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Item 1. Business

2025-03-28 compared with 2024-03-26 · 213 added, 320 removed, 598 unchanged (47% of the section changed)

We are a clinical-stage biopharmaceutical company developing our novel class of highly specific and selective antibody-based therapeutics for the treatment of solid tumor cancer.

We are a clinical-stage biopharmaceutical company developing our novel class of highly specific and selective antibody-based therapeutics for the treatment of solid tumor cancers.

Our conditionally active biologics (“CAB” or “CABs”) capitalize on our proprietary discoveries with respect to tumor biology, enabling us to target known and widely validated tumor antigens that have previously been difficult or impossible to target.

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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.

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.

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.

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, (“ADCs”), T cell-engaging bispecific antibodies and chimeric antigen receptor T cells, or CAR-T cells.

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

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

We have also developed antibodies for immuno-oncology and for bispecific, T cell engagement.

The bispecific CAB antibodies are comprised of two different binding specificities, which allows the antibody to bind to two specific targets at the same time, generally one target on the tumor cell and one target on an immune system cell.

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.

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 our lead product candidates through regulatory approval and commercialization.

o BA3182 (CAB-EpCAM x CAB-CD3) :

Our first bispecific candidate demonstrated in its investigational new drug (“IND”)-enabling studies a more than 100-fold improvement in the therapeutic window, as compared to a non-CAB anti-EpCAM bispecific antibody.

We are advancing 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 cancers are adenocarcinoma (American Cancer Society 2022).

o Mecbotamab vedotin (BA3011):

Clinical data from our Phase 1 and Phase 2 part 1 trials with mecbotamab vedotin are supportive of its development in metastatic sarcomas, a set of cancers with a high unmet clinical need, and in metastatic non-small cell lung cancer (“NSCLC”) with KRAS mutations.

In addition, we have obtained Food and Drug Administration (“FDA”) clearance to initiate a potentially registration-enabling Phase 2/3 trial in NSCLC in 2 nd Line + or 3 rd Line + population.

o Ozuriftamab vedotin (BA3021):

In our Phase 1 trial, we have observed antitumor activity in NSCLC, melanoma and squamous cell carcinoma of head and neck (“SCCHN”) in patients who had failed programmed cell death protein 1 (“PD-1”) therapy, and we have an ongoing Phase 2 trial of ozuriftamab vedotin in SCCHN with fast-track designation from the FDA.

• Leverage our CAB platform to develop and enhance pre-clinical assets, including several 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 for our Phase 1 clinical asset, BA3182, that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially fatal immune responses.

For example, BA3182 demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window as compared to a non-CAB anti-EpCAM bispecific antibody.

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

Combining our CAB technology with our next generation CAB-ADC platform replaces the traditional peptide linker with a novel sugar-based linker to deliver the MMAE payload.

It is expected that this new CAB-ADC system will further reduce off-target, off-tumor toxicity and thereby expand the therapeutic window.

• Maintain and strengthen our intellectual property portfolio.

As of February 1, 2025, we had a total of 752 patents and patent applications with 479 issued patents, 13 allowed applications and 260 pending applications covering our CAB technology and product candidates.

This broad patent coverage was designed such that protection of our product candidates is not dependent on any single patent but rather, each product candidate is covered by several layers of protection.

We plan to continue to maintain, monitor, enforce and defend our intellectual property.

• Enter into collaborations to maximize the value of our platform and pipeline.

Given the potential of our technology to generate novel product candidates addressing a wide variety of solid tumors, we may opportunistically enter into strategic collaborations around specific geographic regions, indications, combinations and companion diagnostics.

We may also explore collaboration arrangements to commercialize any product candidates where we believe the resources and expertise of the third party could be beneficial.

We are currently seeking partnering opportunities across our portfolio, including for our clinical-stage programs, Ozuriftamab Vedotin and Evalstotug.

These collaborations could advance and accelerate our programs to maximize their market potential and expand the worldwide commercial potential of our CAB technology and assets.

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.

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Mecbotamab vedotin (BA3011):

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.

Our 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.

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.

Multiple therapeutic agents that target AXL have been developed and investigated in clinical trials.

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

Several therapeutic agents that target AXL have been developed and investigated in clinical trials, and several small-molecule AXL kinase inhibitors have been developed by others;

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.

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

The core antibody is conjugated using a cleavable linker attached to the well-known and proven toxin monomethyl auristatin E, or MMAE.

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Upon binding of mecbotamab vedotin to AXL on the surface of tumor cells, it is internalized and the MMAE cytotoxin is released, thus killing the cancer cell.

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 Products Development (OOPD) at the FDA has granted Orphan Drug Designation to mecbotamab vedotin for the treatment of soft tissue sarcoma.

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

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.

We are conducting a Phase 2 study (BA3011-002) in AXL positive NSCLC patients who have previously progressed on programmed cell death protein 1 (“PD-1”)/programmed cell death ligand 1 (“PD-L1”), epidermal growth factor receptor (“EGFR”), or anaplastic lymphoma kinase (“ALK”) inhibitor therapy.

We are also conducting a potentially registrational Phase 2 study in sarcoma.

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

We have conducted a Phase 2 study (BA3011-002) in NSCLC patients who have previously progressed on PD-1 / programmed cell death ligand 1 (“PD-L1”), epidermal growth factor receptor (“EGFR”), or anaplastic lymphoma kinase (“ALK”) inhibitor therapy.

We also conducted a Phase 2 study in sarcoma in patients who were ineligible for chemotherapy or have received at least one regimen containing anthracycline.

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

Both the monotherapy and combination treatment are broadly well tolerated with most events being low grade and reversible with no clinically meaningful on-target toxicity observed during the course of treatment.

Drug-related adverse events appear likely to have been related to free-circulating MMAE payload-associated toxicity including reversible neutropenia, elevated liver function test and hyperglycemia which were all manageable and with low incidence.

Our Phase 2 study in NSCLC has shown promising long-term survival in heavily pre-treated mutated KRAS NSCLC patients with mecbotamab vedotin at Q2W both as monotherapy and in combination with nivolumab.

We have conducted a Phase 2, single-arm trial with mecbotamab vedotin monotherapy in patients with undifferentiated pleomorphic sarcoma (“UPS”) who have experienced prior treatment failure.

We continue to see encouraging efficacy in AXL positive UPS patients, however, there is a potential need for a companion diagnostic and a likely requirement of a randomized trial in UPS.

As a result, we may prioritize the larger, recently identified mutated KRAS NSCLC opportunity which shows high correlation with AXL expression, thereby utilizing an approved readily available companion diagnostic for KRAS mutations.

Both soft tissue and bone sarcoma, as well as other indications, remain promising for potential future development.

Ozuriftabmab vedotin (BA3021):

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;

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

ROR2 is overexpressed across many different solid tumors, including breast, lung, pancreatic, renal, ovarian, and colorectal cancers, SCCHN, and melanoma;

its tumoral expression is further enhanced among those treated with PD-1 checkpoint inhibitors.

