We are a clinical-stage biopharmaceutical company developing our novel class of highly specific and selective antibody-based therapeutics for the treatment of solid tumor cancer.
−Removed: Our conditionally active biologics (“CAB”
−Removed: or “CABs”) capitalize on our proprietary discoveries with respect to tumor biology, enabling us to target known and widely validated tumor antigens that have previously been difficult or impossible to target.
+Added: Our conditionally active biologics (“CAB” or “CABs”) capitalize on our proprietary discoveries with respect to tumor biology, enabling us to target known and widely validated tumor antigens that have previously been difficult or impossible to target.
Our novel CAB therapeutic candidates exploit characteristic pH differences between the tumor microenvironment and healthy tissue.
Unlike healthy tissue, the tumor microenvironment is acidic, and we have designed our antibodies to selectively bind to their targets on cancer cells under acidic pH conditions but not on targets in normal tissues.
−Removed: Our approach is to identify the necessary targeting and potency required for cancer cell destruction, while aiming to eliminate or greatly reduce on-target, off-tumor toxicity—one of the fundamental challenges of existing cancer therapies.
+Added: Our approach is to identify the necessary targeting and potency required for cancer cell destruction, while aiming to eliminate or greatly reduce on-target, off-tumor toxicity—one of the fundamental challenges of existing cancer therapies.
The enhanced selectivity of our CAB technology has the potential to greatly improve the benefit-risk ratio for the patient and allows us to deliver desired drug levels either as monotherapy or utilizing unique multi-targeted or combination therapies that are currently difficult or impossible to develop.
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By exploiting our novel understanding of tumor biology, we believe that our proprietary CAB technology has the potential to transform antibody-based cancer therapy.
−Removed: Our goal is to develop well-tolerated, novel cancer therapies that provide cures or extended survival to ensure patients’
−Removed: improved quality of life.
+Added: Our goal is to develop well-tolerated, novel cancer therapies that provide cures or extended survival to ensure patients’ improved quality of life.
Studies have shown that, as a drug class, antibodies have transformed oncology treatment and include some of the best-selling therapies on the biopharmaceutical market.
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Initially, we applied the reversible binding and precision capability of our CAB technology to advance next-generation ADC therapies.
−Removed: We also generated antibodies for immuno-oncology and more recently, for bispecific, T cell engagement.
+Added: We have also developed antibodies for immuno-oncology and for bispecific, T cell engagement.
The bispecific CAB antibodies are comprised of two different binding specificities, which allows the antibody to bind to two specific targets at the same time, generally one target on the tumor cell and one target on an immune system cell.
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Upon binding of mecbotamab vedotin to AXL on the surface of tumor cells, it is internalized and the MMAE cytotoxin is released, thus killing the cancer cell.
−Removed: We have developed a biomarker assay that quantifies the AXL Tumor membrane Percent Score (0-100%), or TmPS.
−Removed: The TmPS measures the percentage of cancer cells within the tumor that expresses the AXL target expression generally on the tumor membrane which, consistent with industry standard, we use to identify those patients who we believe will be the most likely to respond to our product candidates.
−Removed: In several tumor types, we believe that the larger percentage of cells expressing the target on the tumor membrane, the more likely it is that our product candidates may have the potential to provide clinical benefit.
We are developing mecbotamab vedotin as a potential therapeutic for multiple solid tumor types, including soft tissue and bone sarcoma and non-small cell lung cancer (NSCLC), with other potential indications in the future.
−Removed: The Office of Orphan Drug Products (OODP) at the FDA has granted Orphan Drug Designation to mecbotamab vedotin for the treatment of soft tissue sarcoma.
+Added: The Office of Orphan Products Development (OOPD) at the FDA has granted Orphan Drug Designation to mecbotamab vedotin for the treatment of soft tissue sarcoma.
Phase 1 results in sarcoma patients indicated mecbotamab vedotin was generally well-tolerated in this refractory sarcoma population.
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Dose-limiting toxicities were limited to free circulating MMAE payload-associated toxicity at the highest dose tested, including reversible neutropenia.
−Removed: Higher levels of AXL tumor membrane expression correlated with response to treatment.
−Removed: Overall, we believe mecbotamab vedotin has the potential for a favorable benefit-risk profile, and importantly this is one of the few studies employing a biomarker that is not only highly expressed in sarcomas,
−Removed: but also may help select patients across multiple sarcoma subtypes who may benefit from therapy.
−Removed: In our ongoing potentially registration-enabling sarcoma Phase 2 study, patients are enrolled for therapy by prescreening for AXL expression.
−Removed: We are also conducting a Phase 2 study (BA3011-002) in AXL positive NSCLC patients who have previously progressed on PD-1/L1, EGFR, or ALK inhibitor therapy.
+Added: We are conducting a Phase 2 study (BA3011-002) in AXL positive NSCLC patients who have previously progressed on programmed cell death protein 1 (“PD-1”)/programmed cell death ligand 1 (“PD-L1”), epidermal growth factor receptor (“EGFR”), or anaplastic lymphoma kinase (“ALK”) inhibitor therapy.
+Added: We are also conducting a potentially registrational Phase 2 study in sarcoma.
In both Phase 2 indications, we are enrolling patients either as a monotherapy or in combination with the PD-1 inhibitor nivolumab.
−Removed: In addition, a multi-center investigator-initiated Phase 2 clinical trial of mecbotamab vedotin in combination with a PD-1 inhibitor in patients with platinum-resistant ovarian cancer is underway.
Ozuriftabmab vedotin (BA3021):
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Genetic inactivation of ROR2 in metastatic melanoma cells was shown to prevent metastases of these tumor cells in mice.
−Removed: ROR2 also has essential roles in normal cells and in early development.
+Added: has essential roles in normal cells and in early development.
Inactivation of ROR2 is lethal in mice with defects observed in the heart, nervous system and skeleton.
Less severe mutations in ROR2 in humans is associated with skeletal diseases Robinow syndrome and brachydactyly type B.
−Removed: Employing a similar approach as with mecbotamab vedotin, we developed a TmPS quantitative assay based on ROR2 tumor membrane expression that we use to identify those patients who we believe will be the most likely to respond to our product candidates.
Ozuriftamab vedotin is a CAB anti-ROR2 ADC consisting of a CAB anti-ROR2 humanized IgG1 monoclonal antibody conjugated to MMAE using a cleavable linker.
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Upon binding of ozuriftamab vedotin to ROR2 on the surface of tumor cells, it is internalized and the MMAE cytotoxin is released, thus killing the cancer cell.
−Removed: We are developing ozuriftamab vedotin as a potential therapeutic for multiple solid tumor types, including NSCLC, melanoma, and cancer of the head and neck.
+Added: We are developing ozuriftamab vedotin as a potential therapeutic for multiple solid tumor types, including melanoma and SCCHN.
Based on Phase 1 data, we believe ozuriftamab vedotin has broad potential as a cancer therapy for patients with advanced solid tumors who have experienced prior failure of PD-1 blockade.
−Removed: We are enrolling a Phase 2 trial of ozuriftamab vedotin monotherapy or in combination with a PD-1 inhibitor in patients with ROR2 positive melanoma who have previously progressed on PD-1/L1 inhibitor and patients with ROR2 high NSCLC who have previously progressed on PD-1/L1, EGFR or ALK inhibitor therapy.
−Removed: A Phase 2 study in patients with ROR2 positive SCCHN has begun.
−Removed: In addition, a multi-center investigator-initiated Phase 2 clinical trial of ozuriftamab vedotin in combination with a PD-1 inhibitor in patients with platinum-resistant ovarian cancer is underway.
−Removed: Our third clinical stage product candidate, BA3071, is a CAB anti-CTLA-4 antibody that is being developed as an immuno-oncology agent with the goal of delivering at least the efficacy of approved CTLA-4 antibodies, such as ipilimumab, but with lower toxicity rate as a result of the CAB’s unique tumor microenvironment-restricted binding.
+Added: We are enrolling a Phase 2 trial of ozuriftamab vedotin monotherapy or in combination with a PD-1 inhibitor in patients with ROR2 positive melanoma who have previously progressed on PD-1/L1 inhibitor.
+Added: We are also conducting a Phase 2 study in patients with SCCHN.
+Added: Evalstotug (BA3071):
+Added: Our third clinical stage product candidate, evalstotug, is a CAB anti-CTLA-4 antibody that is being developed as an immuno-oncology agent with the goal of delivering at least the efficacy of approved CTLA-4 antibodies, such as ipilimumab, but with lower toxicity rate as a result of the CAB’s unique tumor microenvironment-restricted binding.
CTLA-4, or cytotoxic T-lymphocyte-associated antigen 4, is an immune checkpoint involved in regulating T-cell activation.
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however, cancer cells often take advantage of this pathway to prevent immune destruction of the tumor.
−Removed: Ipilimumab and recently approved tremelimumab currently are the only anti-CTLA-4 monoclonal antibodies approved by the FDA.
+Added: Ipilimumab and tremelimumab currently are the only anti-CTLA-4 monoclonal antibodies approved by the FDA.
Ipilimumab is approved as a single agent for the treatment of melanoma, and in combination with an anti-PD-1 antibody for the treatment of multiple solid tumors, including melanoma, RCC, colorectal cancer and NSCLC, and tremelimumab is approved in combination with an anti-PD-L-1 antibody for the treatment of unresectable hepatocellular carcinoma and NSCLC.
Patients treated with these checkpoint inhibitors face a risk of a number of adverse events associated with inappropriate activation of the immune system beyond the tumor site including severe and sometimes fatal enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy.
−Removed: Consequently, and for example, usage and dosage of ipilimumab is highly limited due to its safety profile, resulting in the average number of doses on therapy not exceeding four doses.
−Removed: We are developing BA3071 as a potential therapeutic for multiple solid tumor indications, possibly including renal cell carcinoma, NSCLC, small cell lung cancer, hepatocellular carcinoma, melanoma, bladder cancer, gastric cancer and cervical cancer.
−Removed: We have initiated a Phase 1/2 dose-escalation trial of BA3071 as monotherapy and in combination with an anti-PD-1 antibody with expansion cohorts to be enrolled upon identification of the recommended dose.
−Removed: CAB EpCAM x CD3 (BA3182):
+Added: Consequently, usage and dosage of ipilimumab is highly limited due to its safety profile.
+Added: We are developing evalstotug as a potential therapeutic for multiple solid tumor indications.
+Added: We have initiated a Phase 1/2 dose-escalation trial of evalstotug as monotherapy and in combination with an anti-PD-1 antibody.
+Added: We have also initiated our Phase 2 study of evalstotug for treatment-refractory melanoma and carcinomas, and treatment-naïve melanoma and NSCLC, at a dose of 350mg and more recently 700mg.
+Added: We are currently evaluating the 1000mg dose level in our Phase 1 study and potentially will in Phase 2 once Phase 1 is cleared.
+Added: Patients receiving evalstotug at 700mg and 1000mg will be treated with prophylactic tocilizumab to help reduce risks associated with the release of cytokines into the blood from immune cells that have been activated by the treatment.
+Added: BA3182 (CAB-EpCAM x CAB-CD3):
+Added: Our first bispecific candidate, BA3182, is being investigated in a Phase 1 study in advanced adenocarcinoma.
We have leveraged our CAB technology to develop bispecific antibodies, which bind both a tumor-specific antigen and a T cell receptor using CAB antigen-binding domains.
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There are multiple structural variants of antibodies and other antigen-binding domains being used by others to construct bispecific product candidates, some of which are being tested clinically.
−Removed: However, similar to CAR-T cells and blinatumomab, many of these bispecific product candidates have increased risks of generating life-threatening cytokine release syndrome due to systemic immune activation.
+Added: However, similar to CAR-T cells and blinatumomab, many of these bispecific product candidates have increased risks of generating life-threatening cytokine release syndrome and other potential adverse events due to systemic immune activation and the wide expression of EpCAM, or epithelial cell adhesion molecule.
We have applied our CAB antibody technology to develop bispecific CAB antibodies in which one or both antigen-binding domains are active only in the tumor microenvironment.
−Removed: An example of this approach is our CAB EpCAM x CD3 bispecific.
−Removed: EpCAM, or epithelial cell adhesion molecule, is a protein that is over-expressed in many cancers including carcinomas derived from colon, intestine, breast, lung and prostate.
+Added: An example of this approach is our BA3182 bispecific.
+Added: EpCAM is a protein that is over-expressed in many cancers including carcinomas derived from colon, intestine, breast, lung and prostate.
