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Item 1. Business

2024-04-01 compared with 2023-03-28 · 418 added, 441 removed, 592 unchanged (59% of the section changed)

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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.

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 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.

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.

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

However, accumulation of senescent cells with Senescence-Associated Phenotype (“SASP”) pro-inflammatory factors has been implicated as a major source of chronic sterile inflammation leading to many aging-related pathologies.

SASP factors, including pro-inflammatory cytokines, chemokines, and proteinases, drive an inflammation cycle.

However, accumulation of senescent cells with Senescence-Associated Phenotype (“SASP”) proinflammatory factors has been implicated as a major source of chronic sterile inflammation leading to many aging-related pathologies.

SASP factors, including proinflammatory cytokines, chemokines, and proteinases, drive an inflammation cycle.

Senescence is considered a stress response and can be induced by a wide range of intrinsic and extrinsic insults.

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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 pro-inflammatory cytokines.

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.

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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.

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.

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Preclinical research and preliminary results from first-in-human clinical trials indicate that our immunotherapeutic approach may achieve success for cancer indications, and many other age-related diseases and conditions.

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

Novel Bifunctional Immunotherapeutic with TGF-β

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

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 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.

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 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.”

The paper highlights preclinical data from in vitro and in vivo studies demonstrating the potential of HCW9218 as a novel immunostimulant with the ability to simultaneously lessen immunosuppression in patients with cancer.

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

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

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

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

Tumor cells can undergo senescence and secrete pro-inflammatory factors, or SASP factors, in response to chemotherapy, a process referred to a therapy-induced senescence (“TIS”).

SASP factors promote TIS cancer cells to re-enter the growth cycle with stem-like characteristics which can result in disease relapse and metastasis.

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

In healthy tissue, TGF-β

is transiently activated in response to tissue injury, resulting in collagen production and, ultimately, healing of the tissue.

However, when TGF-β

becomes continuously active, studies have shown that it induces pathological effects associated with inflammation.

In preclinical animal tumor models, HCW9218 treatment reduced the immunosuppressive tumor microenvironment and enhanced immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells, thus improving the efficacy of chemotherapy.

Additionally, HCW9218 treatment following chemotherapy further enhanced anti-tumor activity of tumor antigen-specific and anti-programmed death-ligand 1 (“PD-L1”) antibodies in tumor-bearing mice.

The results of these studies have been published by our scientific research team in April 2022 in the peer-reviewed journal, Molecular Therapy , entitled “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells.”

We believe these findings support the clinical development of HCW9218 in combination with standard-of-care anti-cancer therapies, including chemotherapies, therapeutic antibodies and immune checkpoint inhibitors, for patients with cancer.

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 designed to activate and expand regulatory T (“T reg ”) cells to suppress the activity of inflammasome-bearing cells and the inflammatory factors which they secrete.

This molecule is a single-chain, IL-2-based fusion protein.

Inflammasomes are expressed in innate immune cells.

When these cells are stimulated by various signals, the inflammasomes become active and the cells release inflammatory factors.

In certain conditions, these signaling pathways persist leading to chronic inflammatory responses and associated tissue destruction.

Preclinical studies in mouse models have demonstrated the ability of HCW9302 to activate T reg cells and reduce inflammation-related diseases, supporting the potential of HCW9302 to treat a wide variety of autoimmune and age-related diseases.

The Company published a paper in January 2023 that was authored by our scientific research team in the peer-reviewed journal, Frontiers in Immunology , entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice.”

The paper highlights preclinical data from in vitro and in vivo studies demonstrating the potential of HCW9302 as a novel immunotherapeutic with the ability to suppress the progression of atherosclerosis.

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.

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

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

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.

As described in our Frontiers in Immunology paper, we found that HCW9302 exhibited a longer serum half-life with an approximately 1,000-fold higher affinity for the IL2Rα

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 pro-inflammatory diseases.

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 have successfully developed over 30 molecules that can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches.

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.

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Clinical Development Strategy

HCW Biologics has a two-pronged clinical development strategy based on its two lead product candidates.

Currently, we are managing our clinical trials internally.

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;

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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.

HCW9218 is currently being evaluated in two clinical trials.

The Company has selected difficult-to-treat cancer indications as the gateway indication.

We believe the bifunctionality of HCW9218 will allow it to be effective against solid tumor cancers because it simultaneously provides immunostimulation of natural killer (“NK”) cells and effector T cells to enhance the cytotoxicity of immune cells against tumor targets, while reducing immunosuppression associated with solid tumors by capturing and neutralizing TGF-β.

A Company-sponsored, multi-center Phase 1b/2 clinical trial is being conducted to evaluate HCW9218 in advanced pancreatic cancer.

An Investigator-sponsored Phase 1 clinical study to evaluate HCW9218 in chemo-refractory/chemo-resistant solid tumors is being conducted by the Masonic Cancer Center, University of Minnesota.

There have been no dose-limiting toxicities reported for either trial.

For Phase 2 studies, we expect to evaluate HCW9218 in patients as a second line treatment and/or as an adjuvant therapy with standard-of-care treatments.

From the solid tumor trial, we intend to narrow the indication to one type of cancer, such as ovarian cancer.

Advancing HCW9218 to Phase 2 clinical trials depends on successfully completing the Phase 1 trial, identifying the Recommended Phase 2 Dose (“RP2D”), securing clinical sites for the Phase 2 study, and receiving authorization from the FDA to proceed.

Extensive, rigorous preclinical testing and research is being conducted to identify expanded indications for future clinical development.

We believe that HCW9218 represents a new class of safe and effective senescent cell reducing and senomorphic drugs for the treatment of a broad range of inflammaging indications, including cancer, metabolic dysfunctions, fibrosis-related pathologies, as well as neuro-inflammation and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s Diseases.

HCW9302 is a preclinical molecule which is a fusion protein 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 issue of its dose-limiting toxicities.

Preclinical studies demonstrated the HCW9302 exhibited 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 disease.

For our lead molecule HCW9302, the Company plans to use an autoimmune disease as the gateway indication for clinical development.

If we are successful in advancing the clinical development of HCW9302, we intend to expand to other pro-inflammatory indications.

The Company expects to complete the activities required to prepare an Investigational New Drug (“IND”) application in the first half of 2023.

We expect to submit an IND application for a Phase 1b/2 clinical study to evaluate HCW9302 in an autoimmune disease to the FDA in the second half of 2023.

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

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.

Out-Licensing, Cooperative Agreements and Strategic Collaborations

We continue to pursue our strategy of out-licensing certain rights outside of our focus area for our existing molecules and discovery programs created with our TOBI discovery platform, 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 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 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.

