10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2023

FOR THE TRANSITION PERIOD FROM___________TO___________

Commission File Number 001-40656

TENAYA THERAPEUTICS, INC.

(Exact name of Registrant as specified in its Charter)

171 Oyster Point Boulevard, Suite 500South San Francisco, CA 94080

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (650) 825-6990

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

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

Common Stock $0.0001 par value per share TNYA Nasdaq Global Select Market

Securities registered pursuant to Section 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 ☐ No ☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒

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. Yes ☒ No ☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted 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 such files). Yes ☒ No ☐

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

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

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. ☐

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. ☐

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. ☐

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). ☐

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

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant, based on the closing price of the shares of common stock on the Nasdaq Global Select Stock Market on June 30, 2023 was approximately $271.5 million.

The number of shares of Registrant’s Common Stock outstanding as of March 1, 2024 was 78,516,142.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the definitive proxy statement for the Registrant’s 2023 Annual Meeting of Stockholders are incorporated by reference in Part III of this Form 10-K. Such definitive proxy statementwill be filed with the Securities and Exchange Commission within 120 days after the end of the Registrant’s 2023 fiscal year ended December 31, 2023.

Table of Contents

Page

PART I

Item 1. Business 3

Item 1A. Risk Factors 36

Item 1B. Unresolved Staff Comments 87

Item 1C. Cybersecurity 87

Item 2. Properties 88

Item 3. Legal Proceedings 88

Item 4. Mine Safety Disclosures 88

PART II

Item 6. Reserved 89

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 98

Item 8. Financial Statements and Supplementary Data 99

Item 9A. Controls and Procedures 119

Item 9B. Other Information 120

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 120

PART III

Item 10. Directors, Executive Officers and Corporate Governance 121

Item 11. Executive Compensation 121

Item 14. Principal Accounting Fees and Services 121

PART IV

Item 15. Exhibits, Financial Statement Schedules 122

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K, or Annual Report, contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (Securities Act) and Section 21E of the Securities Exchange Act of 1934, as amended (Exchange Act). All statements other than statements of historical facts contained in this Annual Report, including statements regarding our future results of operations and financial position, business strategy, development plans, planned preclinical studies and clinical trials, future results of clinical trials, expected research and development costs, regulatory strategy, timing and likelihood of success, as well as plans and objectives of management for future operations, are forward-looking statements. In some cases, investors 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,” “vision,” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements include, but are not limited to, statements about:

•

our vision to change the treatment paradigm for heart disease;

•

the ability of our ongoing preclinical studies and ongoing or planned clinical trials to demonstrate safety and efficacy of our product candidates, and other positive results;

•

the timing, dosing, patient enrollment and populations, progress, and results of preclinical studies and ongoing or planned clinical trials for our current product candidates and other product candidates we may develop;

•

the timing, scope and likelihood of regulatory filings and approvals, including timing of investigational new drugs (INDs), clinical trial applications (CTAs), U.S. Food and Drug Administration (FDA) approvals, and final regulatory approval of our current product candidates and any other future product candidates;

•

our ability to develop and advance our current product candidates and programs into, and successfully complete, clinical trials;

•

the size and the number of patients of the market opportunities we address with our product candidates;

•

our manufacturing, commercialization, and marketing capabilities and strategy;

•

our competitive position and the success of competing therapies that are or may become available;

•

our plans relating to the further development of our product candidates, including additional indications and targets we may pursue;

•

the impact of existing laws and regulations and regulatory developments in the United States, Europe and other jurisdictions;

•

our intellectual property position, including the scope and length of protection we are able to establish and maintain for intellectual property rights covering our current product candidates and other product candidates we may develop, including the extensions of existing patent terms where available, the validity of intellectual property rights held by third parties, and our ability not to infringe, misappropriate or otherwise violate any third-party intellectual property rights;

•

our continued reliance on third parties to conduct additional preclinical studies and clinical trials of our product candidates, and for the development and manufacture of our product candidates for preclinical studies and clinical trials;

•

our ability to obtain, and negotiate favorable terms of, any collaboration, partnership, licensing or other arrangements that may be necessary or desirable to develop, manufacture or commercialize our product candidates;