Expression of EpCAM has been extensively associated with cell growth and proliferation of both healthy and cancer cells.
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Over 20% of patients experienced dose-limiting toxicities, and at these required low doses, there was only one unconfirmed partial response observed among 65 patients.
−Removed: Our first bispecific candidate, CAB EpCAM x CD3 received IND clearance from the FDA in February 2023.
−Removed: We are conducting IND-enabling studies for two additional CAB product candidates, B7-H3 x CD3, a bispecific antibody, and one next-generation CAB ADC, Nectin-4.
−Removed: We also are evaluating additional candidates including EGFR x CD3 bispecific, Nectin4 x CD3 bispecific, and B7-H4 as a next-generation CAB ADC candidate.
−Removed: Overall, we are advancing multiple pre-clinical assets with potential INDs in the 2023 to 2024 timeframe.
+Added: We are also completing Investigational New Drug (IND) enabling studies for our next-generation CAB ADC, Nectin-4 with an expected IND in 2024.
+Added: Additional in-process CAB candidates including B7 H3 x CD3 bispecific, EGFR x CD3 bispecific, Nectin4 x CD3 bispecific, and
+Added: B7-H4 as a next-generation CAB ADC candidate have been positioned for partnering and portfolio prioritization in favor of our Phase 2 potential registrational trial enabling studies.
Our mission is to develop and commercialize innovative antibody-based therapeutics for the treatment of solid tumors that are designed to bind depending on the physical and chemical properties of tumors and their microenvironment.
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• Advance our lead product candidates through regulatory approval and commercialization.
−Removed: o Mecbotamab vedotin:
+Added: o Mecbotamab vedotin (BA3011):
Clinical data from our Phase 1 and Phase 2 part 1 trials with mecbotamab vedotin are supportive of its development in metastatic sarcomas, a set of cancers with a high unmet clinical need, and in metastatic PD-1 failure NSCLC.
We are conducting a potentially registration-enabling Phase 2 trial for mecbotamab vedotin in undifferentiated pleomorphic sarcoma, or UPS, patients (12 years of age or older).
−Removed: In addition, we are planning to discuss with the FDA initiating a potentially registration-enabling Phase 2 trial in NSCLC later this year.
−Removed: In both studies, we are using a quantitative biomarker assay/TmPS score to identify likely responders and to help enrich our clinical trial programs.
−Removed: o Ozuriftamab vedotin:
−Removed: We have observed antitumor activity in PD-1 failure NSCLC, melanoma and SCCHN patients in our Phase 1 trial and have initiated Phase 2 trials of ozuriftamab vedotin in each of these indications.
−Removed: We are using a quantitative biomarker assay/TmPS score to identify based on the TmPS score the likely responders and to help enrich our clinical trial programs.
−Removed: o CAB BA3071 anti CTLA-4 immune checkpoint inhibitor:
−Removed: The design of BA3071 is to provide the efficacy similar to that of ipilimumab, an anti-CTLA-4 monoclonal antibody approved by the FDA, but with a significantly enhanced safety profile.
+Added: In addition, we have obtained FDA clearance to initiate a potentially registration-enabling Phase 2/3 trial in NSCLC in 2 nd Line + or 3 rd Line + population.
+Added: o Ozuriftamab vedotin (BA3021):
+Added: We have observed antitumor activity in PD-1 failure NSCLC, melanoma and SCCHN patients in our Phase 1 trial and have initiated Phase 2 trials of ozuriftamab vedotin in the melanoma and SCCHN indications.
+Added: o Evalstotug (BA3071):
+Added: Evalstotug is designed to provide the efficacy similar to that of ipilimumab, an anti-CTLA-4 monoclonal antibody approved by the FDA, but with the potential of a significantly enhanced safety profile due to the conditional binding properties of CABs.
This may allow for patients to be treated at higher dosage and/or for more cycles of treatment in combination with an anti-PD-1 antibody that may lead to better therapeutic results.
−Removed: o CAB EpCAM x CAB CD3 (BA3182) :
−Removed: Our first bispecific candidate with an investigational new drug application, or IND, cleared by FDA, demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.
−Removed: We are initiating a Phase 1 study in advanced adenocarcinoma.
+Added: To date, we have observed objective responses and disease control among patients treated in our Phase 1 study at 350mg in combination with anti-PD-1 antibody, and have seen limited adverse events of Grade 3 or higher, suggesting an improved safety profile for evalstotug.
+Added: o BA3182 (CAB-EpCAM x CAB-CD3) :
+Added: Our first bispecific candidate with an IND, cleared by FDA, demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.
+Added: We have initiated a Phase 1 study in advanced adenocarcinoma.
Carcinoma is the most common form of cancer and adenocarcinoma is the most common subtype.
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Almost all prostate and breast cancers are adenocarcinoma, and about 96% of colorectal and 40% of non-small cell lung cancers are adenocarcinoma (American Cancer Society 2022).
−Removed: Advance into clinical development multiple CAB bispecific and next generation CAB ADC candidates to further address areas of high unmet needs in treating solid tumors.
−Removed: We have shown in preclinical experiments, including in EpCAM x CD3, that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially fatal immune responses.
−Removed: For example, our first CAB EpCAM x CAB CD3 (BA3182) demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.
+Added: • Enhance pre-clinical assets with multiple CAB bispecific and next generation CAB ADC candidates to further address areas of high unmet needs in treating solid tumors.
+Added: We have shown in preclinical experiments, including for our Phase 1 clinical asset, BA3182, that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially fatal immune responses.
+Added: For example, BA3182 demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.
We believe that our next generation CAB-ADC platform further widens that therapeutic window by enhancing the linker-payload system.
−Removed: Combining our CAB technology with our newly developed next generation CAB-ADC platform replaces the traditional peptide linker with a novel sugar-based linker to deliver the MMAE payload.
+Added: Combining our CAB technology with our next generation CAB-ADC platform replaces the traditional peptide linker with a novel sugar-based linker to deliver the MMAE payload.
It is expected that this new CAB ADC system will further reduce off-target, off-tumor toxicity and thereby expand the therapeutic window.
• Maintain and strengthen our intellectual property portfolio.
−Removed: As of March 1, 2023, we had a total of 711 patents and patent applications with 435 issued patents, 5 allowed applications and 271 pending applications covering our CAB technology and product candidates.
+Added: As of February 1, 2024, we had a total of 752 patents and patent applications with 479 issued patents, 13 allowed applications and 260 pending applications covering our CAB technology and product candidates.
This broad patent coverage was designed such that protection of our product candidates is not dependent on any single patent but rather, each product candidate provides multiple layers of protection.
We plan to continue to maintain, monitor, enforce and defend our intellectual property.
−Removed: Selectively enter into collaborations to maximize the value of our platform and pipeline.
+Added: • Enter into collaborations to maximize the value of our platform and pipeline.
Given the potential of our technology to generate novel product candidates addressing a wide variety of solid tumors, we may opportunistically enter into strategic collaborations around specific geographic regions, indications, combinations and companion diagnostics.
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Drug developers might develop an antibody that is exquisitely specific against its target, but due to the expression of the target on non-tumor cells, systemic administration can result in dose-limiting toxicities from on-target, off-tumor activity.
−Removed: For example, cetuximab targets an antigen that is highly expressed in colorectal cancer, but this antigen is also expressed in epidermal cells throughout the body.
−Removed: Consequently, treatment with cetuximab results in over 80% of patients developing skin toxicities that can severely impact patients’
−Removed: physical, psychological and social well-being and can lead to treatment discontinuation and dose reduction.
−Removed: These examples, however, only represent antibodies where the therapeutic benefit clearly outweighs the consequences associated with the adverse events.
−Removed: There are many potential protein targets that do not offer such clear-cut therapeutic windows.
The majority of anticancer antibody-based drug products are consequently limited to a small subset of potential tumor antigens.
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CAB leverages the low pH found in the tumor microenvironment
−Removed: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer.
+Added: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors cancer cells that interact with surrounding cytokines and cells through the circulatory and lymphatic systems to influence the development and progression of cancer.
The tumor microenvironment has conditions distinct from the normal cellular and extracellular environments found in non-cancerous tissue, blood or other parts of a normal body.
It has been long appreciated that the extracellular milieu inside and surrounding the growing tumor mass is distinct and unique.
−Removed: One of the most profound physicochemical differences between the tumor microenvironment and normal cellular environment is an increase in lactic acid and an associated decrease in pH in the tumor microenvironment from the normal physiological pH of about 7.4 or higher.
+Added: One of the most profound physicochemical differences between the tumor microenvironment and normal cellular microenvironment is an increase in lactic acid and an associated decrease in pH in the tumor microenvironment from the normal physiological pH of about 7.4 or higher.
While the tumor is acidic, some of the most acidic regions of tumors can be observed at the edge of the tumors, just at the interface with the surrounding tissue or blood, according to a paper published in 2019 in the journal Cancer Research.
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Certain regions within the tumor and in the cells at the edge of tumors took up some of the highest concentration of the probe, indicating that these areas had pH substantially lower than 6.5.
−Removed: These findings are important when considering the
−Removed: design of therapies for solid tumors because they point to the fact that while the overall tumor is acidic, the most accessible and rapidly growing portions of tumors are likely to have some of the lowest pHs.
+Added: These findings are important when considering the design of therapies for solid tumors because they point to the fact that while the overall tumor is acidic, the most accessible and rapidly growing portions of tumors are likely to have some of the lowest pHs.
One reason for the low pH in tumors compared to normal cells is that there are distinct differences in the metabolic processes found in normal and cancer cells.
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In comparison, cancer cells have switched their mechanism of energy production preferentially to the non-oxygen-dependent process known as glycolysis, even in the presence and availability of oxygen.
−Removed: This process switch was first described nearly a century ago and is the basis of modern tumor screening technologies.
+Added: This process switch, known as the Warburg Effect, was first described nearly a century ago and is the basis of modern tumor screening technologies, such as Positron Emission Tomography or PET scanning.
The dependence of a tumor cell on glycolysis results in the tumor cell metabolizing up to 200 times more glucose than a healthy cell and causing the secretion of significant levels of lactic acid into the tumor microenvironment.
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In some cancers, the pH goes as low as 5.8, an extremely low level given the normal, slightly alkaline, pH in the body.
−Removed: The body’s blood holds its pH within a tight range around a pH of 7.4, with normal tissue typically being even more alkaline, even in the non-cancerous regions of tissues afflicted with cancer.
−Removed: Tumors not only have characteristically low pH, which assists them in reducing the body’s immune defenses, along with acidity they also generate other aberrant conditions and secrete other chemicals and proteins into the tumor microenvironment that may stimulate tumor growth, promote the development of new blood vessels or angiogenesis, degrade surrounding tissues allowing the tumor to spread or metastasize or actively suppress detection and destruction by the immune system.
−Removed: In view of our preclinical studies and clinical trial results and the substantial supporting scientific literature, we believe that there is an opportunity to develop cancer therapies with improved selectivity for tumors by taking advantage of changes in pH, as do our initial product candidates, as well as in the conditions and levels of temperature, pressure and chemical composition in the tumor microenvironment.
+Added: The body’s blood holds its pH within a tight range around a pH of 7.4, with normal tissue typically being even more alkaline in the non-cancerous regions of tissues afflicted with cancer.
+Added: Tumors not only have characteristically low pH, which assists them in reducing the body’s immune defenses, along with acidity they also generate other aberrant conditions and secrete other chemicals and proteins into the tumor microenvironment that can stimulate tumor growth,
+Added: promote the development of new blood vessels or angiogenesis, degrade surrounding tissues allowing the tumor to spread or metastasize or actively suppress detection and destruction by the immune system.
+Added: In view of our preclinical studies and clinical trial results and the substantial supporting scientific literature, we believe that there is an opportunity to develop cancer therapies with improved selectivity for tumors by taking advantage of changes in pH, as do our existing product candidates, as well as in the conditions and levels of temperature, pressure and chemical composition in the tumor microenvironment.
Our CAB technology
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CAB proteins have increased binding activity as the pH in the microenvironment becomes acidic, while being inactive in normal physiological environments.
−Removed: We discovered a novel chemical switch mechanism that underpins this binding activity that involves physiological-occurring chemicals, such as bicarbonate and hydrogen sulfide.
+Added: We discovered a novel chemical switch mechanism that underpins this binding activity that involves physiologically occurring chemicals, such as bicarbonate and hydrogen sulfide.
