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Additional risks not currently known to us or that we currently deem to be immaterial may adversely impact our business in the future.
−Removed: Additionally, many of these risks and uncertainties are currently elevated by and may or will continue to be elevated by the COVID-19 pandemic.
−Removed: Risks Related to the Development and Commercialization of U2 and UKONIQ ® (umbralisib)
−Removed: We face substantial uncertainty regarding whether FDA will approve U2 and whether we will be able to maintain approval of UKONIQ in its currently marketed indications in light of the FDA’s plan to hold an ODAC meeting in March or April 2022 to discuss the benefit-risk of U2 in CLL and SLL and the benefit risk of UKONIQ in R/R FL and MZL.
−Removed: If we are unable to obtain regulatory approval for U2 or if we are unable to maintain current approvals of UKONIQ, our business will be materially harmed.
−Removed: In November 2021, the Company announced that FDA plans to host a meeting of the Oncologic Drugs Advisory Committee (ODAC) in connection with its review of the pending Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for U2 for the treatment of adult patients with CLL and SLL.
−Removed: The potential questions and discussion topics for the ODAC include:
−Removed: the benefit-risk of the U2 combination for the treatment of CLL or SLL, and the benefit-risk of UKONIQ for R/R MZL and FL.
−Removed: In addition, as part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including adverse events (serious and Grade 3-4), discontinuations due to adverse events, and dose modifications, is expected to be reviewed.
−Removed: The FDA’s concerns giving rise to the ODAC meeting stem from an early analysis of overall survival from the UNITY-CLL trial, which showed a possible increased risk of death in patients receiving U2 compared to the control arm of obinutuzumab plus chlorambucil.
−Removed: Due to the concerns that prompted the ODAC meeting, the FDA also placed the Company’s clinical trials investigating U2 and its components in CLL and NHL, on partial clinical hold in January 2022.
−Removed: As part of the partial clinical hold, no new patients may be enrolled to the impacted studies, however patients on these studies who are deriving clinical benefit can continue on therapy once they have been reconsented.
−Removed: Most studies included in the partial clinical hold were already closed to new enrollment or were on TG administrative hold to new enrollment at the time FDA imposed the partial clinical hold.
−Removed: TG expects to provide an update on the partial clinical hold only upon completion of the ODAC meeting.
−Removed: Additionally, in February 2022, the FDA released a Drug Safety Communication in which it announced that it is investigating a possible increased risk of death with UKONIQ as a result of the initial UNITY-CLL overall survival results and is re-evaluating the benefit-risk profile of UKONIQ for its approved indications.
−Removed: The FDA encouraged healthcare providers to review patients’ progress on UKONIQ and discuss with them the risks and benefits of continuing UKONIQ in the context of other available treatments.
−Removed: The communication also encouraged patients to speak with their healthcare providers about the risks and benefits of UKONIQ and possible alternative treatments.
−Removed: The FDA's plan to convene an ODAC, issuance of a partial clinical hold on selected studies of U2 and its components, and release of the Drug Safety Communication have adversely affected our business, and we expect that these agency actions will continue to do so until the FDA makes a decision on the BLA/sNDA for U2 for the treatment of CLL and SLL.
−Removed: In light of the FDA’s plan to hold an ODAC meeting, we face substantial uncertainty regarding whether FDA will approve U2 and whether we will be able to maintain approval of UKONIQ.
−Removed: The ODAC and the FDA may rely on a different data set from UNITY-CLL, have a different interpretation of the results of that study, and reach a different assessment of the benefit-risk profile of U2 and UKONIQ than we do.
−Removed: The ODAC may recommend against approving U2 and against maintaining the current approvals of UKONIQ or may provide advisory input that adversely impacts the commercial opportunity for U2 and UKONIQ.
−Removed: Although we anticipate that the ODAC meeting will be scheduled in March or April 2022, we do not know how long it will take after the ODAC convenes for the FDA to make a decision on our BLA/sNDA and the benefit-risk of UKONIQ in its approved indications.
−Removed: The full extent of the planned ODAC meeting is unknown.
−Removed: Even if the ODAC recommends approval of U2 and continued approval of UKONIQ, the FDA may not agree with that recommendation if it determines that the applicable regulatory criteria for approval are not satisfied or the FDA may require inclusion of warnings or limitations in the labeling that are not acceptable to patients or healthcare providers.
−Removed: If we are unable to obtain regulatory approval for U2 or maintain approval of UKONIQ, our business will be materially harmed.
−Removed: Furthermore, our business will be adversely affected if the partial clinical hold cannot be favorably resolved in a
−Removed: timely manner or if such regulatory concerns lead to more burdensome clinical or preclinical studies that cause significant delay or expense in the research or development of U2 or UKONIQ.
Risks Related to Commercialization
−Removed: If we obtain FDA approval of U2 in CLL/SLL or ublituximab in RMS and do not achieve broad market acceptance among physicians, patients, healthcare payors, and the medical community, the revenues that we generate from product sales will be limited.
−Removed: We have one marketed product, UKONIQ, which received accelerated approval from the FDA on February 5, 2021 for the treatment of R/R MZL in adult patients who have received at least one prior anti-CD20-based regimen and R/R FL in adult patients who have received at least three prior lines of systemic therapy.
−Removed: The FDA is currently reviewing our BLA and sNDA requesting approval of U2 as a treatment for patients with CLL/SLL and our BLA for ublituximab for the treatment of RMS.
−Removed: While we have initiated the commercial launch of UKONIQ in the U.S.
−Removed: and have started internal planning for potential commercialization of ublituximab, we have limited experience as a commercial company and our ability to successfully overcome the risks associated with commercializing drugs in the biopharmaceutical industry, including the risk that our products do not achieve an adequate level of acceptance, remains uncertain.
−Removed: UKONIQ as well as other drugs that we may bring to the market in the future, including ublituximab, may not gain market acceptance by physicians, patients, third-party payors and others in the healthcare community.
−Removed: If our products do not achieve an adequate level of acceptance, we may not generate significant revenues or meet our revenue projections or guidance, and we may not become profitable.
−Removed: The degree of market acceptance of UKONIQ, as well as any future product candidates for which we obtain approval such as U2 in CLL/SLL and ublituximab in RMS, will depend on a number of factors, including:
+Added: If we obtain FDA approval for a product candidate and do not achieve broad market acceptance among physicians, patients, healthcare payors, and the medical community, the revenues that we generate from product sales will be limited.
+Added: We currently have one marketed product, BRIUMVI, which received approval from the FDA on December 28, 2022, for the treatment of relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
+Added: While we have initiated the commercial launch of BRIUMVI in the U.S., we have limited experience as a commercial company, and our ability to successfully overcome the risks associated with commercializing drugs in the biopharmaceutical industry, including the risk that our products do not achieve an adequate level of acceptance, remains uncertain.
+Added: BRIUMVI, as well as other drugs that we may bring to the market in the future, may not gain market acceptance by physicians, patients, third-party payors and others in the healthcare community.
+Added: As a result, we may not generate significant revenues or meet our revenue projections or guidance and may not become profitable.
+Added: The degree of market acceptance of BRIUMVI, as well as any future product candidates for which we may receive approval, will depend on a number of factors, including:
● the timing of our receipt of marketing approvals, the terms of such approvals, and the countries in which such approvals are obtained;
● the efficacy, safety and tolerability as demonstrated in clinical trials and as compared to alternative treatments;
−Removed: ● the timing of market introduction of any of our product candidates as well as competitive products;
+Added: ● the timing of market introduction of BRIUMVI and any of our product candidates, as well as competitive products;
● the indications for which our products are approved, and other aspects of the approved labeling for such products;
−Removed: ● acceptance by physicians, major operators of cancer or neurology clinics, and patients of our products as safe, tolerable and effective treatments;
+Added: ● acceptance by physicians, advanced practitioners, major operators of neurology clinics, and patients of our products as safe, tolerable and effective treatments;
● the potential and perceived advantages or disadvantages of our products compared to alternative treatments;
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● favorable or unfavorable publicity relating to our products or relating to the Company.
−Removed: The COVID-19 pandemic continues to present a substantial global public health risk and economic challenge.
−Removed: The measures to control the spread of COVID-19 have impacted our approach to the commercial launch of UKONIQ and may impact our ability to successfully launch ublituximab, if approved.
−Removed: We initiated commercial sales of UKONIQ in February 2021 in an environment in which the measures taken by state and local governments as well as hospitals and oncology clinics to control the spread of COVID-19 significantly limited our opportunities for in-person interactions, including for example, interactions with physicians, hospitals, payors, and other customers at medical congresses.
−Removed: As a result of COVID-19 variants, many of the interactions our field personnel have with healthcare providers and other customers continue to be virtual.
−Removed: We cannot ensure that remote methods will be effective or as effective as in-person interactions.
−Removed: Other factors related to the COVID-19 pandemic that could impact commercialization of our products include delays in demand due to a reduction in medical visits by patients, impacts on the healthcare system and overall economy and increases in the number of uninsured or underinsured patients.
−Removed: Patients and healthcare providers have raised concerns that immunosuppressive products, like anti-CD20 antibodies and other B-cell targeted agents, may increase the risk of acquiring COVID-19 or lead to more severe complications upon
−Removed: These concerns may impact the commercial potential for ublituximab and other immunosuppressive products that we have in development.
−Removed: In addition, our office-based employees, consultants, vendors and certain customer segments are continuing to work remotely and many of our commercialization efforts are happening virtually.
−Removed: The length of time and full extent to which the COVID-19 pandemic directly or indirectly impacts our commercialization efforts depends on future developments that are highly uncertain, subject to change and are difficult to predict, including, whether, even after pandemic-related restrictions ease, there is a shift in how pharmaceutical field representatives interact with healthcare providers that could have a negative effect on our future business and operations.
+Added: In addition, the COVID-19 pandemic could impact commercialization of BRIUMVI.
+Added: Patients and healthcare providers have raised concerns that immunosuppressive products like anti-CD20 antibodies and other B-cell targeted agents may increase the risk of acquiring COVID-19 or lead to more severe complications or outcomes upon infection, including death.
+Added: These concerns may impact the commercial potential for BRIUMVI and other immunosuppressive products that we have in development.
+Added: The length of time and full extent to which the COVID-19 pandemic directly or indirectly impacts our commercialization efforts depends on future developments that are highly uncertain, subject to change and are difficult to predict.
For a discussion of additional pandemic-related risks to our business, see below under the heading “ Risks Related to the COVID-19 Pandemic.
−Removed: If UKONIQ or any future products for which we receive regulatory approval, including U2 in CLL/SLL and ublituximab in RMS, do not achieve an adequate level of acceptance by physicians, hospitals, healthcare payors and patients, we may not generate sufficient revenue from these products and we may not become or remain profitable, which would have a material adverse effect on our business.
−Removed: We may be subject to limitations on the indicated uses or requirements to fulfill certain post-marketing requirements to the satisfaction of regulatory authorities or may be unable to maintain marketing approval for UKONIQ or future products that we may bring to market.
−Removed: Regulatory approvals for any of our product candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or contain requirements for potentially costly post-marketing testing, including Phase IV clinical trials, and surveillance to monitor the safety and efficacy of the approved product candidate.
−Removed: With respect to the FDA’s approval of UKONIQ for relapsed or refractory MZL and FL, we received accelerated approval and are subject to certain post-approval requirements.
−Removed: For example, we will need to conduct a confirmatory clinical trial, which will involve a Phase 3 trial that may be expensive and time-consuming and difficult to complete with the time frame expected by the FDA.
−Removed: Moreover, the confirmatory clinical trial may not confirm the benefit making the MZL and FL indications for UKONIQ subject to withdrawal of continued approval by the FDA or voluntary withdrawal by the Company, which could significantly harm our business.
−Removed: In addition, we will need to conduct additional clinical studies to address post-marketing commitments and post-marketing requirements related to further assessing the drug-drug interaction profile of UKONIQ and its safety, efficacy, and pharmacokinetic properties in certain at-risk populations.
−Removed: These studies are highly specialized in their design and conduct and are associated with considerable expenses, and based on the outcome, could result in further labeling restrictions that could impair or restrict the way in which we are able to market UKONIQ, or negatively impact its overall clinical profile.
−Removed: In addition, with respect to UKONIQ, and any product candidate that the FDA or a comparable foreign regulatory authority approves, the manufacturing processes, labeling, packaging, distribution, import, export, adverse event reporting, storage, advertising, promotion and recordkeeping for the product will be subject to extensive and ongoing regulatory requirements.
−Removed: These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with current Good Manufacturing Practices, or GMPs, with Good Clinical Practices, or GCPs, for any clinical trials that we conduct post-approval, and with Good Laboratory Practices, or GLPs, for any nonclinical studies.
+Added: If BRIUMVI, or any future product candidates for which we receive regulatory approval, do not achieve an adequate level of acceptance by physicians, hospitals, healthcare payors and patients, we may not generate sufficient revenue from these products and we may not become or remain profitable, which would have a material adverse effect on our business.
+Added: We may be subject to limitations on the indicated uses or requirements to fulfill certain post-marketing requirements to the satisfaction of regulatory authorities or may be unable to maintain marketing approval for BRIUMVI or future products that we may bring to market.
+Added: Regulatory approvals for our product or any of our product candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or contain requirements for potentially costly post-marketing testing, including Phase IV clinical trials, and surveillance to monitor the safety and efficacy of the approved product candidate.
+Added: For example, with respect to the FDA’s approval of BRIUMVI for RMS, maintenance of this approval is subject to certain post-marketing requirements and commitments, including long-term safety studies, as well as studies to evaluate the effects of BRIUMVI in pregnant women and pediatric populations, among others.
+Added: These studies are highly specialized in their design and conduct and are associated with considerable expenses, and based on the outcome, could result in further labeling restrictions that could impair or restrict the way in which we are able to market BRIUMVI, or negatively impact its overall clinical profile.
+Added: In addition, with respect to BRIUMVI and any product candidate that the FDA or a comparable foreign regulatory authority approves, the manufacturing processes, testing, labeling, packaging, distribution, import, export, adverse event reporting, storage, advertising, promotion and recordkeeping for the product will be subject to extensive and ongoing regulatory requirements.
+Added: These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with current Good Manufacturing Practices (GMPs), with Good Clinical Practices (GCPs), for any clinical trials that we conduct post-approval, and with Good Laboratory Practices (GLPs), for any nonclinical studies.
Later discovery of previously unknown problems with a product or with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things, restrictions on the marketing or manufacturing of the product, withdrawal of the product from the market, mandatory safety labeling changes or product recalls, suspension or revocation of product approvals, product seizure or detention, refusal to permit the import or export of products, and injunctions or the imposition of civil or criminal penalties, all of which would adversely affect our business, prospects and ability to achieve or sustain profitability.
−Removed: UKONIQ, and any of our product candidates for which we in the future obtain approval, may after approval be found to cause undesirable side effects that could result in significant negative consequences following commercialization.
−Removed: As UKONIQ or any future approved products are used more widely or for a longer duration after being brought to market, data may emerge from clinical studies, including confirmatory or other post-marketing studies, or from adverse event reporting that may affect the commercial potential of our products.
−Removed: For example, as additional patients are exposed for longer durations to UKONIQ in the commercial and clinical settings, it is unknown whether greater frequency and/or severity of adverse events are likely to occur or whether an acceptable safety and tolerability profile will continue to be demonstrated.
−Removed: If we or others identify unexpected side effects, caused by UKONIQ or our product candidates following introduction into the market, a number of potentially significant negative consequences could result, including:
+Added: BRIUMVI, and any of our product candidates for which we in the future obtain approval, may, after approval, be found to cause undesirable side effects that could result in significant negative consequences following commercialization.
+Added: As BRIUMVI or any future approved products are used more widely or for a longer duration after being brought to market, data may emerge from clinical studies, including confirmatory or other post-marketing studies, or from adverse event reporting, that may affect the commercial potential of our products.
+Added: For example, as additional patients are exposed for longer durations to a product in the commercial and clinical settings, it is unknown whether greater frequency and/or severity of adverse events are likely to occur or whether an acceptable safety and tolerability profile will continue to be demonstrated.
+Added: If we or others identify unexpected side effects, caused by BRIUMVI or our product candidates following introduction into the market, a number of potentially significant negative consequences could result, including:
● regulatory authorities may withdraw or limit the use (indication) of such products;
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Any one or a combination of these events could prevent us from maintaining regulatory approval and achieving or maintaining market acceptance of the affected product or could substantially increase the costs and expenses of commercializing the affected product, which in turn could significantly impact our ability to successfully commercialize our drug candidates and generate revenues.
−Removed: The incidence and prevalence for target patient populations of UKONIQ and our product candidates, including U2 in CLL/SLL and ublituximab in RMS, have not been established with precision.
−Removed: If the market opportunities for UKONIQ and our product candidates are smaller than we estimate or if any approval that we obtain is based on a narrower definition of the patient population, our revenue and ability to achieve profitability will be adversely affected, possibly materially.
−Removed: The precise incidence and/or prevalence of R/R MZL after one prior anti-CD20-based regimen, R/R FL after three prior lines of systemic therapy, CLL, and RMS are unknown.
−Removed: Our projections of both the number of patients within our FDA-approved indications for UKONIQ and target indications for U2 in CLL/SLL and ublituximab in RMS, as well as the subset of these patients who have the potential to benefit from treatment with our products, are based on estimates.
+Added: The incidence and prevalence for target patient populations of BRIUMVI and our product candidates, including TG-1701 and TG-1801 in B-cell disorders, have not been established with precision.
+Added: If the market opportunities for BRIUMVI and our product candidates are smaller than we estimate or if any approval that we obtain is based on a narrower definition of the patient population, our revenue and ability to achieve profitability will be adversely affected.
+Added: The precise incidence and/or prevalence of RMS are unknown.
+Added: Our projections of ublituximab in RMS, as well as the subset of these patients who have the potential to benefit from treatment with our products are based on estimates and our current knowledge and understanding of the disease.
These estimates are typically based on one-on-one and group interactions with target physicians and other sources available at the time we make the estimates, including the scientific literature, healthcare utilization databases and market research.
−Removed: Although we believe our estimates are reasonable, many factors may limit their accuracy.
+Added: Although we believe our estimates are reasonable, and although there has been no material adverse condition in the market so far, many factors may limit their accuracy.
For example, the sources we use to make the estimates may prove to be incorrect.
Further, new studies may change the estimated incidence or prevalence of these diseases and the number of patients may turn out to be lower than expected.
−Removed: The total addressable market opportunity for UKONIQ in MZL and FL, U2 in CLL/SLL, and ublituximab in RMS will ultimately depend upon, among other things, the scope of the final approved indication and other elements of the approved prescribing information, acceptance by the medical community, patient access, and drug pricing and reimbursement.
+Added: The total addressable market opportunity for BRIUMVI ultimately depends upon, among other things, the approved prescribing information, acceptance by the medical community, patient access, and drug pricing and reimbursement.
The number of patients in major markets, including the number of addressable patients in those markets, may turn out to be lower than expected, patients may not be otherwise amenable to treatment with our drugs, new patients may become increasingly difficult to identify or gain access to, or patients and physicians may choose to utilize competitive products, all of which would adversely affect our results of operations and our business.
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Large pharmaceutical companies have extensive experience in clinical testing and obtaining regulatory approval for drugs.
−Removed: Additionally, many universities and private and public research institutes are active in cancer research, some in direct competition with us.
+Added: Additionally, many universities and private and public research institutes are active in research in the same diseases that we are, including in the fields of neurology and immunology, some in direct competition with us.
We may also compete with these organizations to recruit scientists and clinical development personnel.
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New developments, including the development of other pharmaceutical technologies and methods of treating disease, occur in the pharmaceutical and life sciences industries at a rapid pace.
