CytoMed Therapeutics Limited (GDTC) Risk Analysis

Our product candidates may have undesirable side effects that could result in us or HSA and/or other relevant regulatory authorities requiring us to interrupt, delay or discontinue clinical trials and could result in a more restrictive label than anticipated or the delay or denial of regulatory approvals. Our clinical trials may demonstrate a high and unacceptable level of severity and prevalence of side effects or unexpected characteristics. As of the date of this annual report, our evaluation of our product candidates is limited to pre-clinical studies. As such, there can be no guarantee that any toxicity, and/or other adverse events, will not occur in human subjects during clinical trials. While scientific data suggests that gamma delta T cell-based therapies may be better-tolerated as compared to alpha beta T cell-based therapies due to biologic differences between these cell types, there can be no assurance that patients will not experience cytokine release syndrome, neurotoxicity, GvHD or other serious adverse events. Severe adverse events associated with our product candidates, CTM-N2D, iPSC-gdNKT and CTM-GDT may also develop, since targeting NKG2DLs is not yet a well-characterized modality. NKG2D targets multiple ligands, and the landscape of ligand expression is currently not fully understood. For example, there are risks that NKG2DLs may be expressed on either known or an as-yet-underappreciated population of healthy cells. Therefore, such cells may also be targeted by CTM-N2D, iPSC-gdNKT and CTM-GDT and lead to adverse events of unknown frequency and severity. Such adverse events may cause delays in completion of our clinical programs. If unacceptable side effects arise in the development of our product candidates such that there is no longer a positive benefit risk, our clinical trials may be suspended or terminated, or the regulatory authorities may deny approval of our product candidates for any or all targeted clinical trial indications. Treatment-related side effects could also affect patient enrollment or the successful completion clinical trial by enrolled patients or result in potential product liability claims. In addition, these side effects may not be adequately identified or managed by the relevant medical personnel, and inadequate training in identifying or managing the potential side effects of our product candidates could result in patient injury or death.

Identifying and qualifying suitable patients to participate in our clinical trials is vital to our development of our product candidates. We need the enrollment of a sufficient number of patients suitable to undergo such clinical trials, including patients who are suffering from the disease that the product candidate is intended to treat and who meet other eligibility criteria for any clinical trial of a new product candidate. The rate of patient enrollment, which is a pivotal factor in determining the timing of clinical trials, is dependent on many factors beyond our control, including: - our ability to locate and set up clinical trial sites;   - the size and nature of the patient population;   - the design and eligibility criteria of the clinical trial;   - the physical proximity of patients to clinical sites;   - the patient referral practices and protocols of medical practitioners;   - changing medical practice patterns or guidelines related to the clinical trial indications we are investigating;   - competing clinical trials or approved therapies which are seen as an attractive alternative to patients and their medical practitioners;   - perceived risks and benefits of the product candidate under study, including as a result of adverse effects observed in similar or competing therapies;   - our ability to obtain and maintain consent to our clinical trials from patients which may be affected as a result of various reasons, including but not limited to, patients' unwillingness to participate in our clinical trials due to the pandemics, epidemics, or outbreaks of infectious diseases, including future outbreaks of COVID-19 variants, Respiratory Syncytial Virus ("RSV"), or the flu;   - the risk that enrolled patients will drop out of our clinical trial or die before completion of the clinical trial;   - our patients failing to complete a clinical trial or returning for post-treatment follow-up; and   - our ability to manufacture or obtain the requisite materials for a patient and clinical trial. In addition, we will compete with many other ongoing clinical trials in sourcing for and recruiting patients for our expected clinical trials. Our clinical trials may also compete with other clinical trials for product candidates that are in a similar cellular immunotherapy area as our product candidates. This competition could reduce the number and profiles of available patients, as some patients may opt to enroll in a clinical trial conducted by one of our competitors instead of ours. Since the number of qualified clinical investigators is limited, we may conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of patients who are available for our clinical trials at such clinical trial site. If we are unable to enroll a sufficient number of patients in our clinical trials in a timely manner, completion of our clinical trials may be delayed or may not be achieved, which would prevent us from commercializing our product candidates which in turn, could also cause us to fail to meet milestone deadlines required to maintain intellectual property licenses upon which we rely.