These molecules are negatively charged at physiological conditions and interact with positive charged areas on the protein surface.
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CAB antibodies have human or humanized antibody sequences, a characteristic that reduces the risk of immunogenicity compared to emerging technologies in the field, which is supported by both our preclinical and clinical data.
−Removed: Our CAB antibodies have been designed to be active in the acidic, lower pH of the tumor microenvironment and inactive under the alkaline pH’s of 7.4 and above found in normal physiological conditions.
+Added: Our CAB antibodies have been designed to be active in the acidic, lower pH of the tumor microenvironment and inactive under the alkaline pH of 7.4 and above found in normal physiological conditions.
In a quantitative in vitro binding assay, we compared a CAB antibody and a non-CAB antibody that both bind to the target AXL with matched strength of binding to the target, or affinities, when measured at pH 6.0.
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The wide therapeutic window imparted by tumor-specific targeting enables CAB antibodies to be modified with cytotoxic drugs to create ADCs.
−Removed: Similarly, bispecific antibodies can be developed using CAB antibody domains targeting pairs of targets that direct T cells to attack the tumor, which may exhibit unacceptable toxicities such as cytokine release syndrome and neurological toxicity if constructed using traditional antibody domains.
+Added: Similarly, bispecific antibodies can be developed using CAB antibody domains targeting pairs of targets that direct T cells to attack the tumor, thereby reducing the likelihood of unacceptable normal tissue injury if constructed using traditional antibody domains.
• Increased drug exposure to tumors.
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Limited binding to targets outside of tumors effectively increases their half-life in plasma.
−Removed: The phenomenon of Target-mediated Drug Disposition, or TMDD, is a well-known limitation facing the development of many biologics which CAB antibodies can significantly reduce.
+Added: The phenomenon of TMDD, is a well-known limitation facing the development of many biologics which CAB antibodies can significantly reduce.
• Broader universe of tumor-specific antigens that can be targeted.
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CAB antibodies with pH-dependent binding have the potential to significantly reduce the potential risk of systemic toxicities caused by expression of targets on normal tissues.
−Removed: Through the use of our proprietary technology, we have developed CAB antibodies, which we believe have specificity for tumors, while avoiding binding to the same antigen target expressed on many normal tissues.
+Added: We have developed CAB antibodies through the use of our proprietary technology, which we believe have specificity for tumors, while avoiding binding to the same antigen target expressed on many normal tissues.
This allows us to develop therapeutics against targets that are expressed at high levels on tumor cells but are also present on normal cells and tissues, without the toxicities associated with traditional antibodies.
−Removed: While our lead product candidates primarily exploit the differences in pH between the tumor microenvironment and healthy tissue, there is a potential for other yet to be identified PaCS molecules in disease related microenvironments, whether controlled through pH, concentration, or other molecular characteristics (intra- or intermolecularly) for enhancing a drug’s therapeutic index.
+Added: While our lead product candidates primarily exploit the differences in pH between the tumor microenvironment and healthy tissue, there is a potential for other yet to be identified PaCS molecules in disease related microenvironments, whether controlled through pH, concentration, or other molecular characteristics (intra- or intermolecularly) for enhancing a drug’s therapeutic index.
Potential new therapeutic candidates addressing these opportunities are not limited to antibodies, but may also include small molecules, encompassing lipids, sugars and nucleic acid-based agents or drugs.
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Phase 1 clinical trial
−Removed: We have conducted a Phase 1 trial of mecbotamab vedotin in patients with advanced solid tumors, including sarcoma, pancreatic cancer and NSCLC who were refractory or resistant to standard therapies.
+Added: We have conducted a Phase 1 trial of mecbotamab vedotin in patients with advanced solid tumors, including sarcoma, pancreatic cancer, adenoid cystic carcinoma (ACC), and NSCLC who were refractory or resistant to standard therapies.
In the Phase 1 trial, patients were treated with doses of mecbotamab vedotin ranging from 0.3 mg/kg to 3 mg/kg once every three weeks (Q3W) or doses ranging from 1.2 mg/kg to 1.8 mg/kg twice every three weeks on days 1 and 8 (2Q3W).
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neutropenia and anemia), transient liver enzyme elevations (AEs:
−Removed: AST/ALT increased) or metabolic disturbances (AEs:
+Added: aspartate aminotransferase (“AST”)/ alanine aminotransferase (“ALT”) increased) or metabolic disturbances (AEs:
hyperglycemia, hyponatremia, hypokalemia).
−Removed: At a dose of 2.4 mg/kg Q3W mecbotamab vedotin, two patients experienced dose-limiting toxicities:
−Removed: one with Grade 3 febrile neutropenia and the other with Grade 4 hyperglycemia.
−Removed: Dosing continued at the 2.4 mg/kg with prophylactic administration of pegfilgrastim without any additional dose limiting toxicities.
We have not observed adverse events that appear to be related to on-target injury of normal, AXL expressing tissues, i.e., on-target, off-tumor toxicity, consistent with the increase in tumor selectivity from the CAB technology.
The estimated half-life of mecbotamab vedotin was approximately four days.
−Removed: We identified a preliminary correlation between tumoral expression of AXL and the observed antitumor clinical response.
−Removed: To select for patients who were most likely to experience clinical benefit, we developed and validated, as required by CLIA (the Clinical Laboratory Improvement Amendments, or CLIA, which establishes federal quality standards for laboratory testing), an AXL immunohistochemical assay to quantify the level of target expression on the tumor membrane and cytoplasm.
−Removed: We observed that most sarcoma patients screened for enrollment had tumors that expressed high levels of AXL.
Phase 2 Clinical Development
−Removed: We are conducting two Phase 2, potentially registration-enabling trials with mecbotamab vedotin in NSCLC and sarcoma.
−Removed: We are conducting further dose optimization in Phase 2, part 1 using a more frequent, intense-dosing regime that will be compared to the doses used in
−Removed: Phase 1 and/or 2.
−Removed: We also intend to initiate discussions with the FDA regarding our plans for a potentially registration-enabling Phase 2, part 2 study.
−Removed: This overlapping approach is intended to allow the company to maintain its overall development timelines, while further aligning with FDA’s Project Optimus goals that encourage testing of multiple doses to optimize a patient’s treatment risk/benefit.
−Removed: Prior to seeking accelerated approval for either indication, we will seek feedback from the FDA and evaluate our ability to obtain accelerated approval.
−Removed: The FDA requires that the sponsor verify and describe the clinical benefit as a condition of accelerated approval, which is generally in the form of at least one adequate and well-controlled post-marketing confirmatory clinical trial.
−Removed: Therefore, we plan to submit our proposed confirmatory trial design for FDA feedback and commence enrollment prior to our BLA submission.
−Removed: Additionally, a multi-center investigator-initiated trial of mecbotamab vedotin led by the Canadian Cancer Trials Group, or CCTG, in platinum-resistant ovarian cancer patients is underway.
−Removed: The following table illustrates each of the different dosing schedules under evaluation for mecbotamab vedotin.
−Removed: All cycles (28 days)
−Removed: All cycles (21 days)
−Removed: Cycle 1 (21 days)
−Removed: Cycle 2 (28 days) and subsequent cycles
−Removed: a all doses will be capped at 100 kg for patients with body weight > 100 kg;
−Removed: not applicable as not part of the 21-day cycle
−Removed: Sarcoma Phase 2 trial:
−Removed: This open-label, two-part Phase 2 trial evaluates the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in adult and adolescent patients with AXL-expressing TmPS >= 50%, and advanced, refractory measurable sarcoma.
−Removed: Patients receive either mecbotamab vedotin alone or in combination with an anti-PD-1 agent.
−Removed: Part 1 antitumor activity has exceeded predefined criteria for advancing trials for UPS, osteosarcoma, liposarcoma, and synovial sarcoma.
−Removed: Combination dosing is fully enrolled and enrollment continues for Ewing and other bone sarcomas.
−Removed: Phase 2, part 2 is enrolling patients with UPS, for which efficacy was observed in either Phase 1 and in Phase 2 part 1.
−Removed: Specifically, a total of 11 patients with undifferentiated pleomorphic sarcoma (UPS) were enrolled in BA3011-001 study as of the data cutoff date 18 January 2023.
−Removed: 5 patients (50%) achieved partial response among those 10 patients with TmPS ≥
−Removed: The median duration of response exceeded 8 months, the median PFS was 10.9 months (95% CI:
−Removed: 1.4, NE) and PFS rate at 12 weeks was 60% (95%CI:
−Removed: Part 2 will enroll a total of approximately 80 patients with locally advanced unresectable or metastatic UPS with high AXL expression.
−Removed: Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.
+Added: UPS Phase 2 trial:
+Added: We are conducting a Phase 2, single-arm, potentially registration-enabling trial with mecbotamab vedotin monotherapy in patients with UPS who have experienced prior treatment failure.
+Added: We believe UPS represents a critical unmet need and we are exploring accelerated approval options for patients otherwise suffering from uncontrolled sarcoma with few effective treatment options.
+Added: While it is acknowledged that a randomized confirmatory trial is typically employed to confirm clinical benefit.
+Added: Given the marked rarity of UPS patients, it may be possible, subject to future agreement with the FDA, to confirm clinical benefit by enrolling additional UPS patients in a prospective clinical trial with the purpose of providing regulators with extended follow-up that adequately characterizes disease control and overall tolerability.
+Added: A variety of trial options are under consideration to meet anticipated requirements associated with confirmation of clinical benefit.
+Added: The open-label, two-part Phase 2 trial evaluates the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in adult and adolescent patients, and advanced, refractory measurable sarcoma.
+Added: Patients received either mecbotamab vedotin alone or in combination with an anti-PD-1 agent.
+Added: Part 1 antitumor activity has exceeded predefined criteria for advancing trials for UPS, osteosarcoma, liposarcoma, synovial sarcoma, chondrosarcoma, and chordoma.
+Added: Part 1 of the trial employing the 1.8 mg/kg dose delivered every other week is now fully enrolled, and a clinical update was presented as an oral presentation at the ESMO Sarcoma and Rare Cancers Congress in March 2024.
+Added: As noted above, our ongoing Phase 2, part 2, potentially registrational trial employing the 1.8 mg/kg dose delivered on days 1 and 8 of a three-week cycle (2Q3W) is enrolling patients with locally advanced unresectable or metastatic UPS.
+Added: Primary endpoints include overall response rate (ORR), AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.
Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), best overall response (BOR), disease control rate (DCR), time to response (TTR), progression-free rate (PFR) at 12 weeks, overall survival (OS), and percent change from baseline in tumor size.
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Additionally, patients must have received no more than three prior systemic regimens.
−Removed: Enrolled patients will receive open-label BA3011 treatment.
−Removed: Initially, approximately 40 patients will be enrolled in a 1:1 ratio to receive mecbotamab vedotin 2Q3W or 3Q4W regimens as shown in the table above.
−Removed: Randomization will be stratified by number of prior systemic treatments (≤
−Removed: A planned interim analysis will be performed after these 40 patients have an opportunity to be followed for at least 12 weeks.
−Removed: To facilitate the selection of an optimized dosing regimen, efficacy, safety, and an integrated PK and exposure-response analysis will be performed based on all UPS patients in Phase 1, Phase 2 part 1, and the 40 UPS patients initially enrolled in Phase 2 part 2.
+Added: Enrolled patients are receiving open-label mecbotamab vedotin treatment.
+Added: A planned interim analysis will be performed after all patients in Phase 2, part 2 have an opportunity to be followed for at least 12 weeks.
+Added: Efficacy, safety, and an integrated PK and exposure-response analysis will be performed based on all UPS patients in Phase 1, Phase 2 part 1, and the UPS patients initially enrolled in Phase 2 part 2.
NSCLC Phase 2 trial:
−Removed: This ongoing multi-center, open-label, Phase 2 study is designed to evaluate the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in patients with AXL-expressing TmPS >=1%, metastatic NSCLC who have measurable disease by RECIST v1.1 criteria.
+Added: This ongoing multi-center, open-label, Phase 2 study is designed to evaluate the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in patients with metastatic NSCLC who have measurable disease by RECIST v1.1 criteria.
Enrolled patients must have had prior disease progression on a PD-1/L-1 inhibitor.
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Phase 1/2 clinical trial
−Removed: A Phase 1/2 clinical trial of ozuriftamab vedotin in patients with locally advanced unresectable or metastatic solid tumors including NSCLC and melanoma is being conducted.
