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Item 1. Business

2025-03-28 compared with 2024-04-01 · 519 added, 450 removed, 560 unchanged (63% of the section changed)

HCW Biologics Inc.

is a clinical-stage biopharmaceutical company focused on discovering and developing novel immunotherapies to lengthen health span by disrupting the link between chronic, low-grade inflammation and age-related diseases.

We believe age-related, chronic, low-grade inflammation, or “inflammaging,” is a significant contributing factor to several diseases and conditions, such as cancer, cardiovascular disease, diabetes, neurodegenerative diseases, and autoimmune diseases.

The induction and retention of low-grade inflammation in an aging human body is mainly the result of the accumulation of non-proliferative but metabolically active senescent cells, which can also be caused by persistent activation of protein complexes, known as inflammasomes, in innate immune cells.

These two elements share common mechanisms in promoting secretion of proinflammatory proteins and in many cases interact to drive senescence, and thus, inflammaging.

Our novel approach is to reduce senescent cells and eliminate the proinflammatory factors they secrete systemically through multiple pathways.

We believe our approach has the potential to fundamentally change the treatment of age-related diseases.

(“HCWB” or the “Company”) is a clinical-stage biopharmaceutical company developing proprietary immunotherapies to treat diseases promoted by chronic inflammation, especially age-related and senescence-associated diseases.

Our immunotherapeutics represent a new class of drug that we believe has the potential to fundamentally change the treatment of cancer and many other diseases and conditions that are promoted by chronic inflammation — and in doing so, improve patients’ quality of life and possibly extend longevity.

While chronic inflammation is possible at any age, it is more common as we age.

In this case, the condition is known as inflammaging.

Chronic inflammation, including inflammaging, is believed to be a significant contributing factor to the cause for senescence-associated diseases and conditions that diminish health span, including many types of cancer, autoimmune diseases, and neurodegenerative diseases, as well as indications that impact quality-of-life that are not life-threatening.

Senescence is a physiologic process important in promoting wound healing, tissue homeostasis, regeneration, embryogenesis, fibrosis regulation, and tumorigenesis suppression.

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Over time, these insults cause normal tissue cells to enter a senescent state of irreversible growth arrest accompanied by the release of SASP factors.

The inflammation cycle promoted by SASP factors also activates inflammasomes.

As the first line of defense to infections or tissue injuries, the innate immune system activates inflammasomes to initiate protective immune responses.

Similar to senescent cells, prolonged activation of inflammasomes promote the release of highly proinflammatory cytokines.

Unresolved activation of inflammasomes due to chronic infection or persistent tissue injury leads to chronic low-grade inflammation, which perpetuates this cycle.

We have combined our deep understanding of disease-related immunology with our expertise in advanced protein engineering to develop our TOBI TM discovery platform, or Tissue factOr-Based fusIon discovery platform, for the design of category-defining immunotherapeutic drugs.

Our focus is to develop protein-based immunotherapies that are administered by subcutaneous injection.

We have selected two molecules as our lead product candidates:

HCW9218 and HCW9302.

HCW9218 is a bifunctional immunotherapeutic designed with the capabilities to neutralize transforming growth factor-β and stimulate immune cells, targeting senescent cells and the SASP factors they secrete.

HCW9302 is designed to activate and expand regulatory T cells, which deactivate inflammasomes.

We have chosen these product candidates because we believe they have the potential to become transformative immunotherapeutics for the treatment of a broad range of age-related diseases, and both can be administered to patients by subcutaneous injection.

The inflammation cycle promoted by SASP factors also activates immune cells.

Similar to senescent cells, prolonged activation of immune cells promote the release of highly proinflammatory cytokines.

Unresolved activation of immune cells leads to chronic low-grade inflammation, which perpetuates this cycle.

Studies have shown that strategies to reduce or eliminate senescent cells can delay, prevent, and improve age-related dysfunctions, including cancer.

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We believe our lead product candidates represent a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic drugs for the treatment of age-related diseases.

Novel Bifunctional Immunotherapeutic with TGF-β Trap

HCW9218 is a proprietary molecule designed to treat the impact of accumulated senescent cells and the SASP factors which they secrete by eliminating senescent cells ( i.e.

, senescent cell reducing effect) and reducing SASP factors ( i.e.

, senomorphic effect).

This proprietary molecule is a heterodimeric, bifunctional fusion protein complex comprised of extracellular domains of the human transforming growth factor-β (“TGF-β”) receptor II, as a TGF-β trap for TGF-β neutralization, and a human interleukin (“IL”)-15/IL-15 receptor α complex for immune cell stimulation.

Together, the activities of these domains drive senescent cell clearance and SASP factor neutralization.

The Company believes it has demonstrated the potential to increase the efficacy of chemotherapy when HCW9218 is used in combination with chemotherapy in the treatment of cancer.

Chemotherapy is the current standard-of-care treatment for most forms of cancer.

However, these treatments often result in toxicity and unwanted side effects.

This drives senescence and the secretion of proinflammatory SASP factors, a process resulting in therapy-induced senescence (“TIS”).

One of the most aggressive, immunosuppressive SASP factors is TGF-β, well known for its role in cancer progression.

Our data has shown that HCW9218 treatment reduces immunosuppressive activities in the tumor microenvironment (“TME”), and enhances immune cell infiltration and cytotoxicity in tumors to eliminate TIS cancer cells, which can improve the efficacy of chemotherapy treatments.

The Company believes it has also demonstrated the potential to boost the performance of immune checkpoint inhibitors in extensive animal testing in different “cold” tumor models when used in combination with HCW9218.

While immune checkpoint inhibitors are considered a breakthrough therapy that has revolutionized the way cancer is treated, the response rates among patients remains stubbornly low in many of the most common cancer indications.

The Company published a paper in October 2021 authored by our scientific research team in the peer-reviewed journal, Molecular Therapy , entitled “Bifunctional TGF-β trap/IL-15 Protein Complex Elicits Potent NK Cell and CD8 + T Cell Immunity Against Solid Tumors,” which supports these findings.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

We believe HCW9218 has unique features that allow it to boost the performance of immune checkpoint inhibitors:

• HCW9218 infiltrates into the secondary lymphoid tissues and solid tumors.

• HCW9218 activates, expands and induces tumor trafficking of progenitor exhausted stem-like and transitory CD8 + T cells.

• HCW9218 induces Natural Killer (“NK”) cell and CD8 + T cell activation, proliferation, and infiltration into the tumor microenvironment which correlates with disease stabilization.

• HCW9218 significantly reduced blood levels of TGF-β in cancer patients in a dose-dependent manner, without causing treatment-emergent skin lesions and bleeding events previously reported with TGF-β antagonists in clinic.

For the longer-term, we believe HCW9218 may have much broader therapeutic potential beyond cancer to other age-related diseases and conditions because of its ability to promote cell-mediated mechanisms to reduce senescent cells and alleviate the proinflammatory factors they secrete.

Scientists from the Company hypothesized that HCW9218 is an immunotherapeutic agent that rejuvenates a dysfunctional immune system and neutralizes TGF-β, and can act as an effective senescent-cell reducing and senomorphic drug.

Novel Immunotherapeutic for T reg Expansion

HCW9302 is a preclinical fusion protein molecule that contains two IL-2 domains linked by an extracellular tissue factor domain.

Recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use.

HCW9302 is designed to overcome the most restrictive issues of IL-2’s dose-limiting toxicities.

Preclinical studies demonstrated that HCW9302 exhibited a longer serum half-life and was well tolerated, offering support for the potential of HCW9302 to treat a wide variety of autoimmune and pro-inflammatory, age-related diseases.

The Company has developed two different drug discovery and development platforms, our legacy TOBI (Tissue factOr-Based fusIon) platform and our newly developed targeted platform technology – the T-cell Receptor β Chain constant region (“TRBC”) platform:

• The TOBI platform is designed to engineer multi-functional fusion protein molecules and protein complexes.

It employs a Tissue Factor (“TF”) scaffold that can be packaged with multiple protein targets, including cytokines, chemokines, ligands, receptors, and single-chain antibodies.

• The Company invented its second-generation platform, the TRBC platform, to create novel immunotherapeutics designed to treat diseases, including cancer, as well as improve quality-of-life conditions.

The immunotherapeutics created using the TRBC platform include multi-specific cytokines, targeted second-generation immune checkpoint inhibitors, and immune-cell engagers, which have the capabilities to activate subsets of immune cells that specifically target cancerous or infected cells.

As of July 13, 2024, the Company, Dr.

Wong, Altor BioScience, LLC, NantCell, Inc.

and ImmunityBio, Inc.

(collectively, Altor BioScience, LLC, NantCell, Inc.

and ImmunityBio Inc.

will be referred to herein as “ImmunityBio”), entered into a Settlement Agreement that is described in Part I, Item 3.

– “Legal Proceedings” below.

The Settlement Agreement eliminated the uncertainty of the outcome of the previously disclosed Arbitration proceedings and provided clarity for the future direction and emphasis of our clinical development strategy.

The settlement involved intellectual property the Company developed based on our proprietary TOBI TM drug discovery platform and its unique Tissue-Factor scaffold used to create protein-fusion molecules.

Our clinical development program is based on a few select lead product candidates which will be evaluated in Company-sponsored clinical trials in autoimmune disorders, solid tumors and quality-of-life conditions.

We have a large portfolio of non-core programs and assets and, for these, we anticipate that clinical development will be conducted through licensing agreements and other business development transactions.

HCWB has an experienced team led by Dr.

Wong, our Founder and CEO, who discovered and developed the immunotherapeutic Anktiva® (also known as ALT-803, an IL-15 agonist receptor) through pivotal trials.

This blockbuster immunotherapeutic treatment for cancer was sold to ImmunityBio, Inc.

in 2017 in a $1.0 billion acquisition.

Anktiva® was approved by the U.S.

Food and Drug Administration (“FDA”) for a bladder cancer indication in 2024.

Clinical-Stage Compounds

Novel Immunotherapeutics for T reg Expansion

HCW9302 is an injectable, first-in-kind interleukin 2 (“IL-2”) fusion protein complex constructed using the Company’s proprietary TOBI platform technology.

Its mechanism of action involves binding to IL-2αβγ receptors predominantly expressed on regulatory T (“T reg ”) cells, thereby activating and expanding T reg cells that can suppress unwanted immune and inflammatory responses.

The FDA recently cleared us to initiate a Phase 1 clinical study using HCW9302 to treat alopecia areata.

Our strategy is to expand to other indications upon successful completion of the Phase 1 study.

HCW9302 is a fusion protein molecule that contains two IL-2 domains linked by an extracellular tissue factor domain.

IL-2 signaling is essential for homeostasis of T reg cells.

Since recombinant IL-2 has an unfavorable pharmacokinetic profile and induces cytokine release syndrome limiting its therapeutic use, our challenge was to create an immunotherapeutic with the therapeutic advantages of IL-2 but that was well tolerated.

HCW9302 addresses this challenge.

We found that HCW9302 exhibited a longer serum half-life with an approximately 1,000-fold higher affinity for the IL2Rα than IL-2.

Unfortunately, recombinant IL-2 has an unfavorable pharmacokinetic profile and induces cytokine release syndrome limiting its therapeutic use.

HCW9302 provides a potential solution to this problem.

It is designed to have the therapeutic advantages of IL-2 while being well tolerated.

In our preclinical and non-human primate studies, we found that HCW9302 exhibited a longer serum half-life with an approximately 1,000-fold higher affinity for the IL2Rα than IL-2.

In addition, preclinical studies have shown HCW9302 can be administered at a dosing range that expanded and activated T reg cells but not CD4 + effector T cells.

We believe that these studies support the clinical development of HCW9302 as a potential therapeutic agent for treatment of autoimmune and proinflammatory diseases.

Other Compounds under Development

Using our TOBI platform, we created over 30 molecules that can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches.

This modular and tunable technology has allowed us to generate a novel pipeline of internally-developed product candidates capable of activating and targeting desired immune responses and blocking unwanted immunosuppressive activities.

We have a library of fusion molecules with cytokines, chemokines, ligands, receptors, and internally-developed single-chain antibodies.

CD4 + effector T cells (also known as helper T cells) are crucial for immune responses, but under certain conditions, their excessive activation can lead to negative effects like inflammation, tissue damage, and autoimmune reactions, particularly when they become dysregulated and target self-antigens, contributing to conditions like multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

We believe our preclinical studies in relevant animal models of dermatological conditions, graft rejection, atherosclerosis, diabetes, and neurodegenerative diseases as well as IND-enabling studies conducted in non-human primates support the clinical development of HCW9302 as a potential therapeutic agent for treatment of autoimmune and proinflammatory diseases.

HCW9201 + HCW9206:

Novel Immunotherapeutic for Memory-Like Natural Killer Cell

On December 24, 2020, the Company entered into an exclusive worldwide license with Wugen, Inc.

(“Wugen”) for ex vivo rights for two of its proprietary molecules.

Wugen is evaluating natural killer (“NK”) cell therapy generated using HCW9206 in combination with HCW9201 in clinical trials in cancer indications.

HCW9206 has a unique design consisting of a multi-functional compound constructed with three powerful cytokines:

IL-7, IL-15, and IL-21.

It is designed to stimulate T cell proliferation and activation, enhance NK cell cytotoxicity, and improve overall immune surveillance against pathogens or tumors.

HCW9201 + HCW9206, known as WU-NK-101, is Wugen’s lead memory NK cell therapy product and is comprised of cells optimized for anti-cancer function.

WU-NK-101 cells possess a unique cytokine-induced memory-like phenotype that supports enhanced anti-tumor activity, robust trafficking, superior proliferation capacity, and metabolic flexibility, all of which contribute to treatment resilience in the adverse tumor microenvironment.

Wugen is currently evaluating WU-NK-101 in a Phase 1 open-label study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of WU-NK-101 in combination with cetuximab in patients with advanced and/or metastatic colorectal cancer (Cohort 1), and in patients with advanced and/or metastatic squamous cell carcinoma of head and neck (Cohort 2).

The overall study will be comprised of two phases, a Dose Escalation Phase, and a Cohort Expansion Phase.

The Company retained the in vivo rights to HCW9201 and HCW9206, as well as the manufacturing rights.

Wugen obtains clinical supply from the Company under the provisions of a development supply agreement.

Clinical-Stage Compound Awaiting Completion of Supply Agreement with ImmunityBio

Novel Bifunctional Immunotherapeutic with TGF-β Trap

HCW9218 is a clinical-stage bifunctional molecule that is designed to impact senescence by reducing senescent cells (i.e., senescent-cell-reducing effect) and eliminating the proinflammatory factors they secrete (i.e., senomorphic effect).

Subcutaneous administration of HCW9218 activates NK cells, innate lymphoid group-1, and CD8 + T cells, and neutralizes TGF-β.