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A similar correlation between ROR2 expression level and overall survival was observed in NSCLC and metastatic melanoma.

Genetic inactivation of ROR2 in metastatic melanoma cells was shown to prevent metastases of these tumor cells in mice.

has essential roles in normal cells and in early development.

Genetic inactivation of ROR2 in metastatic

melanoma cells was shown to prevent metastases of these tumor cells in mice.

ROR2 also has essential roles in normal cells and in early development.

Inactivation of ROR2 is lethal in mice with defects observed in the heart, nervous system and skeleton.

Less severe mutations in ROR2 in humans is associated with skeletal diseases Robinow syndrome and brachydactyly type B.

Less severe mutations in ROR2 in humans is associated with skeletal diseases such as Robinow syndrome and brachydactyly type B.

Ozuriftamab vedotin is a CAB anti-ROR2 ADC consisting of a CAB anti-ROR2 humanized IgG1 monoclonal antibody conjugated to MMAE using a cleavable linker.

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Upon binding of ozuriftamab vedotin to ROR2 on the surface of tumor cells, it is internalized and the MMAE cytotoxin is released, thus killing the cancer cell.

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

Based on Phase 1 data, we believe ozuriftamab vedotin has broad potential as a cancer therapy for patients with advanced solid tumors who have experienced prior failure of PD-1 blockade.

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.

We are also conducting a Phase 2 study in patients with SCCHN.

We are prioritizing SCCHN for ozuriftamab vedotin as a therapeutic indication for development over other possible indications in solid tumors, including melanoma and triple negative breast cancer.

We have conducted Phase 2 studies in melanoma, NSCLC, and SCCHN treated with ozuriftamab vedotin as a monotherapy or in combination with a PD-1 inhibitor, nivolumab.

Ozuriftamab vedotin has shown promising overall response rates in SCCHN and the FDA has granted Fast-Track designation for ozuriftamab vedotin in SCCHN.

We believe that 1.8 mg/kg of ozuriftamab vedotin delivered every other week satisfies dose optimization requirements, which will be confirmed prior to initiation of a Phase 3 study in SCCHN.

Evalstotug (BA3071):

Our third clinical stage product candidate, evalstotug, is a CAB anti-CTLA-4 antibody that is being developed as an immuno-oncology agent with the goal of delivering at least the efficacy of approved CTLA-4 antibodies, such as ipilimumab, but with lower toxicity rate as a result of the CAB’s unique tumor microenvironment-restricted binding.

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

Our clinical stage product candidate, evalstotug, is a CAB anti-CTLA-4 antibody that is being developed as an immuno-oncology agent with the goal of delivering at least the efficacy of approved CTLA-4 antibodies, such as ipilimumab, but with lower toxicity rate as a result of the CAB’s unique tumor microenvironment-restricted binding.

Cytotoxic T-lymphocyte-associated antigen 4 (“CTLA-4”), is an immune checkpoint involved in regulating T-cell activation.

The primary role of immune checkpoints is to prevent autoimmune attacks against normal tissue in the body;

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Ipilimumab and tremelimumab currently are the only anti-CTLA-4 monoclonal antibodies approved by the FDA.

Ipilimumab is approved as a single agent for the treatment of melanoma, and in combination with an anti-PD-1 antibody for the treatment of multiple solid tumors, including melanoma, RCC, colorectal cancer and NSCLC, and tremelimumab is approved in combination with an anti-PD-L-1 antibody for the treatment of unresectable hepatocellular carcinoma and NSCLC.

Patients treated with these checkpoint inhibitors face a risk of a number of adverse events associated with inappropriate activation of the immune system beyond the tumor site including severe and sometimes fatal enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy.

Consequently, usage and dosage of ipilimumab is highly limited due to its safety profile.

We are developing evalstotug as a potential therapeutic for multiple solid tumor indications.

We have initiated a Phase 1/2 dose-escalation trial of evalstotug as monotherapy and in combination with an anti-PD-1 antibody.

We have also initiated our Phase 2 study of evalstotug for treatment-refractory melanoma and carcinomas, and treatment-naïve melanoma and NSCLC, at a dose of 350mg and more recently 700mg.

We are currently evaluating the 1000mg dose level in our Phase 1 study and potentially will in Phase 2 once Phase 1 is cleared.

Patients receiving evalstotug at 700mg and 1000mg will be treated with prophylactic tocilizumab to help reduce risks associated with the release of cytokines into the blood from immune cells that have been activated by the treatment.

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 several solid tumors, including melanoma, renal cell carcinoma, 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 the risk 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, usage and dosage of these checkpoint inhibitors is highly limited due to their safety profile.

We are developing evalstotug as a potential therapeutic for solid tumor indications.

We have completed a dose-escalation trial of evalstotug as monotherapy and in combination with an anti-PD-1 antibody.

We have reached the planned maximum dose of 1000 mg with maximum tolerated dose (“MTD”) not being reached.

A Phase 2 study was initiated at a dose of either 350mg or 700mg in combination with the PD-1 inhibitor, pembrolizumab, for dose optimization.

Evalstotug has shown promising efficacy in several indications.

Most related adverse events in the Phase 1 and 2 were low grade with acceptable tolerability.

BA3182 (CAB-EpCAM x CAB-CD3):

Our first bispecific candidate, BA3182, is being investigated in a Phase 1 study in advanced adenocarcinoma.

We have leveraged our CAB technology to develop bispecific antibodies, which bind both a tumor-specific antigen and a T cell receptor using CAB antigen-binding domains.

Our bispecific candidate, BA3182, is currently being investigated in a Phase 1 dose escalation study in advanced adenocarcinoma.

We have leveraged our CAB technology to develop bispecific antibodies, which bind both a tumor-specific antigen and a T cell receptor using dual 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.

A common design feature for a bispecific antibody is to include a T cell engager component ( i.e.

A common design feature for a bispecific antibody is to include a T cell engager component ( e.g.

, CD3 receptor), such that one antigen-binding domain recognizes a surface-expressed tumor antigen and the other antigen-binding domain binds to and activates CD3+ T cells.

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The first FDA-approved bispecific antibody was a T cell engager, blinatumomab, which contained antigen-binding domains for CD19, an antigen found on B-cell leukemias, and CD3, a T cell activating receptor.

There are multiple structural variants of antibodies and other antigen-binding domains being used by others to construct bispecific product candidates, some of which are being tested clinically.

However, similar to CAR-T cells and blinatumomab, many of these bispecific product candidates have increased risks of generating life-threatening cytokine release syndrome and other potential adverse events due to systemic immune activation and the wide expression of EpCAM, or epithelial cell adhesion molecule.

We have applied our CAB antibody technology to develop bispecific CAB antibodies in which one or both antigen-binding domains are active only in the tumor microenvironment.

There are many structural variants of antibodies and other antigen-binding domains being used by others to construct bispecific product candidates, some of which are being tested clinically.

