A study to assess how ALZ-801 affects laboratory tests and symptoms of Alzheimer's disease in patients who have a specific genotype (APOE4).

Prior treatment

• Has a brain MRI at screening indicative of significant abnormality, including, but not limited to, prior hemorrhage (> 1 cm) or large infarct (> 1 cm), > 2 lacunar infarcts outside the brain stem, severe white matter changes (Fazekas grade 3), superficial hemosiderosis > 1 cm, aneurysm, vascular malformation, subdural hematoma, space-occupying lesion (e.g., abscess or brain tumor such as meningioma), or ventricular enlargement consistent with normal pressure hydrocephalus. Note: Ventricular enlargement consistent with AD atrophy (hydrocephalus ex-vacuo) is not exclusionary Note: Subjects who have > 10 microbleeds, require approval by Sponsor Medical Monitor
• Has donated blood within 8 weeks prior to the Screening – Part 2 Visit.
• Has a history of alcohol or drug dependence or abuse within 2 years of the Screening – Part 2 Visit or tests positive for drugs of abuse (i.e., amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine) at the Screening – Part 2 Visit. Note 1: If positive for opiates, the subject must be taking prescription medicines for pain and be on a stable dose of medication for more than 4 weeks prior to the Screening – Part 2 Visit. Note 2: If positive for benzodiazepines, the subject must be taking prescription medicines containing benzodiazepines and be on a permitted dose according to Table 3.
• Has participated in a clinical study of any potential disease-modifying AD treatment, and received active drug within 6 months prior to the Screening – Part 2 Visit [see Table 3].
• Has participated in a clinical study and received active treatment with an anti-amyloid or anti-tau vaccine [see Table 3].
• Has received any of the treatments listed in Table 3 more recently than the indicated period before the Screening – Part 2 Visit.
• Anticipates receiving any of the treatment listed in Table 3, during the current clinical study (unless meeting criteria for exceptions to prohibition as listed in Table 3).
• Were noncompliant (<70%) with the study medication or, in the Investigator’s or Sponsor’s opinion, with the study procedures in the core study.
• Were noncompliant (<70%) with the study medication or, in the Investigator’s or Sponsor’s opinion, with the study procedures in the LTE Year 1.
• Has a medically confirmed history of recent cerebral infarct or recent transient ischemic attack (within 1 year prior to the Screening – Part 2 Visit).
• Has a medically confirmed history of recent myocardial infarction or unstable, untreated coronary artery disease, or angina pectoris (within 1 year prior to the Screening – Part 2 Visit).

Other illness

• Has a lifetime history of schizophrenia, schizoaffective disorder, or bipolar disorder.
• Has a diagnosis of neurodegenerative disorder other than AD.
• Has any significant medical condition (e.g., uncontrolled cardiovascular, GI, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, or other major disease or malignancy) that is unstable and that would either: (a) place the subject at undue risk from administration of study drug or from undergoing study procedures, or (b) interfere with the interpretation of safety or efficacy evaluations obtained in the course of the study.
• Is unable to swallow ALZ-801 tablets or has a known intolerance or hypersensitivity to tramiprosate or any of the excipients contained in the ALZ-801 tablets.
• Has positive serology for the human immunodeficiency virus (HIV) or for hepatitis B or C virus.
  • Long-Term Extension Year 1 (Weeks 104-160) - 1. Withdrew from core study before completing the Week 104 visit.
• Has a current diagnosis of Major Depressive Disorder (MDD) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition. Subjects who do not meet current criteria for MDD and who are on stable doses of antidepressants or mood stabilizers may be included in the study at the discretion of the Investigator [see Table 3].
• Has a history of suicidal behavior or has ongoing suicidal ideation.
• Has a history of cancer, diagnosed and treated within the last 3 years prior to the Screening – Part 2 Visit, with the exception of the following: (a) treated basal cell carcinoma of the skin, or (b) treated in situ or Stage 1 cancers of skin (squamous cell only), colon, prostate, breast, or colon (requires approval by the Medical Monitor).