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.

On December 3, 2022, under a Cooperative Research and Development Agreement (“CRADA”), the National Cancer Institute (“NCI”) and HCW Biologics are collaborating to perform a Phase 1b/2 clinical study to evaluate the safety and tolerability of HCW Biologics’

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.”

The Principal Investigator at NCI is 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.

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

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.

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.

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.

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Clinical Development Update

The Company's lead immunotherapeutic programs are summarized in the table below:

There is an ongoing Company-sponsored Phase 1b/2 clinical trial to evaluate HCW9218 in patients with advanced chemo-refractory/chemo-resistant pancreatic cancer.

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

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

The clinical development progress of the Company's lead immunotherapeutic programs are 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.

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.

HCW Biologics has retained all other rights to HCW9201 and HCW9206, including, but not limited to, manufacturing rights and injectable rights.

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.

There are currently four clinical sites participating in this trial, including the NCI Center for Cancer Research, Medical University of South Carolina (an NCI-designated Comprehensive Cancer Center), Washington University in St.

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

A preliminary human data readout is expected in the first half of 2023.

We expect to complete the Phase 1b portion of this study in 2023.

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

HCW9218 reached the clinical stage of its development in the first half of 2022, with the initiation of a Phase 1 clinical trial by the Masonic Cancer Center, University of Minnesota (“UMN”) to evaluate HCW9218 in the treatment of solid tumor cancers that progressed after at the least of two lines of standard-of-care treatment.

UMN presented preliminary human data from the solid tumor trial in a poster presentation at the 2022 Society for Immunotherapy of Cancer annual conference in November 2022.

Analysis of blood samples and biopsies taken from participants in the Phase 1 study shows encouraging preliminary results for the level of immune system responses after HCW9218 administration, as well as no incidence of mucosal bleeding caused by the HCW9218 TGF-β

Based on the results of the Phase 1 study, we expect to complete selection of the recommended Phase 2 dose in the first half of 2023.

IND-Enabling Activities for HCW9302

For HCW9302, IND-enabling activities are expected to be completed in the first half of 2023.

We plan to submit an IND to the FDA for a Phase 1b/2 clinical trial to evaluate HCW9302 in an autoimmune disorder in the second half of 2023.

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.

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, 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.

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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 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 pro-inflammatory 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:

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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 pro-inflammatory 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.

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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.

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.

“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

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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 Senescence Cell Clearance and Senomorphic for SASP Neutralization

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.

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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.

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.

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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

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 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.

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.

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.

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

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, 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;

, 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-1ß).

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;

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 pro-inflammatory 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.

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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”

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.

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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.

In RNA-Seq analysis performed on whole aorta of WD-fed ApoE deficient mice, we found that HCW9302 treatment resulted in changes of gene expression profiles consistent with reduced atherosclerotic lesions and enhanced tissue regeneration.

For more details, see the Company’s pivotal scientific paper, entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

published in Frontiers in Immunology in January 2023 .

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

Our strategy for efficiently validating our approach includes the following key components:

Focus on cancer indications in initial clinical development of our lead product candidate, HCW9218, in indications with high unmet medical need or where side effects of standard-of-care therapy diminishes health span.

Cancer is our gateway indication.

We are focusing on difficult-to-treat indications for which there is high unmet medical needs.

If we are able to successfully complete our ongoing Phase 1/1b trials in cancer studies and establish safety and dosage, we intend to expand to indications other age-related diseases.

Clinical trials allow us to evaluate the development of our novel immunotherapeutics as we attempt to augment the efficacy of chemotherapy against cancer while minimizing its side effects.

As and to the extent we advance in clinical trials for cancer, we are initially focusing on clinical trials to evaluate HCW9218 as an adjuvant therapy to existing standard-of-care treatments.

Because of our highly efficient design for neutralizing TGF-β, we have targeted cancer indications with TGF-β

mediated immunosuppression and a fibrotic tumor microenvironment ( i.e.

, pancreatic and ovarian).

We plan to advance well-characterized immunotherapeutics with multiple mechanisms of action:

effector immune cell activation, suppression of TGF-β, reduction of senescent cells, and reduction of SASP ( i.e.

, senomorphics).

Focus on autoimmune indications with high unmet medical need in initial clinical development of our lead product candidate, HCW9302.

IND-enabling activities and toxicology studies required for submission of an IND to evaluate HCW9302 in an autoimmune indication are expected to be completed in the first half of 2023, followed soon thereafter with an IND submission to evaluate HCW9302 in an autoimmune indication.

We have not yet submitted the IND, nor can we guarantee when the IND will be submitted, if at all.

Leverage established clinical trial network.

Our management team has extensive experience managing clinical trials, enabling us to reduce dependency on a contract research organization for our trials.

Our founder and clinical development team have a track record of success in developing immuno-oncology therapeutics from bench to bedside.

For our active clinical trials to evaluate HCW9218 in cancer indications, most of the clinical sites are NCI-designated Comprehensive Cancer Centers.

These clinical sites service large regions and due to their excellence often attract patients far from their local regions.

Identify non-dilutive financing events that allow us to advance the clinical development of our lead product candidates.

We intend to pursue several different avenues for non-dilutive financing events, including out-licensing non-core applications and market rights, cooperative agreements, strategic collaborations and project financing.

Explore co-development deals with big pharma for lead molecules in the longer term.

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

Our Internally-Developed Tissue factOr-Based fusIon (“TOBI”) Platform

Our TOBI discovery platform is a new approach to construct multi-functional fusion proteins and fusion protein complexes using a novel TF protein scaffold.

The extracellular domain of human TF was selected as it has a rigid elongated structure comprised mainly of ß-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.

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.

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.

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.

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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

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.

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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.

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.

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

HCW9218 is comprised of extracellular domains of the human TGF-β

receptor II and a human IL-15/IL-15 receptor α

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 exhibited TGF-β

neutralizing activity in vitro and sequestered plasma TGF-β

in mice and non-human primates.

In animal models, HCW9218 displayed strong anti-tumor activity mediated by NK cells and CD8 + T cells, and increased infiltration of NK cells and CD8 + T cells into tumors.

HCW9218 was well tolerated in preclinical studies, with a half-life sufficient to provide long lasting biological activity.

HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors and other age-related diseases.

As we state in our published scientific papers reporting results of preclinical studies, we also observed that HCW9218 could enhance the anti-tumor efficacy of immune checkpoint blockade (anti-PD-L1 antibody, α-PD-L1) via T-cell infiltration into the tumor avoiding immunosuppressive factors in the tumor microenvironment, or TME.

