What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2023-03-23 compared with 2022-02-28 · 292 added, 505 removed, 725 unchanged (52% of the section changed)

5 unchanged sentences

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 broad applicability of our CAB technology allows us to develop a wide array of product candidate modalities, such as monoclonal antibodies, antibody-drug conjugates, or ADCs, T cell-engaging bispecific antibodies and chimeric antigen receptor T cells, or CAR-T cells.

A key advantage of our application of the CAB technology to antibodies is that it allows us to selectively target antigens on tumor cells and minimizes or eliminates binding to these antigens on normal cells, which reduces the toxicity associated with traditional approaches.

We have initiated potentially registration-enabling Phase 2 trials for our two latest stage CAB ADC product candidates targeting multiple cancer indications with mecbotamab vedotin (BA3011) targeting AXL in sarcoma and NSCLC and ozuriftamab vedotin (BA3021) targeting ROR2 in non-small cell lung cancer (NSCLC), melanoma, and head and neck cancer (SCCHN).

Food and Drug Administration, or the FDA, has reviewed the trial designs, but has not yet opined on whether the Phase 2 clinical trials will be sufficient to support regulatory approval.

However, we intend to ask the FDA to consider this further at the upcoming interim data review point or points for these trials and indications.

While we cannot assure you that the FDA will agree that the current clinical plan will be sufficient to support approval, the trial has been designed to allow us to adjust the clinical plan, if needed, after the interim read-out in order to better align with any potential FDA requirements.

We are also supporting investigator-initiated trials for both mecbotamab vedotin and ozuriftamab vedotin in platinum-resistant ovarian cancer.

We have observed encouraging initial clinical signs of response to treatment and a wide therapeutic window for a range of dosage and duration.

Mecbotamab vedotin and ozuriftamab vedotin have the potential to address large unmet medical needs in indications that together account for more than 350,000 new cases of solid tumor cancers and 150,000 deaths per year in the United States alone.

Additionally, we have initiated Phase 1 trials for multiple cancer indications in 2021 with dosing expect in the first half of 2022 for our CAB immuno-oncology antibody BA3071 targeting CTLA-4.

BA3071 is designed to overcome the toxicity limitations of the currently approved anti-CTLA-4 antibodies and to improve patient outcomes.

We also have several candidates in our IND-enabling preclinical pipeline that include CAB bispecific and ADC antibodies targeting unmet medical needs in multiple types of solid tumors.

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.

Additionally, the combination of reversible binding with the selective, precision capability of our CAB technology enables both increased antibody potency and reduced toxicity.

By exploiting our novel understanding of tumor biology, we believe that our proprietary CAB technology has the potential to transform antibody-based cancer therapy.

Our goal is to develop well-tolerated, novel cancer therapies that provide cures or extended survival to ensure patients’

1 unchanged sentence

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.

While therapeutic antibodies have emerged as one of the most successful strategies for both solid and blood-based, or hematologic, malignancies, toxicity has narrowed the therapeutic window and ultimate potential of impacting disease, as many of the key targets on tumor cells are also prevalent on normal cells.

The biology of tumor formation, or tumorigenesis, yields a unique microenvironment consisting of a complex mixture of tumor cells, stromal fibroblasts, endothelial cells and immune cells like microglia, macrophages and lymphocytes and the non-cellular components of extracellular matrix such as collagen, fibronectin, hyaluronan and laminin, among others.

The process of tumor formation creates an altered, unique microenvironment in and around the tumor that is also physically and chemically distinct from healthy tissue, with regard to temperature, pressure, chemical composition and especially the acidity or pH.

The tumorigenesis-driven shifts in microenvironment conditions further weaken the immune response and promote tumor growth.

We have created and patented our CAB technology to enable the development of antibodies that are active in the tumor microenvironment, but inactive under normal physiological conditions, while ensuring target-specific binding on cancer cells.

Our CAB technology aims to uniquely exploit the fundamental pH differences between the tumor and healthy tissue, increasing antibody binding selectivity and thereby potentially eliminating or greatly reducing healthy cell on-target, off-tumor toxicity.

This enhanced selectivity 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.

Additionally, the combination of reversible binding with the selective, precision capability of our CAB technology enables both increased antibody potency and reduced toxicity.

By exploiting our novel understanding of tumor biology, we believe that our proprietary CAB technology has the potential to transform antibody-based cancer therapy.

Initially, we applied the reversible binding and precision capability of our CAB technology to develop next-generation ADC therapies.

Traditional ADCs are a class of biologic drugs that are designed by attaching a toxic small molecule payload to an antibody, which then targets a specific antigen expressed on the target cell, but unfortunately, in most cases, this target is also present on normal tissue.

Binding to the target on normal tissue leads to high on-target, off-tumor toxicity, which reduces the utility of traditional ADCs.

Our CAB ADCs are designed to selectively bind to the antigens found in acidic pH conditions found in the tumor microenvironment, which has the potential to reduce off-tumor toxicity and related consequences.

In addition, we developed CAB antibodies to immuno-oncology targets such as CTLA-4 for antitumor activity.

We believe that our CAB technology can reduce the limitations resulting from systemic toxicities and expand the utility of this immuno-oncology therapy.

We are also creating bispecific, T cell engaging, CAB antibodies that 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.

This is a powerful approach to harness cytotoxic T cells to directly kill tumor cells with reduced toxicity.

In 2021, we published a paper in the Proceedings of the National Academy of Sciences ("PNAS") describing a novel mechanism using physiological chemicals as Protein-activated Chemical Switches TM , or PaCS TM , for generating CAB antibodies.

Initially, we applied the reversible binding and precision capability of our CAB technology to advance next-generation ADC therapies.

We also generated antibodies for immuno-oncology and more recently, 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.

We believe that there is significant potential to improve therapeutics for our patients with our proprietary CAB antibody technology across well-validated oncology targets in solid tumors.

1 unchanged sentence

Mecbotamab vedotin (BA3011):

Our lead product candidate, mecbotamab vedotin, or BA3011, is a CAB ADC that targets AXL, a protein kinase receptor that is highly expressed on the surface of many tumors.

Our lead clinical stage product candidate, mecbotamab vedotin, or BA3011, is a CAB ADC that targets AXL, a protein kinase receptor that is expressed on the surface of many tumors.

AXL is considered to be a driver of many cellular processes that are critical for the development, growth and spread of tumors, including proliferation, invasiveness and migration, stemness, which is related to core stem cell properties such as self-renewal and differentiation, angiogenesis, or the growth of blood vessels, and immune modulation.

In preclinical studies, we have observed that BA3011 binds to AXL under conditions that reflect those in tumors.

AXL has also been shown to be involved in the epithelial-mesenchymal transition, or EMT, a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells, or MSCs.

AXL has been shown to be involved in the epithelial-mesenchymal transition, or EMT, a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells, or MSCs.

MSCs are home to developing aggressive tumors, where they exacerbate cancer cell proliferation, motility, invasion and metastasis, foster angiogenesis, promote tumor fibrosis and suppress antitumor immune responses.

1 unchanged sentence

A number of small-molecule AXL kinase inhibitors have been developed;

however, the majority of these inhibitors, including one that has been approved, are not highly selective for AXL.

Although other non-CAB anti-AXL antibodies and ADCs have shown encouraging clinical signs of antitumor activity;

adverse events, such as high-grade constipation and peripheral neuropathy, were particularly pronounced and led to discontinuation of clinical development of some candidates.

however, the majority of these inhibitors, including one that is approved, are not highly selective for AXL.

Although other non-CAB anti-AXL antibodies and ADCs have shown encouraging clinical signs of antitumor activity, adverse events, such as high-grade constipation and peripheral neuropathy, were particularly pronounced and led to discontinuation of clinical development of some candidates.

Mecbotamab vedotin is an ADC consisting of a CAB humanized immunoglobulin G, or IgG1, anti-AXL monoclonal antibody.

4 unchanged sentences

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.

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, non-small cell lung cancer (NSCLC) and ovarian cancer, with other potential indications in the future.

The Office of Orphan Drug Products (OODP) at the FDA granted Orphan Drug Designation to mecbotamab vedotin for the treatment of soft tissue sarcoma, and Phase 1 results in sarcoma patients were presented at the Connective Tissue Oncology Society (CTOS) 2021 Annual Meeting.

Mecbotamab vedotin was generally well tolerated in this refractory sarcoma population.

In the Phase 1 study, few patients discontinued due to an adverse event (two patients out of 26 or 7.7%) compared to discontinuation rates in most other clinical trials of ADCs.

No clinically meaningful on-target toxicity to normal AXL-expressing tissue was observed over baseline levels.

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.

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.

Phase 1 results in sarcoma patients indicated mecbotamab vedotin was generally well-tolerated in this refractory sarcoma population.

Few patients discontinued due to an adverse event and no clinically meaningful on-target toxicity to normal AXL-expressing tissue was observed over baseline levels.

Dose-limiting toxicities were limited to free circulating MMAE payload-associated toxicity at the highest dose tested, including reversible neutropenia.

Higher levels of AXL tumor membrane expression correlated with response to treatment.

Of the seven sarcoma patients who had an AXL TmPS of greater than or equal to 70%, four of these obtained a confirmed partial response, including patients with leiomyosarcoma, undifferentiated pleomorphic sarcoma, and Ewing sarcoma.

Prolonged response to therapy was observed in this ongoing study with the duration of response ranging from 33 to more than 60 weeks.

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 putative biomarker which is not only highly expressed in sarcomas, but also may help select patients across multiple sarcoma subtypes who may benefit from therapy.

In the ongoing potentially registration-enabling sarcoma Phase 2 study, patients are enrolled for therapy by prescreening for AXL expression.

We are also conducting a Phase 2 study (BA3011-002) in AXL high NSCLC patients who have previously progressed on PD-1/L1, EGFR, or ALK inhibitor therapy.

Planned interim analyses in the sarcoma and NSCLC trials are anticipated at the end of the first quarter and in the second quarter of 2022, respectively.

In both Phase 2 indications, we are enrolling patients either as a monotherapy or in combination with a PD-1 inhibitor.

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 has begun enrollment and is expected to enroll approximately 20 patients.

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,

but also may help select patients across multiple sarcoma subtypes who may benefit from therapy.

In our ongoing potentially registration-enabling sarcoma Phase 2 study, patients are enrolled for therapy by prescreening for AXL expression.

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.

In both Phase 2 indications, we are enrolling patients either as a monotherapy or in combination with the PD-1 inhibitor nivolumab.

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):

We are developing our second product candidate, ozuriftamab vedotin or BA3021, a CAB antibody drug conjugate directed against ROR2, or Receptor Tyrosine Kinase Like Orphan Receptor 2.

We are developing our second clinical stage product candidate, ozuriftamab vedotin or BA3021, a CAB antibody drug conjugate directed against ROR2, or Receptor Tyrosine Kinase Like Orphan Receptor 2.

