Summit Therapeutics (SMMT) Risk Analysis

We have and plan to continue investing a significant portion of our efforts and financial resources in the development of ivonescimab, which is still in clinical development. Our ability to generate product revenues, which may not occur for several years, if ever, will depend heavily on the successful development and commercialization of ivonescimab. The success of this product candidate depends on a number of factors, including, but not limited to, the following: - our ability to use preclinical data and data of patients from Akeso's clinical trials in China supporting registration studies and regulatory approval;- successful completion of global clinical development;- receipt of clinical trial approvals and future marketing approvals from applicable regulatory authorities in all the countries where we intend to conduct clinical trials or seek marketing approval; the costs of post-marketing studies, if any, that could be required by regulatory authorities in jurisdictions where approval is obtained;- establishing supply chain and commercial manufacturing arrangements with third-party manufacturers;- obtaining and maintaining patent and trade secret protection and regulatory exclusivity;- enforcing our rights in our intellectual property portfolio;- establishing sales, marketing and distribution capabilities;- launching commercial sales of ivonescimab if and when approved, whether alone or in collaboration with others;- acceptance of ivonescimab, if and when approved, by patients, the medical community and third-party payors;- obtaining timely and adequate pricing and reimbursement from payors;- ensuring no disruption in supply or lack of sufficient quantities of ivonescimab;- effectively competing with other therapies; and - maintaining an acceptable safety profile of ivonescimab during development and following approval. Risks and uncertainties related to these factors could cause us to experience significant delays or an inability to successfully commercialize ivonescimab, which would materially harm our business.

Clinical development can take several years to complete and is an expensive process with inherent uncertainty in outcomes. Failure can occur at any time during the clinical development process. The results of preclinical studies and early clinical trials of ivonescimab, conducted by us or Akeso, may not be predictive of the results of our later-stage clinical trials. Similarly, initial or interim results of a clinical trial may not be predictive of the final results and results for one indication, in one cohort, or in one of the primary endpoints or secondary endpoints, may not be predictive of the success in additional indications, with different cohorts or in additional primary or secondary endpoints. Drug candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. Several factors can lead to significant variability in safety and/or efficacy results between different trials of the same drug candidate, including changes in trial procedures set forth in protocols, differences in the size, type and geographic location of the patient populations, including genetic differences, patient adherence to the dosing regimen, and other trial protocol elements and the rate of dropout among clinical trial participants. In the case of any trials we conduct, results may differ from earlier trials due to the larger number of clinical trial sites and additional countries involved in such later trials. Results may differ materially in clinical trials held across multiple cohorts or subgroups, which could lead to unfavorable regulatory or health authority decisions. If ongoing Phase II or Phase III clinical trials conducted by Summit or Akeso involving ivonescimab, or future clinical trial results, are unfavorable, the size and scope, including the number of patients, primary and secondary endpoints, and population of patients, of ongoing and future clinical trials could be impacted. Further, we may incur additional product development costs, experience delays or become unable to obtain regulatory approval of ivonescimab for the whole clinical trial or the approved label may be restricted to one cohort or subgroup, thereby adversely affecting our business.

We may not be able to initiate or continue clinical trials for our product candidates for several factors including inability to get required regulatory approvals to initiate clinical trials in all the planned countries, as well as inability to locate and enroll a sufficient number of eligible patients to participate in these clinical trials. For our clinical trials of ivonescimab, we need to identify potential patients, potentially test them for specific diagnoses and enroll them. In addition, our competitors in NSCLC have ongoing clinical trials for product candidates that could be competitive with our product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors' product candidates or choose not to enroll in any clinical trials for various reasons, including due to fears of contagious diseases, illnesses or side effects. Patient enrollment is affected by several factors, including, but not limited to: - severity of the disease under investigation;- eligibility criteria for the clinical trial in question;- perceived risks and benefits of the product candidate under study;- competition for patients, time and resources at clinical trials sites from other investigational therapies in clinical trials that target the same patient population;- changes in the standard of care, including new clinical trial data;- approval of other therapies to treat the indication that is being investigated in the clinical trial;- efforts to facilitate timely enrollment in clinical trials;- patient referral practices of physicians;- the ability to monitor patients adequately during and after treatment; and - proximity and availability of clinical trial sites for prospective patients. Enrollment delays in our clinical trials may result in increased development costs for our product candidates, which would cause the value of our company to decline and limit our ability to obtain additional financing. Our inability to enroll a sufficient number of patients in our planned clinical trials of ivonescimab or any other planned clinical trials would result in significant delays, may generate a limited data set from which no meaningful conclusions could be made, or may require us to abandon one or more clinical trials altogether.

