Risk Factors Dashboard

Once a year, publicly traded companies issue a comprehensive report of their business, called a 10-K. A component mandated in the 10-K is the ‘Risk Factors’ section, where companies disclose any major potential risks that they may face. This dashboard highlights all major changes and additions in new 10K reports, allowing investors to quickly identify new potential risks and opportunities.

Risk Factors - HSAQ

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Item 1A. Risk Factors” in this Annual Report on Form 10-K. These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us.

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements. All statements other than statements of historical facts contained in this report, including statements regarding our future results of operations and financial position, business strategy, product candidates, planned preclinical studies and clinical trials, results of clinical trials, research and development costs, regulatory approvals, timing, and likelihood of success, as well as plans and objectives of management for future operations, are forward-looking statements. These statements involve known and unknown risks, uncertainties, and other important factors that are in some cases beyond our control and may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements.

In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “would,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential,” or “continue” or the negative of these terms or other similar expressions. Forward-looking statements contained in this report include, but are not limited to, statements about:

our ability to raise financing in the future;
our success in retaining or recruiting, or changes required in, our officers, key employees or directors;
our ability and/or the ability of third-party vendors and partners to manufacture our product candidates;
our ability to source critical components or materials for the manufacture of our product candidates;
our ability to achieve and sustain profitability;
our ability to achieve our projected development and commercialization goals;
the rate of progress, costs and results of our clinical studies and research and development activities;
market acceptance of our product candidates, if approved;
our ability to compete successfully with larger companies in a highly competitive industry;
changes in our operating results, which make future operations results difficult to predict;
serious adverse events, undesirable side effects that could halt the clinical development, regulatory approval or certification, of our product candidates;
our ability to manage growth or control costs related to growth;
economic conditions that may adversely affect our business, financial condition and stock price;
our reliance on third parties to drive successful marketing and sale of our initial product candidates, if approved;
our reliance on third parties to manufacture and provide important materials and components for our products and product candidates;
our and our partners’ abilities to obtain necessary regulatory approvals and certifications for our product candidates in an uncomplicated and inexpensive manner;
our ability to maintain compliance with regulatory and post-marketing requirements;

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adverse medical events, failure or malfunctions in connection with our product candidates and possible subjection to regulatory sanctions;
healthcare costs containment pressures and legislative or administrative reforms which affect coverage and reimbursement practices of third-party payors;
our ability to protect or enforce our intellectual property, unpatented trade secrets, know-how and other proprietary technology;
our ability to obtain necessary intellectual property rights from third parties;
our ability to protect our trademarks, trade names and build our names recognition;
our ability to maintain the listing of our common stock on The Nasdaq Stock Market LLC (“Nasdaq”);
our ability to fund our operations into the second half of 2026 based on our cash, cash equivalents, marketable securities, and potential future payments or revenues discussed under the heading “Liquidity and Capital Resources—Funding Requirements” in Item 7 (Management’s Discussion and Analysis of Financial Condition and Results of Operations) of this Annual Report on Form 10-K.
the success of our licensing agreements; and
our public securities’ liquidity and trading.

We have based these forward-looking statements largely on our current expectations and projections about our business, the industry in which we operate and financial trends that we believe may affect our business, financial condition, results of operations, and prospects, and these forward-looking statements are not guarantees of future performance or development. These forward-looking statements speak only as of the date of this report and are subject to a number of risks, uncertainties, and assumptions described under the heading “Item 1A. Risk Factors” in Part I of this Annual Report on Form 10-K. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. We do not plan to publicly update or revise any forward-looking statements contained herein whether as a result of any new information, future events, or otherwise, except as required by law.

In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this report, and, while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and you are cautioned not to unduly rely upon these statements.

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SUMMARY OF RISK FACTORS

The following is a summary of some of the risks and uncertainties that could materially adversely affect our business, financial condition and results of operations. This summary should be read together with the more detailed description of each risk factor disclosed under “Item 1A Risk Factors” contained in Part I of this Annual Report on Form 10-K.