ROR2 is overexpressed across many different solid tumors, including breast, lung, pancreatic, renal, ovarian, and colorectal cancers, squamous cell cancer of the head and neck, or SCCHN, and melanoma;

11 unchanged sentences

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.

We are developing ozuriftamab vedotin as a potential therapeutic for multiple solid tumor types, including NSCLC, melanoma, and ovarian cancer.

We are developing ozuriftamab vedotin as a potential therapeutic for multiple solid tumor types, including NSCLC, melanoma, and cancer of the head and neck.

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.

We are enrolling a Phase 2 trial of ozuriftamab vedotin monotherapy or in combination with a PD-1 inhibitor in patients with ROR2 high 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.

A Phase 2 study in patients with ROR2 high SCCHN is anticipated to begin dosing patients in first half of 2022.

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 has begun enrollment.

Our third 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.

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.

A Phase 2 study in patients with ROR2 positive SCCHN has begun.

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.

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.

CTLA-4, or cytotoxic T-lymphocyte-associated antigen 4, is an immune checkpoint involved in regulating T-cell activation.

1 unchanged sentence

however, cancer cells often take advantage of this pathway to prevent immune destruction of the tumor.

Ipilimumab currently is the only anti-CTLA-4 monoclonal antibody approved by the FDA.

It is approved in combination with an anti-PD-1 antibody, nivolumab, for the treatment of multiple solid tumors, including melanoma, RCC, colorectal cancer and NSCLC.

Patients treated with ipilimumab 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.

The usage and dosage of ipilimumab is highly limited due to its safety profile, resulting in the average number of cycles on therapy not exceeding four cycles.

Ipilimumab and recently approved 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.

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.

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.

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.

Bispecific antibody programs:

We have also 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.

CAB EpCAM x CD3 (BA3182):

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.

A bispecific antibody is a type of engineered antibody that can simultaneously bind two separate and unique antigens, unlike conventional monospecific antibodies that only bind to one type of target.

6 unchanged sentences

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.

An example of this approach is our EpCAM x CD3 bispecific.

An example of this approach is our CAB EpCAM x CD3 bispecific.

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.

5 unchanged sentences

Solitomab, an EpCAM x CD3 bispecific led to over 95% of patients in a Phase 1 dose-escalation trial to experience at least one Grade 3 or above adverse event.

Over 20% of patients experienced dose-limiting toxicities and there was only one unconfirmed partial response observed among 65 patients at these low doses.

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.

We are conducting IND-enabling studies for two CAB bispecific antibody product candidates, EpCAM/CD3 and B7-H3/CD3, and one next-generation CAB ADC, Nectin-4.

We presently plan to file INDs in 2022 for EpCAM/CD3 and in 2023 for Nectin-4 and B7-H3/CD3.

We also are evaluating additional candidates including EGFR/CD3 bispecific and B7-H4 as a next-generation CAB ADC candidate.

Overall, we are advancing multiple pre-clinical assets and expect to file one IND in 2022, with the potential to submit up to three additional US INDs in 2023 for our CAB bispecific or ADC molecules.

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.

Our first bispecific candidate, CAB EpCAM x CD3 received IND clearance from the FDA in February 2023.

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.

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.

Overall, we are advancing multiple pre-clinical assets with potential INDs in the 2023 to 2024 timeframe.

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.

Our CAB technology enables us to generate antibodies that bind to their targets under conditions found in the tumor, but not in healthy tissue.

Therefore, we are able to generate antibodies to targets that to this point have been undruggable due to the lack of sufficient therapeutic window with existing antibody technologies.

We are also able to use these antibodies to engage targets that exist not only in tumors, but in healthy tissue as well.

This has the potential to reduce side effects and toxicity, one of the fundamental challenges of cancer therapies today, thereby expanding the realm of potential therapeutic antibodies.

We believe that our proprietary technology and approach have the potential to transform cancer therapy by decreasing systemic toxicities and improving efficacy.

We believe that our proprietary CAB technology and approach have the potential to transform cancer therapy by decreasing systemic toxicities and improving efficacy.

Our strategy to achieve this mission is as follows:

Advance mecbotamab vedotin through regulatory approval and commercialization.

Clinical data from our Phase 1 trial with mecbotamab vedotin are supportive of its development in sarcomas, a set of cancers with a high unmet clinical need.

We have initiated a potentially registration-enabling Phase 2 trial for mecbotamab vedotin in treatment refractory sarcoma patients (12 years of age or older), with an AXL TmPS of 50%, patients with an AXL TmPS equal or greater to 70% as the group for the primary analyses, and, if successful, we believe we can further advance mecbotamab vedotin through regulatory approval and commercialization.

In addition, we have initiated a potentially registration-enabling Phase 2 trial in NSCLC using a primary AXL TmPS of 1%.

We are using a quantitative biomarker assay/TmPS score to identify likely responders and to help enrich our clinical trial programs.

Advance ozuriftamab vedotin in PD-1/L1 refractory tumors through regulatory approval and commercialization.

We have observed antitumor activity in PD-1 refractory NSCLC and melanoma patients in our Phase 1 trial and have initiated a Phase 2 trial of ozuriftamab vedotin in each of these indications.

We are using a quantitative biomarker assay/TmPS score to identify and stratify based the TmPS score the likely responders and to help enrich our clinical trial programs.

Advance BA3071 as a CAB- anti CTLA-4 immune checkpoint inhibitor to restrict T-cell activation to the tumor microenvironment.

The design of BA3071 is to provide the efficacy of ipilimumab, the only anti-CTLA-4 monoclonal antibody approved by the FDA, but with a significantly enhanced safety profile.

Advance our lead product candidates through regulatory approval and commercialization.

o Mecbotamab vedotin:

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).

In addition, we are planning to discuss with the FDA initiating a potentially registration-enabling Phase 2 trial in NSCLC later this year.

In both studies, we are using a quantitative biomarker assay/TmPS score to identify likely responders and to help enrich our clinical trial programs.

o Ozuriftamab vedotin:

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.

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.

o CAB BA3071 anti CTLA-4 immune checkpoint inhibitor:

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.

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.

o CAB EpCAM x CAB CD3 (BA3182) :

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.

We are initiating a Phase 1 study in advanced adenocarcinoma.

Carcinoma is the most common form of cancer and adenocarcinoma is the most common subtype.

Adenocarcinoma is most prevalent in the lung, prostate, breast, pancreas, esophagus, colon/rectum and stomach.

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).

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.

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.

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.

We believe that our next generation CAB-ADC platform further widens that therapeutic window by enhancing the linker-payload system.

In addition, our first CAB EpCAM/CAB CD3 bispecific has recently demonstrated IND-enabling studies with a more than 80-fold improvement in the therapeutic window.

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.

1 unchanged sentence

Maintain and strengthen our intellectual property portfolio.

As of December 31, 2021, we had a total of 584 patents and patent applications with 319 issued patents, 8 allowed applications and 257 pending applications covering our CAB technology and product candidates.

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.

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.

6 unchanged sentences

Challenges in developing antibody-based therapies for solid tumors

Monoclonal antibody therapeutics have been approved for over 30 targets for multiple diseases, most commonly cancer.

Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules.

Monoclonal antibody therapeutics have been approved for dozens of therapeutic targets, most commonly cancer.

Antibodies have become the backbone of the pharmaceutical industry, which previously relied on small molecules.

Treatment with monoclonal antibodies has established itself as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors.

27 unchanged sentences

While nearly all tumor cells took up this peptide, normal tissue cells did not take up this peptide except in the liver and kidney, which was expected in a pH-independent manner in order to be metabolized and excreted.

As shown in the figure described below, 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.

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.

Shown below is a tumor “heat”

map identifying the tumor cells that are surrounded by an acid microenvironment.

Exploiting the established ability of pHLIP to label the membrane of cells exclusively under acidic conditions (≤

pH 6.5) in vivo , the cells within the acidic areas of the tumor in vivo can be identified at the histological level.

Mice harboring human breast tumor xenografts were administered Cy7-labeled, or dyed, pHLIP peptide and the tumor tissues were later removed and processed for imaging.

Shown on the left is a micrograph of the tumor with the cell-based segmentation data overlayed, including positional information relative to tumor edge.

The degree of positivity generated in the above analysis was used to identify a 0-3+ positive cells.

Note that the acidic areas extend beyond the traditional hypoxic core of the tumor into the aerobic and oxygenated cells at the invasive fronts at the tumor–stroma interface in vivo .

Shown on the right is the breakdown of cancer cells types that are identified by pHLIP acidic cell staining in vivo .

A majority of the cells identified are oxygenated and actively replicating tumor cells, and even the non-dividing cancers cells still maintain an acidic environment.

Tumor “Heat”

Tumors are highly acidic based on the uptake of pHLIP, a pH-sensitive probe.

While the entire tumor is acidic, the lowest pH cells are observed in the replicating cells, which are glycolytic and often oxygenated, i.e.

, the Warburg Effect.

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.

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.

6 unchanged sentences

In some cancers, the pH goes as low as 5.8, an extremely low level given the normal, slightly alkaline, pH in the body.

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.

These pH differences provide a clear correlation between low pH and cancer, one that is borne out in the aforementioned experiments that measure the uptake by cells of the peptide pH tracer pHLIP.

These cells are found to have high levels of lactate dehydrogenase, an enzyme that produces the sugar lactate, i.e., lactic acid.

Lactate production and secretion are well-known features of glycolysis.

Similarly, there is a strong correlation between the uptake of pHLIP and the expression of markers of aggressive tumor growth such as Ki67.

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.

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.

2 unchanged sentences

Our CABs are based on our patented protein discovery and engineering technology.

We invented, developed and refined this technology, which we believe selectively activates the binding of proteins and antibodies to targeted cells in the tumor microenvironment based on differences in local conditions such as pH, temperature, pressure or chemical composition compared to normal healthy tissue.

We invented, developed, and refined this technology, which we believe selectively enables the binding of proteins and antibodies to targeted cells in the tumor microenvironment based on differences in local conditions such as pH, temperature, or chemical composition compared to normal healthy tissue.

We have shown that activity of our CAB biologics is reversible;

15 unchanged sentences

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.

As shown in the figure below, binding of the CAB antibody was highly sensitive to pH with binding becoming much weaker as it approached pH 7.0 and almost undetectable at a physiological pH of 7.4.

The binding of the CAB antibody was highly sensitive to pH with binding becoming much weaker as it approached pH 7.0 and almost undetectable at a physiological pH of 7.4.

In contrast, a non-CAB antibody to AXL showed indiscriminate and experimentally equivalent binding across the entire pH range tested, including at pH 7.4 of normal cells.

Our CAB development process is capable of identifying CAB antibodies with a range of sensitivities to pH.

pH-dependent binding of CAB AXL antibodies vs.

non-CAB AXL antibodies

CAB antibodies have pH-dependent binding.

Traditional antibodies do not have pH-dependent binding in the pH range tested.

Low pH-dependent CAB antibodies are far less likely to bind to targets outside of tumors, resulting in a number of potential advantages over traditional antibodies:

9 unchanged sentences

Limited binding to targets outside of tumors effectively increases their half-life in plasma.