We have applied our CAB antibody technology to develop bispecific CAB antibodies in which both antigen-binding domains are active only in the tumor microenvironment.

An example of this approach is our BA3182 bispecific.

EpCAM is a protein that is over-expressed in many cancers including carcinomas derived from colon, intestine, breast, lung and prostate.

Epithelial cell adhesion molecule (“EpCAM”) is a protein that is over-expressed in many cancers including carcinomas derived from colon, intestine, breast, lung and prostate.

Expression of EpCAM has been extensively associated with cell growth and proliferation of both healthy and cancer cells.

EpCAM was one of the first cancer-associated antigens discovered, however in the forty years since, its clinical impact as a target for therapeutic antibodies in cancer has been limited.

EpCAM was one of the first cancer-associated antigens discovered;

however, in the forty years since, its clinical impact as a target for therapeutic antibodies in cancer has been limited.

One of the problems with targeting EpCAM is its broad expression in the basolateral membranes of normal epithelial cells.

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Bispecific constructs targeting EpCAM have also not lived up to expectations.

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 at these required low doses, there was only one unconfirmed partial response observed among 65 patients.

We are also completing Investigational New Drug (IND) enabling studies for our next-generation CAB ADC, Nectin-4 with an expected IND in 2024.

Additional in-process CAB candidates including B7 H3 x CD3 bispecific, EGFR x CD3 bispecific, Nectin4 x CD3 bispecific, and

B7-H4 as a next-generation CAB ADC candidate have been positioned for partnering and portfolio prioritization in favor of our Phase 2 potential registrational trial enabling studies.

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 our lead product candidates through regulatory approval and commercialization.

o Mecbotamab vedotin (BA3011):

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 have obtained FDA clearance to initiate a potentially registration-enabling Phase 2/3 trial in NSCLC in 2 nd Line + or 3 rd Line + population.

o Ozuriftamab vedotin (BA3021):

We have observed antitumor activity in PD-1 failure NSCLC, melanoma and SCCHN patients in our Phase 1 trial and have initiated Phase 2 trials of ozuriftamab vedotin in the melanoma and SCCHN indications.

o Evalstotug (BA3071):

Evalstotug is designed to provide the efficacy similar to that of ipilimumab, an anti-CTLA-4 monoclonal antibody approved by the FDA, but with the potential of a significantly enhanced safety profile due to the conditional binding properties of CABs.

This may allow for patients to be treated at higher dosage and/or for more cycles of treatment in combination with an anti-PD-1 antibody that may lead to better therapeutic results.

To date, we have observed objective responses and disease control among patients treated in our Phase 1 study at 350mg in combination with anti-PD-1 antibody, and have seen limited adverse events of Grade 3 or higher, suggesting an improved safety profile for evalstotug.

o BA3182 (CAB-EpCAM x CAB-CD3) :

Our first bispecific candidate with an IND, cleared by FDA, demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.

We have initiated a Phase 1 study in advanced adenocarcinoma.

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

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).

• Enhance pre-clinical assets with multiple CAB bispecific and next generation CAB ADC candidates to further address areas of high unmet needs in treating solid tumors.

For example, BA3182 demonstrated in its IND-enabling studies a more than 100-fold improvement in the therapeutic window.

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

Combining our CAB technology with our next generation CAB-ADC platform replaces the traditional peptide linker with a novel sugar-based linker to deliver the MMAE payload.

It is expected that this new CAB ADC system will further reduce off-target, off-tumor toxicity and thereby expand the therapeutic window.

• Maintain and strengthen our intellectual property portfolio.

As of February 1, 2024, we had a total of 752 patents and patent applications with 479 issued patents, 13 allowed applications and 260 pending applications covering our CAB technology and product candidates.

This broad patent coverage was designed such that protection of our product candidates is not dependent on any single patent but rather, each product candidate provides multiple layers of protection.

We plan to continue to maintain, monitor, enforce and defend our intellectual property.

• Enter into collaborations to maximize the value of our platform and pipeline.

We may also explore collaboration arrangements to commercialize any product candidates where we believe the resources and expertise of the third party could be beneficial.

These collaborations could advance and accelerate our programs to maximize their market potential and expand the worldwide commercial potential of our CAB technology and assets.

Our technology

Challenges in developing antibody-based therapies for solid tumors

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.

Oncology targets of safe, effective antibodies fall into two broad categories:

• Antibodies targeting antigens, usually proteins, preferentially expressed on the surface of cancer cells, against which antibodies are used to directly bind and inhibit or destroy these cells;

• Antibodies targeting antigens affecting directly or indirectly tumor cells and non-tumor cells that activate the immune system or induce other changes in the tumor, such as limiting the growth of tumor-related blood vessels.

There are significant limitations of targeting important antigens with traditional antibodies that can result in reduced efficacy, difficulties related to dosing, decreased durability, and drug-related toxicities, all of which significantly limit the potential for cures with traditional antibodies:

• Increased toxicity :

Antigens are typically expressed in many normal tissues, which for traditional antibodies, including ADCs, could lead to significant on-target, off-tumor toxicity reducing dosing and durability.

• Target-mediated drug disposition limitation :

Target-mediated drug disposition, or TMDD, is the phenomenon in which a drug binds somewhat indiscriminately to its pharmacological target on normal tissue as well as on the intended diseased tissue, thereby causing the antibody to be depleted more rapidly from circulation.

As a consequence, the pharmacokinetic characteristics of the drug can be adversely impacted, leading to reduced half-life, lower tumor exposure, which requires more frequent or higher dosing that increases toxicity and ultimately can result in undesirable side-effects, patient treatment-related inconveniences and greater costs.

• Immunogenicity :

Antibodies also can be sensitive to modifications that can lead to immunogenicity, or a strong negative immune system response from the body, which can induce anti-drug antibodies that can reduce efficacy or lead to severe infusion reactions, thereby restricting the potential improvements that could be made with emerging technologies.

Solitomab, a third-party, non-CAB EpCAM x CD3 bispecific tested in the clinical by Amgen, 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 at tolerated doses only one unconfirmed partial response was observed among 65 patients.

In our Phase 1 dose escalation study, we have observed several patients with tumor reduction, including one colorectal patient with stable disease for more than one year and we continue to dose escalate.

Preclinical candidates

BA3361 (CAB-Nectin-4-ADC)

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

The CAB selectivity to target Nectin-4 in the tumor microenvironment is critical in providing the necessary safety to deliver the drug conjugate selectively to cancerous tissue.

A clinical candidate was selected from a set of lead molecules that were characterized by multiple assays including functional assays.

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

We have received FDA clearance of our IND for BA3361.

Bispecific preclinical candidates

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 believe our CAB bispecific antibodies may allow for increased efficacy through more potent T cell activation, higher doses or administration in combination with other immuno-oncology therapies, such as checkpoint inhibitors.

We have shown in preclinical experiments that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially fatal immune responses.

