huma-20241231

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

___________________________________

FORM 10-K

___________________________________

(Mark One)

For the fiscal year ended December 31, 2024

For the transition period from to

Commission file number 001-39532

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Humacyte, Inc.

(Exact name of registrant as specified in its charter)

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2525 East North Carolina Highway 54

(Address of principal executive offices) (Zip code)

(919) 313-9633

(Registrant's telephone number, including area code)

Securities registered pursuant to 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, par value $0.0001 per share HUMA The Nasdaq Stock Market LLC

Securities registered pursuant to 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes o Nox

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes o Nox

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports); and (2) has been subject to such filing requirements for the past 90 days. Yesx No o

Indicate by check mark whether the registrant has submitted electronically and posted on its corporate web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files). Yesx No o

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one):

Large accelerated filer o Accelerated filer o

Non-accelerated filer x Smaller reporting company x

Emerging growth company x

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. o

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C.7262(b)) by the registered public accounting firm that prepared or issued its audit report. o

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. o

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). o

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act).Yes o No x

As of June 30, 2024, the last business day of the registrant’s most recently completed second fiscal quarter, the aggregate market value of common stock held by non-affiliates of the registrant was approximately $453.2 million (based on the closing price of the registrant’s common stock as reported on The Nasdaq Global Select Market on that date).

As of March 27, 2025, 155,118,816 shares of common stock, par value $0.0001, were issued and outstanding.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s Proxy Statement relative to the 2025 Annual Meeting of Shareholders are incorporated by reference in Part III hereof.

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Page No.

PART I

Item 1. Business 5

Item 1A. Risk Factors 59

Item 1B. Unresolved Staff Comments 95

Item 1C. Cybersecurity 96

Item 2. Properties 97

Item 3. Legal Proceedings 97

Item 4. Mine Safety Disclosures 98

PART II

Item 6. [Reserved] 99

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 113

Item 8. Financial Statements and Supplementary Data 114

Item 9A. Controls and Procedures 156

Item 9B. Other Information 157

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 157

PART III

Item 10. Directors, Executive Officers and Corporate Governance 158

Item 11. Executive Compensation 158

Item 14. Principal Accountant Fees and Services 158

PART IV

Item 15. Exhibits and Financial Statement Schedules 159

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FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainties. “Forward-looking statements,” as that term is defined in the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 (the “Exchange Act”) are statements that are not historical facts and involve a number of risks and uncertainties.These statements include, without limitation, statements regarding the financial position, business strategy and the plans and objectives of management for future operations. These statements constitute projections, forecasts and forward-looking statements, and are not guarantees of performance. Such statements can be identified by the fact that they do not relate strictly to historical or current facts. When used therein, words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “strive,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. Such statements are based on the beliefs of, as well as assumptions made by and information currently available to, our management.

Forward-looking statements may include, for example, statements about:

•our plans and ability to commercialize SymvessTM (acellular tissue engineered vessel-tyod or “ATEVTM”) and, if approved by regulatory authorities, our product candidates, successfully and on our anticipated timelines;

•the degree of market acceptance of and the availability of third-party coverage and reimbursement for Symvess and, if approved by regulatory authorities, our product candidates;

•our ability to manufacture Symvess and, if approved by regulatory authorities, our product candidates in sufficient quantities to satisfy our clinical trial and commercial needs;

•the expected size of the target populations for Symvess and, if approved by regulatory authorities, our product candidates;

•the anticipated benefits of our ATEVs relative to existing alternatives;

•our assessment of the competitive landscape;

•our plans and ability to execute product development, process development and preclinical development efforts successfully and on our anticipated timelines;

•our plans, anticipated timeline and ability to file applications for, and obtain marketing approvals from the United States (“U.S.”) Food and Drug Administration (“FDA”) and other regulatory authorities, including the European Medicines Agency (“EMA”), for our ATEVs and product candidates;

•our ability to design, initiate and successfully complete clinical trials and other studies for our product candidates and our plans and expectations regarding our ongoing or planned clinical trials, including for our V007 and V012 Phase 3 clinical trials;

•the outcome of our ongoing discussions with the FDA concerning the design of our clinical trials;

•our anticipated growth rate and market opportunities;

•our ability to use our proprietary scientific technology platform to build a pipeline of additional product candidates;

•the characteristics and performance of our ATEVs;

•our expectations regarding our strategic partnership with Fresenius Medical Care Holdings, Inc. (“Fresenius Medical Care”) to sell, market and distribute our 6 millimeter ATEV for certain specified indications and in specified markets, if approved by regulatory authorities;

•the performance of other third parties on which we rely, including our third-party manufacturers, our licensors, our suppliers and the organizations conducting our clinical trials;

•our ability to obtain and maintain intellectual property protection for our product candidates as well as our ability to operate our business without infringing, misappropriating or otherwise violating the intellectual property rights of others;

•our ability to maintain the confidentiality of our trade secrets, particularly with respect to our manufacturing process;

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•our compliance with applicable laws and regulatory requirements, including FDA regulations, healthcare laws and regulations, and anti-corruption laws;

•our involvement in existing or potential claims and legal proceedings, and the merits, potential outcomes and effects of both existing and potential claims and legal proceedings, as well as regulatory determinations, on our business, prospects, financial condition and results of operations;

•our ability to attract, retain and motivate qualified personnel and to manage our growth effectively;

•our estimates regarding how long our existing cash and cash equivalents will be sufficient to fund our anticipated operating expenses, capital expenditures and debt service obligations;

•our future financial performance and capital requirements, including our ability to raise additional capital in the future;

•our ability to implement and maintain effective internal controls;

•the potential liquidity and trading of our securities; and

•the impact of the overall global economy and increasing interest rates and inflation on our business.

We caution readers not to place undue reliance on any such forward-looking statements, which speak only as of the date they are made. Any forward-looking statements are based on information current as of the date of this Annual Report on Form 10-K and speak only as of the date on which such statements are made. Actual events or results may differ materially from the results, plans, intentions or expectations anticipated in these forward-looking statements as a result of a variety of factors, many of which are beyond our control. More information on factors that could cause actual results to differ materially from those anticipated is included from time to time in our reports filed with the Securities and Exchange Commission (the “SEC”), including, but not limited to, those described in the sections of this Annual Report on Form 10-K titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.” We disclaim any obligation, except as specifically required by law, to publicly update or revise any such statements to reflect any change in our expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements.

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PART I

Item 1. Business

Business Overview

Executive Summary

Humacyte, Inc. is a commercial-stage biotechnology platform company developing universally implantable, bioengineered human tissues at commercial scale, and in the first quarter of 2025 commenced the United States commercial launch of our first FDA-approved product. We are pioneering the development and manufacture of off-the-shelf, universally implantable, bioengineered human tissues, advanced tissue constructs and organ systems with the goal of improving the lives of patients and transforming the practice of medicine. We believe our regenerative medicine technology has the potential to overcome limitations in existing standards of care and address the lack of significant innovation in products that support tissue repair, reconstruction and replacement. We are leveraging our novel, scalable technology platform to develop proprietary, bioengineered, acellular human tissues for use in the treatment of diseases and conditions across a range of anatomic locations in multiple therapeutic areas.

We are initially using our proprietary, scientific technology platform to engineer and manufacture acellular tissue engineered vessels, or ATEVsTM. On December 19, 2024, the FDA granted full approval for the ATEV under the brand name SymvessTM for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and autologous vein graft is not feasible. Our ATEVs are designed to be easily implanted into any patient without inducing a foreign body response or leading to immune rejection. We are developing a portfolio, or “cabinet”, of ATEVs with varying diameters and lengths. The ATEV cabinet is initially targeting the vascular repair, reconstruction and replacement market, including vascular trauma, arteriovenous (“AV”) access for hemodialysis, and peripheral artery disease (“PAD”). We are also developing the ATEV for coronary artery bypass grafting (“CABG”) and pediatric heart surgery. Over the longer term, we are developing our ATEV for the delivery of cellular therapies, including pancreatic islet cell transplantation to treat Type 1 diabetes (our BioVascular PancreasTM or “BVP”). We will continue to explore the application of our technology across a broad range of markets and indications including the development of urinary conduit, trachea, esophagus and other novel cell delivery systems.

For the ATEV, we believe there is substantial clinical demand for safe and effective vascular conduits to replace and repair blood vessels throughout the body. Vascular injuries resulting from trauma are common in civilian and military populations, frequently resulting in the loss of either life or limb. Existing treatment options in the vascular repair, reconstruction and replacement market include the use of autologous vessels and synthetic grafts, which we believe suffer from significant limitations. For example, the use of autologous veins to repair traumatic vascular injuries can lead to significant morbidity associated with the surgical wounds created for vein harvest and prolonged times to restore blood flow to injured limbs, leading to an increased risk of complications such as amputation and reperfusion injury. In addition, in many instances of vascular trauma the patient may not have adequate vein available, or the time between injury and treatment is too long to make autologous graft repair feasible. Synthetic grafts are often contraindicated in the setting of vascular trauma due to wound contamination that contributes to higher infection risk that can lead to prolonged hospitalization and limb loss. Given the competitive advantages our ATEVs are designed to have over existing vascular substitutes, we believe that ATEVs have the potential to become the standard of care and lead to improved patient outcomes and lower healthcare costs.

As of December 31, 2024, our ATEVs have been implanted in approximately 601 patients. In addition to vascular trauma, we and our collaborators are currently conducting Phase 3 and Phase 2 trials of our 6 millimeter ATEV in AV access for hemodialysis and PAD. We were granted Fast Track designation by the FDA for our 6 millimeter ATEV for use in AV access for hemodialysis in 2014. We also received the first Regenerative Medicine Advanced Therapy (“RMAT”) designation from the FDA, for the creation of vascular access for performing hemodialysis, in March 2017. In May 2023, we were granted the RMAT designation for the ATEV for urgent arterial repair following extremity vascular trauma, and in June 2024, we were granted the RMAT designation for the ATEV for patients with advanced PAD. In addition, in 2018 our ATEV product candidate was assigned a priority designation by the Secretary of Defense under Public Law 115-92, enacted to expedite the FDA’s review of products that are intended to diagnose, treat or prevent serious or life-threatening conditions facing American military personnel. In September 2023, we announced positive topline results from our V005 Phase 2/3 trial in vascular trauma, and in December 2023 we filed a Biologics License Application (“BLA”) for urgent arterial repair following extremity vascular trauma when synthetic graft is not indicated, and autologous vein use is not feasible. In February 2024, the FDA accepted the BLA filing, granted Priority Review and set a Prescription Drug User Fee

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Act (“PDUFA”) date, the FDA action date for its regulatory decision regarding the BLA, of August 10, 2024. On August 9, 2024, the FDA informed us that it required additional time to complete its review of the BLA for the vascular trauma indication. On December 19, 2024, the FDA granted full approval for Symvess (acellular tissue engineered vessel-tyod) for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and autologous vein graft is not feasible.

In April 2023, we announced completion of enrollment of our V007 Phase 3 trial of the ATEV for use in AV access for hemodialysis. In July 2024, we announced positive topline results from our V007 Phase 3 trial, where the ATEV met the co-primary endpoints in the study. Dependent upon interim results from our ongoing V012 Phase 3 trial of the ATEV for use in AV access for hemodialysis in women, we plan to submit a supplemental BLA for the ATEV to the FDA for an indication in AV access for hemodialysis in the second half of 2026.

We have developed a novel paradigm for manufacturing human tissues that is intended to mimic key aspects of human physiology. We have an 83,000 square foot bioprocessing facility housing our modular manufacturing process with the ability to manufacture ATEVs of different diameters and lengths at commercial scale. As we continue to expand production, we believe we will have the ability to take advantage of economies of scale to reduce costs of production. We believe our established, controlled manufacturing process demonstrates a significant competitive advantage in the regenerative medicine market.

Our technology is protected by our patent portfolio, which includes certain patents licensed from parties as well as intellectual property generated internally at Humacyte. Our patent portfolio is comprised of 15 families of patents, many of which generally relate to the scaffolds used to make Symvess and our product candidates, the composition of Symvess and our product candidates and systems and methods of manufacturing Symvess and our product candidates. For more information, see “— Intellectual Property” below.

We intend to continue to shape our commercial and distribution strategy by indication and pursue collaborations with partners in markets where such partners provide strategic opportunities in launching our product candidates and enabling access to specific patient populations.

Our world-class senior management team and board of directors will be instrumental in helping us achieve our goals. Our President and Chief Executive Officer, Laura Niklason M.D., PhD., who founded Legacy Humacyte (as defined below), is an internationally respected physician scientist and a world leader in regenerative medicine technologies. Dr. Niklason is also a member of three national academies — Inventors, Medicine and Engineering. Our current Chair of the Board is Kathleen Sebelius, the former Secretary of the Department of Health and Human Services (“HHS”), and the former Governor of Kansas.

Merger

On August 26, 2021 (the “Closing Date”), Humacyte, Inc. (“Legacy Humacyte”), a Delaware corporation, and Alpha Healthcare Acquisition Corp. (“AHAC”), a Delaware corporation, consummated a merger pursuant to that certain Business Combination Agreement, dated as of February 17, 2021 (the “Merger Agreement”), by and among Legacy Humacyte, AHAC and Hunter Merger Sub (“Merger Sub”), a Delaware corporation and wholly owned subsidiary of AHAC. As contemplated by the Merger Agreement, Merger Sub merged with and into Legacy Humacyte, with Legacy Humacyte continuing as the surviving corporation and as a wholly owned subsidiary of AHAC (the “Merger” and collectively with the other transactions described in the Merger Agreement, the “Reverse Recapitalization”). On the Closing Date, AHAC changed its name to Humacyte, Inc. and Legacy Humacyte changed its name to Humacyte Global, Inc.

Unless the context indicates otherwise, references in this Annual Report on Form 10-K to the “Company,” “Humacyte,” “we,” “us,” “our” and similar terms refer to Humacyte, Inc. (formerly known as Alpha Healthcare Acquisition Corp.) and its consolidated subsidiaries (including Humacyte Global, Inc.) following the Merger. References to “AHAC” refer to Alpha Healthcare Acquisition Corp. prior to the Merger.