The phenomenon of TMDD is a well-known limitation facing the development of many biologics which CAB antibodies can significantly reduce.

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.

Broader universe of tumor-specific antigens that can be targeted.

2 unchanged sentences

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.

An important emerging class of antibodies is ADCs.

An ADC is a modified antibody that generally has a chemotherapy agent attached to the antibody to enable more targeted chemotherapy treatment of a tumor.

Unfortunately, ADCs frequently bind to targets on normal cells and can lead to severe toxicities.

In order to evaluate the CAB technology’s ability to eliminate the on-target, off-tumor toxicities, we generated two ADCs during our preclinical testing:

one using a CAB antibody to AXL and another using a traditional non-CAB AXL antibody.

Within three days of dosing non-human primates with the traditional non-CAB ADC, the levels of alanine aminotransferase, or ALT, a sign of liver toxicity, increased sharply.

Dosing with the CAB ADC resulted in minimal increase in ALT, supporting that on-target, off-tumor toxicity is reduced with the CAB ADC.

We also observed that the plasma concentration and half-life of the CAB ADC were higher than that of the traditional non-CAB ADC.

We demonstrated a dose dependency of this observation, which indicates that the primary driver of this absence of TMDD effect with CAB ADC is due to the reduced binding of the CAB ADC to AXL outside of the tumor microenvironment.

Our CAB technology was studied in robust Phase 1 clinical trials for our two leading clinical programs, which have shown the following:

Objective antitumor responses :

We observed multiple confirmed partial clinical responses (at least 30% reduction in tumor size for at least two consecutive time points) in our Phase 1 data for both mecbotamab vedotin and ozuriftamab vedotin, including in one patient tumor volume shrinkage of more than 90% and another with a complete response (CR), and several patients who remain without tumor progression for more than one year.

Antitumor activity correlates with a proprietary biomarker :

The presence of the relevant target on a high percentage of tumor cells appeared to correlate with increased antitumor activity.

Safety and tolerability :

Mecbotamab vedotin and ozuriftamab vedotin were generally well-tolerated at the recommended Phase 2 dose range, which is positively differentiated from both preclinical and cross-trial trial results for a similar non-CAB ADC.

Side- effects have been generally manageable with our CAB ADC product candidates, with some patients able to receive more than a year of treatment.

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.

This allows us to develop therapeutics against targets that are expressed at high levels on tumors cells but are also present on normal cells and tissues, without the toxicities associated with traditional antibodies.

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.

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.

1 unchanged sentence

Further, it is expected that PaCS protein-chemical systems are important naturally occurring regulatory systems linked to a range of disease-related microenvironments, including cancer, inflammation and cellular senescence.

Clinical trials

Mecbotamab Vedotin (BA3011)

Programs in clinical development

Mecbotamab Vedotin (BA3011) targeting AXL

Phase 1 clinical trial

We have completed 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.

In the Phase 1 trial, a total of 60 patients, including 26 patients with sarcoma, 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).

The Phase 1 sarcoma patients on average had received four or more prior lines of therapy.

The solid tumor types enrolled in this study were:

soft tissue sarcoma (22 subjects), pancreatic (12 subjects), NSCLC (4 subjects), colorectal (4 subjects), melanoma (3 subjects), bladder (2 subjects), endometrial (2 subjects), Ewing sarcoma (2 subjects), non-TNBC, osteosarcoma, chondrosarcoma, myoepithelial carcinoma, adenoid cystic carcinoma, small cell lung, renal cell carcinoma and mesothelioma of the pleura (1 subject each).

The main goals of this trial were to evaluate the safety, tolerability, antitumor activity, pharmacokinetics and immunogenicity of BA3011 in solid tumor patients.

Based upon the overall safety and response rates, the recommended Phase 2 dose was determined to be 1.8 mg/kg delivered every two weeks (Q2W).

Antitumor activity

We evaluated overall response (OR), one of our secondary endpoints, and observed five confirmed partial responses (a reduction of at least 30% in the size of the tumor), four in patients with sarcomas and one with NSCLC.

These responses have been shown to be durable (8-15 months in sarcoma patients;

duration of response, or DoR, is one of our secondary endpoints).

Further, additional patients have experienced prolonged progression-free intervals, a period of time where the existing tumor did not measurably increase in size by more than 20% and no new tumors were known to develop.

The toxicities observed were consistent with those described with MMAE-based ADCs and were well-tolerated at the exposure subsequently employed for Phase 2.

Importantly we have not observed adverse events that appeared 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.

Antitumor response over time by AXL expression for evaluable sarcoma patients enrolled in Phase 1 trial at all BA3011 doses tested

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.

An independent board-certified pathologist scored all samples according to this TmPS scoring scheme determined by us during the clinical validation phase, as well as during the Phase 1 trial.

We observed that approximately 57% of sarcoma patients screened for enrollment had an AXL TmPS of 70% or above.

In addition, we identified a correlation between the expression of AXL on the membrane of tumor cells and the observed antitumor clinical response as shown in the figure below.

Four of seven sarcoma patients with a confirmed AXL TmPS of 70% or above who were dosed with 1.8 mg/kg of BA3011 Q3W or 2Q3W achieved a confirmed partial response.

Change in sum of target lesions (best response) by AXL TmPS category for Phase 1 evaluable patients at all BA3011 doses tested

Focusing on the subset of sarcoma patients who were dosed with 1.8 mg/kg Q3W or 2Q3W of BA3011 with TmPS of 70%, we observed a correlation of the AXL TmPS and antitumor response.

As shown below, five out of six patients with multiple subtypes of sarcoma experienced reductions in tumor volume and four of these five patients achieved confirmed partial responses (observed response for at least two consecutive time points).

We are confirming this observed correlation and the TmPS cut-off of 70% or more in our ongoing Phase 2 studies.

Best response for sarcoma patients with confirmed TmPS of 70% or above administered 1.8mg/kg Q3W or 2Q3W

One patient with leiomyosarcoma who had experienced failure of multiple prior treatments had a 37% reduction in tumor volume while receiving 1.8 mg/kg Q3W BA3011, as shown in the figure below.

After over a year of treatment with BA3011, the residual tumor mass was reduced to a sufficient degree, enabling a successful surgical resection.

CT scan of leiomyosarcoma patient after BA3011 treatment

CT scan of a 70 mm leiomyosarcoma tumor which decreased in size with BA3011 treatment (confirmed PR) and after a year of therapy was removed by surgical resection.

Of the four patients with NSCLC enrolled in our Phase 1 clinical trial, two were AXL negative with a TmPS of 0%, one was not evaluable, and one was AXL positive with a TmPS of 80%.

Prior to BA3011 treatment, the AXL positive patient with stage IV adenocarcinoma experienced failure from prior treatments, including treatment with a PD-1 inhibitor (pembrolizumab).

As shown below, this patient experienced a partial response characterized by approximately 70% tumor shrinkage with BA3011 delivered at 1.8 mg/kg on days 1 and 8, every three weeks (2Q3W).

One of four NSCLC patients enrolled in Phase 1 BA3011 trial was the only patient with an AXL TmPS >=70%.and had a partial response.

Mecbotamab vedotin was generally well-tolerated.

We have not observed adverse events that appear to be related to on-target injury of normal, AXL-expressing tissues.

We believe that toxicities observed at the maximally tolerated dose and lower were manageable and off-target effects of free MMAE were consistent with those described with other marketed MMAE-based ADCs.

The estimated half-life of mecbotamab vedotin was approximately four days, which is twice the 1.9-day half-life reported for enapotamab vedotin, a non-CAB ADC targeting AXL.

We believe this difference may be due to the decreased TMDD resulting from the lack of binding of mecbotamab vedotin to AXL outside of tumors.

In the Phase 1 trial, the Grade 3 or greater adverse events, or AEs, or serious adverse events, or SAEs, deemed related to mecbotamab vedotin were consistent with MMAE-based toxicity and could generally be classified as either reversible myelosuppression (AEs:

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.

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).

The main goals of this trial were to evaluate the safety, tolerability, antitumor activity, pharmacokinetics and immunogenicity of mecbotamab vedotin in solid tumor patients.

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).

In the Phase 1 studies, mecbotamab vedotin was generally well-tolerated.

Grade 3 or greater adverse events, or AEs, or serious adverse events, or SAEs, deemed related to mecbotamab vedotin were consistent with MMAE-based toxicity and could generally be classified as either reversible myelosuppression (AEs:

neutropenia and anemia), transient liver enzyme elevations (AEs:

AST/ALT increased) or metabolic disturbances (AEs:

hyponatremia, hypokalemia).

There were 24 (37.5%) subjects who reported a serious TEAE (SAE), and in 7 (10.9%) of those subjects that serious TEAE was considered related to treatment..

At the anticipated Phase 2 exposure level (1.8mg/kg Q2W), BA3011 was generally well-tolerated.

For 1.8 mg 1Q3W there were 2 subjects (22% ;

2/9) who experienced treatment related Grade 3-4 AEs (, vomiting and neutrophil count decrease);for 1.8 mg 2Q3W there were 13 subjects (52%;13/25) who experienced treatment related Grade 3-4 AEs ( neutropenia (x3), hypokalemia (x3), , anemia, nausea, febrile neutropenia, fatigue, lymphocyte count decrease, blood bilirubin increase and lipase increase)For 1.8mg/kg Q3W, there were 4 subjects who experienced an SAE (44%;

neutrophil count decrease, intestinal obstruction, lower limb fracture, and sepsis caused by E.

for 1.8mg/kg 2Q3W there were11 subjects who experienced an SAE (44%;

nausea, pyrexia, lipase increased, hyponatremia, syncope, corneal perforation, hypercalcaemia, gastritis, pneumonia, hepatic encephalopathy, and edema of lower extremities) and of these SAEs, fewer were deemed related to treatment by the investigator (for 1.8mg/kg Q3W:

1 SAE (11.1%;

neutrophil count decrease);

1.8mg/kg 2Q3W:

hepatic encephalopathy, lipase increased and gastritis).

For 1.8mg/kg 2Q3W, 2 related AEs led to treatment discontinuation (Grade 2 peripheral neuropathy and Grade 2 fatigue).

No AEs led to treatment discontinuation for 1.8mg/kg Q3W.

Overview of adverse events in mecbotamab vedotin (BA3011) Phase 1 trial for patients administered 1.8mg/kg Q3W (d1) or 2Q3W (d1,8) (safety population)

Characteristic

1.8 mg/kg Q3W

1.8 mg/kg 2Q3W

Related AEs with CTCAE1 Grade 3 or 4 2

Any related serious AEs 2

AEs leading to death

Related AEs leading to death 2

Related AEs leading to treatment discontinuation 2

Common Terminology Criteria for Adverse Events.

The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which is utilized for AE reporting.

A grading (severity) scale is provided for each AE term.

As assessed by the investigator.

Missing responses are counted as related.