BA3142 (CAB-B7-H3 x CAB-CD3)

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

The lead molecule was characterized by multiple assays including functional assays, and by preclinical efficacy studies in a xenograft model of human pharyngeal cancer using mice with a humanized immune system.

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.

Cell line development and in vivo efficacy study are completed.

We have manufactured sufficient supply of BA3142 to enable the Company to complete an IND and initiate a Phase 1 clinical trial in the near term with additional funding or through a partnership.

CAB-Nectin 4 x CAB-CD3 (formerly BA3362)

We out-licensed a pre-clinical Nectin 4 T-cell engager to Context Therapeutics in 2024.

See further discussion in the Licensing and Strategic Collaboration section below.

These assets are in varying stages of development and have been positioned for partnering.

Our CAB technology

The fundamental specificity challenge with traditional monoclonal antibody-based therapy is that there are few known antigens that are specific to tumors and absent in non-cancerous tissues.

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We believe that our novel approach to increase the selectivity of antibody-based therapeutics while maintaining their potency may have the potential to fundamentally transform the development of anticancer therapeutics and expand the universe of targets for novel antibody-based therapies.

CAB leverages the low pH found in the tumor microenvironment

The tumor microenvironment has been widely implicated in tumorigenesis because it harbors cancer cells that interact with surrounding cytokines and cells through the circulatory and lymphatic systems to influence the development and progression of cancer.

The tumor microenvironment has conditions distinct from the normal cellular and extracellular environments found in non-cancerous tissue, blood or other parts of a normal body.

It has been long appreciated that the extracellular milieu inside and surrounding the growing tumor mass is distinct and unique.

One of the most profound physicochemical differences between the tumor microenvironment and normal cellular microenvironment is an increase in lactic acid and an associated decrease in pH in the tumor microenvironment from the normal physiological pH of about 7.4 or higher.

While the tumor is acidic, some of the most acidic regions of tumors can be observed at the edge of the tumors, just at the interface with the surrounding tissue or blood, according to a paper published in 2019 in the journal Cancer Research.

In this study, pH low insertion peptide, or pHLIP, a peptide that is taken up by cells at a pH below 6.5, was injected into human tumor-bearing mice.

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.

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.

Normal cells generate the energy they need primarily through the oxygen-dependent process called oxidative phosphorylation.

In comparison, cancer cells have switched their mechanism of energy production preferentially to the non-oxygen-dependent process known as glycolysis, even in the presence and availability of oxygen.

This process switch, known as the Warburg Effect, was first described nearly a century ago and is the basis of modern tumor screening technologies, such as Positron Emission Tomography or PET scanning.

The dependence of a tumor cell on glycolysis results in the tumor cell metabolizing up to 200 times more glucose than a healthy cell and causing the secretion of significant levels of lactic acid into the tumor microenvironment.

This inherent buildup of lactic acid in the tumor microenvironment has been shown to reduce immune cell function and modulate other defense mechanisms of the body, promoting tumor growth and tumor survival.

The presence of lactic acid in the tumor microenvironment causes it to have a distinctly acidic pH of less than 6.8 and even lower at the tumor cell surface, a pH so low that it is rarely found in the body except in organs designed for low pH, such as the stomach, where antibodies in the blood do not access, and in special circumstances, such as cancer.

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 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 can 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.

In view of our preclinical studies and clinical trial results and the substantial supporting scientific literature, we believe that there is an opportunity to develop cancer therapies with improved selectivity for tumors by taking advantage of changes in pH, as do our existing product candidates, as well as in the conditions and levels of temperature, pressure and chemical composition in the tumor microenvironment.

Our CAB technology

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

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Under acidic conditions found in the tumor microenvironment, these charged molecules are neutralized by the H+ ions and released from the protein surface, uniquely allowing CAB antibodies to bind to their target and attack the tumor cell.

We refer to this novel physiological mechanism, used for generating CABs, as Protein-associated Chemical Switch(es) TM or PaCS TM mechanism.

We refer to this novel physiological mechanism, used for generating CABs, as Protein-associated Chemical Switch(es) TM or PaCS mechanism.

The ability to design conditionally active therapeutics with strong selectivity over narrower pH ranges using the PaCS mechanism, offers the opportunity to greatly enhance both the safety and potency of future therapies for solid tumors.

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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.

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.

The binding of the CAB antibody was highly sensitive to pH with binding becoming much weaker as pH approached 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.

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:

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

• Wide therapeutic window.

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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 (“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.

There are few highly prevalent tumor-specific antigens expressed on solid tumors that are not expressed at some level in normal tissues, particularly for solid tumors, which represent approximately 90% of tumor types.

There are few highly prevalent tumor-specific antigens expressed on solid tumors, which represent approximately 90% of tumor types, that are not expressed at some level in normal tissues.

While some targets, such as EGFR, can be targeted by traditional antibodies with some acceptable level of toxicity in a subset of patients, many other potential targets cannot.

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.

We have developed CAB antibodies through the use of our proprietary technology, which we believe have specificity for tumors, while avoiding binding to the same antigen target expressed on many normal tissues.

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 tumor cells but are also present on normal cells and tissues, without the toxicities associated with traditional antibodies.

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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.

Programs in clinical development

Mecbotamab Vedotin (BA3011) targeting AXL

Phase 1 clinical trial

We have conducted a Phase 1 trial of mecbotamab vedotin in patients with advanced solid tumors, including sarcoma, pancreatic cancer, adenoid cystic carcinoma (ACC), and NSCLC who were refractory or resistant to standard therapies.

In the Phase 1 trial, patients were treated with doses of mecbotamab vedotin ranging from 0.3 mg/kg to 3 mg/kg once every three weeks (Q3W) or doses ranging from 1.2 mg/kg to 1.8 mg/kg twice every three weeks on days 1 and 8 (2Q3W).

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:

aspartate aminotransferase (“AST”)/ alanine aminotransferase (“ALT”) increased) or metabolic disturbances (AEs:

hyperglycemia, hyponatremia, hypokalemia).

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.

Phase 2 Clinical Development

UPS Phase 2 trial:

We are conducting a Phase 2, single-arm, potentially registration-enabling trial with mecbotamab vedotin monotherapy in patients with UPS who have experienced prior treatment failure.

We believe UPS represents a critical unmet need and we are exploring accelerated approval options for patients otherwise suffering from uncontrolled sarcoma with few effective treatment options.

While it is acknowledged that a randomized confirmatory trial is typically employed to confirm clinical benefit.

Given the marked rarity of UPS patients, it may be possible, subject to future agreement with the FDA, to confirm clinical benefit by enrolling additional UPS patients in a prospective clinical trial with the purpose of providing regulators with extended follow-up that adequately characterizes disease control and overall tolerability.

A variety of trial options are under consideration to meet anticipated requirements associated with confirmation of clinical benefit.

The open-label, two-part Phase 2 trial evaluates the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in adult and adolescent patients, and advanced, refractory measurable sarcoma.