−Removed: These developments may render our product candidates obsolete or noncompetitive.
+Added: These developments may render our product or product candidates obsolete or noncompetitive.
Compared to us, many of our potential competitors have substantially greater:
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● capital resources.
−Removed: We will also face competition from these third parties in recruiting and retaining qualified personnel, establishing clinical trial sites, patient registration for clinical trials, and in identifying and in-licensing new product candidates.
−Removed: UKONIQ, as well as any products that we are able to commercialize in the future, may become subject to unfavorable pricing regulations or third-party payor coverage and reimbursement policies, which would harm our business.
+Added: We will also face competition from these third parties in recruiting and retaining qualified personnel, establishing clinical trial sites, patient registration for clinical trials, and in identifying and in-licensing new products and product candidates.
+Added: BRIUMVI, as well as any products that we are able to commercialize in the future, may become subject to unfavorable pricing regulations or third-party payor coverage and reimbursement policies, which would harm our business.
The regulations that govern regulatory approvals, pricing and reimbursement for new drugs vary widely from country to country.
+Added: Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals.
Some countries require approval of the sale price of a drug before it can be marketed.
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As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay our commercial launch of the drug candidate, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the drug candidate in that country.
−Removed: Adverse pricing limitations may hinder our ability to recoup our investment in one or more products, even if our product candidates obtain marketing approval.
+Added: Adverse pricing limitations may hinder our ability to recoup our investment in one or more products, even if more of our product candidates obtain marketing approval.
Eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution.
Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent.
−Removed: In addition, if we are successful in obtaining FDA approval for ublituximab for the treatment of CLL/SLL and RMS, we will need to identify and execute a pricing strategy that takes into account the value of the product in each indication independently to realize the product’s full potential in both indications.
−Removed: If we are unable to identify and execute such a strategy, the pricing of ublituximab across indications may not be optimal, which may have a material adverse impact on the sales in one or both of the indications and on our overall business.
Our ability to commercialize any product successfully also will depend in part on the extent to which coverage and reimbursement for our products and related treatments will be available from government authorities, private health insurers and other organizations.
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Payors may restrict coverage of some products by using formularies under which only selected drugs are covered, variable co-payments that make drugs that are not preferred by the payor more expensive for patients, and utilization management controls, such as requirements for prior authorization or failure first on another type of treatment.
−Removed: Payors may target higher-
−Removed: priced drugs for imposition of these obstacles to coverage, and consequently our products may be subject to payer-driven restrictions.
+Added: Payors may target higher-priced drugs for imposition of these obstacles to coverage, and consequently our products may be subject to payer-driven restrictions.
Additionally, in countries where patients have access to insurance, as in the U.S., insurance co-payment amounts or other benefit limits may represent a barrier to obtaining or continuing use of our products that receive regulatory approval.
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The calculations necessary to determine the prices reported are complex and the failure to report prices accurately may expose us to penalties.
−Removed: If, in the future, we are unable to expand our commercial operations, including sales and marketing capabilities or enter into agreements with third parties to sell and market our drug candidates, we may not be successful in commercializing our product candidates if and when they are approved, and we may not be able to generate any revenue.
+Added: If we are unable to expand our commercialization operations, we may not be successful in commercializing BRIUMVI or any product candidate, if and when such product candidates are approved, and we may not be able to generate any revenue.
+Added: Commercialization of pharmaceutical products is an extremely complex and highly capital and resource intensive process, even for established companies with existing infrastructure and significantly greater resources than we have, challenges have occurred.
We have made and continue to make significant investments in our commercial organization and infrastructure.
−Removed: We have hired and continue to hire marketing, sales, and medical support personnel and have built processes and systems to support the commercialization of UKONIQ in the U.S.
−Removed: We are expanding our commercialization team and infrastructure in planning for the potential commercial launches of U2 in CLL/SLL and ublituximab in RMS prior to knowing whether the FDA will accept or approve the necessary regulatory submissions.
−Removed: It is possible that either or both FDA approvals are unexpectedly delayed or are not received at all.
−Removed: For example, in November 2021, the FDA notified the Company that it planned to discuss the benefit-risk profile of U2 in CLL/SLL as well as UKONIQ in the approved indications during an ODAC meeting to be held in March or April 2022.
−Removed: Given the timing of the ODAC, the Company anticipates it is unlikely that the FDA will make a decision on the BLA/sNDA by the PDUFA goal date of March 25, 2022.
−Removed: See “Risks Related to the Development and Commercialization of U2 and UKONIQ.” A significant delay in regulatory approval will cause us to incur delays that may impede or significantly delay our ability to generate revenue while incurring significant expenses, which would have a material adverse effect on the Company.
−Removed: There are risks involved with establishing our own sales, marketing, and other commercialization capabilities.
−Removed: For example, recruiting and training a sales force is both expensive and time-consuming, and could potentially delay any drug launch.
−Removed: If the commercial launch of a product candidate (e.g., U2 in CLL/SLL or ublituximab in MS) for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses.
−Removed: This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.
−Removed: Factors that may inhibit our efforts to commercialize UKONIQ and our product candidates on our own and generate product revenues include:
−Removed: ● our inability to recruit and retain adequate numbers of effective sales and marketing personnel;
−Removed: ● the costs and time associated with the initial and ongoing training of sales and marketing personnel on the applicable disease states, products, competitors, and legal and regulatory compliance matters;
−Removed: ● the inability of sales personnel to obtain access to physicians or to effectively promote UKONIQ or any future drugs;
−Removed: ● the lack of complementary drugs to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines;
+Added: We built processes and systems to support the commercialization of UKONIQ in the U.S.
+Added: Although we withdrew UKONIQ from sale, we are using and expanding upon many of those systems and processes to market BRIUMVI following its commercial launch on January 26, 2023.
+Added: There are risks involved with establishing our own commercialization capabilities.
+Added: For example, if we are unable to recruit and retain adequate numbers of effective personnel to support the ongoing commercialization of BRIUMVI, we may not be successful in marketing and selling the product.
+Added: Additional factors that may inhibit our efforts to commercialize BRIUMVI and our other product candidates on our own and generate product revenues include:
+Added: ● the costs and time associated with the initial and ongoing training of commercialization personnel on the applicable disease states, products, competitors, and legal and regulatory compliance matters;
+Added: ● the inability of commercialization personnel to obtain access to physicians or to effectively promote or provide education about BRIUMVI and any future approved products;
+Added: ● the lack of complementary drugs to be offered by the Company, which may put us at a competitive disadvantage relative to companies with more extensive product lines;
+Added: ● decisions by third-party payors to deny reimbursement of or delay coverage decisions regarding BRIUMVI or following approval of any product candidates;
● our ability to maintain a healthcare compliance program including effective mechanisms for compliance monitoring;
−Removed: ● unforeseen costs and expenses associated with creating a sales and marketing organization.
−Removed: In the future, we may choose to participate in sales activities with collaborators for some of our product candidates if and when they are approved.
+Added: ● the timing of product availability for commercial sale following approval and continued product supply;
+Added: ● unforeseen costs and expenses associated with creating a commercialization organization
+Added: In the future, we may choose to participate in sales activities with collaborators for our product and for our product candidates if and when they are approved, particularly for regions outside the U.S.
However, there are also risks with entering into these types of arrangements with third parties to perform sales, marketing and distribution services.
For example, we may not be able to enter into such arrangements on terms that are favorable to us.
−Removed: Our drug revenues or the profitability of these drug revenues to us are likely to be lower than if we were to market and sell any product candidates that we develop ourselves.
−Removed: In addition, we likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our product candidates effectively.
−Removed: If we do not establish sales and marketing capabilities
−Removed: successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing our drug candidates.
+Added: Our drug revenues or the profitability of these drug revenues to us are likely to be lower than if we were to market and sell any products or product candidates that we develop ourselves.
+Added: In addition, we likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our product or product candidates effectively.
+Added: If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing our drug candidates.
Further, our business, results of operations, financial condition and prospects will be materially adversely affected.
−Removed: We are also planning for expansion into certain European markets.
+Added: We may expand into certain European markets.
Building and maintaining an infrastructure outside the United States is expensive, complex, resource intensive and time consuming.
−Removed: Like the situation described above in the U.S., we will need to establish our infrastructure in planning for potential commercial launches in Europe prior to knowing whether the regulatory authorities will accept or approve our regulatory submissions or approve any of our products at an appropriate price.
−Removed: In either case we will incur delays that may impede or significantly delay our ability to generate revenue in those international markets and at the same time will incur significant expenses.
−Removed: If this were to occur, it could materially and adversely affect our business operations and financial condition.
+Added: We have not undertaken significant commercialization activities outside of the U.S., including in the EU, where the potential market opportunity for ublituximab, if approved, is smaller than the U.S.
+Added: If we were to do so, we would expect to incur significant expenses in establishing an infrastructure to commercialize outside the U.S.
+Added: If this were to occur, depending on the expenses incurred, it could have a negative impact our cash resources.
Product liability lawsuits against us could cause us to incur substantial liabilities and could limit commercialization of any drug candidates that we may develop.
−Removed: We face an inherent risk of product liability exposure related to the testing of our product candidates in human clinical trials, and an even greater risk in connection with the commercialization of UKONIQ and any other product candidates for which we may receive marketing authorization in the future.
−Removed: If we cannot successfully defend ourselves against claims that UKONIQ or our product candidates caused injuries, we could incur substantial liabilities.
+Added: We face an inherent risk of product liability exposure related to the testing of our product candidates in human clinical trials, and an even greater risk in connection with the commercialization of BRIUMVI and any other products for which we may receive marketing authorization in the future.
+Added: If we cannot successfully defend ourselves against claims that BRIUMVI or any of our product candidates caused injuries, we could incur substantial liabilities.
Regardless of merit or eventual outcome, liability claims may result in:
2 unchanged sentences
● withdrawal of clinical trial participants;
−Removed: ● significant costs to defend the related litigation;
+Added: ● significant costs to defend the related litigation, including the risk that any individuals who may face such related litigation may in turn seek to recover from us;
● substantial monetary awards to trial participants or patients;
● loss of revenue;
−Removed: ● the inability to commercialize any product candidates that we may develop.
+Added: ● the inability to commercialize any products or product candidates that we may develop.
Although we maintain product liability insurance coverage, it may not be adequate to cover all liabilities that we may incur.
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We commenced operations in January 2012.
−Removed: Our operations to date have been limited primarily to organizing and staffing our company, business planning, raising capital, developing our technology, identifying potential drug candidates, undertaking pre-clinical studies and clinical trials, commercializing our only marketed product UKONIQ, which received FDA approval in February 2021, and preparing for potential commercialization of ublituximab.
−Removed: We are transitioning from a company with a research and development focus to a company capable of supporting commercial activities, potentially across hematology and neurology as well as in the U.S.
+Added: To date, our operations have been limited primarily to organizing and staffing our company, business planning, raising capital, developing our technology, identifying potential drug candidates, undertaking pre-clinical studies and clinical trials, commercializing UKONIQ (which we withdrew from sale), and launching BRIUMVI.
+Added: We are transitioning from a company with a research and development focus and commercialization capabilities in oncology to a company capable of supporting commercial activities in neurology and immunology in the U.S.
and outside the U.S.
−Removed: We may not be successful in such a transition.
−Removed: Since inception, we have focused our efforts and financial resources on clinical trials, manufacturing of our drug candidates, and preparing to support a commercial product.
−Removed: To date, we have financed our operations primarily through public offerings of our common stock and a debt financing.
+Added: This transition involves a wide variety of risks, and we may not be successful in such transition.
+Added: Since inception, we have focused our efforts and financial resources on clinical trials, manufacturing of our product and product candidates, and preparing to support a commercial product.
+Added: To date, we have financed our operations primarily through public offerings of our common stock and debt financing.
Since inception, we have incurred significant operating losses.
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Our prior losses, combined with expected future losses, have had, and will continue to have an adverse effect on our stockholders’ deficit and working capital.
−Removed: Other than the FDA approval of UKONIQ, we have not obtained marketing approval for any of our product candidates, which are in preclinical or clinical development stages.
−Removed: We expect to continue to incur significant research and development expenses in connection with continuing our existing clinical trials and beginning additional clinical trials.
−Removed: In addition, we expect to continue to incur significant sales, marketing and outsourced-manufacturing expenses as we commercialize UKONIQ and plan for the possible commercialization of ublituximab in CLL/SLL and RMS, if approved.
−Removed: Because of the numerous risks and uncertainties associated
−Removed: with developing pharmaceuticals, we are unable to predict the extent of any future losses or when we will become profitable, if at all.
+Added: BRIUMVI is currently our only marketed product.
+Added: We expect to continue to incur significant research and development expenses and we expect to continue to incur significant commercialization and outsourced-manufacturing expenses as we commercialize BRIUMVI.
+Added: Because of the numerous risks and uncertainties associated with developing pharmaceuticals, we are unable to predict the extent of any future losses or when we will become profitable, if at all.
Even if we do become profitable, we may not be able to sustain or increase our profitability on a quarterly or annual basis.
Our ability to become profitable depends upon our ability to generate substantial revenue.
−Removed: To date, we have not generated any significant revenue from our product sales, and it is uncertain when and if we will generate any significant revenue from the sale of our products in the future.
−Removed: Furthermore, no assurance can be given that we will meet revenue projections or guidance.
−Removed: To obtain significant and sustained revenues and meet our revenue projections or guidance, we must succeed, either alone or with others, in (i) developing and obtaining regulatory approval for our product candidates, including ublituximab, and for additional indications of UKONIQ;
+Added: We have not generated any significant revenue from sales of any of our products.
+Added: It is uncertain when and if we will generate any significant revenue from the sale of our product or any product candidates, if approved, in the future.
+Added: Furthermore, no assurance can be given that we will meet revenue projections or guidance with respect to BRIUMVI or our product candidates, if approved.
+Added: To obtain significant and sustained revenues and meet our revenue projections or guidance, we must succeed, either alone or with others, in (i) obtaining and maintaining regulatory approval for our product and product candidates;
and (ii) manufacturing and marketing our products and product candidates.
−Removed: Accordingly, we do not expect to generate significant and sustained revenue unless and until we obtain marketing approval of ublituximab and additional indications of UKONIQ and/or one of our other product candidates.
−Removed: Our ability to generate significant and sustained revenue or meet revenue projections or guidance depends on a number of factors, including, but not limited to, our ability to:
+Added: Our ability to generate sustained revenue depends on a number of factors, including, but not limited to, our ability to:
● successfully complete clinical trials that meet their clinical endpoints;
● initiate and successfully complete all safety, pharmacokinetic, biodistribution, and non-clinical studies required to obtain U.S.
−Removed: and foreign marketing approval for our product candidates;
−Removed: ● obtain approval from the FDA and foreign equivalents to market and sell our product candidates, including ublituximab in CLL /SLL and RMS, and maintain FDA approval of UKONIQ for relapsed or refractory MZL and FL;
−Removed: ● establish commercial manufacturing capabilities with third parties that are satisfactory to the regulatory authorities, cost effective, and that are capable of providing commercial supply of our product candidates, or, in the case of UKONIQ, maintain these capabilities;
−Removed: ● expand on our commercial infrastructure to commercialize ublituximab, our other product candidates, and additional indications of UKONIQ, if approved, by increasing the size of our sales force and commercialization infrastructure and/or entering into collaborations with third parties;
−Removed: ● achieve market acceptance of UKONIQ and our product candidates, if approved, in the medical community and with third-party payors.
+Added: and foreign marketing approval for our product and product candidates;
+Added: ● obtain approval from the FDA and foreign equivalents to market and sell our product and product candidates, and maintain FDA approval of BRIUMVI for RMS;
+Added: ● establish and maintain commercial manufacturing capabilities with third parties that are satisfactory to the regulatory authorities, cost effective, and that are capable of providing commercial supply of our product and product candidates;
+Added: ● expand on our commercialization infrastructure to commercialize BRIUMVI, and/or entering into collaborations with third parties;
+Added: ● achieve market acceptance of BRIUMVI and any other products for which we may receive regulatory approval in the medical community and with third-party payors.
If we are unable to generate significant and sustained revenues, we will not become profitable and we will be unable to continue our operations without continued funding.
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The development of pharmaceuticals is capital-intensive.
−Removed: We are currently advancing our most advanced drug candidates, ublituximab, cosibelimab, TG-1701 and TG-1801, and UKONIQ for additional indications through clinical development.
−Removed: While we may experience short-term decreases in clinical trial expenses as our larger Phase 3 clinical trials complete and before our Phase 1 and 2 programs can advance into Phase 2 and 3, we do expect over time our overall expenses will increase in connection with our ongoing activities, particularly as we continue the research and development of, initiate or continue clinical trials of, seek marketing approval for, and expand our infrastructure to commercialize our product candidates and additional indications of UKONIQ.
−Removed: Moreover, in anticipation of potential regulatory approvals for UKONIQ and ublituximab in CLL/SLL and for ublituximab in RMS, we will need to expend substantial resources on BLA support, including preparation for the ODAC meeting on U2 in CLL and SLL over the next 6 to 12 months, and on manufacturing support over the next 12 to 18 months, which could exceed any cost savings associated with lower clinical trial expenses during the same period.
−Removed: While this timing is our current estimate, the amount and timing of our future funding requirements will depend on many factors, including, but not limited to, the following:
−Removed: ● the progress of our clinical trials, including expenses to support the trials and milestone payments that may become payable under our license agreements;
−Removed: ● developments relating to the COVID-19 pandemic in the U.S.
−Removed: and around the world;
−Removed: ● the costs and timing of regulatory approvals;
+Added: We are currently advancing our early-stage drug candidates, TG-1701 and TG-1801 in ongoing Phase 1 studies to identify tolerable and efficacious doses, we are also advancing BRIUMVI for long-term tolerability in an Open-Label Extension of the Phase 3 ULTIMATE I and II trials and anticipate conducting additional clinical studies in the near future including those necessary to satisfy post-approval commitments for regulatory authorities.
+Added: Moreover, now that we have launched BRIUMVI, we will need to expend substantial resources on maintaining approvals, continuing commercialization, and manufacturing over the next 6 to 12 months.
+Added: The amount and timing of our future funding requirements will depend on many factors, including, but not limited to, the following:
+Added: ● the success of the commercialization of BRIUMVI and any other products for which we receive regulatory approval;
● the costs and timing of clinical and commercial manufacturing supply arrangements for each product and product candidate;
● the costs of expanding our sales, distribution, and other commercialization capabilities;
−Removed: ● the success of the commercialization of UKONIQ and any product candidates, if approved;
+Added: ● the costs and timing of regulatory approvals;
+Added: ● the progress of our clinical trials, including expenses to support the trials and milestone payments that may become payable under our license agreements;
● our ability to establish and maintain strategic collaborations, including licensing and other arrangements;
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Additional sources of financing to continue our operations in the future might not be available on favorable terms, if at all.
−Removed: If we do not succeed in raising additional funds on acceptable terms, we might be unable to complete planned preclinical studies and clinical trials or obtain approval of any of our product candidates from the FDA or any foreign regulatory authorities.
−Removed: In addition, we could be forced to discontinue product development, reduce or forego sales, marketing and medical educational efforts that are required for successful commercialization of UKONIQ, ublituximab (if approved), or any of our other product candidates and otherwise forego attractive business opportunities.
−Removed: Any additional sources of financing will likely involve the issuance of our equity securities, which would have a dilutive effect to stockholders.
−Removed: Currently, other than UKONIQ, our products are investigational and have not been approved by the FDA or any foreign regulatory authority for sale.