+Added: A Phase 1/2 single-arm clinical trial of ozuriftamab vedotin monotherapy in patients with locally advanced unresectable or metastatic solid tumors in melanoma is being conducted.
Patients were treated with doses of ozuriftamab vedotin ranging from 0.3 mg/kg to 3.3 mg/kg once every three weeks (Q3W) or doses ranging from 1.5 mg/kg to 1.8 mg/kg twice every three weeks on days 1 and 8 (2Q3W).
Based upon the overall safety and response rates, the initial recommended Phase 2 dose was determined to be 1.8 mg/kg delivered every two weeks (Q2W).
−Removed: Further dose optimization is being conducted.
−Removed: The following table illustrates each of the different dosing schedules under evaluation for ozuriftamab vedotin.
−Removed: All cycles (28 days)
−Removed: All cycles (21 days)
−Removed: Cycle 1 (21 days)
−Removed: Cycle 2 (28 days) and subsequent cycles
−Removed: a all doses will be capped at 100 kg for patients with body weight > 100 kg;
−Removed: not applicable as not part of the 21-day cycle
−Removed: In the Phase 1 component of the trial, treatment with ozuriftamab vedotin resulted in a durable complete response, or CR, in one out of one patient with metastatic melanoma who tested positive for ROR2 tumor membrane expression.
−Removed: This patient remains progression free approximately 3 years after initiating therapy.
−Removed: A second CR was achieved by one out of one evaluable melanoma patient in the Phase 2 component of the trial.
−Removed: In addition, two out of four patients with NSCLC who tested positive for ROR2 tumor membrane expression (~31% and ~49% tumor reduction) and one out of one patient who tested positive for ROR2 tumor membrane expression with advanced head and neck cancer (~64% tumor reduction) achieved partial responses.
−Removed: All of these patients had previously been treated with PD-1 therapy.
−Removed: Note that one of the ROR2 positive NSCLC patients that did not achieve a partial response was administered ozuriftamab vedotin at a suboptimal dose of 1.2 mg/kg 2Q3W as part of the dose escalation phase of the study.
+Added: In the Phase 1 component of the trial, treatment with ozuriftamab vedotin resulted in multiple responders in patients with treatment-refractory solid tumors, including melanoma, NSCLC, and head and neck cancer.
+Added: All of these patients had previously progressed following PD-1 therapy.
Similar to mecbotamab vedotin, ozuriftamab vedotin continues to be generally well-tolerated.
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Phase 2 Clinical Development
−Removed: A Phase 2 open-label trial to evaluate the efficacy and safety of ozuriftamab vedotin alone and in combination with an anti-PD-1 agent in patients who have experienced prior disease progression on a PD1/L1 inhibitor and have a ROR2 TmPS of 1% or more is ongoing and metastatic NSCLC or melanoma who have measurable disease.
−Removed: Prior to seeking accelerated approval for either indication, we will seek feedback from the FDA and evaluate our ability to obtain accelerated approval.
−Removed: If acceptable, we plan to submit our proposed confirmatory trial design for FDA feedback and commence enrollment prior to our BLA submission.
−Removed: Approximately 60 ROR2 expressing NSCLC and 40 ROR2 agnostic melanoma patients with locally advanced unresectable solid tumors or metastatic disease are being enrolled.
−Removed: Enrolled patients are assigned to receive either ozuriftamab vedotin alone or in combination with an anti-PD-1 agent employing a dose and schedule as described in the table above.
−Removed: Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.
−Removed: Key secondary endpoints include DOR, PFS, BOR, DCR, TTR, progression-free rate (PFR) at 12 weeks, OS, and percent change from baseline in tumor size.
−Removed: We have also initiated a Phase 2 clinical trial of ozuriftamab vedotin as monotherapy in head and neck squamous cell carcinoma (SCCHN).
−Removed: The Phase 2 trial studying SCCHN is enrolling 40 patients who had experienced prior failure of a PD-1 agent delivered either as monotherapy or in combination with chemotherapy.
+Added: A Phase 2 open-label trial to evaluate the efficacy and safety of ozuriftamab vedotin alone and in combination with an anti-PD-1 agent in patients who have experienced prior disease progression on a PD-1/L1 inhibitor is ongoing in melanoma who have measurable disease.
+Added: Primary endpoints include ORR, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.
+Added: Key secondary endpoints include DOR, PFS, BOR, DCR, TTR, PFR at 12 weeks, OS, and percent change from baseline in tumor size.
+Added: We have also completed enrollment for a Phase 2 clinical trial of ozuriftamab vedotin as monotherapy in SCCHN using 1.8mg/kg with either Q2W or 2Q3 dosing.
Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.
−Removed: Key secondary endpoints include DOR, PFS, BOR, DCR, TTR, progression-free rate (PFR) at 12 weeks, OS, and percent change from baseline in tumor size.
−Removed: Additionally, a multi-center investigator-initiated trial of ozuriftamab vedotin led by CCTG in platinum-resistant ovarian cancer patients continues.
−Removed: CAB CTLA4 (BA3071)
−Removed: The Phase 1 dose-escalation trial of BA3071 in advanced solid tumor patients continues enrollment in the dose-escalation portion of the trial.
−Removed: We are evaluating the safety and tolerability of BA3071 at doses ranging from 7mg Q3W to 700mg Q3W as monotherapy and in combination with an anti-PD-1 antibody.
−Removed: CAB EpCAM x CAB CD3 (BA3182)
−Removed: In February 2023 we received from the FDA clearance of our IND application to evaluate our CAB bispecific antibody product candidate BA3182 (CAB EpCAM x CAB CD3) for the treatment of advanced adenocarcinoma.
+Added: Key secondary endpoints include DOR, PFS, BOR, DCR, TTR, PFR at 12 weeks, OS, and percent change from baseline in tumor size.
+Added: Evalstotug (BA3071) targeting CTLA4
+Added: The Phase 1 dose-escalation trial of evalstotug in advanced solid tumor patients continues enrollment in the dose-escalation portion of the trial.
+Added: We are evaluating the safety and tolerability of evalstotug at doses ranging from 7mg Q3W to 1000mg Q3W as monotherapy and in combination with an anti-PD-1 antibody.
+Added: A Phase 2 open-label trial to evaluate the efficacy and safety of evalstotug alone and in combination with an anti-PD-1 agent, and also in combination with chemotherapy for 1 st Line NSCLC, in patients who have treatment-refractory melanoma and carcinoma and who have treatment-naïve metastatic melanoma and NSCLC is underway.
+Added: To date, we have observed limited adverse events of Grade 3 or higher in our Phase 1 study at 350mg in combination with PD-1 suggesting an improved safety profile for evalstotug.
+Added: Prior to seeking accelerated approval for any proposed indication, we will seek feedback from the FDA and evaluate our ability to obtain accelerated approval.
+Added: If acceptable, we plan to submit our proposed confirmatory trial design for FDA feedback and commence enrollment prior to our Biologics License Application (“BLA”) submission.
+Added: BA3182 (CAB-EpCAM x CAB-CD3)
+Added: We are conducting a Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and antitumor activity of BA3182, a conditionally active biologic (CAB)-bispecific T-cell engager antibody construct targeting EpCAM in patients with advanced adenocarcinoma.
BA3182 is designed with an EpCAM binding domain and a CD3 binding domain, both binding domains with CAB activity (Dual-CAB).
−Removed: In our preclinical studies, we showed that a dosage of 1mg per kilogram of this construct twice per week in mice, which is roughly equivalent to 0.25 mg per kilogram in non-human primates, had a potent antitumor activity in a HCT116, a human colorectal carcinoma cell line, xenograft model in mice with a humanized immune system.
+Added: In our preclinical studies, we showed that a dosage of 1mg per kilogram of this construct twice per week in mice, which is roughly equivalent to
+Added: 0.25 mg per kilogram in non-human primates, had a potent antitumor activity in a HCT116, a human colorectal carcinoma cell line, xenograft model in mice with a humanized immune system.
Preclinical safety findings
−Removed: While there was no observable difference in antitumor efficacy between antibodies with CAB domains and those with conventional non-CAB antigen-binding domains, a conventional EpCAM x CD3 bispecific antibody led to a much higher level of undesirable systemic immune activation than the CAB EpCAM x CAB CD3 bispecific antibody in non-human primates.
+Added: While there was no observable difference in antitumor efficacy between antibodies with CAB domains and those with conventional non-CAB antigen-binding domains, a conventional EpCAM x CD3 bispecific antibody led to a much higher level of undesirable systemic immune activation than the CAB-EpCAM x CAB-CD3 (BA3182) bispecific antibody in non-human primates.
Preclinical candidates
−Removed: CAB Nectin-4-ADC (BA3361)
+Added: BA3361 (CAB-Nectin-4-ADC)
Nectin-4 is widely expressed and has adhesive roles in normal tissues.
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In addition to the assay performance, the lead candidate demonstrated high binding under tumor conditions and little to no binding under normal physiological conditions.
−Removed: CAB B7-H4-ADC (BA3151)
+Added: We plan to submit an IND for BA3361 in 2024.
+Added: BA3151 (CAB-B7-H4-ADC)
B7-H4 is highly expressed on numerous tumor tissues and the expression level directly correlates with adverse clinical and pathological features.
A set of lead molecules were characterized in vitro including functional assays and in vivo efficacy models.
−Removed: Selection of the lead
−Removed: candidate was based on criteria including high binding activity under tumor conditions and low binding activity under normal physiological conditions.
−Removed: CAB B7-H3 x CAB CD3 (BA3142)
+Added: Selection of the lead candidate was based on criteria including high binding activity under tumor conditions and low binding activity under normal physiological conditions.
+Added: BA3142 (CAB-B7-H3 x CAB-CD3)
We believe that our CAB technology opens up the opportunity for the creation of a broad set of bispecific product candidates with antitumor potential.
Through these CAB bispecific antibodies, we believe we can activate T cells directly in tumors using CAB domains targeting tumor-specific antigens.
−Removed: Our CAB bispecific antibodies are not expected to lead to systemic immune activation, which we believe may allow for increased efficacy through more potent T cell activation, higher doses or administration in combination with other immuno-oncology therapies, such as checkpoint inhibitors.
+Added: We believe our CAB bispecific antibodies may allow for increased efficacy through more potent T cell activation, higher doses or administration in combination with other immuno-oncology therapies, such as checkpoint inhibitors.
We have shown in preclinical experiments that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially fatal immune responses.
−Removed: In February 2023 we received from the FDA clearance of our IND application to evaluate our CAB bispecific antibody product candidate BA3182 (CAB EpCAM x CAB CD3) and we are conducting IND enabling studies in other bispecific antibody candidates.
+Added: In February 2023 we received from the FDA clearance of our IND application to evaluate our CAB bispecific antibody product candidate BA3182, which is now part of an ongoing Phase 1/2 clinical study.
Our second bispecific product candidate, BA3142, is a dual-CAB T-cell engager targeting B7-H3, a protein expressed on many solid tumors.
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The lead molecule showed antitumor activity comparable to a non-CAB antibody, while demonstrating lower binding and functional activity under physiological conditions, as expected for a CAB bispecific antibody.
−Removed: CAB EGFR x CAB CD3
+Added: Cell line development and in vivo efficacy study are completed.
+Added: CAB-EGFR bispecific programs
Targeting EGFR with a CAB bispecific antibody is expected to provide benefit since the target is widely expressed in healthy tissue, such as skin, which would otherwise result in on-target, off-tumor toxicity if targeted by a non-CAB antibody.
2 unchanged sentences
a mono-CAB (EGFR x CAB-CD3) and a dual-CAB (CAB-EGFR x CAB-CD3).
−Removed: CAB Nectin 4 x CAB CD3 (BA3362)
+Added: BA3362 (CAB-Nectin 4 x CAB-CD3)
BA3362 is a dual CAB bispecific product candidate.
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There are several companies in various stages of clinical development of ADCs, one of the key features of our product candidates mecbotamab vedotin and ozuriftamab vedotin.
−Removed: Currently, there are multiple approved ADCs and many more in clinical development, the vast majority of which were being developed for the treatment of cancer.
−Removed: Certain other companies are also pursuing antibody therapies in immuno-oncology, such as Seattle Genetics.
+Added: Currently, there are multiple approved ADCs and many more in clinical development, the vast majority of which are being developed for the treatment of cancer.
+Added: Certain other companies are also pursuing antibody therapies in immuno-oncology.