Patients received 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, synovial sarcoma, chondrosarcoma, and chordoma.

Part 1 of the trial employing the 1.8 mg/kg dose delivered every other week is now fully enrolled, and a clinical update was presented as an oral presentation at the ESMO Sarcoma and Rare Cancers Congress in March 2024.

As noted above, our ongoing Phase 2, part 2, potentially registrational trial employing the 1.8 mg/kg dose delivered on days 1 and 8 of a three-week cycle (2Q3W) is enrolling patients with locally advanced unresectable or metastatic UPS.

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

Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), best overall response (BOR), disease control rate (DCR), time to response (TTR), progression-free rate (PFR) at 12 weeks, overall survival (OS), and percent change from baseline in tumor size.

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 are receiving open-label mecbotamab vedotin treatment.

A planned interim analysis will be performed after all patients in Phase 2, part 2 have an opportunity to be followed for at least 12 weeks.

Efficacy, safety, and an integrated PK and exposure-response analysis will be performed based on all UPS patients in Phase 1, Phase 2 part 1, and the UPS patients initially enrolled in Phase 2 part 2.

NSCLC Phase 2 trial:

This ongoing multi-center, open-label, Phase 2 study is designed to evaluate the efficacy and safety of mecbotamab vedotin alone and in combination with an anti-PD-1 agent in patients with metastatic NSCLC who have measurable disease by RECIST v1.1 criteria.

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

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

A Phase 1/2 single-arm clinical trial of ozuriftamab vedotin monotherapy in patients with locally advanced unresectable or metastatic solid tumors in melanoma is being conducted.

Patients were treated with doses of ozuriftamab vedotin ranging from 0.3 mg/kg to 3.3 mg/kg once every three weeks (Q3W) or doses ranging from 1.5 mg/kg to 1.8 mg/kg twice every three weeks on days 1 and 8 (2Q3W).

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

In the Phase 1 component of the trial, treatment with ozuriftamab vedotin resulted in multiple responders in patients with treatment-refractory solid tumors, including melanoma, NSCLC, and head and neck cancer.

All of these patients had previously progressed following PD-1 therapy.

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.

We believe that reported toxicities were consistent with off-target effects of free MMAE consistent with those described with other marketed MMAE-based ADCs.

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

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

AST/ALT increased) or metabolic disturbances (AEs:

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 PD-1/L1 inhibitor is ongoing in melanoma who have measurable disease.

Primary endpoints include ORR, 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.

We have also completed enrollment for a Phase 2 clinical trial of ozuriftamab vedotin as monotherapy in SCCHN using 1.8mg/kg with either Q2W or 2Q3 dosing.

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

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

Evalstotug (BA3071) targeting CTLA4

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

We are evaluating the safety and tolerability of evalstotug at doses ranging from 7mg Q3W to 1000mg Q3W as monotherapy and in combination with an anti-PD-1 antibody.

A Phase 2 open-label trial to evaluate the efficacy and safety of evalstotug alone and in combination with an anti-PD-1 agent, and also in combination with chemotherapy for 1 st Line NSCLC, in patients who have treatment-refractory melanoma and carcinoma and who have treatment-naïve metastatic melanoma and NSCLC is underway.

To date, we have observed limited adverse events of Grade 3 or higher in our Phase 1 study at 350mg in combination with PD-1 suggesting an improved safety profile for evalstotug.

Prior to seeking accelerated approval for any proposed 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 Biologics License Application (“BLA”) submission.

BA3182 (CAB-EpCAM x CAB-CD3)

We are conducting a Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and antitumor activity of BA3182, a conditionally active biologic (CAB)-bispecific T-cell engager antibody construct targeting EpCAM in patients with advanced adenocarcinoma.

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

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 (BA3182) bispecific antibody in non-human primates.

Preclinical candidates

BA3361 (CAB-Nectin-4-ADC)

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

The CAB selectivity to target Nectin-4 in the tumor microenvironment is critical in providing the necessary safety to deliver the drug conjugate selectively to cancerous tissue.

A clinical candidate was selected from a set of lead molecules that were characterized by multiple assays including functional assays.

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

We plan to submit an IND for BA3361 in 2024.

BA3151 (CAB-B7-H4-ADC)

B7-H4 is highly expressed on numerous tumor tissues and the expression level directly correlates with adverse clinical and pathological features.

A set of lead molecules were characterized in vitro including functional assays and in vivo efficacy models.

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

BA3142 (CAB-B7-H3 x CAB-CD3)

We believe that our CAB technology opens up the opportunity for the creation of a broad set of bispecific product candidates with antitumor potential.

Through these CAB bispecific antibodies, we believe we can activate T cells directly in tumors using CAB domains targeting tumor-specific antigens.

In February 2023 we received from the FDA clearance of our IND application to evaluate our CAB bispecific antibody product candidate BA3182, which is now part of an ongoing Phase 1/2 clinical study.

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

The lead molecule was characterized by multiple assays including functional assays, and by efficacy studies in a xenograft model of human pharyngeal cancer using mice with a humanized immune system.

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.

Cell line development and in vivo efficacy study are completed.

CAB-EGFR bispecific programs

Targeting EGFR with a CAB bispecific antibody is expected to provide benefit since the target is widely expressed in healthy tissue, such as skin, which would otherwise result in on-target, off-tumor toxicity if targeted by a non-CAB antibody.

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.

Two molecules are in development:

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

BA3362 (CAB-Nectin 4 x CAB-CD3)

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.

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

Currently, there are multiple approved ADCs and many more in clinical development, the vast majority of which are being developed for the treatment of cancer.

Currently, there are several approved ADCs and many more in clinical development, the vast majority of which are being developed for the treatment of cancer.

Certain other companies are also pursuing antibody therapies in immuno-oncology.

Although we do not believe competing companies have selective CAB technology, there is a wide array of activity in multiple areas of immune-based cellular therapies for oncology.

Although we do not believe competing companies have selective CAB technology, there is a wide array of activity in immune-based cellular therapies for oncology.

In addition, if any of our product candidates are approved in oncology indications such as pancreatic, breast and other cancers, they may compete with existing biologics and small molecule therapies, or may be used in combination with existing therapies.

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Manufacturing

Our CAB antibodies are designed and produced using our patented Comprehensive Integrated Antibody Optimization TM , or CIAO!

TM , technology.

Our CAB antibodies are designed and produced using our patented Comprehensive Integrated Antibody Optimization TM (“CIAO!”) 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.

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Furthermore, the raw materials for our product candidates may be sourced, in some cases, from a single-source supplier.

As part of the manufacture and design process for our product

candidates, we rely on internal, scientific and manufacturing know-how and trade secrets and the know-how and trade secrets of third-party manufacturers.

As part of the manufacture and design process for our product candidates, we rely on internal, scientific and manufacturing know-how and trade secrets and the know-how and trade secrets of third-party manufacturers.

We also contract with additional third parties for the filling, labeling, packaging, storage and distribution of investigational drug products.