In the Settlement Agreement reached with ImmunityBio on July 13, 2024, the Company agreed to transfer rights to develop HCW9218 for cancer indications to ImmunityBio.

HCW Biologics retained exclusive rights to develop treatments for all other age-related diseases other than cancer using HCW9218.

In future clinical development, we will be able to use the HCW9218 Recommended Phase 2 Dose (“RP2D”) and other learnings based on findings in the Phase 1 and Phase 1b cancer studies, which wrapped up at the beginning of 2024.

These studies include:

• A single-center Investigator-sponsored Phase 1 clinical trial was initiated in May 2022 and patient enrollment, dosing and the safety-evaluation period for this study were completed in February 2024.

In this study, the Masonic Cancer Center, University of Minnesota (“UMN”) evaluated HCW9218 in patients with solid tumor cancers that progressed after at least two lines of standard-of-care treatment.

Geller, M.D., M.S., Professor and Division Director of Gynecologic Oncology in the Department of Obstetrics, Gynecology and Women’s Health at UMN, served as a Principal Investigator of this trial.

At the time that the Phase 1 study was completed in February, over 70% of patients with ovarian cancer (5/7) showed evidence of stable disease.

• A multi-center Company-sponsored Phase 1b/2 clinical trial was initiated in October 2022 and patient enrollment, dosing and the safety-evaluation period for the Phase 1b portion of the study were completed in February 2024.

In this study, 15 patients have received at least one dose of HCW9218 and completed the 28-day safety evaluation period, with no dose-limiting toxicities (“DLTs”).

At the time that the Phase 1b portion of the study was completed in February 2024, 13% (2/15) of patients who participated in the study showed evidence of stable disease.

The Company had the non-exclusive rights to develop HCW9218 treatment for ovarian cancer in a neoadjuvant setting, based on a Phase 2 clinical study sponsored by the University of Pittsburgh Medical Center (“UPMC”).

Under the terms of the Settlement Agreement, UPMC had until year end of 2024 to launch this study, but failed to do so.

Thus, the Company terminated this study.

Under the Settlement Agreement, the Company agreed to transfer the HCW9218 master cell line to ImmunityBio.

In turn, ImmunityBio agreed to enter into a supply agreement with the Company by the end of January 2025 to ensure the Company had adequate clinical supply of HCW9218 available to carry on clinical studies.

As of the reporting date, a draft of the supply agreement has not been provided by ImmunityBio.

Until the supply agreement is in place, any plans for our further development of HCW9218 must be delayed.

Preclinical Compounds

Multi-Functional Immune Cell Stimulator

This product candidate is the subject of the exclusive worldwide license agreement the Company entered with WY Biotech Co., Ltd.

(“WY Biotech”), a China-based company specializing in the early-stage development of recombinant protein drugs and gene/cell therapies, on November 17, 2024 (the “WY Biotech License”).

Under the WY Biotech License, WY Biotech has rights to in vivo applications for HCW11-006.

The Company retains ex vivo rights.

Under the terms of the WY Biotech license agreement, the Company has an “opt-in right” for United States, Canada, Central America, and South America markets for no cost, that may be exercised after the completion of a Phase 1 trial in China.

WY Biotech is responsible for all of the costs for the Phase 1 clinical study.

HCW11-006 was constructed using the TRBC drug development platform.

It combines several different immune functional domains on our new protein scaffold platform as part of our Class I portfolio.

Our preclinical studies demonstrated that this multi-functional product candidate is highly effective at inducing CD8 + T cell and NK cell responses without triggering unwanted side effects in human immune cell and animal models.

HCW11-006 also exhibited anti-tumor efficacy in relevant solid tumor animal models.

We believe it has the potential to be one of the most potent immunostimulatory agents we have developed during our team members’ 30 years of biotech research.

Additional studies are being conducted to verify that HCW11-006 should combine well with other therapies, including immune checkpoint inhibitors, immune cell engagers, therapeutic antibodies, and CAR-T therapies, which the Company is conducting with world leaders in these areas.

The Company and collaborators intend to share their findings in a pivotal scientific paper published in a top-tier peer-reviewed journal.

Other Preclinical Programs

Our future clinical development will focus on our T-cell Receptor β Chain constant region (“TRBC”) drug discovery and development platform.

The Company has constructed over 50 compounds using the TRBC platform, which we group into three different classes, as defined by their construction and potential mechanism of action.

We are in the process of selecting lead compounds for each program, and then to determine from the compounds selected which ones we will develop on our own and those we will develop with a partner through out-licensing arrangements or other business development transactions.

The table below summarizes our preclinical programs by classes:

Preclinical TRBC-Based Molecules Drug Development Programs

Description of Programs

Multi-functional immune cell stimulators

• HCW11-006 is the selected lead product candidate for this class.

• Potent immunostimulatory agent to use in combination with standard-of-care therapy.

• Preclinical studies in human immune cells animal models demonstrate HCW11-006 is highly effective at inducing CD8 + T cell and NK cell responses without triggering unwanted side effects.

• HCW11-006 also exhibits anti-tumor efficacy in relevant solid tumor animal models.

• Prioritized for development through exclusive, worldwide license with WY Biotech.

Second-generation immune checkpoint inhibitors

• We have a group of compounds in this class and are currently assessing them in order to identify the strongest candidate for clinical development.

• Developing a second-generation Keytruda® for oncology & other senescence associated indications.

• Prioritized for in-house development.

Multi-specific targeting fusions and immune cell engagers

• Class III TRBC Molecules are second-generation immune-cell engagers capable of targeting tissue factor and other cell-surface antigens associated with diseased cells.

These drugs work by recruiting and activating T-cells or NK cells, types of white blood cell, to recognize and attack cancer cells.

• Our first compound in this class is HCW11-018, and we are collaborating with others to develop versions with different targeting capabilities.

• The size and scale of the GLP preclinical and clinical studies required for the development of Class III Molecules is more appropriate for well-capitalized Big Pharma.

• Prioritized for development through licensing with Big Pharma.

Clinical Development Strategy

Our goal is to develop transformative immunotherapies to lengthen health span by disrupting the link between cellular senescence, chronic inflammation, and age-related diseases and conditions.

Based on extensive preclinical research and human data from clinical trials, we believe that our data point toward the possibility that we have created a new class of immunotherapeutics for cancer and other age-related diseases, and beyond that to slow down or reverse the effects of aging itself.

Our clinical development strategy is a two-pronged strategy based on our two lead compounds, HCW9218 and HCW9302.

HCW9218 is a clinical-stage drug candidate designed to be both a senescent-cell reducing and senomorphic drug.

Multiple preclinical studies have revealed that increased normal tissue cellular senescence can promote tumor progression, creating a link between aging and cancer, including diminished health span and reduced overall survival in patients.

Thus, cancer indications were selected as the gateway indication for clinical development for HCW9218.

Now that clinical studies have begun, we will use the human data from these studies to inform us on the indications we will target for advancement to Phase 2 clinical trials.

HCW9302 is a preclinical drug candidate designed to address chronic inflammatory responses and associated tissue destruction typical of autoimmune disease.

Thus, we selected an autoimmune disease as the gateway indication for HCW9302.

Based on clinical data from the Phase 1/1b clinical trials, we have determined that we will advance clinical studies to evaluate HCW9218 in combination with standard-of-care treatments in ovarian cancer and pancreatic cancer.

We entered into an agreement with UPMC to conduct an Investigator-sponsored Phase 2 clinical trial to evaluate HCW9218 in patients with metastatic advanced stage ovarian cancer in combination with neoadjuvant chemotherapy.

Study enrollment is expected to begin in the first half of 2024.

We are also in negotiations with the National Cancer Institute (“NCI”) and other NCI-designated Comprehensive Cancer Centers as possible clinical sites for Phase 2 studies in pancreatic cancer, additional studies in ovarian cancer and studies in other difficult-to-treat cancer indications.

Our ability to advance other Phase 2 clinical studies to evaluate HCW9218 depends on ensuring we have sufficient funding to complete the study, securing clinical sites and receiving authorization from the FDA to proceed.

A key component to our clinical development strategy is our focus on the most efficient, cost-effective method of administration of our drugs upon commercialization, which we believe is subcutaneous injection.

The fusion protein compounds we created have demonstrated the ability to activate the immune system in vivo and ex vivo as an injectable or cell-based strategy;

however, we have chosen to focus clinical development on immunotherapeutics administered by subcutaneous injection.

We believe that our chosen method of administration will align with growing concerns about the costs associated with health care treatments.

Our vision is to simplify administration by developing injectable treatments that can be administered in a physician’s office or, in some instances, self-administered at home.

Our relationships with leading research institutions have been a major contributor to our success.

We will continue to foster the relationships with the NCI, the National Institutes of Health, NCI-designated Comprehensive Cancer Centers and other world-class research organizations as collaborators, sponsors and clinical sites.

These institutions bring deep experience and expertise that supports correlative studies and publication of findings that we believe will support our effort to establish our immunotherapeutics as a new class of treatment for cancer and other age-related diseases.

Based on human-data read-out from clinical studies and extensive preclinical research, we believe that our data point toward the possibility we have created a new class of immunotherapeutics for cancer and other age-related diseases, and beyond therapies that to slow down or reverse the effects of aging itself.

We have constructed second-generation immunotherapeutics that we believe could represent a new class of drugs with the potential to fundamentally transform the treatment of diseases and conditions promoted by chronic inflammation, especially those related to aging – enhancing health span through the treatment for indications that enhance quality-of-life and extending longevity by developing treatments for indications for which there are no known cures.

The future of the Company’s clinical development will be primarily based on the molecules we have constructed with the TRBC drug development platform.

These compounds offer the potential to treat oncology, autoimmune diseases, infectious diseases, and chronic inflammatory conditions, offering broader therapeutic targets and more adaptable solutions compared to the Company’s TOBI platform.

The TRBC platform’s flexibility and capacity to bind multiple targets allow for more precise and potentially more effective treatments.

By targeting specific cell-surface antigens, these novel therapeutics can improve patient clinical outcomes, offering potential benefits across a wider range of indications.

The Company will select molecules for in-house development and those which are strong candidates to be developed with a partner through a licensing agreement.

In settling the Arbitration with ImmunityBio, the Company removed uncertainty regarding our rights to TOBI-based molecules.

With this clarity, we forged a new path for our clinical development for molecules created with the TOBI platform.

We will continue to develop HCW9302, our lead product candidate, for which the FDA recently cleared us to initiate a Phase 1 clinical study in alopecia areata.

Our strategy is to expand to other indications upon successful completion of the Phase 1 study.

We are less certain about the path forward for HCW9218, now a Phase 2 compound.

We have exclusive rights to develop HCW9218 for non-oncology indications, but due to uncertainty of clinical supply from the sole source, ImmunityBio, it might not be practical for the Company to pursue clinical development of HCW9218.

The TOBI platform will not be used to develop any new compounds for future clinical development.

Out-Licensing, Cooperative Agreements and Strategic Collaborations

We continue to pursue our strategy of out-licensing certain rights outside of our focus areas, which includes our existing molecules other than our lead product candidates of HCW9218 and HCW9302, and markets such as Greater China, as further discussed under “—Out-License Programs.” We plan to expand our out-licensing discussions to include marketing rights to those regions outside of our focus area.

We believe the potential for cooperative agreements and collaborations is growing for HCW Biologics, since we are now a clinical-stage company with human data, peer-reviewed research publications, CMC manufacturing and issued patents on fundamental intellectual property.

We signed our first out-license agreement at the end of 2020, when we entered into an exclusive worldwide license (the “Wugen License”) with Wugen, Inc.

(“Wugen”), a company that specializes in cell-based therapies for cancer.

We continue to pursue our strategy of out-licensing certain rights outside of our focus areas, as further discussed under “—Out-License Programs.” The Company continues to evaluate its portfolio to identify compounds which may be good candidates for licensing or other collaborations, where it will be to our advantage to leverage the expertise and financial strength of a partner in the development of a compound or market.

We signed our first out-license agreement at the end of 2020, when we entered into an exclusive worldwide license (the “Wugen License”) with Wugen, a company that specializes in cell-based therapies for cancer.

Wugen licensed limited rights to develop, manufacture, and commercialize cell-based therapy treatments for cancer based on two of our internally-developed, multi-cytokine fusion protein molecules, HCW9201 and HCW9206.

Wugen has created an off-the-shelf treatment called WU-NK-101 based on the licensed molecules.

WU-NK-101 is Wugen’s lead memory-like NK cell therapy product and is comprised of cells optimized for anti-cancer function.

A Phase 1 clinical trial of WU-NK-101 for patients with relapsed or refractory (r/r) acute myelogenous leukemia (“AML”) was initiated in August 2023.

The FDA has also granted Orphan Drug Designation to WU-NK-101 for the treatment of AML.

Under a Cooperative Research and Development Agreement (“CRADA”) entered into on December 3, 2022, NCI is collaborating with us to perform a Phase 1b/2 clinical study to evaluate the safety and tolerability of our lead product candidate, HCW9218, in patients with advanced/metastatic and chemo-refractory/chemo-resistant pancreatic cancer.

The CRADA is entitled, “A Phase 1b/2 Study of HCW9218, a Bifunctional TGF-β Antagonist/IL-15 Protein Complex, for Advanced Pancreatic Cancer.”

Additionally, we are exploring potential cooperative agreements with pharmaceutical companies for joint Phase 2 clinical trials to evaluate HCW9218 in cancer indications when used as an adjuvant therapy to a standard-of-care treatment.

This type of arrangement would allow us to evaluate HCW9218 in combination with other cancer treatments with some assistance in offsetting the costs of a Phase 2 randomized trial.

The indications we would target for study in these trials are ovarian and pancreatic cancer, although the targeted indication(s) may change as discussions continue.

While we are encouraged by the interest shown by these pharma companies, there are no assurances that we will enter into cooperative arrangements for Phase 2 clinical trials to evaluate HCW9218 in combination with cancer therapies.

Clinical Development Update

The clinical development progress of the Company's lead immunotherapeutic programs are summarized in the table below:

Wugen has created an off-the-shelf NK-cell treatment called WU-NK-101 based on the licensed molecules.

On November 17, 2024, HCW Biologics entered into an exclusive worldwide license agreement with WY Biotech for the rights to develop and commercialize in vivo applications of one of HCWB’s preclinical product candidates, HCW11-006.

WY Biotech Co., Ltd.

is a China-based company specializing in the early-stage development of recombinant protein drugs and gene/cell therapies.

HCW Biologics has a payment-free, milestone-free, and royalty-free option to recapture the development and commercialization rights of this molecule for in vivo applications in the United States, Canada, Central America, and South America (“Opt-in Territory”) after the conclusion of the Phase 1 clinical trial.