HCW9218 Enhances Anti-Tumor Activity of Immune Checkpoint Blockade

Molecular Therapy, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,”

Chaturvedi, P., et al., April 2022.

Moreover, HCW9218 enhanced the anti-tumor efficacy of chemotherapy against human pancreatic tumors in xenograft mouse models.

Induction of senescence tumor cells in human SW1990 pancreatic cancer cells was observed following treatment with nab-paclitaxel and gemcitabine (A+G), standard-of-care chemotherapies (left panel).

Further, HCW9218 treatment significantly enhanced A+G chemotherapy activity by controlling tumor growth and prolonging survival of SW1990 tumor-bearing mice (center and right panels).

We believe that the results of these studies support clinical development of HCW9218 in combination with chemotherapies and other immune therapies in patients with solid tumors, including pancreatic cancer.

HCW9218 Enhances Anti-Tumor Efficacy of Chemotherapy

Against Human SW1990 Pancreatic Tumor Cells in Xenograft Mouse Models

Molecular Therapy, “Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells,”

Chaturvedi, P., et al., April 2022.

HCW9218 is a clinical-stage program, currently active in two Phase 1/1b clinical trials to evaluate HCW9218 in cancer indications.

At the 2022 Society for Immunotherapy of Cancer (“SITC”) conference, a preliminary human clinical data readout was presented by the Principal Investigator of the Phase 1 clinical trial to evaluate HCW9218 monotherapy in chemo-refractory/chemo-resistant solid tumor cancers sponsored by Masonic Cancer Center, University of Minnesota.

Data showed all subjects had a robust proliferation of blood NK cells, ranging from 77% to 97% Ki67-positivity by Day 8 after dosing for each treatment cycle.

HCW9218-mediated increases in blood NK cell percentages and counts were also observed.

Responses were sustained through Day 15, a biological effect beyond that previously observed for other IL-15 agonists.

These results are depicted in the graph below.

Preliminary Human Data Readout UMN Trial from SITC 2022:

NK Cell Responses

In addition, preliminary human data of this clinical trial also showed that there was a modest increase in blood CD8 + T cell proliferation at Day 8 after each treatment cycle.

The results are depicted in the graph below.

Preliminary Human Data Readout UMN Trial from SITC 2022:

HCW9218-Mediated Changes % of Ki67 + CD8 + T Cells

The preliminary data of this clinical trial also showed that there was a 50% reduction of the serum TGF-β1 in subjects treated at the 0.25 mg/kg HCW9218 dose level.

The 0.50 mg/kg HCW9218 dose level was able to almost completely neutralize serum TGF-β1.

HCW9218 treatment did not change serum levels of IL-1α, IL-1β, IL-6, IFN, or TNF.

These results are depicted in the graph below.

Together, these results verify that HCW9218 stimulates immune cells and reduces TGF-β

activity in patients with cancer in a dose- and schedule-dependent manner, consistent with our published results observed in preclinical tumor efficacy models.

Preliminary Human Data Readout UMN Trial from SITC 2022:

Reduction of Serum TGF-β

Cancer and Other Age-Related Diseases

HCW9218 is being evaluated for the treatment of cancer indications in two clinical trials.

The first is a Company-sponsored, multi-center Phase 1b/2 clinical trial for a dose escalation study of HCW9218 as monotherapy in patients with chemo-refractory/chemo-resistant pancreatic cancer.

There are currently four clinical sites participating in this trial, including the Center for Cancer Research, Medical University of South Carolina (an NCI-designated Comprehensive Cancer Center), Washington University in St.

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

We may enroll up to 24 patients in four clinical sites for the Phase 1b part of the pancreatic trial.

The primary objectives of the Phase 1b study is to determine safety, maximum tolerated dose, and the recommended Phase 2 dose, or RP2D.

To date, there have been no dose-limiting toxicities reported in this trial.

We expect to complete the Phase 1b study to evaluate HCW9218 in pancreatic cancer in 2023.

After determining the RP2D, we expect to submit an IND protocol amendment to the FDA for the Phase 2 portion of this clinical trial to include patients receiving HCW9218 as an adjunct to chemotherapy.

In the Phase 2 dose expansion portion, we intend to enroll up to 40 patients at the RP2D with primary objectives to determine the 6-month progression free survival rate and evaluate the safety profile of HCW9218.

The secondary objectives of this study are to determine the objective response rate, overall survival, time to progression, and duration of response.

However, there can be no assurance that we will be able to advance to a Phase 2 study, since we have not yet completed the Phase 1b study, and we have not established safety and RP2D.

Moreover, there can be no assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all, when we apply for authorization to proceed with a Phase 2 study.

In the event we do not receive feedback on a timely basis, or we are required to change the design of our clinical protocol or address other feedback, clinical development of our products would be delayed and our costs may increase.

The second active clinical trial to evaluate HCW9218 in a cancer indication is an Investigator-sponsored trial for the Phase 1 portion of a clinical trial for dose escalation study of HCW9218 as a monotherapy in solid tumors, such as breast, ovarian, prostate and colorectal cancers.

The sponsor is the Masonic Cancer Center at the University of Minnesota, a leading NCI-designated cancer center.

The trial is designed as a dose escalation study of HCW9218 to identify the maximum tolerated dose for future evaluation.

Depending on the toxicities observed in the treated patients, between 12 and 24 patients may be enrolled.

To date, there have been no dose-limiting toxicities reported in this trial.

Based on results of the Phase 1 study to evaluate HCW9218 in solid tumors, we expect to select RP2D in the in the first half of 2023.

If we are successful in completing the objectives of the Phase 1 study, we intend to advance at least one Phase 2 study to evaluate HCW9218 in a single cancer indication, such as ovarian cancer.

However, we have not yet completed the Phase 1 study to evaluate HCW9218 in solid tumor cancers, and we have not established safety and RP2D.

Further, there can be no assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all, when we apply to the FDA for authorization to proceed with a Phase 2 study.

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.

If and when we advance to the next phase of our clinical studies, we intend to evaluate HCW9218 in two cancer indications that are two of the most difficult-to-treat and thus deadliest of cancers:

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, 64,050 Americans are expected to be diagnosed with pancreatic cancer in the United States, and more than 50,550 are expected to die from the disease.

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.

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• 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 woman.

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.

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However, in some countries the figure is much lower.

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

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 63 years or older.

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.

T reg cells achieve this immunoregulatory control through multiple suppressive mechanisms.

Alternations in T reg cell development, homeostasis or function can predispose these cells to affect a variety of disease conditions including allergy, autoimmunity, graft rejection, cancer, and response to immunotherapies.

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.

We have employed our TOBI platform to create HCW9302, an 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.

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.

For further details, 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.

