ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 |
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 FOR THE TRANSITION PERIOD FROM TO |
(State or other jurisdiction of incorporation or organization) |
(I.R.S. Employer Identification No.) | |
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N/A | |
(Address of principal executive offices) |
(Zip Code) |
Title of each class |
Trading Symbol(s) |
Name of each exchange on which registered | ||
(Nasdaq Capital Market) |
Large accelerated filer |
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Accelerated filer |
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Smaller reporting company |
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Emerging growth company |
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PART I |
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Item 1. |
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Item 1A. |
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Item 1B. |
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Item 2. |
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Item 3. |
113 | |||||
Item 4. |
114 | |||||
PART II |
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Item 5. |
115 | |||||
Item 6. |
116 | |||||
Item 7. |
117 | |||||
Item 7A. |
134 | |||||
Item 8. |
134 | |||||
Item 9. |
134 | |||||
Item 9A. |
134 | |||||
Item 9B. |
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PART III |
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Item 10. |
141 | |||||
Item 11. |
141 | |||||
Item 12. |
141 | |||||
Item 13. |
141 | |||||
Item 14. |
141 | |||||
PART IV |
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Item 15. |
142 | |||||
Item 16 |
142 |
• | Novel Tetravalent Format 2 bispecific antibodies to simultaneously bind two different targets, with two binding sites for each target. The ability to bind in this way is known as tetravalency. This unique tetravalent format is designed to enable our mAb2 bispecific antibodies to achieve more efficient crosslinking, clustering or conditionality than other bispecific antibodies, and therefore have the potential to elicit improved biological responses and enable our mAb2 bispecific antibodies to overcome tumor evasion pathways. These three key characteristics are described further below: |
• | Crosslinking |
• | Clustering. 2 bispecific antibodies have F-star’s distinct binding sites, they can potentially induce more potent clustering than non-tetravalent bispecific antibody formats. |
• | Conditionality. 2 bispecific antibodies so that targets are only activated when they are simultaneously bound. |
• | Natural Human Antibody Format. 2 bispecific antibodies are designed to conserve the natural human antibody format, with greater than 95% identity, allowing us to leverage the following advantages: |
• | Minimal systemic toxicity. 2 bispecific antibodies use a natural human antibody format, without synthetic linkers and domains, there is lower potential for systemic toxicity than traditional and bispecific antibodies. |
• | Low immunogenicity risk. 2 bispecific antibodies and the low number of modifications we engineer into our mAb2 bispecific antibodies is designed to help mitigate immunogenicity risk, or the risk that the immune system recognizes the mAb2 bispecific antibody as foreign, potentially resulting in lower exposure and toxicity. |
• | Ease of manufacturability. 2 bispecific antibodies through established manufacturing processes readily and at large scale with typical industry time and cost standards and without potentially complicating additions, such as domain assembly or other modifications. |
• | Rapidly accelerating the clinical development of our three novel mAb 2 product candidates and novel cyclic dinucleotide, SB 11285, to treat a range of advanced cancers. 2 product candidates represent potentially best-in-class proof-of-concept PD-1/PD-L1 (LAG-3 and PD-L1). In addition to FS118, we are currently evaluating FS120, FS222 and SB 11285 for safety, tolerability and efficacy in Phase 1 clinical trials in patients with advanced cancers. All of our product candidates have the potential to address multiple immune evasion pathways that limit the effect of current immuno-oncology therapies. |
• | Initially focusing our development strategy on tumors where checkpoint inhibitors are currently utilized but are poor long-term treatment options, and then subsequently broadening to other tumor types. co-expression and/or resistance to current checkpoint therapies. We believe our mAb2 bispecific antibodies and SB 11285 may also ultimately deliver therapeutic benefit in a broader range of tumors, expanding beyond the initial indications we may pursue. We believe our development strategy best serves the patient, can be efficiently pursued by our organization, and has the potential to lead to a rapid development strategy and regulatory pathway to market. For example, we have identified several tumor types which have a strong fit with the potential FS118 mechanism of action, including appropriate target expression that would be candidates for accelerated approval pathways. |
• | Leveraging the transformational potential of our modular antibody technology platform to create a leading immuno-oncology pipeline of differentiated clinical assets capable of improving patient outcomes. 2 bispecific antibodies have a number of potential advantages, compared to other modalities, resulting from their novel tetravalent and natural human |
