A Study of ML-007C-MA for the Treatment of Hallucinations and Delusions Associated with Alzheimer’s Disease Psychosis

Prior treatment

• Under the care of hospice, bed-bound, or receiving end-of-life palliative care
• Has current uncontrolled hypertension or any of the following on vital signs assessment at Screening or Visit 2 (Baseline): a. Systolic BP >155 mmHg or <90 mmHg b. Diastolic BP >90 mmHg c. Pulse rate <50 bpm d. Orthostatic hypotension, defined as a decrease of ≥ 30 mmHg in systolic BP or a decrease of ≥ 20 mmHg in diastolic BP within 1-2 minutes of standing compared to the previous supine/semi-recumbent blood pressure, OR development of symptoms Note: Repeat vital sign results for determination of eligibility will be allowed in limited circumstances only after approval from the medical monitor.
• Any known unintentional weight loss ≥7% of usual body weight over 6 months before Screening, or evidence of chronic dehydration
• Is at significant risk of suicidal behavior at the time of Screening based on investigator judgment or has a GCAS score of 3 or 4 based on investigator’s assessment of behavior within the 3 months prior to Screening or since-last-visit at Visit 2 (Baseline).
• Previously participated in any clinical study with ML-007 or ML-007C-MA.
• Received or may have received an investigational drug, biological product or device within 90 days before Baseline (or 6 months for investigational Alzheimer’s disease-modifying therapies).
• Requires skilled nursing care (procedures that can only be administered by a registered nurse or doctor, such as, but not limited to, intravenous administration of medication, procedures related to insertion or care of suprapubic catheters, and nasopharyngeal/tracheostomy aspiration).

Other illness

• Meets or has met DSM-5 criteria for alcohol or substance use disorder within the past 12 months (excluding caffeine and nicotine)
• Positive urine drug screen at Screening. Exceptions: Participants with a positive urine drug screen resulting from use of prescription or over-the-counter medications, products or foods may be allowed after a repeat urine drug screen and only with approval of the medical monitor. Participants who test positive for THC at Screening may be allowed after approval by the medical monitor if the participant agrees to abstain during the study, substance use disorder has been ruled out by the investigator, and the cannabis use is not considered a precipitating factor for the current psychotic episode.
• Psychotic symptoms that are primarily attributable to substance abuse or a medical, neurological or psychiatric condition other than Alzheimer’s disease (eg, delirium, schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder, mood disorder with psychotic features, Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia).
• Evidence of a CNS disorder other than Alzheimer’s disease that is the primary cause of, or a significant contributor to the participant’s dementia.
• MRI or CT finding consistent with a clinically significant CNS disease or abnormality other than Alzheimer’s disease that is significantly contributing to the dementia presentation according to the investigator or any of the following MRI/CT findings: a. Intracranial mass lesion (including but not limited to meningioma [>1 cm3 with evidence of peritumoral edema] or glioma) or subdural hematoma b. Arteriovenous malformation or cerebral aneurysm considered to be at risk for rupture/hemorrhage c. Evidence of >4 hemosiderin deposits (definite microhemorrhage or superficial siderosis) or evidence of hemorrhagic stroke d. Intracranial aneurysm >5 mm
• Has had an amyloid PET brain scan or CSF Alzheimer’s disease biomarker test in the past 6 months with results inconsistent with a diagnosis of AD according to the investigator and medical monitor.
• Evidence of a clinically significant and/or unstable medical condition that, in the opinion of the investigator or medical monitor, could substantially impair cognition, compromise participant safety, interfere with the participant’s ability to comply with study procedures or substantially impair the evaluation of efficacy or safety assessments. (See protocol for specific medical exclusions).

Lab values

• Clinically significant abnormal laboratory value(s) at Screening as determined by the investigator, or any of the following at Screening: a. Platelets ≤75,000/mm3. b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female c. Neutrophils, absolute ≤1000/mm3 d. AST >2 × ULN e. ALT >2 × ULN f. Total bilirubin >1.5 × ULN. Note: Participants with documented history of Gilbert’s Syndrome may be enrolled if indirect bilirubin is ≤3 × ULN provided direct bilirubin is ≤ULN g. eGFR <45 mL/min/1.73 m2 h. Hemoglobin (Hb) A l c >8.5% i. Positive result for hepatitis C antibody with detectable or indeterminate viral RNA levels, or positive result for HIV antibody, or hepatitis B surface antigen, or rapid plasma reagin (RPR) Note: Repeat clinical safety laboratory results for determination of eligibility will be allowed in limited circumstances only after approval from the medical monitor.
• Allergy or other intolerance to ML-007, or their excipients, including hereditary galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. Participants who have had tolerability issues from taking a muscarinic agent(s) previously should be discussed with the medical monitor.