We believe that our CAB AXL ADC, mecbotamab vedotin, compares favorably to enapotamab vedotin, a non-CAB AXL ADC with regard to safety and key pharmacokinetic properties.

Comparing across the two Phase 1 trials, both ADCs:

(i) were designed to deliver 4 MMAE molecules per antibody (DAR4 loading), (ii) employed similar ADC doses and (iii) enrolled comparable patients with advanced cancer who had experienced treatment failure of prior regimens (see figure below).

As a key difference, mecbotamab vedotin was designed to only bind to the AXL target expressed by tumor while enapotamab vedotin would be anticipated to bind to the AXL target throughout the body.

Notably, the estimated half-life of mecbotamab vedotin was approximately four days, which is twice the 1.9-day half-life reported for enapotamab vedotin.

We believe this difference may be due to the decreased TMDD resulting from the lack of binding of mecbotamab vedotin to AXL outside of tumors.

With respect to reported toxicity comparisons, constipation is believed to be an on-target delivery of MMAE to normal gut tissues that express the AXL target.

Despite including a risk mitigation plan in enapotamab vedotin’s trial protocol (a prophylactic stool-softener medication in all patients), the clinical data presented at ASCO 2019 showed that AEs of constipation Grade 1-2 were reported in 49% of the patients and Grade 3-4 in 9% of patients.

The rate of constipation reported with mecbotamab vedotin (26% Grade 1-2 and 43% Grade 3-4) was approximately 2 or 3-fold lower for Grade 1-2 and Grade 3-4 TAEs, respectively.

We believe the lower observed rates of constipation observed among the mecbotamab vedotin treated patients were typical for an advanced cancer population who commonly receive pain medications that can also cause constipation.

While supportive of a reduced toxicity benefit from CAB technology, these comparisons are derived from cross-trial analyses, and would not be included as part of our labeling.

Adverse events, such as peripheral neuropathy, are commonly seen with other ADCs and may be due to free circulating MMAE.

Clinical data presented at ASCO 2019 for enapotamab vedotin showed that 38% of the patients had peripheral neuropathy (all Grades) with 2 patients reporting Grade 3-4 AEs.

The rate of peripheral neuropathy (all Grade;

no Grade 3-4) reported for mecbotamab vedotin (28%) was meaningfully lower than the rate reported with enapotamab vedotin and is believed to be due to the advantageous pharmacokinetic characteristics of a CAB ADC vs.

a non-CAB ADC.

hyperglycemia, hyponatremia, hypokalemia).

At a dose of 2.4 mg/kg Q3W mecbotamab vedotin, two patients experienced dose-limiting toxicities:

1 unchanged sentence

Dosing continued at the 2.4 mg/kg with prophylactic administration of pegfilgrastim without any additional dose limiting toxicities.

Dosing above 2.4 mg/kg was terminated due to one patient who experienced Grade 4 febrile neutropenia and cardio-respiratory arrest at 3 mg/kg likely related to delayed hepatic and renal excretion of MMAE.

Phase 2 clinical trial

We are conducting a Phase 2, potentially registration-enabling trial with mecbotamab vedotin, enrolling 90 soft-tissue and bone sarcoma patients, with interim analysis anticipated in early 2022 and the complete data set expected in 2023.

In addition, we have initiated a Phase 2 trial in NSCLC with mecbotamab vedotin as monotherapy and in combination with an anti-PD-1 agent in patients who have experienced prior disease progression on a PD-1/L1 inhibitor and have a TmPS of 1% or greater.

The FDA has reviewed the trial designs, but has not opined on whether Phase 2 clinical trials will be sufficient to support regulatory approval.

However, we intend to ask the FDA to consider this further at the planned interim data review point or points for each clinical trial.

We cannot assure you that the FDA will agree that such data will be sufficient to support approval.

A summary of our clinical development plan for mecbotamab vedotin is below.

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 has begun enrollment.

Clinical development plan for mecbotamab vedotin (BA3011), which includes multiple Phase 2 trials

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.

We identified a preliminary correlation between tumoral expression of AXL and the observed antitumor clinical response.

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.

We observed that most sarcoma patients screened for enrollment had tumors that expressed high levels of AXL.

Phase 2 Clinical Development

We are conducting two Phase 2, potentially registration-enabling trials with mecbotamab vedotin in NSCLC and sarcoma.

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

Phase 1 and/or 2.

We also intend to initiate discussions with the FDA regarding our plans for a potentially registration-enabling Phase 2, part 2 study.

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.

Prior to seeking accelerated approval for either indication, we will seek feedback from the FDA and evaluate our ability to obtain accelerated approval.

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.

Therefore, we plan to submit our proposed confirmatory trial design for FDA feedback and commence enrollment prior to our BLA submission.

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.

The following table illustrates each of the different dosing schedules under evaluation for mecbotamab vedotin.

All cycles (28 days)

All cycles (21 days)

Cycle 1 (21 days)

Cycle 2 (28 days) and subsequent cycles

a all doses will be capped at 100 kg for patients with body weight > 100 kg;

not applicable as not part of the 21-day cycle

Sarcoma Phase 2 trial:

This Phase 2 trial is an open-label trial to evaluate 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 >= 70%, and advanced, refractory sarcoma who have measurable disease by RECIST Version 1.1 criteria and have documented progression according to RECIST Version 1.1 criteria within the six months prior to enrollment.

In addition, there is an exploratory cohort of patients with AXL-expressing TmPS of 50-69%.

To enroll, patients either had to be ineligible for chemotherapy or had received at least one regimen containing anthracycline and a maximum of three previous lines of systemic therapy for metastatic disease (no more than two lines of combination regimens), including pazopanib, trabectedin, eribulin mesylate or tazemetostat, if applicable, per regional prescribing information.

Patients who met the enrollment criteria were assigned to receive either mecbotamab vedotin alone or in combination with an anti-PD-1 agent (for patients 18 years old and above:

240 mg every two weeks (Q2W);

for patients 12-17 years old:

3 mg/kg Q2W IV infusion).

Patients with tumors showing B-cell infiltration (per immunohistochemistry, or IHC, assay) are preferentially assigned to receive mecbotamab vedotin in combination with an anti-PD-1 agent.

Based on data from the Phase 1 part of the trial, the dose of mecbotamab vedotin for Phase 2 is 1.8 mg/kg Q2W.

In Part 1 of this Phase 2 trial, seven cohorts of approximately 10 patients per sarcoma subtype in the monotherapy arm are enrolled:

Soft tissue sarcoma:

Leiomyosarcoma

Synovial sarcoma

All other soft tissue sarcomas, except gastro intestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory myofibroblastic tumor and malignant mesothelioma

Bone sarcoma :

Ewing sarcoma

Other bone sarcomas, including undifferentiated pleomorphic sarcoma, malignant fibrous histiocytoma, and chondrosarcoma

In addition, two combination cohorts (mecbotamab vedotin with an anti-PD-1 agent) are enrolling up to approximately 10 patients each, of any sarcoma subtype.

Patients in one arm will have a tumor showing B-cell infiltration and patients in the other arm will not.

Tumor assessment occurs approximately every 6 weeks from cycle 1 day 1 of treatment, or C1D1, until 12 weeks, and every 8 weeks thereafter.

Pharmacokinetic, pharmacodynamic, immunogenicity and biomarker assessments will also be performed at various time points.

An interim analysis is conducted for each subtype or treatment after approximately 10 patients in the subtype or treatment have been followed for at least 12 weeks after the initiation of treatment.

Following interim analysis, accrual to the subtype or to a treatment (i.e., mecbotamab vedotin alone or in combination with an anti-PD-1 agent) may proceed to Part 2 of the trial if one or more patients with a response (i.e., confirmed or unconfirmed complete response or partial response) or progression-free rate at 12 weeks is >= 40%.

Several cohorts already have qualified to proceed to this Part 2 of the trial.

Approximately 150 additional patients may be enrolled for sarcoma subtypes that meet the threshold.

The accrual of patients to a specific subtype or to one or both treatment regimen(s) (i.e., mecbotamab vedotin alone and/or mecbotamab vedotin in combination with an anti-PD-1 agent) can be put on hold at any time based on evaluation of available data or by the Independent Data Monitoring Committee, or IDMC, at any time upon review of safety data.

Treatment for all enrolled patients will continue until disease progression, unacceptable toxicity, or other reason for treatment discontinuation.

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.

Patients receive either mecbotamab vedotin alone or in combination with an anti-PD-1 agent.

Part 1 antitumor activity has exceeded predefined criteria for advancing trials for UPS, osteosarcoma, liposarcoma, and synovial sarcoma.

Combination dosing is fully enrolled and enrollment continues for Ewing and other bone sarcomas.

Phase 2, part 2 is enrolling patients with UPS, for which efficacy was observed in either Phase 1 and in Phase 2 part 1.

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.

5 patients (50%) achieved partial response among those 10 patients with TmPS ≥

The median duration of response exceeded 8 months, the median PFS was 10.9 months (95% CI:

1.4, NE) and PFS rate at 12 weeks was 60% (95%CI:

Part 2 will enroll a total of approximately 80 patients with locally advanced unresectable or metastatic UPS with high AXL expression.

Primary endpoints include overall response rate, 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.

Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

Additionally, patients must have received no more than three prior systemic regimens.

Enrolled patients will receive open-label BA3011 treatment.

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.

Randomization will be stratified by number of prior systemic treatments (≤

A planned interim analysis will be performed after these 40 patients have an opportunity to be followed for at least 12 weeks.

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.

NSCLC Phase 2 trial:

This is a multi-center, open-label, Phase 2 study 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 and have documented progression according to RECIST v1.1 criteria within the 6 months prior to enrollment.

To enroll, patients must have prior disease progression on a PD-1/L-1 inhibitor (either monotherapy or in combination with another therapy such as ipilimumab).

Patients with EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have had disease progression on FDA-approved therapy for these aberrations.

Patients who meet enrollment criteria will be assigned to receive either mecbotamab vedotin alone or in combination with an anti-PD-1 agent (240 mg every 2 weeks (Q2W)).

For the first 20 patients (Part 1), treatment assignment will be determined by the sponsor and the medical monitor based on the patient’s prior experience with PD-1/L1 treatment.

To be eligible for the PD-1 combination arm, patients must have acceptably tolerated prior PD-1/L1 treatment.

In Part 2, up to approximately 200 additional patients may be enrolled depending on observed efficacy at interim analysis.

If both monotherapy and combination therapy are further pursued post interim analysis, patients that have acceptably tolerated prior PD-1/L1 treatment will be randomized 1:1 to receive either mecbotamab vedotin alone or mecbotamab vedotin in combination with an anti-PD-1 agent.

Randomization will be stratified according to histology (squamous vs.

non-squamous) and the number of prior systemic regimens (< 2 vs.

Patients that have not acceptably tolerated prior PD-1/L1 treatment will be assigned to the mecbotamab vedotin monotherapy arm of the study.

Based on data from the Phase 1 study, the dose of mecbotamab vedotin for Phase 2 is 1.8 mg/kg Q2W.