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Our Approach

We have developed an approach that relies on two key complementary elements to address the significant market opportunity for the global treatment of patients in need of vascular replacement, repair and reconstruction, vascular access for dialysis and potential future indications including complex tissue and organ replacement and treatment of Type-1 diabetes:

•our proprietary scientific and engineering technology platform allows us to grow human tissues, which are ultimately decellularized and therefore expected to be non-immunogenic and universally implantable; and

•our novel, scalable manufacturing paradigm is designed to allow us to produce thousands of ATEVs per year with the ability to expand manufacturing capacity and breadth to meet expected future global demand and the planned expansion of our pipeline of product candidates.

Over time, we intend to develop a readily available “cabinet” of ATEVs of varying diameters and lengths to address the significant unmet needs across multiple potential indications in vascular repair, reconstruction and replacement.

Our Proprietary Scientific Technology Platform

Our proprietary scientific technology platform uses primary human aortic vascular cells from a working cell stock that have been isolated from donor tissues and cryopreserved. The working cell stock is expanded using traditional cell culture techniques, and the cells are transferred onto a biocompatible, biodegradable polymer mesh within a flexible, single-use bioreactor bag. Over the course of weeks, the cells proliferate and build extracellular matrix while the polymer mesh degrades. The resulting bioengineered vessel is comprised of the aortic vascular cells and their deposited extracellular matrix. After completion of the culture period, we decellularize the bioengineered vessel using a proprietary combination of solutions. The resulting ATEV retains the extracellular matrix constituents and, therefore, the biomechanical properties of the bioengineered vessel, but is cleansed of the cells and cellular components that could induce a foreign body response or immune rejection following implantation. Our functionally closed system allows for the ATEV to be grown, decellularized and ultimately shipped within the same flexible bioreactor bag. Our ATEVs are designed to be shipped to hospitals, trauma centers and outpatient surgical settings, where they can then be refrigerated for immediate use by removing each ATEV from its packaging.

The following image summarizes key information about our proprietary scientific technology platform:

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Our Novel Manufacturing Paradigm

We have developed a novel paradigm for manufacturing human tissues that is intended to mimic key aspects of human physiology. Our proprietary manufacturing process was designed with a modular approach allowing us to produce ATEVs in smaller batches for clinical trials and scale out to larger batches for commercial manufacturing. In 2021 we commenced supplying our ongoing clinical trials with ATEVs produced in our current, commercial-scale LUNA200TM system, which consists of 20 growth drawers per production unit for a total of 200 ATEVs per batch. Each growth drawer is capable of producing ten 42cm ATEVs, each of which is contained within an individual bioreactor bag. Inside a LUNA200, a tubing network connects all ATEVs, allowing the entire system to share nutritive media. In this way, a single LUNA200 can produce up to 200 ATEVs (42cm in length) per batch while maintaining the critical operating parameters, such as biomechanical pulsing, that affect growth. The FDA inspected our manufacturing facility in April 2024 as part of its review and approval of our BLA in extremity vascular trauma, and we are using this facility to provide product for the United States commercial launch in that indication which commenced in the first quarter of 2025.

Our current 83,000 square foot manufacturing facility has space to further expand manufacturing capacity as needed to over 40 LUNA200 systems. Currently, eight LUNA200 systems are installed and operational.

We believe that the LUNA200 can produce ATEVs in diameter sizes from 3mm to 10mm and lengths from 10cm to 42cm, making the equipment suitable for the varied array of product candidates in our pipeline. We currently intend to introduce a 13cm-long ATEV line extension after the commercial launch of the 42cm ATEV, for surgeries that require shorter segments of ATEV in the setting of vascular trauma and repair. Using our existing LUNA200 manufacturing equipment without modification, we believe we have the ability to generate 400 ATEVs (13cm in length) or 200 ATEVs (42cm in length) per manufactured batch. We have designed our manufacturing system to be functionally closed, to utilize single-use disposable materials with aseptic connections, and to be highly automated, which allows us to control and maximize ATEV production.

Based on observations to date, the ATEV has withstood maximal pressures that are comparable to those reported for native arteries. For example, the human aorta is reported to have rupture strengths around 1,400 mmHg, while human cerebral arteries rupture around 1,800 mmHg. We have observed ATEVs withstanding maximal pressures of approximately 3,200 mmHg before rupturing, making their mechanical properties on par with native human blood vessels.

Our Market Opportunity

We are a biotechnology company that has commenced the U.S. commercial launch of one FDA-approved product, with Phase 3 clinical trials in two indications and a strong pipeline for additional products and indications. Additionally, we have had significant interest from surgeons to use our ATEV in life and limb saving surgeries as demonstrated by their requests to the FDA to use our ATEV in multiple expanded access (compassionate use) cases where no alternative was available, as well as requests from Ukrainian surgeons that led to a humanitarian program conducted during the conflict in that country.

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Our Initial Market Opportunity in Vascular Repair, Reconstruction and Replacement

We believe there is a significant market opportunity for our technology across a number of important clinical areas within vascular reconstruction and replacement including vascular trauma, AV access for hemodialysis, PAD, and adult cardiac surgery. To treat these diseases and conditions, patients often require invasive vascular and cardiovascular surgery, which involves the use of alternative vascular synthetic materials or autologous vessels harvested from elsewhere in the body. For more information about our evaluation of market opportunity, see “Risk Factors — Risks Related to the Development and Commercialization of Our Product Candidates — The sizes of the market opportunities for our product candidates have not been established with precision and are estimates that management believes to be reasonable. If these market opportunities are smaller than we estimate or if any approval that we obtain is based on a narrower definition of the relevant patient population, our revenue and ability to achieve profitability might be materially and adversely affected.”

Vascular Trauma: Arterial injuries resulting from vascular trauma are common in military and civilian populations, frequently resulting in the loss of life or limb. In military populations, as the rate of battlefield fatalities has been declining due to faster evacuations and more robust protection from body armor, the rate of survivable vascular injuries has been increasing. In civilian populations, trauma injuries are primarily caused by motor vehicle, workplace and sporting accidents, gun violence, mass casualty terrorist attacks, stabbings, blunt trauma, and iatrogenic injuries (injuries caused by medical treatment or examination). We estimate that central or peripheral vascular injuries in civilian patients account for approximately 150,000 of all injuries reported in global trauma patients. Furthermore, these injuries account for greater than 20% of all trauma-related deaths.

Civilian patients with central or peripheral vascular injuries are estimated to account for approximately 80,000 of all injuries reported in trauma patients in the United States, inclusive of urgent and iatrogenic vascular trauma injuries, and account for greater than 20% of all trauma-related deaths. Based on an analysis of the Definitive Healthcare Claims (DHC) Database 2023, we estimate that approximately 26,000 patients per year will be eligible for the ATEV within the United States (analysis was based on inclusion of patients with major repairs to injuries of the extremities, and the exclusion of patients with vein injuries, injuries to the torso, head, neck, wrist, hand, ankle or foot, or who received ligation or endovascular repair).

We believe our ATEVs are a promising alternative that can address critical gaps in existing treatment options for acute vascular injuries due to trauma. We have developed our ATEVs with the goal of providing an effective solution in all time-constrained surgical environments and in resource-limited, infection prone civilian and battlefield conditions. The ability to provide immediately available, non-immunogenic, universally implantable human vessels that have low rates of infection represents a clinically significant advantage over existing treatment options. In addition, the Budget Impact Model for the ATEV, published in the Journal of Medical Economics in March 2025, reported that the ATEV was projected to be cost saving for both trauma centers and third-party payors, primarily due to reductions in the costs related to amputations and conduit infections.

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AV Access for Hemodialysis: An estimated $5 to $6 billion per year is spent on hospital admissions in hemodialysis patients with infection and access complications. In 2024, over 555,000 patients received hemodialysis in the United States. Annually, at least 160,000 existing or new dialysis patients require a new AV access in the U.S. and an additional 150,000 patients require a new AV access in Europe and Japan.

Hemodialysis patients are a chronically ill population, suffering an average of 1.8 hospital admissions, three visits to the emergency department, and four days hospitalized for infections each year. The two most common causes of hospital admissions in hemodialysis patients are infection and access complications. For hemodialysis patients, an infected access site can lead to sepsis, a life-threatening complication that is the most expensive cause for hospitalization in the United States and carries at least a 10% overall mortality rate.

We believe that our ATEVs, when used as AV access for hemodialysis, can decrease infections and dialysis access failures, which would improve patient outcomes and lower the burden of dialysis costs on the healthcare system. We expect to file a BLA with the FDA in the second half of 2026 seeking approval for the use of ATEV in AV access for hemodialysis, and to target our commercialization efforts particularly toward those patients who are at high risk of fistula failure or non-maturation, such as women and male patients with two risk factors, such as obesity and diabetes.

Peripheral Artery Disease: PAD is a cardiovascular disease of blood vessels located outside the brain and heart. Atherosclerosis, which is the buildup of plaque along the artery walls, usually affects arteries in the legs, but it can also affect arteries that carry blood from the heart to the head, arms, kidneys, and intestines. We believe our ATEVs can be used as a bypass conduit in patients suffering from PAD in the legs. Peripheral arterial bypass procedures are common with over 230,000 PAD-related procedures reported annually in the U.S. There are over 200,000 peripheral bypass procedures per year in Europe, and approximately 220,000 per year in Asia.

While endovascular techniques have become more available over the past ten years to treat an array of vascular occlusions, depending on the nature and length of the blockage these types of treatment options have had limited success and durability as compared to conventional surgical bypass. Both angioplasty and stenting procedures provide near term success, however long-term durability has remained a question, as highlighted in the results of the recent BEST-CLI clinical trial published in the New England Journal of Medicine demonstrating that patients treated with surgical bypass had fewer major amputations and less need for repeat procedures than those treated with endovascular therapy.

Type I Diabetes: Type 1 diabetes, caused by auto-immune destruction of insulin-producing cells in the islets of the pancreas, is a devastating disease affecting more than 1.7 million people in the United States, and costing at least $10 billion to $14 billion annually. In the EU4 (France, Germany, Italy and Spain) and the UK, the number of patients suffering with Type 1 diabetes is estimated at approximately 1.5 million. Even with the newer insulin delivery technologies, less than one-third of patients achieve consistent target blood sugar levels.

Pancreas transplantation is limited due to the associated morbidity and cost of a whole pancreas organ transplantation procedure. As an alternative to pancreas transplantation, the “Edmonton Protocol” has been developed whereby insulin producing cells are transplanted into the portal vein in the liver. However, the majority of the injected cells are lost to inflammation and clotting, and only 16% of Type 1 diabetes patients who receive the Protocol are cured long term.

We believe our ATEVs present a means to deliver a therapeutic number of pancreatic islets to patients with Type 1 diabetes. Pancreatic islets are embedded on the outer surface of our ATEV and may be implanted as an AV graft, analogous to the outpatient procedure done for hemodialysis access. After implantation, the islets may have the potential to sense blood glucose and then respond by secreting appropriate levels of insulin to maintain proper glucose levels in the blood. We have termed this new paradigm for pancreatic islet cell delivery the BioVascular Pancreas or “BVPTM.”

We believe that a reliable, low-risk, and easily implantable islet cell delivery method that could ensure the survival and functionality of a therapeutic number of islet cells in a human adult would be transformational for the treatment of Type 1 diabetes.

Coronary Artery Bypass Graft: CABG is a surgery used to treat a blockage or narrowing of one or more of the coronary arteries to restore the blood supply to the heart muscle. We believe our ATEVs can replace existing vascular substitutes and improve patient outcomes, particularly in obese patients or those suffering from diabetes, in whom the risks of saphenous vein harvesting are more substantial. CABG procedures are common, with more than 200,000 CABG procedures reported annually in the U.S. and over 765,000 annual CABG procedures globally.

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Typically, a CABG operation involves the use of both the patient’s own artery and vein. In patients who are obese, have diabetes, or who are very elderly, there are higher risks for vein harvest complications, including failure to heal the vein harvest incision, infection, and prolonged swelling of the operative leg. Furthermore, complications from the vein harvest incision site are more common than complications from the chest incision in CABG patients. It is estimated that approximately 20% of patients requiring bypass surgery have no suitable grafts available, with sources reporting as high as 45% of CABG patients are without suitable autologous vein. In preclinical testing, we have evaluated a small diameter ATEV (“sdATEV”) which is 3.5mm in diameter and 20cm in length for use as a CABG conduit. Testing has been performed in non-human primates, pigs and sheep. We plan to utilize the collective preclinical data on the sdATEV to support an Investigational New Drug (“IND”) application to the FDA for CABG during 2025.

Pediatric Heart Surgery: We have evaluated in preclinical testing a smaller diameter ATEV product for use in pediatric heart surgery as a Blalock Taussig (“BT”) shunt. The BT shunt is a surgical procedure that is used to increase pulmonary blood flow for the treatment of babies born with a complex congenital heart defect called Tetralogy of Fallot, a common type of “blue baby syndrome”. In 2024, there were approximately 1,800 babies born in the United States with Tetralogy of Fallot. The BT shunt is a life-saving procedure for these babies, and we plan to submit an orphan drug application for use of our ATEV as a BT shunt for infants born with cyanotic congenital heart defects. Although 3 – 4mm inner diameter expanded polytetrafluoroethylene (“ePTFE”) grafts are currently used as the most common BT shunt, they suffer from limitations that impact morbidity and mortality in these infants.

Our Product Pipeline

The following table highlights key information about the most active programs within our current product pipeline:

We began clinical evaluations of our ATEVs in December 2012, with the enrollment of the first Phase 2 patient in our V001 hemodialysis access trial in Europe. Since then, we have completed two pivotal and one Phase 2 trials in the United States, and currently have one pivotal trial actively enrolling and two trials in long-term follow-up. In clinical trials and in expanded access cases, ATEVs have been implanted in approximately 85 clinical centers in seven countries around the world, and by more than 100 practicing surgeons.

Overview of Clinical Trials Assessing the Safety and Efficacy of the ATEV in Multiple Indications

Vascular Trauma

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Dialysis Access

Peripheral Artery Disease

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** PP: Primary Patency, which is the interval of time of access placement until any intervention designed to maintain or reestablish patency, access thrombosis, or the time of measurement of patency, i.e. patent without interventions.

SP: Secondary Patency, which is the interval from the time of access placement until abandonment, i.e. patent with or without interventions.