•

the pricing and reimbursement of our current product candidates and other product candidates we may develop, if approved, including any increase in demand as a result of the availability of reimbursement from the government and third-party payors;

•

the rate and degree of market acceptance and clinical utility of our current product candidates and other product candidates we may develop;

•

our estimates regarding expenses, operating losses, future revenue, cash outlays, capital requirements and needs for additional financing, including expenses arising as a result of being a public company;

•

our financial performance;

•

our facilities;

•

the period over which we estimate our existing cash, cash equivalents and investments in marketable securities will be sufficient to fund our future operating expenses and capital expenditure requirements;

•

the impact of critical accounting policies on investor’s ability to understand our financial performance; and

•

our expectations regarding the period during which we will remain an emerging growth company under the JOBS Act.

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 Annual Report and are subject to a number of risks, uncertainties and assumptions described in the section titled “Risk Factors” and elsewhere in this Annual Report. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified, investors 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. Except as required by applicable law, 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.

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 Annual 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 investors are cautioned not to unduly rely upon these statements.

PART I

Item 1. Business.

Overview

We are a clinical-stage biotechnology company committed to a bold mission: to discover, develop and deliver potentially curative therapies that address the underlying drivers of heart disease. Heart disease is the leading cause of death in the world, representing an estimated 32% of all global fatalities. In the United States (U.S.), one in every five deaths is attributable to heart disease, and an estimated 40,000 infants are born each year with congenital heart conditions. While there is a clear need for improved treatments, the rate of cardiovascular drug product approvals has declined in recent years and few of the approved treatments address the underlying cause of such diseases.

Our collective understanding of the links between heart disease and genetic factors is increasing exponentially, creating new opportunities for the advancement of novel disease-modifying therapeutics that target the underlying cause of disease. Roughly one-third to one-half of all heart diseases are linked to genetic risks, regardless of major racial and ethnic backgrounds, and there are over 250 known genetically defined disorders where the primary source of morbidity and mortality involves the heart. Leveraging this improved understanding of the genetic causes of heart disease, as well as an increased recognition that precision medicine initiatives may accelerate the advancement of scientific breakthroughs, our vision is to change the treatment paradigm for heart disease and in doing so, improve and extend the lives of patients.

Our goal is to build a leading fully-integrated biopharmaceutical company focused on precision medicines for heart disease. We believe that our drug development efforts benefit from a deep understanding of the underlying causes of disease for specific subpopulations of patients within both rare and prevalent forms of heart disease. We have invested in differentiated capabilities that enable target identification, target validation, and drug discovery that is anchored in human genetics and the use of human disease models. These capabilities, and the insights they enable, allow us to generate promising leads for drug development in a modality agnostic manner, and help us to prioritize the best approaches to address the underlying disease biology using a range of methods, including but not restricted to gene therapy, gene editing, small molecules, gene silencing, and regenerative medicine approaches. We have to date made a deliberate effort to internalize and integrate the capabilities necessary to design, develop, and manufacture medicines that are based on the use of AAVs as the method of delivery to the heart, which are most relevant for our efforts in gene therapy, gene editing, or cardiac regeneration. For programs addressing relatively rare conditions – for example, potentially curative genetic medicines for genetic cardiomyopathies – our strategy is to develop, manufacture, and commercialize at least some of these programs on our own, although we may selectively consider partnerships to access technology, accelerate our progress, or improve our global reach to patients. Where our discovery efforts lead to product candidates intended for relatively prevalent indications – for example, small molecules or genetic medicines for heart failure with preserved ejection fraction (HFpEF) – our strategy is to out-license or partner such programs earlier during preclinical or clinical development.

Our Product Pipeline

We are advancing a deep and diverse pipeline of product candidates intended to target the underlying causes of rare and highly prevalent forms of heart disease.

Each of our most advanced product candidates, TN-201, TN-401, and TN-301, emerged from an initial examination of the genetic underpinnings of heart conditions and has progressed to clinical stage with the support of our proprietary internal capabilities.

