Introduction

Last week’s article covered preclinical research, the second stage in the drug development pipeline, and current AI applications to help revolutionize the process. Companies such as Insilico Medicine, Escientia, and Atomwise are paving the way with AI integration and have been signing contracts with big companies. After preclinical research, the drug is deemed ready to be tested on humans and heads into clinical trials. Clinical trials consist of three phases each with a different individual purpose, but as a whole, the goal is to ensure the drug is safe and effective enough to be released to the public. Phase 1 consists of approximately 50 or fewer participants and during this phase, scientists are searching for a safe dosage of the new treatment, method of intake, and the side effects on the human body. Phase II consists of less than 100 participants and scientists are studying how the treatment affects the body and how productive it is against the disease. Phase III requires many participants, usually 100+. This trial compares the new treatment to the current one to find the better treatment to release to the public.

Information about Phase I

According to the FDA, the study consists of 20 to 100 healthy volunteers or individuals with the disease or condition of interest. The average length of the study can take several months and scientists are ultimately trying to find the right dosage and the full effects of the drug. The NIH defines it as the first step in testing a new treatment in humans. Phase I trials are also referred to as pharmacokinetics trials (understanding how the body handles/processes the drug). The actual process starts with the approval of the Investigational New Drug Application (IND) by the FDA approval team. The IND consists of information for all the previous stages: preclinical

research and drug discovery and development. manufacturing information, information about the investigator, and more. While reviewing the IND,  the FDA review team will confirm with the data given that the drug is safe enough to start performing tests on humans. Throughout all the phases, the FDA will review if the clinical sites are maintaining Good Clinical Practice (GCP). Although the drug has passed through IND and is hypothetically safe to be tested on humans, there are cases where the drugs still have effects outside of those listed during the previous stages. During the IND, the lead scientists must also decide what they want to accomplish during these trials. Scientists then look for volunteers who are willing to test the drug. The majority of the time, the volunteers consist of healthy people but in some cases, they test it on individuals who have the disease. While picking volunteers for these groups there is an inclusion and exclusion criteria that must be met. The inclusion criteria, in general, consider age, gene mutations, or diagnosis of the disease, and voluntarily signed consent. General exclusion criteria factors include age, previous conditions and medications, health status, allergies, etc.

There are more specific criteria for different cases as each clinical trial is testing a different compound, ranging from treating bacteria in the water to a global pandemic. Once groups are formed with the volunteers experiments begin with different groups testing different dosages and intake methods. At the end of Phase I, scientists have found the highest dose of the new treatment that can be given safely without severe side effects, discovered all possible side effects, and determined the drug is safe to be distributed and used amongst the general public. To provide an example of both extremes for this criteria, we will be using the “Clinical Exploration Study of YOLT-203 in the Treatment of Type 1 Primary Hyperoxaluria (PH1)” and “Evaluation of Alkaline Water Effect on Salivary Streptococcus mutans in Children.” The inclusion criteria for the study of YOLT-203 is very defined as there are five requirements: the volunteer must be older than two years old, have the AGXT gene mutation and be diagnosed with primary hyperoxaluria, have at least 0.7 mmol of urinary oxalate excretion at least two times a day, if treated with vitamin B6; the patient must continue for 90 days before enrollment and maintain it throughout the study, and sign the form on consent voluntarily. On the other hand, the study of alkaline water’s effect has one inclusion criterion: children aged 10-12 years. The same is true for the exclusion criteria as the YOLT study has 13 statements while the water study has three. During Phase I, scientists are not testing the efficacy of the drug, just the safety of it before the sample size grows in Phase II. Some reasons for failure during this stage are inadequate study design, harmful side effects, etc. The drug is cleared to move onto Phase II once scientists have determined it to be safe from its Phase I results. According to the FDA, about 70% of drugs move on to the next phase.

