iPSC-based Drug Repurposing for ALS Medicine (iDReAM) Study

\[Phase 1 part\] Inclusion criteria: 1. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study. To be additionaly signed by a delegate signer if the subject is unable to handwrite. 2. Patients aged ≥20 years and \<80 years at the time of informed consent 3. Patients with positive already-reported SOD1 gene mutation and progressive muscle weakness; sporadic ALS patients who are categorized as either "Definite ALS" or "Probable ALS" or "Probable-laboratory supported ALS" in the Updated Awaji Criteria for the diagnosis of ALS 4. Patients at Grade 1 or 2 in the Japan ALS Severity Scale of the grant-in-aid program for chronic diseases from the Japanese Ministry of Health, Labour and Welfare; patients with positive SOD1 mutation of Grade 1, 2 or 3 5. Patients with ALS that occurred within 2 years at the time of the first registration; patients with positive SOD1 mutation within 5 years after disease onset 6. Patients who can visit hospital regularly as outpatients 7. Patients with change in total ALSFRS-R score during the observation period are -1 to -3 points 8. Urine pregnancy test (for females of childbearing potential) negative at screening Female patients of nonchildbearing potential must meet at least 1 of the following criteria: 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state; 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 3. Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential. Male and female patients of childbearing potential must agree to use one highly effective method of contraception as outlined in this protocol, throughout the study and for at least 28 days after the last dose of investigational product. 9. Patients with appropriate renal function as defined as follows at the time of the first and second registrations a. Serum creatinine ≤1.5 × upper limit of normal (ULN) or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution. 10. Patients with appropriate hepatic function as defined as follows at the time of the first and second registrations b. Total serum bilirubin ≤1.5 × ULN unless the patient has documented Gilbert syndrome; c. AST and ALT ≤2.5 × ULN 11. Able to take oral tablets 12. Patients whose acute effect of previous treatment has recovered to the baseline or CTCAE v.4.03 ≤ Grade 1 at the time of the first and second registrations 13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion criteria: 1. Patients with tracheostomy 2. Patients who have used non-invasive ventilation due to ALS symptoms 3. Patients whose %FVCs are less than 70% at the time of first and second registrations 4. Patients who have nerve conduction study findings of demyelination such as conduction block 5. Patients who are taking edaravone; patients who started riluzole or edaravone after start of the observation period; patients who changed the dosage of riluzole after start of the observation period 6. Patients with bulbar type ALS with dysphagia and dysarthria 7. Patients with cognitive impairment 8. Pregnant female patients; breastfeeding female patients; fertile male and female patients of childbearing potential who are unwilling or unable to use 1 highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product 9. History of clinically significant or uncontrolled cardiac disease including: * History of, or active, congestive heart failure; * Uncontrolled angina or hypertension within 3 months prior to registration; * Myocardial infarction within 12 months prior to registration; * Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); * Diagnosed or suspected congenital or acquired prolonged QT interval history or prolonged QTc (QTcF should not exceed 500 msec); * Unexplained syncope 10. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval 11. Patient who is taking the following medicines during study drugs administration. a Combination of warfarin or other anticoagulation. Combination of therapeutic anticoagulant therapy with low molecular weight heparin is acceptable b Src or c-Abl inhibitors c Other treatments for cancer d Drugs known to prolong the QT interval or predispose to Torsades de Pointe e Current or anticipated use of a strong or moderate CYP3A inhibitor and inducer f Drugs affecting gastric pH such as Proton pump inhibitors (e.g., lansoprazole) 12. History of malignancy within 5 years prior to registration with the exception of basal cell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least 12 months 13. Patients who were enrolled in other clinical study within 12 weeks before the first registration, or are expected to be enrolled in other clinical study using a study drug during this study 14. Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations 15. Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 16. Recent or ongoing clinically significant GI disorder (eg, Crohn's disease, ulcerative colitis, or prior total or partial gastrectomy). 17. Patients with chronic obstructive pulmonary disease 18. Major surgery or radiotherapy within 14 days prior to registration at the time of the first registration 19. Patient who fulfills the conditions: 1. Neutrophil count (ANC) \<1,500/mm3 or white blood cell \<3,000/mm3 at the time of the first and second registration 2. Hemoglobin \<9.0 g/dL at the time of the first and second registrations 3. Platelet count \<100,000/L at the time of the first and second registrations 20. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study 21. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study \[Phase 2 part\] Inclusion criteria: 1. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study. To be additionally signed by a delegate signer if the subject is unable to handwrite. 