antibody formats, which may result in improved efficacy, minimized toxicity and simplified manufacturability. We believe our technology has the potential to be matched with any disease target in a modular “plug-and-play” 2 product candidates. We also believe these benefits may provide multiple opportunities to consistently generate clinical candidates that could potentially address the needs of patients who are without adequate therapeutic options. |
• | Leveraging and continuing to build our extensive intellectual property portfolio in order to protect our dominant position in mAb 2 bispecific antibodies and our STING agonist program. 2 technology and associated mAb2 product pipeline. In addition, we have STING pathway-related filings, including those of a patent family relating to the composition of matter of the STING agonist SB 11285. This patent estate relates to our mAb2 bispecific format and STING agonist program and aims to provide us with robust intellectual property exclusivity and prohibit use of our technology by third parties. We intend to continue to seek additional patent protection as we develop additional novel mAb2 product candidates. |
• | Crosslinking. |
• | Clustering. |
• | Conditionality. |
targets simultaneously, usually in the tumor microenvironment. Conversely, where one antigen is bound by the bispecific antibody resulting in immune activation without the need for simultaneous binding to the other target, conditionality does not exist. When there is conditional activity, increased localized anti-tumor activity can be elicited, while, in the absence of conditional activity, there is greater risk for systemic toxicity. |
• | Tetravalent crosslinking. 2 bispecific antibodies is designed to allow for more efficient target cell crosslinking than certain bispecific antibodies because there is an additional, second set of dual binding sites in the Fc region, and both sets can be engineered to engage with antigens that are found on both tumor cells and immune cells. For our mAb2 product candidates that target tumor-associated antigens, such as PD-L1 (FS118 and FS222), crosslinking also supports safety by targeting the mAb2 product candidates to the tumor, localizing the immune activation and thereby minimizing systemic toxicities. |
• | Optimal clustering. 2 bispecific antibodies has our distinct binding sites, two for each antigen, they are designed to potentially induce more potent activation of multiple cellular receptors, including those on single cells, |
than other bispecific antibodies. This is particularly useful for our mAb 2 product candidates FS120 and FS222, which activate the costimulatory molecule CD137 which clustering for potent activation. |
• | Conditionality. 2 bispecific antibodies may be able to activate the immune system through binding to only one antigen, the greatest effect is expected to be seen when both antigens are bound at the same time, as observed with FS118. Additionally, through selection of target antigens and precise engineering of the dual antigen binding sites, we aim to increase the activity of our immunostimulatory mAb2 bispecific antibodies at the tumor site, as observed with FS222 preclinically. We believe that we can potentially increase the safety of our mAb2 product candidates compared to other bispecific antibodies which bind to their targets only monovalently and cannot be engineered for such optimal antigen binding. |
• | Plug-and-play plug-and-play 2 bispecific antibodies. Our Fcabs contain new target binding sites resulting from minimal modifications made in the Fc domain of the existing antibody structure. We routinely generate, in parallel, Fcabs that bind to human targets as well as those that bind to mouse targets. From these mouse Fcabs, we generate mouse mAb2 bispecific antibody equivalents that can be used to test activity in animal models. The modular nature of the technology enables the rapid generation of novel mAb2 product candidates. |
• | Minimized systemic toxicity. 2 bispecific antibodies to prevent binding to Fc gamma receptors and eliminate Fc gamma receptor-mediated crosslinking. As a result, our mAb2 bispecific antibodies can potentially improve immune activation while minimizing systemic toxicity. |
• | Low immunogenicity risk. 2 bispecific antibodies and the low number of modifications we engineer into our mAb2 bispecific antibodies is designed to help mitigate immunogenicity risk. |
• | Ease of manufacturability. 2 bispecific antibodies through established manufacturing processes readily and at large scale without potentially complicating additions, such as domain assembly or other modifications. Our mAb2 bispecific antibodies also have pharmacologic properties consistent with other traditional antibody products, potentially allowing dosing to be adjusted based on patient response and off-the-shelf |
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Our most advanced product candidate, FS118, aims to rescue checkpoint inhibitor treatment failures and is a mAb 2 bispecific antibody targeting two receptors, PD-L1 and LAG-3, both of which are established pivotal targets in immuno-oncology. We are currently conducting in a proof-of-concept PD-1/PD-L1 PD-1/PD-L1 |
