A Study to Investigate the Safety and Efficacy of TMP-301 Compared to Placebo in Adult Patients With Alcohol Use Disorder

Inclusion Criteria:

1. Provision of signed and dated Informed Consent Form (ICF) with a stated willingnessto comply with all study procedures and availability for the duration of the study.A breathalyzer test must be <0.05% at the time of ICF signing. Participants who havea blood alcohol content between 0.02 and 0.04% inclusive at Screening will beassessed for competency to consent using the UBACC scale. Participants must have apassing score of ≥ 15 during the Screening period to consent and be eligible forrandomization.

2. Adult female or male, 18 to 65 years of age inclusive, at the time of screening.

3. Alcohol use disorder, moderate or severe by DSM-5 diagnostic criteria (i.e., ≥4 outof 11 symptoms present using the SCID-5-CT diagnostic interview) at screening forthe previous 12 months.

4. At least 8 heavy drinking days over the previous 4 weeks (by Timeline Follow Back)at screening.

• Heavy Drinking Days (HDD): ≥4 drinks/day for females, ≥5 drinks/ day for males.

• A standard drink is defined as 12 ounces (350 ml) of 5% beer, 5 ounces (150 ml)of 12% wine, or 1.5 ounces (44 ml) of 80-proof (40%) distilled spirits.

5. Seeking treatment for AUD, with a desire to reduce or cease alcohol use atscreening.

6. Breathalyzer <0.05% at baseline..

7. BMI of ≥18.0 to ≤40.0 kg/m2 at screening.

8. No clinically significant findings (in the investigator's opinion) on physical exam,ECG, vital signs, or clinical laboratory tests at screening. The following criteriamust be met:

• Systolic Blood Pressure (SBP) 90-140 mmHg, and Diastolic Blood Pressure (DBP) 50-90 mmHg, inclusive (average of three readings) at screening and baseline.

• Alanine transaminase (ALT) and Aspartate transferase (AST) < 3x upper limit ofnormal, and total bilirubin < upper limit of normal (isolated elevated totalbilirubin is allowed if Gilbert's syndrome is the suspected etiology)..

• Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m2

• Negative urine drug screen for cocaine or stimulants at screening and baseline

9. Able to communicate well and understand written instructions.

10. Agree to practice highly effective birth control starting at screening andcontinuing for 30 days (females) or 90 days (males) after study treatment ends.

11. For females any of the following (no donation of eggs/ova is allowed):

• Abstinence from heterosexual intercourse.
• Postmenopausal: absence of menses ≥ 12 months (without an alternativemedical condition) and Follicle-Stimulating Hormone (FSH) ≥ 40 mIU/mL atscreening.
• Surgically sterile: bilateral oophorectomy, salpingectomy, tubal ligation,or hysterectomy ≥180 days prior to screening.
• Contraceptive implant or intrauterine device.

2. For males any of the following (no donation of sperm is allowed):

• Abstinence from heterosexual intercourse.
• Male condom with spermicide or male condom with vaginal spermicide (gel,foam, or suppository).
• Surgically sterile: post vasectomy or bilateral orchiectomy

Exclusion Criteria:

1. History of hypersensitivity to TMP-301 or other mGluR5 antagonists.

2. Evidence of suicidal risk as assessed by the Columbia-Suicide Severity Rating Scaleat screening or baseline as follows:

• Suicidal Ideation Section: "Yes" on item 4 or 5 if within 6 months of screeningor between screening and baseline.

• Suicidal Behavior Section: "Yes" on any item (except non-suicidalself-injurious behavior) if within 2 years of screening or between screeningand baseline.

3. Significant risk of acute alcohol withdrawal syndrome (either of the following):

• Any history of Delirium Tremens or seizures from alcohol withdrawal.

• Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score >7 atscreening or baseline.

4. Any history of seizures, except febrile seizures as a child.

5. Other (non-alcohol) substance use disorders (by DSM-5) as follows:

• Any cocaine or stimulant use disorder

• Moderate or severe use disorder of all other substances (mild allowed).

6. Use of the following within the last 90 days or ≥ 5 times the half-life prior torandomization:

• Pharmacotherapy for any substance use disorder (e.g.: disulfiram, acamprosate,modafinil, topiramate, or baclofen).

• Use of prescribed methylphenidate or other stimulant.

• Use of any Glucagon-like peptide 1 (GLP-1) agonist for any indication.

7. Past or current history of any mental, behavioral, or neurodevelopmental disorder asdefined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or significant risk of developing a psychosis (assessed by PRIME screen) ora personal history of psychotic symptoms (hallucinations or delusions) with orwithout a formal psychiatric diagnosis.