Other

• Clinically significant abnormal ECG finding at Screening or Baseline in the opinion of the investigator, or any of the following ECG findings at Screening or Baseline based on the average of a triplicate set of ECGs: a. QTcF interval >450 msec in men or >470 ms in women, unless due to ventricular pacing b. QRS interval >120 msec (unless right bundle branch block) c. PR interval >210 msec Note: Repeat ECG results for determination of eligibility will be allowed in limited circumstances only after approval from the medical monitor.
• Has a positive pregnancy test at Screening or Baseline (only for WOCBP) or is lactating.
• Participant or care partner is an employee or a family member of an employee of MapLight Therapeutics, Inc. or the investigator/study center.
• Participant is judged by the investigator of Sponsor to be inappropriate for the study.
• Significant improvement of psychotic symptoms between Screening and Visit 2 (Baseline), defined as a decrease of ≥30% on the NPI-C H+D score.
• Current moderate or severe major depressive episode (within 3 months of Screening), according to DSM-5 criteria.

• Willing and able to provide written informed consent, or, if deemed lacking in the capacity to provide informed consent, the following requirements for consent must be met: a. The participant’s LAR must provide written informed consent. AND b. The participant will provide written (if capable) informed assent
• Has a CGI-S hallucinations and delusions domain-specific score ≥4 at Screening and Visit 2 (Baseline).
• Has an MMSE score of 6 to 26, inclusive, at Screening
• Has an MRI or CT scan of the brain (completed within the past 3 years) taken during or subsequent to the onset of cognitive impairment. If not available, a non-contrast brain MRI or non-contrast head CT must be completed during Screening
• Willing and able to discontinue all prohibited concomitant medications to meet protocol washout and medication stability requirements before randomization (Table 2). Investigators should not withdraw a participant’s prohibited medication for the purpose of enrolling them into the study unless discontinuation of the medication is deemed to be clinically appropriate (eg, symptom are not well-controlled or the participant cannot tolerate the current medication).
• WOCBP and men who are sexually active with WOCBP must be willing to adhere to contraception requirements and ova/sperm donation restrictions provided in Section 13.2. Women must meet 1 of the following criteria to be considered not of childbearing potential: a. Postmenopausal (spontaneous amenorrhea for at least 12 months before dosing without alternative medical explanation) or FSH levels ≥40 mIU/mL at screening. b. Surgically sterile (bilateral oophorectomy, hysterectomy, or bilateral salpingectomy at least 3 months before dosing).
• Age 55 to 90 years old, inclusive, at time of informed consent
• BMI ≥18.5 kg/m2 at Screening and Baseline
• Meets clinical criteria for Possible Alzheimer’s disease or Probable Alzheimer’s disease dementia per NIA AA guidelines [McKhann et al. 2011] and has a positive Core 1 biomarker consistent with AD pathology in accordance with the Alzheimer’s Association Workgroup [Jack et al. 2024] using either of the following: a. A plasma biomarker assessed at Screening using an appropriate assay that meets Health Authority expectations. OR b. Under limited circumstances and only after medical monitor approval, evidence from one of the following biomarker tests may be allowed in lieu of the Screening plasma biomarker: - Amyloid positron emission tomography (PET) performed with an appropriate tracer that meets Health Authority expectations, including but may not be limited to [18F]-florbetapir, [18F]-florbetaben, or [18F]-flutemetamol. -Aβ42/40 ratio in CSF, pTau181/Aβ42 ratio in CSF, or t-tau/Aβ42 ratio in CSF using an appropriate assay that meets Health Authority expectations. - Historical results from an appropriate plasma assay that meets Health Authority expectations.
• Presence of psychotic symptoms per International Psychogeriatric Association’s criteria [Cummings et al. 2020] for at least 2 months before Screening.
• Has a designated care partner who mets the following criteria: a. Care partner is in contact with the participant frequently enough to accurately report on the participant’s symptoms and on participant’s compliance with taking the study drug, in the investigator’s opinion. b. Care partner is fluent in the local language in which the study assessments will be administered. c. Care partner agrees to participate in study assessments accompany the participant to every study visit,and provide written consent to participate in the study.e
• Has sufficient verbal ability in the local language in which study assessments will be administered to satisfactorily comply with study procedures (corrective measures such as hearing aids and reading glasses are allowed, if necessary) and is willing and able to attend clinic visits. Participants who can attend clinic visits using a wheelchair or other ambulatory assistive device are permitted.
• Has resided at the same home, residential assisted living, or nursing home facility for a minimum of 6 weeks before Screening and is expected to remain in the living situation throughout the study.
• Has an NPI-C H+D score of ≥6 and meet at least 1 of the following criteria at Screening and Visit 2 (Baseline): a. Moderate to severe delusions, defined as NPI-C Delusions domain score of ≥2 on at least 2 of the 8 items. b. Moderate to severe hallucinations, defined as NPI-C Hallucinations domain score ≥2 on at least 2 of the 7 items.