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As of December 31, 2024, approximately 601 patients worldwide have received our ATEVs in clinical trials, and expanded access and humanitarian programs, for the treatment of vascular trauma, AV access for hemodialysis, PAD, and in expanded access cases resulting in approximately 1,277 subject-years of exposure to the ATEV. Our cumulative ATEV exposure is approximately 993 subject-years in the hemodialysis access population, 168 subject-years in the PAD population, and 115 subject-years in the arterial trauma population. The longest our ATEV has been in a patient and used for dialysis is more than ten years and there have been more than 117,000 estimated dialysis sessions using our ATEVs. A total of 29 expanded access/compassionate use cases have been granted by the FDA, and another 28 patients with severe PAD have been treated with the ATEV under an investigator IND at the Mayo Clinic. Lastly, 19 patients suffering vascular injuries during the conflict in Ukraine have been treated with the ATEV under a humanitarian program. Throughout all of these trials and other programs, we have observed that our ATEVs functioned as intended and provided functional blood flow to affected limbs. We have also observed consistent durability with a strong tolerability profile. Furthermore, we have observed no evidence of clinically relevant immunologic reactions to our ATEVs, supporting the potential use of our ATEVs as off-the-shelf, universally implantable, bioengineered human tissues.

Overall, the ATEV has functioned well and as intended, across ten different clinical trials in three clinical indications. The ATEV has been implanted in approximately 601 patients, across more than 85 clinical sites in seven countries, over more than ten years as of December 31, 2024. We have observed zero instances of clinical rejection of the ATEV in any clinical trial over the past ten years, suggesting that the ATEV was not immunologically rejected after implantation.

Based on clinical trial results to date, we have observed that the ATEVs have a low infection rate, with an infection rate averaging approximately 1.0% or less per patient-year in our AV access trials, and low infection rates in our trauma and PAD trials (ranging from 0% to approximately 2%, depending on the trial and indication). Vascular graft infections are a potentially serious complication and can result in adverse outcomes such as sepsis, hospitalization, long-term antibiotic use, repeat procedures and even death.

ATEVs Remodel with Host Cells After Implantation

Additionally, based on clinical samples obtained during our Phase 2 AV access trials and published in three peer reviewed journals, The Lancet in 2016, Science Translational Medicine in 2019, and in the Journal of Vascular Surgery in 2020, we observed that the ATEV became populated with healthy, vascular cells from the patient. As described in these publications, over time the patient’s cells have been observed to transform the ATEV into a multi-layered living tissue similar to native blood vessels. In these trials we have also observed ongoing cellular repair of ATEV tissues that had been previously injured during cannulation with dialysis needles, which suggests that the recellularized ATEV may be capable of self-healing. The image below shows an ATEV that had been implanted in a hemodialysis patient for 44 weeks, that had developed alpha-actin positive vascular smooth muscle cells throughout the wall (red staining in the left-hand panel), and had developed a layer of CD31+ endothelial cells on the inner luminal surface of the ATEV (line of red endothelial cells indicated in the right-hand panel).

Histological Images of ATEV Repopulated with the Patient’s Own Vascular Cells

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ATEVs Low Rate of Infection

In July 2023, a preclinical study that supported a possible scientific basis for the low rates of infection that have been observed in clinical trials of the ATEV was published in the Journal of Vascular Surgery – Vascular Science. This work compared the infection resistance of the ATEV to ePTFE grafts, which are made of plastic. The laboratory results suggest that the bioengineered human tissue of the ATEV may have superior compatibility with the body's own neutrophils (white blood cells that combat bacterial infections) as compared to ePTFE. Histology and laboratory analyses performed in the preclinical study suggests that while human white blood cells die when they come in contact with ePTFE, the cells survive and function in contact with the ATEV, which may improve the ability of the ATEV to fight dangerous infections once implanted in the body.

Indication #1: Use of ATEV to Repair Extremity Vascular Trauma

Overview of Vascular Trauma

Arterial injuries resulting from vascular trauma are common in military and civilian populations, frequently resulting in the loss of life or limb. In military populations, as the rate of battlefield fatalities has been declining due to faster evacuations and more robust protection from body armor, the rate of survivable vascular injuries has been increasing. In civilian populations, trauma injuries are primarily caused by motor vehicle, workplace and sporting accidents, gun violence, mass casualty terrorist attacks, stabbings, blunt trauma and iatrogenic injuries (injuries caused by medical treatment or examination). Consequently, we believe there is an increasingly urgent unmet need for novel materials that are immediately available for permanent vascular repair for both civilian and military vascular trauma.

Options in Surgical Treatment of Vascular Trauma

Autologous vein is the preferred conduit for vascular repair. However, harvesting of autologous vein is not always feasible, due to damage to vein or lower limb, prior vein harvest, inadequate size of the vein or venous disease. Harvesting autologous vein is a serious operation that requires additional time and resources. Delaying the time from injury to operative intervention from less than one hour, to three hours or greater, more than doubles the risk of limb amputation. Limb amputation, in turn, almost triples the length of intensive care unit stay, nearly doubles the length of hospital stay, and is devastating to patient quality of life. Additionally, the morbidity associated with saphenous vein harvest includes surgical site infections, chronic pain, and limb swelling. Synthetic materials have been shown to be inferior to autologous vein in resistance to infection and durability and, therefore, are generally only used for vascular repair when autologous vein is not an option.

The ATEV as a Solution for Vascular Trauma

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Humacyte has a strong working relationship with the Department of Defense (“DoD”) that has led to a partnership over the last decade to support their unmet need to reconstruct and repair vascular injuries through the development of our ATEVs. As a result of this collaboration and partnership with the DoD, we anticipate Humacyte would supply ATEVs for use in military hospitals to treat injured soldiers and veterans. The DoD assigned a priority designation to the ATEV technology under Public Law 115-92. Under this law, FDA and DoD work together to expedite the development and review of critical technologies and therapies requested by DoD. Additionally, we have received an approximately $6.8 million grant from the DoD for the development of our ATEVs for vascular reconstruction and repair.

FDA Approval of ATEV for Extremity Vascular Trauma

In May 2023, the FDA granted RMAT designation for use of the ATEV in urgent arterial repair following extremity vascular trauma. In December 2023, the Company filed a BLA with the FDA for urgent arterial repair following extremity vascular trauma when synthetic graft is not indicated, and autologous vein use is not feasible. The BLA submission was supported by results from the V005 Phase 2/3 clinical trial, and real-world outcomes from the treatment of wartime injuries in Ukraine, both of which are described below. In February 2024, the FDA accepted the BLA filing and granted Priority Review, setting a PDUFA date of August 10, 2024. On August 9, 2024, the FDA informed us that it required additional time to complete its review of the BLA for the vascular trauma indication. On December 19, 2024, the FDA granted full approval for SymvessTM (acellular tissue engineered vessel-tyod) for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and autologous vein graft is not feasible.

V005 Phase 2/3 Civilian Trial for Vascular Trauma

Trial Design: Our V005 civilian trial was a single-arm, multi-center, non-randomized clinical trial to evaluate the efficacy, safety and tolerability of our 6 millimeter ATEV in replacement or reconstruction of vascular tissues in patients with life or limb-threatening vascular trauma for whom the standard of care, saphenous vein, was not feasible or available for vascular repair. As a single-arm study, the comparators for the ATEV results were derived from a systematic literature review and meta-analysis of studies evaluating synthetic grafts in vascular injury repair. A total of 72 patients were enrolled in the V005 trial, of which 51 had vascular injury of the extremities and comprised the primary evaluation group for the study. The primary efficacy endpoint was patency of the ATEV at 30 days, with 30-day rates of infection and amputation comprising the secondary endpoints.

V005 Trial Results:

For the primary analysis group of 51 patients with extremity injury, the range of trauma injuries in V005 were broad, including penetrating trauma cases and blunt injury cases. Mechanisms of injury included motor vehicle accidents, gunshot wounds, industrial accidents, and falls in the V005 trial. The ATEVs were placed throughout the body, including in the lower limbs and upper limbs and were used to repair the axillary artery, femoral artery, popliteal artery and vein, and the brachial artery. Many of the injuries treated in the V005 trial were contaminated injuries that are at elevated risk of graft infection.

The most common reasons reported by clinicians for using the ATEV in the V005 trial instead of the standard of care, saphenous vein, was the need to avoid the time required to harvest saphenous vein (32.3%), the quality of the patient’s vein (25.8%), and concomitant injuries to the vein (16.1%), suggesting that the ready, off-the-shelf feature of the ATEV has the potential to save valuable time for surgeons in the restoration of blood flow.

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The V005 trial met its objectives. V005 results included in the BLA submission to the FDA and published in JAMA Surgery, an American Medical Association peer-reviewed journal, in November 2024, are summarized in the following table.

V005 Phase 2/3 ATEV Results in Vascular Trauma Compared to Synthetic Graft Benchmark

Conduit Infections 2.0% 8.4%

In the package insert for Symvess, the FDA applied a different imputing methodology for V005 Symvess patients who did not have a day 30 assessment. For patients who missed day 30 follow-up due to unrelated death or loss of follow-up, patients were imputed as treatment failures (i.e., loss of patency, and failure of limb salvage). The FDA also added three more patients enrolled after data cutoff.

V005 Phase 2/3 ATEV Results in Vascular Trauma in Package Insert

30-Day Endpoint V005 TrialATEV Extremity Group (n=54) (%)*

Primary Patency 66.7%

Secondary Patency 72.2%

Conduit Infections 1.9%

Limb Salvage 75.9%

* Nine patients not available for Day 30 assessment were imputed as failures for patency and limb salvage estimation.

This imputing methodology used in the package insert was different than that used in the synthetic graft benchmark publications. The FDA elected to exclude the synthetic graft comparator from the package insert.

The safety profile of the ATEV in the V005 trial was consistent with previous studies and there were no cases of clinical rejection of the ATEV. A summary of adverse events (“AEs”) for the duration of the study (mean duration of follow up is 295 days) is included in the table below.

V005 Phase 2/3 ATEV Adverse Events

Adverse Event V005 Trial - ATEV Extremity Group (n=51)Number of Patients (%)

Total Adverse Events 50 (98.0%)

Non-Fatal Serious Adverse Events 28 (54.9%)

Deaths: At Day 30Over Duration of Study 3 (5.9%)4 (7.8%)

ATEV Infections 2 (3.9%)

ATEV Rupture 1 (2.0%)

ATEV Occlusion/Thrombosis 15 (29.4%)

Pseudoaneurysm 1 (2.0%)

Aneurysm 1 (2.0%)

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There were no unexpected safety signals for the ATEV in the V005 trial. The most common AEs were thrombosis, anemia, pyrexia, thrombocytopenia, constipation, nausea, peripheral edema, and tachycardia. The most common non-fatal Serious Adverse Events (“SAEs”) were thrombosis, anastomotic stenosis, wound infection, muscle necrosis, wound infection, hemorrhage shock, and cardiac arrest. Deaths occurring prior to day 30 were adjudicated as not casually related to the ATEV by an Independent Adjudication Committee.

We believe the V005 trial results indicate that for patients in need of extremity arterial repair, when use of autologous vein was not suitable, and who were at high-risk level for wound infection, the ATEV may offer an effective option for revascularization. A case study from the trial is shown in the figure below, a photograph of an ATEV that was used to repair both an artery and a vein in the knee of a patient who suffered a gunshot wound. This patient was doing well at the 30-day follow-up visit with both repairs remaining patent and functional.

Intra-operative photograph of ATEV repair of popliteal artery (left) and vein (right) in V005 subject.

Ukraine Humanitarian Program, - V017 Trial

V017 Background and Results:

In the second quarter of 2022, Humacyte launched a humanitarian initiative to provide its ATEVs to hospitals in Ukraine for the treatment of wounded civilians and soldiers with vascular trauma injuries. Ukrainian surgeons presented patient outcomes from the use of the ATEV to treat wartime vascular trauma at two vascular conferences in December 2022, the VI Congress of Vascular Surgeons, Phlebologists, and Angiologists of Ukraine in Kyiv, Ukraine, and the 11th Munich Vascular Conference (MAC) 2022. The surgeons described long-standing limitations in vascular tissue repair and replacement as well as the injuries that they have observed during the Russian-Ukrainian conflict. Surgeons utilized the ATEV to treat patients with wartime injuries including blast trauma, shrapnel injuries, and gunshot wounds. The surgeons observed that access to the ATEV, a biologic conduit, has improved their ability to perform vascular reconstructions by eliminating the need to harvest a venous conduit. A total of 19 vascular patients were treated under this humanitarian program, and results from 16 of these patients were published in JAMA Surgery in November 2024, along with results from the V005 trial.

The FDA advised Humacyte to include in the BLA submission patient outcomes from the Ukraine humanitarian program. We refer to the results for the 16 patients from Ukraine with extremity vascular trauma who provided consent for use of their results in the BLA filing as the V017 trial. A high success rate for the 16 extremity patients in the V017 trial was observed, despite the presence of contaminated wound beds, as summarized in the table below.

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V017 Ukraine Humanitarian ATEV Results in Vascular Trauma

30-Day Endpoint V017 Trial ATEV Extremity Group (%)

Primary Patency 93.8%

Secondary Patency 93.8%

Conduit Infections 0.0%

Amputations 0.0%

The safety profile of the ATEV in the V017 trial was consistent with previous studies and there were no cases of clinical rejection of the ATEV. A summary of AEs for the duration of the study (mean duration of follow up is 139 days) is included in the table below.

V017 Ukraine Humanitarian ATEV Adverse Events

Adverse Event V017 Trial - ATEV Extremity Group (n=16)Number of Patients (%)

Total Adverse Events 4 (25.0%)

Non-Fatal Serious Adverse Events 1 (6.3%)

Deaths: At Day 30Over Duration of Study 0 (0.0%)0 (0.0%)

ATEV Infections 0 (0.0%)

ATEV Rupture* 1 (6.3%)

ATEV Occlusion/Thrombosis 1 (6.3%)

Pseudoaneurysm 0 (0.0%)

Aneurysm 0 (0.0%)

*One ATEV rupture associated with extensive shrapnel remnants in the wound that caused bleeding.

In the figure below, photographs are shown of the first patient treated under the humanitarian program in Ukraine. The patient was a 42-year-old male who suffered a gunshot wound in the leg which damaged his femoral artery. The patient was initially treated using synthetic graft which became infected, and the patient experienced critical right lower extremity ischemia. The ATEV was implanted as a right superficial femoral artery reconstruction to achieve wound healing and limb salvage. After three months, the ATEV was reported to have retained primary patency with no evidence of ATEV infection.

Intra-operative photographs of attempted synthetic graft repair of femoral artery (left) and subsequent repair with ATEV (right) in patient from Ukraine humanitarian program.

