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 thatthe patient has been informed of all pertinent aspects of the study. To be additionalysigned 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 muscleweakness; sporadic ALS patients who are categorized as either "Definite ALS" or "Probable ALS" or "Probable-laboratory supported ALS" in the Updated Awaji Criteriafor the diagnosis of ALS
4. Patients at Grade 1 or 2 in the Japan ALS Severity Scale of the grant-in-aid programfor 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 followingcriteria:
9. Achieved postmenopausal status, defined as follows: cessation of regular mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; status may be confirmed with a serum follicle stimulatinghormone (FSH) level confirming the postmenopausal state;
10. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
11. Have medically confirmed ovarian failure. All other female patients (includingfemale patients with tubal ligations) are considered to be of childbearingpotential. Male and female patients of childbearing potential must agree to use one highlyeffective method of contraception as outlined in this protocol, throughout the studyand for at least 28 days after the last dose of investigational product.
12. Patients with appropriate renal function as defined as follows at the time of thefirst and second registrations a. Serum creatinine ≤1.5 × upper limit of normal (ULN) or estimated creatinineclearance ≥60 mL/min as calculated using the method standard for the institution.
13. Patients with appropriate hepatic function as defined as follows at the time of thefirst and second registrations b. Total serum bilirubin ≤1.5 × ULN unless the patienthas documented Gilbert syndrome; c. AST and ALT ≤2.5 × ULN
14. Able to take oral tablets
15. Patients whose acute effect of previous treatment has recovered to the baseline orCTCAE v.4.03 ≤ Grade 1 at the time of the first and second registrations
16. 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 conductionblock
5. Patients who are taking edaravone; patients who started riluzole or edaravone afterstart of the observation period; patients who changed the dosage of riluzole afterstart 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 femalepatients of childbearing potential who are unwilling or unable to use 1 highlyeffective methods of contraception as outlined in this protocol for the duration ofthe 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 orprolonged QTc (QTcF should not exceed 500 msec);
• Unexplained syncope

10. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on theQT interval
11. Patient who is taking the following medicines during study drugs administration. a Combination of warfarin or other anticoagulation. Combination of therapeuticanticoagulant therapy with low molecular weight heparin is acceptable b Src or c-Ablinhibitors c Other treatments for cancer d Drugs known to prolong the QT interval orpredispose to Torsades de Pointe e Current or anticipated use of a strong or moderateCYP3A inhibitor and inducer f Drugs affecting gastric pH such as Proton pumpinhibitors (e.g., lansoprazole)
12. History of malignancy within 5 years prior to registration with the exception of basalcell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancer that is consideredadequately 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 firstregistration, or are expected to be enrolled in other clinical study using a studydrug during this study
14. Known prior or suspected severe hypersensitivity to study drugs or any component intheir formulations
15. Patients with active, uncontrolled bacterial, fungal, or viral infection, includinghepatitis 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, ulcerativecolitis, 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 thefirst registration
19. Patient who fulfills the conditions:
20. Neutrophil count (ANC) <1,500/mm3 or white blood cell <3,000/mm3 at the time ofthe first and second registration
21. Hemoglobin <9.0 g/dL at the time of the first and second registrations
22. Platelet count <100,000/L at the time of the first and second registrations
23. Other acute or chronic medical or psychiatric condition including recent (within thepast year) or active suicidal ideation or behavior or laboratory abnormality that mayincrease the risk associated with study participation or investigational productadministration or may interfere with the interpretation of study results and, in thejudgment of the investigator, would make the participant inappropriate for entry intothis study
24. Investigator site staff members directly involved in the conduct of the study andtheir family members, site staff members otherwise supervised by the investigator, orPfizer employees, including their family members, directly involved in the conduct ofthe study

[Phase 2 part] Inclusion criteria:

