's will be continuously assessed as they are reported or observed and reviewed daily from post dose of Investigational product (IP) on Day 1 until Day 21 (Follow‐Up Visit).; ; 2. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day ‐1 and Day 1 pre‐dose (within 60 minutes prior to dosing), then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post‐dose), Day 2 (24 & 36 hrs post‐dose), Day 3 (48 & 60 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose), Day 9 (pre‐second dose), Day 10, (pre‐second dose) and then Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 &12 hrs post‐second dose), Day 11 (24 & 36 hrs post‐second dose), Day 12 (48 & 60 hrs post‐second dose), Day 13 (72 hrs post‐second dose), Day 14 (96 hrs post‐second dose) and Day 21 (post‐last dose Follow‐Up Visit).; ‐ Blood pressure will be assessed pre dose using a sphygmomanometer (blood pressure cuff ). Blood pressure readings will be collected in triplicate and will be measured with 1‐3 min interval between readings at screening only. Blood pressure will be measured with participant in a sitting position for at least5 minutes at screening, and participant in a supine position for at least 5 minutes at other visits; ‐ Heart Rate will be assessed pre dose and post dose by counting the number of heart beats.; ‐ Tympanic Temperature will be assessed pre dose and post dose using a tympanic thermometer.; ‐ Respiratory rate will be assessed pre dose and post dose by observing the number of breaths a participant takes.; ; 3. Single 12‐lead ECG will be performed at all scheduled time points after at least 10 minutes supine Day 1 pre‐dose (within 60 minutes prior to dosing) and then Day 1 (0.5, 1, 2, 3, 4, 6 and 12 hours post‐dose), Day 2 (24hrs post‐dose), Day 3 (48hrs post‐dose),Day 4 (72hrs post‐dose), Day 5 (96 hrs post‐dose), Day 10 (pre‐second dose) and then Day 10 (0.5, 1, 2, 3, 4, 6 and 12 hours post‐second dose), Day 11 (24hrs post‐second dose), Day 12 (48hrs post‐second dose), Day 13 (72hrs post‐second dose), Day 14 (96 hrs post‐second dose) and Day 21 (post‐last dose Follow‐Up Visit). The recommended order for assessments required at the same time point is ECG, vital signs, blood collection.; ; 4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted and fed conditions, will be collected via venepuncture at the Screening Visit and Day ‐1 (if required), Day 1 (2 hrs post‐dose), Day 2 (24 hrs post‐dose), Day 3 (48 hrs post‐dose), Day 4(72 hrs post‐dose), Day 5 (96 hrs post‐dose), Day 9 (pre‐second dose) Day 10 under fed conditions (2 hrs post‐second dose), Day11 (24 hrs post‐second dose), Day 12 (48 hrs post‐second dose), Day 13 (72 hrs post‐second dose), Day 14(96 hrs post‐second dose), and Day 21 (post‐last dose Follow‐Up Visit).; ; 5. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the CRU. Urinalysis will be performed at Screening Visit and Day ‐1 (if required(, Day 1 (2 hrs post‐dose), Day 2 (24 hrs post‐dose), Day 3 (48 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose), Day 9 (pre‐second dose) Day 10 (2 hrs post‐second dose), Day 11 (24 hrs post‐second dose), Day 12(48 hrs post‐second dose), Day 13 (72 hrs post‐second dose), Day 14 (96 hrs post‐second dose), and Day 21 (Follow‐Up Visit).] PART 2 (MAD); To evaluate the safety and tolerability of ascending multiple oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12‐lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.[1. AE's and Serious Adverse Events (SAE's) will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class (SOC) and preferred terms (PT). AE's and SAE's will be continuously assessed as they are reported or observed and reviewed daily from post dose of Investigational product (IP) on Day 1 until the follow up visit on Day 21.; ; 2. Single 12‐lead ECG will be performed at all scheduled time points after at least 10 minutes supine at Screening, within 60mins pre‐dose and within 3 hours post‐dose on Day 1, Day 4, Day 7 and Day 10 then Day 14 and Day 21 (Follow‐Up Visit).; ; 3. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day ‐1, Days 1 ‐10 (within 60 minutes pre‐dose and 3 hours post dose), then Day 11, Day 12, Day 13, Day 14 and Day 21 (Follow‐Up Visit),; ‐ Blood pressure will be assessed pre dose using a sphygmomanometer (blood pressure cuff ). Blood pressure readings will be collected in triplicate and will be measured with 1‐3 min interval between readings at screening only. Blood pressure will be measured with participant in a sitting position for at least5 minutes at screening, and participant in a supine position for at least 5 minutes at other visits; ‐ Heart Rate will be assessed pre dose and post dose by counting the number of heart beats.; ‐ Tympanic Temperature will be assessed pre dose and post dose using a tympanic thermometer.; ‐ Respiratory rate will be assessed pre dose and post dose by observing the number of breaths a participant takes.; ; 4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted conditions will be collected via venepuncture at the Screening Visit and Day ‐1 (if required) and post‐dose on Day 1, Day 4, Day 7, Day 10, Day 14 and Day 21 (Follow‐Up Visit).; ; 5. