Amyotrophic Lateral Sclerosis
Conditions
Keywords
PET, ALS, Microglia, CSF
Brief summary
It was an open label study to evaluate safety, tolerability and brain microglia response in participants with Amyotrophic Lateral Sclerosis (ALS) following multiple doses of BLZ945.
Detailed description
The purpose of the study was to identify a dose (or doses) of BLZ945, that measurably decrease(s) 18 KDa Translocator Protein (TSPO) binding in the brain of participants with ALS. The study also aimed to evaluate the safety and tolerability of BLZ945 in participants with ALS at different doses and dosing regimens, and safety related effects on extracellular matrix (ECM) accumulation. This was an exploratory, adaptive , open label study of approximately 16 participants in cohorts of 4 participants per cohort at increasing doses of BLZ945 with the last dose determined after the completion of cohorts 1 to 3. Each cohort received treatment for 4 days and continued with a 32 day follow up period with an end of study visit at day 36. After completion of the 4 initial cohorts a fifth cohort was initiated with two parallel arms receiving BLZ945 for up to 12 weeks at two different treatment regimens, either once weekly or 4 days of treatment followed by 10 days off drug.
Interventions
DRUGBLZ945
Investigational drug capsules taken orally or via enteral infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study is an exploratory, adaptive, open-label study of single or multiple cycles of BLZ945 in participants with ALS. Cohorts 1-4 are not randomized, while Cohort 5 is randomized in open label two treatment arms. Cohorts 1-4 have single group design and Cohort 5 has parallel design.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Able to communicate well with the investigator, to understand and comply with the study visits and procedures of the study * Written informed consent must be obtained before any assessment is performed. * Male and female participants who are 18 years old or older at screening, and who are diagnosed with familial or sporadic ALS according to the World Federation of Neurology Revised El Escorial criteria of either bulbar or limb onset. * Disease duration from symptoms onset no longer than 48 months at the screening visit. * Females of childbearing potential must have a negative pregnancy test at screening and/or baseline. * Treatment with approved ALS therapies is allowed, but participants need to be on a stable dose and regimen for at least 30 days prior to baseline. * Having completed the Core Treatment Period to be able to continue in the Extended Treatment Period.
Exclusion criteria
* A history of clinically significant ECG abnormalities * Active medical or neurologic diseases other than ALS, that in the opinion of the investigator would limit their participation in the current study. * Use of other investigational drugs within 5 half-lives of screening, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations. * History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes. * Presence of human immunodeficiency virus (HIV) infection based on screening lab results. * Evidence of active or latent tuberculosis as assessed by Quantiferon testing at the screening visit. * Positive serology for hepatitis B surface antigen, or hepatitis C antibodies confirmed by an appropriate licensed test at screening. * Signs or symptoms, in the judgement of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to the screening visit. * Cardiac disorders, such as recent cardiac history (within 6 months of screening) of acute coronary syndrome, acute heart failure, or significant ventricular arrhythmia at the screening visit or participants with a history of severe pulmonary hypertension. Participants with cardiac failure class 3 or 4 of the NYHA classification, or history of reduced LVEF or individuals with implanted cardiac pacemaker, or defibrillator. * Significant hematological laboratory abnormalities. * Clinical evidence of liver disease or liver injury or any of the following hepatic conditions at the screening visit: * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after last dose of BLZ945. * Pregnant or nursing female participants * Sexually active males unless they use a condom during intercourse while taking the drug during treatment, for 14 days after stopping BLZ945 and should not father a child in this period. * History or presence of impaired renal function at the screening visit. * Active suicidal ideation. * History of drug abuse or harmful alcohol use within the 12 months prior to dosing within the judgement of the investigator, or evidence of such abuse as indicated by the laboratory assays conducted during screening. * Active GI conditions such as Barrett's esophagus, achalasia, esophageal varices and active or history of esophageal cancer, pre-existing pancreatic disease at screening visit. * History of active vasculitis or history of autoimmune disease autoimmune disease associated with vasculitis (eg., RA, SLE, Sjögrens disease, scleroderma). * History or active cardiac valve disorder, congenital valve disease, or other clinical condition that might affect cardiac valve function * Use of systemic anticoagulation that cannot be temporarily paused before study procedures * Abnormal values on CT scan or echocardiography, signs of vasculitis, or evidence of a significant medical condition meeting treatment discontinuation criteria will be exclusionary for continuation in the extended treatment period. * Participants who are planning to initiate treatment with an additional approved ALS therapy in the next 24 weeks are not allowed to continue in the extended treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 5: Adverse Events Related to Extracellular Matrix (ECM) Accumulation | Up to Day 84 | Number of patients with adverse events related to ECM accumulation |
| Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Baseline, day 84 | \[11C\]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. \[11C\]PBR28 imaging was used to measure microglial volume at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of \[11C\]-PBR28 in different brain regions after BLZ945 treatment |
| Cohort 5: Change From Baseline in Esophageal Wall Thickness | Baseline, Day 84 | Mean change from baseline in esophageal wall thickness measured in mm |
| Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Baseline, Day 84 | Cardiac valve thickness on a three point ordinal scale. Categorized by imaging vendor into three semiquantitative (normal, mild-moderate and severe) categories |
| Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Baseline, Day 84 | Cardiac valve stenosis on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories |
| Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Baseline, Day 84 | Cardiac valve regurgitation severity on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories |
| Cohort 5: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | Baseline, day 84 | Mean change from baseline in Left Ventricular Ejection Fraction. LVEF is defined as the percentage of blood volume ejected from the left ventricle during systole (contraction phase) relative to the total volume of blood present in the ventricle at the end of diastole (relaxation phase). |
| Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Baseline, day 5 | \[11C\]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. \[11C\]PBR28 imaging was used to measure microglial volume at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of \[11C\]-PBR28 in different brain regions after BLZ945 treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only) | Measured by Cmax - The maximum plasma concentration of BLZ945 |
| Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only) | Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945. Actual recorded sampling times were taken into consideration for the calculation of PK parameters. |
| Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only) | Measured by AUC - Area under the curve of BLZ945 AUC0-24h is the AUC calculated from time zero to 24 hours after dosing (end of a dosing interval). AUClast is the AUC from time zero to the last measurable concentration sampling time. |
| Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. | Measured by T1/2 - The elimination half-life of BLZ945 |
| Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study treatment up to 32 days after last dose (Day 36) for Cohorts 1-4 and up to 4 weeks after last dose (Day 330) for Cohort 5. *Maximum duration of exposure in Cohort 5 was 302 days. 302 + 28 days of FU=330 days | Incidence and severity of AEs and SAEs by treatment group. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5. For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE |
| Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | pre-dose, 0-4, 4-8, 8-12 and 12-24 hours after BLZ945 dosing on Day 1 and Day 4 | Urine renal clearance (CLR) of BLZ945 |
Countries
Finland, Sweden, United States
Participant flow
Pre-assignment details
There was a screening and baseline period of up to 42 days for part 1 (Cohorts1-4) and of 6 weeks for part 2 (Cohort 5)
Participants by arm
| Arm | Count |
|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) BLZ945 300mg | 4 |
| BLZ945 600mg - Cohort 2 (Part 1) BLZ945 600mg | 4 |
| BLZ945 800mg - Cohort 4 (Part 1) BLZ945 800mg | 4 |
| BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 1200mg | 4 |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg (4 days on/10 days off) | 6 |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) BLZ945 800mg (once weekly) | 6 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 2 (Cohort 5) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 (Cohort 5) | Death | 0 | 0 | 0 | 0 | 0 | 2 |
| Part 2 (Cohort 5) | Study terminated by sponsor | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 (Cohort 5) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BLZ945 300mg - Cohort 1 (Part 1) | Total | BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | BLZ945 1200mg - Cohort 3 (Part 1) | BLZ945 800mg - Cohort 4 (Part 1) | BLZ945 600mg - Cohort 2 (Part 1) |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 50.5 years | 60.5 years | 62.5 years | 55.5 years | 64 years | 65.5 years | 59.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 27 Participants | 6 Participants | 6 Participants | 4 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 10 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 18 Participants | 4 Participants | 5 Participants | 2 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 6 | 2 / 6 | 2 / 28 |
| other Total, other adverse events | 2 / 4 | 2 / 4 | 4 / 4 | 4 / 4 | 6 / 6 | 6 / 6 | 24 / 28 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 4 | 0 / 6 | 4 / 6 | 5 / 28 |
Outcome results
Primary
Cohort 5: Adverse Events Related to Extracellular Matrix (ECM) Accumulation
Number of patients with adverse events related to ECM accumulation
Time frame: Up to Day 84
Population: Full analysis set, participants in cohort 5 that received any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Adverse Events Related to Extracellular Matrix (ECM) Accumulation | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Adverse Events Related to Extracellular Matrix (ECM) Accumulation | 2 Participants |
Primary
Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline
Cardiac valve regurgitation severity on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories
Time frame: Baseline, Day 84
Population: Full analysis set, participants in cohort 5 that received any study drug with a valid assessment for the outcome measure
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Baseline | Mild | 1 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Day 84 | Mild | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Baseline | Mild | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Normal | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Normal | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Mild | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Baseline | Normal | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Mild | 3 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Day 84 | Normal | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Normal | 1 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Baseline | Normal | 5 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Mild | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Day 84 | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Baseline | Normal | 3 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Baseline | Mild | 3 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Day 84 | Normal | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Day 84 | Mild | 01 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Mild | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Aortic valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Mitral valve - Day 84 | Mild | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Normal | 4 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Mild | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Pulmonary valve - Day 84 | Normal | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Mild | 4 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Regurgitation Severity at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Normal | 1 Participants |
Primary
Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline
Cardiac valve stenosis on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories
Time frame: Baseline, Day 84
Population: Full analysis set, participants in cohort 5 that received any study drug with a valid assessment for the outcome measure
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Baseline | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Day 84 | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Baseline | Mild | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Day 84 | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Day 84 | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Baseline | Mild | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Tricuspid valve - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Mitral valve - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Stenosis at Day 84 Compared to Baseline | Aortic valve - Baseline | Normal | 6 Participants |
Primary
Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline
Cardiac valve thickness on a three point ordinal scale. Categorized by imaging vendor into three semiquantitative (normal, mild-moderate and severe) categories
Time frame: Baseline, Day 84
Population: Full analysis set, participants in cohort 5 that received any study drug with a valid assessment for the outcome measure
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Baseline | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Baseline | Mild- Moderate | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Aortic valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Pulmonary valve thickness - Day 84 | Mild- Moderate | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Day 84 | Normal | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Tricuspid valve thickness - Baseline | Normal | 6 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Cardiac Valve Thickness at Day 84 Compared to Baseline | Mitral valve thickness - Baseline | Normal | 5 Participants |
Primary
Cohort 5: Change From Baseline in Esophageal Wall Thickness
Mean change from baseline in esophageal wall thickness measured in mm
Time frame: Baseline, Day 84
Population: Full analysis set, participants in cohort 5 that received any study drug with a valid assessment for the outcome measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Wall thickness average | 0.258 mm | Standard Deviation 0.799 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Middle third Wall Thickness | 0.235 mm | Standard Deviation 0.0212 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Upper third Wall Thickness | 0.500 mm | Standard Deviation 1.4284 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Lower third Wall Thickness | 0.040 mm | Standard Deviation 0.9475 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Middle third Wall Thickness | 2.795 mm | Standard Deviation 2.6234 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Wall thickness average | 0.758 mm | Standard Deviation 2.1708 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Lower third Wall Thickness | -1.400 mm | Standard Deviation 2.9981 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Change From Baseline in Esophageal Wall Thickness | Upper third Wall Thickness | 0.880 mm | Standard Deviation 0.891 |
Primary
Cohort 5: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
Mean change from baseline in Left Ventricular Ejection Fraction. LVEF is defined as the percentage of blood volume ejected from the left ventricle during systole (contraction phase) relative to the total volume of blood present in the ventricle at the end of diastole (relaxation phase).