−Removed: Therefore, for the foreseeable future, we will have to fund all of our operations and capital expenditures from sales of UKONIQ in the U.S., cash on hand and amounts raised in future offerings or financings.
+Added: If we do not succeed in raising additional funds on acceptable terms, we could be forced to discontinue product development, reduce or forego commercialization efforts that are required for successful commercialization of BRIUMVI, or any of our product candidates and otherwise forego attractive business opportunities.
+Added: Any additional sources of financing may involve the issuance of our equity securities, which would have a dilutive effect to stockholders.
+Added: Currently, other than BRIUMVI, our products are investigational and have not been approved by the FDA or any foreign regulatory authority for sale.
+Added: For the foreseeable future, we will have to fund all our operations and capital expenditures from sales of BRIUMVI in the U.S., cash on hand, and amounts raised in future offerings or financings.
Accordingly, our prospects must be considered in light of the uncertainties, risks, expenses and difficulties frequently encountered by companies in the early stages of commercial operations and the competitive environment in which we operate.
Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or drug candidates and occupy valuable management time and resources.
−Removed: Until such time, if ever, as we can generate substantial drug revenues, we expect to finance our cash needs through a combination of public and private equity offerings, debt financings, collaborations, strategic alliances and licensing arrangements.
+Added: Until such time, if ever, as we can generate substantial revenues, we expect to finance our cash needs through a combination of public and private equity offerings, debt financings, collaborations, strategic alliances and licensing arrangements.
We do not have any committed external source of funds, other than funds already borrowed under the loan and security agreement that we entered into with Hercules in February 2019, and which was expanded in December 2021 ( see Note 6 to our consolidated financial statements for more information).
To the extent that we raise additional capital through the sale of common stock or securities convertible or exchangeable into common stock, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that materially adversely affect the rights of our common stockholders.
−Removed: We may also seek funds through collaborations, strategic alliances or licensing arrangements with third parties at a time that is not desirable to us and we may be required to relinquish valuable rights to some intellectual property, future revenue streams, research programs or drug candidates or to grant licenses on terms that may not be favorable to us, any of which may have a material adverse effect on our business, operating results and prospects.
+Added: We may also seek funds through collaborations, strategic alliances or licensing arrangements with third parties at a time that is not desirable to us and we may be required to relinquish valuable rights to some intellectual property, future revenue streams, research programs or products and product candidates or to grant licenses on terms that may not be favorable to us, any of which may have a material adverse effect on our business, operating results and prospects.
Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures, or declaring dividends.
+Added: We cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us, if at all, which could limit our ability to expand our business operations and could harm our overall business prospects.
See our risk factors below under the heading “Risks Related to Our Indebtedness.”
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Dislocations in the financial markets have generally made equity and debt financing more difficult to obtain and may have a material adverse effect on our ability to meet our fundraising needs.
−Removed: We cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us, if at all.
Moreover, the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may cause the market price of our shares to decline.
Long-term commercialization and product candidate development timelines and projections in this report are based on the assumption of further financing.
−Removed: The timelines and projections in this report are predicated upon the assumption that we will raise additional financing in the future to continue our long-term commercialization efforts and the development of our product candidates.
+Added: The timelines and projections in this report are predicated upon the assumption that we will raise additional financing in the future to continue our long-term commercialization efforts and the development of our product and product candidates.
In the event we do not successfully raise subsequent financing, such commercialization and product development activities may be curtailed commensurate with the magnitude of the shortfall.
If our commercialization or product development activities are slowed or stopped, we would be unable to meet the timelines and projections outlined in this filing.
−Removed: Failure to progress our commercialization activities or the development of our product candidates as anticipated will have a negative effect on our business, future prospects, and ability to obtain further financing on acceptable terms, if at all, and the value of the enterprise.
+Added: Failure to progress our commercialization activities or the development of our product and product candidates as anticipated will have a negative effect on our business, future prospects, and ability to obtain further financing on acceptable terms, if at all, and the value of the enterprise.
Due to limited resources, we may fail to capitalize on programs or product candidates that may present a greater commercial opportunity or for which there is a greater likelihood of success.
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Our level of indebtedness and debt service obligations could adversely affect our financial condition and may make it more difficult for us to fund our operations.
−Removed: In February 2019, we entered into a Loan and Security Agreement (the Loan Agreement), with Hercules Capital, Inc., a Maryland corporation (Hercules) and on December 30, 2021 (the First Amendment Closing Date), the Company entered into an Amended and Restated Loan and Security Agreement (the Amended Loan Agreement) with Hercules.
−Removed: Under the Amended Loan Agreement, Hercules increased the aggregate principal amount of the loan, available at the Company’s option, from $60.0 million to $200.0 million (the Amended Term Loan) (see Note 6 to our consolidated financial statements for more information).
−Removed: A first advance of $70.0 was million drawn at the First Amendment Closing Date, a portion of which was used to refinance the current outstanding loan balance of approximately $7.8 million.
−Removed: All obligations under the Amended Loan Agreement are secured by substantially all of our existing property and assets, excluding intellectual property.
+Added: In February 2019, we entered into a Loan and Security Agreement, with Hercules Capital, Inc., a Maryland corporation (Hercules) and on December 30, 2021 (the First Amendment Closing Date), the Company entered into an Amended and Restated Loan and Security Agreement (the Amended Loan Agreement) with Hercules.
+Added: Under the Amended Loan Agreement, Hercules increased the aggregate principal amount of the loan, available at the Company’s option, from $60.0 million to $200.0 million (see Note 6 to our consolidated financial statements for more information).
+Added: A first advance of $70.0 million was drawn at the First Amendment Closing Date, a portion of which was used to refinance the then outstanding loan balance of approximately $7.8 million.
+Added: Now that we have received approval for BRIUMVI, we have the option to request an additional $45.0 million under the Amended Loan Agreement.
+Added: Such option will lapse if not elected by March 31, 2023.
+Added: We have the option to request additional loan advances, in an aggregate principal amount of up to $65.0 million under the Amended Loan Agreement.
+Added: All obligations under the Amended Loan Agreement are secured by substantially all our existing property and assets, excluding intellectual property.
This indebtedness may create additional financing risk for us, particularly if our business or prevailing financial market conditions are not conducive to paying off or refinancing its outstanding debt obligations at maturity.
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We may not have cash available in an amount sufficient to enable us to make interest or principal payments on our indebtedness when due.
−Removed: Failure to satisfy our current and future debt obligations under the Amended Loan Agreement, or the breach of any of its covenants, subject to specified cure periods with respect to certain breaches, could result in an event of default and, as a result, Hercules could accelerate all of the amounts due.
+Added: Failure to satisfy our current and future debt obligations under the Amended Loan Agreement, or the breach of any of its covenants, subject to specified cure periods with respect to certain breaches, could result in an event of default and, as a result, Hercules could accelerate all the amounts due.
In the event of an acceleration of amounts due under the Amended Loan Agreement as a result of an event of default, we may not have enough available cash or be able to raise additional funds through equity or debt financings to repay such indebtedness at the time of such acceleration.
In that case, we may be required to delay, limit, reduce or terminate our product candidate development or commercialization efforts or grant to others rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.
−Removed: Hercules could also exercise its rights as collateral agent to take possession and dispose of the collateral securing the Term Loan for its benefit, which collateral includes substantially all of our property other than intellectual property.
+Added: Hercules could also exercise its rights as collateral agent to take possession and dispose of the collateral securing the term loan for its benefit, which collateral includes substantially all our property other than intellectual property.
Our business, financial condition and results of operations could be materially adversely affected as a result of any of these events.
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Risks Related to Drug Development and Regulatory Approval
−Removed: If we are unable to obtain regulatory approval for our product candidates and ultimately cannot commercialize one or more of them, or experience significant delays in doing so, our business will be materially harmed.
−Removed: We have invested substantially all of our efforts and financial resources in the identification and pre-clinical and clinical development of UKONIQ and our product candidates, including ublituximab, cosibelimab, TG-1701 and TG-1801, and building a commercial infrastructure.
−Removed: Our ability to generate revenues from product sales will depend completely on the successful completion of our current and future Phase 3 and registration-directed clinical trials and commercialization of our product candidates, including ublituximab and additional indications of UKONIQ, which may never occur.
−Removed: Each of our product candidates will require additional non-clinical or clinical development, regulatory approval in multiple jurisdictions, and we will need to obtain sufficient clinical and commercial supply.
+Added: If we are unable to obtain and maintain regulatory approval for our product candidates and ultimately cannot successfully commercialize our product or product candidates, or experience significant delays in doing so, our business will be materially harmed.
+Added: On April 15, 2022, we announced our voluntary withdrawal of the pending BLA and sNDA for U2 to treat CLL and SLL and the voluntary withdrawal of UKONIQ from the market.
+Added: We are still assessing the impact, if any, of the withdrawal of the BLA and sNDA for U2 and the withdrawal of UKONIQ from sale.
+Added: Our ability to generate revenues from product sales will depend largely on the successful commercialization of BRIUMVI.
+Added: Each of our product candidates will require additional non-clinical or clinical development, regulatory approval, and sufficient clinical and commercial supply.
The success of our development programs and achievement of regulatory approval of our product candidates will depend on several factors, including the following:
● successful completion of our clinical programs with positive results that support a finding of effectiveness and an acceptable safety profile of our product candidates in the intended populations within the timeframes we have projected;
−Removed: ● INDs and clinical trial applications, or CTAs, being cleared/approved such that our product candidates can commence clinical trials;
+Added: ● INDs and clinical trial applications (CTAs), being cleared/approved such that our product candidates can commence clinical trials;
● successful initiation and completion of preclinical studies and successful initiation of, enrollment in, and completion of clinical trials;
● sufficiency of our financial and other resources to complete the necessary preclinical studies and clinical trials;
−Removed: ● receipt of regulatory approvals from applicable regulatory authorities for our product candidates, including U2 in CLL and ublituximab in RMS;
+Added: ● receipt of regulatory approvals from applicable regulatory authorities for our product candidates;
● establishing commercially viable arrangements with third-party manufacturers for clinical supply and commercial manufacturing;
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The outcome of preclinical development testing and early clinical trials may not be predictive of the outcome of later clinical trials, and interim results of a clinical trial do not necessarily predict final results.
−Removed: 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 product candidates.
−Removed: Once a product candidate has displayed sufficient preclinical data to warrant clinical investigation, we will be required to demonstrate through adequate and well-controlled clinical trials that our product candidates are effective with a favorable benefit-
−Removed: risk profile for use in populations for their target indications before we can seek regulatory approvals for their commercial sale.
+Added: Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval.
+Added: Once a product candidate has displayed sufficient preclinical data to warrant clinical investigation, we will be required to demonstrate, through adequate and well-controlled clinical trials, that our product candidates are effective with a favorable benefit-risk profile for use in populations for their target indications before we can seek regulatory approvals for their commercial sale.
Many drug candidates fail in the early stages of clinical development for safety and tolerability issues or for insufficient clinical activity, despite promising pre-clinical results.
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In addition, larger scale Phase 3 studies, which are often conducted internationally, are inherently subject to increased operational risks compared to earlier stage studies, including the risk that the results could vary on a region to region or country to country basis, which could materially adversely affect the outcome of the study or the opinion of the validity of the study results by applicable regulatory agencies.
−Removed: From time to time, we may publicly disclose top-line or preliminary data from our clinical trials, which is based on a preliminary analysis of then available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial.
+Added: From time to time, we may publicly disclose top-line or preliminary data from our clinical trials, which is based on a preliminary analysis of available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial.
We also make assumptions, estimations, calculations and conclusions as part of our analyses of such data, and we may not have received or had the opportunity to fully and carefully evaluate all data from the particular study or trial, including all endpoints and safety data.
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Interim data from clinical trials that we may complete 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.
−Removed: For example, time-to-event based endpoints such as duration of response (DOR) and PFS have the potential to change, sometimes drastically, with longer follow-up.
+Added: For example, time-to-event based endpoints such as duration of response (DOR) and progression-free survival (PFS) have the potential to change with longer follow-up.
In addition, as patients continue on therapy, there can be no assurance given that the final safety data from studies, once fully analyzed, will be consistent with prior safety data presented, will be differentiated from other similar agents in the same class, will support continued development, or will be favorable enough to support regulatory approvals for the indications studied.
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The information we choose to publicly disclose regarding a particular study or clinical trial is based on what is typically extensive information, and regulators or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure.
−Removed: If the interim, top-line or preliminary data that we report differ from final results, or if others, including regulatory authorities, disagree with the conclusions we have reached, our ability to obtain approval for, or successfully commercialize, our product candidates may be harmed, which could harm our business, operating results, prospects or financial condition.
+Added: If the interim, top-line or preliminary data that we report differ from final results, or if others, including regulatory authorities, disagree with the conclusions we have reached, our ability to obtain approval for, or successfully commercialize, our product or product candidates may be harmed, which could harm our business, operating results, prospects or financial condition.
Many of the results reported in our early clinical trials rely on local investigator-assessed efficacy outcomes which may be subject to greater variability or subjectivity than results assessed in a blinded, independent, centrally reviewed manner, often required of later phase, adequate and well-controlled registration-directed clinical trials.
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Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete pre-clinical studies and then conduct extensive clinical trials to demonstrate the safety and efficacy of our product candidates in humans.
−Removed: Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome.
−Removed: It is impossible to predict when or if our product candidates will prove effective and safe in humans or will receive regulatory approval or will have a differentiated safety and tolerability profile.
+Added: Clinical testing is expensive, is difficult to design and implement, can take many years to complete and is uncertain as to outcome.
+Added: It is impossible to predict when or if our product candidates will prove effective and safe in humans, will receive regulatory approval or will have a differentiated safety and tolerability profile.
A failure of one or more clinical trials can occur at any stage of testing.
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Even if our clinical trials produce positive results, there can be no guarantee that the positive outcomes will be replicated in future studies either within the same indication as previously evaluated or in alternate indications and settings.
−Removed: Successful completion of our clinical trials is a prerequisite to submitting a New Drug Application (NDA) or a BLA to the FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for each product candidate and, consequently, the ultimate approval and commercial marketing of our product candidates.
+Added: Successful completion of our clinical trials is a prerequisite to submitting an NDA or a BLA to the FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for each product candidate and, consequently, the ultimate approval and commercial marketing of our product candidates.
We do not know whether any of our ongoing or future clinical trials for our product candidates will be completed on schedule, if at all.
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We are aware that other companies are currently conducting or planning clinical trials that seek to enroll patients with the same diseases that we are studying.
−Removed: We may experience numerous unforeseen events, such as the COVID-19 pandemic, that could delay or prevent our ability to complete current clinical trials, initiate new trials, receive marketing approval or commercialize our product candidates, including:
+Added: We may experience unforeseen events, such as the COVID-19 pandemic, that could delay or prevent our ability to complete current clinical trials, initiate new trials, receive marketing approval or commercialize our product candidates, including:
● the FDA or other regulatory authorities may require us to submit additional data or impose other requirements before permitting us to initiate a clinical trial;
● the FDA or other regulatory authorities or institutional review boards (IRBs) or ethics committees (ECs) may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site or in a country;
−Removed: we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective trial sites and prospective CROs, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
+Added: we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective trial sites and prospective clinical research organizations (CROs), the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
● clinical trials of our drug candidates may produce negative or inconclusive results, and we may decide, or regulatory authorities may require us, to conduct additional pre-clinical studies or clinical trials or we may decide to abandon drug development programs;
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● the cost of clinical trials of our product candidates may be greater than we anticipate;
−Removed: ● the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate, including, without limitation, as a result of disruptions to our supply chains caused by the COVID-19 pandemic and related work stoppages across the globe;
+Added: ● the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate, including, without limitation, as a result of disruptions to our supply chains caused by global health crises, such as the COVID-19 pandemic, international conflicts such as the Russian invasion of Ukraine, economic instability, or natural disasters;
● regulatory authorities may revise the requirements for approving our product candidates, or such requirements may not be as we anticipate;
● our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulatory authorities, IRBs or ECs to suspend or terminate the trials, or reports may arise from pre-clinical or clinical testing of other therapies in the same or a similar class that raise safety or efficacy concerns about our product candidates.
−Removed: We also could encounter delays if a clinical trial is suspended or terminated by us, by the IRBs of the institutions in which such trials are being conducted, by the DSMB for such trial or by the FDA or other regulatory authorities.
+Added: We also could encounter delays if a clinical trial is suspended or terminated by us, by the IRBs of the institutions in which such trials are being conducted, by the Data and Safety Monitoring Board (DSMB) for such trial or by the FDA or other regulatory authorities.
Such regulatory authorities may impose a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a drug, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.
−Removed: For example, in January 2022, the FDA imposed a partial clinical hold on the Company’s clinical trials investigating UKONIQ and ublituximab in CLL and NHL as a result of concerns stemming from an initial overall survival analysis from the UNITY-CLL study that showed that a possible increased risk of death in patients receiving U2 compared to the control arm of obinutuzumab plus chlorambucil.
−Removed: See “ Risks Related to the Development and Commercialization of U2 and UKONIQ.” In addition to the FDA, the DSMB for our clinical trials may recommend modification to the study design or closure of the study entirely based on the DSMB’s interpretation of the benefit-risk of the study.
+Added: In addition to the FDA, the DSMB for our clinical trials may recommend modification to the study design or closure of the study entirely based on the DSMB’s interpretation of the benefit-risk of the study.
While we develop charters that guide the nature of the DSMB meetings, their analysis and interpretation of study data occurs independently from us and is wholly within their control.
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Many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our product candidates.
−Removed: Negative or inconclusive results from the clinical trials we conduct or unanticipated adverse medical events could cause us to have to repeat or terminate the clinical trials.
+Added: Negative or inconclusive results from the clinical trials we conduct, unanticipated adverse medical events, or changes in regulatory policy could cause us to have to repeat or terminate the clinical trials.
If we are required to repeat or conduct additional clinical trials or other testing of our drug candidates beyond those that we currently contemplate, if we are unable to successfully complete clinical trials of our drug candidates or other testing, if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we may:
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● have the drug removed from the market after obtaining marketing approval.
+Added: In addition, changes in regulatory policy could cause us to have to repeat or conduct additional clinical trials or change our clinical development strategy.
Our drug development costs will also increase if we experience delays in testing or regulatory approvals.
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We may also incur additional costs if enrollment is increased.
−Removed: All of our current Phase 3 and registration-directed clinical trials, such as UNITY-CLL, UNITY-NHL and ULTIMATE I and II, enrolled a larger number of patients than our initial projections, adding significant costs to those studies over and above what had been projected.
In addition, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services.
If these relationships and any related compensation result in perceived or actual conflicts of interest, the integrity of the data generated at the applicable clinical trial site, or the FDA’s willingness to accept such data, may be jeopardized.
−Removed: Our product candidates may cause undesirable side effects that could delay or prevent their regulatory approval, or impact their availability and commercial potential after approval.
−Removed: Unacceptable or undesirable adverse events caused by any of our product candidates that we take into clinical trials could cause either us, a DSMB, or regulatory authorities to interrupt, delay, modify or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other regulatory authorities.
+Added: Our product or product candidates may cause undesirable side effects that could delay or prevent their regulatory approval, or impact their availability and commercial potential after approval.
+Added: Unacceptable or undesirable adverse events caused by BRIUMVI or any of our product candidates that we take into clinical trials could cause either of, a DSMB, or regulatory authorities to interrupt, delay, modify or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other regulatory authorities.
This, in turn, could prevent us from commercializing the affected product candidate and generating revenues from its sale.
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Any of these occurrences may harm our business, financial condition and prospects significantly.