We are currently conducting IND-enabling activities required to prepare for submission of an IND to evaluate HCW9302, administered by subcutaneous injection.

The timing for this submission will depend on the completion of nonclinical toxicology studies and testing and release of drug product, as well as finalizing the clinical protocol.

The nonclinical toxicology studies are expected to be completed in the first half of 2023.

We intend to follow with the submission of an IND for a Phase 1b/2 clinical trial to evaluate HCW9302 in an autoimmune indication, which we expect to occur in the second half of 2023.

However, we have not submitted the IND for the planned trial, and we cannot provide any assurance that the FDA will authorize us to initiate our planned clinical trials on a timely basis, or at all.

Moreover, if the FDA does not allow our initial clinical trial to proceed, we may be required to conduct additional preclinical testing or other IND-enabling activities, which would result in further delay and additional costs.

The two graphs below illustrate the results of characterization studies.

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

Results of Characterization Studies

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.

For more details, see our paper entitled, “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,”

published in Frontiers in Immunology.

Autoimmune and Pro-inflammatory Diseases

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

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 determine the safe and effective dose level and regimen of HCW9302 from our initial clinical trial in an autoimmune indication, which we have preliminarily determined will be alopecia areata, and then we intend to apply the dose level and treatment regimens established in initial clinical studies to evaluate HCW9302 for other autoimmune and pro-inflammatory diseases, such as atherosclerosis.

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.

HCW Biologics holds the rights to the injectable form of HCW9206 and e x vivo rights are licensed to Wugen.

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.

(“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.)

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 ML-NK cell therapies, infused cells are supported in vivo by recombinant human IL-2.

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.

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 .

Out-License Programs

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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.

We established our first out-license arrangement in December 2020, when we entered into an exclusive worldwide license agreement with Wugen for rights to develop cell therapy-based treatments using two HCWB internally-developed fusion protein molecules and improvements thereto, including clinical-stage and preclinical stage fusion molecules, HCW9201 and HCW9206, respectively (the “Wugen License”).

We established our first out-license arrangement in December 2020, when the Company entered into the Wugen License, an exclusive worldwide license agreement with Wugen for rights to develop cell therapy-based treatments using two of our internally-developed fusion protein molecules and improvements thereto, including clinical-stage and preclinical stage fusion molecules, HCW9201 and HCW9206, respectively.

We believe these molecules are capable of generating highly activated cells in a short time frame and large-scale NK cell expansion without relying on feeder cells.

Wugen has exercised its right to sublicense their rights for Greater

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”).

In the United States, Wugen will soon initiate a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML.

WU-NK 101 is a treatment based on the HCWB licensed molecules.

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.

We retained 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.

On June 18, 2021, the Company entered into a master services agreement with Wugen for the supply of materials for clinical development of licensed products.

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

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.

On June 18, 2021, we entered into a master services agreement with Wugen for the supply of materials for clinical development of licensed products.

Thereafter, each purchase transaction must be accompanied by a statement-of-work.

The Company plans to enter into commercialization supply agreement when Wugen enters the commercial stage of their company.

According to the terms of the Wugen exclusive license, Wugen will fund all future clinical development and commercialization activities for any indications utilizing the licensed molecules for cell-based therapy as covered by the license.

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

We plan to enter into a commercialization supply agreement when Wugen enters its commercial stage.

According to the terms of the Wugen License, Wugen will fund all future clinical development and commercialization activities for any indications utilizing the licensed molecules for cell-based therapy as covered by the Wugen License.

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 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.

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.

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Fusion Domains

IL-7, IL-15, IL-21

NK cell and T cell stimulation

Injectable for cancer,

Vaccine efficacy

IL-18, IL-15, IL-12, anti-CD16 scFv

NK cell stimulation

IL-7, IL-15, IL-21, CD137L

NK cell and CD8 + T cell stimulation

Anti-CD3, anti-CD28 scFvs

T cell/T reg stimulation

Cancer, inflammatory diseases

TGRßRII tetramer

Cancer, fibrotic diseases

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

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Inflammatory and age-related disease

Undisclosed target

Senescent cell inhibition and targeting

Inflammatory and age-related disease

Undisclosed target

T reg binding, activation, inhibition, and targeting

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Manufacturing

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

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.

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.

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.

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 adequate to support clinical trials.

As of December 31, 2022, we successfully completed cGMP production of five molecules, HCW9101, HCW9201, HCW9206, HCW9218, and HCW9302.

This includes clinical grade materials required to complete the toxicology studies for HCW9218 and HCW9302, as well as the quantities required for Phase 1/1b/2 clinical trials to evaluate both molecules.

Manufacturing, quality control procedures, and vialing will continue for several molecules in 2023, including additional clinical and research grade materials for our licensee, Wugen.

(“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.

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.

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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 for clinical trials we expect to initiate in the next 12-24 months.

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.

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

We expect this facility to be operational in the second half of 2024.

The Company has the flexibility to complete the buildout of the manufacturing facility on a longer schedule, should we choose to delay completion.

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

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

In the meantime, we will continue to manufacture clinical-grade material with third-party manufacturers.

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In addition to patents, we also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our competitive position.

We seek to protect our internally-developed technology, in part, through confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and potential collaborator.

We also rely on trade secrets relating to our manufacturing process and on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of inflammaging that may be important for the development of our business.

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Internally-Developed Intellectual Property

As of December 31, 2022, the United States Patent and Trademark Office (the “USPTO”) has granted HCW Biologics two fundamental patents:

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:

• 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, 2022, in addition to these two issued patents, we have 105 pending patent applications worldwide, including 15 pending U.S.

utility patent applications, six pending provisional U.S.

patent applications, one pending Patent Cooperation

Treaty (“PCT”) application, eight Hong Kong applications, and 76 total pending non-U.S.

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.

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Single-Chain Chimeric Polypeptides Patent Family

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

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.

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

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

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.

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

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.

As of December 2023, this family, which includes claims encompassing HCW9218, HCW9201, HCW9206, HCW9228, HCW9207, and HCW9212, includes U.S.

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

utility patent applications, 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, 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.

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

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Methods of Culturing and Methods of Expansion and Proliferation

These two families include 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 2022, these two families, which include methods of using HCW9201 and HCW9206, include two pending U.S.

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.

As of December 2023, these two families, which include methods of using HCW9201 and HCW9206, include U.S.

11,730,762, U.S.

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.

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Treating Age Related Disorders

These four families include 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 2022, these four families, which include methods of using HCW9218, HCW9228 and HCW9302, include four pending U.S.

utility patent applications, one pending PCT application, and 23 pending patent applications filed in Europe, Australia, Canada, Israel, Japan, Hong Kong, South Korea, New Zealand, Singapore and China.