Although we do not believe competing companies have selective CAB technology, there is a wide array of activity in multiple areas of immune-based cellular therapies for oncology.
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The level of generic competition and the availability of reimbursement from government and other third-party payors will also significantly affect the pricing and competitiveness of our products.
−Removed: In addition, our competitors also may obtain FDA or other regulatory approval for their products more
−Removed: rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
+Added: In addition, our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
Manufacturing
12 unchanged sentences
Furthermore, the raw materials for our product candidates may be sourced, in some cases, from a single-source supplier.
−Removed: As part of the manufacture and design process for our product candidates, we rely on internal, scientific and manufacturing know-how and trade secrets and the know-how and trade secrets of third-party manufacturers.
+Added: As part of the manufacture and design process for our product
+Added: candidates, we rely on internal, scientific and manufacturing know-how and trade secrets and the know-how and trade secrets of third-party manufacturers.
We also contract with additional third parties for the filling, labeling, packaging, storage and distribution of investigational drug products.
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Collaborations
−Removed: We intend to selectively enter into collaborations to maximize the value of our platform and pipeline.
+Added: We intend to selectively enter into collaborations with preclinical and/or clinical assets, particularly where potential collaborators can both accelerate and maximize a therapeutic's market potential.
License Agreements and Strategic Collaborations
Collaboration and Supply Agreement with Bristol-Myers Squibb
−Removed: On January 5, 2022, we and Bristol-Myers Squibb Company (“BMS”) entered into a clinical trial collaboration and supply agreement (the “BMS Agreement”).
−Removed: Under the terms of the BMS Agreement, BioAtla and BMS will collaborate on clinical trials of separate combination therapies using two of BioAtla’s CAB ADCs, mecbotamab vedotin and ozuriftamab vedotin, each in combination with Opdivo® (nivolumab), BMS’
−Removed: proprietary anti-PD-1 monoclonal antibody product.
+Added: On January 5, 2022, we and Bristol-Myers Squibb Company (“BMS”) entered into a clinical trial collaboration and supply agreement (the “BMS Agreement”).
+Added: Under the terms of the BMS Agreement, BioAtla and BMS will collaborate on clinical trials of separate combination therapies using two of BioAtla’s CAB ADCs, mecbotamab vedotin (BA3011) and ozuriftamab vedotin (BA3021), each in combination with Opdivo® (nivolumab), BMS’ proprietary anti-PD-1 monoclonal antibody product.
We serve as the study sponsor of the scheduled studies and are responsible for costs associated with the trial execution.
4 unchanged sentences
In April 2019, we entered into a Global Co-Development and Collaboration Agreement with BeiGene, Ltd.
−Removed: which, as amended in December 2019 and October 2020, provided for the development, manufacturing and commercialization of BioAtla’s investigational CAB CTLA-4 antibody, BA3071.
−Removed: Under the terms of our BeiGene collaboration, BeiGene was generally responsible for developing the CAB CTLA-4 antibody and for global regulatory filings and commercialization.
+Added: which, as amended in December 2019 and October 2020, provided for the development, manufacturing and commercialization of BioAtla’s investigational CAB CTLA-4 antibody, evalstotug (BA3071).
+Added: Under the terms of our BeiGene collaboration, BeiGene was generally responsible for developing evalstotug and for global regulatory filings and commercialization.
We received a total of $25 million in payments from BeiGene.
On November 19, 2021, we entered into Amendment No.
−Removed: 3 to the Global Co-Development and Collaboration Agreement (“Amendment No.
+Added: 3 to the Global Co-Development and Collaboration Agreement (“Amendment No.
Under Amendment No.
−Removed: 3, the collaboration agreement was terminated, subject to survival of certain provisions, and BeiGene handed back rights to certain know-how and materials received under the collaboration agreement and we assumed responsibility for the development and commercialization of BA3071, in addition to other standard provisions.
+Added: 3, the collaboration agreement was terminated, subject to survival of certain provisions, and BeiGene handed back rights to certain know-how and materials received under the collaboration agreement and we assumed responsibility for the development and commercialization of evalstotug, in addition to other standard provisions.
As consideration for Amendment No.
−Removed: 3, we agreed to pay BeiGene mid-single digit royalties on sales worldwide and on a limited basis will share in any upfront and milestone payments received through a sublicense of BA3071.
−Removed: Exclusive License Agreement with Inversagen, LLC
−Removed: In March 2019, we entered into an Exclusive License Agreement with Inversagen, LLC, as amended in July 2020.
−Removed: Under the terms of the agreement, we granted Inversagen an exclusive, worldwide, royalty-bearing license under certain patents and know-how controlled by us to develop, make, have made, sell, have sold, offer for sale and import CAB-antibodies for the field of diseases associated with aging, outside of cancer, and an immuno-oncology antibody.
−Removed: We may perform development services under the agreement and will be reimbursed by Inversagen for our costs.
−Removed: Commencing on the first commercial sale of the CAB-antibodies and immuno-oncology antibody subject to the agreement, Inversagen will pay us royalties in the mid-single digits, which represents a variable interest held by us.
−Removed: We have an option for a period of 10 years to acquire the sole and exclusive rights solely to develop, make, have made, use, sell, have sold, offer for sale and import the immuno-oncology antibody in
−Removed: the field worldwide (except for the People’s Republic of China, Hong Kong, Taiwan and Macau) in return for royalty payments in the low-single digits during the applicable royalty term.
−Removed: For both royalties paid to us by Inversagen and, upon exercise of our option, royalties paid to Inversagen by us, the royalty term, on a product-by-product basis, is the period of time commencing on the first commercial sale of such product in a country and ending upon the later to occur of (i) expiration of the last-to-expire valid claim of the patent rights controlled by us or by Inversagen covering the manufacture, use, sale, offer for sale or import of such product, (ii) 10 years following the first commercial sale of such product in such country and (iii) the expiration of regulatory exclusivity for such product in such country.
−Removed: Unless earlier terminated, the agreement continues in effect so long as Inversagen or any of its affiliates, licensees or sublicensees are developing or commercializing the CAB-antibodies or immuno-oncology antibody in the field or we or any of our affiliates, licensees or sublicensees are developing or commercializing the CAB-antibodies or immuno-oncology antibody outside the field.
−Removed: We can also terminate the agreement with 30 days prior written notice for Inversagen’s failure to pay.
−Removed: No payments have been made to date.
+Added: 3, we agreed to pay BeiGene mid-single digit royalties on sales worldwide and on a limited basis will share in any upfront and milestone payments received through a sublicense of evalstotug.
Amended and Restated Exclusive Rights Agreement with Himalaya Therapeutics SEZC
6 unchanged sentences
We are eligible to receive up to $77.5 million in upfront payments and potential milestones.
−Removed: Exclusive License Agreement with BioAtla Holdings, LLC
−Removed: In January 2020, we entered into an Exclusive License Agreement with BioAtla Holdings, LLC, as amended in July 2020.
−Removed: Under the terms of the agreement, we granted BioAtla Holdings an exclusive, worldwide license under certain patents and know-how controlled by us to develop, make, have made, use, sell, have sold, offer for sale and import CAB antibodies for certain targets in the field of Adoptive Cell Therapy, or ACT (CAR-T).
−Removed: Commencing on the first commercial sale of the CAB antibodies subject to the agreement, BioAtla Holdings will pay us royalties in the mid-single digits, which represents a variable interest held by us.
−Removed: We have an option for a period of 10 years to acquire the sole and exclusive rights solely to develop, make, have made, use, sell, have sold, offer for sale and import the ACT preparations and ACT treatments in the ACT field worldwide (except for the People’s Republic of China, Hong Kong, Taiwan and Macau) in return for royalty payments in the low-single digits during the applicable royalty term.
−Removed: For both royalties paid to us by BioAtla Holdings and, upon exercise of our option, royalties paid to BioAtla Holdings by us, the royalty term, on a product-by-product basis, is the period of time commencing on the first commercial sale of such product in a country and ending upon the expiration of the last-to-expire valid claim of the patent rights controlled by us or by BioAtla Holdings covering the manufacture, use, sale, offer for sale or import of such product.
−Removed: We will not owe BioAtla Holdings any milestone or royalty payments unless we exercise our option to acquire the rights to the ACT preparations and ACT treatments.
−Removed: During the term of the agreement, we agreed not to develop, make, have made, use, sell, have sold, offer for sale or import any CAB ACT treatment in the field of ACT.
−Removed: Unless earlier terminated, the agreement continues in effect so long as BioAtla Holdings or any of its affiliates, licensees or sublicensees are developing or commercializing the ACT preparations and treatments in the ACT field or we or any of our affiliates, licensees or sublicensees are developing or commercializing any CAB non-ACT product for any indication outside the ACT field.
−Removed: The agreement may be terminated only by the mutual written agreement of the parties.
−Removed: No payments have been made to date.
−Removed: In addition, effective January 2020, we entered into a Royalty Sharing Agreement whereby we agreed to share with BioAtla Holdings 50% of the royalties we receive under the license agreement with EXUMA Biotech Corp.
−Removed: (formerly F1 Oncology, Inc.) described below.
−Removed: Amended and Restated Exclusive License Agreement with EXUMA Biotech Corp
−Removed: In May 2016, we entered into an Exclusive License Agreement with EXUMA Biotech Corp.
−Removed: (“EXUMA”, formerly F1 Oncology, Inc.) and its affiliates, which, as amended in July 2016 and November 2017 and as amended and restated in November 2019, granted an exclusive, worldwide, sublicensable license under certain patents and know-how controlled by us to develop, manufacture and commercialize four CAB ACT (CAR-T) preparations and treatments for cancer.
−Removed: EXUMA granted us an exclusive, worldwide, royalty free, fully paid-up, sublicensable license under certain patents and know-how controlled by EXUMA and EXUMA’s interest in technology jointly developed under the agreement to develop, manufacture and commercialize non-ACT CAB products for any indication.
−Removed: EXUMA is obligated to pay us during the royalty term, on a product-by-product basis and country-by-country basis, mid-single-digit royalties based on annual net sales of certain EXUMA ACT products, subject to certain adjustments.
−Removed: The term during which EXUMA is obligated to pay royalties under the agreement with respect to any particular product in any particular country, will begin on the first commercial sale of such product in such country and will end on the date of expiration of the last-to-expire of certain product-related patent rights in such country.
−Removed: Unless earlier terminated, the agreement continues in effect so long as EXUMA or any of its affiliates, licensees or sublicensees are developing or commercializing any EXUMA products in the ACT field or we or any of our affiliates, licensees or sublicensees are developing or commercializing any CAB products for any indication outside the ACT field.
−Removed: The agreement may be terminated only by the mutual written agreement of the parties.
−Removed: CHO-S Cell Line License Agreement with Life Technologies Corporation
−Removed: On June 28, 2018, we entered into the CHO-S Cell Line License Agreement with Life Technologies Corporation.
−Removed: Under the terms of the agreement, Life Technologies Corporation provides and grants to us a worldwide, non-exclusive, royalty-free, non-sublicensable license to use certain CHO-S cells to make, or have made, recombinant proteins for clinical or commercial purposes and to seek regulatory approval for the sale of such recombinant proteins in exchange for a one-time, non-refundable, non-creditable license fee of $400,000.
−Removed: No royalties are due by us to Life Technologies Corporation under the agreement.
−Removed: Additional specific lots of Life Technologies Corporation’s recombinant proteins may be ordered by us for an additional fee of $50,000 per lot.
−Removed: The term of the agreement continues in perpetuity unless terminated by either party.
Intellectual property
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We also apply for patents covering developments and technologies for purpose of preventing third parties from developing competing products.
−Removed: Inventions related to various aspects of our core technologies have already been protected by issued and pending patent applications.
−Removed: As of March 1, 2023, we had 711 patents and patent applications with 435 issued patents, 5 allowed applications, and 271 pending applications.
+Added: Inventions related to various aspects of our core technologies have already been protected by issued and pending
+Added: patent applications.
+Added: As of February 1, 2024, we had 752 patents and patent applications with 479 issued patents, 13 allowed applications, and 260 pending applications.
We recognize that the ability to obtain patent protection and the degree of such protection depends on a number of factors, including the extent of the prior art, the novelty of the invention, the obviousness of the invention and the ability to satisfy the enablement and written description requirements of the patent laws.
1 unchanged sentence
We file our applications with the U.S.
−Removed: Patent and Trademark Office to establish a priority filing date.