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Combined V005 and V017 Results of ATEV for Vascular Trauma

The BLA submission was supported by the combined results from the V005 (civilian) Phase 2/3 clinical trial and real-world outcomes from the treatment of wartime injuries in Ukraine in the V017 (military) trial. Combined results included in the BLA submission to the FDA and published in JAMA Surgery in November 2024 are summarized in the following table. The Synthetic Graft Benchmark publications included a combination of civilian and military injuries.

Combined V005 Phase 2/3 ATEV and V017 Ukraine Real-World Results in Vascular Trauma

Compared to Synthetic Graft Benchmark

Conduit Infection Rate 2.0% 0.0% 0.9% 8.4%

Death Rate (all causes) 5.9% 0.0% 3.5% 3.4%

The ATEV demonstrated a higher 30-day secondary patency rate, and patients treated with the ATEV were only 40% as likely to lose blood flow through their conduit after one month compared to the rate historically reported for synthetic grafts, which is a key period for recovery after traumatic injury.In addition, patients treated with the ATEV had approximately 1/5th the amputation rate, and approximately 1/9th rate of infection compared to that historically reported for synthetic grafts.

BLA Approval and Indication

On December 19, 2024, the FDA granted full approval for the ATEV for use in adults with extremity vascular trauma. The granted indication language was: “for use in adults as a vascular conduit for extremity arterial injury when urgent revascularization is needed to avoid imminent limb loss, and when autologous vein graft is not feasible.” Although Humacyte had originally filed for an indication of use that included when “autologous vein was not feasible and synthetic graft was not indicated,” the FDA granted an indication for when “autologous vein is not feasible,” a broader indication of use without the restriction of “when synthetic graft was not indicated.”

Budget Impact Model

In March 2025, the Budget Impact Model for Symvess was published in the Journal of Medical Economics. The publication reported that Symvess was projected to be cost saving for both trauma centers and third-party payers, primarily due to reductions in the costs related to amputations and conduit infections. This publication used inputs from the PROOVIT vascular trauma registry, databases of hospital charges and insurance claims, published literature, and expert opinion to evaluate the economic impact from the perspective of Level I trauma centers and third-party commercial, Medicare and Medicaid payors. The publication was developed in collaboration with health economists and vascular surgeons to ensure that current practices in extremity arterial trauma practices were reflected, and that current health economic modeling standards were followed. Based on the model, the per-patient cost for trauma centers of treating patients with Symvess is estimated to be less than the cost of treating trauma patients with synthetic and other non-autologous grafts as shown in the graph below.

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Symvess (ATEV) Budget Impact Model

Estimated Per-Patient Cost for Trauma Centers

The model also showed greater savings for third-party payors (compared to trauma centers) due to the avoidance of late complications occurring after patients’ release from the hospital as shown in the graph below.

Symvess (ATEV) Budget Impact Model

Estimated Per-Patient Cost for Third-Party Payors

The major drivers of cost savings in the Budget Impact Model associated with Symvess across all stakeholders were attributed to reductions in the rate of vascular conduit infection and amputation.

Proposed Indication #2: Use of the ATEV for AV Access for Hemodialysis

Overview of Hemodialysis and Existing Methods of AV Access for Hemodialysis

End-stage renal disease (“ESRD”) develops when chronic kidney disease progresses to a point where either dialysis or a kidney transplant is required for the patient to survive. For hemodialysis to be conducted, a point of vascular access to the patient’s circulatory system must be created, termed vascular access, so that blood can be transported from the body to the dialyzer and then back to the body. The demand for vascular access conduits includes the need for both new hemodialysis patients who have progressed to ESRD requiring an initial access, and existing patients that require the replacement of their existing access. There are currently three traditional methods for obtaining vascular access for hemodialysis: an AV fistula, a synthetic graft, and a catheter. Each of these vascular access methods has substantial limitations, as outlined below:

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Three Traditional Methods for Obtaining Vascular Access for Hemodialysis

Fistula. An AV fistula is created by surgically connecting a vein to an artery, typically in the patient’s arm. Fistulae are often considered the preferred means of access for hemodialysis due to lower infection rates of approximately 0.5% – 1.5% per patient-year as well as long-term durability. However, many patients are not suitable candidates for fistula placement, including women and patients with small vessel anatomy, advanced age, obesity, diabetes or other comorbidities. Approximately 40% of patients who undergo surgery for fistula creation will not gain any benefit from the surgery because the fistula lacks sufficient vein enlargement and increased blood flow, a process called fistula maturation, that is necessary for hemodialysis. Additionally, during the period in which the fistula is maturing, catheters are generally used to provide the patient access for dialysis. There is a high risk of infection and morbidity, and health care cost, associated with prolonged catheter dependence while waiting for the fistula to mature.

Catheters. A catheter, which is tunneled underneath the skin and placed directly into a large vein in the patient, is generally the least desirable access solution. Given the time necessary for fistulae to mature, the vast majority of patients in the United States begin hemodialysis using a catheter while awaiting fistula maturation. Catheters have rates of blood stream infections as high as 200% per patient-year, with high associated morbidity and health care costs.

Synthetic graft. A synthetic graft, typically made from ePTFE and sewn between an artery and vein in the patient’s arm, is generally used in patients who are not candidates for fistulae. The drawbacks of synthetic grafts include higher infection rates, which can be as high as 10% – 15% per patient-year, and gradual degradation of the non-healing ePTFE graft material caused by persistent needle punctures. A recent systematic meta-analysis measuring the functional patency of ePTFE grafts shows that, on average, only 70% of ePTFE dialysis access grafts remain functional one year after implantation.

Distribution of Hemodialysis Access Modes in Use in the United States

Access Type Fistulae Catheters Synthetic Grafts

Incident Patients: At Initiation of Hemodialysis 16.7 % 80.3 % 3.0 %

Prevalent Patients: For Ongoing Hemodialysis 64.5 % 18.9 % 16.6 %

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Overview of ATEV Experience in Hemodialysis Access: A table listing our clinical trials of the ATEV in hemodialysis access is included below. We have implanted the ATEV into approximately 418 total patients for hemodialysis access, for a total of more than 993 patient-years of exposure, as of December 31, 2024. Throughout these trials, we have observed consistent and sustained high primary and secondary patency rates. We have observed zero instances of clinical rejection of any ATEV in any hemodialysis access trial.

Implantation of ATEV for Hemodialysis

We have also observed in multiple clinical trials that our ATEVs had a low infection susceptibility during use for hemodialysis, with a rate lower than 1% per patient-year across all studies. The low infection susceptibility we observed in our trials of our ATEVs may be a result of the ATEV’s potential to become a living tissue as it becomes populated by cells from the patient’s body. Since living tissues are known to have resisted infection due to interactions with host white blood cells and immunological defense systems, it is possible that the repopulated ATEV resists infection for the same reasons that native arteries and veins resist infections, as is observed with autogenous fistulas.

We have also observed early evidence of potential healing from the cells that repopulate the ATEV after needle puncture for hemodialysis. In examining ATEV explanted segments we have observed healed needle cannulation tracts with cells expressing smooth muscle markers. This self-healing indicates that the ATEV may have repaired itself while being used as a hemodialysis access, which we believe is a distinct feature not present in synthetic materials, and, to our knowledge, has not been observed before for any other regenerative medicine product.

Our Current Phase 2 and Phase 3 Trials of the ATEV in Hemodialysis Access

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SP: Secondary Patency, which is the interval from the time of access placement until abandonment, i.e. patent with or without interventions.

Long-Term Data from Early Phase 2 Trials in Hemodialysis: V001 and V003

Phase 2 Trial Design and Current Outcomes: We have completed or are in long-term follow-up on two open-label Phase 2 trials in 60 hemodialysis patients in the United States and Poland from December 2012 through May 2014, which we refer to as our V003 trial and V001 trial, respectively. Both the V001 and V003 studies were designed as single-arm trials to assess the safety and efficacy of the ATEV for hemodialysis access, with assessments of patency at 6, 12, 18 and 24 months. In the 60 patients enrolled in these two studies, blood flow through all ATEVs was appropriate for hemodialysis, averaging over 1,200 mL/minute. Secondary patency for the two combined trials was 97% at six months, 89% at 12-months, and 81% at 18-months. These results compare favorably to published reports of secondary patency for fistula of 51% – 61% at six months and 75% at 12 months. Long-term results from the V001 trial showing five-year secondary patency of 58% were published in the European Journal of Vascular and Endovascular Surgery companion journal EJVES Vascular Forum in February 2022, and patients from the V001 trial are currently in a 10-year follow-up period.

Images and long-term results from Phase 2 V001 trial of ATEV in AV Access

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Phase 3 V006 AV Access Study

Trial Design: Our V006 HUMANITY study was a prospective, multi-center, multinational, open-label, randomized, two-arm, comparative study. Eligible study subjects were randomized to receive either a ATEV or a commercially available ePTFE graft and followed to 24 months post-implantation by routine study visits. After 24 months, subjects with a patent conduit are followed to five years post-implantation using a questionnaire at six-month intervals to ascertain patient and conduit status. The primary endpoint for the V006 HUMANITY trial was a non-inferiority analysis of secondary patency compared to ePTFE, to be assessed when all subjects are at least 18 months post-implantation. There were a total of 37 sites that participated in the study, enrolling a combined total of 355 subjects.

24-Month Results: The V006 study enrolled 355 subjects who were roughly equally matched in terms of demographics and co-morbidities. ATEV subjects trended older (p=0.06) and had more prior strokes (p=0.02) than did ePTFE subjects.

Phase 3 V006 HUMANITY trial subject demographics

Asian / Other (%) 3.4% 2.3% NS

Body Mass Index (BMI) 29.2 28.9 NS

Hypertension (%) 79.8% 79.7% NS

Cardiac Disease (%) 50.6% 57.1% NS

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The secondary patency of the ATEV was greater than that of ePTFE at six and 12 months but lower at 18 and 24 months, an outcome that had not been modelled in the V006 trial design. As per the pre-specified Cox Proportional Hazards test, the ATEV did not achieve its primary efficacy endpoint regarding secondary patency. In terms of safety, the ATEV had a statistically significant lower rate of conduit infections compared to ePTFE. Substantial differences in antibiotic use and need for hospitalization for infection were also noted in the V006 trial, all favoring the ATEV. The safety advantage of the ATEV over ePTFE may be clinically important as infection and sepsis are the second most common cause of death in dialysis patients.

Phase 3 V006 HUMANITY trial secondary patency results

Secondary Patency 6 months 12 months 18 months 24 months

Cox Proportional Hazards Model for Time to Loss of Secondary Patency

Estimate 95% CI

Phase 3 V006 HUMANITY trial rates of infection

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The reported SAEs related to the ATEV and ePTFE in the V006 trial, in this patient population, which typically has a high prevalence of existing medical conditions, are detailed in the table below.

SAEs Reported in V006 Phase 3 Clinical Study in AV Access

Description of SAE Number of SAEs(% of total subjects)

ATEV ePTFE

General disorders and administration conditions:

Implant site extravasation 0(0.0)% 1(0.6)%

Infections and infestations:

Vascular access site infection 0(0.0)% 5(2.8)%

Injury, poisoning and procedural complications:

Anastomotic stenosis 1(0.6)% (0.0)%

Vascular access site hematomas 1(0.6)% (0.0)%

Vascular access site hemorrhage 0(0.0)% 3(1.7)%

Vascular access site pain 1(0.6)% 0(0.0)%

Vascular access site pseudoaneurysm 10(5.6)% 0(0.0)%

Vascular access site rupture 2(1.1)% 0(0.0)%

Vascular access site thrombosis 41(23.2)% 28(15.7)%

Skin and subcutaneous tissue disorders:

Vascular disorders:

Subclavian vein occlusion 0(0.0)% 1(0.6)%

Venous stenosis 3(1.7)% 9(5.1)%

Overall, although the primary efficacy endpoint concerning secondary patency was not met, the ATEV performed in the V006 trial as was expected, based upon ATEV performance in previous Phase 2 trials in hemodialysis and in other clinical applications. This outcome was due at least in part to unexpectedly high patency of the ePTFE grafts, particularly after 12 months. While the cause of this unexpectedly high patency is not clear, it is possible that study-mandated ultrasounds and examinations may have led to more aggressive vigilance with ePTFE grafts to maintain patency. In addition, the age and comorbidities of ATEV subjects in V006 was somewhat worse than for ePTFE subjects.

In the V006 trial, the ATEV displayed significantly fewer infections than did the ePTFE grafts. This was associated with fewer instances of immune sensitization in ATEV subjects as compared to ePTFE subjects, which could translate to easier kidney transplantation at future times. Similar to prior studies, we observed that the ATEV had good durability, blood flow rates and diameters similar to ePTFE grafts, and also host cell remodelling that was superior to that of ePTFE grafts.

Phase 3 V007 AV Access Study

Trial Design: In April 2023 we completed enrollment of a Phase 3 trial, called V007, in 242 patients with ESRD. V007 is a Phase 3, prospective, multi-center, open label, randomized, two-arm comparative study conducted in the United States. The V007 trial is designed to assess the usability of the ATEV for dialysis at six and 12 months as a comparison to autogenous fistulas, which are known to exhibit a high rate of early maturation failure of approximately 40% at six months. Patients in the study are randomized to receive either the ATEV for vascular access or an autogenous AV fistula. The objective of V007 is to compare the safety and efficacy of our 6 millimeter ATEV to autogenous AV fistula for functional hemodialysis access.

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Eligible study subjects in V007 are randomized to receive either an ATEV or an autogenous fistula and followed to 24 months post-implantation by routine study visits. Efficacy endpoints include useability for dialysis at six and 12 months, as well as a comparison of secondary patency via a time-to-event analysis of all subjects at 12 months. Additional safety endpoints include the rate of dialysis access-related infections for ATEV and fistula subjects.

One-Year Results: As of December 31, 2024, there were 242 patients enrolled in the V007 trial, and enrollment was completed in April 2023. Demographics of the patients enrolled in V007 are summarized in the following table.

Phase 3 V007 trial subject demographics

Topline results were reported in August 2024 and expanded results, including subgroup analyses, were presented at the American Society of Nephrology’s (ASN) Kidney Week 2024, the premier nephrology meeting, in October 2024. In the V007 trial, the ATEV demonstrated superior function and patency at six and 12 months (co-primary endpoints) compared to AVF, the current standard of care for hemodialysis, as summarized in the following table.