Time frame: Baseline, day 84
Population: Full analysis set, participants in cohort 5 that received any study drug with a valid assessment for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 1.533 Percentage of LVEF | Standard Deviation 2.9713 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohort 5: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 5.021 Percentage of LVEF | Standard Deviation 2.0796 |
Primary
Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan
\[11C\]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. \[11C\]PBR28 imaging was used to measure microglial volume at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of \[11C\]-PBR28 in different brain regions after BLZ945 treatment
Time frame: Baseline, day 84
Population: PD analysis set, all participants in cohort 5 with available PD data and no protocol deviations with relevant impact on PD data and with a valid assessment of the outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Brain Stem - day 84 | -26.10 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellar White Matter - day 84 | -22.40 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellum - day 84 | -19.40 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Frontal Lobe - day 84 | -21.53 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Occipital Lobe - day 84 | -17.76 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Thalamus - day 84 | -29.39 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Whole Brain - day 84 | -20.51 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Precentral gyrus - day 84 | -21.95 Percent change from baseline |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohort 5 (PET Sub-study): Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Basal Ganglia - day 84 | -17.80 Percent change from baseline |
Primary
Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan
\[11C\]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. \[11C\]PBR28 imaging was used to measure microglial volume at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of \[11C\]-PBR28 in different brain regions after BLZ945 treatment
Time frame: Baseline, day 5
Population: PD analysis set, all participants in cohorts 1-4 with available PD data and no protocol deviations with relevant impact on PD data and with a valid assessment of the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Thalamus - day 5 | -8.00 Percent change from baseline | Standard Deviation 22.581 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellum - day 5 | -3.53 Percent change from baseline | Standard Deviation 20.459 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Brain Stem - day 5 | -7.10 Percent change from baseline | Standard Deviation 20.89 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellar White Matter - day 5 | -4.41 Percent change from baseline | Standard Deviation 20.678 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Basal Ganglia - day 5 | -3.70 Percent change from baseline | Standard Deviation 22.729 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Whole Brain - day 5 | -0.95 Percent change from baseline | Standard Deviation 26.606 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Occipital Lobe - day 5 | -3.01 Percent change from baseline | Standard Deviation 23.217 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Frontal Lobe - day 5 | 1.33 Percent change from baseline | Standard Deviation 30.101 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Precentral gyrus - day 5 | 0.67 Percent change from baseline | Standard Deviation 33.825 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellar White Matter - day 5 | -14.11 Percent change from baseline | Standard Deviation 11.904 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Occipital Lobe - day 5 | -11.50 Percent change from baseline | Standard Deviation 10.457 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Whole Brain - day 5 | -15.59 Percent change from baseline | Standard Deviation 14.716 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Brain Stem - day 5 | -10.00 Percent change from baseline | Standard Deviation 13.464 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Precentral gyrus - day 5 | -20.33 Percent change from baseline | Standard Deviation 16.458 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellum - day 5 | -10.06 Percent change from baseline | Standard Deviation 8.365 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Basal Ganglia - day 5 | -15.18 Percent change from baseline | Standard Deviation 16.343 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Frontal Lobe - day 5 | -18.67 Percent change from baseline | Standard Deviation 15.881 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Thalamus - day 5 | -14.85 Percent change from baseline | Standard Deviation 13.466 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Occipital Lobe - day 5 | 14.18 Percent change from baseline | Standard Deviation 36.595 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Whole Brain - day 5 | 12.22 Percent change from baseline | Standard Deviation 34.922 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Thalamus - day 5 | 13.89 Percent change from baseline | Standard Deviation 42.938 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Frontal Lobe - day 5 | 9.10 Percent change from baseline | Standard Deviation 29.745 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Basal Ganglia - day 5 | 13.27 Percent change from baseline | Standard Deviation 35.504 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellar White Matter - day 5 | 27.65 Percent change from baseline | Standard Deviation 60.112 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Brain Stem - day 5 | 50.56 Percent change from baseline | Standard Deviation 100.838 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Precentral gyrus - day 5 | 9.90 Percent change from baseline | Standard Deviation 31.57 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellum - day 5 | 17.52 Percent change from baseline | Standard Deviation 44.628 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Whole Brain - day 5 | -7.72 Percent change from baseline | Standard Deviation 0.326 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Precentral gyrus - day 5 | -9.63 Percent change