−Removed: For example, as a result of concerns stemming from an initial overall survival analysis from the UNITY-CLL study that showed that a possible increased risk of death in patients receiving U2 compared to the control arm of obinutuzumab plus chlorambucil, the FDA took a number of regulatory actions, including placing selected clinical studies of U2 and UKONIQ on partial clinical hold and planning an ODAC meeting to discuss the approvability of U2 in CLL and SLL and UKONIQ in R/R MZL and FL.
−Removed: These developments have harmed our business and likely will continue to adversely impact our financial conditions and prospects until the FDA makes a decision on the approvability of U2 in CLL and SLL.
−Removed: See “ Risks Related to the Development and Commercialization of U2 and UKONIQ .”
Many compounds that initially showed promise in early-stage testing have later been found to cause side effects that prevented further development of the compound.
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If any of our product candidates cause unacceptable adverse events in clinical trials, we may not be able to obtain marketing approval and generate revenues from its sale, or even if approved for sale may lack differentiation from competitive products, which could have a material adverse impact on our business and operations.
−Removed: Many of our ongoing and planned clinical studies involve combinations of two or more drugs.
−Removed: In drug combination clinical development, there is an inherent risk of drug-drug interactions between combination agents that may affect each component’s individual pharmacologic properties and the overall efficacy and safety of the combination regimen.
−Removed: Both ublituximab and UKONIQ are being evaluated in combination with each other, as well as with a variety of other active anti-cancer agents, which may cause unforeseen toxicities, or impact the severity, duration, and incidence of adverse events observed compared to those seen in the single-agent studies of these agents.
−Removed: We also intend to explore multiple combination studies involving cosibelimab, TG-1701, and TG-1801.
−Removed: Further, with multi-drug combinations, it is often difficult to interpret or properly assign attribution of an adverse event to any one particular agent, introducing the risk that toxicity caused by a component of a combination regimen could have a material adverse impact on the development of our product candidates.
−Removed: There can be no assurances given that the combination regimens being studied will display tolerability or efficacy suitable to warrant further testing or produce data that is sufficient to obtain marketing approval.
−Removed: Any product candidates we may advance through clinical development are subject to extensive regulation, which can be costly and time consuming, cause unanticipated delays or prevent the receipt of the required approvals.
−Removed: The clinical development, manufacturing, labeling, packaging, storage, record-keeping, advertising, promotion, import, export, marketing and distribution, and pharmacovigilance and adverse event reporting of our product candidates or any future product candidates are subject to extensive regulation by the FDA in the United States and by comparable regulatory authorities worldwide.
+Added: Any products or product candidates we may advance through clinical development are subject to extensive regulation, which can be costly and time consuming, cause unanticipated delays or prevent the receipt of the required approvals.
+Added: The clinical development, manufacturing, labeling, packaging, storage, record-keeping, advertising, promotion, import, export, marketing and distribution, and pharmacovigilance and adverse event reporting of our product or product candidates or any future product candidates are subject to extensive regulation by the FDA in the United States and by comparable regulatory authorities worldwide.
In the United States, we are not permitted to market a product candidate until we receive approval of a BLA or NDA from the FDA.
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The FDA and foreign regulatory authorities have substantial discretion in the pharmaceutical product approval process, including the ability to delay, limit or deny approval of a product candidate for many reasons.
−Removed: During the regulatory review process, the FDA or other regulatory authorities may disagree with or not accept our clinical trial design, may have questions about the potential impact of our study design on conclusions that can be drawn from the data, may interpret results differently than we do, and may change its view on the criteria that must be met for approval.
+Added: During the regulatory review process, the FDA or other regulatory authorities may disagree with or not accept our clinical trial design, may have questions about the potential impact of our study design on conclusions that can be drawn from the data, may interpret results differently than we do, may apply the results of our trials in one disease to the review of a regulatory application for a different disease even if the doses and therapeutic areas are distinct, and may change its view on the criteria that must be met for approval.
This could happen even for a protocol that has received a SPA.
−Removed: In September 2015, we announced a Phase 3 clinical trial for U2 for patients with CLL, which is being conducted pursuant to a SPA with the FDA (UNITY-CLL).
−Removed: In addition to the SPA for UNITY-CLL, in August 2017 we announced SPAs for the ULTIMATE I and II studies evaluating ublituximab in RMS.
−Removed: There have been examples of companies that have been granted SPAs and have ultimately failed to obtain final approval to market their drugs.
−Removed: Even if the primary endpoint in a Phase 3 clinical trial is achieved, a SPA does not guarantee approval.
−Removed: In the UNITY-CLL study, the primary endpoint
−Removed: of progression-free survival was achieved, however, the FDA is planning an ODAC meeting to discuss an initial overall survival analysis, which was not included as a secondary endpoint in the study’s statistical analysis plan.
−Removed: Despite the SPA and the achievement of the primary endpoint in the UNITY-CLL study, the approvability of U2 in CLL and SLL remains highly uncertain.
−Removed: See “ Risks Related to the Development and Commercialization of U2 and UKONIQ.”
−Removed: Furthermore, some of our clinical trials may be conducted as open-label studies, meaning that trial participants, investigators, site staff, some employees of our contract research organizations, and our field-level employees (e.g., clinical research associates and monitors), among others, have knowledge of treatment arm assignments on a patient-level, which has the potential to introduce bias into study conduct.
+Added: There is no guarantee that the FDA will not delay, limit or deny approval of our product candidates in the future.
+Added: Furthermore, some of our clinical trials may be conducted as open-label studies, meaning that trial participants, investigators, site staff, some employees of our CROs, and our field-level employees (e.g., clinical research associates and monitors), among others, have knowledge of treatment arm assignments on a patient-level, which has the potential to introduce bias into study conduct.
Further, even when our clinical trials are double-blind, double-dummy studies, unblinding of treatment arm assignment may occur from time to time, for example, on the occurrence of unexpected safety events which may necessitate understanding of study treatment.
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The FDA may also seek the guidance of an outside advisory committee in evaluating (among other things) clinical data and safety and effectiveness considerations prior to making its final decision.
−Removed: These issues could cause a delay in the FDA’s review or lead the FDA to deny approval.
+Added: These issues could cause a delay in the FDA’s review, lead the FDA to deny approval, or lead the Company to withdraw a regulatory application.
Other reasons that the FDA or regulatory authorities around the world may delay, limit or deny approval of a product candidate, include:
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● the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval;
−Removed: ● interruptions or delays in the operations of the FDA and foreign regulatory authorities as a result of the COVID-19 pandemic may negatively impact review, inspection, and approval timelines.
−Removed: Even if we succeed in obtaining regulatory approval, the FDA may require post-marketing studies, including additional clinical trials such as those necessary to assess drug interactions or activity of a product in specific populations which also may be costly.
−Removed: For example, as part of the accelerated approval of UKONIQ for relapsed or refractory MZL and FL, continued approval for those indications is contingent upon verification and description of clinical benefit in a confirmatory trial.
−Removed: The outcomes of post-marketing studies may also impact product labeling and therefore there can be no guarantee that the product attributes contained in the initial prescribing information will be maintained as future studies produce data.
−Removed: This includes, without limitation, additional results from studies evaluating drug-drug interactions and patients with certain comorbidities (e.g., hepatic or renal impairment or cardiac risks) among others that may restrict the use of an approved product in select populations or introduce dose modifications or contraindicated concomitant medications that have the potential to impact the utility of a product or its perceived product profile among prescribers.
+Added: ● interruptions or delays in the operations of the FDA and foreign regulatory authorities as a result of global health or economic crises, such as the COVID-19 pandemic, international conflict, or national disasters may negatively impact review, inspection, and approval timelines.
+Added: Even if we succeed in obtaining regulatory approval for a product candidate, the FDA may require post-marketing studies, including additional clinical trials such as those necessary to assess drug interactions or activity of a product in specific populations, which may be costly.
+Added: The outcomes of post-marketing studies may impact product labeling and therefore, there can be no guarantee that the product attributes contained in the initial prescribing information will be maintained as future studies produce data.
+Added: This includes, without limitation, additional results from studies evaluating drug-drug interactions and patients with certain comorbidities that may restrict the use of an approved product in select populations or introduce dose modifications or contraindicated concomitant medications that have the potential to impact the utility of a product or its perceived product profile among prescribers.
Post-marketing studies may also lead to the introduction of new warnings in the product prescribing information.
−Removed: For example, post-marketing studies may lead to the addition of a
−Removed: boxed warning for UKONIQ.
−Removed: The inclusion of a boxed warning or other required warning language or the addition of limitations to the use of the product within the indicated population could significantly impact our ability to successfully market our product candidates.
−Removed: Finally, the FDA may require adoption of a REMS program requiring prescriber training or a post-marketing registry or may restrict the marketing and dissemination of our products.
−Removed: Any requirements to conduct post-approval studies or fulfill special post-approval requirements could impact our ability to commercialize our product candidates and increase our costs.
+Added: The FDA may require adoption of a REMS program requiring prescriber training or a post-marketing registry or may restrict the marketing and dissemination of our products.
+Added: Finally, failure to complete a post-marketing commitment by the applicable post-marketing milestone date may lead to withdrawal of the product or indication.
+Added: Any requirements to conduct post-approval studies or fulfill special post-approval requirements could impact our ability to commercialize our product or product candidates and increase our costs.
A Breakthrough Therapy or Fast Track designation by the FDA may not actually lead to a faster development or regulatory review or approval process.
We may seek Breakthrough Therapy or Fast Track designation for some of our drug candidates.
−Removed: For example, in January 2019, the FDA granted Breakthrough Therapy designation to UKONIQ for the treatment of adult patients with MZL who have received at least one prior anti-CD20 regimen, and in October 2020, the FDA granted Fast Track designation to the investigation of ublituximab in combination with UKONIQ for the treatment of adult patients with CLL.
If a drug is intended for the treatment of a serious or life-threatening condition, and the drug demonstrates the potential to address an unmet medical need for this condition, the Sponsor may apply for Fast Track designation or Breakthrough Therapy designation, the latter of which has more significant requirements.
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Neither Breakthrough Therapy nor Fast Track designation guarantees Priority Review of an NDA or BLA application.
−Removed: Despite receiving Fast Track designation for U2 for the treatment of adult patients with CLL, the FDA granted the BLA a standard review timeline.
−Removed: The FDA may also withdraw a Breakthrough Therapy or Fast Track designation if it believes that the designation is no longer supported by data from our clinical development program.
−Removed: We have received orphan drug designation for some of our drug candidates for specified indications, and we may seek additional orphan drug designations for other indications and some of our other drug candidates.
+Added: We may seek orphan drug designation for some of our drug candidates.
However, we may be unsuccessful in obtaining or may be unable to maintain the benefits associated with orphan drug designation, including the potential for market exclusivity.
−Removed: Ublituximab as monotherapy received orphan drug designation from the FDA for the treatment of MZL (nodal and extranodal) in September 2013, for the treatment of CLL in August 2010, and received orphan drug designation by the EMA for the treatment of CLL in November 2009.
−Removed: We also obtained orphan drug designation for umbralisib as monotherapy for the treatment of CLL in August 2016, all three types of MZL (nodal, extranodal and splenic) in April 2019, and FL in March 2020.
−Removed: In January 2017, we announced that the FDA granted orphan drug designation covering the combination of ublituximab and umbralisib for the treatment of patients with CLL and DLBCL.
−Removed: As part of our business strategy, we may seek orphan drug designation for our other drug candidates;
−Removed: however, we may be unsuccessful.
Regulatory authorities in some jurisdictions, including the United States, the European Union, and the United Kingdom, may designate drugs for relatively small patient populations as orphan drugs.
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Orphan drug designations are required to be maintained through annual reporting and are subject to re-evaluation.
−Removed: Based on the evolving data and development plans for our product candidates and changing incidence and prevalence rates for our intended indications, there can be no guarantee that we will be able to successfully maintain our orphan drug designations for any of our products.
+Added: Based on the evolving data and development plans for our product candidates and changing incidence and prevalence rates for our intended indications, there can be no guarantee that we will be able to successfully maintain orphan drug designations that we have for certain of our drug candidates or that we will be successful in obtaining orphan designation for other drug candidates in the future.
Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes FDA or EMA from approving another marketing application for the same drug or biologic for that time period.
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Orphan drug designation neither shortens the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process.
−Removed: While we intend to seek additional orphan drug designation for our other drug candidates, we may never receive such designations.
+Added: While we intend to seek orphan drug designation for our other drug candidates, we may never receive such designations.
Even if we receive orphan drug designation for any of our drug candidates, there is no guarantee that we will enjoy the benefits of those designations or obtain orphan drug exclusivity.
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Orphan Drug Act may be subject to amendments that could reduce the period of marketing exclusivity or change the qualifications for orphan drug designation, which could adversely impact our products or product candidates that have or may be eligible for orphan drug designation.
−Removed: We are conducting clinical trials, and anticipate additional clinical trials, for product candidates at sites outside the United States, and the FDA may not accept data from trials conducted in such locations or clinical trial activities in such locations may be impacted by political conditions, including international conflict.
−Removed: Many of our Phase 3 and registration-directed clinical trials across our MS and oncology programs, including UNITY-CLL, UNITY-NHL and ULTIMATE I and II and related extension studies, utilize international clinical research sites.
+Added: We are conducting clinical trials and anticipate conducting additional clinical trials for our product and product candidates at sites outside the United States, and the FDA may not accept data from trials conducted in such locations or clinical trial activities in such locations may be impacted by political conditions, including international conflict.
+Added: Many of our Phase 3 and registration-directed clinical trials across our multiple sclerosis and oncology programs, including ULTIMATE I and II and related extension studies, utilize international clinical research sites.
We work with what we believe are reputable CROs and clinical research sites in conducting our studies internationally.
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In addition, our clinical studies with sites outside the United States may be adversely impacted by international conflict.
−Removed: For example, tensions between Ukraine and Russia have escalated in recent months, culminating in Russia's recent invasion of Ukraine.
+Added: For example, in February 2022, Russia initiated a full-scale military invasion of Ukraine.
In one or both countries, as well as neighboring countries that may be impacted by this conflict (e.g.
Poland, Slovakia, Belarus, Georgia), we have clinical trial sites for our RMS and/or oncology programs.
−Removed: The political and physical conditions in these countries may disrupt our ability to supply investigational drug product to impacted sites, impact patients’ ability to partake in the clinical trial, or result in suspension of clinical trial activities at impacted sites.
−Removed: While we do not believe this conflict will have a material impact on our current regulatory submissions for approval of ublituximab in RMS or U2 in CLL or our overall business, given the rapidly evolving situation and the potential to expand beyond Ukraine and Russia, the full impact of the conflict remains uncertain.
−Removed: An approval of one of our product candidates in the United States would not assure approval of that candidate in foreign jurisdictions.
+Added: While no clinical trials are actively enrolling patients in these territories, there are a number of trial subjects in long-term treatment and follow-up.
+Added: The political and physical conditions in Russia and Ukraine have disrupted our ability to supply investigational drug product to impacted sites;
+Added: impacted patients’ ability to partake in our clinical trials and our ability to gather data on those patients, including long-term follow-up data;
+Added: and resulted in suspension of clinical trial activities at impacted sites.
+Added: Furthermore, the United States and its European allies have imposed significant new sanctions against Russia and Belarus, including regional embargoes, full blocking sanctions, and other restrictions targeting major Russian financial institutions.
+Added: Specifically, such sanctions have included, among other things, a prohibition on doing business with certain Russian companies, officials, and oligarchs;
+Added: a commitment by certain countries and the European Union to remove selected Russian banks from the Society for Worldwide Interbank Financial Telecommunications (SWIFT) electronic banking network that connects banks globally;
+Added: and restrictive measures to prevent the Russian Central Bank from undermining the impact of the sanctions.
+Added: Our ability to conduct clinical trials in Russia, Belarus, Ukraine and elsewhere in the region may also become restricted under applicable sanctions laws.
+Added: The conflict, as well as government responses, has resulted in global economic instability, which could affect our supply chain and commercialization efforts.
+Added: While we do not believe this conflict will have a material impact on product development or our overall business, given the rapidly evolving situation and the potential to expand beyond Ukraine and Russia, the full impact of the conflict remains uncertain.
+Added: Approval of one of our product candidates in the United States would not assure approval of that candidate in foreign jurisdictions.
We intend to seek product approvals in certain countries outside of the United States.
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As a general matter, however, the foreign regulatory approval process involves a lengthy and challenging process with risks similar or identical to the risks associated with the FDA approval discussed above.
−Removed: Therefore, we cannot guarantee that we, or future collaborators, will obtain approvals of our product candidates in any foreign jurisdiction on a timely basis, if at all.
−Removed: Failure to receive approval in certain foreign markets could significantly impact the full market potential of our product candidates and may negatively impact the regulatory process in other countries.
−Removed: Furthermore, if we obtain regulatory approval for a product candidate in a foreign jurisdiction, we will
−Removed: be subject to the burden of complying with complex regulatory, legal, and other requirements that could be costly and could subject us to additional risks and uncertainties.
−Removed: We have product candidates still under development and are also preparing for commercial manufacturing activities, and as such clinical and commercial manufacturing site additions, scale-up and process improvements implemented in the production of those product candidates may affect their ultimate activity or function.
−Removed: Many of our product candidates are currently manufactured in relatively small batches for use in pre-clinical and clinical studies.
−Removed: Process improvements implemented to date have changed, and process improvements in the future may change, the activity and/or analytical profile of the product candidates, which may affect the safety and efficacy of the products.
−Removed: For instance, the manufacturing process for ublituximab has undergone several process improvements during the clinical trial process which have resulted in analytical differences between the materials.
−Removed: Such process improvements continued during the conduct of the Phase 3 study and materials from more than one manufacturing process were utilized in the Phase 3 UNITY-CLL trial and the Phase 3 ULTIMATE I and II trials.
−Removed: While analytical differences exist between those materials, we do not believe the differences will alter the safety or efficacy profile of ublituximab.
−Removed: However, it is possible that additional and/or different adverse events may appear among patients exposed to drug product manufactured under one process compared to the other, or that adverse events may arise with greater frequency, intensity and duration among patients exposed to drug product manufactured under one process compared to the other.
−Removed: Additionally, the efficacy of ublituximab may also be negatively impacted by such process changes.
−Removed: Given the uncertainty of the impact on product specifications, quality and performance, process improvements made during Phase 3 development carry a higher level of risk than those made prior to Phase 3 development.
−Removed: If there are significant differences in product attributes between the two materials, we may need to conduct additional analyses of the Phase 3 study(ies) to confirm that there is no difference in safety or efficacy between the product made by each process in order to allow us to utilize data from all enrolled patients, as well as be able to integrate clinical safety and/or efficacy results across studies to support any potential marketing application.
−Removed: There can be no assurance given that such analyses will be successful in demonstrating that there are no clinical differences between these drug products, which could substantially impact the approvability of the combination of UKONIQ and ublituximab based on the results of the UNITY-CLL study.
−Removed: In such circumstances, that would have a material adverse effect on the Company.
−Removed: Further, no assurance can be given that the material manufactured from any future optimized processes, if any, for ublituximab or any of our product candidates will perform comparably to the product candidates as manufactured to date which could result in an unexpected safety or efficacy outcome as compared to the data published or presented to date.
+Added: Therefore, we cannot guarantee that we, or future collaborators, will obtain approvals of our product and product candidates in any foreign jurisdiction on a timely basis, if at all.
+Added: Failure to receive approval in certain foreign markets could significantly impact the full market potential of our product and product candidates and may negatively impact the regulatory process in other countries.
+Added: Furthermore, if we obtain regulatory approval for a product or product candidate in a foreign jurisdiction, we will be subject to the burden of complying with complex regulatory, legal, and other requirements that could be costly and could subject us to additional risks and uncertainties.