We have a history of net losses, and we expect to continue to incur losses for the foreseeable future. If we ever achieve profitability, we may not be able to sustain it.
Our ability to timely raise capital in the future may be limited, or may be unavailable on acceptable terms, if at all. The failure to raise capital when needed could harm our business, operating results and financial condition. Debt or equity issued to raise additional capital may reduce the value of our common stock.
The clinical study process required to obtain regulatory approvals or certifications carries substantial risks and is lengthy and expensive with uncertain outcomes. If our clinical studies are unsuccessful or significantly delayed, or if we do not complete our clinical studies, our business may be harmed.
Failures or perceived failures in our clinical studies will delay and may prevent our product candidate development and regulatory approval or certification process, damage our business prospects and negatively affect our reputation and competitive position.
Even if we obtain all necessary U.S. Food and Drug Administration (“FDA”) approvals, our product candidates may not achieve or maintain market acceptance and may be subject to additional regulatory requirements post-approval.
We may be unable to compete successfully with larger companies in highly competitive industries.
The sizes of the markets for product candidates have not been established with precision, and may be smaller than we estimate.
Interim, “top-line” and preliminary data from our clinical studies that we announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures that could result in material changes in the final data.
Our product candidates have in the past and may in the future be associated with serious adverse events, undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval or certification, limit their commercial potential or result in significant negative consequences.
We, in conjunction with our partners, intend to expand sales of our products internationally in the future, but we and our partners may experience difficulties in obtaining regulatory approval or certification or in successfully marketing and distributing our products internationally even if approved or certified. A variety of risks associated with marketing and distributing our products internationally could materially adversely affect our business.
We may expend our limited resources to pursue a particular product or indication and fail to capitalize on products or indications that may be more profitable or for which there is a greater likelihood of success.
We are, and expect to continue to be, highly dependent on partners to drive the successful marketing and sale of our initial product candidates. There is no assurance that we will be able to form and properly manage partnerships. There is no assurance that partnerships will be successful.
We did not meet the target achievement dates relating to certain milestone payments, and we do not expect to meet certain other target achievement dates relating to additional milestone payments, under the Terumo

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Agreement, and we may not be able to restructure the Terumo Agreement in a manner that provides us with a satisfactory amount of additional capital.
We expect to be highly dependent on partners and third-party vendors to manufacture and provide important materials and components for our products and product candidates. There is no assurance that we will be able properly manage our supply chain. Further, we currently do not have redundancy built into our supply chain.
We have limited pharmaceutical manufacturing experience and our contract manufacturing organizations (CMOs) may experience development or manufacturing problems or delays in producing our products and planned or future products that could limit or prevent the potential growth of our revenue or increase our losses.
Even if a product candidate receives regulatory approval or certification, our products will remain subject to regulatory scrutiny and post-marketing requirements. Failure to comply with post-marketing regulatory requirements could subject us or our partners to enforcement actions, including substantial penalties, and might require us or our partners to recall or withdraw a product from the market.
Our medical device products, if approved or certified, may cause or contribute to adverse medical events or be subject to failures or malfunctions that we are required to report to the FDA or similar foreign regulatory authorities, and if we fail to do so, we would be subject to sanctions that could harm our reputation, business, financial condition and results of operations. The discovery of serious safety issues with our products, or a recall of our products either voluntarily or at the direction of the FDA or another governmental authority, could have a negative impact on us.
Healthcare cost-containment pressures and legislative or administrative reforms resulting in restrictive coverage and reimbursement practices of third-party payors could decrease the demand for our products, the prices that customers are willing to pay for those products and the number of procedures performed using our devices, which could have an adverse effect on our business.
Our information technology systems, or those of any of our CROs, manufacturers, other contractors, consultants, collaborators or potential future collaborators, may fail or suffer security or data privacy breaches or other unauthorized or improper access to, use of, or destruction of our proprietary or confidential data, employee data, or personal data, which could result in additional costs, loss of revenue, significant liabilities, harm to our brand and material disruption of our operations.
We may not effectively be able to protect or enforce our intellectual property, which could have a material adverse effect on our business, financial condition, results of operations and prospects.
If we cannot protect and control unpatented trade secrets, know-how and other proprietary technology, we may suffer competitive harm.
We may be involved in litigation or other proceedings relating to patent, trade secret and other intellectual property rights, which could cause substantial costs and liability.
We may need to obtain intellectual property rights from third parties, and may not be successful in obtaining necessary rights to develop any future product through acquisitions and in-licenses.
If our trademarks and trade names are not adequately protected, then we may not be able to build name recognition in our markets of interest and our business may be adversely affected.
The future sales, or the perception of future sales, of shares by existing stockholders and future exercise of registration rights may adversely affect the market price of our common stock.

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PART I

Item 1. Business

Our Vision

Our vision is to accelerate medical innovation to patients through risk-reward-sharing partnerships with leading medical device companies.

Our Company

We are a biomedical innovation company accelerating high-impact technologies to patients through risk-reward sharing partnerships with leading medical device companies. Our partnership-enabled business model focuses on forging strategic collaborations with leading medical device companies to drive successful global commercialization of products we develop. We are led by a highly accomplished, multidisciplinary management team and a board of directors with extensive experience in all phases of therapeutic device development. Our business was formed in 2018 by assembling a pipeline of multiple late-stage clinical product candidates originally developed by our founding team. Our lead product candidate is BackBeat Cardiac Neuromodulation Therapy (“BackBeat CNT”) for the treatment of hypertension (“HTN”), the leading risk factor for death worldwide. We have an exclusive license and collaboration agreement with Medtronic, Inc. for the development and commercialization of BackBeat CNT for the treatment of HTN in patients indicated for a cardiac pacemaker. We are also developing the Virtue Sirolimus AngioInfusion Balloon (“Virtue SAB”) for the treatment of atherosclerotic artery disease, the leading cause of mortality worldwide. We have a strategic collaboration with Terumo Medical Corporation (“Terumo”) for the development and commercialization of Virtue SAB for the treatment of coronary and peripheral artery disease.