1. Evidence of a personally signed and dated informed consent document indicating thatthe patient has been informed of all pertinent aspects of the study. To beadditionally 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 ElEscorial 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 programfor 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 firstregistration
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.Feedingbehavior (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 followingcriteria:
9. Achieved postmenopausal status, defined as follows: cessation of regular mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; status may be confirmed with a serum follicle stimulatinghormone (FSH) level confirming the postmenopausal state;
10. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
11. Have medically confirmed ovarian failure. All other female patients (includingfemale patients with tubal ligations) are considered to be of childbearingpotential.
12. Patients with appropriate renal function as defined as follows at the time of thefirst and second registrations a. Estimated creatinine clearance or eGFR ≥60 mL/min (mild renal impairment) ascalculated using the method standard for the institution (the CKD-EPI equation isrecommended, other methods such as Cockcroft-Gault or MDRD may be used. The samemethod should be applied throughout the study period.).
13. Patients with appropriate hepatic function as defined as follows at the time of thefirst and second registrations
14. Total serum bilirubin 1.5 × ULN unless the patient has documented Gilbertsyndrome;
15. AST and ALT 2.5 × ULN
16. Patients who can consistently take the investigational drug and other oral tabletswith water throughout the study period.
17. 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 atthe time of the first and second registrations. Excluding the case where theinvestigator (sub-investigator) judges that the event is not a safety risk.
18. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,and other study procedures Exclusion criteria:
19. Patients with tracheostomy
20. Patients who had decreased respiratory function and complained of dyspnea at the timeof 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).
21. Patients whose %FVCs are at least 80 % at the time of first and second registrations
22. Patients who have nerve conduction study findings of demyelination such as conductionblock
23. 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; patientswho started edaravone after start of the observation period
24. Patients who started riluzole after start of the observation period; patients whochanged the dosage of riluzole after start of the observation period
25. Patients with bulbar-onset type ALS with dysphagia and dysarthria
26. Patients with Parkinson's disease and syndromes, schizophrenia, cognitive impairment,and other comorbidities that may have a significant impact on the evaluation of drugefficacy
27. Patients with a history of spinal surgery such as cervical spondylosis or discherniation after the onset of ALS, or patients who were scheduled to undergo surgeryduring the study period
28. Patients whose symptoms could not be ruled out as symptoms of a disease that requiresdifferential diagnosis, such as cervical spondylosis or multifocal motor neuropathy.
29. Pregnant female patients; breastfeeding female patients
30. 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 orprolonged QTc (QTcF should not exceed 500 msec);
• Unexplained syncope

13. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on theQT interval
14. Patient who is taking the following medicines during study drugs administration. Referto Prohibited Medications. a Combination of warfarin or other anticoagulation. Combination of low molecularweight heparin is acceptable b Src or c-Abl inhibitors c Drugs known to prolong the QTinterval or predispose to Torsades de Pointe d Current or anticipated use of a strongor moderate CYP3A inhibitor and inducer e Drugs affecting gastric pH such as Protonpump inhibitors (e.g., lansoprazole)
15. History of malignancy within 5 years prior to the first registration with theexception of basal cell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancerthat 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 firstregistration, or are expected to be enrolled in other clinical study using a studydrug during this study
17. Known prior or suspected severe hypersensitivity to study drugs or any component intheir formulations
18. Patients with active, uncontrolled bacterial, fungal, or viral infection, includinghepatitis 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, ulcerativecolitis, 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 firstregistration
22. Patient who fulfills the conditions:
23. Neutrophil count (ANC) <1,500/mm3 or white blood cell <3,000/ mm3 at the time ofthe first and second registration
24. Hemoglobin <9.0 g/dL at the time of the first and second registrations
25. Platelet count <100,000/μL at the time of the first and second registrations
26. Other acute or chronic medical or psychiatric condition including recent (within thepast year) or active suicidal ideation or behavior or laboratory abnormality that mayincrease the risk associated with study participation or investigational productadministration or may interfere with the interpretation of study results and, in thejudgment of the investigator, would make the participant inappropriate for entry intothis study
27. Investigator site staff members directly involved in the conduct of the study andtheir family members, site staff members otherwise supervised by the investigator, orPfizer employees, including their family members, directly involved in the conduct ofthe study