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the CRU. Urinalysis will be performed at Screening Visit and Day ‐1 (if required) and post‐dose on Day 1, Day4, Day 7, Day 10, Day 14 and Day 21 (Follow‐Up Visit).] SECONDARY OUTCOME: Exploratory Objective ‐ Part 1 (SAD) ; To explore the metabolite identification of SIR9900 in urine after a single 30 mg and/or 100 mg dose ofSIR9900. ; ; Identification of SIR9900 metabolites and semi‐quantification of SIR9900 in urine after a single 30 mg and/or 100 mg dose.[Urine samples for analysis will be collected Day 1 pre‐dose (within 60 minutes prior to dosing) from each participant in the 30 mg and 100mg cohorts. Urine samples for analysis will be collected again during the 0‐4, 4‐8, 8‐12, 12‐24, 24‐48, 48‐72and 72‐96 hour periods post‐dose. Urine collections could also be used for identification of metabolites.] Exploratory Objective ‐ Part 1 Cohort 3 Food Effect (FE) ; To explore the metabolite identification of SIR9900 in urine after a single 30 mg dose of SIR9900. ; ; Identification of SIR9900 metabolites and semi‐quantification of SIR9900 in urine after a single 30 mg dose. Period 1 only.[Urine samples will be collected for analysis in Period 1 only, Day 1 pre‐dose (within 60 minutes prior to dosing) from each participant. Urine samples analysis will be collected again during the 0‐4, 4‐8, 8‐12, 12‐24, 24‐48, 48‐72 and 72‐96 hour periods post‐dose. Urine collections could also be used for identification of metabolites.] Exploratory Objective ‐ Part 2 (MAD) ; To explore the metabolite identification of SIR9900 in plasma after multiple doses of 30 mg and/or 100mg. ; ; Identification of SIR9900 metabolites and semi‐quantification of SIR9900 in plasma after 30mg and/or 100mg multiple doses.[Blood plasma samples to help with the identification of metabolites in the 30 mg and/or 100 mg cohorts in the future will be collected Day 1 pre‐dose (within 30 minutes prior to dosing) and then Day 1, (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hrs post‐dose). Days 2 to 9 pre‐dose (within 30 minutes prior to dosing and 3 hrs post‐dose, Day 10 pre‐dose (within 30 minutes prior to dosing) and then Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hrs post‐dose). Day 11 (24 & 36hrs post‐dose), Day 12 (48 & 60 hrs post‐dose), Day 13 (72 hrs post dose) and Day 14 (96hrs post‐dose).] Part 1 (SAD) ; To characterize the pharmacodynamic (PD) profile of SIR9900 after ascending single oral doses in healthy participants. ; ; Level of p‐RIPK1 proteins and possibly other biomarkers as deemed necessary.[Blood samples will be collected for pharmacodynamic (PD analysis) via venepuncture Day 1 pre‐dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 2 (24 hrs post‐dose), Day 4 (72 hrs post‐dose) and Day 5 (96 hrs post‐dose).] Part 1 (SAD) ; To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending single oral doses in healthy participants. ; ; Plasma PK parameters following ascending single doses including but not limited to: ; Cmax, ; Tmax, ; AUC0‐24h, ; AUClast, ; CL/F, ; Vd/F.[Blood samples for Plasma pharmacokinetic (PK) will be collected via venepuncture on Day 1 pre‐dose (within 30 minutes prior to dosing), then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hrs post‐dose), Day 2 (24 & 36 hrs post‐dose), Day 3 (48 & 60 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose).] Part 1 (SAD) ; To characterize the urine PK profile of SIR9900 after single oral doses of 30 mg and 100 mg in healthy participants. ; ; Urine PK parameters following single 30 mg and 100 mg doses including but not limited to: Ae(0‐t), ; fe,24%, ; CLr.[Urine samples for pharmacokinetic (PK) analysis will be collected Day 1 pre‐dose (within 60 minutes prior to dosing) from each participant in the 30 mg cohorts. Urine samples for PK analysis will be collected again during the 0‐4, 4‐8,8‐12, 12‐24, 24‐48, 48‐72 and 72‐96 hour periods post‐dose (all urine to be collected for each period).] Part 1 Cohort 3 Food Effect (FE) ; To characterize the pharmacodynamic (PD) profile of SIR9900 after a single 30 mg dose in healthy participants (Period 1 only) ; ; Level of p‐RIPK1 proteins and possibly other biomarkers as deemed necessary.[Blood samples will be collected for pharmacodynamic (PD analysis) in period 1 only, via venepuncture Day 1 pre‐dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 2 (24 hrs post‐dose), Day 4 (72 hrs post‐dose) and Day 5 (96 hrs post‐dose).] Part 1 Cohort 3 Food Effect (FE) ; To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending single oral doses in healthy participants in a fasted state. ; ; Plasma PK parameters following ascending single doses including but not limited to: ; Cmax, ; Tmax, ; AUC0‐24h, ; AUClast, ; t1/2, ; AUCinf, ; Lambda z, ; CL/F, ; Vd/F.