+Added: We have product candidates still under development and are also engaging manufacturing partners in commercial manufacturing activities, and as such clinical and commercial manufacturing site additions and process improvements implemented in the production of our product and product candidates may affect their timely delivery or quality.
+Added: We have limited experience in manufacturing products for clinical or commercial purposes.
+Added: We currently do not have any manufacturing capabilities of our own.
+Added: We have established a contract manufacturing relationship for the commercial supply of BRIUMVI with Samsung Biologics.
+Added: As with any supply program, obtaining materials of sufficient quality and quantity to meet the requirements of the market demand for BRIUMVI and our development programs cannot be guaranteed and we cannot ensure that we will be successful in these endeavors.
+Added: To the extent possible and commercially practicable, we plan to develop back-up strategies for raw materials, manufacturing and testing services for our commercial products.
+Added: Given the long lead times and cost of establishing additional commercial manufacturing sites we expect that we will rely on single contract manufacturers to produce our commercial products under current Good Manufacturing Practice, or cGMP, regulations for many years.
+Added: Our commercial manufacturing partners have a limited number of facilities in which our product candidates can be produced and will have limited experience in manufacturing our product candidates in quantities sufficient for commercialization.
+Added: Our third-party manufacturers will have other clients and may have other priorities that could affect their ability to perform the work satisfactorily and/or on a timely basis.
+Added: Both of these occurrences would be beyond our control.
+Added: We expect to similarly rely on contract manufacturing relationships for our development programs and any products that we may in-license or acquire in the future.
+Added: However, there can be no assurance that we will be able to successfully contract with such manufacturers on terms acceptable to us, or at all.
+Added: Contract manufacturers are subject to ongoing periodic and unannounced inspections by the FDA, the Drug Enforcement Administration if applicable, and corresponding state agencies to ensure strict compliance with cGMP and other state and federal regulations.
+Added: Where manufactured products are globally registered, similar regulatory inspection burdens are applicable from each and every marketed territory.
+Added: If our manufacturing partners are inspected and deemed out of compliance with cGMPs, product recalls could result, inventory could be destroyed, production could be stopped, and supplies could be delayed or otherwise disrupted.
+Added: If we need to change manufacturers either before or after commercialization, the FDA and corresponding foreign regulatory agencies may need to approve these new manufacturers in advance, which will involve testing, regulatory submissions, and additional inspections to ensure compliance with FDA regulations and standards and may require significant lead times and delay.
+Added: Furthermore, switching manufacturers may be difficult because the number of potential manufacturers is limited.
+Added: It may be difficult or impossible for us to find a replacement manufacturer quickly or on terms acceptable to us, or at all.
+Added: Some of our product and product candidates are currently manufactured in relatively small batches for use in pre-clinical and clinical studies.
+Added: Process improvements implemented to date have changed, and process improvements in the future may change, the activity and/or analytical profile of the product or product candidates, which may affect the safety and efficacy of the products.
+Added: It is possible that additional and/or different adverse events may appear among patients exposed to drug product manufactured under one process compared to the other, or that adverse events may arise with greater frequency, intensity and duration among patients exposed to drug product manufactured under one process compared to the other.
+Added: Further, no assurance can be given that the material manufactured from any future optimized processes, if any, for ublituximab or any of our product candidates will perform comparably to the product or product candidates as manufactured to date which could result in an unexpected safety or efficacy outcome as compared to the data published or presented to date.
Similarly, following each round of process improvements, if any, for any of our drug candidates, future clinical trial results conducted with the new material will be subject to uncertainty related to the effects, if any, of those additional process improvements that were made.
−Removed: In addition, with the FDA approval of UKONIQ and as we move closer to commercialization of ublituximab, we are scaling-up production to ensure adequate commercial supply.
−Removed: This is an expensive process and there can be no assurance given that such scale-up will be successful in providing pharmaceutical product that is of sufficient quantity, or of a quality that is consistent with our previously established specifications, or that meets the requirements set by regulatory agencies under which we may seek approval of our product candidates.
−Removed: If scale-up were not to succeed, our ability to supply our anticipated market at a reasonable cost of goods would be negatively impacted.
−Removed: In such an event, that would have a material adverse effect on the Company.
−Removed: Scale up could also require additional process improvement that might be required to accommodate new and larger equipment utilized in the scaled-up process.
−Removed: If that were to occur and we could not demonstrate to the FDA that the materials were analytically substantially similar, we might be required to run additional clinical testing to demonstrate that they are substantially similar.
−Removed: That would entail a significant delay and significant increase in total cost, all of which would have a material adverse effect on the Company.
Risks Related to Governmental Regulation of Pharmaceutical Industry and Legal Compliance Matters
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Beyond the ACA, there has been increasing legislative, regulatory and enforcement interest with respect to prescription drug pricing practices.
−Removed: With the election of President Biden and changes in make-up of the Senate following the 2020 election, we face uncertainties with respect to executive and legislative actions relating to drug pricing.
Proposals that may garner bipartisan legislative support or become legislation through reconciliation include adding a cap on out-of-pocket spending under Medicare Part D, authorizing Medicare to negotiate certain drugs covered by Medicare Parts D and B directly with manufacturers, and imposing limits on increases in drug prices.
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In the event there is a modification to the biologic exclusivity period or other steps taken to facilitate biosimilar or generic approvals, we could experience biosimilar/generic competition of any products for which we receive FDA approval at an earlier time than currently anticipated.
+Added: Most recently, on August 16, 2022, President Biden signed into law the Inflation Reduction Act of 2022 (the Act), which, among other provisions, included several measures intended to lower the cost of prescription drugs and related healthcare reforms.
+Added: Specifically, the Act authorizes and directs the Department of Health and Human Services (the DHHS) to set drug price caps for certain high-cost Medicare Part B and Part D qualified drugs, with the initial list of drugs to be selected by September 1, 2023, and the first year of maximum price applicability to begin in 2026.
+Added: The Act further authorizes the DHHS to penalize pharmaceutical manufacturers that increase the price of certain Medicare Part B and Part D drugs faster than the rate of inflation.
+Added: Finally, the Act creates significant changes to the Medicare Part D benefit design by capping Part D beneficiaries’ annual out-of-pocket spending at $2,000 beginning in 2025.
+Added: We cannot be sure whether additional or related legislation or rulemaking will be issued or enacted, or what impact, if any, such changes will have on the profitability of any of our drug candidates, if approved for commercial use, in the future.
At the state level, individual states are experiencing significant economic pressure within their state Medicaid programs and responding to public concern over the cost of healthcare.
−Removed: The economic impact of the COVID-19 pandemic has further exacerbated state budgetary pressures.
States, including California, Florida, Nevada and Maine, among others, have responded to these pressures with a range of legislative enactments and policy proposals designed to control prescription drug prices by, for example, allowing importation of pharmaceutical products from jurisdictions outside the U.S., imposing price controls on state drug purchases, consolidating state drug purchasing to a single purchaser, and imposing transparency measures around prescription drug prices and marketing costs.
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Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs, or any significant taxes or fees imposed as part of any broader deficit reduction effort or legislative replacement to the Budget Control Act, or otherwise, could have an adverse impact on our anticipated product revenues.
−Removed: Furthermore, legislative and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for drugs.
+Added: Furthermore, legislative and regulatory proposals have been made to expand post-approval requirements, make changes the Orphan Drug Act and related guidance, and restrict sales and promotional activities for drugs.
We cannot be sure whether additional legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or what the impact of such changes on the marketing approvals of our product candidates, if any, may be.
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These measures vary by country and may include, among other things, non-coverage decisions, patient access restrictions, international price referencing, mandatory discounts or rebates, and cross-border sales of prescription drugs.
−Removed: These measures may adversely affect our ability to generate revenues or commercialize our product candidates in certain international markets.
+Added: These measures may adversely affect our ability to generate revenues or commercialize our product or product candidates in certain international markets.
There likely will continue to be pressure on prescription drug prices globally and legislative and regulatory proposals, including at the federal and state levels in the U.S., directed at broadening the availability of health care and containing or lowering the cost of health care products and services.
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Our relationships with customers and third-party payors will be subject to applicable fraud and abuse laws, false claims laws, transparency and disclosure laws, health information and security laws, and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion from government healthcare programs, contractual damages, reputational harm and diminished profits and future earnings.
−Removed: With the FDA approval of UKONIQ in February 2021, we became subject to additional extensive healthcare statutory and regulatory requirements and oversight by the federal government and the states and foreign governments in which we conduct our business.
+Added: With the FDA approval of BRIUMVI in December 2022, we are subject to additional extensive healthcare statutory and regulatory requirements and oversight by the federal government and the states and foreign governments in which we conduct our business.
Healthcare providers and third-party payors play a primary role in the recommendation and prescription of any drug candidates for which we obtain marketing approval.
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In addition, the government may assert that a claim including items and services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act;
−Removed: ● the federal Health Insurance Portability and Accountability Act of 1996 (or HIPAA) imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
+Added: ● the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
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federal laws, including the Medicaid Drug Rebate Program, that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs;
−Removed: the Drug Supply Chain Security Act, or DSCSA, which imposes obligations on entities in the commercial product supply chain, including manufacturers, to identify and track prescription drugs as they are distributed in the U.S.;
+Added: the Drug Supply Chain Security Act (DSCSA), which imposes obligations on entities in the commercial product supply chain, including manufacturers, to identify and track prescription drugs as they are distributed in the U.S.;
● state law equivalents of some of the above federal laws, such as anti-kickback and false claims laws that may apply to items or services reimbursed by any third-party payor, including commercial insurers, state transparency laws, state laws limiting interactions between pharmaceutical manufacturers and members of the healthcare industry, 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 federal laws, thus complicating compliance efforts.
−Removed: In the U.S., to help patients who have no or inadequate insurance coverage of UKONIQ, we have a patient support program that we administer in conjunction with a patient support program vendor and other third parties.
+Added: As we continue commercialization of BRIUMVI, we are taking steps to provide patient support services to help patients access the product.
+Added: Our patient support program will be administered in conjunction with a patient support program vendor and other third parties.
There has been heightened governmental scrutiny over the scope of patient support programs and the manner in which drug manufacturers and their vendors operate such programs.
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If we or our vendors are deemed to fail to comply with relevant laws, regulations or government guidance in the operation of these programs, we could be subject to damages, fines, penalties or other criminal, civil or administrative sanctions or enforcement actions.
−Removed: Ensuring that our future business arrangements with third parties comply with applicable healthcare laws and regulations will involve substantial costs.
+Added: Ensuring that our business arrangements with third parties comply with applicable healthcare laws and regulations involves substantial costs.
It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.
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Our approach to compliance may evolve over time in light of these types of developments.
−Removed: Additionally, the potential safe harbors available under the AKS are subject to change through legislative and regulatory action, and we may decide to adjust our business practices or be subject to heightened scrutiny as a result.
−Removed: If our operations, including anticipated activities to be conducted by our sales team, were to be found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government-funded healthcare programs, such as Medicare and Medicaid, qui tam actions brought by individual whistleblowers in the name of the government, and the curtailment or restructuring of our operations.
+Added: Additionally, the potential safe harbors available under the Anti-Kickback Statute are subject to change through legislative and regulatory action, and we may decide to adjust our business practices or be subject to heightened scrutiny as a result.
+Added: If our operations, including activities to be conducted by our sales team, were to be found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government-funded healthcare programs, such as Medicare and Medicaid, qui tam actions brought by individual whistleblowers in the name of the government, and the curtailment or restructuring of our operations.
If we violate applicable data privacy and security laws, we may be subject to penalties, including civil and criminal penalties, damages, fines and the curtailment or restructuring of our operations.
−Removed: We may be subject to privacy and security laws in the various jurisdictions in which we operate, obtain or store personally identifiable information.
+Added: We may be subject to privacy and security laws in the various jurisdictions in which we operate, obtain or store personal information.
The legislative and regulatory landscape for privacy and data protection continues to evolve, and there has been an increasing focus on privacy and data protection issues with the potential to affect our business.
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For example, at the federal level, our operations may be affected by the data privacy and security provisions of HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations.
−Removed: Although we are not currently directly subject to HIPAA, HIPAA affects the ability of healthcare providers and other entities with which we may interact, including clinical trial sites, to disclose patient health information to us.
−Removed: Under Section 5(a) of the Federal Trade Commission Act, or the FTCA, the FTC expects a company’s data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities.
+Added: HIPAA affects the ability of healthcare providers and other entities with which we may interact, including clinical trial sites, to disclose patient health information to us.
+Added: Under Section 5(a) of the Federal Trade Commission Act (the FTCA), the FTC expects a company’s data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities.
Medical data is considered sensitive data that merits stronger safeguards.
−Removed: States may also impose requirements, for example the California Consumer Privacy Act, or the CCPA, went into effect in January 2020 creating data privacy obligations for covered companies and providing privacy rights to California residents, including the right to opt out of certain disclosures of their information.
+Added: States may also impose requirements, for example the California Consumer Privacy Act (the CCPA), went into effect in January 2020 creating data privacy obligations for covered companies and providing privacy rights to California residents, including the right to opt out of certain disclosures of their information.
+Added: Colorado, Connecticut, Utah and Virginia have also enacted data privacy statutes, and both California and Colorado are also undergoing rulemaking procedures to finalize regulatory regimes to supplement their privacy statutes.
Numerous other jurisdictions regulate the privacy and security of personally identifiable data.
−Removed: For example, the processing of personal data in the European Economic Area, or the EEA, is subject to the General Data Protection Regulation, or the GDPR, which took effect in May 2018.
+Added: For example, the processing of personal data in the European Economic Area (the EEA), is subject to the General Data Protection Regulation (GDPR), which took effect in May 2018.
The GDPR increases obligations with respect to clinical trials conducted in the EEA, such as in relation to the provision of fair processing notices, exercising data subject rights and reporting certain data breaches to regulators and affected individuals, as well as how we document our relationships with third parties that process GDPR-covered personal data on our behalf.
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In all interactions with foreign regulatory authorities and other government agencies, we are exposed to liability risks under the Foreign Corrupt Practices Act or similar anti-bribery laws.
−Removed: Any product for which we obtain marketing approval could be subject to restrictions or withdrawal from the market and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with products.
+Added: Any product for which we obtain marketing approval, including BRIUMVI, could be subject to restrictions or withdrawal from the market and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with products.
Any regulatory approvals that we receive for our drug candidates may be subject to limitations on the indicated uses for which the drug may be marketed or to conditions of approval that may require potentially costly post-marketing clinical trials or surveillance to monitor safety and efficacy of the drug candidate.
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If we, or our respective suppliers, third-party contractors, clinical investigators or collaborators are slow to adapt, or are unable to adapt, to changes in existing regulatory requirements or adoption of new regulatory requirements or policies, we, our subsidiaries, or our respective collaborators may be subject to the actions listed above, including losing marketing approval for products, resulting in decreased revenue from milestones, product sales or royalties.
−Removed: Our third-party manufacturers may use hazardous materials in the production of UKONIQ and our product candidates and if so, they must comply with environmental laws and regulations, which can be expensive and restrict how we or they do business.
−Removed: Manufacturing activities for the production of UKONIQ and our product candidates involve the controlled storage, use, and disposal of hazardous materials, including the components of our product candidates, and other hazardous compounds.
−Removed: Our third-party manufacturers and we are subject to federal, state, and local laws and regulations governing the use, manufacture, storage, handling, release, disposal of, and exposure to, these hazardous materials.
+Added: If we or any of our contract manufacturers and suppliers fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could seriously harm our business.
+Added: Our third-party manufacturers, suppliers, and we are subject to federal, state, and local laws and regulations governing the use, manufacture, storage, handling, release, disposal of, and exposure to, hazardous and regulated materials.
Violation of these laws and regulations could lead to substantial fines and penalties.
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We rely on third parties to help conduct our planned clinical trials.
−Removed: If these third parties do not perform their services as required, we may not be able to obtain regulatory approval for or commercialize our product candidates when expected or at all.
−Removed: In order to submit an Investigational New Drug application (IND), BLA, or NDA to the FDA and maintain these applications, it is necessary to submit all information on the clinical, non-clinical, chemistry, manufacturing, controls and quality aspects of the product candidate.
+Added: If these third parties do not perform their services as required, we may not be able to obtain regulatory approval for or commercialize our product or product candidates when expected or at all.
+Added: In order to submit an IND, BLA, or NDA to the FDA and maintain these applications, it is necessary to submit all information on the clinical, non-clinical, chemistry, manufacturing, controls and quality aspects of the product candidate.
Clinical trial applications and marketing authorization applications for foreign regulatory bodies have substantially similar requirements.
We rely on our third-party contractors and our licensing partners to provide portions of this data.
−Removed: If we are unable to obtain this data, or the data is not sufficient to meet the regulatory requirements, we may experience significant delays in our development programs.
+Added: If we are unable to obtain this data, or the data is not sufficient to meet the regulatory requirements, we may experience significant delays in our development programs and commercialization efforts.
Additionally, we use CROs to assist in the conduct of our current clinical trials and expect to use such services for future clinical trials and we rely upon medical institutions, clinical investigators and contract laboratories to conduct our trials in accordance with our clinical protocols and appropriate regulations.
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There is no guarantee that any CROs, investigators and other third parties will devote adequate time and resources to our clinical trials or perform as contractually required.
−Removed: If any third parties upon whom we rely for administration and conduct of our clinical trials fail to meet expected deadlines, fail to adhere to its clinical protocols or otherwise perform in a substandard manner, our clinical trials may be extended, delayed or terminated, and we may not be able to commercialize our product candidates.
+Added: If any third parties upon whom we rely for administration and conduct of our clinical trials fail to meet expected deadlines, fail to adhere to its clinical protocols or otherwise perform in a substandard manner, our clinical trials may be extended, delayed or terminated, and we may not be able to commercialize our product or product candidates.
In addition to the third parties identified above, we are also heavily reliant on the conduct of our patients enrolled to our studies by our third-party investigators.
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If any of our clinical trial sites terminates for any reason, we may experience the loss of follow-up information on patients enrolled in our ongoing clinical trials unless we are able to transfer the care of those patients to another qualified clinical trial site.
−Removed: If any of our clinical trial sites is required by the FDA or IRB to close down due to data management or patient management or any other issues, we may lose patients.
+Added: If any of our clinical trial sites is required by the FDA or IRB to close down due to data management or patient management or any other issues, we may lose clinical trial subjects.
Whether conducted through a CRO or through our internal staff, we are solely responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable protocol, legal and regulatory requirements and scientific standards, and our reliance on CROs will not relieve us of our regulatory responsibilities.
−Removed: For any violations of laws and regulations during the conduct of our clinical trials, we could be subject to warning letters or other enforcement actions that may include civil penalties up to and including criminal prosecution.
+Added: For any violations of laws and regulations during the conduct of our clinical trials, we could be subject to warning letters or other enforcement actions that may include civil penalties or criminal prosecution.
We and our CROs are required to comply with regulations, including GCP guidelines for conducting, monitoring, recording and reporting the results of clinical trials to ensure that the data and results are scientifically credible and accurate, and that the trial patients are adequately informed of the potential risks of participating in clinical trials and their rights are protected.
−Removed: These regulations are enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area and comparable foreign regulatory authorities
−Removed: for any drug candidates in clinical development.
+Added: These regulations are enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area and comparable foreign regulatory authorities for any drug candidates in clinical development.
The FDA enforces GCP regulations through periodic inspections of clinical trial sponsors, clinical investigators, CROs, institutional review boards, and non-clinical laboratories.
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If any of our relationships with these third-party CROs terminate, we may not be able to enter into arrangements with alternative CROs.
−Removed: If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any clinical trials such CROs are associated with may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for or successfully commercialize our product candidates.