+Added: Patent and Trademark Office (the “USPTO”) to establish a priority filing date.
Generally, we initially file provisional applications.
5 unchanged sentences
Subsequently, when appropriate, we pursue patent applications in foreign countries.
−Removed: The PCT system for filing international patent applications is used.
+Added: The Patent Cooperation Treaty (“PCT”) system for filing international patent applications is used.
This system allows a single application to be filed within 12 months of the original priority date of the patent application designating all 157 PCT member states (including countries in South, Central and North America, Africa, Europe, Asia and Australia) in which national/regional patent applications can later be pursued based on the international patent application filed under the PCT.
6 unchanged sentences
Our policy of avoiding patent infringement is diligently executed.
−Removed: To the best of our knowledge as of the date of this prospectus, we have freedom to operate on all of our technologies and product candidates.
+Added: To the best of our knowledge as of the date of this Annual Report on Form 10-K, we have freedom to operate on all of our technologies and product candidates.
The patent positions of biotechnology and biopharmaceutical companies like ours are generally uncertain and involve complex legal, scientific and factual issues.
3 unchanged sentences
Any patents that we hold may be challenged, circumvented or invalidated by third parties.
−Removed: For a more comprehensive discussion of the risks related to our patents, please see “Risk factors—Risks related to our intellectual property.”
+Added: For a more comprehensive discussion of the risks related to our patents, please see “Risk factors—Risks related to our intellectual property.”
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.
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It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us.
−Removed: These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us are to be kept confidential and not disclosed to third parties except in specific circumstances.
−Removed: Our agreements with employees and consultants also provide that all inventions conceived by the employee in the course of employment or work with us or from the employee’s or consultant’s use of our confidential information are our exclusive property.
−Removed: For a more comprehensive discussion of the risks related to our trade secrets, please see “Risk factors—Risks related to our intellectual property.”
+Added: These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us are to be kept confidential and not disclosed to third parties except in specific circumstances.
+Added: Our agreements with employees and consultants also provide that all inventions
+Added: conceived by the employee in the course of employment or work with us or from the employee’s or consultant’s use of our confidential information are our exclusive property.
+Added: For a more comprehensive discussion of the risks related to our trade secrets, please see “Risk factors—Risks related to our intellectual property.”
Company-owned patents
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Composition of matter claims issuing from this application would not expire before 2037.
−Removed: BA3071 is covered by a number of filings, including a published PCT application filed in 2019 that entered the national phase in 2021.
−Removed: Applications have been granted in Australia, Israel, New Zealand, and the United States and are pending in 18 jurisdictions, including most major market countries.
+Added: Evalstotug is covered by a number of filings, including a published PCT application filed in 2019 that entered the national phase in 2021.
+Added: Applications have been granted in Australia, Israel, Korea, New Zealand, and the United States and are pending in 18 jurisdictions, including most major market countries.
Composition of matter claims issuing from this application would not expire before 2039.
5 unchanged sentences
We also have 27 issued U.S.
−Removed: patents covering various aspects of the manufacturing methods used to generate CAB antibodies that have patent terms expiring from 2030 to 2037.
−Removed: We also have 2 issued patents in the U.S.
−Removed: protecting our method of manufacturing conditionally active multi-specific antibodies that have patent terms expiring from 2033 to 2034.
+Added: patents covering various aspects of the manufacturing methods used to generate CAB antibodies that have patent terms expiring from 2030 to 2038, excluding in potential patent term extensions.
Out-licensed patents
−Removed: Himalaya Therapeutics SEZC has exclusive rights to patents/patent applications in China, Macao, Hong Kong and Taiwan relating to ROR2 (Patent applications 2017800294276 (China), and patent application 106115891 (Taiwan), both titled Anti-ROR2 antibodies and their immunoconjugates and uses thereof) and relating to AXL (Patent applications 201780023876X (China), and patent application 106112687 (Taiwan), both titled Anti-AXL antibodies and their immunoconjugates and uses thereof).
+Added: Himalaya Therapeutics SEZC has exclusive rights to patents/patent applications in China, Macao, Hong Kong and Taiwan relating to ROR2 (patent application 2017800294276 (China) and patent application 106115891 (Taiwan), both titled “Anti-ROR2 antibodies and their immunoconjugates and uses thereof”) and relating to AXL (patent applications 201780023876X (China) and patent application 106112687 (Taiwan), both titled “Anti-AXL antibodies and their immunoconjugates and uses thereof”).
Additionally, Himalaya Therapeutics SEZC has exclusive worldwide rights to patents/patent applications relating to IL-22 (Patent applications 108119613 and PCT/US19/35395, both titled “Anti-IL-22 antibodies, antibody fragments and their immunoconjugates and uses thereof”) and relating to HER2 (patent application USP 62/964,747 titled “Conditionally active anti-HER2 antibodies”).
−Removed: BioAtla Holdings, LLC has exclusive worldwide rights to all patents for the field of ACT (CAR-T), excluding the targets licensed to EXUMA Biotech Corp (“EXUMA”).
+Added: BioAtla Holdings, LLC has exclusive worldwide rights to all patents for the field of adoptive cell immunotherapy “ACT” (chimeric antigen receptor (CAR) T-cell (“CAR-T”)), excluding the targets licensed to EXUMA Biotech Corp (“EXUMA”).
Inversagen, LLC has exclusive worldwide rights to all patents solely in the field of diseases associated with aging (outside of cancer), diagnostics related thereto and an immuno-oncology antibody.
−Removed: EXUMA has an exclusive worldwide license to all patents solely to develop, make, have made, use, sell, have sold, offer for sale and import adoptive cell therapy (CAR-T) products to four named targets for the treatment of cancer.
−Removed: EXUMA’s rights under the agreement exclude the right to grant sublicenses to third parties to discover, develop or manufacture any CAB ACT or any component of our CAB ACT technology, except as used in or incorporated into EXUMA’s ACTs for cancer.
+Added: EXUMA has an exclusive worldwide license to all patents solely to develop, make, have made, use, sell, have sold, offer for sale and import CAR-T products to four named targets for the treatment of cancer.
+Added: EXUMA’s rights under the agreement exclude the right to grant sublicenses to third parties to discover, develop or manufacture any CAB ACT or any component of our CAB ACT technology, except as used in or incorporated into EXUMA’s ACTs for cancer.
Government regulation and product approval
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In the United States, the FDA regulates biologic products under the Federal Food, Drug, and Cosmetic Act, or the FDCA, the Public Health Service Act, or the PHSA, and regulations and guidance implementing these laws.
−Removed: The FDCA, PHSA and their corresponding regulations, and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacturing, safety, purity, potency, labeling, packaging, storage, record keeping, approval, distribution, post-approval monitoring and reporting, sampling, import, export, advertising and other promotional practices involving biologic products.
+Added: The FDCA, PHSA and their corresponding regulations, and
+Added: other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacturing, safety, purity, potency, labeling, packaging, storage, record keeping, approval, distribution, post-approval monitoring and reporting, sampling, import, export, advertising and other promotional practices involving biologic products.
Biological products used for the prevention, treatment or cure of a disease or condition of a human being are subject to regulation under the FDCA, except the section of the FDCA that governs the approval of new drug applications, or NDAs.
−Removed: Biological products are approved for marketing under provisions of the PHSA, via a Biologic License Application, or BLA.
+Added: Biological products are approved for marketing under provisions of the PHSA, via a BLA.
However, the application process and requirements for approval of BLAs are very similar to those for NDAs, and biologics are associated with similar approval risks and costs as drugs.
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The process generally involves the following:
−Removed: Completion of extensive preclinical laboratory tests and in vivo studies in accordance with the FDA’s current good laboratory practice, or GLP, regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;
+Added: • Completion of extensive preclinical laboratory tests and in vivo studies in accordance with the FDA’s current good laboratory practice, or GLP, regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;
• Submission to the FDA of an IND, which must become effective before clinical trials may begin;
• Approval by an independent institutional review board, or IRB, reviewing each clinical site before each clinical trial may be initiated;
−Removed: Performance of adequate and well-controlled clinical trials in accordance with the FDA’s IND regulations, GCP requirements, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed biologic product candidate for its intended use;
+Added: • Performance of adequate and well-controlled clinical trials in accordance with the FDA’s IND regulations, good clinical practice (“GCP”) requirements, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed biologic product candidate for its intended use;
• Preparation and submission to the FDA of a BLA for marketing approval that includes substantial evidence of safety, purity and potency from results of nonclinical testing and clinical trials;
• A determination by the FDA within 60 days of its receipt of a BLA to file the application;
−Removed: Satisfactory completion of FDA pre-approval inspections of the manufacturing facility or facilities where the biologic product candidate is produced to assess compliance with cGMPs and to assure that the facilities, methods and controls are adequate to preserve the biologic product candidate’s identity, safety, strength, quality, potency and purity;
+Added: • Satisfactory completion of FDA pre-approval inspections of the manufacturing facility or facilities where the biologic product candidate is produced to assess compliance with cGMPs and to assure that the facilities, methods and controls are adequate to preserve the biologic product candidate’s identity, safety, strength, quality, potency and purity;
• Satisfactory completion of any potential FDA audits of the nonclinical and clinical trial sites that generated the data in support of the BLA to assure compliance with GCPs and integrity of the clinical data;
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Further, each clinical trial must be reviewed and approved by an IRB at or servicing each institution at which the clinical trial will be conducted.
−Removed: An IRB is charged with protecting the welfare and rights of trial participants and considers items such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.
+Added: charged with protecting the welfare and rights of trial participants and considers items such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.
The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject, or his or her legal representative, reviews and approves the study protocol, and must monitor the clinical trial until completed.
1 unchanged sentence
The biologic product candidate initially is introduced into a small number of healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution or excretion.
−Removed: If possible, a Phase 1 clinical trial may also seek to gain an early understanding of the product candidate’s effectiveness.
+Added: If possible, a Phase 1 clinical trial may also seek to gain an early understanding of the product candidate’s effectiveness.
In the case of some product candidates for severe or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.
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The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including non-compliance with regulatory requirements or a finding that the patients are being exposed to an unacceptable health risk.
−Removed: Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients.
+Added: Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients.
Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.
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FDA approval of a BLA must be obtained before commercial marketing of the biologic product.
−Removed: The results of the preclinical tests and clinical trials, together with detailed information relating to the product’s pharmacology, chemistry, manufacturing controls, or CMC, and proposed labeling, among other things, are submitted to the FDA as part of the BLA requesting approval to market the product for one or more indications.
+Added: The results of the preclinical tests and clinical trials, together with detailed information relating to the product’s pharmacology, chemistry, manufacturing controls, or CMC, and proposed labeling, among other things, are submitted to the FDA as part of the BLA requesting approval to market the product for one or more indications.
The cost of preparing and submitting a BLA is substantial.
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Once the submission is filed by the FDA, the FDA begins an in-depth, substantive review of the BLA.
−Removed: The FDA reviews the BLA to determine, among other things, whether the proposed product candidate is safe and effective for its intended use, has an acceptable purity profile and whether the product candidate is being manufactured in accordance with cGMPs to assure and preserve the product candidate’s identity, safety, strength, quality, potency and purity.
+Added: The FDA reviews the BLA to determine, among other things, whether the proposed product candidate is safe and effective for its intended use, has an acceptable purity profile and whether the product candidate is being manufactured in accordance with cGMPs to assure and preserve the product candidate’s identity, safety, strength, quality, potency and purity.
The FDA may refer applications for novel biologic products or biologic products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.
The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions on approval.
−Removed: During the product approval process, the FDA also will determine whether a risk evaluation and mitigation study, or REMS, is necessary to assure the safe use of the product candidate.
+Added: During the product approval process, the FDA also will determine whether a risk evaluation and mitigation strategy, or REMS, is necessary to assure the safe use of the product candidate.
REMS involve additional risk minimization strategies to ensure that the benefits of the product outweigh the potential risks.
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The review process and the PDUFA goal date for both standard and priority review BLAs may be extended by three months if the FDA requests or the BLA sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.
−Removed: If a product candidate receives regulatory approval, the FDA may require post-marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biologic product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.
+Added: If a product candidate receives regulatory approval, the FDA may require post-marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biologic product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.
Compliance with cGMP requirements
3 unchanged sentences
Establishments may be subject to periodic, unannounced inspections by government authorities to ensure compliance with cGMP requirements and other laws.