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.

As of December 2023, 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.

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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As of December 2023, this family, which includes composition claims for HCW9106, includes one pending U.S.

utility patent application and five pending patent applications filed in Australia, Canada, Europe, China, and Japan.

utility patent application and six pending patent applications filed in Australia, Canada, Europe, China, Hong Kong, and Japan.

The earliest predicted expiration date of any patent issuing from a patent application in this family of applications is 2041.

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methods of inducing differentiation of an immune cell into a memory or memory-like immune cell (in vitro or in vivo);

methods of stimulating an immune cell ( in vitro or i n vivo );

methods of stimulating an immune cell (in vitro or in vivo);

and methods of inducing or increasing proliferation of an immune cell (in vitro or in vivo).

Indications covered in the portfolio broadly include cancers, including solid and hematological cancers;

Indications covered in the portfolio broadly include cancers, including solid tumors and hematological cancers;

age-related diseases;

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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 filed four pending U.S.

We have 2 registered U.S.

trademarks and two pending U.S.

trademark applications for our corporate name and corporate logo.

We have an International Registration for the mark HCW BIOLOGICS for pharmaceutical research and development services, among other related services, in Class 42 and four national trademark applications pending therefrom with one registration issued in the European Union.

In the future, we intend to file applications for trademark registrations in connection with our Company, our product candidates, and other technologies in various jurisdictions, including the United States as the products are further developed.

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The term of the agreement will expire on a product-by-product and country-by-country basis, upon the later of (i) the expiration of the last-to-expire valid patent claim or (ii) ten (10) years from the first commercial sale of such product.

As consideration for the Wugen License, HCWB received shares of Wugen’s common stock, which are currently equivalent to a 5.8% ownership interest in Wugen.

We may receive additional payments in the future, based upon the occurrence of certain development milestones with a value of over $200 million.

As consideration for the Wugen License, HCWB received shares of Wugen’s common stock, which was equivalent to a 5.6% ownership interest in Wugen as of December 31, 2023.

We may receive additional payments in the future, based upon the occurrence of certain development milestones.

We will be eligible to receive additional payments for commercialization milestones as well as single-digit royalties for commercial sales once product sales commence.

We retained all other rights and use of the licensed molecules outside of Wugen’s right to use the molecules to develop, manufacture, and commercialize cellular therapy products.

Wugen’s rights are limited to use of the licensed molecules in cellular therapy products, which are pharmaceutical or biological products, processes or therapies that contain or comprise cells (including without limitation, CIML NK cells or T cells) that have been engineered, modified, or otherwise manipulated ex vivo , but excludes regulatory T cell-based cellular therapy products.

We retained all other rights and use of the licensed molecules outside of Wugen’s right to use the molecules to develop, manufacture, and commercialize cellular therapy products.

Our retained rights include use of the molecules for injectable therapy product, regulatory T cell-based cellular therapy products, and manufacturing rights to the licensed molecules.

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Contract Research Agreements

We have certain contract research agreements with contractors that were entered during the two years ended December 31, 2022 for the (i) screening and identification of specific human antibodies to three particular proteins that influence the cellular-senescence process, (ii) hybridoma development, (iii) cell line improvement, and (iv) research to support pre-clinical studies.

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.

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Any product candidates that we successfully develop and commercialize may compete with existing therapies and new therapies that may become available in the future.

Many of the companies which we are competing against, or which we may compete against in the future, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.

Many of the companies we are competing against, or which we may compete against in the future, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.

In addition, we face a constantly changing competitive landscape because of numerous mergers and acquisitions in the pharmaceutical and biotechnology industry, which will concentrate resources among a smaller number of large pharmaceutical companies.

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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 with currently approved therapies, and potentially those currently in development if they are approved.

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.

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.

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

We intend to expand to other indications, such as the treatment of fibrotic diseases, including NAFLD, or non-alcoholic fatty liver disease.

NAFLD is an umbrella term that encompasses the entire spectrum of fatty liver disease, from isolated steatosis to NASH, or non-alcoholic steatohepatitis.

There are currently no FDA approved therapies for the treatment of NAFLD.

Instead, doctors will treat the underlying condition, such as obesity.

Most of the drugs currently in development for NAFLD are focused on decreasing liver fat or improving liver inflammation as opposed to direct liver anti-fibrotic approaches.

There are a number of companies developing product candidates for NAFLD including Pliant Therapeutics, Intercept, Pfizer, Gilead, AbbVie, Novartis, AstraZeneca, Eli Lilly & Company, GlaxoSmithKline, Amgen, Bristol Myers Squibb Company, Johnson & Johnson, Merck & Co., Genentech, a member of The Roche Group, Sanofi, Takeda Pharmaceuticals, Novo Nordisk, Genfit, Madrigal Pharmaceuticals, Viking Therapeutics, Cirius Therapeutics, NGM Biopharmaceuticals, Akero Therapeutics and Metacrine.

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 (in partnership with Eli Lilly & Company), Genentech, a member of The Roche Group, Merck & Co., Bristol Myers Squibb Company, and Celgene, a subsidiary of Bristol Myers Squibb Company.

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.

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.

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.

For instance, Kite Pharma and Novartis are investigating CAR-T treatments for autoimmune conditions like multiple sclerosis (MS) and systemic lupus erythematosus.

Similarly, Bluebird Bio is exploring CAR-T cell therapy for diseases such as sickle cell disease and beta-thalassemia, which involve autoimmune components.

Autolus Therapeutics is also targeting both cancer and autoimmune diseases like multiple myeloma, acute lymphoblastic leukemia, multiple sclerosis, and systemic sclerosis with CAR-T therapies.

This trend underscores a burgeoning interest in utilizing CAR-T cell therapy beyond oncology to tackle autoimmune disorders.

We could see a reduction or elimination of our commercial opportunity if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we or our collaborators may develop.

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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.

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.

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

and its product, Keytruda.

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.

The following list summarizes key immune checkpoint inhibitors along the companies that own these drugs and their patent expiration dates:

Associated Company

Key Patent Expiration Date

Pembrolizumab (Keytruda)

Nivolumab (Opdivo)

Bristol Myers Squibb

Atezolizumab (Tecentriq)

Genentech (Roche)

Durvalumab (Imfinzi)

Cemiplimab (Libtayo)

Regeneron Pharmaceuticals and Sanofi

Avelumab (Bavencio)

Merck KGaA and Pfizer

Government Regulation

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In the United States, biological products are subject to extensive regulation by the FDA.

The Federal Food, Drug, and Cosmetic Act (the “FDC Act”), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.

Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDC Act, with the exception that the section of the FDC Act which governs the approval of drugs via New Drug Applications (“NDAs”), does not apply to the approval of biologics.

In contrast, biologics are approved for marketing under provisions of the Public Health Service Act (“PHSA”), via a Biologics License Application (“BLA”).

However, the application process and requirements for approval of BLAs are very similar to those for NDAs.

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(i) in compliance with federal regulations;

(ii) in compliance with Good Clinical Practice (“GCP”), an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators, and monitors;

as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated.

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Imposition of a clinical hold may be full or partial.

The study protocol and informed consent information for patients in clinical trials must also be submitted to an institutional review board (“IRB”), for approval.

The IRB will also monitor the clinical trial until completed.

An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements, or may impose other conditions.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

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FDA approval of the BLA is required before marketing and distribution of the product may begin in the United States.

The BLA must include the results of all preclinical, clinical, and other testing and a compilation of data relating to the product’s pharmacology, chemistry, manufacture, and controls.

The cost of preparing and submitting a BLA is substantial.

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A BLA for a biologic that has been designated as an orphan drug is not subject to an application fee, unless the BLA includes an indication for other than a rare disease or condition.

The FDA has 60 days from its receipt of a BLA to determine whether the application will be filed based on the FDA’s determination that it is adequately organized and sufficiently complete to permit substantive review.

Once the submission is filed, the FDA begins an in-depth review.

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The review process for both standard and priority reviews may be extended by the FDA for three or more additional months to consider certain late-submitted information, or information intended to clarify information already provided in the BLA submission.

The FDA may also refer applications for novel biologic products, as well as biologic products that present difficult questions of safety or efficacy, to be reviewed by an advisory committee—typically a panel that includes clinicians, statisticians and other experts—for review, evaluation, and a recommendation as to whether the BLA should be approved.

The FDA is not bound by the recommendation of an advisory committee, but generally follows such recommendations.

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A complete response letter generally outlines the deficiencies in the BLA submission and may require substantial additional testing, or information, in order for the FDA to reconsider the application for approval.

If, or when, those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the BLA, the FDA will issue an approval letter.

The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

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.

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

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”).

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

The requirement for a REMS can materially affect the potential market and profitability of the product.

Moreover, the FDA may require substantial post-approval testing and surveillance to monitor the product’s safety or efficacy.

Once granted, product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.

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The sponsor of an investigational biological product may request that the FDA designate the product candidate for a specific indication as a fast track product concurrent with, or after, the submission of the IND for the product candidate.

FDA must determine if the product candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

For fast-track products, sponsors may have more frequent interactions with the FDA and the FDA may initiate review of sections of a fast-track product’s BLA before the application is complete.

This “rolling review”

is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast-track product may be effective.

FDA must determine if the product candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

For fast-track products, sponsors may have more frequent interactions with the FDA and the FDA may initiate review of sections of a fast-track product’s BLA before the application is complete.

This “rolling review” is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast-track product may be effective.

The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.

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Under the breakthrough therapy program, the sponsor of a new product candidate may request that the FDA designate the product candidate for a specific indication as a breakthrough therapy concurrent with, or after, the filing of the IND for the product candidate.

The FDA must determine if the product candidate qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request.

The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical studies in an efficient manner.

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Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large studies to demonstrate a clinical or survival benefit.

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

These confirmatory trials must be completed with due diligence and, in some cases, the FDA may require that the trial be designed, initiated, and/or fully enrolled prior to approval.

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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.

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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Regenerative Medicine Advanced Therapy Designation

The Regenerative Medicine Advanced Therapy (“RMAT”) designation is an expedited program for the advancement and approval of regenerative medicine products that are intended to treat, modify, reverse, or cure a serious condition and where preliminary clinical evidence indicates the potential to address unmet medical needs for life-threatening diseases or conditions.

Similar to Breakthrough Therapy designation, the RMAT allows companies developing regenerative medicine therapies to work earlier, more closely, and frequently with the FDA, and RMAT-designated products may be eligible for priority review and accelerated approval.

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Pediatric Information

Under the Pediatric Research Equity Act (“PREA”), BLAs or supplements to BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and

administration for each pediatric subpopulation for which the biological product is safe and effective.

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

Unless otherwise required by regulation, the PREA does not apply to any biological product for an indication for which orphan designation has been granted except that PREA will apply to an original BLA for a new active ingredient that is orphan-designated if the drug is a molecularly targeted cancer product intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

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

Conditions for exclusivity include the FDA’s determination that information relating to the use of a new biologic in the pediatric population may produce health benefits in that population, FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe.

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

Applications under the BPCA are treated as priority applications.

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As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.

If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the lot manufacturing history and the results of all of the manufacturer’s tests performed on the lot.

The FDA may also perform certain confirmatory tests on lots of some products, such as viral vaccines, before allowing the manufacturer to release the lots for distribution.

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Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.

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.

Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of Health and Human Services 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.

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.

The first biosimilar was approved in 2015, and the first interchangeable product was approved in 2021.

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Most states also have statutes or regulations similar to the federal Anti-Kickback Statute and civil False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

Other federal statutes pertaining to healthcare fraud and abuse include the civil monetary penalties statute, which prohibits, among other things, the offer or payment of remuneration to a Medicaid or Medicare beneficiary that the offeror or payor knows or should know is likely to influence the beneficiary to order or receive a reimbursable item or service from a particular supplier, and the additional federal criminal statutes created by the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which prohibit, among other things, knowingly and willfully executing or attempting to execute a scheme to defraud any healthcare benefit program or obtain by means of false or fraudulent pretenses, representations or promises any money or property owned by or under the control of any healthcare benefit program in connection with the delivery of or payment for healthcare benefits, items or services.

business associates and their subcontractors that perform certain services involving the storage, use or disclosure of individually identifiable health information, including mandatory contractual terms, with respect to safeguarding the privacy, security, and transmission of individually identifiable health information, and require notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information.

HITECH increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”) and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, impose obligations on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their business associates and their subcontractors that perform certain services involving the storage, use or disclosure of individually identifiable health information, including mandatory contractual terms, with respect to safeguarding the privacy, security, and transmission of individually identifiable health information, and require notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information.

In addition, many state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, and often are not preempted by HIPAA.

Further, pursuant to the ACA, the Centers for Medicare & Medicaid Services (“CMS”), issued a final rule that requires certain manufacturers of prescription drugs to collect and annually report information on certain payments or transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Further, pursuant to the federal Physician Payments Sunshine Act, enacted as part of the ACA, the Centers for Medicare & Medicaid Services (“CMS”), issued a final rule that requires certain manufacturers of approved prescription drugs that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program, with certain exceptions, to collect and annually report information on certain payments or transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), physician assistants, certain types of advance practice nurses and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

The reported data is made available in searchable form on a public website on an annual basis.

