Benzinga | Sep 30, 2021 09:26AM EDT

Adial Pharmaceuticals Announces Greater Than 50% Of Patients Expected To Complete ONWARD Phase 3 Trial Of AD04 For Treatment Of Alcohol Use Disorder Have Completed Full 24-Week Treatment Period; Says Trial Completion Anticipated Q1 2022

Adial Pharmaceuticals, Inc. (NASDAQ:ADIL, ADILW))))) ("Adial" or the "Company"), a clinical-stage biopharmaceutical company focused on developing therapies for the treatment and prevention of addiction and related disorders, announces that greater than 50% of patients expected to complete the ONWARD(tm) Phase 3 trial evaluating AD04 as a therapeutic agent for the treatment of Alcohol Use Disorder (AUD) in persons with certain target genotypes related to the serotonin transporter and receptor genes have completed the full, 24-week, treatment period.



ONWARD is a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, pivotal Phase 3 clinical trial to evaluate the efficacy, safety and tolerability of AD04 in patients with AUD and selected polymorphisms in the serotonin transporter and receptor genes.

The intended primary endpoint for analysis of efficacy is the change from baseline in the monthly number of heavy drinking days (HDDs) during the last 8 weeks (weeks 16-24) of the 24-week treatment period, where heavy drinking is defined as the consumption of 5 or more drinks/day for men and 4 or more drinks/day for women.

Drinking levels are self-reported using the timeline follow-back (TLFB) method. The TLFB method is a daily calendar for alcohol consumption and employs memory aids to prompt recall. The TLFB has been used extensively in pharmacotherapy trials for AUD and other substance abuse disorders. Baseline is the 4-week period prior to the screening visit. For each subsequent clinic visit, alcohol consumption is recorded as the number of drinks per day.

Patients have been randomized based on a one-to-one (placebo-to-AD04) ratio, so that approximately 50% of enrolled patients will be in the placebo group and 50% in the AD04 group. Both placebo and active clinical trial material were manufactured in two batches of equal amounts and are light-yellow, oval tablets for oral administration with each tablet weighing approximately 80 mg. Placebo and active tablets are indistinguishable from each other. The active tablets have 0.33 mg of AD04's active ingredient, Ondansetron, in place of a similar volume of excipient (i.e., starch) in the placebo. They have been packaged in blister-packs of 18 tablets, which allows for 7-days of dosing plus 2-days extra to allow for flexibility in appointment scheduling. During packaging, the clinical trial material was coded so that neither the Company, the doctors, nor the patients can determine whether a package contains placebo or active tablets (i.e., double-blinding).

Adverse events are monitored by the Company's Chief Medical Officer; Crown CRO (the contract research organization running ONWARD), and the trial's Data Monitoring Committee. Clinical trial material can be unblinded in the event one of these safety reviewers determines unblinding is necessary to ensure the safety of any particular trial patient on a case-by case basis. To date, no situations have arisen where it was determined unblinding would be warranted, and therefore, no trial patients have had their dosing unblinded to determine if they were taking placebo or active tablets.

ONWARD is being conducted in 25 clinical sites in six countries in Scandinavia and Central and Eastern Europe: Sweden, Finland, Poland, Latvia, Bulgaria and Croatia. The Coordinating Principal Investigator is Professor Hannu E.R. Alho, Emeritus Professor of Addiction Medicine at the University of Helsinki.

Patients are genetically screened prior to enrollment in the ONWARD trial so that only genetically positive patients are enrolled. A total of 1216 people were genetically screened with 403 showing genetic positivity for the AD04 target genotypes (i.e., 33%).

Behavioral therapy (i.e., counseling) is administered to all trial patients so that the placebo or drug will be an adjunct therapy to behavioral therapy. This was required by the regulatory authorities because behavioral therapy is considered the standard of care. A successful approval would therefore likely result in a label stating that AD04 should be administered in combination with behavioral therapy. This would be expected to be similar to psychiatric drugs, such as anti-depressants. The Company agreed that use of a standardized counseling protocol in the trial would be important and the Company's Chief Medical Officer provided training for all clinical sites to administer the behavioral therapy. All clinical sites have been certified for using this protocol.

In order to qualify for enrollment in ONWARD, in addition to having the genotype, patients had to meet the following additional requirements (i.e., inclusion criteria), among others:

* Male or female over the age of 18 years old;

* Qualify as having AUD under the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [Criteria can be found here];

* Have experienced 6 or more heavy drinking days in the previous 4 weeks;

* Have not been abstinent for more than 14 days in the previous 4 weeks; and

* Expression of a desire to reduce or stop alcohol consumption (i.e., are treatment seeking).