−Removed: As a result, we believe that our financial results and the commercial prospects for our product candidates in the subject indication would be harmed, our costs could increase and our ability to generate revenue could be delayed.
−Removed: We contract with third parties for the manufacture of UKONIQ for commercial supply and of our product candidates for pre-clinical development and clinical trials, and we expect to continue to do so, including for commercial supply of ublituximab.
+Added: If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any clinical trials such CROs are associated with may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for or successfully commercialize our product or product candidates.
+Added: As a result, we believe that our financial results and the commercial prospects for our product or product candidates in the subject indication would be harmed, our costs could increase and our ability to generate revenue could be delayed.
+Added: We contract with third parties for the manufacture of BRIUMVI for commercial supply, as well as all of our clinical product supply, and we expect to continue to do so.
This reliance on third parties increases the risk that we will not have sufficient quantities of our products or product candidates or such quantities at an acceptable cost or quality, which could delay, prevent or impair our development or commercialization efforts.
We do not currently own or operate, nor do we have any plans to establish in the future, any manufacturing facilities.
−Removed: We rely, and expect to continue to rely, on third parties for the manufacture, packaging and labeling of any products that we commercialize and our product candidates for pre-clinical development and clinical testing.
−Removed: In some circumstances, our licensor has entered into arrangements with contract manufacturers to supply product for our clinical and commercial demand.
+Added: We rely, and expect to continue to rely, on third parties for the manufacture, testing, packaging and labeling of any products that we commercialize and our product candidates for pre-clinical development and clinical testing.
+Added: For example, we currently rely on Samsung Biologics for clinical and commercial supply of ublituximab.
Our reliance on third parties increases the risk that we will not have sufficient quantities of our products or product candidates or such quantities at an acceptable cost or quality, which could delay, prevent or impair our development or commercialization efforts.
−Removed: The facilities used by contract manufacturers to manufacture our drug candidates typically undergo inspections by the FDA or a comparable foreign regulatory to verify compliance with applicable cGMP regulations.
−Removed: Such inspections may be conducted after we submit our marketing applications to or receive marketing approval from the FDA or a comparable foreign regulatory authority.
+Added: The facilities used by contract manufacturers to manufacture, test, package, and label our product and product candidates typically undergo periodic inspections by the FDA or a comparable foreign regulatory authority to verify compliance with applicable cGMP regulations.
+Added: Additional inspections may be conducted after we submit our marketing applications to or receive marketing approval from the FDA or a comparable foreign regulatory authority.
Although the FDA and other regulators impose requirements regarding our selection, qualification, oversight, and monitoring of our contract manufacturers and hold us responsible for the ultimate compliance of our products, we do not directly control the manufacturing process of our third-party contract manufacturers and are subject to risks associated with their ability to comply with cGMPs in connection with the manufacture of our products and product candidates.
−Removed: If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others and the compliance concerns cannot be resolved, remediated, or otherwise addressed to the FDA’s satisfaction in a timely manner during the review of our NDAs or BLAs, it may negatively impact our ability to obtain regulatory approval for our drug candidates or obtain approval within projected timelines.
+Added: If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others and the compliance concerns cannot be resolved, remediated, or otherwise addressed to the FDA’s or others’ satisfaction in a timely manner during the review of any marketing applications that we submit, it may negatively impact our ability to obtain regulatory approval for our drug candidates or obtain approval within projected timelines.
We cannot guarantee the ability of our third-party manufacturers to maintain compliance with cGMP regulations, including having adequate quality control, quality assurance and qualified personnel.
Further, our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of products or product candidates, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect our business and supplies of our products or product candidates.
−Removed: For umbralisib and certain of our product candidates, we do not have long-term supply agreements with contract manufacturers.
−Removed: For these product candidates, we purchase our required drug supply, including the drug product and drug substance on a purchase order basis.
−Removed: We may be unable to establish or maintain agreements with third-party manufacturers for these products or product candidates or do so on acceptable terms.
−Removed: No assurance can be given that long-term, scalable manufacturers can be identified or that they can make clinical and commercial supplies of our product candidates that meet the product specifications of previously manufactured batches, or are of a sufficient quality, or at an appropriate scale and cost to make it commercially feasible.
−Removed: If they are unable to do so, it could have a material adverse impact on our business.
−Removed: Even if we are able to establish and maintain long-term agreements with third-party manufacturers as we have with ublituximab, reliance on third-party manufacturers entails additional risks, including:
+Added: Our reliance on third-party manufacturers entails additional risks, including:
● reliance on the third party for regulatory compliance and quality assurance;
−Removed: ● the possible breach of the manufacturing or supply agreement by the third party;
+Added: ● the possible breach of the manufacturing, supply or quality agreement by the third party;
● the possible misappropriation of our proprietary information, including our trade secrets and know-how;
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If a new contract manufacturer is not successful in replicating the product or experiences delays, or if regulatory authorities impose unforeseen requirements with respect to product comparability from multiple manufacturing sources, we may experience delays in clinical development or an interruption in our commercial supply.
−Removed: No assurance can be given that any new manufacturer will be successful or that material manufactured by a new
−Removed: manufacturer will perform comparably to UKONIQ or ublituximab as manufactured to date or that the relevant regulatory agencies will agree with our interpretation of comparability.
−Removed: Any significant delays or gaps in supply of UKONIQ, ublituximab, or other product candidates may adversely affect our clinical development program, our ability to commercialize any drugs that receive marketing approval on a timely and competitive basis, and our future profit margins.
−Removed: We also rely on other third parties to store and distribute drug supplies for our clinical trials and for commercial demand for UKONIQ and expect to continue to do so for any other product candidates that may receive approval, including ublituximab.
+Added: No assurance can be given that any new manufacturer will be successful or that material manufactured by a new manufacturer will perform comparably to product manufactured by the previous manufacturer or that the relevant regulatory agencies will agree with our interpretation of comparability.
+Added: Any significant delays or gaps in supply of commercial or clinical products may adversely affect our clinical development program, our ability to commercialize any drugs that receive marketing approval on a timely and competitive basis, and our future profit margins.
+Added: We also rely on other third parties to store and distribute drug supplies for our clinical trials and for commercial demand for BRIUMVI and expect to continue to do so for any other potential commercial products.
Any performance failure on the part of our distributors could delay clinical development or marketing approval of any future product candidates or commercialization of our products, producing additional losses and depriving us of potential product revenue.
−Removed: The third parties upon whom we rely for the supply of starting materials, intermediates, active pharmaceutical ingredient (API)/drug substance, drug product, and other materials used in our drug candidates are our sole source of supply, and the loss or disruption of any of these suppliers, including as a result of the COVID-19 pandemic, could significantly harm our business.
+Added: The third parties upon whom we rely for the supply of starting materials, intermediates, active pharmaceutical ingredient (API)/drug substance, drug product, and other materials used in our drug candidates are our sole source of supply, and the loss or disruption of any of these suppliers could significantly harm our business.
The starting materials, intermediates, API/drug substance, and drug product used in many of our drug candidates are currently supplied to us from single-source suppliers.
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It is expected that many of our manufacturing partners will be sole source suppliers from single site locations for the foreseeable future.
−Removed: Various raw materials, components, and testing services required for our products may also be single sourced.
+Added: Various raw materials, components, and testing services required for our product and product candidates may also be single sourced.
We are not certain that our single-source suppliers will be able to supply sufficient quantities of their products or on the timelines necessary to meet our needs, either because of the nature of our agreements with those suppliers, our limited experience with those suppliers, our relative importance as a customer to those suppliers, international political conflicts that may impact trade or the supply chain within a particular region, public health emergencies such as the COVID-19 pandemic or natural disasters that may cause those suppliers to stop work for a period of time or lead to a sudden increase in demand for selected materials resulting in short-term unavailability of such materials.
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Although the pandemic has not had a material adverse effect on our supply chain to date, no assurance can be given that it will not in the future if the situation persists or worsens.
−Removed: UKONIQ is manufactured in India, ublituximab is manufactured in South Korea, and TG-1701 is manufactured in China.
−Removed: Each of these countries continues to be, or has been, subject to government-imposed quarantines and travel restrictions due to the COVID-19 pandemic, which, in some cases, have resulted in reduced operations at manufacturing and research locations and time-limited shutdowns.
−Removed: Our contract manufacturers for UKONIQ and ublituximab are continuing operations at varying levels of capacity.
−Removed: We have worked closely with our contract manufacturer for UKONIQ to plan for anticipated commercial supply needs.
−Removed: We also are working closely with our contract manufacturer for ublituximab to plan for our anticipated commercial supply needs if we are successful in obtaining FDA approval of the product.
In addition to potential disruptions at our contract manufacturers, there may be unfavorable changes in the availability or cost of raw materials, intermediates or other materials that we need for clinical and commercial production, which may result in higher costs or supply chain interruptions.
−Removed: We will continue to monitor the situation very closely with our contract manufacturers and suppliers.
We continually evaluate our supply chains to identify potential risks and needs for additional manufacturers and other suppliers for the production of our products and product candidates.
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While we seek to maintain adequate inventory of materials necessary for the production of our products and product candidates, any supply interruption or delay, or our inability to identify alternate sources at acceptable prices in a timely manner could impede, delay, limit or prevent our commercialization and development efforts, which could harm our business, results of operations, financial condition and prospects.
−Removed: Because we have in-licensed UKONIQ and our product candidates from third parties, any dispute with or non-performance by our licensors will adversely affect our ability to develop and commercialize the applicable product or product candidate.
−Removed: Because we license UKONIQ and our product candidates from third parties and we expect to continue to in-license additional product candidates, if there is any dispute between us and our licensor regarding our rights under a license agreement, our ability to develop and commercialize the applicable product or product candidate may be adversely affected.
+Added: Because we have in-licensed BRIUMVI and our product candidates from third parties, any dispute with or non-performance by our licensors will adversely affect our ability to develop and commercialize the applicable product or product candidate.
+Added: Because we license BRIUMVI and our product candidates from third parties and we expect to continue to in-license additional product candidates, if there is any dispute between us and our licensor regarding our rights under a license agreement, our ability to develop and commercialize the applicable product or product candidate may be adversely affected.
Disputes may arise with the third parties from whom we license our products and product candidates for a variety of reasons, including:
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● the priority of invention of patented technology.
−Removed: In addition, the agreements under which we currently license UKONIQ and our product candidates from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations, or may conflict in such a way that puts us in breach of one or more agreements, which would make us susceptible to lengthy and expensive disputes with one or more of our licensing partners.
+Added: In addition, the agreements under which we currently license BRIUMVI and our product candidates from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations, or may conflict in such a way that puts us in breach of one or more agreements, which would make us susceptible to lengthy and expensive disputes with one or more of our licensing partners.
The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
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If the scope of our patent protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and drugs similar or identical to ours, and our ability to successfully commercialize our technology and drugs may be impaired.
−Removed: Our commercial success in part depends on obtaining and maintaining patent protection and trade secret protection in the United States and other countries with respect to any product we commercialize, including UKONIQ, our product candidates, their formulations and uses and the methods we use to manufacture them, as well as successfully defending these patents against third-party challenges.
+Added: Our commercial success in part depends on obtaining and maintaining patent protection and trade secret protection in the United States and other countries with respect to any product we commercialize, including BRIUMVI, our product candidates, their formulations and uses and the methods we use to manufacture them, as well as successfully defending these patents against third-party challenges.
We seek to protect our proprietary and intellectual property position by filing patent applications in the United States and abroad related to our novel technologies and product candidates, and by maintenance of our trade secrets through proper procedures.
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We cannot provide any assurances that any of our patents have, or that any of our pending patent applications that mature into issued patents will include, claims with a scope sufficient to protect any of our products.
−Removed: In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States.
+Added: In addition, the laws of foreign countries may not protect our patent rights to the same extent as the patent laws of the United States.
Furthermore, patents have a limited lifespan.
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Given the amount of time required for the development, testing and regulatory review of new drug candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.
−Removed: As a result, our owned patent portfolio may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing drugs similar or identical to our product candidates, including generic versions of such drugs.
−Removed: Currently, the composition of matter patent for ublituximab and UKONIQ are granted in both the United States and EU, among other countries.
−Removed: A method of use patent covering the combination of ublituximab and UKONIQ has also been granted in the United States, Europe, Japan, and several other territories.
−Removed: Additionally, several method of use patents for ublituximab and UKONIQ in various indications and settings have also been applied for but have not yet been issued or have been issued in certain territories but not under all jurisdictions in which such applications have been filed.
−Removed: There can be no guarantee that any patents for which an application has already been filed, nor
−Removed: any patents filed in the future, for cosibelimab, TG-1701 and TG-1801 or for our pre-clinical product candidates will be granted in any or all jurisdictions in which they were filed, or that all claims initially included in such patent applications will be allowed in the final patent that is issued.
−Removed: The patent application process is subject to numerous risks and uncertainties, and there can be no assurance that we or our partners will be successful in protecting our product candidates by obtaining and defending patents, or what the scope of an issued patent may ultimately be.
+Added: As a result, our patent portfolio may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing drugs similar or identical to our product or product candidates, including generic versions of such drugs.
+Added: Currently, we have several granted patents in the United States and EU, among other countries, and several pending patent applications that have not yet been issued or have been issued in certain jurisdictions but not all jurisdictions in which such applications have been filed.
+Added: There can be no guarantee that any pending patent applications, nor any patent applications filed in the future will be granted in any or all jurisdictions in which they were filed, or that all patent claims initially submitted for examination in such patent applications will be allowed in the patent that is eventually granted, if at all.
+Added: The patent prosecution process is subject to numerous risks and uncertainties, and there can be no assurance of the scope of patent claims that will ultimately be allowed, if at all, and no assurance that we or our partners will be successful in protecting our product and product candidates by obtaining and defending patents.
These risks and uncertainties include the following:
−Removed: ● the patent applications that we or our licensors file may not result in any patents being issued;
+Added: ● the patent applications that we or our licensors file may not issue as patent;
● patents that may be issued or in-licensed may be challenged, invalidated, modified, revoked or circumvented, or otherwise may not provide any competitive advantage;
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If we do not win the filing race, we will not be entitled to inventive priority;
−Removed: ● our competitors, many of which have substantially greater resources than we do, and many of which have made significant investments in competing technologies, may seek, or may already have obtained, patents that will limit, interfere with, or eliminate its ability to file new patent applications or make, use, and sell our potential products either in the United States or in international markets;
−Removed: ● there may be significant pressure on the United States government and other international governmental bodies to limit the scope of patent protection both inside and outside the United States for disease treatments that prove successful as a matter of public policy regarding worldwide health concerns;
−Removed: ● countries other than the United States may have less restrictive patent laws than those upheld by United States courts, allowing foreign competitors the ability to exploit these laws to create, develop, and market competing products.
−Removed: If patents are not issued that protect our products or product candidates, it could have a material adverse effect on our financial condition and results of operations.
+Added: ● our competitors, many of whom have substantially greater resources than we do, and many of whom have made significant investments in competing technologies, may seek, or may already have obtained, patents that will limit, interfere with, or eliminate our ability to file new patent applications covering our products, or make, use, and/or sell our products either in the United States or in international markets;
+Added: ● there may be significant pressure on the United States government and other international governmental bodies to limit the scope of patent protection both inside and outside the United States for disease treatments that prove successful as a matter of public policy regarding worldwide health concerns, which could limit our ability to fully monetize our intellectual property rights;
+Added: ● countries other than the United States may have less restrictive patent laws than those of the United States, allowing foreign competitors to exploit such less restrictive patent laws to make, use, and/or sell competing products in their respective jurisdictions.
+Added: If we are not able to obtain patents that protect our product and product candidates, it could have a material adverse effect on our financial condition and results of operations.
In addition, the patent prosecution process is expensive and time-consuming, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner.
Further, with respect to some of the pending patent applications covering our drug candidates, prosecution has yet to commence.
−Removed: Patent prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the USPTO have been significantly narrowed by the time they issue, if at all.
+Added: Patent prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the USPTO can be significantly narrowed by the time they issue, if at all.
It is also possible that we will fail to identify any patentable aspects of our research and development output and methodology, and, even if we do, an opportunity to obtain patent protection may have passed.
−Removed: Given the uncertain and time-consuming process of filing patent applications and prosecuting them, it is possible that our product(s) or process(es) originally covered by the scope of the patent application may have changed or been modified, leaving our product(s) or process(es) without patent protection.
−Removed: Moreover, in some circumstances, we do not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from third parties.
+Added: Given the uncertain and time-consuming process of filing patent applications and prosecuting them, it is possible that our product(s) or process(es) originally covered by the scope of our patent applications may change or be modified throughout the patent prosecution process, leaving our product(s) or process(es) without patent protection.
+Added: Moreover, in some circumstances, we do not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, that cover technology licensed from third parties.
Therefore, these patents and applications may not be prosecuted and enforced in a manner consistent with the best interests of our business.
If our licensors or we fail to appropriately prosecute and maintain patent protection or trade secret protection for one or more products or product candidates, our ability to develop and commercialize such drugs may be adversely affected and we may not be able to prevent competitors from making, using and selling competing products.
−Removed: This failure to properly protect the intellectual property rights relating to these product candidates could impair our ability to compete in the market and adversely affect our ability to generate revenues and achieve profitability, which would have a material adverse effect on our financial condition and results of operations.
−Removed: Furthermore, should we enter into other collaborations, including out-licensing or partnerships, we may be required to consult with or cede control to collaborators regarding the prosecution, maintenance and enforcement of licensed patents.
−Removed: Therefore, these patents and applications may not be prosecuted and enforced in a manner consistent with the best interests of our business.
+Added: This failure to properly protect the intellectual property rights relating to our product and product candidates could impair our ability to compete in the market and adversely affect our ability to generate revenues and achieve profitability, which would have a material adverse effect on our financial condition and results of operations.
+Added: Furthermore, should we enter into other collaborations, including out-licensing, joint development projects, or other partnerships, we may be required to consult with or cede control to collaborators regarding the prosecution, maintenance and enforcement of patents licensed or developed under such collaborations.
+Added: Therefore, such patents and patent applications may not be prosecuted and enforced in a manner consistent with the best interests of our business.
The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions, and has in recent years been the subject of much litigation.
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The patent situation outside the United States is even more uncertain.
−Removed: The laws of foreign countries may not protect our rights to the same extent as the laws of the United States, and we may fail to seek or obtain patent protection in all major markets.
−Removed: For example, European patent law restricts the patentability of methods of treatment of the human body more than United States law does.
+Added: The patent laws of foreign countries may not protect our patent rights to the same extent as the laws of the United States, and we may fail to seek or obtain patent protection in all major markets.
+Added: For example, European patent law restricts the patentability of methods of treatment of the human body more than United States patent law does.
Our pending and future patent applications may not result in patents being issued which protect our technology or products, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products.
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and other countries may diminish the value of our patents or narrow the scope of our patent protection.
−Removed: For example, the federal courts of the United States have taken an
−Removed: increasingly dim view of the patent eligibility of certain subject matter, such as naturally occurring nucleic acid sequences, amino acid sequences and certain methods of utilizing same, which include their detection in a biological sample and diagnostic conclusions arising from their detection.
+Added: For example, the federal courts of the United States have taken an increasingly dim view of the patent eligibility of certain subject matter, such as naturally occurring nucleic acid sequences, amino acid sequences and certain methods of utilizing same, which include their detection in a biological sample and diagnostic conclusions arising from their detection.
Such subject matter, which had long been a staple of the biotechnology and biopharmaceutical industry to protect their discoveries, is now considered, with few exceptions, ineligible in the first instance for protection under the patent laws of the United States.
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The Leahy-Smith Act includes a number of significant changes to United States patent law.