WY Biotech is financially responsible for all costs associated with research and development, manufacturing, clinical development, regulatory approval, and commercialization for the molecule

As reported in the Company’s Form 8-K filed with the SEC on March 19, 2025, on March 18, 2025, the Company and WY Biotech agreed to amend the WY Biotech License Agreement.

The Company has now completed extensive preclinical studies that further support our belief in the potential for HCW11-006 for both an in vivo and ex vivo therapy.

The in vivo therapy is licensed by WY Biotech, however, the Company retained all rights to the ex vivo therapy and applications as a reagent in cell-based therapy treatments, including cell-based therapies, such as CAR-T therapies.

The Company considers WY Biotech License provisions for the Opt-In Right to take over the development of HCW11-006 for the Americas markets to be an important feature of the WY Biotech License.

We believe our right to recapture this market is a potentially high value opportunity.

Further, we will be able to base our decision to opt-in on the human-data read-out from a Phase 1 clinical trial, which will mitigate our development risks and provide valuable clinical information about the potential for the indications we will use for Phase 2 clinical studies.

HCW Biologics Clinical Development Pipeline

The clinical development progress of our lead immunotherapeutic programs is summarized in the table below:

HCW Biologics Pipeline

Investigator-sponsored Phase 1 clinical trial with University of Minnesota to evaluate HCW9218 in patients with chemo-refractory/chemo-resistant solid tumors, including ovarian, prostate, breast and colorectal cancers.

Investigator-sponsored Phase 2 clinical trial with University of Pittsburgh Medical Center with metastatic advanced stage ovarian cancer patients to evaluate HCW9218 in a combination with neoadjuvant chemotherapy.

Company-sponsored Phase 1b/2 clinical trial with five clinical sites, including the National Cancer Institute, to evaluate HCW9218 in patients with advanced chemo-refractory/chemo-resistant pancreatic cancer.

As a result of the Settlement Agreement and Release HCWB entered into with ImmunityBio on July 13, 2024, the Company retains perpetual, exclusive worldwide rights to develop immunotherapeutic treatments based on HCW9218 for aging-related diseases other than cancer.

Our ability to continue development of HCW9218 depends on a supply agreement with ImmunityBio, who controls the master cell bank.

ImmunityBio is obligated under the terms of the Settlement Agreement to enter into a supply agreement with the Company not later than January 2025.

As of the reporting date, we have not received a draft of the supply agreement.

WY Biotech holds the exclusive worldwide license rights to HCW11-006 for in vivo applications.

Wugen holds an exclusive worldwide license for the ex vivo rights for two of our molecules, HCW9201 and HCW9206, with rights limited to the development of cell-based therapy treatments for cancer using the licensed molecules.

Wugen’s lead clinical program, WU-NK-101, is based on molecules licensed from our Company.

Wugen holds an exclusive worldwide license for two of our molecules, HCW9201 and HCW9206.

The Wugen License conveys limited rights to develop cell-based therapy treatments for cancer using the licensed molecules.

We have retained all other rights to HCW9201 and HCW9206, including, but not limited to, manufacturing rights and injectable rights.

Phase 1 Clinical Trial to Evaluate HCW9218 in Solid Tumors

This single-center Investigator-sponsored Phase 1 clinical trial was initiated in May 2022 and patient enrollment, dosing and safety-evaluation period for this study were completed in February 2024.

Geller, M.D., M.S., Professor and Division Director of Gynecologic Oncology in the Department of Obstetrics, Gynecology and Women’s Health at UMN, serves as a Principal Investigator of this trial.

At the time that the Phase 1 study was completed in February, over 70% of patients with ovarian cancer (5/7) showed evidence of stable disease.

A total of 18 patients participated in this study by the end of February 2024, with at least one dose of HCW9218 administered to each participant.

While two dose-limiting toxicities (“DLTs”) were experienced, neither of these events triggered stopping rules and the study established Recommended Phase 2 Dose (“RP2D”).

The most frequent treatment-related adverse events (at least possibly related to the study medication) were injections site reactions (100% of patients), flu-like symptoms (87% of patients) and decreased lymphocyte counts (93% of patients), all of which are consistent with previous clinical experience with IL-15-based therapies.

A clinical data readout at the 2023 Society for Immunotherapy of Cancer conference (“SITC”), was based on 15 patients who were enrolled in this study as of October 16, 2023.

The findings presented at SITC included:

• HCW9218 was administered subcutaneously once every three weeks for up to six cycles at dose levels (“DL”) - 0.25 mg/kg (DL1), 0.5 mg/kg (DL2), 0.8 mg/kg (DL3) or 1.2 mg/kg (DL4).

The median number of cycles was three.

• 87% (13/15) of patients had >4 lines of prior therapy.

Tumor types included:

Ovarian (n=6), Colorectal (n=4), Rectal (n=3), and Liver (n=2).

• 53% (8/15) of patients treated with HCW9218 were evaluated in a post-treatment tumor assessment, including biopsies and scanning.

Tumor types included:

Ovarian (n=3), Colorectal (n=3), Rectal (n= 1) and Liver (n=1).

• 66% (2/3) of patients with ovarian cancer who underwent post-treatment assessments showed stable disease.

(By November 2023, 5 out of 6 patients with ovarian cancer showed stable disease.

By the end of the study in February 2024, 5 out of 7 patients with ovarian cancer showed stable disease.)

• While there were no complete or partial responses, 50% (4/8) of patients evaluated in post-treatment tumor assessments exhibited stable disease following HCW9218 treatment.

Patients showed stable disease lasting over 6 months.

Stable disease was observed from DL2, DL3 and DL4.

• Repeated HCW9218 administration at up to the highest planned dose level was well tolerated by patients with chemotherapy-refractory advanced solid tumors, which has provided support for the RP2D level for future studies of HCW9218.

• Analysis of patients’ pre- and post-treatment blood and tumor biopsy specimens revealed that HCW9218 induced NK cell and CD8 + T cell activation, proliferation, and infiltration into the tumor microenvironment which correlated with disease stabilization.

• HCW9218 significantly reduced blood levels of TGF-β in cancer patients in a dose-dependent manner, without causing treatment-emergent skin lesions or bleeding events previously reported with TGF-β antagonists in clinical studies.

In November 2023, UMN updated their assessment of disease response after treatment with HCW9218.

Data continued to support evaluating HCW9218 in patients with ovarian cancer in Phase 2 clinical trials.

Preliminary Human Data Readout Phase 1 UMN Trial

Ovarian Cancer Patients

Disease Response for Patients with Post-Treatment Assessment

November 2023

Masonic Cancer Center, University of Minnesota.

Phase 2 Clinical Trial to Evaluate HCW9218 in Ovarian Cancer in Combination with a Neoadjuvant Chemotherapy

We entered into an agreement with University of Pittsburgh Medical Center (“UPMC”) to conduct an Investigator-sponsored Phase 2 clinical trial to evaluate HCW9218 in patients with metastatic advanced stage ovarian cancer in combination with neoadjuvant chemotherapy.

Patient enrollment for this study is expected to begin in the first half of 2024.

Designed as a randomized trial, the primary objectives of this study are to evaluate the safety and tolerability of HCW9218 with chemotherapy and the efficacy of the combined regimens in terms of complete pathologic response rate.

In the arm of the study that relates to the evaluation of HCW9218, UPMC estimates approximately 33 patients will participate.

The estimated duration of treatment is an average of 6–8 cycles of treatment (3–4 cycles prior to and after surgery), then maintenance therapy for 12 months, for a total of up to 20 months of treatment with HCW9218.

Phase 1b/2 Clinical Trial to Evaluate HCW9218 in Pancreatic Cancer

This multi-center Company-sponsored Phase 1b/2 clinical trial was initiated in October 2022 and patient enrollment, dosing and safety-evaluation period for the Phase 1b portion of the study were completed in February 2024.

In this study, 15 patients have received at least one dose of HCW9218 and completed the 28-day safety evaluation period, with no DLTs.

At the time that the Phase 1b portion of the study was completed in February 2024, 13% (2/15) of patients who participated in the study showed evidence of stable disease.

We are currently evaluating the safety profile of multidose HCW9218 administration at escalating dose levels.

Five clinical sites participated in the Phase 1b portion of this study, including the NCI Center for Cancer Research, Medical University of South Carolina (an NCI-designated Cancer Center), Washington University in St.

Louis (an NCI-designated Comprehensive Cancer Center), Cleveland Clinic (an NCI-designated Comprehensive Cancer Center) and HonorHealth Research Institute.

In this study, the initial characterization of HCW9218 safety and pharmacokinetic profiles and results of correlative studies of immune responses are consistent with those observed in the Phase 1 study to evaluate HCW9218 in solid tumors.

All existing clinical sites have expressed an interest in participating in the Phase 2 portion of this study.

We expect the Phase 2 portion of this study will initiate in the second half of 2024.

In addition, we plan to continue to operate under our existing CRADA with NCI, pursuant to which NCI and the Company agreed to collaborate to perform the Phase 2 portion of the clinical study to evaluate HCW9218 in patients with advanced/metastatic pancreatic cancer.

In the Phase 2 portion of the pancreatic study, the Principal Investigator at NCI will continue to be Christine Alewine, M.D., Ph.D.

Alewine is a Lasker Clinical Research Scholar at the National Institutes of Health in the Laboratory of Molecular Biology.

Her research focuses on identifying new treatments for pancreatic cancer including pancreatic adenocarcinoma, adenosquamous carcinoma, and acinar cell carcinoma.

Alewine is board certified in internal medicine and medical oncology.

IND Submission for HCW9302

For HCW9302, IND-enabling activities are completed and the Company plans to submit an IND to the FDA for a Phase 1b/2 clinical trial to evaluate HCW9302 in an autoimmune disorder in the first half of 2024.

Our ability to evaluate HCW9302 in a clinical trial depends on completion of our toxicology studies, preparation and submission of an IND, and obtaining clearance to proceed from the FDA.

We have retained all other rights to HCW9201 and HCW9206, including, but not limited to, manufacturing rights and treatment based on subcutaneous injection.

Novel Immunotherapeutic for T reg Expansion

On January 28, 2025, the Company obtained clearance of its IND from the FDA to initiate a first-in-human Phase 1 dose escalation clinical trial to evaluate one of its lead drug candidates, HCW9302, in patients with moderate-to-severe alopecia areata, a common autoimmune disease in humans that currently has no curative FDA approved treatments.

This will be a Phase 1, open-label, multi-center Company-sponsored trial with competitive enrollment.

The study involves dose escalation to determine the toxicity profile of HCW9302 and to designate a dose level for the Phase 2 expansion phase, or the Recommended Phase 2 Dose (“RP2D”).

Up to five dose levels will be evaluated.

A stepped-down dose level will be provided in the event that unacceptable toxicity is encountered at the planned initial dose level.

In the first stage of the study, HCW9302 will be administered subcutaneously in a single dose.

Depending on the results of the single ascending dose stage, a multi-dose study of HCW9302 administered subcutaneously every 28 days for four consecutive treatments will be considered.

With the start of the first-in-human clinical trial for HCW9302 in alopecia areata, we are one step closer to advancing a potentially transformative immunotherapeutic treatment of autoimmune diseases.

This trial is a milestone for our Company, and the beginning of clinical development of treatments for quality-of-life indications.

While not life-threatening, alopecia areata has no cure and diminishes the quality of life for those suffering with this disease.

Existing treatments may provide some relief of symptoms, but there are often dangerous side effects.

If this Phase 1 study is successful, we intend to rapidly expand clinical development of HCW9302 in Phase 2 studies in patients with other autoimmune diseases and serious inflammatory conditions, including other dermatological conditions, graft rejection, and neurodegenerative diseases.

We believe we have an innovative strategy to treat age-related diseases.

Our unique approach is to utilize our internally-developed TOBI platform to create novel multi-functional immunotherapeutics to rejuvenate the immune system.

With our platform technology, we have generated product candidates that are designed to direct the immune system against solid tumors, therapy-induced senescence and the adverse side effects triggered by existing standard-of-care treatments for solid tumors and hematological cancers.

We have also developed product candidates that are designed to direct the immune system against inflammation allowing for the potential to treat a wide variety of autoimmune and proinflammatory diseases.

Our unique approach is to utilize our internally-developed drug discovery platforms to create novel multi-functional immunotherapeutics to rejuvenate the immune system.

With our platform technologies, we have generated product candidates that are designed to direct the immune system against solid tumors, therapy-induced senescence and the adverse side effects triggered by existing standard-of-care treatments for solid tumors and hematological cancers.

We have developed product candidates that are designed to direct the immune system against inflammation allowing for the potential to treat a wide variety of autoimmune and proinflammatory diseases.

Our approach is to develop immunotherapies that reduce or eliminate the main drivers of chronic inflammation by addressing the underlying development and sustainment of these processes, as depicted in the image below:

1 unchanged sentence

While inflammation is part of the normal repair response for healing, when it becomes prolonged and persists, it is damaging and destructive.

Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation.

Several common molecular pathways have been identified that are associated with chronic low-grade inflammation, especially common as we age.

Our view is that there are two primary underlying processes that drive chronic inflammation:

1) Accumulation of senescent cells and SASP factors, and 2) Activation of inflammasomes.

Senescence is a form of irreversible cell growth arrest accompanied by phenotypic changes, resistance to apoptosis, and activation of damage-sensing signaling pathways.

Senescence is considered a stress response that can be induced by a wide range of intrinsic and extrinsic insults, including oxidative and genotoxic stress, DNA damage, telomere attrition, oncogenic activation, mitochondrial dysfunction, or chemotherapeutic agents.

accumulation of senescent cells and persistent activation of immune cells .

Both of these processes generate pro-inflammatory factors that drive senescence.

These two elements share common mechanisms in promoting secretion of pro-inflammatory proteins and in many cases interact to drive senescence, and thus, inflammaging.

Our novel approach is to reduce senescent cells and eliminate the pro-inflammatory factors they secrete systemically through multiple pathways.

We believe our novel immunotherapeutic approach has the potential to fundamentally change the treatment of age-related diseases.

Senescent cells remain metabolically active and can influence tissue hemostasis, disease, and aging through their SASP factors.

1 unchanged sentence

Senescence also plays a role in tumor suppression.

The accumulation of senescent cells, due to the aging of our immune cells, also drives aging and age-related diseases and conditions.

The accumulation of senescent cells, due to the aging of our immune cells, drives aging and age-related diseases and conditions.

The SASP factors can trigger chronic inflammatory responses and consequently augment chronic inflammatory conditions to promote tumor growth.

2 unchanged sentences

Studies have demonstrated that senescent cells play an adverse role in age-related disorders.

An increasing body of evidence has shown that chemotherapy and radiation, standard-of-care anti-cancer regimens, cause the accumulation of senescent cells both in tumor and normal tissue.

Paradoxically, cellular senescence protects non-dividing cancer cells by limiting the effect of chemotherapeutic drugs and radiation and contributes to chemoresistance, radiation resistance, disease relapse, and systemic side effects.