[Blood samples for Plasma pharmacokinetic (PK) under fasted and fed conditions, will be collected via venepuncture on Day 1 pre‐dose (within 30 minutes prior to dosing), then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post‐dose), Day 2 (24 & 36 hrs post‐dose), Day 3 (48 & 60 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose), Day 9 (pre‐second dose), pre‐second dose on Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post‐second dose), Day 11 (24 & 36hrs post‐second dose), Day 12 (48 & 60 hrs post‐second dose), Day 13 (72 hrs post‐second dose), Day 14 (96 hrs post‐second dose).] Part 1 Cohort 3 Food Effect (FE) ; To characterize the urine PK profile of SIR9900 after single oral doses of 30 mg in healthy participants (Period 1 only). ; ; Urine PK parameters following single 30 mg doses including but not limited to: ; Ae(0‐t), ; fe,24%, ; CLr.[Urine samples for pharmacokinetic (PK) analysis will be collected in Period 1 only, Day 1 pre‐dose (within 60 minutes prior to dosing) from each participant in the 30 mg cohorts. Urine samples for PK analysis will be collected again during the 0‐4, 4‐8, 8‐12, 12‐24, 24‐48, 48‐72 and 72‐96 hour periods post‐dose (all urine to be collected for each period).] Part 1 Cohort 3 Food Effect (FE) ; To evaluate the preliminary food effect on PK profile of a single 30 mg dose of SIR9900 in a fed state. ; ; Following a single 30 mg dose of SIR9900: Plasma PK Parameters to be measured will include but not limited to: ; Cmax, ; Tmax, ; AUCinf, ; AUClast, ; t1/2, ; Lambda z, ; CL/F, ; Vd/F.[Blood samples for Plasma pharmacokinetic (PK) will be collected under fasted and fed conditions via venepuncture Day 1 pre‐dose (within 30 minutes prior to dosing) and then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post‐dose), Day 2 (24 & 36 hrs post‐dose), Day 3 (48 & 60 hrs post‐dose), Day 4 (72 hrs post‐dose), Day 5 (96 hrs post‐dose), Day 10 pre‐second dose and then Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post‐second dose), Day 11 (24 & 36 hrs post‐second dose), Day 12 (48 & 60 hrs post‐second dose), Day 13 (72 hrs post‐second dose), Day 14 (96 hrs post‐second dose).] Part 2 (MAD) ; To characterize the pharmacodynamic (PD) profile of SIR9900 after ascending multiple oral doses in healthy participants. ; ; Level of p RIPK1 proteins and possibly other biomarkers as deemed necessary.[Blood samples will be collected for pharmacodynamic (PD analysis) via venepuncture Day 1 and Day 7 pre‐dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 10 (3 hrs post‐dose) Day 11 (24 hrs post dose), Day 3 (72 hrs post dose) and Day 14 (96 hrs post dose).] Part 2 (MAD) ; To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending multiple oral doses in healthy participants. ; ; Following ascending multiple doses, parameters to be measured will include but not limited to: ; Cmax,ss, ; Cmin,ss, ; Cavg, ; Tmax, ; t1/2, ; AUCtau, ; Lambda z, ; CLss/F, ; Vss/F, ; DF, ; ARAUC/AR Cmax.[Blood samples for Plasma pharmacokinetic (PK) will be collected via venepuncture on Day 1 pre‐dose (within 30 minutes prior to dosing) then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours post‐dose). Days 2, 3, 4, 5, 6, 7, 8 and Day 9 pre‐dose (within 30 minutes prior to dosing) then at 3 hours post‐dose. Day 10 pre‐dose (within 30 minutes prior to dosing) and then (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hrs post‐dose). Day 11 (24 & 36 hrs post‐dose),Day 12 (48 & 60 hrs post‐dose), Day 13 (72 hrs post‐dose) and Day 14 (96hrs post‐dose).] Part 2 (MAD) ; To measure the cerebrospinal fluid (CSF) concentration of SIR9900 after multiple oral doses of 30 mg in healthy adult participants. ; ; CSF concentration of SIR9900 following multiple oral doses of 30 mg.[A CSF sample of approximately 10 mL will be collected from each participant in Part 2 MAD Cohort 3. The CSF sample will be collected once between the Days of 6 to 9 and between 3 to 7 hours post‐dose. One additional blood sample should be collected within 15 minutes after CSF sampling to determine the drug concentration relationship between CSF and blood.] INCLUSION CRITERIA: Potential participants must fulfil all the following inclusion criteria to be eligible for the study: 1. Are capable of signing the Participant Informed Consent Form (PICF) and complying with study procedures. 2. Male or female healthy participants between the ages of 18 and 64 years old, inclusive, for healthy adult volunteer cohorts. 3. Women of childbearing potential (WOCBP) must agree to practice a double method of contraception of a medically acceptable method of contraception with an annual failure rate of less than 1 percent with a barrier contraceptive (such as condom) during the study and for 30 days after discontinuation of study treatment. Unless she is exclusively in same‐se Xrelationships. Women are considered not of childbearing potential if they are surgically sterile (i.e., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation) or greater than 1 year postmenopausal. 4. All male participants with female partne