−Removed: These include changes to transition from a first-to-invent system to a first-to-file system and to the way issued patents are challenged.
+Added: These include the transition from a first-to-invent system to a first-to-file system and changes to the way issued patents are challenged.
The formation of the Patent Trial and Appeal Board now provides a quicker and less expensive process for challenging issued patents.
−Removed: We may be subject to a third-party pre-issuance submission of prior art to the USPTO, or become involved in opposition, derivation, reexamination, inter parties review, post-grant review or interference proceedings challenging our patent rights or the patent rights of others.
+Added: The patents or patent applications owned or filed by us, or by our licensors or other collaborators, may be affected by third-party pre-issuance submissions of prior art to the USPTO, or by opposition, derivation, reexamination, inter parties review, post-grant review or interference proceedings.
The costs of these proceedings could be substantial, and it is possible that our efforts to establish priority of invention would be unsuccessful, resulting in a material adverse effect on our U.S.
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An adverse determination in any such submission, patent office trial, proceeding or litigation could reduce the scope of, render unenforceable, or invalidate, our patent rights, allow third parties to commercialize our technology or products and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent rights.
−Removed: In addition, if the breadth or strength of protection provided by patents and patent applications for our drug candidates is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.
+Added: In addition, if the breadth or strength of protection provided by patents and patent applications for our drug candidates is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future products or product candidates.
The issuance of a patent does not foreclose challenges to its inventorship, scope, validity or enforceability.
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As a result, our owned and licensed patent portfolio may not provide us with enough rights to exclude others from commercializing products similar or identical to ours.
−Removed: Even if our patent applications issue as patents, and they are unchallenged, our issued patents and our pending patents, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our patent claims to circumvent our owned or licensed patents by developing similar or alternative technologies or drugs in a non-infringing manner.
+Added: Even if our patent applications issue as patents, and they are unchallenged, our issued patents and pending patent applications, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our patent claims to circumvent our owned or licensed patents by developing similar or alternative technologies or drugs in a non-infringing manner.
For example, a third party may develop a competitive drug that provides benefits similar to one or more of our products or product candidates but that has a different composition that falls outside the scope of our patent protection.
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In addition, we may in the future be subject to claims by our former employees or consultants asserting an ownership right in our patents or patent applications, as a result of the work they performed on our behalf.
−Removed: Although we have entered into agreements with many of our employees, consultants and advisors and any other third parties who have access to our proprietary know-how, information or technology to assign or grant similar rights to their inventions to us, we cannot be certain that we have executed such agreements with all parties who may have contributed to our intellectual property, nor can we be certain that our agreements with such parties will be upheld in the face of a potential challenge, or that they will not be breached, for which we may not have an adequate remedy.
+Added: Although we have entered into agreements with many of our employees, consultants and advisors and any other third parties who have access to our proprietary know-how, information or technology for the purpose of assigning or granting similar rights to their inventions to us, we cannot be certain that we have executed such agreements with all parties who may have contributed to our intellectual property, nor can we be certain that our agreements with such parties will be upheld in the face of a potential challenge, or that they will not be breached, for which we may not have an adequate remedy.
An adverse determination in any such submission or proceeding may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and drugs, without payment to us, or could limit the duration of the patent protection covering our technology and drug candidates.
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If we fail to maintain the patents and patent applications covering our drugs or procedures, we may not be able to stop a competitor from marketing drugs that are the same as or similar to our products or product candidates, which would have a material adverse effect on our business.
−Removed: If we do not obtain patent term extensions under the Hatch-Waxman Amendments and similar foreign legislation extending the terms of our licensed patents and any future patents we may own, our business may be materially harmed.
+Added: If we do not obtain patent term extensions under the Hatch-Waxman Act and similar foreign legislation extending the terms of our licensed patents and any future patents we may own, our business may be materially harmed.
Depending on the timing, duration, and specifics of any FDA regulatory approval for our drug candidates, one or more of our licensed U.S.
patents or future U.S.
−Removed: patents that we may license or own may be eligible for limited patent term restoration under the Hatch-Waxman Amendments.
−Removed: The Hatch-Waxman Amendments permit a patent term extension of up to five years as compensation for patent term lost during the FDA regulatory review process.
+Added: patents that we may license or own may be eligible for limited patent term restoration under the Hatch-Waxman Act.
+Added: The Hatch-Waxman Act permit a patent term extension of up to five years as compensation for patent term lost during the FDA regulatory review process.
A patent term extension cannot extend the remaining term of a patent beyond 14 years from the date of product approval by the FDA, and only one patent covering the approved product may be extended.
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We may not be granted an extension because of, for example, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements.
−Removed: Moreover, the applicable time period or the scope of the patent protection afforded could be less than we request.
+Added: Moreover, the applicable time period or the scope of the patent protection afforded could be less than what we request.
If we are unable to obtain patent term extension or any term of such extension is less than we request, the period during which we will have the right to exclusively market our product will be shortened and our competitors may obtain earlier approval of competing products, and our ability to generate revenues could be materially adversely affected.
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The legal systems of some countries, including India, China and other developing countries, do not favor the enforcement of patents and other intellectual property rights.
−Removed: This could make it difficult for us to stop the infringement of our patents or the misappropriation of our other intellectual property rights.
+Added: This could make it difficult for us to stop the infringement of our patents or the misappropriation of our other intellectual property.
For example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties.
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Moreover, such proceedings could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us.
−Removed: We may not prevail in
−Removed: any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be meaningful.
+Added: We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be meaningful.
Furthermore, while we intend to protect our intellectual property rights in major markets for our products, we cannot ensure that we will be able to initiate or maintain similar efforts in all jurisdictions in which we may wish to market our products.
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Competitors may infringe our patents or the patents of our licensors.
−Removed: To counter infringement or unauthorized use, we may be required to file infringement claims, which typically are very expensive, time-consuming and disruptive of day-to-day business operations.
+Added: To counter infringement or unauthorized use, we may be required to file infringement claims, which typically are very expensive, time-consuming and disruptive to our day-to-day business operations.
Any claims we assert against accused infringers could provoke these parties to assert counterclaims against us alleging invalidity of our or certain of our subsidiaries’ patents or that we infringe their patents;
−Removed: or provoke those parties to petition the USPTO to institute inter parties review against the asserted patents, which may lead to a finding that all or some of the claims of the patent are invalid.
+Added: or provoke those parties to petition the USPTO to institute inter parties review against the asserted patents, which may lead to a finding that all or some of the claims of the asserted patents are invalid.
In addition, in an infringement proceeding, a court may decide that a patent of ours or our licensors is not valid or is unenforceable or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question.
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Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement.
−Removed: Patents may be unenforceable if someone connected with prosecution of the patent withheld relevant information from the USPTO or made a misleading statement during prosecution.
+Added: Patents may be unenforceable if someone connected with the prosecution of the patent withheld relevant information from the USPTO or made a misleading statement during prosecution.
It is possible that prior art of which we and the patent examiner were unaware during prosecution exists, which could render our patents invalid.
Moreover, it is also possible that prior art may exist that we are aware of but do not believe is relevant to our current or future patents, but that could nevertheless be determined to render our patents invalid.
−Removed: Competing drugs may also be sold in other countries in which our patent coverage might not exist or be as strong.
+Added: Competing drugs may also be sold in other countries in which our patent coverage might not exist or be as strong as in the United States.
If we lose a foreign patent lawsuit, alleging our infringement of a competitor’s patents, we could be prevented from marketing our drugs in one or more foreign countries.
−Removed: Any of these outcomes would have a materially adverse effect on our business.
+Added: Any of these outcomes would have a material adverse effect on our business.
In addition, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.
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Numerous United States and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are developing products, some of which may be directed at claims that overlap with the subject matter of our intellectual property.
−Removed: In addition, because patent applications can take many years to issue, there may be currently pending applications, unknown to us, which may later result in issued patents that our product candidates or proprietary technologies may infringe.
−Removed: Similarly, there may be issued patents relevant to our product candidates of which we are not aware.
+Added: In addition, because patent applications can take many years to issue, there may be currently pending applications, unknown to us, which may later result in issued patents that our product or product candidates or proprietary technologies may infringe.
+Added: Similarly, there may be issued patents relevant to our product or product candidates of which we are not aware.
Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after a first filing, or in some cases not at all.
Therefore, we cannot know with certainty whether we or our licensors were the first to make the inventions claimed in patents or pending patent applications that we own or licensed, or that we or our licensors were the first to file for patent protection of such inventions.
−Removed: We are aware of certain patents that may pose issues for our commercialization of our drug candidates.
+Added: We are aware of certain patents that may pose issues for our commercialization of our product and product candidates.
If we decide to initiate proceedings to challenge the validity of these patents in the future, we may be unsuccessful, as courts or patent offices in the United States and abroad could uphold the validity of any such patents.
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A finding of infringement could prevent us from commercializing our drug candidates or force us to cease some of our business operations, which could materially harm our business.
−Removed: No assurance can be given that patents issued to third parties do not exist, have not been filed, or could not be filed or issued, which contain claims covering its products, technology or methods that may encompass all or a portion of our products and methods.
+Added: No assurance can be given that patents issued to third parties do not exist, have not been filed, or could not be filed or issued, which contain claims covering their products, technology or methods that may encompass all or a portion of our products and methods.
Given the number of patents issued and patent applications filed in our technical areas or fields, we believe there is a risk that third parties may allege they have patent rights encompassing our products or methods.
−Removed: Other product candidates that we may in-license or acquire could be subject to similar risks and uncertainties.
+Added: Other products or product candidates that we may in-license or acquire could be subject to similar risks and uncertainties.
We may need to license certain intellectual property from third parties, and such licenses may not be available or may not be available on commercially reasonable terms.
A third party may hold intellectual property, including patent rights that are important or necessary to the development and commercialization of our products.
−Removed: It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products, in which case we would be required to obtain a license from these third parties, whom may or may not be interested in granting such a license, on commercially reasonable terms, or our business could be harmed, possibly materially.
−Removed: For example, we engage extensively with third parties, including academic institutions, to conduct non-clinical and clinical research on our product candidates.
+Added: It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products, in which case we would be required to obtain a license from these third parties, whom may or may not be interested in granting such a license, on commercially reasonable terms, in which case our business could be harmed, possibly materially.
+Added: For example, we engage extensively with third parties, including academic institutions, to conduct non-clinical and clinical research on our product and product candidates.
While we seek to ensure all material transfer and service agreements governing this research provide us with favorable terms covering newly generated intellectual property, a general principle under which much of this research with academic institutions is conducted provides third-party ownership of newly generated intellectual property, with an exclusive option available for us to obtain a license to such intellectual property.
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We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our collaborators, scientific advisors, employees and consultants, and invention assignment agreements with our consultants and employees.
−Removed: We may not be able to prevent the unauthorized disclosure or use of our technical know-how or other trade secrets by the parties to these agreements, however, despite the existence generally of confidentiality agreements and other contractual restrictions.
+Added: We may not be able to prevent the unauthorized disclosure or use of our technical know-how or other trade secrets by the parties to these agreements, however, despite the existence of confidentiality agreements and other contractual restrictions.
Monitoring unauthorized uses and disclosures is difficult, and we do not know whether the steps we have taken to protect our proprietary technologies will be effective.
−Removed: If any of the collaborators, scientific advisors, employees and consultants who are parties to these agreements breaches or violates the terms of any of these agreements, we may not have adequate remedies for any such breach or violation, and we could lose our trade secrets as a result.
+Added: If any of the collaborators, scientific advisors, employees and consultants who are parties to these agreements breach or violate the terms of any of these agreements, we may not have adequate remedies for any such breach or violation, and we could lose our trade secrets as a result.
Enforcing a claim that a third party illegally obtained and is using our trade secrets, like patent litigation, is expensive and time-consuming, and the outcome is unpredictable.
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Risks Related to Our Business Organization and Governance, Strategy, Employees and Growth Management
−Removed: If we fail to attract and keep key management, commercial, and clinical development personnel, we may be unable to successfully develop or commercialize our product candidates.
+Added: If we fail to attract and keep key management, commercial, and clinical development personnel, we may be unable to successfully develop or commercialize our product and product candidates.
We are highly dependent on the research and development, commercialization, manufacturing, quality, financial and legal expertise of our senior management team as well as the other principal members of our management.
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If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.
−Removed: Recruiting and retaining qualified scientific, clinical, manufacturing and sales and marketing personnel, particularly in MS, will be critical to our success.
+Added: Recruiting and retaining qualified scientific, clinical, manufacturing and medical affairs, and commercial personnel, particularly in MS, will be critical to our success.
The loss of the services of our chief executive officer or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy.
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Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel.
−Removed: We anticipate that the uncertainty around the approvability of U2 in CLL and SLL stemming from the FDA plan to hold an ODAC meeting may make it more challenging to recruit and retain qualified personnel across functions.
−Removed: See “ Risks Related to the Development and Commercialization of U2 and UKONIQ.” In January 2022, we engaged in a streamlining exercise across the Company, reducing headcount and external expenses.
−Removed: That streamlining effort may make retention of key personnel more difficult.
+Added: In January and April 2022, following the withdrawal of the BLA and sNDA for U2 and the withdrawal of UKONIQ from sale, we engaged in streamlining efforts across the Company, reducing headcount and external expenses, primarily related to our oncology commercialization and research and development functions.
+Added: Those streamlining efforts have made and may continue to make retention of key personnel more difficult.
If we are not able to attract and retain the necessary personnel to accomplish our business objectives, we may experience constraints that will significantly impede the achievement of our development and commercialization objectives, our ability to raise additional capital, and our ability to implement our business strategy.
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We cannot assure you that, following any such transaction, we will achieve the expected synergies to justify the transaction.
−Removed: Expanding our business will increase our operating needs.
As of February 16, 2023, we had 226 full-time employees.
−Removed: We expect to increase our number of employees and expand the scope of our operations focused on preparing for potential commercialization of ublituximab in RMS.
−Removed: In addition, in the event the FDA approves U2 for the treatment of CLL and SLL, we will need to expand our operations supporting hematology.
−Removed: Our management and medical, commercial, and scientific personnel, systems and facilities currently in place may not be adequate to support our anticipated future growth.
−Removed: To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel.
−Removed: Also, our management may need to divert a disproportionate amount of its attention away from its day-to-day activities and devote a substantial amount of time to managing these development activities.
−Removed: Due to our limited resources, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel.
+Added: Our management and medical, commercial, and scientific personnel, systems and facilities currently in place, which were largely designed to support research and development and commercialization in oncology, may not be adequate to support our anticipated future growth, particularly in MS.
+Added: To manage our anticipated future growth and focus in neurology and immunology, we must continue to implement and improve our managerial, operational and financial systems, and continue to recruit and train additional qualified personnel.
+Added: Also, our management may need to divert a disproportionate amount of its attention away from its day-to-day activities and devote a substantial amount of time to managing these activities.
+Added: Due to our limited resources, we may not be able to effectively manage the expansion and shift of our operations or recruit and train additional qualified personnel.
This may result in weaknesses in our infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees.
−Removed: To accommodate growth, additional physical expansion of our operations in the future may lead to significant costs, including capital expenditures, and may divert financial resources from other projects, such as the development of our drug candidates.
−Removed: If our management is unable to effectively manage our expected development and expansion, our expenses may increase more than expected, our ability to generate or increase our revenue could be reduced and we may not be able to implement our business strategy.
−Removed: Our future financial performance and our ability to commercialize our drug candidates, if approved, and compete effectively will depend, in part, on our ability to effectively manage the future development and expansion of our business.
−Removed: Additionally, to help manage the expanding needs, we may utilize the services of outside vendors or consultants to perform tasks including clinical trial management, statistics and analysis, regulatory affairs, formulation development, chemistry, manufacturing, controls, and other pharmaceutical development functions.
+Added: If our management is unable to effectively manage our transition to a strategy primarily focused on neurology and immunology, our expenses may increase more than expected our ability to generate or increase our revenue could be reduced and we may not be able to implement our business strategy.
+Added: Our future financial performance and our ability to commercialize our drug candidates, if approved, and compete effectively will depend, in part, on our ability to effectively manage the future development and changes to our business.
+Added: Additionally, to help manage the evolving needs, we may utilize the services of outside vendors or consultants to perform tasks including clinical trial management, statistics and analysis, regulatory affairs, formulation development, chemistry, manufacturing, controls, and other pharmaceutical development functions.
Our growth strategy may also entail expanding our group of contractors or consultants to implement these tasks going forward.
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There can be no assurance that we will be able to manage our existing consultants or find other competent outside contractors and consultants on economically reasonable terms, or at all.
−Removed: If we are not able to effectively expand our organization by hiring new employees and expanding our groups of consultants and contractors, we may be unable to successfully implement the tasks necessary to advance the commercialization of UKONIQ and further develop and commercialize our product candidates and, accordingly, may not achieve our research, development and commercialization goals.
+Added: If we are not able to effectively expand our organization by hiring new employees and expanding our groups of consultants and contractors when needed, we may be unable to successfully implement the tasks necessary to achieve our research, development and commercialization goals.
Certain anti-takeover provisions in our governing documents and Delaware law could make a third-party acquisition of us difficult.
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Certain provisions in our amended and restated certificate of incorporation and restated bylaws may make it more difficult for a third party to acquire us, or discourage a third party from attempting to acquire or control us and may limit the price that certain investors might be willing to pay in the future for shares of our common stock.
−Removed: For example, our amended and restated certificate of incorporation allows us to issue preferred stock without the approval of our stockholders, the issuance of which could decrease the amount of earnings and assets available for distribution to, or affect the rights and powers (including voting rights) of, of our common stockholders.
+Added: For example, our amended and restated certificate of incorporation allows us to issue preferred stock without the approval of our stockholders, the issuance of which could decrease the amount of earnings and assets available for distribution to, or affect the rights and powers, including voting rights, of our common stockholders.
In certain circumstances, such issuance could have the effect of decreasing the market price of our common stock.
11 unchanged sentences
We may have experienced such ownership changes in the past, and we may experience ownership changes in the future as a result of shifts in our stock ownership, some of which are outside our control.
−Removed: As of December 31, 2021, we had federal net operating loss carryforwards of approximately $1,294 million, and our ability to utilize those net operating loss carryforwards could be limited by an ownership change as described above, which could result in increased tax liability to us.
+Added: As of December 31, 2022, we had federal net operating loss carryforwards of approximately $1.4 billion, and our ability to utilize those net operating loss carryforwards could be limited by an ownership change as described above, which could result in increased tax liability to us.
In addition, pursuant to the Tax Act, we may not use net operating loss carry-forwards to reduce our taxable income in any year by more than 80%, and we may not carry back any net operating losses to prior years.
−Removed: On March 27, 2020, the “CARES Act” was signed by the U.S.
+Added: On March 27, 2020, the Coronavirus Aid, Relief, and Economic Security (CARES) Act was signed by President Trump.
Certain provisions of the CARES Act alter the rules regarding net-operating losses for such losses arising in 2018, 2019 and 2020.
13 unchanged sentences
Although we have been the targets of cyber-attacks and cyber-intrusions, the impact on our operations and financial condition has not been material.
−Removed: We expect such cybersecurity threats to continue and become more sophisticated.
+Added: We expect such cybersecurity threats to continue and become more sophisticated, even more so due to the conflict between Russia and Ukraine.
A significant cyber-attack or cyber-intrusion could cause our systems to fail, leakage of confidential information, or business interruption, which could result in a material disruption of our operations, financial loss, or reputational harm.
4 unchanged sentences
Our results of operations could be adversely affected by general conditions in the global economy and in the global financial markets.
−Removed: For example, the COVID-19 pandemic has caused extreme volatility and disruptions in the capital and credit markets.