Cancer chemotherapy efficacy is based on the assumption that treatment-induced apoptosis or necrosis of tumor cells results in prolonged patient survival.

However, in addition to cytotoxic activity, chemotherapy also can cause tumor cells to enter a TIS state with SASP characteristics.

The persistence of viable and metabolically active senescent tumor cells after chemotherapy has been attributed to worse overall survival in patients.

Chemotherapy exposes a stressor to rapidly proliferating cancer cells, which drives them into senescence, triggers paracrine effects of inflammatory factors, or SASP factors, secreted by these senescent cells, and promotes epigenetic changes that induce these cells to more aggressive cancer stemness.

Systemic chemotherapy has also been found to elevate normal tissue senescence.

Multiple studies have revealed that increased normal tissue senescent cells can promote tumor progression, creating a link between aging and cancer.

Breast cancer survivors who received chemotherapy as a part of treatment have been found to have accelerated aging and increased incidence of cancer recurrence.

Survivors from childhood cancers post-chemotherapy treatment also have been found to have high rates of developing secondary cancer, spinal disorders, and pulmonary diseases in adulthood.

Furthermore, it is well established that clinical use of chemotherapies is associated with long-term damage to normal tissues and organs resulting from accumulation of TIS cells and proinflammatory SASP factors.

Therefore, we believe that therapeutic approaches that alleviate chemotherapy-induced senescent cells and SASP factors in normal tissue may lead to a better quality of life for cancer patients.

By leveraging our immunology expertise, we are developing potentially transformative immunotherapy candidates that use T reg cell expansion and senescent cell reduction to address chronic inflammation linked especially to age-related diseases.

Our approach is to develop immunotherapies that reduce or eliminate the main drivers of chronic inflammation by addressing the underlying development and sustainment of these processes.

Using our drug discovery platforms, we have created over 50 molecules, all of which can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches.

These modular and tunable technologies have allowed us to generate a novel pipeline of internally developed product candidates we believe are capable of activating and targeting desired immune responses and blocking unwanted immunosuppressive activities.

Chronic Inflammation with Aging:

Inflammaging is a state of chronic inflammation believed to develop with advancing age.

Accumulation of senescent cells, along with the SASP factors they secrete, has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies.

Demographically, the world is rapidly growing older and more prone to inflammaging.

All countries face major challenges to ensure that their health and social systems are ready to make the most of this demographic shift.

According to the World Health Organization, in 2020, the number of people aged 60 years and older outnumbered children younger than 5 years.

By 2030, 1 in 6 people in the world will be aged 60 years or over.

In 2020, the population aged 60 years and over was estimated to be 1.4 billion people.

By 2050, the world’s population of people aged 60 years and older is expected to double to 2.1 billion people.

As we grow older, a series of complex changes ripple through our immune system.

Rising levels of inflammatory factors lead to unresolved, degenerative immune responses.

Mounting evidence suggests that this inflammation undermines many bodily systems, accelerates biological aging and contributes to age-related diseases, such as cancer, cardiovascular disease, diabetes, and neurodegenerative disease.

SASP Factors Secreted by Senescent Cells Trigger Chronic Inflammatory Responses

Inflammasomes are large, multimeric protein complexes that are another contributing factor to chronic inflammation.

Their assembly in innate immune cells and other cells is triggered by a variety of stimuli and culminates in the activation of Caspase-1 which then cleaves pro-IL-1β to IL-1β.

To date, diverse inflammasomes have been discovered.

Among the various inflammasomes identified, the nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor (“NLR”) family pyrin domain-containing three NLR (“NLRP3”) inflammasome is best characterized.

The NLRs are recognized as the key sensors of pathogens and danger signals triggered by molecules known as PAMPs and DAMPs.

The NLRP3 inflammasome has a two-step activation mechanism:

“priming”, which entails induction of pro-IL-1β and NLRP3, and “activation”, wherein a functional inflammasome complex is assembled following recognition of PAMPs or DAMPs.

The pathology of various diseases, including Alzheimer’s disease, Parkinson’s disease, and atherosclerosis has been linked to hyperactivation of the NLRP3 inflammasome.

Inflammatory Factors Secreted by Activated Inflammasomes Trigger Chronic Inflammatory Responses

Our Approach for the Treatment of Inflammaging

We have identified two lead product candidates that are immunotherapeutics designed to rejuvenate the immune system in order to neutralize or reverse the two primary pathways of inflammaging.

Without addressing both processes, a chronic, low-grade inflammatory environment will persist, resulting in a diverse range of pathological manifestations including cancer, atherosclerosis, diabetes, and neurodegeneration.

Immune Cell Mediated Senescent Cell Clearance and Senomorphic Agent for SASP Neutralization

Senescent cells are caused when a normal cell is exposed to various stress factors, many of which are simply a part of living and aging.

Other stressors are brought about by medical treatments, such as radiation and chemotherapy, resulting in TIS.

The damaging part of senescent cells is that they secrete so-called SASP factors.

SASP factors come in many different types, depending on the stressor and the cell type exposed to that stressor, but one thing they have in common is that they drive chronic, low-grade inflammation.

For example, TGF-β is considered one of the key SASP factors that induces or accelerates and maintains a senescent phenotype in various cell types including fibroblasts, bronchial epithelial cells, and cancers in an autocrine/paracrine manner.

Thus, to neutralize these pathways, a drug must be a senolytic agent that reduces senescent cells, as well as a senomorphic agent that reduces SASP factors.

Current clinical efforts to counteract TIS and age-related senescent cell activity have focused on senolytic chemical drugs that selectively induce senescent cell death and senomorphic chemical drugs that reduce the secretion of SASP factors.

Despite the promise of senolytics and senomorphics, their efficacy in early phase clinical studies reported to date has been limited.

Further, the specificity, toxicity, and optimal treatment schedule of these pharmaceutical agents in the cancer setting have yet to be determined.

We have developed an alternative approach to reduce senescent cells using well-characterized protein immunotherapeutics including those that stimulate effector immune cells and reduce TGF-β activity.

This approach is supported by our findings that TIS tumor cells upregulate NKG2D and other ligands on their surface for efficient recognition and killing by effector NK cells and CD8 + T cells.

Additionally, suppression of TGF-β activity enhances the anti-tumor/anti-senescent cell responses of these immune cells.

HCW9218 is a unique combination of a TGF-β receptor, which neutralizes TGF-β secreted by tumors, combined with IL-15, a potent cytokine that stimulates NK and CD8 + T cell proliferation and cytotoxicity.

In our scientific publications, we reported that HCW9218 can activate immune cells to infiltrate into tumors to directly eliminate TIS cancer cells.

This activity leads to robust anti-tumor activity of HCW9218 following docetaxel chemotherapy (“DTX”) as measured by reduced melanoma tumor growth in mouse models.

Therefore, TGF-β neutralization combined with activation of effector immune cells should be considered as a part of the strategy for senescent cell removal and reduction of SASP factors.

For a more detailed discussion, see the Company’s pivotal scientific paper entitled, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,” published in Molecular Therapy in April 2022.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Using other animal models of age-related diseases and natural aging, we have also found that HCW9218 could act as an effective senescent-cell reducing and senomorphic drug.

Specifically, in the diabetic db/db mouse models, the Company’s scientists showed that subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved gene expression related to glucose tolerance, insulin resistance, and aging index.

Long-term studies in naturally-aged mice also showed that HCW9218 treatment improved the physical performance without compromising the healthspan.

Stable changes were observed in the expression of inflammation and senescence-associated genes in naturally-aged mice, that appeared to ‘turn back the clock’.

That is, treatment with HCW9218 appeared to reverse the expression pattern of key circadian-rhythm genes, as well as genes associated with metabolism and fibrosis in the liver.

The results of these studies suggest that HCW9218 could represent a novel immunotherapeutic approach and a lead example of a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.

For more details, see the Company’s pivotal scientific paper, entitled, “Immunotherapeutic Approach to Reduce Senescent Cells and Alleviate Senescence-Associated Secretory Phenotype in Mice”, published in Aging Cell in May 2023.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Deactivation of Inflammasomes by Activating T reg Cells

To date, therapeutic approaches to reduce aberrant inflammasome activity have focused on inhibitors of various inflammasome components ( i.e.

, NLRP3 and other NLRs, ASC, Caspase-1) and downstream mediators of inflammation ( i.e.

, IL-1β, IL-18, gasdermin D, etc.).

This approach is validated based on the regulatory approval of three biologics that inhibit IL-1β activity (anakinra, a recombinant form of the naturally occurring IL-1Ra;

rilonacept, a soluble chimeric Fc fusion protein of IL-1R1 and IL-1R3;

and canakinumab, a humanized monoclonal antibody specific for neutralizing IL-1β).

Together, these molecules are approved for treatment of cryopyrin-associated periodic syndrome, a multisystemic IL-1β–mediated disease due to a gain of function in NLRP3;

rheumatoid arthritis;

systemic juvenile idiopathic arthritis and other auto-inflammatory diseases.

We believe there is considerable interest in other therapeutics that specifically block inflammasome activity upstream of IL-1β.

However, these product candidates are still in early phase clinical testing and their bioavailability, off- and on-target toxicity, and utility profiles are still being evaluated.

Our approach is to deactivate inflammasome pathways in monocytes and macrophages through the immunosuppressive activities of T reg cells induced by our immunomodulator molecules.

This approach does not rely on inhibiting specific inflammasome components but rather utilizes natural processes of the immune system to attenuate and rebalance chronic self-perpetuating proinflammatory responses.

In relevant animal models, we have observed encouraging results using HCW9302 to activate and expand T reg cells for treatment of atherosclerosis and diabetes.

HCW9302 Reduces Atherosclerotic Plaques Induced by High Fat Diet in ApoE -/- Mice

Preclinical Data Showing Attenuation of Progression of Atherosclerosis

(A) Histochemical staining of aorta root sections and graphical comparisons of the atherosclerotic lesion formation (“H&E”) between control and HCW9302 treated ApoE deficient mice fed with a Western diet (“WD”).

(B) En face analysis of atherosclerotic lesions in the aorta including the arch, thorax, and abdomen from control and HCW9302 treated ApoE deficient mice fed with a WD.

Data in (A,B) are expressed as mean ± SEM (n = 13-14).

Statistical analysis using a 2-tailed, unpaired “t” test.

( C) Heatmap analysis of HCW9302-mediated increases of anti-atherosclerotic transcriptomes.

(D) Reduction of pro-atherosclerotic transcriptomes in aortas of ApoE -deficient mice.

(C,D) The Wald test was used to generate p-values and log2 fold changes for RNA-Seq analysis.

Genes with an adjusted p-value < 0.05 and absolute log2 fold change > 1 were called as differentially expressed genes for each comparison.

Frontiers in Immunology , “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,” Zhu, X., et al., January 2023.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Nonclinical studies in nonhuman primates (“NHPs”) also supported that repeated subcutaneous administration of HCW9302 induced significant proliferation and accumulation of T reg cells and that HCW9302 dose levels that were well tolerated.

HCW9302 treatment did not result in consistent changes in NK cell, CD4 + T cell, CD8 + T cell or B cell accumulation nor did it induce cytokine storm in NHPs.

Subcutaneous HCW9302 exhibited a maximum serum concentration at 6 to 10 hours post-dosing and a 7- to 18-hour half-life in NHPs, considerably longer than that observed for recombinant IL-2 cytokine.

We believe these findings support clinical development of HCW9302 to induce T reg cell responses against pro-inflammatory/autoimmune diseases.

The two graphs below illustrate the results of characterization studies.

HCW9302 exhibits increased biological activity (depicted in the graph on the left) with an extended half-life (depicted in the graph on the right), compared to recombinant human IL-2.

Additionally, we found that HCW9302 exhibited an estimated 1,000-fold higher affinity for IL-2Rα (present on T reg cells) in comparison to IL-2.

HCW9302 could be administered to mice and NHPs at a dosing range that expanded and activated T reg cells but not CD4 + effector T cells.

These findings indicate that HCW9302 is a more suitable immunotherapeutic for expanding and activating T reg cells in vivo than IL-2.

HCW9302 Compared to Recombinant Human IL-2

Increased Biological Activity and Extended Half-Life

Results of Characterization Studies

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Cellular senescence is a biological condition resulting from the impact of stressors, such as chemotherapy, radiation, and pollutants, on human cells.

These stressors reduce natural human cell cytotoxicity, leading to the accumulation of senescent cells and SASP factors.

Considered harmful to neighboring cells, secreted SASP factors also activate a type of protein molecule called inflammasomes that accelerate the increasingly persistent cycle of inflammation.

As we age, senescent cells accumulate, and SASP factors increase, leading to low-grade, chronic inflammation and age-related diseases.

At HCW Biologics, our proprietary immunotherapy platforms rejuvenate the immune system, allowing it to reduce accumulated senescent cells and silence activated inflammasomes.

This disrupts the link between aging and chronic diseases.

Persistently Activated Immune Cells:

Inflammatory Factors They Secreted Trigger Chronic Inflammatory Responses

Immune cells defend against infection or tissue injury.

These activated immune cells persist as we age, even in the absence of infection, and regulate the release of pro-inflammatory factors.

As inflammatory factor levels increase, this fuels a feedback cycle of inflammasome activation and leads to the persistent, low-grade body-wide inflammation associated with many age-related diseases.

Our strategy includes the following key components:

Advance clinical development of HCW9218 in cancer indications based on results of Phase 1/1b clinical trials.

• Data from the Phase 1 clinical trial to evaluate HCW9218 in solid tumors and the Phase 1b clinical trial to evaluate HCW9218 in pancreatic cancer support our choice of ovarian cancer and pancreatic cancer as indications for Phase 2 clinical studies.

• We intend to evaluate HCW9218 in combination with standard-of-care treatments for cancer, such as chemotherapy and immune checkpoint inhibitors in randomized Phase 2 studies.

• Opportunistically, we may evaluate HCW9218 in other difficult-to-treat cancer indications in Phase 2 studies if they are covered by a CRADA with NCI or NIH or are led by a sponsor with funding.

These studies may involve evaluating HCW9218 in combination with treatments for indications not approved by FDA.

Begin evaluating of HCW9218 in age-related diseases beyond cancer.

• We view cancer as our gateway indication to expanding into other age-related diseases.

We intend to begin to investigate other age-related diseases beyond cancer, beginning with indications in dermatology, such as senile lentigo, a harmless skin disease that typically occurs with aging.

Focus on an autoimmune indication for the IND application for our lead product candidate, HCW9302.

• With completion of the IND-enabling activities and toxicology studies required for submission of an IND, we expect to submit an IND application to the FDA to evaluate HCW9302 in an autoimmune indication in the first half of 2024.

We have not yet submitted the IND, nor can we guarantee that the FDA will grant us permission to initiate clinical studies in an autoimmune disorder.