Pre-clinical and clinical trials are costly, time consuming and subject to substantial uncertainty in respect of the outcome. Due to scientific feasibility, safety, efficacy, changing standards of medical care and other variables, our product candidates may fail at any time during the trial. The results from pre-clinical testing or early clinical trials of a product candidate may not accurately indicate or ensure the outcome of later phases of clinical trials of our product candidates. HSA and/or other relevant regulatory authorities may suspend or terminate our clinical trials of any of our product candidate(s) at any time for various reasons, including, but not limited to, a perception that humans participating in such trials are exposed to unacceptable health risks or adverse side effects, or other adverse initial experiences or clinical trial findings. HSA and/or other relevant regulatory authorities may also require us to conduct additional pre-clinical studies or clinical trials due to negative or inconclusive results, or may fail to approve the raw materials, manufacturing processes or facilities of third-party manufacturers upon which we rely, and/or change their approval policies or regulations or their prior guidance to us during clinical development in a manner rendering our clinical data insufficient or unsuitable for approval. In addition, data obtained from our pre-clinical and clinical trials may not be deemed adequate to support the submission of the relevant regulatory filings in our key markets. We cannot guarantee that any pre-clinical studies or clinical trials that we may plan or initiate will be conducted as planned or completed on schedule, if at all. We may fail at any stage in one or more of our clinical trials. We may face circumstances which prevent successful initiation, timely completion, or the desired results of our pre-clinical studies and clinical trials including, but not limited to: - delays and challenges in obtaining requisite regulatory approvals to commence pre-clinical studies and clinical trials on humans;   - delays in reaching agreement on acceptable terms with prospective clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different trial sites;   - our ability to recruit sufficient patients for our clinical trials in a timely manner or at all;- delays in sufficiently developing, characterizing or conducting a manufacturing process suitable for advanced clinical trials;   - delays in reaching an agreement with HSA and/or other relevant regulatory authorities on the planning, design or implementation of our pre-clinical studies and clinical trials;   - changes in regulatory requirements or guidance that may require us to amend or submit new clinical protocols, or the introduction of unanticipated requirements;    - changes in the standard of care on which a clinical development plan was based, which consequently may require new or additional trials;   - lack of quality of our product candidates or other materials necessary to conduct pre-clinical studies or clinical trials of our product candidates;   - clinical trials of our product candidates may have negative or inconclusive results, and as such, we may, or HSA and/or other relevant regulatory authorities may require us, to conduct additional clinical trials or abandon product development programs;   - inability of enrolled patients in foreign countries to adhere to our clinical protocol and process due to differences in healthcare services or cultural customs, or additional administrative burdens associated with foreign regulatory schemes; and   - failure of ourselves or any third-party manufacturers, contractors or suppliers to comply with regulatory requirements, maintain adequate quality controls, or be able to provide sufficient product supply to conduct and complete pre-clinical studies or clinical trials of our product candidates. In addition, the pandemics, epidemics, or outbreaks of infectious diseases, including future outbreaks of COVID-19 variants, Respiratory Syncytial Virus ("RSV"), or the flu, may increase the likelihood that we face such difficulties or delays in initiating, enrolling, conducting or completing our planned and ongoing pre-clinical studies and clinical trials, as applicable. If the pandemics, epidemics, or outbreaks of infectious diseases, including future outbreaks of COVID-19 variants, Respiratory Syncytial Virus ("RSV"), or the flu, could continue to prevent or otherwise obstruct regulatory authorities' conduct of regular inspections, reviews or other regulatory activities, HSA's (or other relevant regulatory authorities) timely review and process our regulatory filings could be severely affected. If we experience delays in the initiation, enrollment or completion of any pre-clinical study or clinical trial of our product candidates, or if any pre-clinical studies or clinical trials of our product candidates are canceled, the commercial prospects of our product candidates may be materially and adversely affected, and our ability to generate product revenues from any of these product candidates will be delayed or not realized at all. In addition, any delays in completing our clinical trials may increase our costs and hold up our product candidate development and approval process.

The results of our pre-clinical studies may not be indicative of future results of clinical trials, and the results of any early-stage clinical trials we commence may not be indicative of the results of the later-stage clinical trials. For example, pre-clinical models as applied to cell therapy in oncology are not sufficiently representative of the clinical setting, and thus cannot always accurately predict clinical activity nor identify all potential risks, and may not provide sufficient guidance as to appropriate dose or administration regimen of a given therapy. In addition, initial success in clinical trials may not be indicative of results obtained when such trials are completed. Interim data from clinical trials that we may conduct are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available. Preliminary data are required to undergo audit and verification procedures that may result in the final data being materially different from the preliminary data we previously announced. Negative differences between preliminary or interim data and final data could materially adversely affect the prospects of any product candidate that is impacted by such data updates.