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Further, certain states require the posting of information relating to clinical studies and their outcomes.

Some states require the reporting of certain drug pricing information, including information pertaining to and justifying price increases.

A growing number of states require the reporting of certain drug pricing information, including information pertaining to and justifying price increases and the price set for newly launched drugs, or to prohibit prescription drug price gouging.

In addition, certain states require pharmaceutical companies to implement compliance programs and/or marketing codes.

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Certain states and local jurisdictions also require the registration of pharmaceutical sales representatives.

Additionally, we may also be subject to state and foreign laws governing the privacy and security of health information in some circumstances, many of which differ from one another in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Compliance with these laws is difficult and time consuming, and companies that do not comply with these state laws face civil penalties.

Efforts to ensure that business arrangements with third parties comply with applicable state, federal, and foreign healthcare laws and regulations involve substantial costs.

If a drug company’s operations are found to be in violation of any such requirements, it may be subject to significant penalties, including civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, the curtailment or restructuring of its operations, loss of eligibility to obtain approvals from the FDA, exclusion from participation in government contracting, healthcare reimbursement or other federal or state government healthcare programs, including Medicare and Medicaid, integrity oversight and reporting obligations, imprisonment, and reputational harm.

Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated.

Any action for an alleged or suspected violation can cause a drug company to incur significant legal expenses and divert management’s attention from the operation of the business, even if such action is successfully defended.

Data Privacy and Security

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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.

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.

In addition, certain state and non-U.S.

laws, such as the General Data Protection Regulation (the “GDPR”) govern the privacy and security of personal information, including health-related information, in certain circumstances.

Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.

For example, the California Consumer Privacy Act (“CCPA”), which went into effect on January 1, 2020, creates new data privacy obligations for covered companies and provides new privacy rights to California residents.

On January 1, 2023, the California Privacy Rights Act (“CPRA”), which substantially amends the CCPA, went into effect.

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

In Europe, the GDPR went into effect in May 2018 and introduces strict requirements for processing the personal data of individuals within the European Economic Area (“EEA”).

Virginia’s Consumer Data Protection Act, which took effect on January 1, 2023, requires businesses subject to the legislation to conduct data protection assessments in certain circumstances and requires opt-in consent from consumers to acquire and process their sensitive personal information, which includes information revealing a consumer’s physical and mental health diagnosis and genetic and biometric information that can identify a consumer.

Colorado enacted the Colorado Privacy Act, and Connecticut enacted the Connecticut Data Privacy Act, each of which took effect on July 1, 2023, and Utah enacted the Consumer Privacy Act, which became effective on December 31, 2023, and each of these laws may increase the complexity, variation in requirements, restrictions, and potential legal risks, and could require increased compliance costs and changes in business practices and policies.

Other states have also enacted, proposed, or are considering proposing, data privacy laws, which could further complicate compliance efforts, increase our potential liability and adversely affect our business.

In Europe, the GDPR went into effect in May 2018 and introduces strict requirements for processing the personal data of individuals within the European Economic Area (“EEA”).

Further, recent legal developments in Europe have created complexity and compliance uncertainty regarding certain transfers of personal data from the EEA.

For example, on July 16, 2020, the Court of Justice of the European Union invalidated the EU-U.S.

Privacy Shield Framework (the “Privacy Shield”) under which personal data could be transferred from the EEA to United States entities who had self-certified under the Privacy Shield scheme.

Moreover, it is uncertain whether the standard contractual clauses will also be invalidated by the European courts or legislature.

Companies that must comply with the GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.

Additionally, following the United Kingdom’s withdrawal from the European Union and the EEA, companies have to comply with the GDPR and the GDPR as incorporated into United Kingdom national law, the latter regime having the ability to separately fine up to the greater of £17.5 million or 4% of global turnover.

The relationship between the United Kingdom and the European Union in relation to certain aspects of data protection law remains unclear, for example around how data can lawfully be transferred between each jurisdiction.

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

On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried out by Congress, to reduce drug prices and drug payment.

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

These proposals recently culminated in the enactment of the Inflation Reduction Act (“IRA”) in August 2022, which will, among other things, allow HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D, although only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

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

Beginning in January 2023 for Medicare Part B and October 2022 for Medicare Part D, the IRA will also penalize drug manufacturers that increase prices of Medicare Part B and Part D drugs at a rate greater than the rate of inflation.

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

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

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.

Only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

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

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

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

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

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

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

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

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

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

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

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

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.

We expect that additional state and federal healthcare reform measures could be adopted in the future.

Further, it is possible that governmental action is taken in response to a new COVID‑19 variant or future pandemic.

Other Government Regulation Outside of the United States

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Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.

Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application (a “CTA”), much like the IND prior to the commencement of human clinical trials.

The requirements and process governing the conduct of clinical trials, including requirements to conduct additional clinical trials, product licensing, safety reporting, post-authorization requirements, marketing and promotion, interactions with healthcare professionals, pricing, and reimbursement may vary widely from country to country.

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Drug and Biologic Development Process

The conduct of clinical trials is currently governed by the EU Clinical Trials Directive 2001/20/EC (“Clinical Trials Directive”), and will be replaced by the EU Clinical Trials Regulation (EU) No.

536/2014 (“Clinical Trials Regulation”), once the latter comes into effect.

The Clinical Trials Regulation introduces a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU.

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The approval must be obtained from two separate entities:

the National Competent Authority (“NCA”), and one or more Ethics Committees.

The NCA of the EU Member States in which the clinical trial will be conducted must authorize the conduct of the trial, and the independent Ethics Committee must grant a positive opinion in relation to the conduct of the clinical trial in the relevant EU Member State before the commencement of the trial.

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If an approval is issued, the sponsor may start the clinical trial in all concerned Member States.

However, a concerned EU Member State may in limited circumstances declare an “opt-out”

from an approval and prevent the clinical trial form being conducted in such Member State.

However, a concerned EU Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial form being conducted in such Member State.

The Clinical Trials Regulation also aims to streamline and simplify the rules on safety reporting and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database.

Under both the current regime and the new Clinical Trials Regulation, national laws, regulations, and the applicable Good Clinical Practice and Good Laboratory Practice standards must also be respected during the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (“ICH”), guidelines on Good Clinical Practice (“GCP”), and the ethical principles that have their origin in the Declaration of Helsinki.

During the development of a medicinal product, the European Medicines Agency (“EMA”), and national regulators within the EU provide the opportunity for dialogue and guidance on the development program, usually in the form of scientific advice.

