Study of Safety and Proof of the Mechanism of BLZ945 in ALS Patients

NCT04066244 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: CBLZ945C122012019-000826-22
• Study Type: interventional
• Target: 28
• Locations: 3 countries
• Sites: 4

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.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

PET; ALS; Microglia; CSF

Outcome Measures

Primary Outcomes (8)

• 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

  Baseline, day 5

• 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

  Baseline, day 84

• Cohort 5: Change From Baseline in Esophageal Wall Thickness

  Mean change from baseline in esophageal wall thickness measured in mm

  Baseline, Day 84

• 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

  Baseline, Day 84

• 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

  Baseline, Day 84

• 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

  Baseline, Day 84

• 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).

  Baseline, day 84

• Cohort 5: Adverse Events Related to Extracellular Matrix (ECM) Accumulation

  Number of patients with adverse events related to ECM accumulation

  Up to Day 84

Secondary Outcomes (6)

• 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)

• 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)

• 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)

• 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.

• 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

Study Arms (6)

Cohort 1

OTHER

BLZ945 300mg

Drug: BLZ945

Cohort 2

OTHER

BLZ945 600mg

Drug: BLZ945

Cohort 3

OTHER

BLZ945 1200mg

Drug: BLZ945

Cohort 4

OTHER

BLZ945 800mg

Drug: BLZ945

Cohort 5 Arm #1

OTHER

BLZ945 800mg (4 days treatment + 10 days off)

Drug: BLZ945

Cohort 5 Arm #2

OTHER

BLZ945 800mg (once weekly)

Drug: BLZ945

Interventions

BLZ945 DRUG

Investigational drug capsules taken orally or via enteral infusion

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5 Arm #1; Cohort 5 Arm #2

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (4)

Yale University School of Medicine

New Haven, Connecticut, 06520-8048, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Turku, 20520, Finland

Location

Novartis Investigative Site

Stockholm, 14186, Sweden

Location

Related Links

• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 21, 2019
• First Posted: August 26, 2019
• Study Start: December 30, 2019
• Primary Completion: February 1, 2024
• Study Completion: February 1, 2024
• Last Updated: October 16, 2025
• Results First Posted: March 19, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share

Locations

FI (1); US (2); SE (1)