study of safety and proof of the mechanism of blz945 in als patients

Conditions: Amyotrophic Lateral Sclerosis

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.

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.

Eligibility criteria:
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.

Keywords: pet als microglia csf