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We maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to our product candidates.

We have personnel with significant technical, manufacturing, analytical, quality, including current good manufacturing practices, or cGMPs, and project management experience to oversee our third-party manufacturers and to manage manufacturing and quality data and information for regulatory compliance purposes.

We have personnel with significant technical, manufacturing, analytical, quality, including current good manufacturing practices (“cGMPs”), and project management experience to oversee our third-party manufacturers and to manage manufacturing and quality data and information for regulatory compliance purposes.

Collaborations

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In April 2019, we entered into a Global Co-Development and Collaboration Agreement with BeiGene, Ltd.

which, as amended in December 2019 and October 2020, provided for the development, manufacturing and commercialization of BioAtla’s investigational CAB CTLA-4 antibody, evalstotug (BA3071).

which, as amended in December 2019 and October 2020, provided for the development, manufacturing and commercialization of BioAtla’s investigational CAB

CTLA-4 antibody, evalstotug (BA3071).

Under the terms of our BeiGene collaboration, BeiGene was generally responsible for developing evalstotug and for global regulatory filings and commercialization.

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We are eligible to receive up to $77.5 million in upfront payments and potential milestones.

License Agreement with Context Therapeutics Inc.

In September 2024, the Company entered into a License Agreement (the “Context License Agreement”) with Context Therapeutics Inc.

Under the terms of the Context License Agreement, BioAtla granted Context an exclusive, worldwide license to develop, manufacture and commercialize two licensed antibodies, including BA3362 (renamed by Context as CT-202), the Company’s Nectin-4 x CD3 T cell engaging (TCE) bispecific antibody (the “License”).

The Company also transferred know-how, including any necessary materials Context would need to perform research and development.

In exchange for the License, the Company is eligible to receive up to $133.5 million in aggregate payments, including an upfront cash payment and potential development, regulatory and commercial milestones, as well as tiered mid-single digit to low double-digit royalties on future net sales of the products.

In connection with the execution of the Context License Agreement, the Company also entered into an agreement with Himalaya Therapeutics SECZ, a related party (See Note 8).

Intellectual property

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We also apply for patents covering developments and technologies for purpose of preventing third parties from developing competing products.

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

patent applications.

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

As of February 1, 2025, we had 787 patents and patent applications with 523 issued patents, 7 allowed applications, and 257 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.

We recognize that the ability to obtain patent protection and the degree of such protection depends on several 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.

We file all relevant types of patent applications to protect our intellectual property, including patent applications with claims directed to our processes and products, and applications and uses thereof.

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In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application related to the patent.

patent may be accorded a patent term adjustment, or PTA, under certain circumstances to compensate for delays in granting the patent caused by the United States Patent and Trademark Office.

patent may be accorded a patent term adjustment (“PTA”), under certain circumstances to compensate for delays in granting the patent caused by the United States Patent and Trademark Office.

In some instances, such a PTA may result in a U.S.

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These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us are to be kept confidential and not disclosed to third parties except in specific circumstances.

Our agreements with employees and consultants also provide that all inventions

conceived by the employee in the course of employment or work with us or from the employee’s or consultant’s use of our confidential information are our exclusive property.

Our agreements with employees and consultants also provide that all inventions conceived by the employee in the course of employment or work with us or from the employee’s or consultant’s use of our confidential information are our exclusive property.

For a more comprehensive discussion of the risks related to our trade secrets, please see “Risk factors—Risks related to our intellectual property.”

Company-owned patents

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

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

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.

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

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

Applications have been granted in Australia, Europe, Israel, India, Japan, Korea, Mexico, Taiwan and the United States and are pending in 134 jurisdictions, including most major market countries.

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

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

Applications have been granted in Australia, Israel, Korea, New Zealand, and the United States and are pending in 18 jurisdictions, including most major market countries.

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

Applications have been granted in Australia, Canada, Israel, Japan, Korea, New Zealand, Russia and the United States and are pending in 16 jurisdictions, including most major market countries.

Composition of matter claims issuing from this application would not expire before 2039.

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.

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

As of January 1, 2024, CAB-anti-EpCAM antibodies are covered by 13 national phase filings, including in the United States, an additional PCT application and two non-PCT filings in Taiwan.

As of January 1, 2024, CAB-anti-Nectin-4 antibodies are covered by 12 national phase filings and an application in Taiwan.

Composition of matter claims issuing from these applications would not expire before either 2040 or 2044.

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We also have 30 issued U.S.

patents covering various aspects of the manufacturing methods used to generate CAB antibodies that have patent terms expiring from 2030 to 2038, excluding in potential patent term extensions.

patents covering various aspects of the manufacturing methods used to generate CAB antibodies that have patent terms expiring from 2030 to 2038, excluding potential patent term extensions.

Out-licensed patents

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Additionally, Himalaya Therapeutics SEZC has exclusive worldwide rights to patents/patent applications relating to IL-22 (Patent applications 108119613 and PCT/US19/35395, both titled “Anti-IL-22 antibodies, antibody fragments and their immunoconjugates and uses thereof”) and relating to HER2 (patent application USP 62/964,747 titled “Conditionally active anti-HER2 antibodies”).

In September 2024, the Company granted Context Therapeutics an exclusive worldwide license to develop, manufacture, and commercialize two licensed antibodies, including a CAB Nectin-4 x CD3 T-Cell engaging bispecific antibody, and non-exclusive rights to BioAtla's enabling technology to the extent necessary to exploit the licensed antibodies.

See Note 7 to our financial statements for further details.

BioAtla Holdings, LLC has exclusive worldwide rights to all patents for the field of adoptive cell immunotherapy “ACT” (chimeric antigen receptor (CAR) T-cell (“CAR-T”)), excluding the targets licensed to EXUMA Biotech Corp (“EXUMA”).

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Licensure and Regulation of Biologics in the United States

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, 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.

In the United States, the FDA regulates biologic products under the Federal Food, Drug, and Cosmetic Act (the “FDCA”), the Public Health Service Act (“PHSA”), and regulations and guidance implementing these laws.

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 are approved for marketing under provisions of the PHSA, via a BLA.

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The process generally involves the following:

• Completion of extensive preclinical laboratory tests and in vivo studies in accordance with the FDA’s current good laboratory practice, or GLP, regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;

• Completion of extensive preclinical laboratory tests and in vivo studies in accordance with the FDA’s current good laboratory practice (“GLP”) regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;

• Submission to the FDA of an IND, which must become effective before clinical trials may begin;

• Approval by an independent institutional review board, or IRB, reviewing each clinical site before each clinical trial may be initiated;

• Approval by an independent institutional review board (“IRB”), reviewing each clinical site before each clinical trial may be initiated;

• Performance of adequate and well-controlled clinical trials in accordance with the FDA’s IND regulations, good clinical practice (“GCP”) requirements, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed biologic product candidate for its intended use;

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Further, each clinical trial must be reviewed and approved by an IRB at or servicing each institution at which the clinical trial will be conducted.

charged with protecting the welfare and rights of trial participants and considers items such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

An IRB is charged with protecting the welfare and rights of trial participants and considers items such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject, or his or her legal representative, reviews and approves the study protocol, and must monitor the clinical trial until completed.