A dose reduction to 1.5 mg/kg Q2W may be implemented if deemed warranted by the IDMC.

Tumor assessment will occur approximately every 6 weeks from C1D1 until 12 weeks, and every 8 weeks thereafter.

Pharmacokinetic, pharmacodynamic, immunogenicity and biomarker assessments will be performed at various time points.

An interim analysis will be conducted after approximately 20 patients (e.g.

10 patients on mecbotamab vedotin monotherapy arm and 10 patients in the mecbotamab vedotin and anti-PD-1 agent combination arm) have the potential to be followed for at least 12 weeks after the initiation of investigational product.

Following interim analysis, accrual to a treatment (i.e., mecbotamab vedotin alone or in combination with an anti-PD-1 agent) may be put on hold if the number of patients with a response (i.e., confirmed or unconfirmed complete response, partial response or stable disease) are below a pre-defined threshold.

Depending on observed efficacy at the interim analysis, additional NSCLC patients may be enrolled for a total of up to approximately 200 patients (100 patients in each of the 2 treatment groups) with AXL-expressing, metastatic NSCLC.

The accrual of patients to one or both treatment regimen(s) (i.e., mecbotamab vedotin alone and/or mecbotamab vedotin in combination with an anti-PD-1 agent) can be put on hold at any time based on evaluation of available data.

Treatment for all enrolled patients will continue until disease progression, unacceptable toxicity, or other reason for treatment discontinuation.

Ozuriftamab Vedotin (BA3021)

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.

Enrolled patients must have had prior disease progression on a PD-1/L-1 inhibitor.

Patients with EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberration had to have disease progression on FDA-approved therapy for these aberrations.

Patients receive either mecbotamab vedotin alone or in combination with an anti-PD-1 agent.

Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.

Key secondary endpoints include DOR, PFS, BOR, DCR, TTR, PFR at 12 weeks, OS, and percent change from baseline in tumor size.

Ozuriftamab Vedotin (BA3021) targeting ROR2

Phase 1/2 clinical trial

We have completed the dose escalation part of a Phase 1 clinical trial of ozuriftamab vedotin in patients with locally advanced unresectable or metastatic solid tumors including NSCLC and melanoma, who were refractory or resistant to standard therapies.

As shown below, cohorts 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).

In Phase 1, 60 subjects were enrolled into 9 dose cohorts:

0.3 mg/kg Q3W (1 subject), 0.6 mg/kg Q3W (1 subject), 1.2 mg/kg Q3W (1 subject), 1.8 mg/kg Q3W (3 subjects), 2.4 mg/kg Q3W (16 subjects), 3.0 mg/kg Q3W (19 subject), 3.3 mg/kg Q3W (5 subjects), 1.2 mg/kg 2Q3W (3 subjects), 1.5 mg/kg 2Q3W (3 subjects), and 1.8 mg/kg 2Q3W (8 subjects).

The solid tumor types enrolled in this study were:

soft tissue sarcoma (40 subjects), NSCLC (6 subjects), melanoma (2 subjects), pancreatic (2 subjects), non-TNBC (2 subjects), TNBC (2 subjects), colorectal, GIST, urachus, ampulla of vatter, rectal carcinoid and head and neck (1 subject each).

The main goal of this trial was to evaluate the safety, tolerability, antitumor activity, pharmacokinetic and immunogenicity of ozuriftamab vedotin in solid tumor patients.

Based upon the overall safety and response rates, the recommended Phase 2 dose is 1.8 mg/kg delivered every two weeks (Q2W).

The trial’s objectives were the following:

To define the safety profile, including DLT, and determine the MTD and/or RP2D and other safety parameters for ozuriftamab vedotin in patients with advanced solid tumors.

To assess antitumor activity of ozuriftamab vedotin including endpoints such as OR, DoR, disease control, time-to-response, and ORR, according to RECIST Version 1.1.

To assess the pharmacokinetics of ozuriftamab vedotin.

To evaluate the immunogenicity of ozuriftamab vedotin.

Antitumor activity

We evaluated OR, one of our secondary endpoints, as shown in the figure below.

At various dose levels, treatment with ozuriftamab vedotin has resulted in a complete response in one patient with metastatic melanoma.

This patient remains progression free more than two years after initiating therapy.

In addition, two patients with NSCLC (~31% and ~49% tumor reduction) and one patient with advanced head and neck cancer (~54% tumor reduction) were partial responses.

Of the six NSCLC patients enrolled in the dose escalation phase, two patients achieved a durable partial response (duration of response is one of our secondary endpoints) and a third experienced tumor reduction to a lesser degree (change from baseline in tumor size is one of our secondary endpoints, as shown below).

Similar to the observed correlation of antitumor activity with higher levels of tumoral membrane AXL expression, as shown below, the two NSCLC patients with partial responses to ozuriftamab vedotin had ROR2 TmPS of at least 70%.

We were not able to characterize ROR2 TmPS for the third patient who also experienced tumor shrinkage.

Another patient with late stage NSCLC and bone metastases and a ROR2 TmPS of 100%, treated with a suboptimal dose of ozuriftamab vedotin (1.2mg/kg 2Q3W), experienced tumor shrinkage prior to progression of their metastatic bone lesions.

All NSCLC patients who enrolled in this trial had previously been treated with PD-1 therapy.

NSCLC patients enrolled in ozuriftamab vedotin (BA3021) Phase 1 trial by ROR2 TmPS.

Tumor membrane ROR2 expression was associated with antitumor response in two of the five NSCLC patients with evaluable ROR2 TmPS

Two metastatic melanoma patients were enrolled in the initial part of the trial, as shown below.

The ROR2 positive patient achieved a significant durable partial response (duration of response is one of our secondary endpoints).

Furthermore, this patient, who had previously experienced failure of both nivolumab and nivolumab plus ipilimumab, achieved complete response and remains without disease progression more than two years after initiating ozuriftamab vedotin.

All evaluable metastatic melanoma patients enrolled in ozuriftamab vedotin (BA3021) Phase 1 trial by ROR2 TmPS

The metastatic melanoma patient who achieved a complete response experienced clearance of metastatic lung lesions.

Illustrated below is one of the two lung lesions that cleared.

Moreover, a pretreatment biopsy of an involved, abnormally enlarged cervical lymph node showed active melanoma.

Subsequently, an on-treatment biopsy of the same node demonstrated no evidence of melanoma.

Clearance of lung lesions in metastatic melanoma patient who received ozuriftamab vedotin (BA3021)

Pre-treatment and post-treatment CT scans of one of two lung lesions that were both cleared in a metastatic melanoma patient who received ozuriftamab vedotin (BA3021)

In addition, one head and neck cancer patient achieved a partial response with a 54% reduction in tumor size.

Similar to mecbotamab vedotin, ozuriftamab vedotin was generally well-tolerated.

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.

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).

Further dose optimization is being conducted.

The following table illustrates each of the different dosing schedules under evaluation for ozuriftamab vedotin.

All cycles (28 days)

All cycles (21 days)

Cycle 1 (21 days)

Cycle 2 (28 days) and subsequent cycles

a all doses will be capped at 100 kg for patients with body weight > 100 kg;

not applicable as not part of the 21-day cycle

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.

This patient remains progression free approximately 3 years after initiating therapy.

A second CR was achieved by one out of one evaluable melanoma patient in the Phase 2 component of the trial.

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.

All of these patients had previously been treated with PD-1 therapy.

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.

Similar to mecbotamab vedotin, ozuriftamab vedotin continues to be generally well-tolerated.

We have not observed adverse events that appear to be related to on-target injury of normal, ROR2-expressing tissues.

3 unchanged sentences

AST/ALT increased) or metabolic disturbances (AEs:

hyponatremia, hypokalemia).

There were a total of 24 (40%) patients who experienced an SAE, 12 (20%) of which were serious TEAEs that were considered related to treatment.

At the Phase 2 exposure levels (1.8mg/kg Q2W), ozuriftamab vedotin was generally well tolerated.

For 1.8 mg 1Q3W33.3% (1/3) of subjects experienced treatment-related Grade 3-4 AEs (anemia) and 0% had an SAEs (0);

for 1.8 mg 2Q3W:62% (5/8) of subjects experienced treatment-related Grade 3-4 AEs (fatigue, hyponatremia, multiorgan failure, peripheral neuropathy and hyperglycemia) and 50% experienced an SAEs (4/8%;

infected biloma, pyrexia, multiorgan failure and hyperglycemia).

Three of these SAEs, were deemed related to treatment by the investigator (37.5%;

pyrexia, multiorgan failure and hyperglycemia).

For 1.8mg/kg 2Q3W, one subject (12.5%) experienced a TEAE that led to death and was considered potentially related to study treatment.

The subject was a 47-year-old female with a history of metastatic TNBC previously treated with bilateral mastectomy, radiotherapy, doxorubicin + cyclophosphamide + paclitaxel, capecitabine, nab-paclitaxel, atezolizumab, and sacituzumab govitecan.

According to the investigator, no clear etiology of the subject’s signs and symptoms was identified.

The investigator was unable to identify another clear-cut cause of the subject’s medical deterioration;

however, as these events were temporally following her infusion of study drug, the investigator was unable to rule out that the events were not related.

Given the widespread metastatic tumor and that the measured free MMAE levels were within the range observed in other patients treated at the same dose level, the Investigator could not conclude these events were definitely related to the study drug.

For 1.8mg/kg Q3W, none of the related AEs or SAEs led to treatment discontinuation.

For 1.8mg/kg 2Q3W, one (12.5%) of the related AEs or SAEs (multiorgan failure) led to treatment discontinuation.

Overview of adverse events in ozuriftamab vedotin (BA3021) Phase 1 trial for patients administered 1.8mg/kg Q3W (d1) or 2Q3W (d1,8) (safety population)

Characteristic

1.8 mg/kg (Q3W)

1.8 mg/kg (2Q3W)

Related AEs with CTCAE Grade 3 or 4 1

Any related serious AEs 1

Related AEs leading to death 1

Related AEs leading to treatment discontinuation 1

As assessed by the investigator.

Missing responses are counted as related.

At a dose of 3mg/kg Q3W, two patients experienced dose-limiting toxicities:

one with Grade 3 dyspnea (self-resolved without intervention) and the other with Grade 4 febrile neutropenia (in a subject that did not receive prophylactic pegfilgrastim as directed) which resolved on day 2 of hospitalization.

Clinical development plans

We are conducting a potentially registration-enabling Phase 2 trial for ozuriftamab vedotin monotherapy or in combination with a PD-1 inhibitor in melanoma and NSCLC patients that have experienced prior disease progression on a PD1/L1 inhibitor and have a ROR2 TmPS of 1% or more.

However, we have not discussed with the FDA whether the Phase 2 clinical trials will be sufficient to support regulatory approval and we cannot assure you that the FDA will agree that such data will be sufficient to support approval.

We intend to perform an interim analysis when up to approximately 20 evaluable patients in each indication have the potential to be followed for at least 12 weeks, which we expect to occur in the second half of 2022.