• Individuals with AUD or mild other substance use disorder (except for cocaineor stimulants) may participate.

• Individuals who meet criteria for a current major depressive episode areexcluded.

8. Requires treatment with any psychoactive medications, including any anti-seizuremedications (except medications used for short-term treatment of insomnia).

• Antidepressant medications are allowed if the patients have been on an adequateand stable dose for at least 3 months prior to study treatment dosing with theexception of CYP1A2 substrates or CYP3A4 inhibitors as detailed in Exclusion

20. Having had initiation of, or change in intensity of, psychotherapy or other non-drugtherapies within 6 weeks prior to enrollment or unwillingness to maintain currentpsychotherapeutic and non-drug therapy levels from screening through the or at anytime during the acute treatment phase of the study.

21. Use of other investigational drugs or devices at the time of screening, or within 5half-lives of randomization, or within 30 days, whichever is longer or has been partof any clinical study within 30 days of randomization.

22. Pregnant or nursing (lactating) females.

23. Recent history or active clinically significant manifestations of metabolic,hepatic, renal (including porphyria), hematological, pulmonary, cardiovascular,gastrointestinal, musculoskeletal, dermatological, urogenital, neurological,ophthalmic, or ears, nose, and throat (ENT) disorders, or any other acute or chroniccondition or medication use that, in the Investigator's opinion, would limit thesubject's ability to complete or participate in this clinical study.

24. Concomitant use of agents known to prolong the QT interval unless these can bepermanently discontinued for the duration of study.

25. History or current diagnosis of ECG abnormalities at screening indicatingsignificant risk of safety for subjects participating in the study such as:

• Concomitant clinically significant cardiac arrhythmias, e.g., sustainedventricular tachycardia, and clinically significant second- or third-degreeAtrioventricular (AV) block without a pacemaker.

• History of familial long QT syndrome or known family history of Torsades dePointes.

• QTcF > 450 msec (males); QTcF > 460 msec (females).

• Note: sinus tachycardia, left axis deviation, and nonspecific ST or T wavechanges are not exclusionary.

15. Patients with history of chronic hypertension, unless well controlled by takingantihypertensive treatment at a stable dose for ≥3 months

16. History or presence of malignancy of any organ system (other than localized basalcell carcinoma of the skin or in-situ cervical cancer), treated or untreated, withinthe past 5 years, regardless of whether there was evidence of local recurrence ormetastases.

17. Detectable hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab),or human immunodeficiency virus (HIV) antibody at screening.

• Participants in remission for HCV or HIV, as demonstrated by a sustainedvirological response (undetectable viral load) may be enrolled in the study.

18. Any surgical or medical condition which might significantly alter the absorption,distribution, metabolism, or excretion of drugs, or which may jeopardize the subjectin case of participation in the study.

19. Need/plan to take or substrates of cytochrome P450 (CYP)1A2 or inhibitors of CYP3A4. (Note: CYP1A2 inhibitors are permitted, as they are not expected to increase TMP-301exposures above what was shown to be safe and generally well-tolerated in studyTMP-301- HNV-101.).

• CYP1A2 Substrates: (Exposure could increase when taken with TMP-301):

• alosetron, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine, pimozide,agomelatine, tacrine, clozapine, pirfenidone, theophylline, tacrine,ropivacaine

• CYP3A4 Inhibitors: Could increase TMP-301 exposure at steady- state

• grapefruit juice, Seville orange-containing food (e.g. bitter orange marmalade)or drink (e.g. bitter orange liqueurs including Curaçao and Grand Marnier)

• ketoconazole, diltiazem, verapamil, clarithromycin, itraconazole, erythromycin,fluconazole, ceritinib, cobicistat, idelalisib, indinavir. ritonavir,nefazodone, lopinavir, aprepitant, ciprofloxacin, conivaptan, crizotinib,dronedarone, imatinib

20. Patient cannot:

• Anticipate any significant problems with transportation arrangements oravailable time to travel to the study site and have any plans to move withinthe next months to a location which would make continued participation in thestudy' impractical.

• Be involved in any unresolved legal problems that could jeopardize continuationor completion of the study.

• Have any pending charges for violent crime (not including Driving Under theInfluence (DUI) offenses).

• Have any court case with a pending decision that could prohibit participationor compliance in the study.

21. Living situation precludes an ability to adhere to study visits in the opinion ofthe investigator.

22. Has been previously treated in this study or randomized or treated in any otherstudy employing TMP-301 (i.e., subject may not have received study drug and thenreenrolled).

23. Any condition not identified in the protocol that in the opinion of the investigatorwould confound the evaluation and interpretation of the study data or may put thesubject at risk.