A Study to Investigate Lithium Brain/Plasma Pharmacokinetics and Safety of an AL001 Oral Capsule Compared to a Marketed Immediate-release Lithium Carbonate Capsule in Subjects With Bipolar I Disorder

This study is researching the effects of a new type of crystallized lithium, AL001, on it's ability to reach the brain and have an effect in subjects with bipolar I disorder diagnosis. The investigators will be comparing this to a commonly used type of lithium, lithium carbonate. Investigators want to see if the AL001 can have the same or better effect when compared to lithium carbonate. Past research has shown a greater effect within the body with AL001 when compared to commonly used lithium.

This past research suggests that AL001 may be more effective, potentially allowing for lower doses and fewer side effects. If successful, this new form of lithium could offer a new and safe treatment option for psychiatric and neurological disorders.

This study involves two, 2-week long overnight stays at the main campus of Massachusetts General Hospital (MGH). During these stays, participants will receive lithium carbonate for one stay and the AL001 for the other. There are frequent blood draws and brain MRI scans during two periods of the study to look at how the AL001 is broken down in the body and to see how it reaches the brain. This study will compare AL001 to a study reference treatment of lithium carbonate. The majority of the blood draws and MRIs will occur over a 24 hour period during each 2-week long overnight stay at MGH.

Inclusion criteria

• Subjects with a primary psychiatric diagnosis of Bipolar I Disorder (BD1) between the age of ≥ 18 and ≤65 years who are in reasonably good physical health, as determined by the DSM-5-TR BD1 diagnostic criteria and the Investigator's review of medical and surgical history, physical examination (including neurological examination), 12-lead ECG, vital signs, and clinical laboratory tests.
• Assessment of subject's mental health status will be conducted to avoid enrolling subjects who are on the verge of a manic or depressive episode. Affective stability, defined by a Young Mania Rating Scale (YMRS) rating of ≤ 11 and a Hamilton Depression Rating Scale (HDRS-17) rating of < 16 at the Screening visit and on Day -1 (P1). Subsyndromal depression has not significantly worsened in the 4 weeks prior to randomization on Day -1 (P1) so as to avoid enrolling subjects who are on the verge of a full depressive episode. Assessment of subject's suicidal ideation and behavior (SI/B) using the Columbia-Suicide Severity Rating Scale (C-SSRS) will be conducted to avoid enrolling subjects with concerning results, defined as a history of a suicide attempt in the past two years, past year level 4 or higher suicidal ideation on the C-SSRS, or past month suicidal ideation of any kind. The "Lifetime/Recent" version will be used at screening and the "Since Last Visit" version will be used subsequently.
• Clinically acceptable, stably dosed mood stabilizing medication regimen, including treatment regimens with atypical antipsychotic drugs, for > 30 days prior to Screening visit, with no medication changes planned over the entire study period. See Section 6.3 for a list of medications not allowed for mood stabilization purposes. Exceptions to this may be made on a case-by-case basis following agreement by the Investigator and the Sponsor. Also, subjects with untreated BD1 can be enrolled if deemed adequately stable by the Investigator.
• Able to understand and follow instructions during the study as determined by the Investigator.
• Willing to follow study procedures.
• Willing and able to adhere to study restrictions and to be confined at the clinical research center per protocol requirements.
• Any gender, race, or ethnicity.
• Able to understand and provide written informed consent.
• Males (non-vasectomized and vasectomized) must agree to use barrier contraception during the study until after Treatment Period 2 in-clinic follow-up visit on Day 23 (P2).
• Females must meet one of the following criteria:

Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include:

• Abstinence from heterosexual intercourse from the Screening visit through to at least 30 days after the last dose of the study drug on Day 14 (P2).
• One of the following highly-effective contraceptive methods, used from at least 28 days prior to the Screening visit through to at least 30 days after the last dose of the study drug on Day 14 (P2).