Results from these analyses will drive the decision to expand enrollment in each indication to up to 200 patients, and we expect final data in 2024.

We have initiated a Phase 2 clinical trial for ozuriftamab vedotin in head and neck squamous cell carcinoma (SCCHN).

In the dose escalation part of the ozuriftamab vedotin Phase 2 trial, we observed a partial response (PR) in one ROR2 positive SCCHN patient (TmPS=16%) who was refractory to four prior lines of therapy including treatment with cetuximab and pembrolizumab.

The Phase 2 trial studying SCCHN will enroll 40 patients who had experienced prior failure of PD-1 therapy.

Dosing in the first half of 2022, the patients will receive ozuriftamab vedotin monotherapy.

Additionally, a multi-center investigator-initiated trial of ozuriftamab vedotin led by CCTG in platinum-resistant ovarian cancer patients has begun enrollment.

Phase 2 clinical development plan for ozuriftamab vedotin (BA3021) for multiple indications

NSCLC and Melanoma Phase 2 trial

This Phase 2 trial is an open-label trial to evaluate the efficacy and safety of ozuriftamab vedotin alone and in combination with an anti-PD-1 agent in patients with ROR2-expressing (TmPS >1%) and metastatic NSCLC or melanoma who have measurable disease by RECIST Version 1.1 criteria and have documented progression according to RECIST v1.1 criteria within the 6 months prior to enrollment.

Enrolled patients are assigned to receive either ozuriftamab vedotin alone or in combination with an anti-PD-1 agent (240 mg every 2 weeks (Q2W)).

For the first 20 patients (10 patients in each of the 2 indications) (Part 1), treatment assignment is determined by the sponsor and the medical monitor based on the patient’s prior experience with PD-1/L1 treatment.

To be eligible for the PD-1 combination arm, patients must have acceptably tolerated prior PD-1/L1 treatment.

In Part 2, up to approximately 200 additional patients per indication may be enrolled depending on observed efficacy at interim analysis.

For each indication, if both monotherapy and combination therapy are further pursued post interim analysis, patients that have acceptably tolerated prior PD-1/L1 treatment will be randomized 1:1 to receive either ozuriftamab vedotin alone or ozuriftamab vedotin in combination with an anti-PD-1 agent.

For the NSCLC indication, randomization will be stratified according to histology (squamous vs.

non-squamous) and the number of prior systemic regimens (< 2 vs.

For the melanoma indication, randomization will be stratified according to Eastern Cooperative Oncology Group performance status 0 vs.

1 and the number of prior systemic regimens (< 2 vs.

For both indications, patients that have not acceptably tolerated prior PD-1/L1 treatment will be assigned to the ozuriftamab vedotin monotherapy arm of the study.

Based on data from the Phase 1 part of the study, the dose of ozuriftamab vedotin for Phase 2 is 1.8 mg/kg Q2W.

A dose reduction to 1.5 mg/kg Q2W may be implemented if deemed warranted by the IDMC.

Tumor assessment will occur approximately every 6 weeks from C1D1 until 12 weeks, and every 8 weeks thereafter.

Pharmacokinetic, pharmacodynamic, immunogenicity and biomarker assessments will be performed at various time points.

For each indication, an interim analysis will be conducted after up to approximately 20 patients ( e.g.

10 patients in each treatment group) have the potential to be followed for at least 12 weeks after the initiation of investigational product.

Following interim analysis, accrual to a treatment (i.e., ozuriftamab vedotin alone or in combination with an anti-PD-1 agent) may be put on hold if the number of patients with a response (i.e., confirmed or unconfirmed complete response or partial response) are below a pre-defined threshold.

Depending on observed efficacy at the interim analysis, additional NSCLC and/or melanoma patients may be enrolled for a total of up to approximately 200 patients (100 patients in each of the 2 treatment groups) with ROR2-expressing, metastatic NSCLC and a total of up to approximately 200 patients with ROR2-expressing, metastatic melanoma.

The accrual of patients to a treatment regimen(s) (i.e., ozuriftamab vedotin alone and/or ozuriftamab vedotin in combination with an anti-PD-1 agent) can be put on hold by the sponsor at any time based on evaluation of available data or by the IDMC at any time upon review of safety data.

Treatment for all enrolled patients will continue until disease progression, unacceptable toxicity or other reason for treatment discontinuation.

Preclinical studies

In a mouse colon adenocarcinoma, or MC38, xenograft model in which the human CTLA-4 gene had been introduced, we found that BA3071 had similar antitumor efficacy as a traditional anti-CTLA-4 antibody that is an analog of ipilimumab, or an Ipi-analog.

As shown below, BA3071 led to equivalent tumor regression to ipilimumab out of eight treated mice and in two instances we saw a complete response, or no detectable tumor remaining.

Efficacy in human CTLA-4 engineered mouse model

BA3071 had potent antitumor activity and led to two complete responses in an MC38 tumor cell line model in mice containing the human CTLA-4 gene.

As shown below, examination of the immune cell composition of treated tumors found that those treated with BA3071 antibodies had increased numbers of CD8 T cells than IgG control mice.

CD8 T cells are effector cells that mediate tumor cell killing.

These levels were similar to those observed in tumors treated with the ipilimumab analog.

Tumor infiltrating lymphocytes of human CTLA-4 engineered mice

BA3071 functioned similar to ipilimumab in stimulating CD8 T cells in tumors

In contrast, BA3071 antibodies did not lead to changes in the T cell subsets in peripheral blood, as set forth in the figure below.

The percentage of CD4 effector cells in CAB-treated mice were similar to those observed with the controls.

The percentage of CD4 effector cells in ipilimumab analog-treated mice more than doubled, consistent with systemic inhibition of the CTLA-4 checkpoint.

We believe that the observed tumor-restricted activity of BA3071 will be associated with fewer systemic target-based toxicities.

Normal peripheral blood lymphocytes of human CTLA-4 engineered mice

Unlike the ipilimumab analog, BA3071 did not lead to stimulation of T cells in peripheral blood

Our preclinical toxicity study of BA3071 in non-human primates compares its safety profile to that of ipilimumab.

Specifically, as shown in the figure below, we examined the gastrointestinal toxicities associated with combination therapy with nivolumab.

To examine toxicities, these animals were dosed with high levels of both agents.

Dosing of non-human primates with BA3071 in combination with nivolumab was associated with fewer occurrences of events associated with gastrointestinal toxicity than the combination of ipilimumab and nivolumab.

These animals received 20 mg/kg nivolumab, which represents 12 times the human dose, and either 15 mg/kg of ipilimumab or 15 mg/kg of BA3071, which we estimate is 45 to 60 times the current human dose.

There were 33 gastrointestinal events such as liquid feces, non-formed feces and other gastrointestinal symptoms in the ipilimumab plus nivolumab combination across 29 days and five animals.

There was only a single case of liquid feces in one animal on one day in the BA3071 plus nivolumab treatment group.

Toxicity study of BA3071 comparing its safety profile to ipilimumab

Treatment of non-human primates with a combination of BA3071 and nivolumab resulted in fewer gastrointestinal adverse events than treatment with ipilimumab and nivolumab.

These results were consistent with the preclinical results shown two and three figures above that demonstrated that CAB anti-CTLA-4 antibodies had insignificant target-based activity outside of tumors.

We believe that this non-human primate study provides support for assessing the safety and tolerability of BA3071 in clinical trials.

We anticipate that BA3071 will have a wider therapeutic window than ipilimumab, which may enable it to be better tolerated when used in combination with an anti-PD-1 antibody with the potential to further increase efficacy by allowing administration of higher doses and longer duration of treatment.

Clinical Development Plans

We initiated a Phase 1 dose-escalation trial of BA3071 in advanced solid tumor patients in 2021 and expect our first enrolled patient in the first half of 2022.

We expect this trial will examine the safety and tolerability of BA3071 at doses ranging from 7mg Q3W to 700mg Q3W (equivalent to 10mg/kg of ipilimumab) as monotherapy and in combination with an anti-PD-1 antibody.

CAB-Nectin-4-ADC

hyperglycemia, hyponatremia, hypokalemia).

Phase 2 Clinical Development

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.

Prior to seeking accelerated approval for either indication, we will seek feedback from the FDA and evaluate our ability to obtain accelerated approval.

If acceptable, we plan to submit our proposed confirmatory trial design for FDA feedback and commence enrollment prior to our BLA submission.

Approximately 60 ROR2 expressing NSCLC and 40 ROR2 agnostic melanoma patients with locally advanced unresectable solid tumors or metastatic disease are being enrolled.

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.

Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.

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.

We have also initiated a Phase 2 clinical trial of ozuriftamab vedotin as monotherapy in head and neck squamous cell carcinoma (SCCHN).

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.

Primary endpoints include overall response rate, AEs, SAEs, and changes from baseline in laboratory parameters and vital signs.

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.

Additionally, a multi-center investigator-initiated trial of ozuriftamab vedotin led by CCTG in platinum-resistant ovarian cancer patients continues.

CAB CTLA4 (BA3071)

The Phase 1 dose-escalation trial of BA3071 in advanced solid tumor patients continues enrollment in the dose-escalation portion of the trial.

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.

CAB EpCAM x CAB CD3 (BA3182)

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.

BA3182 is designed with an EpCAM binding domain and a CD3 binding domain, both binding domains with CAB activity (Dual-CAB).

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.

Preclinical safety findings

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.

Preclinical candidates

CAB Nectin-4-ADC (BA3361)

Nectin-4 is widely expressed and has adhesive roles in normal tissues.

2 unchanged sentences

In addition to the assay performance, the lead candidate demonstrated high binding under tumor conditions and little to no binding under normal physiological conditions.

The candidate is in cell line development and a new, highly stable linker was successfully tested in vitro and in vivo.

CAB-B7-H4-ADC

CAB B7-H4-ADC (BA3151)

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.

Selection of the lead candidate was based on criteria including high binding activity under tumor conditions and low binding activity under normal physiological conditions.

Bispecific candidates

We have developed and conducted preclinical studies of an EpCAM x CD3 bispecific candidate, BA3182, with an EpCAM binding domain and a CD3 binding domain , both binding domains with CAB activity (Dual-CAB).

Dosage was 1mg per kilogram twice per week in mice, which is roughly equivalent to 0.25 mg per kilogram in non-human primates.

As shown below, we found this construct had a potent antitumor activity in a HCT116, a human colorectal carcinoma cell line, xenograft model in mice with a humanized immune system.

Selection of the lead

candidate was based on criteria including high binding activity under tumor conditions and low binding activity under normal physiological conditions.

CAB B7-H3 x CAB CD3 (BA3142)

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.

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.

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.

Our second bispecific product candidate, BA3142, is a dual-CAB T-cell engager targeting B7-H3, a protein expressed on many solid tumors.

1 unchanged sentence

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.

CAB EGFR x CAB CD3

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.

A set of lead molecules were characterized by multiple assays including functional assays and all demonstrated high activity at acidic pH with little to no activity under physiological conditions.

