A Randomized Phase 1 / 2 Trial Aiming to Restore UNC13A Function in People living with ALS: FUNCtion ALS

Prior treatment

• Vaccines administered within 4 weeks of a scheduled IMP administration. If a vaccination is required during the trial and the above schedule cannot be adhered to, vaccination should be discussed with the Sponsor and the Medical Monitor.
• Prior investigational and other medications a. Are currently enrolled in any other clinical trial involving either an investigational product or off-label use of a drug or device b. Participated in another clinical trial within 4 weeks, or 5 half-lives of the previous IMP, whichever is greater, prior to the first Screening Visit. If the half-live of an investigational drug is not known, Investigator shall discuss eligibility with the Sponsor. c. Prior exposure to small interfering ribonucleic acids (siRNA), ASOs, stem cell or gene therapy. d. Off-label use of drugs or devices that are being used as disease-modifying therapies in ALS prior to the first Screening Visit. e. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed at least 7 days prior to the Day 1 Visit. If the potential participant or participant experiences an infection within 7 days of a scheduled IMP administration, the Investigator should discuss the rescheduling of the IMP administration with the Sponsor. Medical History and Concurrent Disease
• Recent history of drug or alcohol abuse a. History of alcohol or drug abuse or dependence within 6 months of the first Screening Visit. b. Positive urine screen for drugs of abuse that include methadone, cocaine, and amphetamines; positive urine screen for opiates, barbiturates, or benzodiazepines without a prescription at any time during the first Screening Visit. If the urine drug screen is positive for amphetamines, but there is credible information that intake of amphetamines has not occurred, a retest can be performed. A negative result needs to be confirmed prior to enrollment.
• Medical or recreational use of cannabis may be permitted at the discretion of the Investigator and after a consultation with the Sponsor. If the permitted Investigator considers the cannabis use permissible, and the Medical Monitor. If permitted, it should be listed as concomitant medication.
• Clinically relevant disease other than the primary disease (ALS) that could jeopardize completion of the trial as defined in the protocol, including specifically symptoms indicative of an active psychiatric disorder despite adequate medication within the last 4 weeks prior to the first Screening Visit.
• Tracheostomy anytime, or continuous assisted ventilation (more than 22 hours per day) of any type during the preceding 3 months before the first Screening Visit.
• Participants who are not able to refrain from alcohol in the 24 hours prior to and after each IP administration
• Known to have previously tested positive result for immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B.

Other illness

• Known hypersensitivity or intolerance to ASOs
• Any other conditions which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participation in or completion of the trial.
• Significant pulmonary disorder not attributed to ALS, which may complicate the evaluation of the respiratory function. Intermittent non-invasive ventilation is permitted.
• Any medical condition known to have an association with motor neuron dysfunction or involving neuromuscular weakness or another neurodegenerative disease which might confound trial assessments (Note: Individuals with symptoms of frontotemporal dementia (FTD) can be enrolled, as long as the primary diagnosis is ALS).
• Any contraindication to brain MRI scans, including presence of pacemakers, aneurysm clips, artificial heart valves, implants, metal fragments, or foreign objects in the eyes, skin, or body that constitute a contraindication to having a brain MRI scan.

Lab values

• Clinically significant electrocardiogram (ECG) abnormalities, including, but not limited to (based on on mean values triplicate recordings): a. Prolonged interval between Q and T wave corrected by Fridericia criteria (QTcF) interval (>450 ms for males and > 470 ms for females). b. QRS or T wave morphology that could, in the Investigator’s opinion, render the QT interval assessment unreliable. c. Symptoms of long QT syndrome or has a personal history of cardiac arrhythmias or risk factors for torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.
• Any contraindication to lumbar puncture, IT injections, including but not limited to: a. Clinically relevant thrombocytopenia (platelet count <100,000/mm3) or other coagulation disorders (including, but not limited to, participants receiving coumarin-derived anticoagulants, or low-molecular-weight heparin, and participants diagnosed with hemophilia, Factor X deficiency, or Von Willebrand’s disease). Note: Screening International normalized ratio (INR), PT, aPTT, and platelet counts should be reviewed as part of this assessment of contraindication to lumbar puncture. b. Antiplatelet treatments that cannot be safely interrupted for recommended period, depending on the medication participant is receiving, prior to and after the IMP administration. If in doubt, Investigators should consult on the withholding period with the Sponsor. c. Daily use of anticoagulants that cannot be safely interrupted for the recommended period, depending on the medication participant is receiving, prior to and after the IMP administration. If in doubt, Investigators should consult on the withholding period with the Sponsor. d. Signs/symptoms of increased intracranial pressure (ICP) such as suspected cerebral mass, or current space occupying lesion, that would preclude IT procedures or safety assessments. e. Previous spinal surgery, such as lumbosacral surgery, that could complicate access to the subarachnoid space.
• Clinically significant laboratory findings that could confound the interpretation of the safety of IMP administration including, but not limited to, the list below. If clinically significant laboratory findings are reported and confirmed during the Screening Period, the IMP administration can be postponed (by up to 4 weeks) to allow resolution of the laboratory findings. If a longer delay in IMP administration is advised by the Investigator, the Investigator should consult with the Sponsor. Of note, if Investigators consider a laboratory test result not clinically significant but it meets exclusionary criteria, potential participants may be retested once. a. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin elevations (>3 × upper limit of normal [ULN]). I. Of note: An elevation of AST only (>3 x ULN) with normal serum bilirubin and ALT but elevated creatine kinase is not an exclusion. b. Gamma-glutamyl transferase elevation (>3 × ULN). c. Total bilirubin (Tbil) >2 × ULN unless Gilbert’s syndrome is documented. d. Serum creatinine elevation (>2 × ULN). e. Estimated glomerular filtration rate (eGFR, using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) <60 mL/min/1.73 m2. f. Hemoglobin level <9 g/dL (90 g/L). g. Absolute neutrophil count <1,000 cells/μL.