Focus on diseases with no known FDA-approved treatments.

• Diseases to be targeted include cancer indications, neurodegenerative diseases as well as quality-of-life indications.

• Indications that will be included in our clinical development are promoted by chronic inflammation, especially inflammaging.

Focus on an autoimmune indication for the initial indication for clinical development for our lead product candidate, HCW9302.

• The Company received clearance of its IND from the FDA to initiate a first-in-human Phase 1 dose escalation clinical trial to evaluate one of its lead drug candidates, HCW9302, in patients with moderate-to-severe alopecia areata, a common autoimmune disease in humans that currently has no curative FDA-approved treatments.

• The Company intends to include up to five clinical sites in this study.

Negotiations with clinical sites are currently underway, and the Company estimates the lead site may open and initiate late in the second quarter of 2025 or early in the third quarter of 2025.

Once RP2D and safety is established in a successful Phase 1 study, expand to other carefully selected indications in Phase 2.

• The Company will refine potential expanded indications for Phase 2 clinical studies during Phase 1, conducting further preclinical research with support from Phase 1 clinical data from ancillary studies as well as human data read-outs.

• For HCW9302, we are focused on autoimmune diseases, including alopecia areata, and inflammatory conditions, such as other dermatological conditions, graft rejection, and neurodegenerative diseases.

Continue to build our relationships with leading clinical research centers.

• We expect all of the clinical sites that currently participate in the Phase 1/Phase 1b clinical studies to continue to participate in Phase 2 clinical studies.

Our current clinical sites represent leaders in cancer research and treatment, most of which are NCI-designated Comprehensive Cancer Centers.

In the case of our pancreatic study, the lead clinical site is the NCI itself.

These institutions are centers of excellences and often attract patients from large regions, nationally and internationally.

Identify financing opportunities that allow us to advance the clinical development of our lead product candidates.

• We are exploring a range of financing alternatives to fund our clinical development activities, with a preference for non-dilutive financing transactions, such as CRADAs with the NCI and the National Institutes of Health, strategic collaborations, project financing and other forms of debt financing.

Out-licensing non-core assets and rights will also remain part of our financing strategy.

Explore co-development with big pharma for lead molecules after Phase 2 clinical data is available.

• Our primary goal is to enter a co-development deal on the best terms possible, so we are targeting to enter into a co-development deal after Phase 2 human clinical data is available.

Our Proprietary Tissue factOr-Based fusIon (“TOBI”) Discovery Platform

Our proprietary TOBI discovery platform is a new approach to construct multi-functional fusion proteins and fusion protein complexes using a novel tissue factor (“TF”) protein scaffold.

The extracellular domain of human TF was selected as it has a rigid elongated structure comprised mainly of β-sheets with its N- and C-termini located at distal ends of the polypeptide, permitting genetic fusions of other protein domains without anticipated steric interference.

This TF domain does not interact with the cell membrane phospholipid bilayer and, as a result, does not exhibit procoagulant activity.

This TF domain is expressed at high levels by most cell types and is not expected to be immunogenic in humans.

Consistent with these properties, we found that genetic fusion to the TF domain promoted increased production of difficult-to-express proteins, such as IL-15.

Additionally, the TF fusion proteins could be readily purified by affinity chromatography using an anti-TF antibody and low pH elution conditions, like those used in Protein A-based affinity purification of therapeutic antibodies.

To generate multichain protein complexes, we also incorporated genetic fusions to the human IL-15 and IL-15Rα domains as shown in the figure below.

When co-expressed in CHO cells, the fusion proteins form a soluble stable heterodimeric complex through high-affinity interactions between IL-15 and IL-15Rα domains.

This approach offers an alternative to immunoglobulin (Fc) and other engineered protein scaffolds, which typically require introduction of multiple mutations or other non-human sequences or complicated in vitro assembly/purification methods to generate bi- or multi-specific complexes.

Our internally-developed TOBI discovery platform was featured in an article authored by the Company and published in July 2021 in the peer-reviewed journal Cancer Immunology Research .

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Using the TOBI platform, we have constructed more than 30 fusion complexes comprising various cytokines, ligands, receptors, and single-chain antibodies, including disease-targeting antibodies and immune checkpoint inhibitors.

The modular fusion components are carefully selected to stimulate, inhibit, and/or target specific immune responses using a knowledge-based disease-relevant strategy and in many cases, are designed to provide synergistic and balanced activities for optimal therapeutic benefit.

The resulting fusion proteins are rigorously tested in state-of-the-art cell culture systems and disease-specific animal models to verify their utility for the intended clinical use and targeted indications.

• We believe we can reduce risks related to low patient recruitment and enrollment by continuing to build our relationships with clinical sites who specialize in indications that are being studied in clinical trials.

• We intend to work with the strongest principal investigators who have a passion for the underlying science and search for breakthrough therapeutics.

These investigators tend to have gravitas at their institutions and the broader scientific and medical communities.

We find they can often be advocates for HCW Biologics and our clinical studies.

Balance clinical development of our proprietary molecules between a few in-house development programs and licensing programs with larger biotech companies and big pharma for other molecules.

• For in-house development, we will focus on HCW9302 and second-generation immune checkpoint inhibitors.

After the completion of Phase 1 studies in China, the Company may also elect to exercise our Opt-In Right per the WY Biotech License Agreement, and add HCW11-006 to our in-house development programs for the Americas market.

• We plan to begin actively seeking a partner for the development of the Company’s T-Cell Engager and other Immune Cell Engagers in Q2 2025.

• We will continually assess candidates for clinical development for licensing.

The Company has created over 50 compounds using the TRBC platform which it owns, many of which show bioactivity and potential for development for the treatment of diseases linked to inflammation and aging, such as cancer.

The Company created two novel drug discovery platforms, using two distinctly different scaffolds to anchor the composition of immunotherapeutic fusions.

This results in the creation of molecules with different mechanisms of action, which opens up different pathways for treatment of diseases promoted by chronic inflammation.

Our Proprietary T-Cell Receptor β Chain Constant Region Drug Discovery and Development Platform

HCW Biologics invented the TRBC drug discovery and development platform, a second-generation drug discovery technology platform, to create immunotherapeutics that activate immune responses and specifically target cancerous or infected cells.

The platform utilizes the TRBC protein as a scaffold to build multi-chain chimeric polypeptides, which include target-binding domains and affinity domains, enabling the targeting of specific antigens.

We believe these polypeptides stimulate immune cells, modulating immune functions and signaling pathways.

Molecules created with the TRBC platform integrate multiple protein targets, such as cytokines, single-chain antibodies, and ligands, into a single fusion complex designed to engage immunostimulatory functions and modulate various signaling pathways.

This flexible, adaptable platform has facilitated the development of a groundbreaking pipeline of internally developed product candidates.

This versatile scaffold enables the creation of multiple classes of immunotherapeutic compounds:

Multi-Functional Immune Cell Stimulators – Multifunctional, cytokine-based immunotherapeutic compounds.

Second-Generation Immune Checkpoint Inhibitors – Multifunctional immunotherapeutic fusions which improve the performance of immune checkpoint inhibitors.

Multi-Specific Targeting Fusions and Enhanced Immune Cell Engagers – Constructs with immune-cell engagers targeting cell-surface antigens associated with diseased cells.

T-Cell Receptor β Chain Constant Region (“ TRBC”) Drug Discovery and Development Platform

Our Proprietary Tissue factOr-Based fusIon Development Platform

Our proprietary TOBI development platform is a proprietary immunotherapeutic drug design and discovery platform which enables us to construct multi-domain cytokine-based immunotherapeutics using a Tissue-Factor (“TF”) scaffold.

The domains of TOBI-based molecules are discrete and can be “turned on” and “turned off.” We have evaluated HCW9218, a TOBI-based molecule, in two Phase 1/1b clinical trials and have generated human data that shows that this molecule is capable of achieving the desired immune responses against solid tumors, including ovarian and pancreatic cancer.

Based on other research, we believe that other TOBI-based molecules could activate the designed immune responses against other diseases or infected cells by blocking unwanted autoimmune or inflammatory activities.

Based on a TF scaffold that serves as the “backbone” for the construction of fusion molecules, the TOBI platform packs multiple protein targets, including cytokines, single-chain antibodies, and ligands, into a fusion molecule.

These molecules are capable of engaging immunostimulatory functions and addressing many signaling pathways simultaneously.

Some of these fusion protein complexes have ex vivo as well as in vivo applications.

TOBI also provides a scalable approach for generating large-scale current Good Manufacturing Practice (“cGMP”)-grade heteromeric fusion protein complexes to support clinical applications.

We have used our TOBI platform to construct a proprietary, heterodimeric bifunctional fusion molecule, HCW9218, capable of immuno-stimulatory as well as anti-immunosuppressive activity.

Advances in immuno-stimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment.

However, novel immunotherapeutics with these dual functions are not frequently constructed.

HCW9218 is comprised of extracellular domains of the human TGF-β receptor II and a human IL-15/IL-15 receptor α complex.

HCW9218 potently activates NK cells and CD8 + T cells in vitro and in vivo to promote their proliferative and metabolic activities and enhances their cytotoxicity against tumor targets.

This fusion complex also exhibits TGF-β neutralizing activity in vitro and sequestered plasma TGF-β in mice and NHP.

Pancreatic and Ovarian Cancer

We believe, based on the preliminary results of the ongoing first-in-human Phase 1/1b clinical trials, HCW9218 may have the potential to be an effective immunotherapy against difficult-to-treat solid tumor cancers that are very aggressive malignancies and refractory to other immunotherapies including immune checkpoint blockade.

We are gathering data from ongoing studies in search of preliminary evidence that our approach to decreasing TGF-β levels or signaling may be able to provide clinical benefit.

We intend to continue to evaluate HCW9218 in two cancer indications that are two of the most difficult-to-treat and thus deadliest of cancers:

• Pancreatic cancer has the highest mortality rate of all major cancers.

Incidence rates of pancreatic cancer have gone up by around 1% each year since 2000, and the death rate has very slowly increased each year since the mid-2000s.

In 2023, an estimated 64,050 Americans were diagnosed with pancreatic cancer in the United States, and more than an estimated 50,550 died from the disease.

Worldwide, an estimated 495,773 people were diagnosed with pancreatic cancer and an estimated 466,000 people died from the disease in 2020.

If the cancer is detected at an early stage when surgical removal of the tumor is possible, the 5-year survival rate is 42%.

About 13% of people are diagnosed at this stage.

If the cancer has spread to surrounding tissues or organs, the 5-year survival rate is 14%.

For the 52% of people who are diagnosed after the cancer has spread to a distant part of the body, the 5-year survival rate is 3%.

(See American Society of Clinical Oncology and American Cancer Society.)

• Ovarian cancer ranks 5th in cancer deaths among women in the United States, accounting for more deaths than any other cancer of the female reproductive system.

Worldwide, ovarian cancer is the 7th most common cancer in women.

By 2040, the number of women around the world diagnosed with ovarian cancer is projected to rise almost 42% to 445,721.

The number of women dying from ovarian cancer each year is projected to increase to 313,617 an increase of over 50% from 2020.

Five-year ovarian cancer survival rates vary among countries.

For example, in more developed countries, current rates range from 36% to 46%.

However, in some countries the figure is much lower.

Overall, survival rates fall well below that of other cancers.

This cancer mainly develops in older women.

About half of the women who are diagnosed with ovarian cancer are aged 63 years or older.

(See World Ovarian Cancer Coalition and American Cancer Society.)

We have employed our TOBI platform to create HCW9302, a proprietary IL-2-based fusion molecule, to expand T reg cells in vivo and ex vivo as an injectable or cell-based strategy to reduce inflammation and to treat a wide variety of autoimmune and age-related diseases.

T reg cells are essential mediators of peripheral tolerance and the global immunoregulatory potential in hosts to self and non-self-antigens.

Current research is focused on developing novel therapies to enhance T reg cell functions in vivo through the use of cytokines and small molecule drugs to support endogenous T reg cell proliferation or activation, ex vivo manipulated T reg cells in autologous adoptive cell therapy to promote immunoregulation in settings of autoimmunity, or antigen-specific T reg cells, including chimeric antigen receptor T reg (“CAR-T reg ”) cells, to strengthen tolerance in allergies.

In relevant animal models, we have also observed, in our view, encouraging results using HCW9302 to activate and expand T reg cells for treatment of atherosclerosis and diabetes.

The TOBI discovery platform was featured in an article authored by the Company and published in July 2021 in the peer-reviewed journal Cancer Immunology Research , “ A ‘Prime and Expand’ Strategy Using the Multifunctional Fusion Proteins to Generate Memory-Like NK cells for Cell Therapy,” Shrestha N, et al., July 2024.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

For information about the bi-specific TOBI fusion, HCW9302, and its effects on T reg responses in an inflammatory disease, see Frontiers in Immunology , “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,” Zhu, X., et al., January 2023.

The reference to our paper does not constitute incorporation by reference of the information contained in the paper.

Autoimmune and Proinflammatory Diseases

We have conducted extensive preclinical research on HCW9302 for deactivation of inflammasomes to temper the proinflammatory environment they create in relevant animal models, including those for atherosclerosis.

Our data suggest that HCW9302 functions as a potent agent to stimulate T reg cells that suppress the activity of inflammasome-bearing cells and inflammatory factors.

We intend to begin clinical trials to evaluate HCW9302 in an autoimmune indication, alopecia areata.

• Alopecia areata (“AA”) is a chronic, relapsing, autoimmune disorder that results from the immune system mistakenly attacking hair follicles, leading to hair loss without permanent damage to the follicles.

Alopecia areata often presents as isolated, smooth, nonscarring patches of hair loss, typically on the scalp, but it can occur anywhere with hair growth.

Living with AA can be associated with reduced quality of life, social functioning, and psychological well-being, along with substantial costs to patients and the health care system.

Each person may have a different experience with AA.

Some people may regrow hair, while others do not.

Hair regrowth can be spontaneous, or it can happen following treatment.

For patchy AA, the spontaneous remission rate is 30–50% in the first 6–12 months of the disease, and complete resolution is seen in up to 66% of patients within 5 years.

For alopecia totalis, the rate of spontaneous remission is less than 10%.

Within 20 years, 100% of patients with AA experience disease relapse.

A greater incidence has been reported in females than males, especially in patients with late-onset disease, defined as age greater than 50 years.

There is no cure for AA, which affects an estimated 2% of the global population.

HCW9302 is our leading clinical-stage drug candidate designed to address chronic inflammatory responses and associated tissue destruction typical of autoimmune disease.

Thus, we selected an autoimmune disease as the gateway indication for the clinical development of HCW9302.

HCW9302 is designed to activate and expand T reg cells, suppressing the persistently activated immune cells, inflammasome-bearing cells and their inflammatory factors.

Preclinical studies show it has a 1,000-fold higher affinity for IL2Rα than IL-2, with a longer serum half-life.