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FS120 aims to improve checkpoint inhibitor and chemotherapy outcomes and is a mAb 2 bispecific antibody that is designed to bind to and stimulate OX40 and CD137, two proteins found on the surface of T cells that both function to enhance T cell activity. We are developing FS120 alone and in combination with PD-1/PD-L1 PD-1/PD-L1 co-expression of OX40 and CD137 in the tumor microenvironment, such as gastric and bladder cancer. We initiated a Phase 1 clinical trial in patients with advanced cancers in the fourth quarter of 2020. |
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FS222 aims to improve outcomes in low PD-L1 expressing tumors and is a mAb2 bispecific antibody that is designed to target both the costimulatory CD137 and the inhibitory PD-L1 receptors, which are co-expressed in a number of tumor types including non-small-cell lung cancer, ovarian cancer and gastrointestinal cancers such as colorectal and esophageal cancer. FS222 is aimed at improving outcomes in PD-L1 low tumors. We initiated a Phase 1 clinical trial in patients with advanced cancers for FS222 in late 2020. We believe there is a strong rationale to combine FS222 with other anti-cancer agents, including targeted therapy and chemotherapy, and this can be done within the Phase 1 study. |
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SB 11285 is a next generation cyclic dinucleotide STING agonist designed to improve checkpoint inhibition outcomes as an immunotherapeutic compound for the treatment of selected cancers. We are conducting an open-label, dose-escalation Phase 1 clinical trial with SB 11285 as an IV administered monotherapy, and in combination with an anti-PD-L1 |
• | completion of nonclinical laboratory tests and animal studies according to good laboratory practices, commonly “GLPs”, and applicable requirements for the human use of laboratory animals or other applicable regulations; |
• | submission of an Investigational New Drug (“IND”) application, which must become effective before clinical trials may begin; |
• | approval of the protocol and related documentation by an independent IRB or ethics committee at each clinical trial site before each study may be initiated; |
• | performance of adequate and well-controlled human clinical trials according to the FDA’s IND regulations, current good clinical practices, or “GCPs”, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the investigational product for each proposed indication;; |
• | submission to the FDA of a Biologics License Application (“BLA”) or a New Drug Application (“NDA”), for marketing approval, including payment of application user fees; |
• | satisfactory completion of FDA pre-approval inspections of manufacturing facilities where the biologic or drug is produced to assess compliance with current Good Manufacturing Practice (“GMP”) requirements to assure that the facilities, methods and controls are adequate to preserve the biologic’s or drug’s identity, strength, quality and purity; |
• | potential FDA audits of the nonclinical study and clinical trial sites that generated the data in support of the BLA or NDA; and |
• | FDA review and approval of the BLA or NDA, including satisfactory completion of an FDA advisory committee review of the product candidate, where appropriate or if applicable, which must occur before the biologic or drug can be marketed or sold in the United States. |
• | Phase 1 — the product candidate is initially given to healthy human subjects or patients and tested for safety, dosage tolerance, reactivity, absorption, metabolism, distribution and excretion. These trials may also provide early evidence of effectiveness. During Phase 1 clinical trials, sufficient information about the investigational product’s activity may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinical trials. |
• | Phase 2 — clinical trials are conducted in a limited number of patients in the target population to identify possible adverse effects and safety risks, to evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. Multiple Phase 2 clinical trials may be conducted by the sponsor to obtain information prior to beginning larger and more expensive Phase 3 clinical trials. |
• | Phase 3 — when Phase 2 evaluations demonstrate that a dosage range of the product appears effective and has an acceptable safety profile and provide sufficient information for the design of Phase 3 clinical trials, Phase 3 clinical trials are undertaken to provide statistically significant evidence of clinical efficacy and to further test for safety in an expanded patient population at multiple clinical trial sites. Phase 3 clinical trials are performed after preliminary evidence suggesting effectiveness of the biologic has been obtained, and they are intended to further evaluate dosage, effectiveness and safety, to establish the overall benefit-risk relationship of the investigational biologic, and to provide an adequate basis for product approval by the FDA. |
• | Uncertainty regarding future revenue and access to funding. |