+Added: Key national economies, including the United States, have been affected from time to time by economic downturns or recessions, supply chain constraints, rising inflation, restricted credit, poor liquidity, reduced corporate profitability, debt, equity and foreign exchange market volatility, bankruptcies, rising interest rates, and overall uncertainty with respect to the economy.
+Added: Increasing interest rates in the United States to respond to inflationary pressures and market volatility could negatively impact our results of operations and financial condition.
+Added: In addition, increased interest rates or a general economic downturn or recession could reduce our ability to raise additional capital when needed on acceptable terms, if at all.
+Added: A weak or declining economy, supply disruptions or international trade disputes could also strain our third-party suppliers, possibly resulting in supply disruption.
+Added: Furthermore, the COVID-19 pandemic has caused extreme volatility and disruptions in the capital and credit markets.
+Added: Likewise, the capital and credit markets may be adversely affected by the recent conflict between Russia and Ukraine, the possibility of a wider European or global conflict, and global sanctions imposed in response thereto.
A severe or prolonged economic downturn could result in a variety of risks to our business, including, weakened demand for our drug candidates and our ability to raise additional capital when needed on acceptable terms, if at all.
−Removed: A weak or declining economy could also strain our suppliers, possibly resulting in supply disruption, or cause our customers to delay making payments for our services.
+Added: A weak or declining economy could also strain our suppliers, possibly resulting in supply disruption, or cause our customers to delay making payments for our marketed product and services.
+Added: We cannot anticipate all of the ways in which the foregoing, and the current economic climate and financial market conditions, could adversely impact our business.
Our employees, principal investigators, CROs, CMOs and consultants may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements and insider trading, which could have a material adverse effect on our business.
23 unchanged sentences
Most of the changes applicable to individuals are temporary and apply only to taxable years beginning after December 31, 2017 and before January 1, 2026.
−Removed: For corporations, the Tax Act reduces the top corporate income tax rate to 21% and repeals the corporate alternative minimum tax, limits the deduction for net interest expense, limits the deduction for net operating losses and eliminates net operating loss carrybacks, modifies or repeals many business deductions and credits, shifts the United States toward a more territorial tax
−Removed: system, and imposes new taxes to combat erosion of the U.S.
+Added: For corporations, the Tax Act reduces the top corporate income tax rate to 21% and repeals the corporate alternative minimum tax, limits the deduction for net interest expense, limits the deduction for net operating losses and eliminates net operating loss carrybacks, modifies or repeals many business deductions and credits, shifts the United States toward a more territorial tax system, and imposes new taxes to combat erosion of the U.S.
federal income tax base.
5 unchanged sentences
Risks Related to the COVID-19 Pandemic
−Removed: Major public health issues, and specifically the pandemic caused by COVID-19, could have an adverse impact on our financial condition and results of operations and other aspects of our business.
−Removed: In December 2019, a novel strain of coronavirus which causes a disease referred to as COVID-19, was first detected in Wuhan, China, and has since spread around the world.
−Removed: On March 11, 2020, the World Health Organization declared that the rapidly spreading COVID-19 outbreak had evolved into a pandemic.
−Removed: In response to the pandemic, many governments around the world have implemented a variety of control measures to reduce the spread of COVID-19, including travel restrictions and bans, instructions to residents to practice social distancing, quarantine advisories, shelter-in-place orders and required closures of non-essential businesses.
−Removed: The COVID-19 pandemic has negatively impacted the global economy, disrupted global supply chains, and created significant volatility and disruption of financial markets.
−Removed: The extent to which the COVID-19 pandemic impacts our business and operating results will depend on future developments that are highly uncertain and cannot be accurately predicted, including new information that may emerge concerning the rates of vaccination and efficacy of approved vaccines against the virus and any variant strains of the virus, other actions to contain the virus or treat its impact, and how quickly and to what extent normal economic and operating conditions can resume if and when the pandemic subsides, among others.
−Removed: Should the COVID-19 pandemic persist or worsen and government restrictions continue, our business operations could be materially delayed or interrupted.
−Removed: For instance, our ongoing clinical trials may be delayed or compromised;
−Removed: our ability to conduct new clinical trials may be adversely impacted;
−Removed: our supply chain may be disrupted;
−Removed: health authority inspections of clinical sites or manufacturing facilities, or review of our regulatory submissions may be delayed, and our commercialization efforts may be impacted.
−Removed: For example, during the course of the pandemic the FDA has at points delayed both domestic and foreign facility inspections or conducted “remote interactive evaluations,” which in a variety of circumstances are inclusive of Pre-Approval Inspections (PAIs).
−Removed: We expect the impact of COVID-19 on the FDA’s operations will continue to evolve.
−Removed: It is unknown how long these disruptions could continue, were they to occur.
−Removed: Any delay in our clinical trials, PAIs or in the regulatory review of our pending BLA submission for ublituximab resulting from such disruptions could materially affect the development and commercialization of our product candidates.
−Removed: We currently rely on third parties for certain functions or services in support of our clinical trials and key areas of our operations.
−Removed: These third parties include contract research organizations (CROs), medical institutions and clinical investigators, contract manufacturing organizations, suppliers, and external business partners supporting commercialization of UKONIQ.
−Removed: If these third parties themselves are adversely impacted by restrictions resulting from the COVID-19 outbreak, we will likely experience delays and/or realize additional costs.
−Removed: As a result, our efforts to commercialize UKONIQ and obtain regulatory approvals for, and to commercialize, our product candidates may be delayed or disrupted.
−Removed: In addition, to protect the health of our workforce, starting in March 2020 we asked our office-based employees to work remotely.
−Removed: Although many of the social distancing guidelines and capacity restrictions have been lifted, our office-based employees have continued to work remotely as we plan for office reopening.
−Removed: Third parties on which we rely may also be continuing to use remote working arrangements that they had implemented in response to COVID-19.
−Removed: Our increased reliance on personnel working remotely may negatively impact productivity, including our ability to monitor clinical trials, prepare regulatory applications, and conduct data analysis, or disrupt, delay, or otherwise adversely impact our business.
−Removed: In addition, remote working could increase our cybersecurity risk and make us more susceptible to communication disruptions, any of which could adversely impact our business operations or delay necessary interactions with local and federal regulators, manufacturing sites, research or clinical trial sites and contractors.
−Removed: Our ability to successfully commercialize UKONIQ, and any of our product candidates for which we in the future obtain regulatory approval, also may be adversely impacted by restrictions and safety measures instituted due to COVID-19 and reductions in patient visits to HCPs .
−Removed: For example, reduced access to healthcare providers and institutions as a result of COVID-19 safety protocols has impacted our commercialization activities, including, the manner in which our field teams engage with healthcare providers and facilities.
−Removed: Our compliance monitoring and oversight of interactions and communications with HCPs, payors, and other stakeholders also has been impacted by the remote work environment.
−Removed: The potential economic impact brought by and the duration of the pandemic may be difficult to assess or predict.
−Removed: However, it has already caused, and is likely to result in further, significant disruption of global financial markets.
−Removed: It is likely that the pandemic will cause an economic slowdown of potentially extended duration, and it is possible that it could cause a global recession.
−Removed: This disruption may reduce our ability to access capital either at all or on favorable terms.
−Removed: In addition, a recession, depression or other sustained adverse market event resulting from the spread of COVID-19 could materially and adversely affect our business and the value of our common stock.
−Removed: The ultimate impact of the current pandemic, or any other health epidemic, is highly uncertain and subject to change.
−Removed: We do not yet know the full extent of potential delays or impacts on our business, our clinical trials, our research programs, healthcare systems or the global economy as a whole.
−Removed: However, these effects could have a material adverse effect on our business, financial condition and results of operations.
−Removed: To the extent the COVID-19 pandemic materially adversely affects our business and financial results, it may also have the effect of significantly heightening many of the other risks described in this Risk Factors section.
−Removed: The COVID-19 pandemic could have a material adverse effect on our clinical development program if the pandemic and associated government control measures continue.
−Removed: The ongoing COVID-19 pandemic has presented substantial public health challenges and is impacting the global healthcare system, including the conduct of clinical trials in the U.S.
+Added: The COVID-19 pandemic could have a material adverse effect on our business if new variants continue to circulate and government control measures are reinstated.
+Added: The COVID-19 pandemic presented substantial public health challenges and negatively impacted the global economy, global supply chains, and the global healthcare system, including the conduct of clinical trials in the U.S.
and other parts of the world.
−Removed: New variants continue to circulate, and uncertainty remains as to whether additional restrictions may be implemented to address the spread of new variants.
−Removed: As a result of the COVID-19 pandemic, we may encounter delays in our clinical development program.
−Removed: The majority of our clinical trials involve patients with cancer or those receiving ongoing immunosuppressive therapy who may be at higher risk of infection.
+Added: New variants continue to circulate, and uncertainty remains as to whether restrictions that have been lifted will be reinstated or new measures will be implemented to address the spread of new variants.
+Added: The extent to which the COVID-19 pandemic continues to impact our business and operating results will depend on future developments that cannot be accurately predicted.
+Added: Should the COVID-19 pandemic worsen and government restrictions be reinstated, our business operations could be materially delayed or interrupted.
+Added: For instance, our supply chain may be disrupted;
+Added: health authority inspections of clinical sites, marketing application sponsor, CROs, or manufacturing facilities or review of our regulatory submissions may be delayed;
+Added: and our commercialization efforts may be impacted.
+Added: In addition, we may encounter delays in our clinical development program.
+Added: The majority of our clinical trials involve patients with multiple sclerosis who may be at higher risk of infection.
These patients are thus more likely to be subject to travel restrictions and self-quarantining and may be more likely to withdraw from our clinical trials or unable to complete study assessments, which may affect our ability to meet our projected timelines.
−Removed: Further, we may not be able to complete our clinical trials that we initiated more recently and for which we have not yet completed enrollment in the time frame that we had previously planned.
−Removed: In addition, the pandemic may adversely affect our ability to conduct new trials.
−Removed: Some factors from the COVID-19 outbreak that may delay or otherwise adversely affect our clinical trial programs, as well as adversely impact our business generally, include:
−Removed: ● delays or difficulties in clinical site initiation, including difficulties in recruiting and retaining clinical sites, impacts on compliance with clinical study protocols, delays enrolling patients in our clinical trials, decreased enrollment in our clinical trials or increased rates of patients withdrawing from our clinical trials following enrollment, in each case, as a result of patients contracting COVID-19, being forced to quarantine, experiencing reluctance to seek medical attention in a healthcare facility setting, or otherwise not being able or willing to complete study assessments, particularly for older patients or others with a higher risk of contracting COVID-19;
+Added: Further, patients and healthcare providers have raised concerns that B-cell targeted agents, like anti-CD20 antibodies, may increase the risk of acquiring COVID-19 or lead to more severe complications or outcomes upon infection, including death, which could have a material adverse effect on our product and product candidates by negatively impacting:
+Added: ● the results of clinical trials;
+Added: ● the regulatory review and approval;
+Added: ● the labeling, if approved, including restrictions on use or other warnings, or
+Added: ● their acceptance among patients, healthcare providers, and payors, if approved.
+Added: The pandemic also may adversely affect our ability to complete ongoing clinical trials or conduct new trials.
+Added: Some factors from the COVID-19 outbreak that may delay or otherwise adversely affect our clinical trial programs, as well as adversely impact our business generally, include, among other things:
+Added: ● delays or difficulties in clinical site initiation, including difficulties in recruiting and retaining clinical sites, impacts on compliance with clinical study protocols, delays enrolling patients in our clinical trials, decreased enrollment in our clinical trials or increased rates of patients withdrawing from our clinical trials following enrollment
● impacts to clinical results, including an increased number of observed adverse events, as a result of participants enrolled in our clinical trials contracting COVID-19;
−Removed: ● prioritization by healthcare providers, facilities, lawmakers, and regulators of COVID-19-related healthcare needs or, when the pandemic subsides, to address the potential backlog of patients who have deferred medical procedures during the pendency of the pandemic, which may reduce availability of professionals and resources for clinical trials in other disease areas;
−Removed: ● limitations on travel, including limitations on domestic and international travel, and government-imposed quarantines or restrictions imposed by key third parties that could interrupt key trial activities, such as clinical trial site initiations and monitoring, which could impact the reliability or integrity of subject data and clinical study endpoints;
−Removed: ● interruption of, or delays in receiving, supplies of our product candidates from our contract manufacturing organizations due to staffing shortages, production slowdowns or stoppages or interruption in global shipping that may affect the transport of clinical trial materials;
−Removed: ● disruptions and delays caused by potential workplace, laboratory and office closures and an increased reliance on employees working from home across the healthcare system;
+Added: ● interruption of, or delays in receiving, supplies of our product and product candidates from our contract manufacturing organizations due to staffing shortages, production slowdowns or stoppages or interruption in global shipping that may affect the transport of clinical trial materials;
● disruptions in or delays to regulatory reviews, responses, inspections, or other regulatory activities, including review of marketing applications and approvals of protocol changes or amendments to SPAs, as a result of the spread of COVID-19 affecting the operations of the FDA or other regulatory authorities;
● changes in local regulations as part of a response to the COVID-19 pandemic which may require us to change the ways in which clinical trials are conducted, which may result in unexpected costs, or to discontinue the clinical trials altogether;
−Removed: ● refusal of the FDA to accept data from clinical trials in affected geographies outside the United States;
● negative effects on the quality, completeness, integrity, interpretability, and cost of our clinical study data.
−Removed: The potential disruptions discussed above and other consequences of the COVID-19 pandemic could result in missed study visits or study procedures in our clinical trials, which could lead to an abundance of protocol deviations that impact the interpretability of the trial results.
−Removed: A significant number of deviations may call into question whether the execution of a clinical trial was consistent with the protocol, which is of particular importance where study designs were agreed to as part of a SPA as in the case of our Phase 3 clinical trial for the combination of ublituximab plus UKONIQ for patients with CLL (UNITY-CLL) and our registration program for ublituximab in RMS (ULTIMATE I and II).
−Removed: In extreme cases, significant deviations from the protocol may be considered a violation of the SPA and result in potential rescindment of the SPA agreement, which could adversely affect our ability to use the results of the impacted study to support a future regulatory application.
−Removed: We will continue to monitor the potential impact of COVID-19 on our clinical trial program, however, the full extent to which the COVID-19 pandemic may directly or indirectly impact the progress of our current and planned trials will depend on future developments that are highly uncertain and cannot be accurately predicted.
+Added: The potential disruptions and other impacts discussed above and other consequences of the COVID-19 pandemic could result in missed study visits or study procedures in our clinical trials, which could lead to an abundance of protocol deviations that impact the interpretability of the trial results.
+Added: A significant number of deviations may call into question whether the execution of a clinical trial was consistent with the protocol, which is of particular importance where study designs were agreed to as part of a SPA, as in the case of our Phase 3 clinical trial for ublituximab in RMS.
+Added: In extreme cases, significant deviations from the protocol may be considered a violation of the SPA.
+Added: The impacts of COVID-19 on clinical studies described above may be greater in geographies outside the U.S., including in Eastern European countries where we have a number of study sites for ULTIMATE I and II.
+Added: In the event government-imposed restrictions related to COVID-19 that have been lifted are reinstated or new measures are implemented to address the spread of new variants, our ability to successfully commercialize our product or any of our product candidates for which we in the future obtain regulatory approval also may be adversely impacted.
+Added: In response to the COVID-19 pandemic, many healthcare institutions reduced access of pharmaceutical and biotechnology companies to healthcare providers as part of their safety measures.
+Added: Should limitations on access continue, our commercialization activities, including the manner in which our field teams engage with healthcare providers and facilities, may limit our ability to provide product education and information, which could slow adoption and impact sales.
+Added: We will continue to monitor the potential impact of COVID-19 on our business;
+Added: however, the full extent to which the COVID-19 pandemic may directly or indirectly impact the progress of our current and planned trials will depend on future developments that are uncertain and cannot be accurately predicted.
General Risks
3 unchanged sentences
These factors include:
−Removed: ● publicity regarding actual or potential clinical results relating to products under development by our competitors or us;
+Added: ● reception and success of BRIUMVI in the market;
+Added: ● publicity regarding actual or potential clinical results relating to our product or products under development by our competitors or us;
● delay or failure in initiating, completing or analyzing nonclinical or clinical trials or the unsatisfactory design or results of these trials;
−Removed: ● achievement or rejection of regulatory approvals by our competitors or us;
+Added: ● achievement or rejection of regulatory approvals by us or our competitors;
+Added: ● any delay in our regulatory review for products and product candidates we may develop, and any adverse development or perceived adverse development with respect to the applicable regulatory authority’s review of such filings, including without limitation a change to the projected approval date, scheduling of an advisory committee meeting or issuance of a “refusal to file” letter;
● announcements of technological innovations or new commercial products by our competitors or us;
2 unchanged sentences
● regulatory developments in the United States and foreign countries;
−Removed: ● economic or other crises and other external factors such as the disruptions in the global economy caused by the COVID-19 pandemic;
+Added: ● economic or other crises and other external factors such as the disruptions in the global economy caused by the COVID-19 pandemic and the conflict between Russia and Ukraine;
● period-to-period fluctuations in our revenues and other results of operations;
5 unchanged sentences
These broad market and industry factors may seriously harm the market price of our common stock, regardless of our operating performance.
+Added: As a result of this volatility, investors may not be able to sell their common stock at or above the price paid for the shares.
Because we do not anticipate paying any cash dividends on our capital stock in the foreseeable future, capital appreciation, if any, will be the sole source of gain for our stockholders.
18 unchanged sentences
Moreover, these rules and regulations increase our legal and financial compliance costs and make some activities more time-consuming and costly.
−Removed: For example, these rules and regulations make it more difficult and more expensive for us to obtain director and officer liability insurance, and we may be required to accept reduced policy limits and coverage or incur substantially higher costs to obtain the same or similar coverage.
−Removed: As a result, it may be more difficult for us to attract and retain qualified persons to serve on our Board of Directors, our Board committees or as executive officers.
The Sarbanes-Oxley Act of 2002 requires, among other things, that we maintain effective internal control over financial reporting and disclosure controls and procedures.
8 unchanged sentences
Past lawsuits and any future lawsuits to which we may become a party are subject to inherent uncertainties and will likely be expensive and time-consuming to investigate, defend, and resolve, and will divert our management’s attention and financial and other resources.
−Removed: The outcome of litigation is necessarily uncertain, and we could be forced to expend significant resources in the defense of these and other suits, and we may not prevail.
+Added: The outcome of litigation is necessarily uncertain, and we could be forced to expend significant resources in the defense of these and other suits in which we may not prevail.
Any litigation to which we are a party may result in an onerous or unfavorable judgment that may not be reversed upon appeal or in payments of substantial monetary damages or fines, or we may decide to settle this or other lawsuits on similarly unfavorable terms, which could adversely affect our business, financial condition, results of operations or stock price.
8 unchanged sentences
We cannot predict the number, timing or size of future issuances or the effect, if any, that any future issuances may have on the market price for our common stock.
−Removed: We maintain corporate and executive space in New York, New York, and Edison, New Jersey.
−Removed: We are also currently leasing small office spaces in Raleigh, and North Carolina.
+Added: UNRESOLVED STAFF COMMENTS
+Added: We maintain corporate and executive space in New York, New York, Edison, New Jersey and Morrisville, North Carolina.
+Added: We are also currently leasing small office space in Boca Raton, Florida.
We believe that our existing facilities are adequate to meet our current requirements.
We do not own any real property.
−Removed: LEGAL PROCEEDINGS.
−Removed: We, and our subsidiaries, are not a party to, and our property is not the subject of, any material pending legal proceedings.
−Removed: MINE SAFETY DISCLOSURES.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.