It is well tolerated, effectively expanding T reg cells without activating CD4 + effector T cells (“T eff ” cells).

In a dose toxicity study in non-human primates, we established that HCW9302 induced T reg cell proliferation and accumulation at a dose level with no observed adverse events.

For this study, HCW9302 was administered monthly via subcutaneous injection for six months.

Findings from this IND-enabling study contributed to the development of the clinical strategies for HCW9302 in autoimmune disease indications.

Alopecia Areata

An Updated Review for 2023,” Journal of Cutaneous Medicine and Surgery, published June 2023;

and “Alopecia Areata:

Burden of Disease, Approach to Treatment, and Current Unmet Needs,” Clinical, Cosmetic and Investigational Dermatology, published online March 2023.)

HCW9206 is a fusion protein complex created with our TOBI platform based on common gamma chain (γc) cytokines IL-7, IL-15 and IL-21, which are known to play important roles in NK cell and T cell homeostasis.

We hold the rights to the injectable form of HCW9206, and ex vivo rights are licensed to Wugen.

This molecule is designed to broadly activate the immune system to support expansion of NK cells and T cells ex vivo and in vivo .

We are currently in the discovery stage of an initial program for HCW9206, which is to create an injectable immunotherapeutic to use as an adjuvant for adoptive cell therapy in cancer treatments.

In current NK and Memory-Like-NK cell therapies, infused cells are supported in vivo by recombinant human IL-2.

However, this approach has limitations since IL-2 can only support these infused cells for the short term and may induce T reg cells toward immunosuppression.

We believe our preclinical testing of HCW9206 has demonstrated that this complex can support infused NK cells for a long duration and enable NK cells to sustain cytotoxicity against tumor cells.

In addition, we are currently conducting preclinical studies to investigate use of HCW9206 to enhance vaccine efficacy in different vaccine models as well as to support CAR-T cells in vivo .

On January 28, 2025, the Company obtained clearance from the FDA to evaluate HCW9302 in a Phase 1 clinical trial in patients with alopecia areata (“alopecia”).

In preclinical studies using an alopecia murine model, treatment with HCW9302 protected mice from disease, reducing pathogenic immune cell populations in the skin and skin-draining lymph nodes.

HCW9302 treatment also led to a protective shift in T reg :

T eff balance, with T reg cells dominating in the skin leading to suppression of unwanted autoimmune activity.

These findings suggest HCW9302-induced T reg expansion can alter the course of alopecia areata and promote tolerance, warranting further studies in human patients.

Alopecia is characterized by hair loss in localized areas, the entire scalp, or, in some cases, the whole body.

It occurs when the immune system mistakenly attacks hair follicles, leading to hair loss without causing permanent damage to the follicles.

Patients often experience recurring episodes of hair loss throughout their lives.

While not life threatening, alopecia areata can have a significant negative impact on patients’ quality of life and psychological health.

Existing approved treatments may provide some relief of symptoms, but there are often dangerous side effects.

Alopecia is one of the most prevalent autoimmune diseases in the world, affecting approximately 1 in 1,000 people, with a lifetime incidence of 2% worldwide, or 160 million people.

According to the National Alopecia Areata Foundation, about 7 million people in the United States have alopecia areata.

The condition primarily affects individuals under the age of 30, occurring at similar rates in both males and females.

Many insurance plans may not fully cover alopecia areata treatments, leading to significant out-of-pocket expenses.

More extensive hair loss usually requires more intensive treatment, leading to higher costs.

Hair transplants are considered among the most expensive treatment options, with costs ranging from $7,400 to $25,000 depending on the procedure and the clinic.

Patients report even higher costs due to the need for medications like Janus kinase (“JAK”) inhibitors which can reach upwards of $50,000 annually.

JAK inhibitors have boxed warnings in their labeling due to an increased risk of serious heart-related events, cancer, blood clots, and death.

(See StatsPearls, National Library of Medicine of National Institutes of Health, National Alopecia Areata Foundation.)

Potential Phase 2 Expanded Indications

The goals of the Phase 1 clinical trial are to assess whether the safety profile is acceptable to conduct further studies and establish a RP2D that can increase T reg cells activity in patients participating in the study.

If we achieve the Phase 1 study objectives, the Company plans to progress the clinical development of HCW9302 in patients with alopecia areata as well as other autoimmune diseases and inflammatory conditions, including other dermatologic diseases, organ transplant rejection and neurodegenerative diseases.

Organ Transplant Rejection

Through collaborative research, the Company has performed some preclinical research using HCW9302 in organ transplant rejection.

According to the United Network for Organ Sharing, in 2023, there were a record-breaking 46,632 organ transplants performed in the United States.

This includes both deceased and living donors.

Graft rejection in organ transplantation refers to the phenomenon where the recipient's immune system identifies the transplanted organ as foreign tissue and attacks it, leading to damage and potential failure of the transplanted organ, essentially rejecting it from the body.

This is a major complication following organ transplantation and occurs due to differences in the recipient's immune system compared to the donor's tissue antigens.

Chronic transplant rejection may develop months or years after organ or tissue transplantation.

This condition involves chronic inflammation and immune responses against the transplanted graft, leading to complications and symptoms that vary depending on the transplanted organ.

Neurodegenerative Diseases

The Company’s preclinical work in neurodegenerative diseases to date has focused on Alzheimer’s Disease.

According to the Alzheimer’s Association, for the United States, health care and long-term care costs for people living with dementia are projected to reach $360 billion in 2024 and nearly $1 trillion in 2050.

Further statistics from the Alzheimer’s Association offer a partial explanation for these staggering costs.

Again, these are statistics just for the United States.

• An estimated 6.9 million Americans aged 65 and older are living with Alzheimer's in 2024.

Seventy-three percent are age 75 or older.

• Almost two-thirds of Americans with Alzheimer's are women.

• About 1 in 9 people aged 65 and older (10.9%) has Alzheimer's.

• Alzheimer's disease was the fifth-leading cause of death among people aged 65 and older in 2021.

• By 2050, the number of Americans with Alzheimer’s is projected to rise to nearly 13 million.

Cancer Indications

Class II TRBC Molecules:

Second-Generation Immune Checkpoint Inhibitor

The Company is currently conducting preclinical studies in relevant animal models to identify the strongest candidate in the group of TRBC Molecules classified as second-generation immune checkpoint inhibitors.

Several immune checkpoint inhibitors have been approved for the treatment of a limited number of cancer indications.

There are several clinical studies underway for therapeutics to be used in combination with immune checkpoint inhibitors to broaden the number of indications and improve response rates.

Our focused indications are pancreatic and ovarian cancer.

This market is dominated by a few companies, predominantly Merck & Co.

and its product, Keytruda®.

Leading immune checkpoint inhibitors face a patent cliff in the next few years.

The opportunity presented by the patent expiry of approved immune checkpoint inhibitors lies in the potential for increased competition and availability of generic or biosimilar versions of these drugs which may result in a loss of market exclusivity and revenue as competition.

It may also incentivize innovation and the development of new formulations, combinations, or delivery methods to maintain market share and competitive advantage.

Pancreatic Cancer

Pancreatic cancer, as one of most fatal malignancies, remains a critical issue in the global burden of disease.

This cancer has the highest mortality rate of all major cancers.

In the U.S., pancreatic cancer is currently the third leading cause of cancer-related death after lung and colon and expected to become the second leading cause of cancer-related death by 2030.

alone, an estimated 66,440 Americans were diagnosed with pancreatic cancer and more than 51,750 died from the disease in 2024.

For all stages combined, the five-year relative survival rate is 13%.

For the small percentage (15%) of people diagnosed with local disease, the five-year survival rate is only 44%.

Survival is higher when pancreatic cancer is detected early.

Early diagnoses is difficult because there are few signs or symptoms before it has spread outside of the pancreas.

China, the United States, and Japan had the highest number of pancreatic cancer cases in 2022.

There were approximately 500,000 new cases and 470,000 deaths in 2022.

The table below shows the new cases and the ASR/100,000.

Age-standardized rates (“ASR”) are a summary measure of the rate of disease that a population would have if it had a standard age structure.

Pancreatic Cancer

United States

World Journal of Gastronomy, American Cancer Society, National Cancer Institute, World Cancer Research Fund.)

Ovarian Cancer

Ovarian cancer is one of the leading causes of cancer deaths among women and the deadliest of gynecologic cancers.

Although risk of developing and dying from ovarian cancer is almost twice as high in developed countries, the actual burden (number of cases) is much higher in less developed countries due to population sizes.

For example, China has the largest number of diagnoses per year (34,575), followed by India (26,934), then the United States.

In the United States, ovarian cancer accounts for 2.5% of cancers in women.

In the United States, while ovarian cancer is the 11th most common cancer among women, it is the fifth leading cause of cancer-related death among women.

Worldwide, ovarian cancer is the seventh most common cancer in women.

It is estimated that by 2035, the incidence of ovarian cancer will increase by 55% to 371,000 worldwide, and deaths will increase by 67% to 254,000 worldwide.

Treatment for ovarian cancer usually involves a combination of surgery and chemotherapy.

This cancer mainly develops in older women.

About half of the women who are diagnosed with ovarian cancer are aged 63 years or older.

The most important risk factor for ovarian cancer other than age is a family history of breast or ovarian cancer.

This includes those with inherited gene changes like BRCA1, BRCA2, and Lynch syndrome.

Ovarian cancer survival rates vary widely.

The latest five-year survival rates largely fall between 30% and 50% and in general have begun to improve over the last 20 years.

In the United States, the relative five-year survival rate for ovarian cancer is 50.8%.

Overall, survival rates fall well below that of other cancers.

World Ovarian Cancer Coalition, American Cancer Society and Center for Disease Control and Prevention.)

Class I TRBC Molecules:

Multi-Functional Immune Cell Stimulators

Class I TRBC Molecules combine several different immune functional domains on the TRBC scaffold.

The Company has conducted preclinical studies that demonstrate that this multi-functional group of molecules is highly effective at inducing CD8 + T cell and NK cell responses without triggering unwanted side effects in human immune cells animal models.

HCW11-006 also exhibits anti-tumor efficacy in relevant solid tumor animal models.

In addition to HCW11-006, the Company is investigating various structures with different combinations of cytokines in our quest to identify lead product candidate(s) in this group of molecules.

We anticipate the completion of our efficacy assessment in mice and safety profiling in a small study in non-human primates before the end of 2025.

Results of these studies are expected to show the optimal construction for lead product candidates.

Example of Class I TRBC Molecule

Second-Generation Multi-Functional Immune Cell Stimulator

HCW11-002 is a Class I TRBC molecule that contains the same immune moieties as HCW9218, and it has demonstrated its promising capabilities in stimulating immune cells in preclinical studies.

Based on this potential, the Company is considering accelerating the development of HCW11-002 for senescence-associated indications.

Senescence-Associated Diseases

The Class I TRBC Molecules have potential for the treatment of senescence-associated indications, such as bronchopulmonary dysplasia (“BPD”), chronic deep wrinkles and senile lentigo (age spots) removal.

BPD is a form of chronic lung disease that causes long-term breathing problems in premature babies.

The condition often results in poor growth and development.

An estimated 10,000 to 15,000 babies in the United States develop BPD each year.

There is no known cure for BPD, which involves high morality and morbidities.

Aesthetics treatments represent a large and growing market due to the aging population.

For example, the global botulinum toxin market was valued at $6.4 billion (USD) in 2022 and growing at a CAGR of 11.50% from 2022 to 2030.

The market is expected to reach $15.2 billion (USD) by 2030.

Global Growth Report, Fortune Business Insights.)

Class III TRBC Molecules:

Immune Cell Engagers

Class III TRBC Molecules are second-generation immune-cell engagers capable of targeting tissue factor and other cell-surface antigens associated with diseased cells.

Class III TRBC Molecules are part of a new class of therapeutic treatments based on the development of immune-cell engagers.

Among these are T-cell targeted molecules — antibodies engineered to redirect T cells to recognize and kill cancer cells — that are being developed to treat cancer and tackle issues that could potentially lead to treatment that is more effective and safer for cancer patients.

Recent deal activity indicates that the pharmaceutical industry and the biotech industry have recognized the benefits of Enhanced Immune Cell Engagers, in particular T-Cell Engagers.

Recent notable deals in the immune cell engager space include AbbVie partnering with Xilio Therapeutics to develop antibody-based immunotherapies, with AbbVie paying a significant upfront payment of $52 million;

Candid Therapeutics making multiple collaborations to discover and develop new T-cell engagers, including a deal with Nona Bioscience (“Nona”) where Nona could potentially receive up to $320 million in milestone payments;

and GSK acquiring CMG1A46, a clinical-stage dual CD19 and CD20-targeted T-cell engager from Chimagen for $300 million upfront.

Even though immune-cell engagers have great potential, there are major challenges in the clinical development.

The complexity and scale of the GLP preclinical and clinical studies required for the development of Class III Molecules is more appropriate for well-capitalized pharmaceutical companies or a larger biotech company.

Companies that undertake this challenge must deal with managing potential severe toxicities, among other obstacles.

Further complications arise from potential off-target effects and patient selection for optimal treatment outcomes.

In light of recent transactions coupled with the challenges of clinical development, we plan to take advantage of industry interest in this breakthrough drug strategy.

We intend to develop these molecules through corporate partnering and out-licensing arrangements.

Out-License Programs

We have internally developed over 30 immunotherapeutic molecules and plan to develop additional molecules through our TOBI platform.

Our strategy is to focus on the clinical development of our lead product candidates, HCW9218 and HCW9302, as immunotherapeutics, administered by subcutaneous injection for the treatment of age-related diseases.

Our strategy is to out-license marketing rights to regions and product rights not in our focus area.

We have created over 50 immunotherapeutic molecules with our proprietary drug discovery and development platforms.

We use out-licensing as a strategy for financing as well as clinical development of selected programs, molecules or markets.

We expect out-licensing to provide non-dilutive financing to bolster resources available to fund our core markets and programs and possibly commercialize molecules, with the hope that our licensees achieve success through our licenses.

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Wugen has exercised its right to sublicense their rights for Greater China.

The sublicensee is currently conducting a Phase 1 dose escalation trial with ex vivo cells in patients with relapsed/refractory acute myeloid leukemia (“R/R AML”).

A Phase 1 clinical trial of WU-NK-101 for patients with R/R AML initiated in August 2023.

This study is designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML.

The FDA has also granted Orphan Drug Designation to WU-NK-101 for the treatment of R/R AML.

WU-NK 101 is a treatment based on the Company's licensed molecules.

As licensor, we have limited information rights to clinical data which we are required to treat as nonpublic confidential information.

As licensee, Wugen, a private company, determines when and if clinical data readouts are disclosed to the public.

Wugen presented three abstracts for clinical-stage studies and preclinical data at the American Society of Hematology conference in December 2023.