Lab values

• Has a prothrombin time as measured by INR ≥ 1.5 and a platelet count ≤ 50 x 10^9/L.
• Has clinically relevant abnormalities in serum thyroid-stimulating hormone or calcium. If the subject is taking replacement therapy, corresponding Screening test values must be clinically acceptable.
• Has serum vitamin B12 below the lower limit of normal.
• Has any clinical chemistry laboratory value greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE; version 4.0; National Cancer Institute 2009) Grade 2, unless considered not clinically relevant by the Investigator and the Medical Monitor.
• The subject at Screening has one or more of the following: a. Alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN), OR b. Aspartate aminotransferase (AST) ≥ 3 × ULN, OR c. Total bilirubin (TBL) ≥ 1.5 × ULN.
• Has an estimated glomerular filtration rate < 40 ml/min per 1.73 m2 according to the Modification of Diet in Renal Disease formula [see National Institute of Diabetes and Digestive and Kidney Diseases website for formula https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate-calculators/mdrd-adults-si-units].
• Has a glycosylated hemoglobin (HbA1c) > 8% (National Glycohemoglobin Standardization Program) or 64 mmol/mol (International Federation of Clinical Chemistry) at the Screening – Part 1 Visit.
• Has a history of, or currently has, any clinically significant ECG finding, or a QT interval corrected by Fridericia’s method (QTcF) of > 450 msec for males and > 470 msec for females.
• Had a clinically significant medical, surgical, laboratory, or other abnormality at the Week 104 visit of the core study that would compromise their participation in the LTE or compromise their safety in the opinion of the Investigator.
  • Long-Term Extension Year 2 (Weeks 156-212) - 1. Withdrew from LTE Year 1 before completing the Week 156 visit.
• Had a clinically significant medical, surgical, laboratory, or other abnormality at the Week 156 visit of the LTE Year 1 that would compromise their participation in the continued LTE or compromise their safety in the opinion of the Investigator.
• Has a hemoglobin level < 11 g/dL in male subjects or < 10 g/dL in female subjects, or a hemoglobin level > 16 g/dL.

Age

• Has a history of seizures (excluding febrile seizures of childhood, or a single distant seizure > 10 years). Subjects with a history of one seizure, but without evidence of vascular or mixed dementia, or brain tumor on MRI, may be allowed into the study at the discretion of the Medical Monitor.