Phase 3 V007 trial 12-month results (all patients)

Co-Primary Endpoints ATEV (n=123) AVF (n=119) p-value

Secondary Patency at Month 12 68.3% 62.2%

Difference p-value

Duration of Use Over First 12 Months 7.5 months 6.1 months 1.4 months 0.0162

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Safety events per year of usability in the V007 Phase 3 trial are summarized in the following table.

Phase 3 V007 trial safety results (all patients)

12-Month Safety Summary ATEV AVF

The largest area of difference in AEs was in thrombosis. The majority of ATEV patients with thrombosis, 94%, were successfully treated.

Sub-group analysis was also performed in patient groups that historically have poor outcomes with AV fistula procedures. In female patients, subjects implanted with the ATEV had significantly higher six-month and one-year patency rates than female patients receiving an AV fistula as summarized in the table below.

Phase 3 V007 trial 12-month results (female patients)

Co-Primary Endpoints ATEV (n=37) AVF (n=33) p-value

Secondary Patency at Month 12 81.1% 48.5%

Difference p-value

Duration of Use Over First 12 Months 8.3 months 5.0 months 3.3 months 0.0011

It was also noted in the V007 trial that obese patients (BMI of at least 30) (n=93) implanted with the ATEV had significantly higher six-month and one-year patency rates than obese patients receiving an AV fistula. In addition, diabetic patients implanted with the ATEV had significantly higher six-month and one-year patency rates than diabetic patients receiving an AV fistula. Based on these results, we consider the subgroup of females and males with obesity and diabetes (a subgroup that combined represents over half of dialysis patients), to be a target population that could benefit from the ATEV. Results through 12 months of follow up from the V007 trial in females and males with obesity and diabetes are summarized in the following table.

Phase 3 V007 trial 12-month results – target population

(female patients and males with obesity and diabetes)

Co-Primary Endpoints ATEV (n=56) AVF (n=54) p-value

Secondary Patency at Month 12 76.8% 46.3%

Difference p-value

Duration of Use Over First 12 Months 8.0 months 4.5 months 3.5 months 0.0002

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The ATEV showed no increased in overall safety events per year of usability in the expected target population (all females and males with obesity and diabetes) as summarized in the following table.

Phase 3 V007 trial safety results – target population

(female patients and males with obesity and diabetes)

12-Month Safety Summary ATEV AVF

Phase 3 V012 AV Access Study in Women

In collaboration with our corporate partner Fresenius Medical Care and its subsidiary Frenova Renal Research, we conducted a study to review the outcomes of 178,575 adult patients who received in-center dialysis at Fresenius Kidney Care dialysis centers. Among the areas of study were the complications and cost of treatment by patient demographic. The objective of the study was to further define patient subgroups who could most benefit from the ATEV. The study showed that women, particularly obese and diabetic women, have higher complication rates, including infections and access failures, and higher treatment costs.

Based on the results of the results of this research, we have commenced a clinical study designed to demonstrate the clinical and health economic benefits of the ATEV in women dialysis patients, a high-unmet-need population. We have commenced a Phase 3 trial, which we refer to as the V012 trial, in up to 150 patients with ESRD. V012 is a Phase 3, prospective, multi-center, open label, randomized, two-arm comparative study conducted in the United States. The V012 trial is designed to assess the usability of the ATEV for dialysis in comparison to autogenous fistulas, in female patients currently receiving hemodialysis via catheter. The primary measure of efficacy will be total days free from in-dwelling catheter (“catheter-free days”) until 365 days, or until access abandonment, whichever occurs first. The primary measure of safety will be the number and severity of infections related to all accesses (including catheters) from access creation until 365 days. An interim analysis is planned on the first 80 patients after one-year of follow up, and 76 patients have currently been enrolled in the study.

Planned Supplemental BLA Filing in AV Access

Based on discussions with the FDA, our current plan is to submit a supplemental BLA after interim analysis of V012 study, subject to the results of that interim analysis. This plan would support a supplemental BLA submission in the second half of 2026 dependent upon the rate of enrollment in the V012 study and on the timeline for interim data analysis. Our current expectation is that the supplemental BLA submission would target the subgroups in which the ATEV has showed the best results to date, which are all females and males with risk factors for fistula non-maturation.

Proposed Indication #3: PAD

PAD involves partial or complete occlusion of blood vessels in the peripheral circulation and is a major cause of morbidity and mortality in the developed world. Patients with severe PAD undergo peripheral arterial bypass surgery where a conduit is implanted above and below the area of the arterial obstruction, to provide a “bypass” route for blood to flow around the blocked artery. The vast majority of these operations are performed in the lower limb. Other surgical alternatives include minimally invasive approaches such as stenting and angioplasties that are suitable for smaller atherosclerotic lesions and can delay — but oftentimes not prevent — the ultimate need for surgical revascularization.

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We have observed strong patency rates and no reported cases of infection for the ATEV in PAD in clinical studies to date. We are developing our 6 millimeter ATEV for use as a bypass conduit for patients with PAD. We have conducted two Phase 2 trials to evaluate the safety and efficacy of our 6 millimeter ATEV for use as a bypass conduit with PAD, which we refer to as our V002 and V004 trials. For both of these Phase 2 trials, the ATEV was implanted as a femoral popliteal bypass graft in patients with PAD.

Our Current Phase 2 Trials of the ATEV in PAD

Artery Disease Single-arm follow-up 6-month SP: 84%

ongoing 12-month SP: 84%

Infection Rate/yr: 0%

Number of Rejections: 0

Artery Disease Single-arm 6-month SP: 86%

Infection Rate/yr: 0%

Number of Rejections: 0

Number of Amputations: 0

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SP: Secondary Patency, which is the interval from the time of access placement until abandonment, i.e. patent with or without interventions.

Trial Design: Both our V004 and V002 trials were prospective, open-label, single treatment arm, multi-center studies. We enrolled 20 patients in our V002 trial in Poland, and 15 patients in our V004 trial in the United States. Both trials had the primary objectives of evaluating the safety of the ATEV as a femoral-to-popliteal bypass graft, and determining the primary, primary assisted, and secondary patency over 12 and 24 months.

Current Trial Status and Outcomes: V002 enrolled a total of 20 patients between the ages of 54 and 79 at three clinical sites. 24-month results of the V002 trial were published in 2020. After censoring for three deaths (none of which were determined to be related to the ATEV or the implant procedure), we observed 24-month primary, primary assisted and secondary patency rates of 58%, 58%, and 74%, respectively. We observed through ultrasound data that the ATEVs were mechanically stable during the follow-up period and did not develop aneurysmal dilatation in any patient. Overall, we also determined through the histological assessment of explanted specimens that there were normal vascular cells within the ATEV and there was no infection or signs of immunological reaction to the graft.

There have been no ATEV-related infections reported during the V002 trial as of December 31, 2024, and no amputations of the treated extremity. A sub-set of seven V002 subjects consented for long-term follow-up computerized tomography (“CT”) angiograms, which were obtained at 48 to 52 months after ATEV implantation. In all cases, the ATEV maintained normal architecture and function. A representative image is shown below, taken 50 months post-implantation. Proximal and distal anastomoses of ATEV with recipient’s vasculature are noted, as is the scale bar on the right-hand side of each image. The image presents two views of the same subject, and shows uniform ATEV diameter along the length of the implant.

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A CT Angiogram from a V002 Subject at 51 months after ATEV implantation

Patients in the V002 trial are currently in long-term follow-up out to ten years. In 2022, six-year results from V002 were published in Journal of Vascular Surgery – Vascular Science. The article, entitled “6-Year Outcomes of a Phase 2 Study of Human-Tissue Engineered Blood Vessels for Peripheral Arterial Bypass,” reported overall secondary patency rate of 60% at 72 months, including all patients originally enrolled, as estimated by Kaplan Meier analysis. There was no evidence of graft rejection or infection, and no patients underwent amputation of the affected limb out to six years.

Long-term results from V002 Phase 2 study in PAD

ATEV Infection Rate — 0% 0% 0% 0% 0% 0% 0%

The V004 trial enrolled 15 subjects in the United States, with the 12-month follow-up of the last enrolled patient occurring in December 2020. Patients in the V004 trial included Rutherford 4 and 5 subjects, with severe, debilitating limb ischemia. (Rutherford 4 and 5 patients are classified as patients with pain at rest due to limb ischemia (stage 4), and those patients suffering tissue loss in the limb as a result of ischemia (stage 5)). In addition, enrollment in V004 required that no autologous vein be available for bypass. Hence, the subjects enrolled in the V004 trial had severe and debilitating limb ischemia due to PAD and had no autologous vein that was suitable for lesion bypass and revascularization.

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12-month results from V004 Phase 2 study in PAD

Result from V004 Trial (as of April 2021) Pre-Op 6 mos 12 mos

Secondary Patency — 86% 64%

Rate of Amputation — 0% 0%

VascuQol Quality of Life Assessment 3.1 5.6 5.9

In the V004 trial, ATEV secondary patency was 86% at 6 months, and 64% at 12 months. While lower than patency values observed in the V002 trial, patients in the V004 trial had more severe PAD, which is associated with poorer arterial “run-off” and higher propensity for conduit occlusion. Assessment of Quality of Life by the validated VascuQol assessment demonstrated an increase in overall quality of life for V004 patients at 6 and 12 months. In addition, ankle-brachial index, a measurement of blood pressure in the operative limb, was increased at 6 and 12 months. There were no infections of the ATEV reported in the V004 trial, despite the severity of the PAD and the often-associated tissue infection that can accompany this disease. There were zero reports of clinical ATEV rejection. Lastly, there were zero reported amputations of any operative limb in the first 12 months of follow-up.

Published literature reports of patients with Rutherford stage 4 and 5 PAD and no autologous vein available for revascularization show that outcomes can include amputation. For Rutherford 4 and 5 patients with no vein and no revascularization procedure, amputation rates at 6 months are reported at 31%. For stage 4 and 5 patients who do undergo saphenous vein revascularization, the amputation rate at one year is approximately 10%. The lack of amputation for stage 4 and 5 patients in the V004 trial at one year, none of whom had saphenous vein for revascularization, supports the use of the ATEV in severe PAD.

Examples of the Use of Our 6 millimeter ATEVs in Expanded Access Cases

The FDA has granted use of the ATEV in 29 special expanded access cases through December 31, 2024, the majority of which were patients with chronic limb-threatening ischemia (“CLTI”), the end stage of PAD. Each of these compassionate use cases was conducted under an individual, investigator-initiated IND application with the FDA. Two cases are highlighted below.

70-year-old with Critical Limb Ischemia

The patient is a 70-year-old male with critical limb ischemia and no vein available to perform a bypass, as the vein was previously used for a CABG. He underwent a successful bypass with the ATEV. Imaging at one year demonstrated a patent graft as illustrated below.

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42-year-old with Infected Dacron Graft

An ATEV was used in a 42-year-old female to replace an 8 mm Dacron iliac artery bypass graft that had become infected. The patient refused harvesting of the femoral vein for reconstruction and requested the ATEV. The patient was seen at one, three, six, nine, and 12 months after ATEV implantation. At all visits, the ATEV appeared normal with unobstructed patency. Flow and velocities were normal. At three months, the patient was released to full activity. At six and 12 months, the graft was functioning well. At one-year imaging, the ATEV was patent and appeared remarkably similar to the patient’s native blood vessels. The patient had no signs of infection in the ATEV and continues to have no limitations or complications during normal activity or exercise.

Mayo Clinic Study in Severe PAD

The Mayo Clinic, Rochester, MN, is conducting a study in patients with CLTI under an investigator-initiated IND filed with the FDA. In February 2024, researchers published interim results in the Journal of Vascular Surgery, including their conclusion that in the clinical study the ATEV was a safe, resilient, and effective conduit for arterial bypass and limb salvage. This is an important result since approximately 40% of patients requiring lower extremity bypass do not have saphenous vein available, which is the standard of care for treating this challenging disease state. The presentation reported the outcomes of 29 patients, with a mean age of 71 and having no available vein to use as a bypass graft, who underwent ATEV implantation. Of these 29 patients, 28 (97%) had previously experienced unsuccessful revascularization procedures on the extremity and 21 (72%) had tissue loss or gangrene. Based on the state of this disease, this patient group had a 30-50% one-year risk of amputation. Notably, performing bypass surgery in 24 (83%) of the patients necessitated the fusion of two 42 cm long ATEVs to achieve the required bypass length. Surgeons reported that the operations to implant the ATEV achieved a 100% technical success rate, without any ATEV-related major adverse events reported. At a median follow-up of nine months, the secondary patency rate for patients implanted with the ATEV was 71%. The limb salvage rate was 86%, corresponding to only a 14% amputation rate.

Preclinical Pipeline

Pancreatic Islet Transplantation for Type 1 Diabetes (BioVascular Pancreas)

The BVP is a modification of Humacyte’s ATEV product, leveraging the ATEV to deliver therapeutic cells within close proximity of the patient’s bloodstream. We believe that the ATEV extracellular matrix material is both highly biocompatible, as evidenced by adaptive cellular repopulation after implantation, and also highly angiogenic, as evidenced by extensive formation of microvessels surrounding the ATEV in vivo. These attributes mean that the ATEV may serve as a suitable conduit for delivering large numbers of therapeutic cells to a patient.

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Pancreatic islets, which sense blood glucose and respond by secreting insulin, are destroyed by an auto-immune attack in patients with Type I diabetes. The outer surface of our 42cm ATEV has sufficient surface area to accommodate a monolayer of approximately 800,000 human pancreatic islets, which is approximately the number in an entire adult pancreas, and can reverse diabetes and restore glucose control.

We have performed mathematical modelling studies that predict, we believe, that a 42cm ATEV could maintain viability of a therapeutic number of islets after implantation of the ATEV into the arterial bloodstream, or after implantation as an AV conduit similar to that used for hemodialysis access. Bioreactor experiments have confirmed these mathematical conclusions. Furthermore, we have implanted rat-sized BVPs into the aortas of diabetic rats, and observed that the BVP could restore normal glucose levels in all treated animals, while control animals (“No Flow” in red in figure below) did not restore glucose control.