In order to obtain HSA and/or other relevant regulatory authority approval to market a new biological product we must demonstrate proof of safety, purity and potency or efficacy in humans. We will have to conduct adequate and well-controlled clinical trials in order to meet high safety standards and requirements. We cannot guarantee the timely completion or successful outcome of our pre-clinical testing and studies and cannot determine whether the regulatory authority will accept our proposed clinical programs or if the outcome of our pre-clinical testing and studies will ultimately support the further development of our programs. As a result, we cannot be certain that we can submit any clinical trial or similar applications for our pre-clinical programs on the timelines we expect, if at all, and we cannot be sure that submission of clinical trials or similar applications will result in the regulatory authority or other regulatory authorities allowing clinical trials to begin. Conducting pre-clinical testing is a prolonged, time-consuming and costly process. The period of pre-clinical testing may vary substantially depending on the type, complexity and novelty of the program, and may often take several years or more for each program. Any delays in pre-clinical testing and studies conducted by us or potential future partners may cause us to incur additional operating expenses. The commencement and rate of completion of pre-clinical studies and clinical trials for a product candidate may be delayed by many factors, including, for example: - inability to generate sufficient pre-clinical or other in vivo or in vitro data to support the commencement of clinical trials;   - delays in reaching a consensus with regulatory agencies on clinical trial design; and   - the relevant regulatory authorities not allowing us to rely on previous clinical trial findings of safety and efficacy for other similar but approved products and published scientific literature. Moreover, as standards for pre-clinical assessment are constantly evolving and may change rapidly, even if an agreement with HSA and/or other relevant regulatory authorities on a pre-clinical trial proposal has been made, HSA and/or other relevant regulatory authorities may not accept the proposed clinical trial submission, in which case patient enrollment would be put on partial or complete hold and treatment of enrolled patients could be temporarily put on hold as the product candidate is re-assessed. Even if we commence clinical trials, we cannot guarantee the success of our clinical trials or development efforts.

We cannot assure that CTM-N2D, iPSC-gdNKT, CTM-GDT and CTM-MSC will be safe and effective or will obtain the requisite approvals and licenses for commercialization, on a timely basis or at all. Although some of our employees have prior exposure to clinical trials, regulatory compliance and cGMP manufacturing, we have not previously completed any clinical trials or submitted a marketing approval application to HSA, or similar regulatory approval filings to comparable foreign authorities, for any product candidate, and we cannot be certain that CTM-N2D, iPSC-gdNKT, CTM-GDT and CTM-MSC will be successful in clinical trials or receive the requisite regulatory approvals for the development, commercialization and marketing of CTM-N2D, iPSC-gdNKT, CTM-GDT and CTM-MSC. HSA (or other relevant regulatory authorities) can delay, limit or refuse to grant approval of any of our product candidates for many reasons. For further details about such reasons, please refer to the risk factor entitled "Clinical trials involve a lengthy and costly process with an uncertain outcome, and we may encounter substantial delays due to a variety of reasons outside our control". Any delay in obtaining, or inability to obtain, requisite regulatory approvals will delay or hinder our ability to successfully commercialize CTM-N2D, iPSC-gdNKT, CTM-GDT and CTM-MSC. This may have a material and adverse impact on our business, financial condition, results of operations and growth prospects. Furthermore, as CTM-N2D is our lead product candidate and CTM-GDT is based on the same core proprietary technology, if any of our clinical trials of CTM-N2D encounter safety, efficacy or manufacturing problems, development delays, regulatory issues or other problems, our development plans for CTM-N2D and all of our other product candidates in our pipeline could be significantly hindered, which could materially and adversely affect our business, financial condition, results of operations and growth prospects. In the event we manage to obtain clinical proof-of-concept from our CTM-N2D Phase I trials for relapsed or refractory solid tumors of different types, we may develop CTM-N2D for additional indications. We may not be able to advance any of these clinical trial indications through the development process. Even if we receive regulatory approval to market CTM-N2D for the treatment of any of these additional clinical trial indications, any such additional clinical trial indications may not be successfully commercialized, widely accepted in the marketplace or found to be more effective than other commercially available alternatives. If we are unable to successfully develop and commercialize CTM-N2D for these additional clinical trial indications, our commercial opportunities will be limited.