• | We are a clinical-stage biopharmaceutical company that currently generates no revenue from sales of any products, and we may never be able to develop or commercialize a drug or biologic product candidate. Even if we receive approval to market one or more products, we may never become profitable if we are unable to establish market acceptance, adequate market share or reimbursement from third-party payors. Additionally, if we receive approval, we expect our expenses to increase significantly in order to successfully launch such approved product candidate and such increases may not be commercially feasible. Further, if we cannot generate revenue from the sale of any approved products, we may never become profitable. We have also concluded that substantial doubt exists about our ability to continue as a going concern for a period of at least twelve months from the issuance date of the financial statements. |
• | Clinical trial delays, adverse events, and/or clinical trial results may affect our business adversely. |
• | Clinical development is expensive, time consuming and involves significant risk. If there is a failure of one or more of our clinical trials, at any stage of development, or if we experience serious adverse events, such failure may lead to additional costs to us or impair our ability to generate revenue. In addition, many of the factors, including the incidence of serious adverse events, that cause or lead to a delay in the commencement or completion of a clinical trial may also lead to the denial of marketing approval for our product candidates, which would lead to material harm to our business. |
• | We rely on third parties to manage our clinical programs, manufacture our product candidates and perform other services. |
• | We rely on third-party vendors for key components of the development of our product candidates, including the manufacturing, management of clinical trials and other critical services. If such third-party vendors fail to comply with applicable laws, regulations or guidelines or are unable to obtain the materials needed for the manufacture of our product candidates, we may have a disruption in our clinical trials and potentially, commercial sale of a future approved product. We may not be able to manufacture product candidates or there may be substantial technical or |
logistical challenges to supporting manufacturing demand for product candidates either by us or by our third-party manufacturers. Additionally, as we rely upon these vendors to perform release testing on our product candidate prior to delivery to subjects in our clinical trials or patients being treated with our product candidates, if approved in the future, such subjects or patients could be put at risk for serious harm, and we may face damaging product liability suits. |
• | We are subject to substantial regulation. As a biopharmaceutical company, we are subject to extensive regulation by government and regulatory agencies, such as the FDA and the EMA, among others. We may not receive the governmental approvals needed to market and commercialize our product candidates, which could have a material adverse effect on our financial condition, operations and prospects. The FDA and comparable foreign regulatory authorities have limited experience with mAb 2 products like our product candidates, which may increase the uncertainty surrounding as well as the expenses involved in the regulatory approval process for our product candidates. Such delays, unexpected costs or failure to obtain regulatory approval to market our product candidates could harm our ability to generate product revenue and our business, financial condition, results or operations and prospects may be harmed. Even if we obtain regulatory approval for a product, maintaining such compliance with regulatory requirements will result in additional expenses to us, which may be difficult to maintain. |
• | We are reliant on our intellectual property and are subject to the risk that we will not be able to protect our intellectual property rights. We rely upon a combination of patents, trade secret protection and confidentiality agreements to protect our intellectual property related to our technologies and product candidates. Our commercial success depends on our ability to obtain, maintain and enforce patent and other intellectual property protections for our current and future technologies and product candidates. If we are unable to do so, our business may be materially harmed, our ability to commercialize our product candidates may be limited and our profitability may be delayed or may never occur. |
• | We depend on third party licensing or collaboration agreements. Our business strategy, along with our short- and long-term operating results depend in part on our ability to execute on existing strategic collaborations, including those with Ares Trading S.A, an affiliate of Merck KGaA, Darmstadt, Germany and Denali Therapeutics, and to license or partner with new strategic partners. If disputes arise between us and our partners in such agreements, there may be increased costs due to related litigation or if we decide to fund such programs ourselves. Disputes with partners may lead to substantial delays or possible termination of such agreements or related clinical trials and the need to seek a new partner for the development or commercialization of such product candidate. In addition, if commercialization collaboration partners do not commit sufficient resources to commercialize our future product candidates, and if we are unable to develop the necessary marketing and sales capabilities on our own, we will be unable to generate sufficient product revenue to sustain or grow our business. |