A fee is incurred with each scientific advice procedure.

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Drug Marketing Authorization

In the European Union, medicinal products, including advanced therapy medicinal products (“ATMPs”), are subject to extensive pre- and post-market regulation by regulatory authorities at both the European Union and national levels.

ATMPs comprise gene therapy products, somatic cell therapy products, and tissue engineered products, which are genes, cells, or tissues that have undergone substantial manipulation and that are administered to human beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human tissue.

Pursuant to the ATMP Regulation, the Committee on Advanced Therapies (“CAT”), is responsible in conjunction with the Committee for Medicinal Products for Human Use (“CHMP”) for the evaluation of ATMPs.

The CHMP and CAT are also responsible for providing guidelines on ATMPs.

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Although such guidelines are not legally binding, compliance with them is often necessary to gain and maintain approval for product candidates.

In the European Union and in Iceland, Norway, and Liechtenstein (together the EEA), after completion of all required clinical testing, medicinal products may only be placed on the market after a related Marketing Authorization (“MA”), has been granted.

MAs can be obtained through, amongst others, a centralized procedure, which is compulsory for certain medicinal products such as ATMPs.

The centralized procedure provides for the grant of a single MA by the European Commission (“EC”), that is valid for all 27 EU Member States and, after respective national implementing decisions, in the three additional EEA Member States (Iceland, Norway, and Liechtenstein).

The centralized procedure is compulsory for certain medicinal products, including medicinal products derived from biotechnological processes, orphan medicinal products, ATMPs, and products with a new active substance indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases, and viral diseases.

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Typically, the overall process takes a year or more unless the application is eligible for an accelerated assessment.

All new marketing authorization applications must include a Risk Management Plan (“RMP”), describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the MA.

RMPs and Periodic Safety Update Reports (“PSURs”) are routinely available to third parties requesting access, subject to limited redactions.

Additionally, the holder of a marketing authorization for an ATMP must put in place and maintain a system to ensure that each individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport, and delivery to the relevant healthcare institution where the product is used.

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As in the United States, the European Union also provides opportunities for market and/or data exclusivity.

For example, New Chemical Entities (“NCE”), approved in the European Union generally qualify for eight years of data exclusivity and ten years of market exclusivity.

Data exclusivity is the period during which another applicant cannot rely on the MA holder’s pharmacological, toxicological, and clinical data in support of another MA for the purposes of submitting an application, obtaining marketing authorization or placing the product on the market.

But after eight years, a generic or biosimilar product application may be submitted and generic companies may rely on the MA holder’s data.

For example, New Chemical Entities (“NCE”), approved in the European Union generally qualify for eight years of data exclusivity and ten years of market exclusivity.

But after eight years, a generic or biosimilar product application may be submitted and generic companies may rely on the MA holder’s data.

However, even if a generic or biosimilar product is authorized it cannot be placed on the market in the European Union until the expiration of the 10-year market exclusivity period.

An additional non-cumulative one-year period of marketing exclusivity is possible if during the data exclusivity period (the first eight years of the 10‑year marketing exclusivity period), the MA holder obtains an authorization for one or more new therapeutic indications that are deemed to bring a significant clinical benefit compared to existing therapies.

Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the European Union’s regulatory authorities to include an NCE.

Even if a compound is considered to be an NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the medicinal product if such a company can complete a full marketing authorization application with their own complete database of pharmaceutical tests, preclinical studies, and clinical trials and obtain MA for its product.

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The holder of a marketing authorization for a medicinal product must also comply with EU pharmacovigilance legislation and its related regulations and guidelines, which entail many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of medicinal products.

safety studies to obtain further information on a medicine’s safety, or to measure the effectiveness of risk-management measures, which may be time consuming and expensive and could impact our profitability.

These pharmacovigilance rules can impose on holders of MAs the obligation to conduct a labor intensive collection of data regarding the risks and benefits of marketed medicinal products and to engage in ongoing assessments of those risks and benefits, including the possible requirement to conduct additional clinical studies or post-authorization safety studies to obtain further information on a medicine’s safety, or to measure the effectiveness of risk-management measures, which may be time consuming and expensive and could impact our profitability.

MA holders must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance, who is responsible for oversight of that system.

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If the EC agrees with the opinion, it can adopt a decision varying the existing MA.

Failure by the marketing authorization holder to fulfill the obligations for which the EC’s decision provides can undermine the ongoing validity of the MA.

More generally, non-compliance with pharmacovigilance obligations can lead to the variation, suspension or withdrawal of the MA for the product or imposition of financial penalties or other enforcement measures.

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In addition, other national legislation of individual EU Member States may apply to the advertising and promotion of medicinal products and may differ from one country to another.

These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”) as approved by the competent regulatory authorities.

The SmPC is the document that provides information to physicians concerning the safe and effective use of the medicinal product.

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Anti-Corruption Legislation

In the EU, interactions between pharmaceutical companies and physicians are also governed by strict laws, regulations, industry self-regulation codes of conduct and physicians’

codes of professional conduct both at the EU level and in the individual EU Member States.

In the EU, interactions between pharmaceutical companies and physicians are also governed by strict laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct both at the EU level and in the individual EU Member States.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is prohibited in the European Union.

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Payments made to physicians in certain EU Member States also must be publicly disclosed.

Moreover, agreements with physicians must often be the subject of prior notification and approval by the physician’s employer, his/her regulatory professional organization, and/or the competent authorities of the individual EU Member States.

These requirements are provided in the national laws, industry codes, or professional codes of conduct, applicable in the individual EU Member States.

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Other Markets

Following the UK’s formal departure from the EU on January 31, 2020, the UK entered a transition period to last until December 31, 2020, during which time EU medicines laws will remain applicable to the UK.

After the transition period however, changes may be forthcoming as the terms of the UK and EU’s future relationship are negotiated.

The UK Medicines and Healthcare Products Regulatory Agency has proposed that, subject to being approved by the UK Parliament, a centralized MA will automatically convert into a UK MA.

However, the draft of the “Medicines and Medical Devices Bill 2019-21”

currently discussed in the UK House of Lords does not contain such a provision, but would only authorize the UK government to become active in the field of legislation concerning market authorizations in relation to human medicines.

However, the draft of the “Medicines and Medical Devices Bill 2019-21” currently discussed in the UK House of Lords does not contain such a provision, but would only authorize the UK government to become active in the field of legislation concerning market authorizations in relation to human medicines.

For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary from country to country.

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We consider our relationship with our employees to be good.

Corporate Information

We are located in Miramar, Florida and were incorporated in the state of Delaware in April 2018.

Available Information

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business