−Removed: Discovery of problems may result in a government entity placing restrictions on a product, manufacturer or holder of an approved BLA, and may extend to requested product recalls or requiring withdrawal of the product from the market.
+Added: Discovery of problems may result in a government entity placing restrictions on a product, manufacturer or holder of an approved BLA, and may extend to
+Added: requested product recalls or requiring withdrawal of the product from the market.
The FDA will not approve a BLA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specification.
1 unchanged sentence
The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.
−Removed: Fast track designation may be granted for products that are intended to treat a serious or life-threatening disease or condition for which there is no effective treatment and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.
+Added: Fast track designation may be granted for products that are intended to treat a serious or life-threatening disease or condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.
Fast track designation applies to both the product and the specific indication for which it is being studied.
The sponsor of a new biologic candidate can request the FDA to designate the candidate for a specific indication for fast track status concurrent with, or after, the submission of the IND for the candidate.
−Removed: The FDA must determine if the biologic candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.
−Removed: For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s BLA before the application is complete.
−Removed: This “rolling review”
−Removed: is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective.
+Added: The FDA must determine if the biologic candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.
+Added: For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s BLA before the application is complete.
+Added: This “rolling review” is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective.
The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.
2 unchanged sentences
Under the breakthrough therapy program, the sponsor of a new biologic candidate may request that the FDA designate the candidate for a specific indication as a breakthrough therapy concurrent with, or after, the submission of the IND for the biologic candidate.
−Removed: The FDA must determine if the biological product qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.
+Added: The FDA must determine if the biological product qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.
The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical trials in an efficient manner.
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Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large studies to demonstrate a clinical or survival benefit.
−Removed: The accelerated approval pathway is contingent on the verification and description of the product’s clinical benefit, which is generally in the form of at least one post-approval confirmatory trial.
+Added: The accelerated approval pathway is contingent on the verification and description of the product’s clinical benefit, which is generally in the form of at least one post-approval confirmatory trial.
These confirmatory trials must be completed with due diligence and, in some cases, the FDA may require that the trial be designed, initiated and/or fully enrolled prior to submission of the application or approval.
1 unchanged sentence
All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.
−Removed: The Food and Drug Omnibus Reform Act, or FDORA, was recently enacted, which included provisions related to the accelerated approval pathway.
+Added: The Food and Drug Omnibus Reform Act, or FDORA, included provisions related to the accelerated approval pathway.
Pursuant to FDORA, the FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval.
8 unchanged sentences
Other post-approval requirements applicable to biologic products include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information and complying with electronic record and signature requirements.
−Removed: A sponsor also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities and promotional activities involving the internet.
+Added: A sponsor also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities and promotional activities involving the internet.
Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.
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If a product with orphan designation receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan drug exclusivity.
−Removed: Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same drug for the same indication for seven years, except in certain limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of product supply issues.
−Removed: If a product designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.
+Added: Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same drug for the same indication for seven years, except in certain limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of product supply issues.
+Added: If a product designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to orphan drug exclusivity.
Competitors may receive approval of either a different drug for the same indication or the same drug for a different indication.
−Removed: The period of exclusivity begins on the date that the marketing application is approved by the FDA and applies only to the indication for which the product has been designated.
+Added: The period of exclusivity begins on the date that the marketing application is approved by the FDA and applies only to the indication for which the product has been designated and approved.
The FDA may approve a second application for the same drug for a different use or a second application for a clinically superior version of the drug for the same use.
−Removed: Because healthcare professionals are free to prescribe products for off-label uses, the competitor’s product could be used for the orphan indication despite another product’s orphan exclusivity.
+Added: Because healthcare professionals are free to prescribe products for off-label uses, the competitor’s product could be used for the orphan indication despite another product’s orphan exclusivity.
The FDA cannot, however, approve the same drug made by another manufacturer for the same indication during the market exclusivity period unless it has the consent of the sponsor or the sponsor is unable to provide sufficient quantities.
−Removed: The FDA’s determination of whether two ADCs are the same drug for purposes of orphan drug exclusivity is based on a determination of sameness of the monoclonal antibody element and the functional element of the conjugated molecule.
+Added: The FDA’s determination of whether two ADCs are the same drug for purposes of orphan drug exclusivity is based on a determination of sameness of the monoclonal antibody element and the functional element of the conjugated molecule.
Two ADCs are deemed to be the same product if the complementarity determining region sequences of the antibody and the functional element of the conjugated molecule are the same.
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Approval or clearance of the companion or complementary diagnostic device will ensure that the device has been adequately evaluated and has adequate performance characteristics in the intended population.
−Removed: The review of in vitro companion or complementary diagnostics in conjunction with the review of our products will, therefore, likely involve coordination of review by CDER and the FDA’s Office of In Vitro Diagnostics and Radiological Health.
+Added: The review of in vitro companion or complementary diagnostics in conjunction with the review of our products will, therefore, likely involve coordination of review by the FDA’s Center for Drug Evaluation and Research and Office of In Vitro Diagnostics.
We may partner with a diagnostic provider to develop a companion or complementary diagnostic for certain of our product candidates.
5 unchanged sentences
The two primary types of FDA marketing authorization applicable to a medical device are premarket notification, also called 510(k) clearance, and premarket approval, or PMA.
−Removed: has generally required in vitro companion diagnostics intended to select the patients who will respond to cancer treatment to obtain a PMA for that diagnostic simultaneously with approval of the therapeutic.
+Added: The FDA has generally required in vitro companion diagnostics intended to select the patients who will respond to cancer treatment to obtain a PMA for that diagnostic simultaneously with approval of the therapeutic.
The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer.
−Removed: It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.
+Added: It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.
PMA applications are subject to an application fee.
1 unchanged sentence
In particular, for a diagnostic, the applicant must demonstrate that the diagnostic has adequate sensitivity and specificity, has adequate specimen and reagent stability, and produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.
−Removed: As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.
+Added: As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.
PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.
−Removed: If the FDA’s evaluation of the PMA application is favorable, the FDA typically issues an approvable letter requiring the applicant’s agreement to specific conditions, such as changes in labeling, or specific additional information, such as submission of final labeling, in order to secure final approval of the PMA.
−Removed: If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny approval of the PMA or issue a not approvable letter.
+Added: If the FDA’s evaluation of the PMA application is favorable, the FDA typically issues an approvable letter requiring the applicant’s agreement to specific conditions, such as changes in labeling, or specific additional information, such as submission of final labeling, in order to secure final approval of the PMA.
+Added: If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny approval of the PMA or issue a not approvable letter.
A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable.
6 unchanged sentences
Device manufacturers must also register their establishments and list their devices with the FDA.
−Removed: A medical device manufacturer’s manufacturing processes, and the processes of the device specification developer and repackager/relabeler (if different from the manufacturer) and initial importer (if manufactured outside of the United States) are required to comply with the applicable portions of the QSR, which cover the methods and documentation of the design, testing, production, processes, controls, quality assurance, importation, labeling, packaging and shipping of medical devices.
+Added: A medical device manufacturer’s manufacturing processes, and the processes of the device specification developer and repackager/relabeler (if different from the manufacturer) and initial importer (if manufactured outside of the United States) are required to comply with the applicable portions of the QSR, which cover the methods and documentation of the design, testing, production, processes, controls, quality assurance, importation, labeling, packaging and shipping of medical devices.
Facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA.
4 unchanged sentences
The Best Pharmaceuticals for Children Act, or BPCA, provides a six-month extension of any patent and non-patent exclusivity for a biologic if certain conditions are met.
−Removed: Conditions for exclusivity include the FDA’s determination that information relating to the use of a new biologic in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe.
+Added: Conditions for exclusivity include the FDA’s determination that information relating to the use of a new biologic in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe.
Applications under the BPCA are treated as priority applications, with all of the benefits that designation confers.
4 unchanged sentences
As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.
−Removed: If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the lot manufacturing history and the results of all of the manufacturer’s tests performed on the lot.
−Removed: The FDA may also
−Removed: perform certain confirmatory tests on lots of some products, such as viral vaccines, before allowing the manufacturer to release the lots for distribution.
+Added: If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of the product to the FDA together with a release protocol showing a summary of the lot manufacturing history and the results of all of the manufacturer’s tests performed on the lot.
+Added: The FDA may also perform certain confirmatory tests on lots of some products, such as viral vaccines, before allowing the manufacturer to release the lots for distribution.
In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products.
8 unchanged sentences
In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.
−Removed: During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing the applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.
+Added: During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing the applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.
The BPCIA also created an exclusivity period for biosimilars approved as interchangeable products.
−Removed: At this juncture, it is unclear whether products deemed “interchangeable”
−Removed: by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.
−Removed: The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against approval of an interchangeable biologic for the same condition of use for the earlier of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) eighteen months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar’s application has been approved if a patent lawsuit is ongoing within the 42-month period.
+Added: At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.
+Added: The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against approval of an interchangeable biologic for the same condition of use for the earlier of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) eighteen months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar’s application has been approved if a patent lawsuit is ongoing within the 42-month period.
Patent term restoration and extension
1 unchanged sentence
Assuming grant of the patent for which the extension is sought, the restoration period for a patent covering a product is typically one-half the time between the effective date of the IND involving human beings and the submission date of the BLA, plus the time between the submission date of the BLA and the ultimate approval date.
−Removed: Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date in the United States.
+Added: Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date in the United States.
Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent for which extension is sought.
8 unchanged sentences
Clinical trial approval
−Removed: Pursuant to the currently applicable Clinical Trials Directive 2001/20/EC and the Directive 2005/28/EC on GCP, a system for the approval of clinical trials (excluding non-interventional trials) conducted in the European Union has been implemented through national legislation of the
−Removed: member states.
+Added: Pursuant to the currently applicable Clinical Trials Directive 2001/20/EC and the Directive 2005/28/EC on GCP, a system for the approval of clinical trials (excluding non-interventional trials) conducted in the European Union has been implemented through national legislation of the member states.
Under this system, the sponsor of a clinical trial must submit a request for authorization to the competent national authority of the European Union member state in which the clinical trial is to be conducted, or in multiple member states if the clinical trial is to be conducted in a number of member states.
10 unchanged sentences
PRIME designation in the European Union
−Removed: In March 2016, the EMA launched an initiative to facilitate development of product candidates of major interest from the point of view of public health and in particular from the point of view of therapeutic innovation.
−Removed: The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.
+Added: In March 2016, the European Medicines Agency (the “EMA”) launched an initiative to facilitate development of product candidates of major interest from the point of view of public health and in particular from the point of view of therapeutic innovation.
+Added: The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products
+Added: representing substantial innovation reviewed under the centralized procedure.
Eligibility for the PRIME scheme depends on the availability of adequate preclinical and clinical data to justify a potential major public health interest prior to the initiation of confirmatory clinical trials at the proof-of-concept stage.
18 unchanged sentences
With respect to medicinal products for which a centralized authorization is not mandatory, the applicant may choose between:
−Removed: (i) the national procedure provided for by a specific Member State, for the marketing of the product in its territory, (ii) the decentralized procedure, for drug candidates that are not marketed in any of the Member States but the applicant wishes to market them on more than one EU national
−Removed: territories or (iii) the mutual recognition procedure, which applies to products already authorized in a Member State and whose marketing in other Member States’
−Removed: territories is sought.
+Added: (i) the national procedure provided for by a specific member state, for the marketing of the product in its territory, (ii) the decentralized procedure, for drug candidates that are not marketed in any of the member states but the applicant wishes to market them on more than one EU national territories or (iii) the mutual recognition procedure, which applies to products already authorized in a member state and whose marketing in other member states’ territories is sought.
Regulatory data protection in the European Union
1 unchanged sentence
These exclusivity periods apply only once from the first authorization granted to an applicant for a given active substance and they cannot be renewed when the same marketing authorization holder is granted new authorizations for new indications, strengths, pharmaceutical forms, administration routes or presentations of the same active substance.
−Removed: Data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess another product (either generic, hybrid or biosimilar) application for a period of eight years.
−Removed: During the additional two-year period of market exclusivity, a generic, hybrid or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic, hybrid or biosimilar medicinal product can be marketed until the expiration of the market exclusivity.
+Added: Data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess another product (either generic, hybrid or biosimilar) application for a period of eight years.
+Added: During the additional two-year period of market exclusivity, a generic, hybrid or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic, hybrid or biosimilar medicinal product can be marketed until the expiration of the market exclusivity.
The overall 10-year period will be extended to a maximum of 11 years if, during the first eight years of those 10 years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with existing therapies.