• | We are subject to substantial competition. |
• | We compete with large pharmaceutical companies that have access to significant capital and materially greater manufacturing, marketing, research and drug development resources. We also compete with specialty pharmaceutical companies and biotechnology companies, including but not limited to, such as AstraZeneca plc, BMS, Eli Lilly and Company, MSD, Merck KGaA, Darmstadt, Germany, Novartis, Pfizer, Inc., Genentech, Inc., a subsidiary of the F. Hoffmann-La Roche AG Group and Sanofi, among others, as well as, universities and other research institutions worldwide that are developing drug or biological products for the same indications as us that could be more effective or less costly than our product candidates, which may render our candidates obsolete and noncompetitive. |
• | We have material weaknesses in our internal control over financial reporting. |
• | We will need to hire additional qualified accounting personnel in order to remediate these material weaknesses in our internal control over financial reporting, and we will need to expend any additional resources and efforts that may be necessary to establish and to maintain the effectiveness of our internal control over financial reporting and our disclosure controls and procedures. |
o | We are vulnerable to disruptions and volatility in the financial markets. |
• | We are reliant in part on the financial markets to finance our future capital needs through public equity offerings, debt financings and other funding arrangements. Disruptions and volatility in the financial markets can have a material adverse effect on our ability to access capital and liquidity on acceptable financial terms. Negative and fluctuating economic conditions may present challenges in us obtaining additional capital needed to fund our operations. If we do not obtain funding on a timely basis and on acceptable terms, we may need to delay or discontinue one or more of our programs or the commercialization of our product candidates. |
• | We and others in our industry face cybersecurity risks. |
• | We take protective measures and monitor and develop our systems continuously to protect our technology infrastructure and sensitive data, such as personally identifiable information about our employees and intellectual property, from cyberattacks. However, cybersecurity risks continue to increase for our industry, including for our third party vendors, who may hold some of our data, and the proliferation of new technologies and the increased sophistication and activities of the actors behind such attacks present risks for compromised or lost data, which could result in substantial costs and harm to our reputation as well as delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce such data. |
• | continue to develop and conduct clinical trials for our current product candidates, FS118, FS120, FS222 and SB 11285; |
• | continue the research and development of our product candidates, including completing preclinical studies; |
• | discover and develop additional mAb 2 product candidates and makes further investments in its modular antibody technology platform; |
• | seek regulatory approvals for any product candidates that successfully complete clinical trials; |
• | experience any delays or encounter any issues with any of the above, including but not limited to failed studies, complex results, safety issues or other regulatory challenges; |
• | establish a sales, marketing and distribution infrastructure and scale-up manufacturing capabilities, whether alone or with third parties, to commercialize any product candidates for which we may obtain regulatory approval, if any; |
• | maintain, expand and protect our intellectual property portfolio, including litigation costs associated with defending against alleged patent infringement claims; |
• | add clinical, scientific, operational, financial and management information systems and personnel, including personnel to support our product development and potential future commercialization efforts; |
• | expand our operations in the United States, Europe and other geographies; and |
• | incur additional legal, accounting and other expenses associated with operating as a public company. |
• | the cost, progress, results of the proof-of-concept |
• | the cost, progress, results of the Phase 1 clinical trials of FS120, FS222 and SB 11285 and any later-stage clinical trials for these product candidates; |
• | the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for any future product candidate; |
• | the number of potential new product candidates we identify and decides to develop; |
• | the cost of manufacturing drug supply for the clinical trials of our product candidates; |
• | the time and costs involved in obtaining regulatory approval for our product candidates and any delays we may encounter as a result of evolving regulatory requirements or adverse clinical trial results with respect to any of our product candidates; |