In April 2023, Humacyte and Breakthrough T1D (f/k/a JDRF International) (“JDRF”), the leading global organization funding type 1 diabetes research, announced a collaboration to advance the development of the BVP product candidate. During 2023 and 2024, we performed testing the BVP in primates. In these experiments, researchers observed that insulin-producing cells in the BVP survive for months after implantation into the animal and continue to make insulin after implantation that is measurable in the bloodstream. We consider these results to be extremely encouraging as they support the potential ability of the BVP to deliver a curative number of insulin-producing islets into diabetic subjects. Additional work in large animals is currently ongoing, including using the BVP in diabetic large animals.

Coronary Artery Bypass Graft

Evaluation of 3.5-4mm diameter ATEVs for CABG has been performed over the last four years at Humacyte. We performed a preclinical study at Duke University to evaluate the use of our small diameter ATEV for CABG in adult primates (baboons), and we have also performed studies of the sdATEV in sheep and pig models of CABG surgery, with follow-up times ranging from 1-3 months. The goal of the primate and other large animal studies is to assess patency and function of the small diameter ATEV, as well as host responses and cellular remodeling. ATEVs are followed by ultrasound imaging of the heart, and angiographic imaging of the conduits. In November 2024, researchers presented preclinical results of the sdATEV in a baboon model of CABG at The American Heart Association’s Scientific Sessions 2024 meeting. In the six-month preclinical CABG model, the sdATEV was observed to sustain patency (blood flow), recellularized with the animals’ host cells, and remodeled to effectively reduce the initial size mismatch between the sdATEV and the animals’ native artery. In the preclinical study, the sdATEV was implanted between the aorta and right coronary artery (“RCA”) in five baboons to simulate a CABG procedure. Animals were followed for six months after sdATEV implantation and all sdATEVs maintained patency throughout the study. The baboon study provided an effective model for demonstrating the feasibility, mechanical durability and capacity for host-cell remodeling of the sdATEV for CABG. After implantation, the sdATEV was observed to recellularize with host cells and remodel to effectively reduce the initial size mismatch with the RCA.

Based on discussions with the FDA, we plan to file an IND with the FDA seeking authorization to commence human clinical testing of the sdATEV in CABG.

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Angiography showing adaptive remodeling

of ATEV after implant in baboon CABG model

Pediatric Heart Surgery: Modified Blalock-Taussig-Thomas (mBTT) Shunt

Tetrology of Fallot is a relatively common congenital heart defect, that is often treated using a modified Blalock-Taussig-Thomas (“mBTT”). To support a potential future IND filing with the FDA, we have evaluated the use of our ATEV as an mBTT shunt for up to six months in juvenile primates at the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio.

BT Shunt Implant Schematic

In October 2023, results of the preclinical study were published in the open-access Journal of Thoracic and Cardiovascular Surgery (JTCVS Open). In the study, researchers implanted 3.5mm diameter ATEVs into a juvenile large-animal model of pediatric heart disease. The 3.5mm ATEV was implanted between the subclavian and pulmonary arteries, to mimic a commonly-performed surgical procedure used to treat babies born with Tetralogy of Fallot, one of the most common pediatric heart conditions. The study assessed the ATEV’s patency, structure, and blood flow from one week to six months after the implant. The 3.5mm diameter ATEV has smaller product dimensions but is manufactured using a similar process as Humacyte's 6mm ATEV system currently being evaluated in clinical trials in vascular trauma, AV access for hemodialysis, and PAD. We believe that the production of the functional 3.5mm ATEV is indicative of the potentially broad application of our proprietary bioengineered tissue platform and manufacturing processes.

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Engineered Trachea for Treatment of Severe Airway Injuries

Each year in the United States, approximately 4,000 operations are performed to repair or reconstruct the trachea or mainstem bronchi. But unlike most other connective tissues in the body — such as blood vessel, bone, skin and tendon — there currently are no replacements for tracheal tissue that are in widespread clinical use. For long tracheal or bronchial defects, some sort of tracheal replacement is often needed, yet none exists currently. The lack of a functional tracheal conduit commits patients to, sometimes, slow suffocation.

We have modified the ATEV production process to enable the embedding of a biocompatible medical-grade stent within the wall of the engineered vessel. Combining a non-degradable stent with the degradable polymer scaffold used for ATEV production results in a composite scaffold that can be seeded with smooth muscle cells and grown in culture. After decellularization, the engineered trachea consists of the extracellular matrix contained in the ATEV, along with an embedded stent that prevents the collapse of the engineered airway with inspiration or neck movements.

Summary of Process to Generate Engineered Tracheas

In models where engineered tracheas were implanted into rats and non-human primates, we have observed that the implants repopulate with cells from the host, including cuboidal respiratory epithelium that lines the native airway progressively from two to eight weeks after implantation. We have further observed that the engineered tracheas can function out to two months. Future studies in large animal models are planned.

Photograph (A) of Implantation of Engineered Trachea into Non-Human Primate Airway; Microscope Imaging of Cells Repopulating the Trachea after 2 and 8 weeks (B, C)

Engineered Whole Lung Organs

End-stage lung disease is the fourth leading cause of death in the U.S., and lung transplantation remains severely limited by donor organ shortages. Dr. Niklason’s laboratory at Yale University has pioneered the development of using decellularized native lungs, combined with targeted recellularization of the lung scaffolds within biomimetic bioreactors, to produce whole lungs that are capable of exchanging gas. Gas exchange for several hours has been observed in studies in rodents. Efforts to scale-up the technology to human-sized organs are ongoing.

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Structure of Lung, Scaffold for Lung Engineering, and Implanted Engineered Lung

Manufacturing

We have developed a novel paradigm for manufacturing human tissues that mimics key aspects of human physiology. Recognizing that commercial scale production capacity of bioengineered tissue has been non-existent, we prioritized the development of a scalable, reproduceable, commercial biomanufacturing process. At our 83,000 square foot manufacturing facility in Durham, North Carolina, we have industrialized this concept and created a scalable modular manufacturing process that enables us to engineer our ATEVs in commercial quantities in a system designed for cGMP compliance.

Our proprietary manufacturing process was designed with a modular approach allowing us to produce ATEVs in smaller batches for clinical trials and scale out to larger batches for commercial manufacturing. The current, commercial-scale LUNA200 system utilizes 20 growth drawers holding ten ATEVs each for a total of 200 ATEVs per batch. Since 2021 this system has been utilized to produce clinical product for use in our ongoing Phase 3 trials. The FDA inspected our manufacturing facility in April 2024 as part of its review and approval of our BLA in extremity vascular trauma, and we are using this facility to provide product for the United States commercial launch in that indication which commenced in the first quarter of 2025.

Our manufacturing process utilizes our LUNA200 system, consisting of 20 “growth drawers.” Each growth drawer is capable of producing ten 42cm ATEVs and each ATEV remains contained within an individual bioreactor bag. Inside a LUNA200, a closed tubing network connects all 20 growth drawers as well as the ten bioreactor bags in each drawer, allowing the entire system to share cells and nutritive media. In this way, a single LUNA200 can produce up to 200 ATEVs per batch while maintaining the critical operating parameters that direct growth, creating a gross capacity of approximately 900 ATEVs per system annually.

We have designed the LUNA200 to have the ability to produce ATEVs in diameter sizes from 3mm to 10mm and lengths from 10cm to 42cm, making the equipment suitable for the varied array of product candidates in our pipeline. We intend to introduce a 13cm ATEV line extension after commercial launch of the 42cm ATEV. Using our existing LUNA manufacturing equipment, we can generate 400 13cm ATEVs per batch. Our modular manufacturing platform can be scaled without impacting the operating parameters that support the ATEV growth process. We have designed our manufacturing system to be functionally closed, to utilize single-use disposable materials with aseptic connections, and to be fully automated.

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Modular Manufacturing Platform Allows for Production of Multiple Product Lengths Using the Same Equipment

We currently have eight LUNA200 systems installed, commissioned and qualified in our manufacturing facility, creating an annual gross ATEV capacity of approximately 7,200 ATEVs. Our manufacturing facility contains space to increase capacity in future years to approximately 40 LUNA200 systems in total. As we continue to expand production, we believe that we will have the ability to take advantage of economies of scale and reduce production costs. The initiation and pace of the expansion of vessel capacity will be determined based on our assessment of market opportunity.

We initiate ATEV production using primary human aortic vascular cells from a working cell stock (“WCS”) that is isolated from FDA-compliant donor tissues and cryopreserved. The WCS vials are stored at two separate qualified facilities to mitigate the risk of single site storage. We qualify all new WCSs for use in ATEV manufacturing utilizing biochemical and gene expression assays. Each qualified primary isolation can produce approximately 500,000 to one million ATEVs.

The WCS expanded using traditional cell culture techniques, and the cells are transferred onto a biocompatible, biodegradable polymer mesh within a flexible, single-use bioreactor bag. Cells inoculated onto this tubular mesh are cultured utilizing a proprietary culture medium and subjected to cyclic mechanical stretch for a period of approximately eight weeks. During this period, the cells proliferate and build extracellular matrix while the polymer mesh degrades. The resulting bioengineered vessel is comprised of the aortic vascular cells and their deposited extracellular matrix. After completion of the culture period, we decellularize the bioengineered vessel using a proprietary combination of salts, enzymes and detergents, followed by numerous washes in excipient grade neutral pH buffered saline. The resulting ATEV retains the human extracellular matrix constituents and, therefore, the biomechanical properties of the bioengineered vessel, but cells and cellular components, which could induce a foreign body response or immune rejection following implantation, are removed. After decellularization, our ATEVs are packaged for distribution inside the same flexible bioreactor bag in which they were produced, with sterile phosphate buffered saline as the excipient. Once the package is delivered to the operating room, the ATEV is removed from the bioreactor bag by the surgical staff.

Suppliers

We source critical components and necessary raw materials from vendors that have been approved and qualified through our vendor management program. SeraCare, which was subsequently acquired by LGC Clinical Diagnostics, Inc. (“SeraCare”), is the current single source supplier of human plasma used in our manufacturing process and Confluent Medical Technologies, Inc. (“Confluent”) is the current single source supplier of the polymer mesh we use. We source custom, Humacyte-designed, pre-sterilized (gamma irradiated) assemblies and single-use tubing sets through multiple approved vendors. We source bioprocess solutions, including culture media and decellularization buffers, from a division of Thermo Fisher Scientific, which has a second production site to provide redundant media/buffer production capacity. We continue to explore the development redundant vendors for all critical materials and we manage all vendor changes through a robust change control process.

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Supply Agreement with SeraCare

In January 2014, we entered into a supply agreement with SeraCare for the supply of human plasma, which was amended in October 2018 (as amended, the “SeraCare Agreement”). Under the SeraCare Agreement, we agreed to purchase at least a substantial majority of our human plasma requirements from SeraCare. In the event SeraCare is unable to fulfill our requirements, and subject to certain conditions, we may engage another plasma supplier during the period in which SeraCare is unable to fulfill our requirements. The SeraCare Agreement is subject to annual price modifications in the case of significant changes in SeraCare’s cost of raw materials, with any modification to be determined at least three months prior to the end of the relevant year. The initial term of the SeraCare Agreement expired on October 12, 2023, but automatically extends for subsequent one-year periods unless terminated by either party at least 18 months prior to the end of the initial term. Either party may terminate the SeraCare Agreement for uncured material breach or for the insolvency of the other party at any time. In addition, either party may terminate the SeraCare Agreement without cause upon 12 months’ written notice. We may also terminate the agreement in the event of certain supply interruptions. Each party also agreed to indemnify the other against certain third-party claims up to a specified cap.

Supply Agreement with Confluent

In August 2015, we entered into an agreement for the supply of polymer mesh, which we refer to as the mesh supply agreement, with Biomedical Structures LLC (“Biomedical Structures”). Biomedical Structures’ rights and obligations under the mesh supply agreement were subsequently assigned to Confluent in connection with Confluent’s acquisition of Biomedical Structures in 2016. In 2020, the agreement was amended to align with the growth expected with the transition to commercial distribution following FDA approval. Pursuant to the mesh supply agreement, the price of polymer mesh we purchase from Confluent is subject to potential adjustment if Confluent’s cost of raw materials increases above a specified threshold pursuant to good faith negotiations from both parties, which negotiation Confluent may not request more than once in a 12-month period. The 2020 amendment also provided volume driven discounts. Confluent is obligated to partner with Humacyte in order to establish redundant facilities for the manufacture of the polymer mesh at established contractual volume thresholds. The amended mesh supply agreement has a term of three years, which can be automatically extended for subsequent one-year periods and will continue to do so unless either party provides notice of non-renewal at least 120 days prior to the end of the then-current term or otherwise terminates in accordance with the agreement. We and Confluent are each also permitted to terminate the mesh supply agreement for convenience, however Confluent must provide us with at least 365 days written notice and we are obligated to provide 180 days’ notice, prior to such a termination. In addition, each party is permitted to terminate the mesh supply agreement for an uncured material breach by the other party following failure to remedy the breach during a sixty-day cure period. Both parties have agreed to indemnify one another for certain third-party claims.

Distribution

Commercialization Strategy Within United States and for Earlier-Stage Pipeline Programs

Following the December 2024 FDA approval of Symvess in extremity vascular trauma, we commenced the United States commercial launch in that indication in the first quarter of 2025. For our vascular repair and replacement applications of our technology, including vascular trauma, AV access for dialysis, and the treatment of PAD, we have retained the right to commercialize our ATEV within the United States. In the United States we are commercializing the ATEV through our own direct sales and marketing team and expect to do so also for any additional ATEV indications that may be approved. We own end-to-end commercialization and are pursuing collaborations with appropriate strategic partners who have established distribution channels for specialized markets.

Our first market launch of Symvess for the treatment of extremity vascular trauma in the United States involves a highly concentrated market of approximately 200 Level I Trauma Centers that may be reached with a small field sales forces. Many of the major trauma centers already have familiarity with our ATEVs through their participation in our clinical trials. Our sales launch commenced in the first quarter of 2025 and includes dual targeting of surgeons to create pull-through demand and hospital administration (trauma center Value Analysis Committees) to ensure adoption and uptake of the ATEV in vascular trauma. We have recruited and trained a highly experienced sales team for the commercial launch of Symvess. All ten sales team members are multi-year President’s Club winners, representing the top 10% of achievers in their prior sales organizations. The average hospital medical device and biotech experience of our sales team members exceeds 15 years, all sales team members have experience in vascular surgery and/or trauma surgery, and 80% have previous experience selling regenerative therapies. All team members have experience selling clinically differentiated disruptive technologies and premium priced portfolios.