On January 26, 2023, we consummated the business combination contemplated by the Agreement and Plan of Merger, dated as of July 4, 2022 (as amended, the “Merger Agreement”), by and among HSAC2, a special purpose acquisition company incorporated as a Cayman Islands exempted company in 2020 (“HSAC2”), HSAC Olympus Merger Sub, Inc., a Delaware corporation and wholly owned subsidiary of HSAC2 (“Merger Sub”), and Orchestra BioMed, Inc. (“Legacy Orchestra”). Pursuant to the Merger Agreement, (i) HSAC2 deregistered in the Cayman Islands in accordance with the Companies Act (2022 Revision) (As Revised) of the Cayman Islands and domesticated as a Delaware corporation in accordance with Section 388 of the Delaware General Corporation Law (the “Domestication”) and (ii) Merger Sub merged with and into Legacy Orchestra, with Legacy Orchestra as the surviving company in the merger and, after giving effect to such merger, continuing as a wholly owned subsidiary of Orchestra (the “Merger” and, together with the Domestication and the other transactions contemplated by the Merger Agreement, the “Business Combination”). As part of the Domestication, the Company’s name was changed from “Health Sciences Acquisitions Corporation 2” to “Orchestra BioMed Holdings, Inc.

BackBeat CNT, also known as Atrioventricular Interval Modulation (“AVIM”) therapy, is a bioelectronic therapy candidate designed to substantially and persistently lower blood pressure. BackBeat CNT can be fully integrated as a firmware upgrade to standard cardiac pacemakers which, given HTN is the most common comorbidity in the pacemaker population affecting over 70% of the pacemaker-indicated patients, makes it a potentially attractive therapeutic solution for these patients. Although there is no guarantee BackBeat CNT will be safe and effective, BackBeat CNT showed encouraging results in MODERATO II, a prospective, multi-center, randomized, double-blind pilot study of pacemaker patients with persistent HTN. We estimate that the addressable annual market for pacemaker-indicated patients with HTN comprises more than 750,000 patients worldwide annually and represents a potential annual revenue opportunity of over $2 billion. We also believe BackBeat CNT may offer therapeutic benefit to select high-risk HTN patients not indicated for a pacemaker. We estimate that this additional addressable annual market for high-risk HTN patients comprises more than 2.4 million patients worldwide and represents a potential annual revenue opportunity of more than $8 billion.

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On June 30, 2022, we entered into an exclusive license and collaboration agreement with Medtronic, one of the largest medical device companies in the world, for the development of BackBeat CNT for the treatment of HTN in pacemaker-indicated patients (the “Medtronic Collaboration”). The Medtronic Collaboration provides us with development, clinical and regulatory support for the BACKBEAT pivotal study. Upon regulatory approval, if received, Medtronic will have the exclusive global rights to commercialize BackBeat CNT (AVIM therapy) for this target population. If BackBeat CNT is approved and successfully commercialized, we will share meaningfully in the revenues generated from Medtronic’s sale of BackBeat CNT-enabled pacing systems. Medtronic has a right of first negotiation with respect to BackBeat CNT for the treatment of HTN in non-pacemaker patients.

On September 19, 2023, we announced that the FDA granted us investigational device exemption (“IDE”) approval to initiate our planned BACKBEAT (BradycArdia paCemaKer with AVIM for Blood prEssure treAtmenT) pivotal study (the “BACKBEAT pivotal study”) to treat HTN in patients indicated for a pacemaker. On January 8, 2024, we announced that the first patient was enrolled and randomized into the BACKBEAT pivotal study in late December 2023. For a detailed description of the BACKBEAT pivotal study, see “—BIOELECTRONIC PRODUCT CANDIDATES — BackBeat CNT (AVIM Therapy) for Hypertension and CNT-HF for Heart Failure—Clinical Results—Clinical, Regulatory and Commercialization Pathway—The BACKBEAT Global Pivotal Study.