• | the costs involved in growing our organization to the size and expertise needed to allow for the research, development and potential commercialization of our current or any future product candidates; |
• | fulfilling obligations under our existing collaboration agreements and the entry into new collaboration agreements; |
• | the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending any intellectual property-related claims, including any claims by third parties that we are infringing upon their intellectual property rights; |
• | the cost of commercialization activities and costs involved in the creation of an effective sales, marketing and healthcare compliance organization for any product candidates we develop, if approved; |
• | the potential additional expenses attributable to adjusting our development plans (including any supply related matters) to the COVID-19 pandemic; |
• | the revenue, if any, received from commercial sales of our product candidates for which we receive marketing approval; and |
• | the costs of operating as a public company. |
• | successful and timely completion of preclinical studies, including in vivo |
• | sufficiency of our financial and other resources to complete the necessary preclinical studies and clinical trials; |
• | receiving regulatory approvals or authorizations for conducting our planned clinical trials or future clinical trials; |
• | initiation and successful patient enrollment in and completion of clinical trials on a timely basis; |
• | safety, tolerability and efficacy profiles that are satisfactory to the FDA, the EMA or any other comparable foreign regulatory authority for a product to receive marketing approval; |
• | timely receipt of marketing approvals for our product candidates from applicable regulatory authorities; |
• | the extent of any required post-marketing approval commitments made to applicable regulatory authorities; |
• | establishing and scaling up, either alone or with third-party manufacturers, manufacturing capabilities of clinical supply for our clinical trials and subsequently for commercial manufacturing, if any product candidates are approved; |
• | obtaining and maintaining patent and trade secret protection or regulatory exclusivity for our product candidates, the latter only if they receive marketing approval, both in the United States and internationally; |
• | successfully scaling a sales and marketing organization and launching commercial sales of our product candidates, if approved; |
• | acceptance of our product candidates’ benefits and uses, if approved, by patients, the medical community and third-party payors; |
• | maintaining a continued acceptable safety profile of our product candidates following marketing approval and commercial launch; |
• | effectively competing with companies developing and commercializing other therapies in the same indications targeted by our product candidates; |
• | obtaining and maintaining healthcare coverage and adequate reimbursement from third-party payors for any approved products; and |
• | enforcing and defending intellectual property rights and claims. |
• | delays in or failure to obtain regulatory approval or clearance to commence a clinical trial or inability to comply with conditions imposed by a regulatory authority regarding the scope or design of a clinical trial; |
• | delays or failure in reaching agreement with the FDA or a comparable foreign regulatory authority on appropriate clinical trial designs; |
• | delays in or failure to reach agreement on acceptable terms with prospective contract research organizations (“CROs”), and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites; |
• | inability, delays or failure in identifying and maintaining a sufficient number of clinical trial sites, many of which may already be engaged in other clinical research programs; |
• | delays in or failure to obtain ethics committee/institutional review board (“EC/IRB”) approval at each site participating in the trial; |
• | delays in or failure to recruit a sufficient number of suitable subjects to participate in a trial; |
• | failure to have participants complete a trial or return for post-treatment follow-up, or other inability to monitor patients adequately during or after treatment; |
• | clinical sites or clinical investigators deviating from trial protocol or dropping out of a trial; |
• | delays in adding new clinical trial sites; |
• | failure to manufacture sufficient quantities of a product candidate for use in clinical trials in a timely manner; |
• | delay or failure in developing and validating companion diagnostics, if they are deemed necessary, on a timely basis; |
• | safety or tolerability concerns that could cause us or our collaborators, as applicable, to suspend or terminate a trial if we or our collaborators find that the participants are being exposed to unacceptable health risks; |
• | changes in regulatory requirements, policies and guidelines; |
• | failure of our third-party research contractors, including clinical sites and investigators, to comply with regulatory requirements applicable to the trial, including GCPs, or to meet their contractual obligations to us in a timely manner, or at all; |
• | delays in establishing the appropriate dosage levels for a particular product candidate through clinical trials; |
• | the quality or stability of the product candidate falling below acceptable standards; and |