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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 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 results of the preclinical tests and clinical trials, together with detailed information relating to the product’s pharmacology, chemistry, manufacturing controls (“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.

Under the Prescription Drug User Fee Act, or PDUFA, each BLA must be accompanied by a significant user fee.

Under the Prescription Drug User Fee Act (“PDUFA”), each BLA must be accompanied by a significant user fee.

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

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.

Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

Additionally, no user fees are

assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

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

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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 risk evaluation and mitigation strategy, or 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 strategy (“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.

A REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use, or ETASU.

A REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use (“ETASU”).

ETASU can include, but are not limited to, special training or certification for prescribing or dispensing the product, dispensing the product only under certain circumstances, special monitoring, and the use of patient-specific registries.

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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

requested product recalls or 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.

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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, included provisions related to the accelerated approval pathway.

The Food and Drug Omnibus Reform Act (“FDORA”) included provisions related to the accelerated approval pathway.

Pursuant to FDORA, the FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval.

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In addition, changes to the manufacturing process or facility generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Other post-approval requirements applicable to biologic products include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information and complying with electronic record and signature requirements.

and signature requirements.

A sponsor also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities and promotional activities involving the internet.

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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.

If a product with orphan designation receives the first FDA approval of the drug to treat 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 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.

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Because healthcare professionals are free to prescribe products for off-label uses, the competitor’s product could be used for the orphan indication despite another product’s orphan exclusivity.

The FDA cannot, however, approve the same drug made by another manufacturer for the same indication during the market exclusivity period unless it has the consent of the sponsor or the sponsor is unable to provide sufficient quantities.

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, the new drug product has been demonstrated to be clinically superior, 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.

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In particular, for a diagnostic, the applicant must demonstrate that the diagnostic has adequate sensitivity and specificity, has adequate specimen and reagent stability, and produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.

As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.

As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation (“QSR”), which imposes elaborate testing, control, documentation and other quality assurance requirements.

PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

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Pediatric information

Under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biologic product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product candidate is safe and effective.

Under the Pediatric Research Equity Act (“PREA”), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biologic product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product candidate is safe and effective.

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 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.

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 (“BPCA”) provides a six-month extension of any 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.

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Biosimilars and exclusivity

The Patient Protection and Affordable Care Act, or the ACA, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or BPCIA, which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product.

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

The Patient Protection and Affordable Care Act (the “ACA”), includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product.

The FDA has licensed many 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 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.

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However, complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose some hurdles to biosimilar product implementation which is still being evaluated by the FDA.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.

Under the BPCIA, an application for a biosimilar product referencing an exclusivity-protected biological product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

In addition, the approval of a biosimilar product referencing an exclusivity-protected biological product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing the applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.

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In the United States, a patent claiming a new biologic product, its method of use or its method of manufacture may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent extension of up to five years for patent term lost during product development and FDA regulatory review.

Assuming grant of the patent for which the extension is sought, the restoration period for a patent covering a product is typically one-half the time between the effective date of the IND involving human beings and the submission date of the BLA, plus the time between the submission date of the BLA and the ultimate approval date.

Assuming grant of the patent for which the extension is sought, the restoration period for a patent

covering a product is typically one-half the time between the effective date of the IND involving human beings and the submission date of the BLA, plus the time between the submission date of the BLA and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date in the United States.

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Pursuant to the currently applicable Clinical Trials Directive 2001/20/EC and the Directive 2005/28/EC on GCP, a system for the approval of clinical trials (excluding non-interventional trials) conducted in the European Union has been implemented through national legislation of the member states.

Under this system, the sponsor of a clinical trial must submit a request for authorization to the competent national authority of the European Union member state in which the clinical trial is to be conducted, or in multiple member states if the clinical trial is to be conducted in a number of member states.

Under this system, the sponsor of a clinical trial must submit a request for authorization to the competent national authority each European Union member state in which the clinical trial is to be conducted.

Furthermore, the applicant must obtain a favorable opinion from the competent ethics committee before starting a clinical trial.

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In March 2016, the European Medicines Agency (the “EMA”) launched an initiative to facilitate development of product candidates of major interest from the point of view of public health and in particular from the point of view of therapeutic innovation.

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, (“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.

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More specifically, a kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

Importantly, a dedicated EMA contact (rapporteur) from the Committee for Human Medicinal Products, or CHMP, or Committee for Advanced Therapies in the case of an advanced therapy, are appointed early in the PRIME scheme to provide continuous support and help to build knowledge ahead of a MAA.

Importantly, a dedicated EMA contact (rapporteur) from the Committee for Human Medicinal Products (“CHMP”), or Committee for Advanced Therapies in the case of an advanced therapy, are appointed early in the PRIME scheme to provide continuous support and help to build knowledge ahead of a MAA.

Marketing authorization

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A marketing authorization may be granted only to an applicant established in the European Union.

In order to support the authorization of medicinal products for children, Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the European Union, an applicant must demonstrate compliance with all measures included in an EMA-approved Pediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver or a deferral for one or more of the measures included in the PIP.

In order to support the authorization of medicinal products for children, Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the European Union, an applicant must demonstrate compliance with all measures included in an EMA-approved Pediatric Investigation Plan (“PIP”), covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver or a deferral for one or more of the measures included in the PIP.

The requirement for a PIP also applies to applications for new indications, pharmaceutical forms or routes of administration for medicinal products that are already authorized.

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Patent term extensions in the European Union and other jurisdictions

The European Union also provides for patent term extension through Supplementary Protection Certificates, or SPCs.

The European Union also provides for patent term extension through Supplementary Protection Certificates (“SPCs”).

The rules and requirements for obtaining a SPC are similar to those in the United States.

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For either of these conditions, the applicant must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Union or, if such method exists, the drug for which the orphan designation is requested will be of significant benefit to those affected by that condition.

An orphan drug designation provides a number of benefits, including fee reductions, regulatory and scientific assistance and the possibility to apply for a centralized European Union marketing authorization.

An orphan drug designation provides several benefits, including fee reductions, regulatory and scientific assistance and the possibility to apply for a centralized European Union marketing authorization.

In particular, an orphan drug designation leads to a 10-year period of market exclusivity from the granting of the concerned medicinal product marketing authorization for the particular indication.

During this market exclusivity period, neither the EMA nor the member states can accept an application or grant a marketing authorization for a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar or identical active substance, or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

The market exclusivity period for the authorized therapeutic indication may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation because, for example, the product is sufficiently profitable so as to not to justify market exclusivity.

General Data Protection Regulation (the “GDPR”)

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The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies and obtain compensation for damages resulting from violations of the GDPR.

