ROAD TO THE CURE UPDATE OCTOBER 2016

ICBI SMART Molecules (SMs) technology is poised to translate our most promising scientific breakthroughs into meaningful disease-altering treatments capable of tackling the most complex and vexing medical challenges related to the diseases of the central nervous system (CNS). In spite of the rapid pace of our initial scientific advances, the recent budgetary constraints have slowed down the progress of manufacturing and the market penetration of our potential diagnostic and disease-altering drugs for Parkinson’s and Alzheimer’s diseases. The process of drug development is complex filled with scientific, technical, financial, and regulatory challenges. The average cost (capitalized) to successfully develop a drug from start to finish (FDA Approval) in the US was estimated to be $2.6 billion in 2014 (reference: Tuffs Center for the Drug Development, November, 2014). If one takes into account the time and resources wasted on failed drugs during the same time by the same group of scientists who successfully launched their drug in the market, the cost exceeds $4 billion. The steps involved in developing a drug and getting it through FDA approval are listed below:

1. Basic Research: Disease Target Identification The journey begins with basic research to understand the process behind the disease, often at a cellular or molecular level. It is through better understanding of disease processes and pathways that targets for new treatments are identified. The target might be a gene or protein instrumental to the disease process that a new treatment could interfere with, for example, by blocking an essential receptor or protein such as alpha-synuclein or LRRK2. Equally important is to understand the location of the target receptor or protein. If the target protein is located in the brain, interfering with its function may be almost impossible as most drugs capable of modifying brain diseases do not reach the brain. This is the reason why, so far, there are no curative treatments for Alzheimer’s (AD) and Parkinson’s (PD) diseases.

2. Drug Discovery: FINDING A PROMISING MOLECULE (A “LEAD DRUG CANDIDATE”) THAT COULD BECOME A NEW MEDICINE After understanding the underlying disease pathway and identifying potential targets, we then focus on developing “Targeted Therapy” to narrow the field of potential drugs to one lead drug candidate – a promising molecule that could influence the target and, potentially, become a medicine. Targeted therapy for brain disorders, so far, has been meaningless because most drugs capable of changing the course of AD or PD have failed to reach the brain in concentrations adequate for therapeutic efficacy. Targeted therapy is superior to random screening of tens of thousands of known organic compounds to find the one that may interfere with the function of the pathogen (target protein). Most big pharma have been pursuing the latter approach, although they have turned their attention to targeted therapy during the last 5–10 years. Below are time and cost estimates to identify a lead drug candidate by big pharma; Average Time (ID’ing lead drug candidate) 4–5 years Average Cost $436M ICBI Cost: 5 lead drug candidates in 6 years $ 3.5M 3. Manufacturing under GMP Regulations After identification, the lead drug candidate has to be produced on a big scale for the preclinical studies. Protocols are developed to scale-up the synthesis and purification of the lead drug candidate following FDA’s guidelines for good manufacturing practices (GMP). Time required for manufacturing (Pharma) 6.5 years Total Average Cost through Manufacturing $483M 4. Pre-Clinical Testing Once the drug has been generated in large quantities, the experiments are conducted in test tubes, tissues specimens, and animals to gather information on: Specificity (selectivity) of the lead drug candidate Binding affinity with the target (pathogen) Whether or not the lead candidate can cross the blood-brain barrier to reach the brain How  the drug is absorbed, distributed, metabolized and secreted Best dose to treat the animals Best route of administration (oral, i.v., etc.) Toxicity of drug Therapeutic index of the drug in animals and how does it compare with the existing drugs if any Mechanism of action Average Time for Pre-Clinical Study 7.5 years Average Pharma Cost up to this point     $533M 5. File Investigational New Drug (IND) Application with the FDA

Before any clinical trial can begin, all companies including ICBI must file an investigational new drug (IND) application with the US FDA. The application includes the results of the preclinical work, the candidate drug’s molecular structure, and details on how the investigational medicine is thought to work in the body, a listing of any potential side effects as indicated by the preclinical studies, and manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where, and by whom the studies will be conducted. All INDs are submitted to the FDA and processed in 30 days if there is no additional feedback or restriction given from the agency. In addition to the IND application, all clinical trials must be reviewed, approved, and monitored by the institutional review board (IRB) or ethics committee (EC) at the institutions where the trials will take place. The IRB/EC has the responsibility to protect research participants, and has the right to disapprove the study protocol or require changes before approving the planned clinical trials and allowing any participants to enroll. This process includes the development of appropriate informed consent documents, which will be required from all clinical trial participants. The clinical trial research team, including the nurses and clinical investigators, continually monitor trial participants and collect data that will be carefully reviewed and tracked by the company supporting the research. Whenever a volunteer in the trial experiences a serious adverse drug reaction, the company sponsoring the research must provide a report of the event to the FDA and the IRB. The FDA or the company can stop the trial at any time if problems arise. In some cases, a study may be stopped because the candidate drug is performing so well that it would be unethical to withhold it from the patients in the trail who are not receiving the candidate drug and the company may accelerate development. Companies also ensure that the trials are conducted correctly and with integrity, and that clinical trial results are publicly disclosed at the appropriate time.

Average Time for IND Application 8 year Average Pharma Cost up to this point $550M Note of Importance: The data/discussion published above is for the big pharma where scientists have to go through too many management layers and have numerous meetings over several months to get approval to move onto the next step. In a small company such as ICBI decision-making time is considerably shorter which saves lots  of time and money. If ICBI can raise the needed funds today, we will have IND approval in less than 18 months for our diagnostic product and in 24–27 months for the therapeutic product. Next month we will cover the Clinical Trial Process beginning with Phase 1. “6. Phase 1 Clinical Trial:...”