•

TN-201 gene therapy for hypertrophic cardiomyopathy (HCM) caused by variants in the Myosin Binding Protein C3 (MYBPC3) gene: TN-201 is our adeno-associated virus serotype 9 (AAV9)-based gene therapy being developed to treat the underlying cause of MYBPC3-associated HCM by delivering a working MYBPC3 gene to specific cells of the heart via a single infusion. MYBPC3 mutations are the most common genetic cause of HCM, accounting for approximately 20% of the overall HCM population or more than 115,000 people in the U.S. alone. Patients may experience serious complications such as shortness of breath, fainting and palpitations, significant impairment in overall quality of life, heart failure, and sudden cardiac death. We are currently conducting the Phase 1b MyPeakTM-1 clinical trial in symptomatic adults diagnosed with MYBPC3-associated nonobstructive HCM, for which the first subject was dosed in October 2023 and initial data are anticipated in the second half of 2024. TN-201 has received orphan drug designation from the FDA and orphan medicinal product designation from the European Commission (EC), as well as Fast Track Designation from the FDA.

•

TN-401 gene therapy for arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by variants in the Plakophilin-2 (PKP2) gene: TN-401 is our AAV9-based gene therapy being developed for the treatment of ARVC due to disease-causing variants in the PKP2 gene. PKP2 mutations are the most common genetic cause of ARVC, also known as arrhythmogenic cardiomyopathy (ACM), a condition characterized by arrhythmias, palpitations, lightheadedness, dizziness and fainting that typically strikes before age 40. The prevalence of PKP2-associated ARVC is estimated at more than 70,000 people in the U.S. alone, though it frequently goes undiagnosed as sudden cardiac death is the first sign of disease in nearly one quarter of known cases. We received clearance of our IND application for TN-401 in October 2023 from the FDA and expect to commence patient dosing in the Phase 1b RIDGETM-1 clinical trial of TN-401 in the second half of 2024. TN-401 has received orphan drug designation from the FDA and orphan medicinal product designation from the EC, as well as Fast Track Designation from the FDA.

•

TN-301 small molecule histone deacetylase-6 (HDAC6) inhibitor for the potential treatment of HFpEF: HFpEF accounts for approximately 50 percent of all heart failure, or an estimated 3 million patients in the U.S. alone. We initially discovered the cardioprotective qualities of selective HDAC6 inhibition in a genetic model of dilated cardiomyopathy. In preclinical studies, TN-301 was subsequently shown to reverse many of the signs and symptoms of HFpEF, with evidence of improved cardiac function and glucose tolerance and reduced inflammation and fibrosis. In 2023, we completed Phase 1 clinical testing of TN-301 in healthy volunteers, observing an encouraging safety profile,

suitability for once-daily dosing, and dose-dependent target engagement. Due to the large HFpEF patient population, we believe that TN-301’s late-stage development and commercialization would best be led by a strategic pharmaceutical partner with the global resources to explore the full potential of the molecule and are currently evaluating opportunities to partner TN-301.

In addition to our lead product candidates, we have multiple early-stage programs progressing through preclinical development using various therapeutic approaches, including gene editing, cellular regeneration and gene addition to address other forms of rare and/or prevalent heart disease. Today, our pipeline consists of programs to which we have exclusive worldwide rights and that have emerged from our internal efforts, with select product candidates originating based on intellectual property licensed from academic institutions.

Our Integrated Capabilities

Our distinct suite of integrated capabilities broadly enable target identification and validation, design of AAV-based genetic medicines and in-house manufacturing to support our efforts to discover and develop disease-modifying treatments focused on heart disease. We have invested in our interrelated capabilities, including the use of human-induced Pluripotent Stem Cell (iPSC) and engineered heart tissue disease models, machine learning and phenotypic screening, capsid engineering and novel promoter constructs, to enable the discovery, design, delivery and development of therapeutics that are best suited to a given cardiovascular condition. We have also chosen to have complete ownership of process development, analytical development, and quality control for our gene therapy product candidates and produce our AAV-based gene therapy candidates at our Good Manufacturing Practice (cGMP)-certified Genetic Medicines Manufacturing Center (GMMC) in Union City, California. We continue to invest in complementary new technologies and the optimization of our existing proprietary capabilities with the aim of increasing the safety and efficacy of genetic medicines, accelerating early-stage discovery and preclinical optimization and, reducing the overall cost of goods by increasing manufacturing productivity.