2. Patients aged ≥20 years and ≤75 years at the time of informed consent 3. ALS patients who are categorized as either "Definite ALS" or "Probable ALS in the El Escorial and revised Airlie House criteria for the diagnosis of ALS 4. Patients at Grade 1 or 2 in the Japan ALS Severity Scale of the grant-in- aid program for chronic diseases from the Japanese Ministry of Health, Labour and Welfare 5. Patients with ALS within 2 years of symptom onset at the time of the first registration 6. Patients with change in total ALSFRS-R score during the observation period from -1 to -4 points 7. Patients with score of at least 2 on all items of ALSFRS-R; 4.Writing, 5.Feeding behavior (1) must have at least 2 points on each side. 8. Urine pregnancy test (for females of childbearing potential) negative at screening Female patients of nonchildbearing potential must meet at least 1 of the following criteria: 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state; 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 3. Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential. 9. Patients with appropriate renal function as defined as follows at the time of the first and second registrations a. Estimated creatinine clearance or eGFR ≥60 mL/min (mild renal impairment) as calculated using the method standard for the institution (the CKD-EPI equation is recommended, other methods such as Cockcroft-Gault or MDRD may be used. The same method should be applied throughout the study period.). 10. Patients with appropriate hepatic function as defined as follows at the time of the first and second registrations 1. Total serum bilirubin 1.5 × ULN unless the patient has documented Gilbert syndrome; 2. AST and ALT 2.5 × ULN 11. Patients who can consistently take the investigational drug and other oral tablets with water throughout the study period. 12. Patients whose adverse event during previous treatment has recovered to the baseline (Visit 5: before the start of study drug administration) or CTCAE v.4.03 ≤ Grade 1 at the time of the first and second registrations. Excluding the case where the investigator (sub-investigator) judges that the event is not a safety risk. 13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion criteria: 1. Patients with tracheostomy 2. Patients who had decreased respiratory function and complained of dyspnea at the time of enrollment (One of the three items on the ALSFRS-R related to respiratory (10) dyspnea, (11) orthopnea, or (12) respiratory failure is less than 3 points). 3. Patients whose %FVCs are at least 80 % at the time of first and second registrations 4. Patients who have nerve conduction study findings of demyelination such as conduction block 5. Patients using edaravone within 4 weeks prior to enrollment in the observation period; patients using edaravone at the time of enrollment in the observation period; patients who started edaravone after start of the observation period 6. Patients who started riluzole after start of the observation period; patients who changed the dosage of riluzole after start of the observation period 7. Patients with bulbar-onset type ALS with dysphagia and dysarthria 8. Patients with Parkinson's disease and syndromes, schizophrenia, cognitive impairment, and other comorbidities that may have a significant impact on the evaluation of drug efficacy 9. Patients with a history of spinal surgery such as cervical spondylosis or disc herniation after the onset of ALS, or patients who were scheduled to undergo surgery during the study period 10. Patients whose symptoms could not be ruled out as symptoms of a disease that requires differential diagnosis, such as cervical spondylosis or multifocal motor neuropathy. 11. Pregnant female patients; breastfeeding female patients 12. History of clinically significant or uncontrolled cardiac disease including: * History of, or active, congestive heart failure; * Uncontrolled angina or hypertension within 3 months prior to registration; * Myocardial infarction within 12 months prior to registration; * Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); * Diagnosed or suspected congenital or acquired prolonged QT interval history or prolonged QTc (QTcF should not exceed 500 msec); * Unexplained syncope 13. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval 14. Patient who is taking the following medicines during study drugs administration. Refer to Prohibited Medications. a Combination of warfarin or other anticoagulation. Combination of low molecular weight heparin is acceptable b Src or c-Abl inhibitors c Drugs known to prolong the QT interval or predispose to Torsades de Pointe d Current or anticipated use of a strong or moderate CYP3A inhibitor and inducer e Drugs affecting gastric pH such as Proton pump inhibitors (e.g., lansoprazole) 15. History of malignancy within 5 years prior to the first registration with the exception of basal cell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least 12 months 16. Patients who were enrolled in other clinical study within 12 weeks before the first registration, or are expected to be enrolled in other clinical study using a study drug during this study 17. Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations 18. Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness 19. Recent or ongoing clinically significant GI disorder (eg, Crohn's disease, ulcerative colitis, or prior total or partial gastrectomy). 20. Patients with chronic obstructive pulmonary disease 21. Major surgery within 14 days prior to registration at the time of the first registration 22. Patient who fulfills the conditions: 1. Neutrophil count (ANC) \<1,500/mm3 or white blood cell \<3,000/ mm3 at the time of the first and second registration 2. Hemoglobin \<9.0 g/dL at the time of the first and second registrations 3. Platelet count \<100,000/μL at the time of the first and second registrations 23. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study 24. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study