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We have developed and published a Budget Impact Model based on the clinical results supporting the approval of Symvess, and the estimated reduction in clinical complications potentially achievable by treating specific patients with Symvess versus current standard of care. Based on the model, the per-patient cost of treating patients with Symvess is estimated to be less than the cost of treating trauma patients with synthetic grafts, cryopreserved allografts, or xenografts, as well as other patients at high risk of complications. Major drivers of cost savings associated with Symvess were attributed to reductions in the rate of amputation and vascular conduit infection.

Additionally, we submitted a New Technology Add-On Payment (“NTAP”) application for Symvess to the Centers for Medicare and Medicaid Services (“CMS”) in October 2024. We presented Symvess data at a public Town Hall with the CMS in December 2024. If successful, NTAP reimbursement will begin for discharges on October 1, 2025, offering hospitals additional payment to cover a portion of the costs associated with Symvess.

We expect that the large market potential of earlier-stage applications of our technology platform such as CABG and BVP for diabetes will provide additional collaboration opportunities, and we expect explore strategic partnerships for these product candidates as preclinical and clinical results providing additional proof of concept are generated.

Distribution Agreement with Fresenius Medical Care

We entered into a distribution agreement with Fresenius Medical Care in June 2018 which, as amended as of February 16, 2021, granted Fresenius Medical Care and its affiliates exclusive rights to develop outside the United States and European Union (the “EU”) and commercialize outside of the United States our 6 millimeter x 42cm ATEV and all improvements thereto, and modifications and derivatives thereof (including any changes to the length, diameter or configuration of the foregoing), for use in vascular creation, repair, replacement or construction, including renal replacement therapy for dialysis access, the treatment of PAD, and the treatment of vascular trauma, but excluding coronary artery bypass graft, pediatric heart surgery, or adhering pancreatic islet cells onto the outer surface of the distribution product for use in diabetic patients. Within the United States, Fresenius Medical Care will collaborate with Humacyte in its commercialization of the product in the field, including adoption of the distribution product as a standard of care in patients for which such use is supported by clinical results and health economic analyses.

We are responsible for developing and seeking regulatory approval for the distribution product in the field in the United States. For countries outside the United States, the parties agreed to use commercially reasonable efforts to satisfy certain agreed minimum market entry criteria for the distribution product in the field in such country. For the EU, once such criteria have been satisfied for the applicable country, or if the parties otherwise mutually agree to obtain regulatory approval for the distribution product in the field in the applicable country, we agreed to use commercially reasonable efforts to obtain such regulatory approval (other than pricing approval), and Fresenius Medical Care agreed to use commercially reasonable efforts to obtain the corresponding pricing approval. For the rest of the world (i.e., outside the United States and the EU), once such criteria have been satisfied for the applicable country, or if the parties otherwise mutually agree to obtain regulatory and pricing approval for the distribution product in the field in the applicable country, Fresenius Medical Care agreed to use commercially reasonable efforts to obtain such approvals, and we agreed to use commercially reasonable efforts to support Fresenius Medical Care in its efforts.

Under the distribution agreement, we grant an exclusive, sublicensable license to Fresenius Medical Care under the patents, know-how and regulatory materials controlled by us during the term to commercialize the distribution product in the field outside the United States, subject to our retained rights to carry out our obligations under the distribution agreement. We also grant a non-exclusive, sublicensable license to Fresenius Medical Care under the patents, know-how and regulatory materials controlled by us during the term to develop the distribution product in accordance with the terms of the distribution agreement. In addition, we grant to Fresenius Medical Care, among other things, a perpetual, irrevocable, non-exclusive sublicensable license under the patents and know-how that primarily relate to the distribution product or its manufacture and that were created, conceived or developed solely or jointly by or on behalf of Fresenius Medical Care in the performance of its activities under the distribution agreement.

The distribution agreement provides that we will own all know-how and patents that primarily relate to the distribution product or its manufacture that are created, conceived or developed by or on behalf of either party in the performance of activities under the distribution agreement. Ownership of all other know-how, patents, materials and other intellectual property created, conceived or developed during the performance of activities under the distribution agreement will be determined in accordance with U.S. patent laws for determining inventorship.

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We are obligated to make payments to Fresenius Medical Care based on a share of aggregate net sales by or on behalf of us of the distribution product in the United States in the field. Such revenue-share payments will be a percentage of net sales in the low double digits, without regard to the calendar year in which such net sales are attributable, until such time that we have paid to Fresenius Medical Care a certain total amount, at which time the revenue-share will decrease to a percentage of net sales in the mid-single digits. The amounts that Fresenius Medical Care will be obligated to pay us under the distribution agreement for sales of the distribution product in the field outside of the United States will vary. Fresenius Medical Care agreed to pay us initially, on a country-by-country basis for sales outside of the United States, the amount equal to the average cost of manufacturing our distribution product plus a fixed dollar amount per unit. Following a specified period, on a country-by-country basis outside of the United States, Fresenius Medical Care will pay us a fixed percentage of net sales for each unit sold in such country, such that the Company will receive more than half of such net sales.

The distribution agreement will generally continue on a country-by-country basis until the later of the tenth anniversary of the launch date of the distribution product in the relevant country or (b) the expiration of the last-to-expire valid claim of specified patents in such country. Each party is permitted to terminate the distribution agreement for insolvency of, or, under certain circumstances, including various cure periods, material breach by the other party. Subject to a cure period, Fresenius Medical Care may also terminate the distribution agreement in its entirety or on a country-by-country basis (i) for certain withdrawals of regulatory approval or (ii) for termination or expiration of any of our in-licenses that is necessary for the exercise of Fresenius Medical Care’s rights, or the satisfaction of its obligations, under the distribution agreement. In addition, Fresenius Medical Care may terminate the distribution agreement for convenience on a country-by-country basis upon not less than 12 months’ written notice to us, although Fresenius Medical Care is not permitted to give such notice prior to the end of the second year following launch of the distribution product in such country. Each party is required to indemnify one another for certain third-party claims.

Third-Party Reimbursement

We anticipate that coverage and reimbursement by the CMS and private payors will be essential for most patients and health care providers to afford our treatments, particularly in the applications of renal replacement therapy for dialysis access and the treatment of PAD. Accordingly, sales of our products will depend substantially, both domestically and abroad, on reimbursement by government authorities, private health coverage insurers and other third-party payors. Our strategy around ATEV reimbursement focuses on achieving alignment and agreement from CMS on coding and payment pathways; both are critical to influencing and achieving optimal reimbursement payment from private payor sources. Therefore, Humacyte continues to develop a comprehensive reimbursement strategy including CMS, private payors, and other key stakeholders to ensure a clear and sustainable reimbursement path for all ATEV product opportunities.

We are pursuing a dual regulatory and legislative reimbursement strategy to ensure separate Medicare payment for the ATEV at an appropriate price. The regulatory strategy includes (1) engaging CMS political and career staff directly on coverage, payment, and coding followed by (2) submission of formal applications in these areas once FDA approval is obtained. Currently, no RMAT tissue engineered product has established coverage and reimbursement by CMS, and it is difficult to predict what CMS will decide with respect to coverage and reimbursement for fundamentally novel products. See “Risk Factors — Risks Related to the Development and Commercialization of Our Product Candidates” for further information. Even if we receive marketing approval for our ATEVs, there is uncertainty with respect to third-party coverage and reimbursement of our ATEVs. They may also be subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, any of which could harm our business, prospects, operating results and financial condition.

Containment of healthcare costs has been a priority of federal, state, and foreign governments, and the prices of drug products have been a focus of this effort. Governments have shown significant interest in implementing cost-containment programs. This interest has resulted in significant proposed and enacted reform measures affecting healthcare reimbursement and drug pricing, including the enactment in August 2022 of significant changes to potential Medicare drug product reimbursement through government negotiation of certain drug prices, as well as manufacturer discount and inflation rebate obligations under the Inflation Reduction Act (the “IRA”).

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Intellectual Property

We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of our business, including seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. We also rely on trade secrets relating to our proprietary technology platform and on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position that may be important for the development of our business. We additionally may rely on regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets, and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

As of December 31, 2024, our patent estate is comprised of 15 families of patents. Of these families, 12 are solely owned by Humacyte, one is jointly owned by Humacyte and Global Life Sciences Solutions USA LLC, one is jointly owned by Humacyte and Yale University, one is exclusively licensed to Humacyte from Duke University and one is exclusively licensed to Humacyte from Yale University. For more information regarding these license agreements, see “— License Agreement with Duke University” and “— License Agreements with Yale University.”

Our 15 families of patents are comprised of:

(i)Twelve issued U.S. patents, 73 foreign patents in Austria, Australia, Belgium, Canada, China, Cyprus, Denmark, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Netherlands, Portugal, Spain, Sweden, Switzerland, Turkey, and the UK, seven pending U.S. non-provisional patent applications, and 12 pending foreign applications in Australia, Canada, China, Europe, Japan and Hong Kong, which are solely owned by us,

(ii)three issued U.S. patents, 18 issued foreign patents in Australia, Austria, Belgium, Canada, Denmark, France, Germany, Ireland, Italy, Japan, Netherlands, Spain, Sweden, Switzerland, Turkey, and the UK, one pending U.S. non-provisional patent application, and four pending foreign patent applications in Europe and Canada, which we co-own, and

(iii)one issued U.S. patent, one issued foreign patent in Japan, one pending U.S. non-provisional patent application, and five pending foreign patent applications in Australia, Canada, Europe, Japan, and Hong Kong, which we exclusively license.

Many of these patents and patent applications generally relate to the scaffolds used to make Symvess and our product candidates, the composition of Symvess and our product candidates, and systems and methods of manufacturing Symvess and our product candidates. Excluding any patent term adjustment or patent term extension, the U.S. patent relating to the scaffold used to make Symvess and our product candidates expires in 2032, the U.S. patents relating to the composition of our vessels expire in 2032 and the U.S. patents relating to the systems and methods of manufacturing Symvess and our product candidates expires in 2032. Based on the FDA approval of the ATEV in December 2024, in February 2025 we filed with the U.S. Patent and Trademark Office an application for extension of patent term on one of our U.S. patents relating to the composition of Symvess and our product candidates under 35 U.S.C. § 156. If granted, we estimate that the expiration of the patent will be extended by approximately 50 months. The U.S. patent relating to the entangler machinery used to make tubular scaffolds expires in 2035. Included in our patent portfolio is one U.S. patent expiring in 2040, and multiple pending, Humacyte-owned non-provisional applications relating to the manufacturing of engineered tissues at commercial scale, as well as other technologies and product candidates. If these non-provisional applications are allowed, such additional patents issuing therefrom would be expected to expire around 2043.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, our owned and licensed pending patent applications, and any patent applications that we may in the future file or license from third parties, may not result in the issuance of patents. For more information, see “Risk Factors — Risks Related to Our Intellectual Property.”

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We have also registered trademarks for use in connection with our products. These include registrations for SymvessTM in the United States, Europe, United Kingdom and Ukraine, HUMACYLTM in the United States, Europe, Australia, Canada, China, and Israel; HUMAGRAFTTM in Australia, China, Europe, and Israel; HUMAPASSTM in Europe, Australia, and Israel; and HUMACYTE, in the United States, Europe, Australia, Canada, and Israel. We may pursue additional registrations for future products in markets of interest.

In addition to the above, we have established expertise and development capabilities focused in the areas of preclinical research and development, manufacturing process scale-up, cGMP manufacturing, quality control, quality assurance, compliance, regulatory affairs and clinical trial design and execution. We believe that our focus and expertise will help us develop and expand technology-based applications leveraging our proprietary intellectual property.

Finally, we rely, in some circumstances, on trade secrets to protect our technology. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

In addition to the intellectual property that we have developed internally, we license rights to certain intellectual property that is material to our business prospects. We have summarized our material license agreements below.

License Agreement with Duke University

In March 2006, we entered into a license agreement with Duke University (“Duke”), which was subsequently amended in 2011, 2014, 2015, 2018, 2019 and January 2022 (as amended, the “Duke License Agreement”). Under the Duke License Agreement, Duke granted us a worldwide, exclusive, sublicensable license to certain patents related to decellularized tissue engineering, which we refer to as the patent rights, as well as a non-exclusive license to use and practice certain know-how related to the patent rights. The relevant licensed patent on decellularization of tissue expired in 2021. We have agreed to use commercially reasonable efforts to develop, register, market and sell products utilizing the patent rights, which we refer to as the licensed products. Any services provided to a third party utilizing licensed products are referred to as licensed services. We have also agreed to meet certain benchmarks in our development efforts, including as to development events, clinical trials, regulatory submissions and marketing approval, within specified timeframes. Under the Duke License Agreement, Duke retains the right to use the patent rights for its own educational and research purposes, and to provide the patent rights to other non-profit, governmental or higher-learning institutions for non-commercial purposes without paying royalties or other fees.

In connection with our entry into the Duke License Agreement, we granted equity consideration to Duke in the form of 52,693 shares of our post-Merger common stock. Under the Duke License Agreement, we have also agreed to pay Duke: a low single-digit percentage royalty on eligible sales of licensed products and licensed services, plus a low double-digit percentage of any sublicensing revenue; an annual minimum royalty beginning in 2012, which increases in the calendar year immediately following the first commercial sale of licensed products or licensed services (whichever occurs first); and an additional amount in license fees, as certain scientific milestones are met.

The Duke License Agreement remains effective until the latter of (i) the last of the patent rights expires or (ii) four years after our first commercial sale, unless earlier terminated. Either party may terminate the agreement for fraud, willful misconduct or illegal conduct, or uncured material breach. Duke may terminate the agreement if we become insolvent. Duke may also terminate the license, convert the license into a non-exclusive license or seek assignment of any sublicense if we fail to reach diligence milestones within the applicable time period. If we abandon any claim, patent or patent application, our rights under the license with respect to such patent rights will be terminated in the territory in which we abandon such rights. We may terminate the Duke License Agreement unilaterally upon three months’ prior notice to Duke. We agree to indemnify Duke against certain third-party claims.