• i. Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, or transdermal patch).
• ii. Intrauterine device (with or without hormones)
• iii. Male partner vasectomized at least 6 months prior to the Screening visit.
• One of the following double-barrier contraceptive methods, used from the Screening visit through to at least 30 days after the last dose of the second study drug on Day 14 (P2):

• i. Male condom used simultaneously with diaphragm plus spermicide.
• ii. Male condom used simultaneously with cervical cap plus spermicide.

Or

Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a postmenopausal state (i.e., at least 1 year without menses prior to the Screening visit).

• Able to communicate in English, including speaking, reading, and writing.
• Body mass index (BMI) within 18.0 to 32.0 kg/m2, inclusive, and body weight of at least 50 kg at the time of Screening. Exceptions to this can be made on a case-by-case basis following agreement by the Investigator and the Sponsor.
• ECG recording, after at least 5 minutes of rest in a supine position, without clinically significant abnormalities as determined by the Investigator.

Exclusion criteria

• Clinically significant abnormalities detected by medical history, physical examination, vital sign measurements, ECG findings (including prolonged QT interval), or clinical laboratory findings (as determined by the Investigator) that may affect the safety or successful participation of the subject. Specifically, evidence of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, dermatologic, muscular, or allergic disease or disorder (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) that may affect the safety or successful participation of the subject.
• Well defined diagnosis of drug sensitives with moderate to severe reactions (i.e., full body urticaria, reactions requiring hospitalization, etc.).
• Presence or history of any disorder other than the diagnosis under study that may prevent the successful completion of the study.
• Other severe acute, chronic, or historical medical or psychiatric condition or laboratory abnormality or social circumstance 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 subject inappropriate for entry into this study.
• History of seizure disorder and/or severe head trauma (other than a single childhood febrile seizure).
• Current uncontrolled gastrointestinal disease of moderate to severe nature such as chronic gastritis, peptic ulcers, inflammatory bowel disease, hemorrhagic gastritis, or duodenitis.
• History or presence of acute or chronic liver disease as determined by the Investigator.
• Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the study treatments.
• Current treatment with migraine medications such as triptans, TCAs, or other serotonergic dominant medications.
• Kidney disease (eGFR < 60 mL/minute/1.73 m2).
• Uncontrolled tachy/brady arrhythmias, atrial fibrillation, or coronary heart failure.
• Systemic related exclusions:

• Active cancer (except squamous cell and basal skin cancers) requiring chemo- or radiation therapy.
• Positive test results for HIV, HBV, or HCV (unless quantitative PCR negative for HCV) at Screening.
• Severe hepatic impairment (Child-Pugh Class C).
• Uncontrolled hypertension with a sustained blood pressure > 160/100 mmHg at Screening, or at check-in on Day -1 (P1).
• Fever (body temperature > 101.4°F [38.5°C]), acute upper respiratory, or any other infections at Screening, or at check-in on Day -1 (P1).
• Secondary psychiatric or neurological illnesses other than-and not associated with-bipolar I disorder (e.g., bipolar II disorder exclusively, schizophrenia or other psychotic syndromes, ADHD, anxiety, PTSD, Parkinson's disease and related movement disorders, seizure disorder, and myasthenia gravis) that require treatment with medications included in section 6.3.
• Treatment with haloperidol, first generation antipsychotics, monoamine oxidase inhibitors, or neuromuscular blocking agents. Subjects who have ever received chronic immunosuppressant treatment (excluding topical or oral corticosteroids taken 1 year and 5 years before Screening, respectively).
• Current and during lithium treatment hyponatremia, defined as serum sodium laboratory value outside the standard reference range.
• The regular and long-term use of any medication, supplement, or OTC medication not approved by the Sponsor that can potentially interact with components of AL001 (outlined in section 6.3), within 14 days prior to the Screening visit or at least 6 times the respective elimination half-life, whichever is longer, through the completion of the study on Day 42 (P2). EXCEPTIONS to this include but are not limited to:

• Hormonal contraceptives for females of childbearing potential.
• Acetaminophen (up to 1000 mg TID) at the discretion of the Investigator.
• Low-Dose aspirin for cardio protection.
• Non-medicated ophthalmic products (for lubrication and comfort).
• Clinically acceptable, stably dosed mood stabilizing medication regimen for > 30 days prior to Screening visit, with no medication changes planned over the entire study period. See Section 6.3 for list of medications not allowed for mood stabilization purposes. Exceptions to this may be made on a case-by-case basis following agreement by the Investigator and the Sponsor.
• PRN medications needed for treatment of AE's during the study at the joint discretion of the Investigator and the Sponsor, reviewed on a case-by-case basis.
• Subjects treated with electroconvulsive therapy within 6 months prior to Screening visit.
• Unwilling to refrain from consumption of poppy seeds or quinine (tonic water) 48 hours prior to check-in on Day -1 (P1) until discharge from Period 2 treatment on Day 15 (P2).
• Aspirin/nasal polyposis/asthma syndrome.
• Female who is breastfeeding.
• Female who is pregnant according to the pregnancy test at Screening or on Day -1 (P1); female planning to become pregnant during the study.
• History of adverse or hypersensitivity reaction to lithium, aspirin, salicylate, L-proline, or any investigational or reference article excipient.
• Substance Use Disorder (SUD) / Alcohol Use Disorder (AUD):

• History of substance use (barbiturate, amphetamine, benzodiazepine, cocaine, opiates and cannabis) within the last 12 months or a positive urine drug screen at Screening or Day -1 (P1).
• Admitted alcohol use disorder or history of alcohol use that may interfere with the subject's ability to comply with the protocol requirements or positive ethanol (alcohol) test at Screening or Day -1 (P1).
• More than moderate current alcohol consumption. Subjects will be advised to consume no more than 2 units of alcohol per day and completely abstain from 72 hours prior to any study visit (1 unit is equal to approximately 10 g of pure alcohol, [250 mL] of beer [5%], 1 small glass [100 mL] of wine [12%], or 35 mL of spirits [35%]).
• Demonstrating excess xanthine consumption (e.g., ingests more than 5 cups of coffee or equivalent per day). Also, subject is not willing to refrain from xanthine products for 48 hours prior to check-in on Day -1 (P1) until discharge from Period 2 treatment on Day 15 (P2). The subject is not willing to refrain from grapefruit, pomelo, Seville orange products or juice within 14 days prior to check-in on Day -1 (P1) until discharge from Period 2 treatment on Day 15 (P2). Exceptions may be made on a case-by-case basis following agreement by the Principal Investigator and the Sponsor.
• Participation in a clinical trial and receipt of an investigational medication within 30 days or 5 half-lives (if known), whichever is greater, prior to the first dose of the current study drug.
• Clinically unstable thyroid dysfunction (required due to potential lithium drug-disease interaction).
• Screening MRI-related exclusion criteria: intracranial mass, evidence of other anatomical findings that might affect safety or causes of cognitive/behavioral impairment as assessed by a qualified neurologist. Subjects must not have any implantable medical device (e.g., aneurysm clip, vagus nerve stimulator, cardiac pacemaker) or be reliant on a non-removable medical device (e.g., insulin pump) unless that device is certified as MRI compatible. Known intolerability to MRI neuroimaging procedures.
• Subjects with any past apparent suicide attempt or suicidal behavior, within the past two years or a past year level 4 or higher SI/B (C-SSRS) or past month SI/B (C-SSRS) of any kind.
• Suspected of having or at risk for Brugada Syndrome.
• Central nervous system-related exclusions: Any medical condition that in the Investigator's judgement could affect subject safety and scientific integrity of the study, e.g., untreated hypothyroidism (TSH >10 mIU/L) or vitamin B12 deficiency (vitamin B12 <300 pg/mL) which may contribute to cognitive impairment, delirium, dementia and other encephalopathies.