As licensee, Wugen, a private company, determines when and if clinical data read-outs are disclosed to the public.

We retain manufacturing rights and other rights, including regulatory T cell-based cellular therapy and injectable rights, for licensed molecules under the terms of the Wugen License.

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In addition to an upfront fee which consisted of a significant equity ownership position in Wugen’s common stock, we have the opportunity to receive additional payments for development and commercialization milestones as well as single-digit royalties.

Other TOBI Discovery Programs

Our discovery efforts for new product candidates are focused on characterizing and expanding our library of antibodies and fusion molecules with cytokines, chemokines, ligands, receptors, and internally-developed single-chain antibodies, including fusion domains with increased or decreased biological activity, for cancer and other age-related diseases with an emphasis on neurodegenerative, fibrotic, and autoimmune diseases.

Other TOBI discovery programs are summarized in the table below.

Fusion Molecules

Fusion Domains

T and NK cells stimulation

Cancer and support for cell-based products in vivo

TGRβRII tetramer

TGF-β antagonist

Pulmonary hypertension, neurodegenerative diseases and fibrotic diseases

Anti-CD26 scFv

Senescent cell inhibition and targeting

Inflammatory and age-related disease

Senescent cell inhibition and targeting

Inflammatory and age-related disease

T reg binding, activation, inhibition, and targeting

Inflammatory and age-related disease

WY Biotech Co., Ltd.

On November 17, 2024, HCW Biologics entered into an exclusive, worldwide License, Research, and Co-Development Agreement (the “WY Biotech License Agreement”) with WY Biotech Co., Ltd.

(the “WY Biotech”) for in vivo applications of one of the Company’s preclinical, proprietary molecules, HCW11-006.

Upon the completion of a Phase 1 clinical trial in any jurisdiction, the Company has an “Opt-In Right,” which gives the Company the option to assume all control and responsibility for the development, manufacture and commercialization of HCW11-006 for in vivo applications in the Opt-In Territory.

The “Opt-In Territory” is North America, South America, and Central America.

Upon the completion of the exercise of the Opt-In Right, the Company would be responsible for all costs associated with research and development, manufacturing, clinical development, regulatory approval, and commercialization for the licensed molecule in the Opt-In Territory.

As reported in the Company’s Form 8-K filed with the SEC on March 19, 2025, on March 18, 2025, the Company and WY Biotech agreed to amend the WY Biotech License Agreement.

The Company has now completed extensive preclinical studies that further support our belief in the potential for HCW11-006 for both an in vivo and ex vivo therapy.

The Company considers WY Biotech License provisions for the Opt-In Right to take over the development of HCW11-006 for the Americas markets to be an important feature of the WY Biotech License.

We believe our right to recapture this market is a potentially high value opportunity.

Manufacturing

Our product candidates include proprietary molecules that are multi-specific fusion protein complexes, such as HCW9201, HCW9206, and HCW9218;

bispecific fusion protein complexes, such as HCW9302;

and an internally-developed affinity ligand used in our manufacturing processes, HCW9101, for which we have generated a high-expressing cell line.

We have established internally-developed manufacturing processes for producing these fusion molecules from Chinese hamster ovary (“CHO”) cells at large scale in a cGMP-compliant setting.

For TOBI Molecules, we have established internally developed large scale manufacturing processes for producing these fusion molecules from Chinese hamster ovary (“CHO”) cells in a cGMP-compliant setting.

We have a long-standing relationship with a contract manufacturing organization, EirGenix, Inc.

(“EirGenix”), a third-party global contract development and cGMP manufacturer of biologics, for the manufacture of our internally-developed molecules.

By the end of 2019, we successfully launched cGMP production with manufacturing runs of clinical grade materials adequate to support clinical trials.

As of December 31, 2023, we successfully completed cGMP production of five molecules of our molecules, including HCW9101, HCW9201, HCW9206, HCW9218, and HCW9302.

This includes the quantities of clinical grade materials required to complete the Phase 1/1b/2 clinical trials we have planned during 2024 and 2025, as well as toxicology studies.

We expect manufacturing, quality control procedures, and vialing will continue for several molecules in 2024, including additional clinical and research grade materials for our licensee, Wugen.

By the end of 2019, we successfully launched cGMP production with manufacturing runs of clinical grade materials adequate for support of our clinical trials.

As of December 31, 2024, we have successfully completed cGMP production of five of our molecules (HCW9101, HCW9201, HCW9206, HCW9218, and HCW9302).

The production campaigns include the sufficient quantities of clinical grade materials required to complete the Phase 1 / 2 clinical trials we have planned during 2025 and 2026 for HCW9302.

We currently rely on EirGenix and other third-party manufacturers for the cGMP production of sufficient quantities of our drug product candidates for our clinical trials.

Our management team and other internal personnel have extensive cGMP manufacturing experience which allows for seamless technology transfer our proprietary manufacturing methods, as well as the ability to manage the manufacturing and development processes conducted by third-party manufacturers.

Our management team and other internal personnel have extensive cGMP manufacturing experience which allows for seamless technology transfer of our proprietary manufacturing methods, as well as the ability to manage the manufacturing and development processes conducted by third-party manufacturers.

Our agreements with third-party manufacturers include confidentiality and intellectual property provisions as well as routine quality audits.

However, we currently obtain our products from these manufactures on a per project basis and do not have long-term supply arrangements in place.

However, we currently obtain our products from these manufacturers on a per project basis and do not have long-term supply arrangements in place.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential alternative contract manufacturers available to us on commercially reasonable terms to meet our future production requirements, although we may incur some delay and cost in qualifying and re-establishing the manufacturing processes at an alternative facility.

We endeavor to mitigate this risk by maintaining an inventory of clinical material that is adequate to complete the clinical trials we expect to initiate in the next 12 months.

On August 15, 2022, we purchased a 36,000 square foot building located in Miramar, Florida.

This facility will serve as our new headquarters.

On August 15, 2022, we purchased a 36,000 square foot building located in Miramar, Florida that is intended to serve as our new headquarters.

After refitting this building, we expect to have the capabilities for cGMP clinical drug manufacturing, storage, distribution, and quality testing.

We expect to relocate to this building and complete FDA validation for this facility in the first half of 2025.

We expect to relocate to this building and complete validation of the facility in the first half of 2026.

We have the flexibility to complete the buildout of the manufacturing facility on a longer schedule, should we choose to delay completion.

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Internally-Developed Intellectual Property

As of December 31, 2023, the United States Patent and Trademark Office (the “USPTO”) has granted HCW Biologics five patents, including fundamental patents that protect the underlying technology for our two lead product candidates, HCW9218 and HCW9302, as well as patents that protects the underlying technology and use of the molecule HCW9206, which is licensed to Wugen, conveying rights to develop cell-based therapies for cancer.

We retain all other rights to HCW9206, including manufacturing rights.

Patents that protect the underlying technology for proprietary molecules include:

TOBI Platform and TOBI-Based Molecules

As of December 31, 2024, the United States Patent and Trademark Office (the “USPTO”) has granted ten patents, including fundamental patents that protect the underlying technology for our two lead product candidates, HCW9218 and HCW9302, as well as patents that protect the underlying technology and use of the molecule HCW9206, which is licensed to Wugen, conveying rights to develop cell-based therapies for cancer.

In respect of Wugen, we retain all other rights to HCW9206, including manufacturing rights.

As part of a confidential Settlement Agreement with ImmunityBio, Inc.

in 2024, the Company assigned certain patents and patent applications to ImmunityBio, Inc., yet the Company retained a world-wide exclusive license in respect of the use of TOBI molecules outside of oncology indications.

Licensed patents that protect the underlying technology for proprietary molecules include:

• The USPTO granted U.S.

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This patent contains composition claims for immunotherapeutic multi-chain chimeric polypeptides, supporting our lead drug candidate, HCW9218.

As of December 31, 2023, in addition to five issued U.S.

patents, we have two issued Japanese patents and 105 pending patent applications worldwide, including 19 pending U.S.

utility patent applications, four pending provisional U.S.

patent applications, three pending Patent Cooperation Treaty (“PCT”) application, ten Hong Kong applications, and 84 total pending non-U.S.

national phase patent applications and Taiwan patent applications.

As of December 31, 2024, in addition to a license to ten issued U.S.

patents, we have a license to four issued Japanese patents, two issued Australian patents, one issued Singaporean patent, one issued Taiwanese patent, and 124 pending patent applications worldwide, including 20 pending U.S.

utility patent applications, one pending provisional U.S.

patent application, three pending Patent Cooperation Treaty (“PCT”) applications, nine Hong Kong applications, and 91 total pending non-U.S.

national phase patent applications and Taiwanese patent applications.

HCW Biologics owns 13 pending patent applications worldwide including one pending U.S.

utility patent application, two pending provisional U.S.

patent applications, one Hong Kong application, and nine total pending non-U.S.

national phase patent applications and Taiwanese patent applications.

Our policy is to file patent applications to protect technology, inventions and improvements to inventions that are commercially important to the development of our business.

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Our intellectual property portfolio is continually evolving during prosecution of our applications.

We own multiple families of patent applications that are directed to our TOBI platform technology and our single-chain and multi-chain chimeric polypeptides and methods of use of these polypeptides alone and in combination.

Single-Chain Chimeric Polypeptides Patent Family

This family includes patents and patent applications with claims directed to compositions of various single-chain chimeric polypeptides created using the TOBI platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our single-chain chimeric polypeptides.

We own or license multiple families of patent applications that are directed to our TOBI platform technology and our single-chain and multi-chain chimeric polypeptides and methods of use of these polypeptides alone and in combination.

Single-Chain Chimeric Polypeptides Licensed Patent Family

This family includes licensed patents and patent applications with claims directed to compositions of various single-chain chimeric polypeptides created using the TOBI platform.

These licensed applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our single-chain chimeric polypeptides.

As of December 31, 2024, this family, which includes HCW9302, includes U.S.

11,401,324, two pending U.S.

utility patent applications, one issued Japanese patent, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, New Zealand, Japan, South Korea, China, Singapore, Hong Kong and Taiwan.

11,401,324, 11,987,619, and 12,018,071, one pending U.S.

utility patent application, one issued Japanese patent, and 13 pending patent applications filed in Europe, Australia, Canada, Israel, New Zealand, Japan, South Korea, China, Singapore, Hong Kong and Taiwan.

The earliest predicted expiration date of any patent issuing from a patent application in this family is 2039.

Multi-Chain Chimeric Polypeptides Patent Family

This family includes patents and patent applications with claims directed to compositions of various multi-chain chimeric polypeptides created using the TOBI platform.

These applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our multi-chain chimeric polypeptides.

Multi-Chain Chimeric Polypeptides Licensed Patent Family

This family includes licensed patents and patent applications with claims directed to compositions of various multi-chain chimeric polypeptides created using the TOBI platform.

These licensed applications also include methods of use and manufacture thereof and methods of promoting the activation and proliferation of NK cells or T cells using our multi-chain chimeric polypeptides.

As of December 31, 2024, this family, which includes claims encompassing HCW9218, HCW9201, HCW9206, HCW9228, HCW9207, and HCW9212, includes U.S.

11,518,792, seven pending U.S.

utility patent applications, one issued Japanese patent, and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

11,518,792 and 11,884,712, six pending U.S.

utility patent applications, one issued Japanese patent, one issued Australian patent, one issued Singaporean patent, one issued Taiwanese patent, and 12 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

The earliest predicted expiration date of any patent issuing from a patent application in this family is 2039.

With respect to HCW9218, the composition is claimed in U.S.

11,518,792 and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

With respect to HCW9201, the composition is claimed in one pending U.S.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

With respect to HCW9218, as of December 31, 2024, the composition is claimed in U.S.

11,518,792, four patents issued in Australia, Singapore, Japan and Taiwan, and eight pending patent applications filed in Europe, Canada, Israel, Japan, New Zealand, South Korea, China, and Hong Kong.

With respect to HCW9201, December 31, 2024, the composition is claimed in one allowed U.S.

utility patent application, one issued Singaporean patent, one issued Japanese patent and ten pending patent applications filed in Europe, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed chimeric polypeptides in manufacturing certain cellular therapy products.

With respect to HCW9206, the composition is claimed in one pending U.S.

utility patent application and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

With respect to HCW9206, December 31, 2024, the composition is claimed in U.S.

11,884,712 , one issued Singaporean patent, one issued Japanese patent and 11 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, New Zealand, South Korea, China, Singapore, Hong Kong and Taiwan.

Wugen has obtained an exclusive license to these patent applications limited to use of the licensed polypeptides in manufacturing certain cellular therapy products.

Methods of Culturing and Methods of Expansion and Proliferation

These two families include patents and patent applications with claims directed to methods of promoting the activation and proliferation of NK cells through the use of our single-chain or multi-chain chimeric polypeptides for ex vivo cell therapy use.

These two families include licensed patents and patent applications with claims directed to methods of promoting the activation and proliferation of NK cells through the use of our single-chain or multi-chain chimeric polypeptides for ex vivo cell therapy use.

As of December 2024, these two families, which include methods of using HCW9201 and HCW9206, include U.S.

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11,738,052, two pending U.S.

utility patent applications, and 15 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, South Korea, Singapore, Hong Kong and China.

utility patent applications, one issued Australian patent, one issued Japanese patent, and 16 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, South Korea, Singapore, Hong Kong and China.

The earliest predicted expiration date of any patent issuing from a patent application in the first of these two families is 2039.

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Treating Age Related Disorders

These four families include a patent and patent applications with claims directed to methods of killing or reducing the number of senescent cells in a subject using our single-chain or multi-chain chimeric polypeptides.

These four families include licensed patent and patent applications with claims directed to methods of killing or reducing the number of senescent cells in a subject using our single-chain or multi-chain chimeric polypeptides.

As of December 2024, these four families, which include methods of using HCW9218, HCW9228 and HCW9302, include U.S.

11,672,826, four pending U.S.

utility patent applications, and 33 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, Hong Kong, South Korea, New Zealand, Singapore, and China.

11,672,826, 12,024,545, and 12,115,191, four pending U.S.

utility patent applications, one issued Japanese patent, and 33 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, Hong Kong, South Korea, New Zealand, Singapore, and China.

The earliest predicted expiration date of any patent issuing from a patent application in the first of these three families is 2039.

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Patents that may issue from these HCW Biologics Inc.

owned applications are generally expected to expire between the years 2039 to 2041, subject to possible patent term adjustment and/or extension.

owned or licensed applications are generally expected to expire between the years 2039 to 2041, subject to possible patent term adjustment and/or extension.

The term of individual future patents may vary based on the countries in which they are obtained.

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When possible, we expect to apply for patent term extensions for future patents covering our product candidates and their methods of use.

We have 2 registered U.S.