On February 26, 2024, we announced new data showing sustained, clinically meaningful reduction in 24-hour ambulatory systolic blood pressure (aSBP) in hypertensive pacemaker patients treated with AVIM therapy for over 3 years. Reduction in aSBP measured at 6 months from randomization and therapy activation was the primary endpoint of the MODERATO II study, a European multi-center, double-blind, randomized pilot study involving 47 subjects. Patients randomized to AVIM therapy and antihypertension medication in that study experienced an 11.1 mmHg (p<0.001) reduction in mean aSBP at 6 months follow-up, resulting in a statistically significant difference of 8.1 mmHg compared to control patients who were managed only with antihypertensive medications (p=0.01). Long-term blood pressure results are from a follow-up study of 16 patients originally enrolled in the MODERATO II study. This group included eight patients from the MODERATO II AVIM treatment arm and eight control arm patients that crossed over to AVIM therapy at the end of the 6-month double-blind phase. aSBP was measured in this group of patients an average of 3.6 (±0.6) years following initiation of AVIM therapy. As a group and based on individual paired data, these patients continued to experience a statistically significant, clinically meaningful mean aSBP reduction of 8.9 mmHg at long term follow up which is similar to the mean aSBP reduction of 8.9 mmHg seen in this same group of patients when measured at the 6-month aSBP measurement.

On March 6, 2024, we announced the presentation of results from a pressure-volume (“PV”) loop clinical study of AVIM therapy (also known as BackBeat CNT) in pacemaker-indicated patients with uncontrolled HTN despite the use of antihypertensive medication. The new clinical data demonstrate the favorable hemodynamic impact of AVIM therapy as compared to standard right ventricular (RV) pacing on systolic blood pressure and overall cardiac function when delivered using both conduction system (CSP) as well as standard pacing lead locations. AVIM therapy with pacing leads placed in standard RV (“AVIM RV”) locations, as well as in conduction system pacing (“AVIM CSP”) locations targeting the left bundle branch area (LBBA) regions, respectively, was compared to standard atrial-ventricular (“AV”) sequential pacing (DDD mode pacing or “AV Pacing”). Overall mean results for each variable were calculated using paired measurements for each individual patient using AVIM RV, AVIM CSP and AV Pacing, respectively:

AVIM therapy generated statistically significant reductions (p<0.05) in systolic blood pressure (“SBP”), end diastolic volume (“EDV”), end diastolic pressure (“EDP”), and end systolic volume (“ESV”) using both AVIM RV and AVIM CSP pacing lead locations compared to AV Pacing.
oSBP was reduced by 17.1 mmHg and 19.2 mmHg compared to 1.6 mmHg
oEDV was reduced by 12.6 mL and 18.6 mL compared to 1.4 mL
oEDP was reduced by 2.3 mmHg and 3.6 mmHg compared to an increase of 0.3 mmHg
oESV was reduced by 11.0 mL and 14.1 mL compared to an increase of 1.8 mL
AVIM therapy drove statistically significant (p<0.05) reductions in stroke work (SW) without significantly reducing stroke volume (SV) compared to AV Pacing.
oStroke work (SW) was reduced by 1596 mL and 1870 mL compared to 42 mL
oStroke volume (SV) was not significantly reduced by AVIM RV, AVIM CSP or AV Pacing

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AVIM therapy drove statistically significant (p<0.05) reductions in total peripheral resistance (“TPR”, measured as change in effective arterial elastance or “Ea”) and no change in contractility (measured as change in end-systolic elastance or “Ees”) compared to AV Pacing.
oEffective arterial elastance (“Ea”, a measure of TPR) was reduced by 0.23 mmHg/mL and 0.31 mmHg/mL compared to an increase of 0.04 mmHg/mL
oEes remained unchanged with AVIM RV, AVIM CSP and AV Pacing

Virtue SAB is a proprietary drug/device combination product candidate for the treatment of artery disease that is designed to deliver a proprietary, investigational, extended-release formulation of sirolimus (“SirolimusEFR”) to the vessel wall during balloon angioplasty without the need for balloon coating or a permanent implant. Although there is no guarantee Virtue SAB will prove to be safe and effective, Virtue SAB demonstrated promising three-year clinical data in the treatment of coronary In-Stent Restenois (“ISR”) in the prospective, multi-center SABRE Study.

Virtue SAB was granted Breakthrough Device designation by the FDA, for specific indications relating to the treatment of coronary ISR, coronary small vessel disease and peripheral artery disease below-the-knee. We estimate that these indications will represent an annual global addressable market opportunity of at least $4 billion, based on approximately 3.2 million procedures, as discussed below under “— FOCAL THERAPIES — Virtue SAB for Artery Disease and SirolimusEFR for Local Inflammation in Multiple Indications. — Targeted Unmet Needs and Market Opportunity for Virtue SAB.”

On August 8, 2023, we announced that the FDA granted us investigational device exemption approval with conditions to initiate our planned Virtue ISR-US pivotal study evaluating the efficacy and safety of Virtue SAB for the treatment of patients with coronary ISR. The conditional approval permits us to