Patients meeting the above inclusion criteria were rejected for enrollment in ONWARD based on the following key criteria (i.e., exclusion criteria), among others:

* Withdrawal symptoms requiring medical intervention at either the screening of baseline visit;

* Diagnosis of any of the following concomitant psychiatric disorders: non-treated, unstable schizophrenia, bipolar disorder, other psychotic disorder during the lifetime of the patient;

* Recent (within last 12 months) diagnosis of a major depressive disorder, post-traumatic stress disorder, panic disorder or eating disorder;

* Current or recent treatment with antipsychotics or antidepressants medications, which can have an effect on serotonin receptor or transporter actions, or opiate antagonists (e.g., naltrexone, Vivitrol(r), Selincro(r)), glutamate antagonists (e.g., acamprosate), anticonvulsants (e.g., topiramate), serotonin reuptake inhibitors (e.g., fluoxetine), serotonin antagonists (e.g., buspirone), other antidepressants (e.g., tricyclic antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g., haloperidol), and disulfiram (Antabuse(r));

* Clinically significant untreated and unstable illness, for example, hepatic or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, infectious, neoplastic, or metabolic disturbance;

* Clinically abnormal ECG or significantly abnormal vital signs;

* Clinically significant hepatic disease; and

* Positive pregnancy test (females only).

The ONWARD Phase 3 clinical trial commenced with the opening of a site in Finland in February 2020, and 302 patients have been enrolled. Enrollment was closed on August 30, 2021 immediately after the 302nd patient was randomized for placebo or active treatment and completed the first treatment visit. Since each trial patient undergoes approximately 24 weeks of treatment, the last patient should complete dosing in February 2022. Each patient receives a follow-up call approximately 4 weeks after completing of the full treatment cycle to collect additional safety and tolerability information.

As of the week ending September 24th, 120 patients had successfully completed their participation in the trial, 60 patients had discontinued participation in the trial prior to completion, and 122 patients are still being dosed in the trial. As stated above, the last of these patients is expected to complete dosing in February 2022. Patient retention rates continue to exceed projections.

As each ONWARD trial site discharges its last patient, the Company will work expeditiously to resolve any outstanding data queries at each site so that it can be closed upon the last follow-up call 4 weeks later. Once the last patient completes his or her final dose, which is expected in February 2022, the Company anticipates closing the last site within 6 weeks. Following closure of the last site, the database containing all the information will be "locked," meaning it can no longer be changed; the trial will be unblinded so that it will be known for each patient whether the patient received placebo or active tablets; and data analysis will commence by the Company's outside statisticians. Results will be released expeditiously, likely within a few weeks of the last site closure.

Dr. Bankole Johnson, Adial's Chief Medical Officer, commented, "Having overseen more than 20 AUD and other addiction related clinical trials during the course of my career, I am invigorated by the rapid progress of our ONWARD Phase 3 trial. Just last month we announced we had achieved full enrollment and now we have taken 50% of patients expected to complete the trial through their full trial dosing range of 24-weeks. We remain encouraged by the trial retention rate, which has exceeded our expectations. Importantly, we remain on target to complete all patient dosing in the first quarter of 2022. I would like to thank our team, our CRO and the clinical investigators for their hard work in efficiently advancing this important trial. I look forward with anticipation to trial data with great expectations."

William Stilley, Adial's Chief Executive Officer, stated, "Following years of research and clinical trials, as we move closer to completion of our ONWARD Phase 3 trial of AD04 for the treatment of AUD, we are highly confident that our genetically targeted approach may provide significant promise for those suffering from this devastating disease, which contributes to the annual deaths of more than 3 million people and costs the U.S. economy approximately $250 billion annually. This trial is especially timely given the dramatic increase in the number of persons suffering with this disorder, exacerbated in significant part due to the ongoing effects of the pandemic. In ONWARD, we anticipate demonstrating a favorable safety profile with AD04 with a low occurrence of any side effects and we are optimistic we will meet our primary endpoint. With the ease of oral administration by patients, we believe those suffering from AUD will be more likely to complete their treatment regimen in the real world as compared with current therapies, which are all known to have side effects that we believe, on balance, are more significant than those expected to be demonstrated by AD04. I extend a heartfelt thank you to our entire trial team and our patients that are bringing us closer to a new day in the treatment of alcohol use disorder."