Compliance with the GDPR will

be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.

Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.

Coverage and reimbursement

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healthcare laws and compliance requirements

In the United States, biotechnology company activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare & Medicaid Services, or CMS, other divisions of the U.S.

Department of Health and Human Services, or HHS (e.g., the Office of Inspector General and the Office for Civil Rights), the U.S.

Department of Justice, or the DOJ, and individual U.S.

Department of Health and Human Services (“HHS”) (e.g., the Office of Inspector General and the Office for Civil Rights), the U.S.

Department of Justice (the

“DOJ”), and individual U.S.

Attorney offices within the DOJ, and state and local governments.

The laws biotechnology companies may have to comply with include the anti-fraud and abuse provisions of the Social Security Act, the federal false claims laws, the privacy and security provisions of the Health Insurance Portability and Accountability Act of 1996, or HIPAA, and similar state laws, each as amended, as applicable.

The laws biotechnology companies may have to comply with include the anti-fraud and abuse provisions of the Social Security Act, the federal false claims laws, the privacy and security provisions of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), and similar state laws, each as amended, as applicable.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, recommending or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs.

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The Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and/or formulary managers on the other.

There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

There are several statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

The exceptions and safe harbors are drawn narrowly, and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor.

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Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.

Practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.

Practices may not in all cases meet all the criteria for protection under a statutory exception or regulatory safe harbor.

In addition, the statutory exceptions and regulatory safe harbors are subject to change.

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HIPAA created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Similar to the conditions of the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of such providers, and to report annually certain ownership and investment interests held by physicians and their immediate family members.

Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of such providers, and to report annually certain ownership and investment interests held by physicians and their immediate family members.

Violation of any of the federal and state healthcare laws described above or any other governmental regulations may result in penalties, including without limitation, significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, imprisonment, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, refusal to enter into government contracts, oversight monitoring, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings.

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HIPAA also regulates standardization of data content, codes and formats used in healthcare transactions and standardization of identifiers for health plans and providers.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their regulations, including the final omnibus rule published on January 25, 2013, also imposes certain obligations on the business associates of covered entities that obtain protected health information in providing services to or on behalf of covered entities.

In addition to federal privacy regulations, there are a number of state laws governing confidentiality and security of health information that are applicable to our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), and their regulations, including the final omnibus rule published on January 25, 2013, also imposes certain obligations on the business associates of covered entities that obtain protected health information in providing services to or on behalf of covered entities.

In addition to federal privacy regulations, there are many state laws governing confidentiality and security of health information that are applicable to our business.

In addition to possible federal administrative, civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.

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Additionally, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, and often are not preempted by HIPAA, thus complicating compliance efforts.

For example, the California Consumer Privacy Act, or CCPA, creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

For example, the California Consumer Privacy Act (“CCPA”), creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

The CCPA went into effect on January 1, 2020 and requires covered companies to provide new disclosures to California consumers, provide such consumers new ways to opt-out of certain sales of personal information, and allow for a new cause of action for data breaches.

On November 3, 2020, California voters approved a new privacy law, the California Privacy Rights Act, or the CPRA, which significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain personal information and creating a new state agency to oversee implementation and enforcement efforts.

On November 3, 2020, California voters approved a new privacy law, the California Privacy Rights Act (the “CPRA”), which significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain personal information and creating a new state agency to oversee implementation and enforcement efforts.

The CCPA and CPRA provide for unlimited civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data breach litigation.

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government rebate programs and additional downward pressure on pharmaceutical product prices.

Several healthcare reform proposals culminated in the enactment of the Inflation Reduction Act, or IRA, in August 2022, which, among other things, allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

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.

Negotiations for Medicare Part D products take place in 2024 with the negotiated price taking effect in 2026, and negotiations for Medicare Part B products will begin in 2026 with the negotiated price taking effect in 2028.

In August 2023, HHS announced the ten Medicare Part D drugs and biologics that it selected for negotiations.

HHS will announce the negotiated maximum fair prices by September 1, 2024, and this price cap, which cannot exceed a statutory ceiling price, will go into effect on January 1, 2026.

A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation.

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

Several healthcare reform proposals culminated in the enactment of the Inflation Reduction Act of 2022 (the “IRA”) in August 2022, which, among other things, allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

The negotiated price may not exceed a statutory ceiling price.

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.

For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D products in 2023, negotiations took place in 2024, and the negotiated maximum fair price for each product has been announced.

CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027.

For 2028, an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, 20 Part B or Part D drugs will be selected.

A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if it is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation, and in November 2024, CMS finalized regulations for the Medicare Part B and Part D inflation rebates.

The IRA also extends enhanced subsidies for individuals

purchasing health insurance coverage in ACA marketplaces through plan year 2025.

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

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These provisions have been and may continue to be subject to legal challenges.

For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in multiple lawsuits brought by pharmaceutical manufacturers.

For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in several lawsuits brought by pharmaceutical manufacturers.

Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the biopharmaceutical industry and the pricing of prescription drug products.

Additional state and federal healthcare reform measures could be adopted in the future.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, and marketing cost disclosure and transparency measures, and in some cases, designed to encourage importation from other countries and bulk purchasing.

Human Capital Management

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In addition to our benefits, we offer wellness and stress management support which includes an on-site gym, company-wide wellness activities, wellness resources that are shared with employees each month, an Employee Assistance Program with counseling, and flexible work arrangements.

Diversity and Inclusion .

Inclusion and Belonging .

We believe that an equitable and inclusive environment with diverse teams produces more creative solutions, results in better, more innovative products and services and is crucial to our efforts to attract and retain key talent.

Our current efforts are focused on four primary areas:

• Employee well-being.

We believe everyone plays a crucial role in fostering a safe and healthy workplace.

With employees in diverse roles and functions, we empower them to contribute to a safe working environment, whether they are in a lab or office.

Our policies and practices are designed to not only protect our employees but also to safeguard the surrounding communities where we work.

• Safe work environment.

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• Learning and development opportunities.

To support our employees in reaching their full potential, we offer a wide range of internal and external learning and development opportunities.

To support our employees in reaching their full potential, we offer a wide range of internal and external learning and development opportunities to support a culture of learning.

• Community Involvement.

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We work with local universities to introduce and promote careers in science and biotechnology through internship opportunities.

Employee Communication and Engagement.

We believe that our employees perform at their best when they understand how their contributions align with our overall strategy.

To foster this connection, we prioritize open and transparent communication through several channels, including all hands meetings, company-wide updates and posts on our intranet.

To maintain employee morale, we assess engagement through our managers who gather valuable feedback on career development, work environment and supervisor performance.

Additionally, we track employee turnover rates to gauge satisfaction.

The insights from this feedback are used to shape initiatives that aim to boost employee engagement and enhance the overall employee experience.

Corporate Information

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This Annual Report on Form 10-K contains references to our trademarks and to trademarks belonging to other entities.

Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these

trademarks and trade names.

We do not intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

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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