from baseline | Standard Deviation 1.516 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Basal Ganglia - day 5 | -10.73 Percent change from baseline | Standard Deviation 5.872 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Brain Stem - day 5 | -16.69 Percent change from baseline | Standard Deviation 61.674 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellar White Matter - day 5 | -16.87 Percent change from baseline | Standard Deviation 4.874 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Cerebellum - day 5 | -11.78 Percent change from baseline | Standard Deviation 3.854 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Frontal Lobe - day 5 | -9.70 Percent change from baseline | Standard Deviation 0.224 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Occipital Lobe - day 5 | -5.87 Percent change from baseline | Standard Deviation 0.292 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4 : Change From Baseline in Volume of Distribution (Vt) in Different Brain Regions for [11C]-PBR28 PET Scan | Thalamus - day 5 | -14.14 Percent change from baseline | Standard Deviation 3.521 |
Secondary
Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2
Measured by T1/2 - The elimination half-life of BLZ945
Time frame: Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4.
Population: Participants in the PK analysis set with an available value for the outcome measure at the corresponding timepoint.~The PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study drug, and had no protocol deviations that impacted on PK data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 1 | NA Hours |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 4 | NA Hours |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 4 | NA Hours |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 1 | NA Hours |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 1 | NA Hours |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 4 | NA Hours |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 1 | NA Hours |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 | Day 4 | NA Hours |
Secondary
Cohorts 1-4: Renal Clearance (CLR) of BLZ945
Urine renal clearance (CLR) of BLZ945
Time frame: pre-dose, 0-4, 4-8, 8-12 and 12-24 hours after BLZ945 dosing on Day 1 and Day 4
Population: PK analysis set, participants with at least one available valid PK concentration measurement , who received any study drug, and had no protocol deviations that impact on PK data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 1 | 0.00597 liter/hour (L/hr) | Standard Deviation 0.00184 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 4 | 0.00667 liter/hour (L/hr) | Standard Deviation 0.00127 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 4 | 0.00410 liter/hour (L/hr) | Standard Deviation 0.00205 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 1 | 0.00844 liter/hour (L/hr) | Standard Deviation 0.00675 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 1 | 0.00466 liter/hour (L/hr) | Standard Deviation 0.00312 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 4 | 0.00362 liter/hour (L/hr) | Standard Deviation 0.00262 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 1 | 0.0213 liter/hour (L/hr) | Standard Deviation 0.0258 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-4: Renal Clearance (CLR) of BLZ945 | Day 4 | 0.00550 liter/hour (L/hr) | Standard Deviation 0.00129 |
Secondary
Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Incidence and severity of AEs and SAEs by treatment group. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5. For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE
Time frame: From first dose of study treatment up to 32 days after last dose (Day 36) for Cohorts 1-4 and up to 4 weeks after last dose (Day 330) for Cohort 5. *Maximum duration of exposure in Cohort 5 was 302 days. 302 + 28 days of FU=330 days
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 2 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 0 Participants |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 2 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 1 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 2 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 4 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 4 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 2 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 0 Participants |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 0 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 1 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 4 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 0 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 0 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 4 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 3 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 3 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 2 Participants |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 6 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 5 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 5 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 1 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 5 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 0 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Total AEs | 6 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AEs | 4 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 2 | 5 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 1 | 6 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 4 | 1 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study-drug related AEs leading to discontinuation of study treatment | 3 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 4 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Study drug-related AEs | 5 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 5 | 2 Participants |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of grade 3 | 5 Participants |
Secondary
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC
Measured by AUC - Area under the curve of BLZ945 AUC0-24h is the AUC calculated from time zero to 24 hours after dosing (end of a dosing interval). AUClast is the AUC from time zero to the last measurable concentration sampling time.