Overview of Heart Disease

Heart disease is the leading cause of death in the world, representing an estimated 32% of all global fatalities. The heart is a complex organ due to its biological structure as well as its tightly regulated and coordinated electrophysiological and biomechanical properties. Heart disease comes in many forms, affects individuals at many ages, and is a result of many factors. In each case, the underlying cause could be genetic or due to normal aging or due to environmental factors. Our initial research and development focus has been on the genetics associated with conditions affecting the heart muscle, also known as cardiomyopathies, that can lead to heart failure. Heart failure occurs when the heart cannot pump enough blood to meet the body’s demands. Rates of heart failure are on the rise, and a recent study places the lifetime risk of heart failure at 24%. In spite of recent advancements in heart failure treatment, the five-year mortality rate remains 50%, highlighting the need for improved treatments.

Historically, the most common treatments for heart disease have been aimed at broadly addressing symptoms and the development of novel treatments has been stymied by the need for lengthy studies primarily focused on survival and hospitalization outcomes. Such studies required enrolling large, heterogeneous patient populations in an effort to achieve statistically significant signals of efficacy. Consequently, innovation in heart disease drug development has lagged in comparison to therapeutic areas such as oncology and rare diseases where more targeted approaches have achieved clinical and regulatory success.

Growing Momentum for Precision Approaches

In the past several years, increasing clinical and regulatory validation for more targeted approaches have emerged for precision approaches to heart disease and AAV-based gene therapies. These include FDA draft guidance supporting smaller clinical studies that emphasize the use of clinically meaningful endpoints of “feel and function” and a small but growing number of examples of clinical success and regulatory approvals for disease-modifying treatments geared toward targeted disease populations, including in genetic cardiomyopathies, that have followed similar development and regulatory paths.

A combination of increasing insights into the genetic causes of heart disease and recognition of the importance of genetic testing support the discovery, development and commercial opportunities for precision medicines that target the underlying genetic cause of heart conditions. More than 250 genetically defined disorders are now known where the primary source of morbidity and mortality involves the heart, providing numerous potentially druggable targets for characterization. Updated clinical practice guidelines from the American College of Cardiology,

American Heart Association and European Society of Cardiology recommending genetic testing and family counseling, and the push for mandatory screening of young athletes, are all leading to improved access to genetic testing, patient diagnosis and disease management.

At the same time, the field of gene therapy drug development has matured. The safety and efficacy of genetic medicines, and AAV9-based gene therapies in particular, continues to grow with multiple new regulatory approvals in recent years resulting in thousands of patients dosed worldwide. A study by the Association for Regenerative Medicine found that gene therapies for rare disease havea 2 to 3.5-fold higher likelihood of achieving regulatory approval as compared to other modalities.This report is bolstered by FDA actions with gene therapy sponsors indicating a willingness to consider surrogate markers of efficacy and expedited regulatory review, as well as the FDA’s issuance of important guidance to help streamline the development of gene therapies and mitigate safety and tolerability concerns that can delay development timelines.

We believe with the evolving understanding of heart disease, and the genetic underpinnings of disease in particular, there are significant opportunities where our proprietary capabilities and singular focus will enable us to benefit from and support the evolution towards more precise diagnosis, drug development, and treatment for heart disease.

Our Strategy

Our goal is to become a leading, fully integrated biotechnology company delivering next-generation therapies that address the underlying causes of heart disease. We are taking advantage of an expanded understanding of heart biology and advances in the science of genetics and disease models to discover, develop, manufacture and ultimately commercialize a deep and diverse pipeline of novel heart disease therapies. The key components of our strategy to achieve these goals are:

•

Focus exclusively on heart disease. Heart disease remains a leading cause of death globally, and the unmet medical need remains high. We see significant opportunity to address this sizable market with our dedicated strategy. The heart is a complex organ to target, in part due to the tightly regulated and coordinated electrophysiological and biomechanical properties that can complicate delivery of effective therapies and necessitates a deep understanding of heart biology. Our laser focus leads to insights that underpin our foundational and differentiated capabilities to address challenges that have historically presented barriers to the successful development of novel therapies for the heart.