Studies, using a colorectal cancer model to select the clinical lead, are in progress and are expected to be completed in the first quarter of 2022.

Clinical Development Plans

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.

We have advanced two CAB bispecific antibody product candidates, BA3182 (EpCAM x CD3) and BA3142 (B7H3 x CD3) into preclinical studies, and BA3311 (EGFR x CD3) is a current subject of IND enabling studies.

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.

Two molecules are in development:

a mono-CAB (EGFR x CAB CD3) and a dual-CAB (CAB EGFR x CAB CD3).

CAB Nectin 4 x CAB CD3 (BA3362)

BA3362 is a dual CAB bispecific product candidate.

The cell line development and in vivo efficacy study are completed.

Non-GLP toxicology study in cynomolgus monkeys is in progress.

The biotechnology and biopharmaceutical industries, including the oncology subsector, are characterized by rapid evolution of technologies, competition and strong defense of intellectual property.

2 unchanged sentences

In immuno-oncology, we face substantial competition in the form of competing approaches to targeted antibody therapy in general, as well as competing treatments for the same types of cancer that we would plan to address with our pipeline of product candidates.

There are numerous companies in various stages of clinical development of ADCs, one of the key feature of our product candidates mecbotamab vedotin and ozuriftamab vedotin.

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.

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.

9 unchanged sentences

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.

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.

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

1 unchanged sentence

TM , technology.

The successful evolution, design, and development of a CAB antibody with specific characteristics and qualities require that the

development and manufacturing processes result in the CAB antibody with the desired properties.

The successful evolution, design, and development of a CAB antibody with specific characteristics and qualities require that the development and manufacturing processes result in the CAB antibody with the desired properties.

We have developed our patented process of CIAO!

15 unchanged sentences

We intend to selectively enter into collaborations to maximize the value of our platform and pipeline.

License Agreements

License Agreements and Strategic Collaborations

Collaboration and Supply Agreement with Bristol-Myers Squibb

On January 5, 2022, we and Bristol-Myers Squibb Company (“BMS”) entered into a clinical trial collaboration and supply agreement (the “BMS Agreement”).

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’

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.

BMS provides Opdivo® clinical drug supply at no cost for the combination study trials.

After the completion of the combination therapy trials, we are obligated to provide BMS with a final report of the data resulting from the trial.

The BMS agreement was amended in October 2022 to include additional territories for our combination study trials for mecbotamab vedotin and ozuriftamab vedotin.

Global Co-Development and Collaboration Agreement with BeiGene, Ltd.

2 unchanged sentences

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.

Subject to the terms of the agreement, BeiGene held an exclusive license with BioAtla to develop and manufacture the product candidate globally.

BeiGene was responsible for all costs of development, manufacturing and commercialization globally.

At the time of execution of the BeiGene collaboration, we received a $20 million upfront payment and in December 2019, we received an additional $5 million for the reimbursement of manufacturing costs.

We were eligible to receive subsequent development and regulatory milestones globally and commercial milestones in the BeiGene territory, together with tiered royalties on sales worldwide.

We received a total of $25 million in payments from BeiGene.

On November 19, 2021, we entered into Amendment No.

3 to the Global Co-Development and Collaboration Agreement ( “Amendment No.3”) Under Amendment No.

3 to the Global Co-Development and Collaboration Agreement (“Amendment No.

Under Amendment No.

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.

As consideration for Amendment No.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.

As consideration for Amendment No.

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.

Exclusive License Agreement with Inversagen, LLC

3 unchanged sentences

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.

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 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.

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

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.

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.

31 unchanged sentences

The agreement may be terminated only by the mutual written agreement of the parties.

In connection with the agreement, we received common and preferred stock of EXUMA.

These holdings of EXUMA common and preferred stock were retained by BioAtla Holdings in connection with the LLC Division.

In November 22, 2019, we entered into an Amended and Restated Exclusive License Agreement with EXUMA, which curtailed the rights to certain CAB intellectual property previously licensed to EXUMA in exchange for a one-time, non-refundable, non-creditable license fee of $10,000, but does not change EXUMA’s obligation to pay us royalties on licensed products.

In connection with the Amended and Restated Exclusive License Agreement, BioAtla Holdings sold its EXUMA common and preferred holdings back to EXUMA for consideration of $25,000.

CHO-S Cell Line License Agreement with Life Technologies Corporation

10 unchanged sentences

Inventions related to various aspects of our core technologies have already been protected by issued and pending patent applications.

As of December 31, 2021, we had 584 patents and patent applications with 319 issued, 8 allowed applications and 257 pending applications.

The objectives of our IP strategy are to increase shareholder value by adequately protecting our platform technologies and compositions of matter, discerning and maximizing the value of our patent portfolio, providing a flexible portfolio that is aligned with our business model and maintaining a cost-effective strategy.

We achieve these goals by creating a defensible patent shield, employing most-likely-to-succeed strategies, patenting strategically to reinforce the value of our IP and to minimize costs related to patenting while maximizing value, and by understanding the technology landscape to ensure patentability and freedom to operate.

For our CAB products, we act strategically to maximize patent term by timely filing our patent applications.

As of March 1, 2023, we had 711 patents and patent applications with 435 issued patents, 5 allowed applications, and 271 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.

6 unchanged sentences

In some cases, multiple provisional applications have been filed within a 12-month period to capture incremental developments within the 12-month priority period while obtaining an early filing date for each development.

The corresponding non-provisional patent applications benefit from the provisional applications(s) since the priority date(s) of the these non-provisional patent applications is/are the earlier provisional application filing date(s), and because the patent term of the finally issued patents are calculated from the later, non-provisional patent application filing dates.

The corresponding non-provisional patent applications benefit from the provisional applications(s) since the priority date(s) of these non-provisional patent applications is/are the earlier provisional application filing date(s), and because the patent term of the finally issued patents are calculated from the later, non-provisional patent application filing dates.

This system allows us to obtain an early priority date, add material to the patent application(s) during the priority year, obtain a later start to the patent term and delay prosecution costs, which may save costs in the event that we decide not to pursue examination in an application.

2 unchanged sentences

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.

The PCT searching authority performs a patentability search and issues a non-binding patentability opinion which can be used to evaluate the chances of success for future the national/regional patent applications in foreign countries prior to having to incur the filing and translation costs for such applications.

At the end of a period of 2 1/2 years from the first priority date of the PCT patent application, separate patent applications can be pursued in any of the 157 PCT member states either by direct national filing or, in some cases, by filing through a regional patent organization such as the European Patent Organization.

The PCT system delays expenses, allows a limited evaluation of the chances of success for national/regional patent applications and enables substantial cost savings where applications are abandoned within the first 2 1/2 years of filing.

For all patent applications, we determine the claiming strategy on a case-by-case basis.

Advice of counsel and our business model and needs are always considered.

We file patents containing claims for protection of all useful applications of our proprietary technologies and any products, as well as all new applications or uses we discover for existing technologies and products, assuming these are strategically valuable.

We continuously reassess the number and type of patent applications, as well as the pending and issued patent claims to ensure that maximum patent coverage and value are obtained for our processes, and compositions, given existing patent office rules and regulations.

Further, pending patent claims may be modified during patent prosecution to meet our intellectual property and business needs.

We are attentive to the need to avoid the unauthorized use of patented technology belonging to third parties.

We perform non-infringement searches and analyses for our existing technologies and will continue to do so for future commercial processes and products.

We also perform non-infringement searches and analyses for our existing technologies and will continue to do so for future commercial processes and products.

For our new developments, we regularly perform expert searches and reviews, and monitor patents and patent applications by third-party competitors.

30 unchanged sentences

Mecbotamab vedotin is covered by a number of filings, including a published PCT application filed in 2017 that entered the national phase in 2018.

National phase applications have been granted in Australia, Israel, Japan, and the United States and are pending in 13 jurisdictions, including most major market countries.

Applications have been granted in Australia, Israel, Japan, Korea, Mexico, Singapore, Taiwan, and the United States and are pending in 13 jurisdictions, including most major market countries.

Composition of matter claims issuing from this application would not expire before 2037.

Ozuriftamab vedotin is covered by a number of filings, including a published PCT application filed in 2017 that entered the national phase in 2018.

National phase applications are pending in 14 jurisdictions in addition to the United States, including most major market countries.

Applications have been granted in Europe, Japan, Mexico, and the United States and are pending in 14 jurisdictions, including most major market countries.

Composition of matter claims issuing from this application would not expire before 2037.

BA3071 is covered by a number of filings, including a published PCT application filed in 2019 that entered the national phase in 2021.

In addition to filings made in the non-PCT countries of Argentina and Taiwan, national phase applications are pending in 15 jurisdictions in addition to the United States, including most major market countries.

Applications have been granted in Australia, Israel, 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.

Our pre-clinical stage CAB antibody programs, including CAB-anti-EpCAM antibodies and CAB-anti-Nectin-4 antibodies, are covered by a number of filings.

As of December 31, 2021, CAB-anti-EpCAM antibodies are covered by 10 national phase filings, including the United States, and a non-PCT filing in Taiwan.

CAB-anti-Nectin-4 antibodies are covered by a PCT application and an application in Taiwan.

Our CAB-anti-EpCAM antibody and our preclinical stage CAB-anti-Nectin-4 antibody, are covered by a number of filings.

As of March 1, 2023, CAB-anti-EpCAM antibodies are covered by 13 national phase filings, including the United States, and a non-PCT filing in Taiwan.

As of March 1, 2023, CAB-anti-Nectin-4 antibodies are covered by 13 national phase filings and an application in Taiwan.

Composition of matter claims issuing from these applications would not expire before either 2040 or 2041.

chimeric antigen receptors for modified T-cells, diagnostics using conditionally active antibodies, conditionally active polypeptides, antibodies targeted to senescent cells, conditionally active proteins for neurodegenerative diseases, and conditionally active proteins with pH selectivity.

Core components of our product candidates are protected by company-owned platform applications directed to novel methods of protein evolution, methods of making conditionally active biologics, integrated selection and evolution of antibodies and proteins in expression production hosts, multi-specific antibodies and methods of making, modified antibody regions, conditionally active biological proteins, proteins targeting orthologs, discovery of and production of conditionally active biologic proteins in eukaryotic cell production hosts, conditionally active chimeric antigen receptors for modified T-cells, diagnostics using conditionally active antibodies, conditionally active polypeptides, antibodies targeted to senescent cells, conditionally active proteins for neurodegenerative diseases, and conditionally active proteins with pH selectivity.

We also have 25 issued U.S.

patents covering various aspects of the manufacturing methods used to generate CAB antibodies that have patent terms expiring from 2030 to 2037.

We also have an issued patent in the U.S.

protecting our method of manufacturing conditionally active multi-specific antibodies that has a patent term expiring in 2033.

We also have 2 issued patents in the U.S.

protecting our method of manufacturing conditionally active multi-specific antibodies that have patent terms expiring from 2033 to 2034.

Out-licensed patents

10 unchanged sentences

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.