• | business interruptions resulting from pandemics, such as the ongoing COVID-19 pandemic, or geo-political actions, including war and terrorism, or natural disasters including earthquakes, typhoons, floods and fires. |
• | regulatory authorities may withdraw approvals of such product and require our approved product to be taken off the market, through a recall or other action; |
• | regulatory authorities may require the addition of labeling statements or specific warnings, such as a “black box” warning or a contraindication, to the product’s prescribing information, or require field alerts to be sent to physicians and pharmacies; |
• | regulatory authorities may require a medication guide explaining the risks of such side effects to be distributed to patients, or that we are to implement a risk evaluation and mitigation strategy to ensure that the benefits of the product outweigh its risks (such as through a REMS in the United States that may include a restricted distribution program or educational programs for prescribers); |
• | we may be required to change the way the product is administered; |
• | we may be required to conduct additional clinical trials or costly post-marketing testing and surveillance to monitor the safety of the product; |
• | we may be subject to limitations on how we may promote the product; |
• | sales of the product may decrease significantly; |
• | we may be subject to litigation or product liability claims; and |
• | our reputation may suffer. |
• | size and nature of the patient population and process for identifying potential study subjects; |
• | proximity and availability of clinical trial sites for prospective participants; |
• | the extent of we and our collaborators’ efforts to facilitate timely enrollment in clinical trials; |
• | eligibility and exclusion criteria for the trial; |
• | design of the clinical trial; |
• | safety profile, to date, of the product candidate under study; |
• | perceived risks and benefits of the product candidate under study; |
• | perceived risks and benefits of our approach to treatment of diseases; |
• | competition with other companies for clinical sites and qualified clinical investigators; |
• | severity of the disease under investigation; |
• | degree of progression of the subject’s disease at the time of enrollment; |
• | ability to obtain and maintain the study subject’s informed consent; |
• | risk that enrolled subjects will drop out before completion of the trial; |
• | competing clinical trials and clinicians’ and patients’ perceptions as to the potential advantages of the product candidate being studied in relation to other available therapies, including any new products that may be approved for the indications we are investigating; |
• | patient referral practices of physicians; and |
• | ability to adequately monitor subjects during and after investigational treatment. |
• | The FDA, EMA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials; |
• | we may be unable to demonstrate to the satisfaction of the FDA, the EMA or other comparable foreign regulatory authorities that a mAb 2 product candidate is safe, pure and potent or effective for its proposed indication(s) or that a small-molecule drug product candidate is safe and effective for its proposed indication(s); |
• | the results of clinical trials may not meet the level of statistical significance required by the FDA, the EMA or other comparable foreign regulatory authorities in order to support approval; |
• | we may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks; |
• | the FDA, the EMA or other comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical studies or clinical trials; |
• | the data collected from clinical trials of our product candidates may not be sufficient to support the submission of a Biologics License Application (“BLA”) or New Drug Application (“NDA”), to the FDA or other equivalent marketing authorization application submissions to obtain regulatory approval in the United States, the EU or elsewhere; |
• | upon review of our clinical trial sites and data, the FDA, EMA or comparable foreign regulatory authorities may find our record keeping or the record keeping of our clinical trial sites or investigators to be inadequate; |
• | the FDA, the EMA or other comparable foreign regulatory authorities may find deficiencies with or fail to approve the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; and |
• | the approval policies or regulations of the FDA, the EMA or other comparable foreign regulatory authorities or the laws they enforce may significantly change in a manner rendering our clinical data insufficient for approval. |
• | decreased demand for our products due to negative public perception; |
• | injury to our reputation; |
• | withdrawal of clinical trial participants or difficulties in recruiting new trial participants; |
• | initiation of investigations by regulators; |
• | costs to defend or settle the related litigation; |
• | a diversion of management’s time and our resources; |
• | substantial monetary awards to trial participants or patients; |
• | product recalls, withdrawals or labeling, marketing or promotional restrictions; |
• | loss of revenues from product sales; and |
• | the inability to commercialize any of our product candidates, if approved. |