• Be between the ages of 50 and 80 years, inclusive.
• Be willing to sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study, and that he/she is willing to participate in the study. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the consent form, the subject’s legally authorized representative may sign the consent form with the subject’s assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study. Note: Subjects who participate in the PK Profile Substudy for extended PK sampling will sign an additional consent form specific for the substudy.
• Can complete the cognitive testing procedures. Corrected visual and auditory acuity must be adequate to comply with the protocol.
• Lives at home independently, in a senior living facility, or in an assisted living facility.
• Both subject and caregiver/study partner are fluent in, and able, to read the local language in which study assessments are administered at the study site.
• Subject and caregiver/study partner agree to be compliant with study procedures and appear to have a high probability of completing the study.
• Caregiver/study partner agrees not to administer any prohibited concomitant medications during the study.
• If female, must have a negative serum pregnancy test and EITHER be of non-childbearing potential, described as either: • Post-menopausal (defined as at least 12 months without any menses) prior to the Screening – Part 2 Visit, or • Documented surgically sterile (has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy with or without hysterectomy and greater than 6 weeks have passed since the surgery) OR • If subject is of child-bearing potential, must have a negative urine pregnancy test prior to dosing at baseline, use a highly effective method of contraception (with a failure rate of less than 1% per year when used consistently and correctly) for the duration of the study and for 8 weeks after the last dose of study medication. Note: Highly effective methods include surgical sterilization, intrauterine device (IUD). intrauterine hormone-releasing system (IUS), hormonal contraception associated with inhibition of ovulation (e.g., pills, patches, vaginal ring, or injections). Total abstinence is also acceptable if it is the preferred and usual lifestyle of a subject.
• Has a Screening brain MRI that is not inconsistent with the diagnosis of AD and determined to be of adequate quality. Note: This MRI will provide baseline data for MRI biomarker and safety assessments.
• If treated with an AChEI, subject must be on stable treatment for at least 12 weeks prior to the Screening – Part 2 Visit and must be able to continue on the same dose/regimen for the duration of the study. Note: Memantine is not allowed and must not be taken within 12 weeks of the Screening – Part 2 visit.
• With the exception of a diagnosis of AD and the presence of stable medical conditions is, in the opinion of the Investigator, in good general medical health based upon the results of medical history, physical examination, laboratory tests, vital signs, and ECG.
• Has a body weight ≥ 50 kg.
• If treated with antidepressants, mood stabilizers, or other psychotropic medications, is on a stable dose according to Table 3.
• If taking permitted, non-psychotropic medications for the treatment of non-excluded medical conditions, is on a stable dose according to Table 3.
  • Long-Term Extension Year 1 (Weeks 104-160) - 1. Complete the last visit (Week 104) of the core study.
• Be willing to sign an IRB/IEC-approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the study. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the consent form, the subject’s legally authorized representative may sign the consent form with the subject’s assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
• Agree (subject and caregiver/study partner) to be compliant with study procedures and, in the opinion of the Investigator, have a high probability of completing the study.
• Have stable medical conditions in the opinion of the Investigator.
  • Long-Term Extension Year 2 (Weeks 156-212) - 1. Complete the last visit (Week 156) of the LTE Year 1
• Be willing to sign an IRB/IEC-approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the study. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the consent form, the subject’s legally authorized representative may sign the consent form with the subject’s assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
• Agree (subject and caregiver/study partner) to be compliant with study procedures and, in the opinion of the Investigator, have a high probability of completing the study.
• Have stable medical conditions in the opinion of the Investigator.
• Has a diagnosis of Probable AD Dementia or MCI due to AD in accordance with the National Institute on Aging-Alzheimer’s Association (NIA AA) Working Group Criteria [Albert et al, 2011; McKhann et al, 2011].
  • In addition, to be eligible for dose escalation to TID dosing, the subject must: 5. Have MMSE score <22 at clinic visit between Weeks 156-196 (Visits 5E-8E).
• When the MMSE score is <22, be willing to sign the TID dosing section of the IRB/IEC-approved ICF indicating that he/she understands the TID dose escalation. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the TID dosing section of the consent form, the subject’s legally authorized representative may sign with the subject’s assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
• Have tolerated the BID dose for the last 3 months.
• Deemed by the investigator to be likely to benefit from the TID dose and to complete the LTE Year 2.
• Has a biomarker profile reflecting AD, according to the NIA-AA Research Framework [Jack et al, 2018] defined as follows: a) Positive amyloid PET scan on file prior to Screening OR b) CSF AD biomarker result using the Lumipulse (Fujirebio) assay at Screening with: i. Aβ42/Aβ40 ratio < 0.61 AND ii. p-tau > 61 ng/L OR iii. If p-tau181 concentration = 50 to 61 ng/L, ratio of p tau/Aβ42 > 0.11 OR c) CSF AD biomarker result on file within 12 months prior to Screening that is positive for Aβ42 (below the cut-off) AND p-tau (above the cut-off) OR a p tau181/Aβ42 ratio above the cut-off for that assay (amyloid AND p-tau positive) Note 1: Subjects without a prior CSF result must provide a new CSF sample at the Screening – Part 2 Visit. Note 2: Subjects with a prior positive CSF result (allowing study enrollment) must provide 2 to 3 aliquots of CSF from their prior diagnostic assessment; and the prior CSF result must be recorded.
• Be willing to undergo LP for CSF testing according to the Schedule of Assessments [Table 5].
• Has one of the following apolipoprotein E (APOE) genotypes – either APOE4/4 (homozygous) or APOE3/4 (heterozygous). Note: For subjects with a prior (historical) APOE genotype blood test, the test result must be provided and recorded in the CRF.
• Has an MMSE score at Screening of 22 to 30 inclusive (> 26 for MCI; 22 to 26 for Mild AD).
• Has a CDR Global Score at Screening of 0.5 (MCI, Mild AD) or 1 (Mild AD) and a CDR Memory Box Score of ≥ 0.5.
• Has a reliable caregiver or study partner who is willing and able to sign an informed consent form (ICF), to accompany the subject to study visits, and adhere to study requirements.