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License Agreements with Yale University

Large Diameter ATEV

In August 2019, we entered into a license agreement with Yale University (“Yale”) that granted us a worldwide license to the patents jointly owned with us related to tubular prostheses which are large diameter versions of our ATEVs, which may or may not contain a stent (the “Tubular Prothesis License Agreement”). The license granted under the Tubular Prothesis License Agreement is exclusive in the field of engineered urinary conduits, engineered tracheae/airways and engineered esophagi, except that it is subject to Yale’s non-exclusive right, on behalf of itself and all other non-profit academic institutions, to use the licensed products for research, teaching, and other non-commercial purposes. We have agreed to use reasonable commercial efforts to develop and commercialize the licensed patents and any licensed products and methods, and to use reasonable efforts to make the licensed products available to patients in low and low-middle income countries. We are also obligated to provide Yale periodically an updated and revised copy of our plan, which must indicate progress of our development and commercialization. We may also sublicense our rights without Yale’s prior written consent, but such sublicense is subject to certain conditions.

In connection with our entry into the Tubular Prothesis License Agreement, we paid Yale an upfront cash fee of less than $0.1 million. We have also agreed to pay to Yale: an annual maintenance fee, increasing between the first anniversary of the agreement until the fifth anniversary up to a maximum of less than $0.1 million per year; milestone payments upon achievement of certain regulatory and commercial milestones of $0.2 million and $0.6 million for this license; a low single-digit percentage royalty on worldwide net sales, subject to reductions for third-party license fees; and a low double-digit percentage of sublicensing income.

If we or any of our future sublicensees bring a patent challenge against Yale or assist another party in bringing a patent challenge against Yale, the license fees described above will be subject to certain increases and penalties.

The Tubular Prothesis License Agreement expires on a country-by-country basis on the date on which the last of the patents in such country expires, lapses or is declared invalid. Issued patents and additional patents issuing from this licensed portfolio will expire no earlier than 2032, and the term of each patent may be extended by patent term adjustment, patent term extension, or foreign equivalents thereof. Issued U.S. patent No. 10,172,707 will expire no earlier than 2035. Issued patents and additional patents issuing from this licensed portfolio will expire no earlier than 2032, and the term of each patent may be extended by patent term adjustment, patent term extension, or foreign equivalents thereof. Issued U.S. patent No. 10,172,707 will expire no earlier than 2035. Yale may terminate the Tubular Prothesis License Agreement if we fail to (i) provide written diligence reports, (ii) provide a commercially reasonable diligence plan, (iii) implement the plan in accordance with the obligations under the agreement, or (iv) reach certain research and development milestones within the scheduled timeframe set forth in the agreement; however, any such termination right would be limited in scope to the country or countries to which such failure relates. Yale may also terminate for our non-payment, uncured material breach, failure to obtain adequate insurance, bringing or assisting in bringing of a patent challenge against Yale, abandonment of the research and development of our product or insolvency. We may terminate the Tubular Prothesis License Agreement (i) on 90 days’ prior written notice to Yale, provided we are not in breach of the license agreement and have made all required payments to Yale thereunder and (ii) on written notice to Yale following an uncured material breach. Under certain circumstances, Yale may, at its option, convert the exclusive license to a non-exclusive license if we decline to initiate certain infringement or interference proceedings with respect to the licensed patents. We have agreed to indemnify Yale against certain third-party claims.

BioVascular Pancreas

In August 2019, we entered into a license agreement with Yale that granted us a worldwide license to its patents related to a BVP (the “BVP License Agreement”). The license granted under the BVP License Agreement is exclusive in the field of acellular vascular tissues that deliver pancreatic islet cells to patients, except that it is subject to Yale’s non-exclusive right, on behalf of itself and all other non-profit academic institutions, to use the licensed products for research, teaching, and other non-commercial purposes. We have agreed to use reasonable commercial efforts to develop and commercialize the licensed patents and any licensed products and methods, and to use reasonable efforts to make the licensed products available to patients in low and low-middle income countries. We are also obligated to provide Yale periodically an updated and revised copy of our plan, which must indicate progress of our development and commercialization. We may also sublicense our rights without Yale’s prior written consent, but such sublicense is subject to certain conditions.

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In connection with our entry into the BVP License Agreement, we paid Yale an upfront cash fee of less than $0.1 million. We have also agreed to pay to Yale: an annual maintenance fee, increasing between the first anniversary of the agreement until the fifth anniversary up to a maximum of less than $0.1 million per year; milestone payments upon achievement of certain regulatory and commercial milestones of $0.1 million and $0.2 million for this license; a low single-digit percentage royalty on worldwide net sales, subject to reductions for third-party license fees; and a low double-digit percentage of sublicensing income.

If we or any future sublicensees bring a patent challenge against Yale or assist another party in bringing a patent challenge against Yale, the license fees described above will be subject to certain increases and penalties.

The BVP License Agreement expires on a country-by-country basis on the date on which the last of the patents in such country expires, lapses or is declared invalid. Patents issuing from this licensed portfolio will expire no earlier than 2039, and the term of each patent may be extended by patent term adjustment, patent term extension, or foreign equivalents thereof. Patents issuing from this licensed portfolio will expire no earlier than 2039, and the term of each patent may be extended by patent term adjustment, patent term extension, or foreign equivalents thereof. Yale may terminate the BVP License Agreement if we fail to (i) provide written diligence reports, (ii) provide a commercially reasonable diligence plan, (iii) implement the plan in accordance with the obligations under the agreement, or (iv) reach certain research and development milestones within the scheduled timeframe set forth in the agreement; however, any such termination right would be limited in scope to the country or countries to which such failure relates. Yale may also terminate for our non-payment, uncured material breach, failure to obtain adequate insurance, bringing or assisting in bringing of a patent challenge against Yale, abandonment of the research and development of our product or insolvency. We may terminate the BVP License Agreement (i) on 90 days’ prior written notice to Yale, provided we are not in breach of the license agreement and have made all required payments to Yale thereunder and on written notice to Yale following an uncured material breach. Our rights under the BVP License Agreement will also terminate automatically with respect to a patent application or patent within the licensed patents in a specified country if, upon receipt of written notice from Yale, we do not agree to pay the patent filing, prosecution and maintenance fees incurred by Yale for such patent applications or patents in the specified country. Under certain circumstances, Yale may, at its option, convert the exclusive license to a non-exclusive license if we decline to initiate certain infringement or interference proceedings with respect to the licensed patents. We have agreed to indemnify Yale against certain third-party claims.

Competition

Despite the magnitude and critical nature of the diseases and conditions we are targeting, no significant advances in the open surgical market have been made in the last 35 years, and current treatment and products used in vascular repair, reconstruction and replacement suffer from various drawbacks. The large majority of vascular repair, reconstruction and replacement procedures rely on either harvesting autologous veins or using synthetic grafts. However, each method presents significant limitations as discussed below:

Autologous Veins

The harvest of autologous veins is a serious operation that can result in numerous complications, including infection, chronic pain, and limb swelling that severely impact the patient’s quality of life. In addition, this procedure can often result in long recovery times, increased hospital stays, and increased risk of hospital readmission. In order to obtain an autologous vein, such as a saphenous vein, for use in a surgical procedure, a second operation must be performed on the patient to harvest the vein. The harvesting process must be completed before the bypass procedure occurs and can take significant time to complete, which increases costs related to the additional operative time and staff required to perform the operation. Even if successful, the patient’s recovery time could increase as the patient must recover from two surgical procedures instead of one, further increasing morbidity and cost. Additionally, a significant percentage of patients are not suitable for vein harvesting either due to vein or limb damage, limited vein supply from prior harvest, venous disease or the surgeon’s desire to preserve the vein for future coronary or other bypass procedures. In acute trauma, the time to restore blood flow to injured limbs is delayed when a vein must be harvested from the patient, which puts the limbs at greater risk of reduced function or amputation. For patients suffering from vascular trauma, some types of injury preclude the harvesting of autologous saphenous vein due to concomitant injuries of one or both legs. Furthermore, time is required to prepare the vein harvest site and to remove the vein from the leg, which adds to ischemia time and can increase the risk of tissue and limb loss. Rates of traumatic limb loss are strongly tied to ischemia time, and therefore rapid revascularization using an off-the-shelf ATEV conduit may decrease ischemia time and lead to better outcomes.

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The use of autologous vein for creating an AV fistula for use in hemodialysis is often limited by vein size and location. The vast majority of veins must go through a process of enlargement, known as maturation, prior to use for hemodialysis. For approximately 40% of patients receiving fistulae, the vein does not mature sufficiently to allow for hemodialysis even after six months. Even in patients having adequate veins for fistula creation, the fistula often becomes large, tortuous and disfiguring and can be at risk for sometimes fatal rupture.

Synthetic Grafts

Use of synthetic materials, such as ePTFE and Dacron, while widely available, have known complications, such as continuous chronic risk of infection and clotting inside the graft. Risk of infection is significantly increased in acute battlefield and civilian injuries, as well as in contaminated wounds. The body recognizes any synthetic materials as foreign and, therefore, can mount a host foreign body response following implantation. Synthetic materials also have been shown to be inferior to autologous vein in resisting infection, and generally only are used for vascular repair when autologous vein is not an option.

In hemodialysis access, persistent puncture presents an ongoing risk of graft infection. The annual risk of infection of ePTFE grafts in hemodialysis patients can be as high as 10% – 15% per patient-year. Furthermore, gradual degradation of the non-healing ePTFE graft material caused by persistent needle punctures can eventually lead to graft failure. In traumatic vascular injury, ePTFE grafts are generally contraindicated, due to the high rates of contamination of the wound that can lead to synthetic graft infection and failure.

Two lesser used products, cryopreserved human blood vessels, known as allografts, and animal-derived vessels, known as xenografts, also involve significant limitations.

Cryopreserved Blood Vessels

To eliminate the need for harvesting autologous vein, some surgeons use allogeneic vessels that have been previously harvested from cadavers and cryogenically preserved. These allogeneic vessels are stored at -80 degrees Celsius and must be thawed prior to use, which can take up to 60 minutes. The supply of cryopreserved vessels is limited by the number of cadaveric donors available, and the vessels are often non-uniform in size. In addition, because the vessels contain human cells from a donor, they can generate an immune rejection response that can lead to aneurismal degradation or catastrophic failure. Furthermore, development of antibodies to the implanted cryopreserved human vessel frequently has a detrimental impact on the ability of the patient to receive a transplant in the future. Cryopreserved blood vessels are only rarely used in the treatment of vascular trauma, due to the time required for procurement and thawing, and the high rates of rejection response.

Animal-Derived Vessels

Xenogeneic tissues, including cow, pig or sheep-derived vessels, are used less frequently in vascular surgery, in part due to the risk of thrombosis and structural deterioration over time. The limited clinical data that are available for existing xenografts in vascular reconstruction indicates lower patency rates and higher incidence of complications when compared to autologous vein. Xenografts are all chemically treated in efforts to minimize rejection to animal components, and therefore do not respond like living tissue. Some of these products require rinsing to remove toxic chemicals used for storage.

Our Solution

We believe our ATEVs combine the off-the-shelf availability of synthetic grafts with the regenerative capabilities of autologous vessels. We believe these and other attributes have the potential to address unmet clinical needs in a range of disease states, including atherosclerosis, end-stage kidney disease, coronary artery disease, vascular trauma, pediatric congenital heart disease, airway disease, and others. We believe that the ATEVs multiple key characteristics will drive rapid clinical adoption amongst surgeons and the broader healthcare community:

•Off-the-Shelf: Our “cabinet” of ATEVs of varying diameters and lengths is designed to be stored on-site at facilities such as hospitals, trauma centers and outpatient surgical centers.

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•Immediately Available: When needed, our ATEVs are available for immediate use by opening and removing the ATEV from its original flexible bioreactor bag. Since our ATEV does not need flushing, harvesting or thawing, as is common with other vascular substitute alternatives, we believe hospitals will be able to use our ATEVs for vascular surgery more quickly with smaller surgical teams, reduced logistics and decreased overall cost.

•No Surgical Harvesting: The use of our ATEVs does not subject patients to the serious operation of harvesting an autologous vein, which can result in greater procedure and recovery time, potential scarring and disfigurement, increased costs, and numerous potential health complications.

•Non-Immunogenic and No Foreign Body Response: Given their acellular nature, our ATEVs have the potential to be universally implantable and durable across patients. Because our ATEVs are derived from human tissue (but cleansed of all cells and cellular components), we believe (and have observed in clinical trials to date) that they do not generate the foreign body response associated with the use of synthetic grafts, or the immune response associated with cryopreserved vessels.

•Low Infection Susceptibility: In clinical trials to date, we have observed reduced rates of infection in our ATEVs as compared to synthetic materials. As a result, we believe our ATEVs may be used in complicated and potentially contaminated wounds with fewer patient complications following the initial procedure.

•Uniform and Predictable Size, Structure and Quality: Harvested veins vary in size, structure and quality by donor. We manufacture our ATEVs to precise specifications under controlled quality standards, which will allow surgeons the flexibility to quickly and easily select an ATEV in the appropriate size and shape for each indication.

•Regenerative Potential: Our ATEVs repopulate with the patient’s own vascular cells, creating a living vascular tissue with the associated long-term benefits of self-healing and infection resistance.

We expect our ATEVs will compete with the use of a patient’s own blood vessels, as well as a variety of marketed products, such as conventional synthetic grafts, xenografts, and allografts, as well as developing technologies. We expect the key competitive factors affecting the commercial success of our ATEVs to likely be efficacy, safety, convenience, pricing and reimbursement.

Other Commercial Entities

There are several conventional synthetic grafts made of ePTFE or Dacron presently on the market from companies such as Bard Peripheral Vascular, Inc., W.L. Gore & Associates, Inc., Terumo Medical Systems, and Atrium (Maquet Getinge Group) that are used for both AV access for hemodialysis and vascular repair. Xenograft and allograft products are also available, but not widely used. Xenografts, such as Artegraft® and Procol®, are processed animal-derived vessels, while allografts are processed allogeneic cellular vessels, such as CryoVein® and AngioGRAFT®.

There are also a number of companies of which we are aware that have preclinical and early clinical-stage research programs underway to develop products that could potentially compete with our ATEVs, including NovaHep AB, Xeltis AG, Hancock Jaffe, and Vascudyne Inc. We may face competition from these and other emerging technologies such as bioabsorbable polymetric implants and electrospun or 3D printed tubular conduits.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are more effective, safer, have fewer or less severe side effects, are more convenient or are less expensive than the products that we develop. Our competitors also may obtain FDA or other marketing approval for their products more rapidly than we may obtain the same approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

Government Regulation

Overview

The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements on the research, development, testing, manufacture, quality control, safety, effectiveness, packaging, labeling, storage, record keeping, marketing, advertising and promotion, import/export, and distribution of Symvess and our product candidates.

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