Other

• [CCI], please see protocol not for publication for exclusion criteria 1
• Significant suicide risk, defined by any of the below: a. Suicidal ideation as endorsed on items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) within the past year or during Screening or at the Day 1 Visit. b. Suicidal behaviors within the past year. c. Clinical assessment of significant suicidal risk during clinical interview.
• Any contraindication to local anesthesia, if needed to perform lumbar punctures and IT injections.
• All Sponsor employees, or contractors of the Sponsor, Investigator or site personnel directly affiliated with this trial, and the immediate families of either of these. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted
• Pregnant or breast-feeding females; or females with childbearing potential if no adequate contraceptive measures are used.

• Ability to thoroughly understand the purpose and risks of the trial and provide signed and dated informed consent according to Good Clinical Practice (GCP) and authorization to use Protected Health Information in accordance with national and local participant privacy regulations.
• Male participants: a. Must agree to use at least one highly effective method of contraception from the time of signing the informed consent until at least 24 weeks after the last dose of IMP and not donate sperm for at least 24 weeks after the last IMP administration at which time plasma concentrations of TRCN-1023 are projected to be below the limit of detection.. b. Female partners of male participants must agree to use a highly effective form of contraception (i.e., double-barrier method which includes a condom plus diaphragm with spermicide or condom plus spermicide) from the first Screening Visit and for at least 24 weeks after the last IMP administration. c. If the participant has had
• Participants agree to not share any participant-related trial experience or safety or efficacy information on social media or other public venues.
• Men or women aged ≥18 years and ≤75 years at the time of the first Screening Visit.
• Diagnosis of clinically definite, clinically probable, or clinically probable laboratory supported ALS according to the revised version of the EI Escorial World Federation of Neurology criteria published in 2000 (Brooks et al., 2000)
• Symptom within the past 24 months. Symptoms can include muscle weakness and/or a functional deficit of the upper motor neuron, but not only fasciculations and/or cramps.
• Able to reproducibly perform assessments of [CCI] , defined as [CCI] with variability of [CCI] of the raw values, with a maximum of [CCI] trials permitted. The highest technically acceptable technically [CCI] acceptable [CCI] measurements during the first Screening Visit) must be [CCI] of the predicted value as adjusted for age, sex, and height using the Global Lung Initiative formula published in 2023 (Bowerman et al., 2023).
• Able and willing to meet all trial requirements in the opinion of the Investigator, including travel to the trial center, adherence to procedures, measurements and visits, as defined in the protocol, including but not limited to: a. Brain magnetic resonance imaging (MRI) scans, lumbar punctures, IT injections, blood draws. b. Home assessments [CCO]
• On stable doses of approved ALS medication for at least 4 weeks prior to the first Screening Visit. a. If on riluzole: participants must be on a stable dose (e.g., twice a day BID 50 mg) and are expected to remain at that dose until the final trial visit b. If on edaravone: participants must have completed at least 2 treatment cycles prior to the Screening Period and are expected to remain at a stable dose until the End of Follow-up (EoF) Visit. For participants taking edaravone via IV injection, edaravone treatment must be separated from the IMP administration by at least 1 week.
• Screening values of coagulation parameters including platelet count, International Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be within normal ranges. Out-of-range coagulation parameters deemed not clinically significant by the Investigator can be repeated once. If the out-of-range values persist, but the Investigator deems participants suitable for enrollment, the Investigator should consult with the Sponsor.
• Female participants: a. Childbearing potential, must agree to use at least one highly effective method of contraception from the time of signing the informed consent until at least 112 days after the last dose of IMP, at which time plasma concentrations of TRCN-1023 are projected to be below the limit of detection; b. Postmenopausal (defined as at least 12 months with no menses prior to the first Screening Visit without an alternative medical cause), and as confirmed by follicle stimulating hormone (FSH) measurement at the first Screening Visit (in the absence of 12 months of amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is required) or c. Surgically sterile (i.e., post-hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) at least 1 month prior to the first Screening Visit. d. If not surgically sterile, must have a negative highly sensitive serum beta human chorionic gonadotropin (β-HCG) pregnancy test at the first Screening Visit.