New Chimeric Polypeptide Platform

As of December 31, 2024, HCW Biologics has filed two provisional patent applications related to a new chimeric polypeptide platform.

The new chimeric polypeptide platform will be useful in the generation of polypeptides with therapeutic potential (e.g., useful in the field of inflammaging).

We have two registered U.S.

trademarks and two pending U.S.

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Contracts and Agreements

Wugen Exclusive License Agreement

Wugen Exclusive Worldwide License Agreement

In December 2020, we entered into an exclusive worldwide license agreement with Wugen, for rights to use certain HCWB fusion protein molecules to develop, manufacture, and commercialize their cellular therapy products.

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Wugen funds all future clinical development and commercialization activities for the cellular therapy treatments developed by Wugen using the licensed molecules.

WY Biotech Exclusive Worldwide License Agreement

On November 17, 2024, HCW Biologics entered into an exclusive, worldwide License, Research, and Co-Development Agreement (the “WY Biotech License Agreement”) with WY Biotech Co., Ltd.

(the “WY Biotech”) for one of the Company’s preclinical, proprietary molecules.

As reported in the Company’s Form 8-K filed with the SEC on March 19, 2025, on March 18, 2025, the Company and WY Biotech agreed to amend the WY Biotech License Agreement.

The Company has now completed extensive preclinical studies that further support our belief in the potential for HCW11-006 for both an in vivo and ex vivo therapy.

The Company considers WY Biotech License Agreement provisions for the Opt-In Right to take over the development of HCW11-006 for the Americas markets to be an important feature of the WY Biotech License.

We believe our right to recapture this market is a potentially high value opportunity.

Upon the completion of a Phase 1 clinical trial in any jurisdiction, the Company has an “Opt-In Right,” which gives the Company the option to assume all control and responsibility for the development, manufacture and commercialization of the molecule licensed to WY Biotech in the Opt-In Territory.

The “Opt-In Territory” is North America, South America, and Central America.

Upon the completion of the exercise of the Opt-In Right, the Company will be responsible for all costs associated with research and development, manufacturing, clinical development, regulatory approval, and commercialization for the licensed molecule in the Opt-In Territory.

WY Biotech will pay the Company milestone payments as the licensed molecule advances through clinical trials and the first marketing approval is granted for the first territory in which the WY Biotech retains exclusive rights.

Upon commercialization, the Company will receive double-digit royalties on a product-by-product basis in each jurisdiction in which the WY Biotech retains exclusive rights, subject to adjustment in the event the Company exercises the Opt-In Right.

In addition, the Company will share a substantial portion of the net proceeds from any future transactions entered into by the WY Biotech, involving an exclusive license for the licensed molecule, an assignment of the WY Biotech License Agreement or the sale of the WY Biotech’s business that would permit the buyer to assume exclusive rights under the WY Biotech License Agreement, excluding transactions in the Greater China market.

The Company and WY Biotech have expressed their intent to work cooperatively with respect to the licensed molecule in the development stage, with a global focus for clinical development and partnering.

The WY Biotech License Agreement contains various representations, warranties, affirmative and negative covenants, events of default and related remedies as well as other customary provisions.

Contract Research Agreements

We have certain contract research agreements with contractors that were entered during the two years ended December 31, 2023 for the (i) hybridoma development, (ii) cell line improvement, and (iii) research to support pre-clinical studies.

We own all rights to the resulting intellectual property, including the antibodies, sequences, and data.

We have certain contract research agreements with contractors that were entered during the two years ended December 31, 2024 for the (i) hybridoma development, (ii) cell line improvement for higher manufacturing productivity, and (iii) research to support pre-clinical studies.

In respect of the hybridoma development and cell line improvement agreements, we own all rights to the resulting intellectual property, including the antibodies, sequences, and data.

To date, we have received several sequences and hybridomas from the contractors.

For certain contractors, we are obligated to pay one future milestone payment upon filing and acceptance of an IND for each respective human antibody or protein from cell line;

however no additional future development or financial obligations are due under these contract research agreements.

however, no additional future development or financial obligations are

due under these contract research agreements.

For certain research collaborations agreements, the resulting research intellectual property may be jointly owned or ownership may be based upon inventorship.

In those circumstances, the Company has obtained the exclusive option to an exclusive license for the research intellectual property

The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on internally-developed products.

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These competitors also compete with us in establishing clinical trial sites and patient registration for clinical trials necessary to advance the clinical development of our product candidates.

Although we believe our novel approach is different from most other existing or investigational therapies across the disease areas where we are focusing our development, we will need to compete (or be combined) with currently approved therapies, and potentially those currently in development if they are approved.

Although we believe our novel approaches are different from most other existing or investigational therapies across the disease areas where we are focusing our development, we will need to compete (or be combined) with currently approved therapies, and potentially those currently in development if they are approved.

We are aware of several marketed and investigational products in our leading disease areas, including but not limited to the products and competitors discussed below.

We compete in the segments of the pharmaceutical, biotechnology, and other related markets that develop cancer therapies.

There are many other companies that have commercialized or are developing cancer therapies, including large pharmaceutical and biotechnology companies, such as AstraZeneca/MedImmune, Bristol Myers Squibb Company, Merck & Co., Novartis Pharmaceuticals, Pfizer, and Genentech, a member of The Roche Group.

There are many other companies that have commercialized or are developing cancer therapies, including large pharmaceutical and biotechnology companies, such as Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb Company, Merck & Co., Novartis Pharmaceuticals, Pfizer, and Genentech, a member of The Roche Group.

We face significant competition from pharmaceutical and biotechnology companies that target specific tumor-associated antigens using immune cells or other cytotoxic modalities.

These generally include immune cell redirecting therapeutics ( e.g.

, T cell engagers), adoptive cellular therapies ( e.g.

, CAR-Ts), antibody drug conjugates, targeted radiopharmaceuticals, targeted immunotoxin, and targeted cancer vaccines.

With respect to our lead internally-developed product candidate, HCW9218, we are not aware of any other competing clinical-stage companies with a first-in-class immunotherapeutic that utilizes multiple mechanisms of action, including the cytokine-based activation of immune cells and neutralization of TGF-β immunosuppression.

With respect to our second lead product candidate, HCW9302, there is a growing momentum behind modulating T reg cells as a potential treatment for autoimmune diseases.

We are not aware of other competing clinical-stage companies with a first-in-class immunotherapeutic for deactivation of inflammasomes and reduction of inflammatory cytokines they release through the activation of T reg cells.

We are aware of several other companies developing programs that utilize IL-2 for the selective expansion of T reg cells, including Amgen, Nektar Therapeutics, Genentech, a member of The Roche Group, Merck & Co., Bristol Myers Squibb Company, and Celgene, a subsidiary of Bristol Myers Squibb Company.

These generally include immune cell redirecting therapeutics (e.g., T-cell engagers), adoptive cellular therapies (e.g., CAR-Ts), antibody drug conjugates, targeted radiopharmaceuticals, targeted immunotoxins, and targeted cancer vaccines.

Aging-related diseases are becoming a major focus in biopharma, as researchers and companies work to develop treatments for conditions like Alzheimer's.

Biotech innovators like Altos Labs and Unity Biotechnology are at the forefront, exploring ways to target aging itself by removing senescent cells and modifying metabolic pathways.

In oncology, there's growing interest in using senescence removal to improve the effectiveness of cancer treatments.

Big names in pharma like Pfizer, Johnson & Johnson, and Roche are investing heavily in aging research, seeing not only its potential for regenerative therapies but also its enormous market potential.

As the global population ages, this field is rapidly advancing and becoming a critical area of growth in healthcare.

With respect to our other lead product candidate, HCW9302, there is a growing momentum behind modulating T reg cells as a potential treatment for autoimmune diseases.

We are not aware of other competing clinical-stage companies with a first-in-class immunotherapeutic compound for deactivation of persistently activated immune cells, inflammasomes and reduction of inflammatory cytokines they release through the activation of T reg cells.

Autoimmune diseases, including alopecia areata, atopic dermatitis, and neurodegenerative disorders, are gaining increasing attention in biopharma.

We are initiating clinical development in this area using HCW9302, which recently received IND clearance from FDA for a Phase 1 clinical study for alopecia areata.

We are aware of several other companies developing programs that utilize IL-2 for the selective expansion of T reg cells, including Amgen, Coya Therapeutics, Nektar Therapeutics, Genentech, a member of The Roche Group, Merck & Co., Bristol Myers Squibb Company, and Celgene, a subsidiary of Bristol Myers Squibb Company.

We are also aware of other companies with research or preclinical-stage programs in this area, including Synthorx, Moderna, and Xencor.

We are also aware of other companies with PD-1 agonist programs for the treatment of autoimmune diseases, including AnaptysBio, Celgene, a subsidiary of Bristol Myers Squibb Company, and Eli Lilly & Company.

We are also aware of other companies with PD-1 or CTLA-4 agonist programs for the treatment of autoimmune diseases and transplant, including Coya Therapeutics, AnaptysBio, Celgene, a subsidiary of Bristol Myers Squibb Company, and Eli Lilly & Company.

Additionally, preclinical studies are underway to explore HCW9302’s potential in targeting neurodegenerative diseases.

Collaborations are ongoing with various institutions to better understand the biology of HCW9302 in both transplant models and alopecia.

Several small and large pharmaceutical companies are currently working on low-dose IL-2 treatments for autoimmune diseases.

Moreover, numerous mid- to large-sized biotech companies are seeking partnership opportunities to further explore the potential of HCW9302 in autoimmune diseases.

HCW9302 is suitable for both in vivo subcutaneous injection strategies and T reg cell therapy.

In addition to alopecia areata, future plans include testing this molecule in transplant models, expanding its potential therapeutic applications.

Numerous companies, including Kite Pharma, Novartis, Bluebird Bio, and Autolus Therapeutics, renowned for their CAR-T cell therapies in oncology, are expanding their research to explore the potential of CAR-T therapies in autoimmune diseases.

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Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety, and convenience of our therapeutics, the ease of use and effectiveness of any complementary diagnostics and/or companion diagnostics, and price and levels of reimbursement.

We have a novel approach to the treatment of senescence-associated diseases.

Bronchopulmonary dysplasia (“BPD”) presents unmet needs, particularly in addressing long-term lung damage and inflammation in premature infants.

With growing pharma competition, treatments targeting senescent cell removal from the lungs are emerging as a promising approach to improve lung function and reduce BPD-related complications.

Several immune checkpoint inhibitors have been approved for the treatment of a limited number of cancer indications.

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and its product, Keytruda®.

Recently, several pharmaceutical companies have been licensing various versions of PD-1 from Greater China and other small biotech firms, further reflecting the growing interest in innovative immune-modulating therapies.

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In most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the safety and efficacy of the biologic.

In rare instances, a single Phase 3 trial may be sufficient when either (1) the trial is a large, multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible or (2) the single trial is supported by other confirmatory evidence.

Approval on the basis of a single trial may be subject to a requirement for additional post-approval studies.

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An approval letter authorizes commercial marketing and distribution of the biologic with specific prescribing information for specific indications.

As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”), to help ensure that the benefits of the biologic outweigh the potential risks to patients.

As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”), to help ensure

that the benefits of the biologic outweigh the potential risks to patients.

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

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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 (“FDORA”) was recently enacted, which included provisions related to the accelerated approval pathway.

The Food and Drug Omnibus Reform Act (“FDORA”) was enacted, which includes 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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The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) creates an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA-licensed reference biological product.

Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

Biosimilars are licensed based on the FDA’s findings of safety, purity and potency for a previously-FDA-licensed product called a reference product.

There must be no differences in route of administration, dosage form, and strength, and there must be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency in at least one or more conditions of use for which the reference product is approved.

Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of U.S.

Department of Health and Human Services (“HHA”) waives a required element.

A biosimilar product may be deemed interchangeable with a previously approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Department of Health and Human Services (“HHS”) waives a required element.

A biosimilar product may also meet the higher hurdle of interchangeability such that it can be substituted for a reference product without the intervention of the prescribing health care provider if the sponsor can demonstrate that the biosimilar product can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

The first biosimilar was approved in 2015, and the first interchangeable product was approved in 2021.

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

A reference biologic is granted 12 years of exclusivity from the time of first licensure, or BLA approval, of the reference product, and no application for a biosimilar can be submitted for four years from the date of licensure of the reference product.

Complexities associated with the larger, and often more complex, structures of

biological products, as well as the process by which such products are manufactured, pose significant hurdles to biosimilar product implementation, which are still being evaluated by the FDA.

A reference product is granted 12 years of exclusivity from the time of first licensure, or BLA approval, of the reference product, and during that 12 years of data exclusivity, no application for a biosimilar relying on the reference product can be submitted for four years.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) 18 months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar is approved if a patent lawsuit is ongoing within the 42-month period.

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Entities that are found to be in violation of HIPAA may be subject to significant civil, criminal and administrative fines and penalties, and/or additional reporting and oversight obligations if required to enter into a resolution agreement and corrective action plan with HHS to settle allegations of HIPAA non-compliance.

Further, entities that knowingly obtain, use, or disclose individually identifiable health information maintained by a HIPAA covered entity in a manner that is not authorized or permitted by HIPAA may be subject to criminal penalties.

Further, entities that knowingly obtain, use, or disclose individually identifiable health

information maintained by a HIPAA covered entity in a manner that is not authorized or permitted by HIPAA may be subject to criminal penalties.

Even when HIPAA does not apply, according to the FTC, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act.

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Several healthcare reform proposals recently culminated in the enactment of the Inflation Reduction Act (“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.

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.

For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D products in 2023, negotiations began 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 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 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 these inflation rebates.

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

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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.

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.

We expect that additional state and federal healthcare reform measures could be adopted in the future.

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The CHMP and CAT are also responsible for providing guidelines on ATMPs.

These guidelines provide additional guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs;

These guidelines provide additional guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs and include, among other things, the preclinical

studies required to characterize ATMPs;

the manufacturing and control information that should be submitted in a marketing authorization application;

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This oversight applies both before and after grant of manufacturing licenses and marketing authorizations.

It includes control of compliance with EU good manufacturing practices rules, manufacturing authorizations, pharmacovigilance rules, and requirements governing advertising, promotion, sale, and distribution, recordkeeping, importing, and exporting of medicinal products.

It includes control of

compliance with EU good manufacturing practices rules, manufacturing authorizations, pharmacovigilance rules, and requirements governing advertising, promotion, sale, and distribution, recordkeeping, importing, and exporting of medicinal products.

Failure by us or by any of our third-party partners, including suppliers, manufacturers, and distributors to comply with EU laws and the related national laws of individual EU Member States governing the conduct of clinical trials, manufacturing approval, marketing authorization of medicinal products, and marketing of such products, both before and after grant of marketing authorization, statutory health insurance, bribery and anti-corruption, or other applicable regulatory requirements may result in administrative, civil, or criminal penalties.

65 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business