Time frame: Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only)
Population: Participants in the PK analysis set with an available value for the outcome measure at the corresponding timepoint.~The PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study drug, and had no protocol deviations that impacted on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 4 | 175000 hour * ng/mL | Standard Deviation 14100 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 4 | 170000 hour * ng/mL | Standard Deviation 20300 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 1 | 92600 hour * ng/mL | Standard Deviation 2750 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 1 | 93000 hour * ng/mL | Standard Deviation 2510 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 1 | 203000 hour * ng/mL | Standard Deviation 26800 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 1 | 204000 hour * ng/mL | Standard Deviation 28000 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 4 | 401000 hour * ng/mL | Standard Deviation 88700 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 4 | 399000 hour * ng/mL | Standard Deviation 87800 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 4 | 535000 hour * ng/mL | Standard Deviation 157000 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 1 | 277000 hour * ng/mL | Standard Deviation 99500 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 1 | 278000 hour * ng/mL | Standard Deviation 49600 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 4 | 533000 hour * ng/mL | Standard Deviation 158000 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 4 | 671000 hour * ng/mL | Standard Deviation 43400 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 1 | 391000 hour * ng/mL | Standard Deviation 10600 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUC 0-24h - Day 4 | 680000 hour * ng/mL | Standard Deviation 48300 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 1 | 34100 hour * ng/mL | Standard Deviation 91100 |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 4 | 73400 hour * ng/mL | Standard Deviation 7710 |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC | AUClast - Day 1 | 56900 hour * ng/mL | Standard Deviation 21400 |
Secondary
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax
Measured by Cmax - The maximum plasma concentration of BLZ945
Time frame: Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only)
Population: Participants in the PK analysis set with an available value for the outcome measure at the corresponding timepoint.~The PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study drug, and had no protocol deviations that impacted on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 1 | 6850 ng/mL of BLZ945 | Standard Deviation 780 |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 4 | 12100 ng/mL of BLZ945 | Standard Deviation 2300 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 1 | 16000 ng/mL of BLZ945 | Standard Deviation 2510 |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 4 | 25900 ng/mL of BLZ945 | Standard Deviation 3440 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 1 | 21100 ng/mL of BLZ945 | Standard Deviation 5630 |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 4 | 30700 ng/mL of BLZ945 | Standard Deviation 7800 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 4 | 37600 ng/mL of BLZ945 | Standard Deviation 4270 |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 1 | 25900 ng/mL of BLZ945 | Standard Deviation 2630 |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 4 | 22400 ng/mL of BLZ945 | Standard Deviation 3120 |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax | Day 1 | 19900 ng/mL of BLZ945 | Standard Deviation 5990 |
Secondary
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax
Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945. Actual recorded sampling times were taken into consideration for the calculation of PK parameters.
Time frame: Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only)
Population: Participants in the PK analysis set with an available value for the outcome measure at the corresponding timepoint.~The PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study drug, and had no protocol deviations that impacted on PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 1 | 1.02 hours |
| BLZ945 300mg - Cohort 1 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 4 | 1.01 hours |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 1 | 2.01 hours |
| BLZ945 600mg - Cohort 2 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 4 | 1.50 hours |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 4 | 3.00 hours |
| BLZ945 800mg - Cohort 4 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 1 | 2.01 hours |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 4 | 2.02 hours |
| BLZ945 1200mg - Cohort 3 (Part 1) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 1 | 1.00 hours |
| BLZ945 800mg - Cohort 5 Arm #1 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 4 | 1.49 hours |
| BLZ945 800mg - Cohort 5 Arm #2 (Part 2) | Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax | Day 1 | 2.00 hours |