14 unchanged sentences
Following approval, the holder of the marketing authorization is required to comply with a range of requirements applicable to the manufacturing, marketing, promotion and sale of the medicinal product.
−Removed: These include compliance with the European Union’s stringent pharmacovigilance or safety reporting rules, pursuant to which post-authorization studies and additional monitoring obligations can be imposed.
−Removed: In addition, the manufacturing of authorized products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the EMA’s GMP requirements and comparable requirements of other regulatory bodies in the European Union, which mandate the methods, facilities and controls used in the manufacturing, processing and packing of drugs to assure their safety and identity.
+Added: These include compliance with the European Union’s stringent pharmacovigilance or safety reporting rules, pursuant to which post-authorization studies and additional monitoring obligations can be imposed.
+Added: In addition, the manufacturing of authorized products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the EMA’s good manufacturing practices (“GMP”) requirements and comparable requirements of other regulatory bodies in the European Union, which mandate the methods, facilities and controls used in the manufacturing, processing and packing of drugs to assure their safety and identity.
Finally, the marketing and promotion of authorized products, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the European Union under Directive 2001/83EC, as amended.
6 unchanged sentences
In particular, an orphan drug designation leads to a 10-year period of market exclusivity from the granting of the concerned medicinal product marketing authorization for the particular indication.
−Removed: During this market exclusivity period, neither the EMA nor the member states can accept an application or grant a marketing authorization for a “similar medicinal product.”
−Removed: A “similar medicinal product”
−Removed: is defined as a medicinal product containing a similar or identical active substance, or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.
+Added: During this market exclusivity period, neither the EMA nor the member states can accept an application or grant a marketing authorization for a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar or identical active substance, or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.
The market exclusivity period for the authorized therapeutic indication may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation because, for example, the product is sufficiently profitable so as to not to justify market exclusivity.
−Removed: General Data Protection Regulation
+Added: General Data Protection Regulation (the “GDPR”)
The collection, use, disclosure, transfer or other processing of personal data regarding individuals in the European Union, including personal health data, is subject to the Regulation (EU) No.
1 unchanged sentence
The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches and taking certain measures when engaging third-party processors.
−Removed: The GDPR also imposes strict rules on the transfer of personal data to countries outside the European Union, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global turnover of the preceding financial year, whichever is greater.
+Added: The GDPR also imposes strict rules on the transfer of personal data to countries outside the European Union, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global turnover of the preceding financial year, whichever is greater.
The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies and obtain compensation for damages resulting from violations of the GDPR.
−Removed: Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.
−Removed: Brexit and the regulatory framework in the United Kingdom
−Removed: On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union, commonly referred to as Brexit.
−Removed: Following protracted negotiations, the United Kingdom left the European Union on January 31, 2020.
−Removed: The transition period ended on December 31, 2020.
−Removed: On December 30, 2020, the United Kingdom and EU signed the Trade and Cooperation Agreement (TCA), which includes an agreement on free trade between the two parties.
−Removed: The TCA does not contain wholesale mutual recognition of regulatory regimes for pharmaceuticals as was hoped.
−Removed: There is mutual recognition of cGMP inspections of manufacturing facilities but it does not include reciprocal arrangements for the recognition of batch testing certification, in order to avoid unnecessary re-testing on importation of products.
−Removed: There is considerable uncertainty resulting from a lack of precedent and the complexity of the United Kingdom and the EU’s intertwined legal regimes as to how Brexit will impact the life sciences industry in Europe, including our company, including with respect to ongoing or future clinical trials.
−Removed: Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to restrict or delay efforts to seek regulatory approval in the United Kingdom for any product candidates we may develop, which could significantly and materially harm our business.
−Removed: See “Risk factors—Risks related to regulatory approval and other legal compliance matters—
−Removed: Our relationships with healthcare professionals, clinical investigators, CROs and third-party payors in connection with our current and future business activities may be subject to federal and state healthcare fraud and abuse laws, false claims laws, transparency laws, government price reporting and health information privacy and security laws, which could expose us to significant losses, including, among other things, criminal sanctions, civil penalties, contractual damages, exclusion from governmental healthcare programs, reputational harm, administrative burdens and diminished profits and future earnings”
−Removed: for additional disclosures regarding risks related to privacy laws in the United Kingdom and European Union.
+Added: Compliance with the GDPR will
+Added: be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.
Coverage and reimbursement
25 unchanged sentences
Federal false claims laws, including the federal civil False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
−Removed: As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand”
−Removed: for money or property presented to the U.S.
−Removed: In addition, manufacturers can be held liable under the civil False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause”
−Removed: the submission of false or fraudulent claims.
+Added: As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.
+Added: In addition, manufacturers can be held liable under the civil False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.
Pharmaceutical and other biotechnology companies have been prosecuted under these laws for, among other things, allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.
−Removed: Other companies have been prosecuted for causing false claims to be submitted because of the companies’
−Removed: marketing of the product for unapproved, and thus generally non-reimbursable, uses and purportedly concealing price concessions in the pricing information submitted to the government for government price reporting purposes.
−Removed: HIPAA created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of
−Removed: or payment for healthcare benefits, items or services.
+Added: Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus generally non-reimbursable, uses and purportedly concealing price concessions in the pricing information submitted to the government for government price reporting purposes.
+Added: HIPAA created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
Similar to the 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.
Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.
−Removed: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of such providers, and to report annually certain ownership and investment interests held by physicians and their immediate family members.
−Removed: Violation of any of the federal and state healthcare laws described above or any other governmental regulations may result in penalties, including without limitation, significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, imprisonment, injunctions, private “qui tam”
−Removed: actions brought by individual whistleblowers in the name of the government, refusal to enter into government contracts, oversight monitoring, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings.
+Added: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value
+Added: made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of such providers, and to report annually certain ownership and investment interests held by physicians and their immediate family members.
+Added: Violation of any of the federal and state healthcare laws described above or any other governmental regulations may result in penalties, including without limitation, significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, imprisonment, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, refusal to enter into government contracts, oversight monitoring, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings.
Federal and state data privacy and security laws
3 unchanged sentences
In addition to federal privacy regulations, there are a number of state laws governing confidentiality and security of health information that are applicable to our business.
−Removed: In addition to possible federal administrative, civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.
−Removed: Accordingly, state attorneys general have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.
+Added: In addition to possible federal administrative, civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.
+Added: Accordingly, state attorneys general have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.
New laws and regulations governing privacy and security may be adopted in the future as well.
−Removed: Additionally, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
+Added: Additionally, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, and often are not preempted by HIPAA, thus complicating compliance efforts.
For example, the California Consumer Privacy Act, or CCPA, creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.
The CCPA went into effect on January 1, 2020 and requires covered companies to provide new disclosures to California consumers, provide such consumers new ways to opt-out of certain sales of personal information, and allow for a new cause of action for data breaches.
−Removed: This private right of action may increase the likelihood of, and risks associated with, data breach litigation.
−Removed: On November 3, 2020, California voters approved a new privacy law, the California Privacy Rights Act, or the CPRA, which significantly modifies the CCPA, including by expanding consumers’
−Removed: rights with respect to certain personal information and creating a new state agency to oversee implementation and enforcement efforts.
+Added: On November 3, 2020, California voters approved a new privacy law, the California Privacy Rights Act, or the CPRA, which significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain personal information and creating a new state agency to oversee implementation and enforcement efforts.
+Added: The CCPA and CPRA provide for unlimited civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data breach litigation.
The CPRA took effect in most material respects on January 1, 2023.
4 unchanged sentences
of a new comprehensive federal data privacy law to which we would become subject if it is enacted.
+Added: In addition, Virginia’s Consumer Data Protection Act, which took effect on January 1, 2023, requires businesses subject to the legislation to conduct data protection assessments in certain circumstances and requires opt-in consent from consumers to acquire and process their sensitive personal information, which includes information revealing a consumer’s physical and mental health diagnosis and genetic and biometric information that can identify a consumer.
+Added: Colorado enacted the Colorado Privacy Act, and Connecticut enacted the Connecticut Data Privacy Act, each of which took effect on July 1, 2023, and Utah enacted the Consumer Privacy Act, which became effective on December 31, 2023, and each of these laws may increase the complexity, variation in requirements, restrictions, and potential legal risks, and could require increased compliance costs and changes in business practices and policies.
+Added: Other states have also enacted, proposed, or are considering proposing, data privacy laws.
Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available under such laws, it is possible that some of our current or future business activities, including certain clinical research, sales and marketing practices and the provision of certain items and services to our customers, could be subject to challenge under one or more of such privacy and data security laws.
5 unchanged sentences
government rebate programs and additional downward pressure on pharmaceutical product prices.
−Removed: On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried out by Congress, to reduce drug prices and drug payment.
−Removed: These initiatives recently culminated in the
−Removed: enactment of the Inflation Reduction Act, or IRA, in August 2022, which will, among other things, allow HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D, although only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.
−Removed: The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.
−Removed: Beginning in January 2023 for Medicare Part B and October 2022 for Medicare Part D, the IRA also penalizes drug manufacturers that increase prices of Medicare Part B and Part D drugs at a rate greater than the rate of inflation.
−Removed: The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
−Removed: Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.
+Added: Several healthcare reform proposals culminated in the enactment of the Inflation Reduction Act, or IRA, in August 2022, which, among other things, allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.
+Added: Only high-expenditure single-source biologics that have been
+Added: approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.
+Added: Negotiations for Medicare Part D products take place in 2024 with the negotiated price taking effect in 2026, and negotiations for Medicare Part B products will begin in 2026 with the negotiated price taking effect in 2028.
+Added: In August 2023, HHS announced the ten Medicare Part D drugs and biologics that it selected for negotiations.
+Added: HHS will announce the negotiated maximum fair prices by September 1, 2024, and this price cap, which cannot exceed a statutory ceiling price, will go into effect on January 1, 2026.
+Added: A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.
+Added: The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation.
The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
−Removed: These provisions will take effect progressively starting in 2023, although they may be subject to legal challenges.
+Added: The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: Manufacturers that fail to comply with the IRA may be subject to various penalties, including significant civil monetary penalties.
+Added: These provisions have been and may continue to be subject to legal challenges.
+Added: For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in multiple lawsuits brought by pharmaceutical manufacturers.
+Added: Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the biopharmaceutical industry and the pricing of prescription drug products.
+Added: Additional state and federal healthcare reform measures could be adopted in the future.
Human Capital Management
7 unchanged sentences
We believe that a compensation program with both short-term and long-term awards provides fair and competitive compensation and aligns employee and stockholder interests, including by incentivizing business and individual performance (pay for performance), motivating based on long-term company performance and integrating compensation with our business plans.
−Removed: In addition to cash and equity compensation, we also offer employees benefits such as life and health (medical, dental & vision) insurance, paid time off, paid parental leave, participation in our Employee Stock Purchase Plan and a 401(k) plan.
+Added: In addition to cash and equity compensation, we also offer employees benefits such as life and health (medical, dental & vision) insurance, flexible spending accounts for health and dependent care needs, paid time off, paid parental leave, participation in our Employee Stock Purchase Plan and a 401(k) plan.
+Added: In addition to our benefits, we offer wellness and stress management support which includes an on-site gym, company-wide wellness activities, wellness resources that are shared with employees each month, an Employee Assistance Program with counseling, and flexible work arrangements.
Diversity and Inclusion .
We believe that an equitable and inclusive environment with diverse teams produces more creative solutions, results in better, more innovative products and services and is crucial to our efforts to attract and retain key talent.
−Removed: Our current efforts are focused on three primary areas:
+Added: Our current efforts are focused on four primary areas:
• Safe work environment.
1 unchanged sentence
• Equal employment opportunity.
−Removed: We ensure that our practices and processes attract a diverse range of candidate, and that candidates are recruited, hired, assigned, developed, and promoted based on merit and their alignment to our values.
+Added: We ensure that our practices and processes attract a diverse range of candidate, and that candidates are recruited, hired, paid, assigned, developed, and promoted based on merit and their alignment to our values.
• Learning and development opportunities.
11 unchanged sentences
This Annual Report on Form 10-K contains references to our trademarks and to trademarks belonging to other entities.
−Removed: Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names.
−Removed: We do not intend our use or display of other companies’
−Removed: trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other companies.
+Added: Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these
+Added: trademarks and trade names.
+Added: We do not intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other companies.
Available Information
2 unchanged sentences
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.