• | a covered benefit under its health plan; |
• | safe, effective and medically necessary; |
• | appropriate for the specific patient; |
• | cost-effective; and |
• | neither experimental nor investigational. |
• | the clinical indications for which our product candidates are approved for marketing; |
• | physicians, hospitals, cancer treatment centers and patients considering our product candidates as a safe and effective treatment; |
• | the potential and perceived advantages of our product candidates over alternative treatments; |
• | the prevalence and severity of any side effects; |
• | product labeling or prescribing information requirements of the FDA, the EMA or other comparable foreign regulatory authorities, or any risk mitigation measures that are required to be followed as part of the product’s marketing approval; |
• | limitations or warnings contained in the product labeling approved by the FDA, the EMA or other comparable foreign regulatory authorities, including any restrictions on concomitant use of other medications;; |
• | the timing of market introduction of our product candidates in relation to other potentially competitive products; |
• | the cost and cost-effectiveness of our product candidates in relation to alternative treatments; |
• | the amount of upfront costs or training required for physicians to administer our product candidates; |
• | the availability of coverage and adequate reimbursement from third-party payors and government authorities; |
• | the willingness of patients to pay out-of-pocket |
• | the relative convenience and ease of administration, including as compared to alternative treatments and competitive therapies; |
• | support from patient advocacy groups; |
• | the effectiveness of our sales and marketing efforts and distribution support; and |
• | the presence or perceived risk of potential product liability claims. |
• | the Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, offering, receiving or paying any remuneration (including any kickback, bribe, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, lease, order or recommendation of, any good, facility, item or service, for which payment may be made, in whole or in part, under U.S. federal and state healthcare programs such as Medicare and Medicaid. A person or entity does not need to have actual knowledge of the statute or specific intent to violate it |
• | federal civil and criminal false claims laws and civil monetary penalty laws, including the FCA, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, false or fraudulent claims for payment to, or approval by Medicare, Medicaid, or other federal healthcare programs, knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim or an obligation to pay or transmit money to the federal government, or knowingly concealing or knowingly and improperly avoiding or decreasing or concealing an obligation to pay money to the federal government. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery; |
• | HIPAA, which created new federal criminal and civil statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters. Similar to the Anti-Kickback Statute, a person or entity can be found guilty of violating HIPAA without actual knowledge of the statute or specific intent to violate it; |
• | HIPAA, as amended by HITECH, and their implementing regulations, which impose certain obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security |
and transmission of individually identifiable health information by covered entities subject to the rule, such as health plans, healthcare clearinghouses and certain healthcare providers, as well as their business associates that perform certain services involving the use or disclosure of individually identifiable health information and require notification to affected individuals and regulatory authorities of certain breaches of individually identifiable health information. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions; |
• | federal legislation commonly referred to as Physician Payments Sunshine Act, enacted as part of the ACA, and its implementing regulations, which requires certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program to report annually to the CMS information related to certain payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, chiropractors and, beginning in 2022 for payments and other transfers of value provided in the previous year, certain advanced non-physician healthcare practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members; |
• | analogous state laws and regulations, including: state anti-kickback and false claims laws that may apply to claims involving healthcare items or services reimbursed by any third-party payor, including private insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral source; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information, which requires tracking gifts and other remuneration and items of value provided to healthcare professionals and entities; state and local laws that require the registration of pharmaceutical sales representatives; and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and |
• | European and other foreign law equivalents of each of the laws, including reporting requirements detailing interactions with and payments to healthcare providers. |