Prior to obtaining marketing approval from regulatory authorities (including the FDA, EMA, PMDA or any other regulatory authority in the Licensed Territory) for the sale of ivonescimab, or any other product candidate, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of our product candidates in humans. Clinical testing is expensive, difficult to design and implement, can take many years to complete and is inherently uncertain as to outcome. A failure of one or more clinical trials can occur at any stage of testing. The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results. In particular, due to the small number of patients in our early clinical trials, results from such trials may not be predictive of the outcome of later clinical trials. The design of a clinical trial can determine whether its results will support approval of a product, and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced or completed. We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products. For instance, although we believe that the safety and efficacy data generated in the HARMONi study demonstrates that the ivonescimab regimen offers a potential treatment option for patients impacted by EGFR-mutant NSCLC in this setting with a favorable benefit-risk profile, FDA has noted that a statistically significant OS benefit is necessary to support marketing authorization in this setting. If the FDA does not agree with our analysis of the HARMONi data, they may delay or deny regulatory approval in this proposed indication, require us to resubmit the marketing application with additional data or information, or take other actions that could delay commercialization of ivonescimab and adversely impact our ability to generate revenue, our business and our operations. We cannot predict the results of our ongoing or future clinical trials. Regulatory authorities have substantial discretion in the approval process. They may refuse to accept any application or may decide that our data are insufficient for approval and require additional clinical trials or other studies. In our public communications, we may designate certain of our clinical trials as "pivotal" if we believe that these clinical trials, if successful, will support BLA submissions; however, there can be no assurance that any clinical trial that we designate as "pivotal" will be viewed as sufficient by the FDA, the EMA and other comparable regulatory authorities in other jurisdictions to support regulatory approval. If we are required to conduct additional clinical trials or other testing of any of our product candidates beyond those that are contemplated, we may incur significant additional costs and regulatory approval may be delayed or prevented. There can be no guarantee that the FDA or other regulatory authorities will interpret the results or reach the same conclusions from the data as we do, or fully agree that our development plans are sufficient for submission or approval of a BLA. In the event that the FDA requires us to conduct clinical trials with more patients than planned, to conduct clinical trials with designs or endpoints other than we currently anticipate, we may not have the funding to enlarge or conduct such trials and we may not be able to raise sufficient funding to do so, which could delay or prevent commercialization of our product candidates. In addition, the FDA or other regulatory authorities may change their views on aspects of the clinical programs, including clinical trial designs, or the ability of the trials as designed to support approval of a product. If we are unable to effectively and efficiently resolve and comply with the inquiries and requests of the FDA and other comparable international regulatory authorities, the approval of our product candidates may be delayed, which could delay or prevent commercialization of our product candidates.

The successful development, manufacturing and sale of biologics is a long, expensive and uncertain process. There are unique risks and uncertainties with biologics. For example, access to and supply of necessary biological materials, such as cell lines, may be limited and governmental regulations restrict access to and regulate the transport and use of such materials. In addition, the development, manufacturing and sale of biologics is subject to regulations that are often more complex and extensive than the regulations applicable to other pharmaceutical products. Manufacturing biologics, especially in large quantities, is often complex and may require the use of innovative technologies. Such manufacturing also requires facilities specifically designed and validated for this purpose and sophisticated quality assurance and quality control procedures. Biologics are also frequently costly to manufacture. Failure to successfully develop, manufacture and sell ivonescimab could adversely affect our business.

Notwithstanding our large investment to date and anticipated future expenditures in proprietary technologies, we have not yet developed, and may never successfully develop, any marketed drugs. As a result of pursuing the development of product candidates using our proprietary technologies, we may fail to develop product candidates or address indications based on other scientific approaches that may offer greater commercial potential or for which there is a greater likelihood of success. Research programs to identify new product candidates require substantial technical, financial and human resources. These research programs may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to complete the clinical trials and receive marketing approval for or commercialize our product candidates, including: - clinical trials of our product candidates may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical trials or abandon product development programs;- in clinical trials that include multiple endpoints, unfavorable results in any individual endpoint may limit any regulatory approval or commercialization of the applicable product candidate;- the number of patients required for clinical trials of our product candidates may be larger, and the diversity of the patient population required for our clinical trials may be higher, than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate for various reasons, including due to contagious diseases or illnesses;- our ability to combine data from different regions and countries may be limited due to lack of consistency in data in these regions and countries, potentially delaying or preventing marketing approval for our product in some or all of the Licensed Territory;- in our multi-regional trials, we may experience delays in enrollment across one or more countries and/or regions that could lead to variability in data or the trial missing the required endpoints resulting in lack of approval from regulatory authorities in some or all of the Licensed Territory;- we may be unable to enroll a sufficient number of patients in our clinical trials to ensure adequate statistical power to detect any statistically significant treatment effects;- we or our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all;- regulators, institutional review boards or independent ethics committees may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;- we may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical trial protocols with multiple prospective trial sites;- we may have to suspend or terminate clinical trials of our product candidates for various reasons, including a finding that the participants are being exposed to unacceptable health risks;- regulators, institutional review boards or independent ethics committees may require that we or our investigators materially modify the terms of our clinical research in order to meet additional requirements for receiving marketing approval, including by requiring that we enlarge our trials, broaden the scope of our research, or perform studies in addition to those we currently anticipate, which may delay our ability to obtain marketing approval or impose additional costs;- regulators, institutional review boards or independent ethics committees may require that we or our investigators suspend or terminate clinical research for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;- the supply or quality of our product candidates, comparator drugs or other materials necessary to conduct clinical trials of our product candidates in adolescent patients may be insufficient or inadequate, which may occur if, for example, enrollment for our clinical trial programs are delayed and the clinical supply of ivonescimab or related comparator drug manufactured for such trials was not utilized prior to its expiration and needed to be replaced, or if there were disruptions in our supply chain due to weather conditions, natural disasters or contagious diseases or illnesses, or pandemics or epidemics;- our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators, institutional review boards or independent ethics committees to suspend or terminate the clinical trials;- preclinical tests or clinical trials not beginning as planned, needing to be restructured or not being completed on schedule, or at all; and - data privacy or other laws being implemented that restrict transfer of patient data from one country to another.

All of our product candidates are in clinical or early-stage development and their risk of failure is high. It is impossible to predict when or if any of our product candidates will prove effective or safe in humans or will receive marketing approval. If our product candidates are associated with undesirable side effects or have characteristics that are unexpected, we may need to abandon their development or limit development to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective. Many compounds that initially showed promise in clinical or earlier stage testing have later been found to cause side effects or other safety issues that prevented further development of the compound. If we elect or are forced to suspend or terminate any clinical trial of our product candidates, the commercial prospects of such product candidate will be harmed and our ability to generate product revenues from such product candidate will be delayed or eliminated. Any of these occurrences could materially harm our business.