The FDCA, PHSA and their corresponding regulations govern, among other things, the testing, manufacturing, safety, purity, potency, labeling, packaging, storage, record keeping, distribution, post-approval monitoring and reporting, import, export, advertising and other promotional practices involving biologic products.

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.

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.

19 unchanged sentences

Before testing any biologic product candidate in humans, the product candidate must undergo rigorous preclinical testing.

Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as in vivo studies to assess the potential safety and activity of the product candidate and to establish a rationale for therapeutic use.

Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as in vivo animal studies to assess the potential safety and activity of the product candidate and to establish a rationale for therapeutic use.

The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs.

17 unchanged sentences

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.

The biologic product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.

The biologic product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate a particular indication and to determine dosage tolerance, optimal dosage and dosing schedule.

Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

The biologic product candidate is administered to an expanded patient population at multiple sites to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

The biologic product candidate is administered to an expanded patient population at multiple sites to further evaluate dosage, to demonstrate efficacy and safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and labeling.

10 unchanged sentences

This group provides authorization for whether a trial may move forward at designated checkpoints based on access to certain data from the trial.

Concurrent with clinical trials, companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop additional information about the chemistry and physical characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

Concurrent with clinical trials, companies usually must complete some long-term preclinical testing, such as animal tests of reproductive toxicity and carcinogenicity, and must also develop additional information about the chemistry and physical characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, potency and purity of the final product.

6 unchanged sentences

Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.

In addition, the manufacturer of an investigational biologic in a Phase 2 or Phase 3 clinical trial for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for expanded access to such investigational drug or biologic.

review and approval processes

FDA approval of a BLA must be obtained before commercial marketing of the biologic product.

The results of the preclinical tests and clinical trials, together with detailed information relating to the product’s 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 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.

1 unchanged sentence

The FDA adjusts the PDUFA user fees on an annual basis.

The PDUFA also imposes an annual prescription drug program.

Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

1 unchanged sentence

The applicant under an approved BLA is also subject to an annual program fee.

The FDA reviews a BLA within 60 days of submission to determine if it is substantially complete before the agency files.

The FDA reviews a BLA within 60 days of receipt to determine whether the application will be filed based on the FDA's determination that it is sufficiently complete to permit substantive review.

The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information.

5 unchanged sentences

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions on approval.

During the product approval process, the FDA also will determine whether a REMS is necessary to assure the safe use of the product candidate.

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.

REMS involve additional risk minimization strategies to ensure that the benefits of the product outweigh the potential risks.

14 unchanged sentences

The FDA has agreed to specified performance goals in the review of BLAs under the PDUFA.

One such goal is to review standard BLAs in 10 months after the FDA files the BLA, and priority BLAs in six months, whereupon a review decision is to be made.

One such goal is to review standard BLAs within 10 months after the FDA files the BLA, and priority BLAs within six months, whereupon a review decision is to be made.

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.

5 unchanged sentences

Establishments may be subject to periodic, unannounced inspections by government authorities to ensure compliance with cGMP requirements and other laws.

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 requiring withdrawal of the product from the market.

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.

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.

18 unchanged sentences

A product eligible for accelerated approval may be approved on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions or survives.

In clinical trials, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.

The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.

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.

The accelerated approval pathway is contingent on a sponsor’s agreement to conduct additional post-approval confirmatory studies to verify and describe the product’s clinical benefit.

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.

The Food and Drug Omnibus Reform Act, or FDORA, was recently enacted, which 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.

FDORA also requires the FDA to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion and requires sponsors to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 days following approval and not less frequently than every 180 days thereafter until completion or termination of the study.

FDORA enables the FDA to initiate enforcement action for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened.

13 unchanged sentences

In the United States, pursuant to the Orphan Drug Act, the FDA may grant orphan designation to a biological product intended to treat a rare disease or condition, which is statutorily defined as a condition that affects fewer than 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available the biologic for the disease or condition will be recovered from sales of the product in the United States.

Orphan drug designation qualifies a company for tax credits and market exclusivity for seven years following the date of the product’s marketing approval if granted by the FDA.

An application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product.

A product becomes an orphan when it receives orphan drug designation from the Office of Orphan Products Development at the FDA based on acceptable confidential requests made under the regulatory provisions.

The Office of Orphan Products Development at the FDA grants orphan drug designations based on acceptable confidential requests made under the regulatory provisions.

The product must then go through the review and approval process like any other product.

Orphan drug designation on its own does not convey any advantage in or shorten the duration of the regulatory review and approval process.

Orphan drug designation entitles a company to financial incentives, such as tax credits and user fee waivers, but does not convey any advantage in or shorten the duration of the regulatory review and approval process.

A sponsor may request orphan drug designation of a previously unapproved product or new orphan indication for an already marketed product.

In addition, a sponsor of a product that is otherwise the same product as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent product for the same rare disease or condition if it can present a plausible hypothesis that its product may be clinically superior to the first drug.

In addition, a sponsor of a product that is otherwise the same drug, which includes biologics, as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent product for the same rare disease or condition if it can present a plausible hypothesis that its product may be clinically superior to the first drug.

More than one sponsor may receive orphan drug designation for the same product for the same rare disease or condition, but each sponsor seeking orphan drug designation must file a complete request for designation.

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.

Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same product 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.

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.

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.

Competitors may receive approval of either a different product for the same indication or the same product for a different indication.

Competitors may receive approval of either a different drug for the same indication or the same drug for a different indication.

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.

The FDA may approve a second application for the same product for a different use or a second application for a clinically superior version of the product for the same use.

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.

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 product 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.

The FDA’s determination of whether two ADCs are the same product 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.

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.

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.

1 unchanged sentence

FDA approval and regulation of companion diagnostics

If use of an in vitro diagnostic is essential to the safe and effective use of a drug or biologic product, then the FDA generally will require approval or clearance of that diagnostic, known as a companion diagnostic, at the same time that the FDA approves the therapeutic product.

If use of an in vitro diagnostic is essential to the safe and effective use of a drug or biologic product, then the FDA generally will require approval or clearance of that diagnostic, known as a companion diagnostic, before or at the same time that the FDA approves the therapeutic product.

In August 2014, the FDA issued final guidance clarifying the requirements that will apply to approval of therapeutic products and in vitro companion diagnostics.

According to the guidance, if the FDA determines that a companion diagnostic device is essential to the safe and effective use of a biologic product or indication, the FDA generally will not approve the biologic product or new biologic product indication if the companion diagnostic device is not approved or cleared for that indication.

Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices.

The FDA has also introduced the concept of a complementary diagnostic, which the FDA defines as a test that is not required but which provides significant information about the use of a drug.

A complementary test can help guide treatment strategy and identify which patients are likely to derive the greatest benefit from therapy, and if approved by the FDA information regarding the in vitro diagnostic will be included in the therapeutic product labeling.

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.

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.

We may partner with a diagnostic provider to develop a companion or complementary diagnostic for certain of our product candidates.

Review and approval of a companion or complementary diagnostic is typically done in parallel with development of the therapeutic product.

However, it is possible that the FDA may permit approval of the companion or complementary diagnostic as a post-marketing commitment following a potential regulatory approval.

Under the FDCA, in vitro diagnostics, including companion and complementary diagnostics, are regulated as medical devices.

In the United States, the FDCA and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

Unless an exemption applies, diagnostic tests require marketing clearance or approval from the FDA prior to commercial distribution.

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, approval.

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 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.

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.

20 unchanged sentences

The FDA may grant deferrals for submission of data or full or partial waivers.

Unless otherwise required by regulation, the PREA generally does not apply to any biologic product candidate for an indication for which orphan designation has been granted with the exception of orphan-designated biologics if the biologic is a molecularly targeted cancer product intended for the treatment of an adult cancer and is directed at a molecular target that FDA has determined is substantially relevant to the growth or progression of a pediatric cancer.

The Best Pharmaceuticals for Children Act, or BPCA, provides a six-month extension of any non-patent exclusivity for a biologic if certain conditions are met.

Unless otherwise required by regulation, the PREA generally does not apply to any biologic product candidate for an indication for which orphan designation has been granted with the exception of orphan-designated biologics if the product contains a new active ingredient and is a molecularly targeted cancer product intended for the treatment of an adult cancer and is directed at a molecular target that FDA has determined is substantially relevant to the growth or progression of a pediatric cancer.

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.

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.

Additional controls for biologics

To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined.

The PHSA also provides authority to the FDA to immediately suspend biologics licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases within the United States.

After a BLA is approved, the product may also be subject to official lot release as a condition of approval.

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.

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.

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.

As with drugs, after approval of a BLA, biologics manufacturers must address any safety issues that arise, are subject to recalls or a halt in manufacturing, and are subject to periodic inspection after approval.

Biosimilars and exclusivity

1 unchanged sentence

The FDA has licensed numerous biosimilars under the BPCIA, and has issued several guidance documents outlining an approach to review and approval of biosimilars.

Biosimilarity, which requires that there be no clinically meaningful differences between the proposed biosimilar biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or studies though the FDA has broad discretion to set or waive certain biosimilar licensure data requirements.

Biosimilarity, which requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the proposed biosimilar biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, an assessment of toxicity, and a clinical trial or studies though the FDA has broad discretion to set or waive certain biosimilar licensure data requirements.

Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

6 unchanged sentences

by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser 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.

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

12 unchanged sentences

Clinical trial approval

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.

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.

11 unchanged sentences

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.

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.

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.

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:

(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 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.

84 unchanged sentences

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.

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.

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.

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.

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.

17 unchanged sentences

rights with respect to certain personal information and creating a new state agency to oversee implementation and enforcement efforts.

Many of the CPRA’s provisions will become effective on January 1, 2023.

The CPRA took effect in most material respects on January 1, 2023.

CCPA enforcement thus far has been limited;

it has not been subject to significant litigation and judicial interpretation.

As a result, it remains unclear how various provisions of the CCPA will be interpreted and enforced.

State laws are changing rapidly and there is discussion in the U.S.

8 unchanged sentences

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.

The HHS plan includes, among other reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.

Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included in policy statements and legislation currently being considered by Congress.

It is unclear to what extent these and other statutory, regulatory, and administrative initiatives will be enacted and implemented.

These initiatives recently culminated in the

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.

The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.

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.

The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.

The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

These provisions will take effect progressively starting in 2023, although they may be subject to legal challenges.

Human Capital Management

21 unchanged sentences

Corporate Information

Our business was founded in March 2007 and originally operated as a Delaware limited liability company, BioAtla, LLC.

In July 2020, we converted from a limited liability company into a Delaware corporation pursuant to a statutory conversion and changed our name from BioAtla, LLC to BioAtla, Inc.

Our business and predecessor entity was founded in March 2007.

In July 2020, we converted from a limited liability company into a Delaware corporation pursuant to a statutory conversion and changed our name to BioAtla, Inc.

Our principal executive offices are located at 11085 Torreyana Road, San Diego, California 92121, and our telephone number is (858) 558-0708.

10 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.

What changed 10-K

Item 1. Business