Repurposing Drugs and Phase I Trials

Repurposed drugs must also go through Phase I trials though it may be shorter due to the existing information in the database due to previous processes. The outline of the process is the same for every drug, repurposed or not, however instead of an IND, a repurposed drug requires a sIND to be submitted to the FDA. As mentioned in last week’s article, the length of this stage is determined by how much existing information can determine the safety of the drug. In emergency cases such as pandemics, the FDA can practically skip this phase. For example, during COVID-19, multiple anti-inflammatory drugs or inhaled corticosteroids were repurposed for a temporary cure. These compounds went through a shortened clinical trial due to their medical history showing their safety and effectiveness.

AI and Phase I Integrations

AI has been groundbreaking in the biotechnology industry helping scientists quicken processes and increase accuracy. When discussing the use of AI in clinical trials, the community is divided as the tests in Phase I, II, and III are conducted on humans rather than cell lines or small animals. Earlier this year the idea of using AI in Phase I Environmental Site Assessments (ESAs) was discussed with some professionals in the field. The professionals had concerns about potential AI errors while performing critical tasks such as report writing or data filtering. AI has been implemented in patient recruitment and selection, data collection and management, and analysis. Machine learning is used to filter participants who meet the inclusion criteria and filter out the participants with the exclusion criteria. Once the final group is made, scientists reach out to the participants. While Phase I trials are in progress, “Cutting-edge pharma companies are also using AI to detect patterns within the vast amounts of data generated by clinical trials. '' (Starmind 2023). Some of these patterns are impossible to detect through traditional methods and with AI helping both identify and filter the data in real-time, it quickens the process and ultimately makes the process cheaper. While this is the current state of AI in clinical trials, scientists are looking for ways to become more AI-powered to maximize efficiency and accuracy.

Current News for Phase I

Multiple drugs are heading into Phase I clinical trials at the time of this article. Some names to list are CT-996, AOC 1020, and SSYHD001. CT-996 is an oral GLP-1 receptor agonist to treat type 2 diabetes (T2D) and obesity. The goal of the Phase I trial was to assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of the compound in overweight or obese adults. The third part of the trial is planned for the fourth quarter of this year and aims to enroll 30 participants with obesity and T2D. In the first two sections of Phase I, the compound is likely to progress into Phase II clinical trials. AOC 1020 or  Delpacibart Braxlosiran (del-brax), “... consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DUX4 mRNA. Del-brax is currently in Phase 1/2 development as part of the FORTITUDE™ trial in adults with FSHD. “ (Avidity Biosciences). The compound is going through a three-part Phase 1/2 trial. Scientists are trying to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of AOC 1020 in adult participants with facioscapulohumeral muscular dystrophy. SYHD001 is an ADC drug that has recently entered Phase I trials. SYHD001 was developed by Sanyou Bio and Huadong Medicine. This drug targets cancer treatment by using an antibody that specifically binds to cancer cells, coupled with a cytotoxic agent, to provide targeted therapy while minimizing harm to healthy cells.

Adapted from Altexsoft: An overview of Data Science Processes and Components: Integrating Data Mining, Machine Learning, and Artificial Intelligence for Decision Making

As many companies and teams start the drug pipeline in hopes of making the next big discovery, biotechnology has struggled with uncovering a potential cure for some illnesses such as Alzheimer’s Disease, cancer, and osteoarthritis. Although currently there is no cure, scientists with the help of AI try to discover potential compounds to help combat these illnesses. Scientists have found potential treatments besides traditional cancer therapies. Alzheimer’s currently has been repurposed and new drugs entering the drug development pipeline in hopes of one day becoming the cure.

Phase I of clinical trials is a crucial step for the progress of the drug throughout its process of drug development. As scientists use the previous information and begin testing on small groups of humans, we discover the side effects, reactions to intake methods, and overall safety of the drug before advancing it to the next phase for more participants. Multiple drugs are entering Phase I with a high potential to advance to Phase II so they can be tested for efficacy of the drug on the targeted disease. The healthcare industry continually strived to find cures for diseases such as cancer, Alzheimer’s, etc in hopes of one day leading a drug through Phase I trials before it became FDA-certified and released to the public as an official cure.

Written and Constructed by Joshua Minami, Christopher Korban, Christian Chung

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