•

Develop disease-modifying therapies. We are focused on developing disease-modifying and potentially life-saving novel therapies that target the underlying causes of heart disease. We are particularly interested in areas where there is no current standard-of-care or where we believe the nature and the magnitude of the effect of our therapies will be significant relative to existing standards-of-care. For example, we believe our AAV-based gene therapy candidates for genetically defined conditions have the potential to be curative after a single dose.

•

Target defined sub-populations of patients most likely to respond to our therapies. We seek to focus on patient populations where the genetic cause of the disease is well-established, including genetic cardiomyopathies and other monogenic disorders. We also seek to use different strategies to sub-segment larger heart failure populations through the use of genetics or biomarkers to improve selection of patients with attributes that are more suited to the specific mechanism of action of a given product candidate. We believe this strategy can accelerate clinical development, reduce overall development costs, and improve the probability of clinical and regulatory success.

•

Internalize and integrate core capabilities to support our innovation. Powering our drug discovery engine are genetic insights into cardiac biology, coupled with a suite of core capabilities centered on modality agnostic target discovery and validation and design, production and delivery know-how for AAV-based genetic medicines. We believe the integration of our know-how and innovations in these areas will allow us to generate scientific insights more rapidly and improve the probability of technical and regulatory success of our product candidates. The internalization of these capabilities also reduces our reliance on third parties—be it academic labs, contract research organizations (CROs), or contract development and manufacturing organizations (CDMOs)—providing us better control of our timelines and costs.

•

Advance a deep and diverse pipeline of therapies. The diversity of our programs illustrates the ambition of our vision and the versatility and depth of our scientific approach. Our pipeline includes therapeutics for both rare and prevalent heart diseases across multiple treatment modalities. Our most advanced rare disease programs include two AAV-based gene therapy candidates in early clinical development: TN-201, our product candidate for MYBPC3-associated HCM and TN-401, our product candidate for PKP2-associated ARVC. TN-301, a small molecule inhibitor of HDAC6 intended to address HFpEF has successfully completed a Phase 1 clinical trial. We are also working on several other early-stage programs, that we believe will add to our future pipeline opportunities.

•

Seek partnerships that can expand our reach and accelerate our efforts. We believe our singular focus on heart disease and extensive platform and core capabilities make us a potential partner of choice for academics and larger companies alike who wish to access deep expertise in next-generation therapies for heart disease. We also strategically evaluate collaborations and partnerships with biopharmaceutical companies that may have more robust and complimentary capabilities and resources to accelerate the development and maximize the availability and potential of our product candidates, particularly for more prevalent indications.

•

Become a fully integrated biopharmaceutical company with commercial capabilities. We aim to discover, develop, manufacture, and eventually commercialize therapies, with an initial focus on those therapies for rare disease populations that could be marketed by a relatively small salesforce.

Our Gene Therapy Programs

Gene therapy is a way of treating or preventing diseases or medical conditions caused by genetic mutations. Our initial programs target loss-of-function mutations that affect that gene’s ability to make a protein where the resulting protein deficiency is pathogenic. Gene therapy replaces the mutated gene by delivering a working gene to target cells in order to restore healthy function and thereby address the underlying cause of a disease.

We utilize AAVs, and specifically AAV9, to deliver the therapeutic working gene to target cells of the heart muscle. AAVs are naturally occurring viruses that are not known to cause diseases in people and are the most common viral vectors used in gene therapy. Viral DNA is removed and the resulting viral shell, or capsid, is loaded with a working gene and regulatory elements to ensure preferential delivery to target tissues and successful transduction. AAV9 is the most widely studied and clinically validated capsid and has been proven to transduce human cardiomyocytes.

TN-201: Gene Therapy for MYBPC3-associated HCM

We are developing TN-201, an investigational and potential first-in-class and best-in-class AAV-based gene therapy for MYBPC3-associated HCM. MYBPC3 genetic mutations are the most common cause of familial HCM. These mutations can cause the heart walls of affected individuals to become significantly thickened, leading to fibrosis, abnormal heart rhythms, cardiac dysfunction, heart failure, and increased risk of sudden cardiac death. There are currently no approved therapies that address the underlying cause of MYBPC3-associated HCM.

Overview of HCM

HCM is a condition in which the heart walls become thickened (hypertrophy), resulting in a reduced ability of the left ventricle (LV) to relax and fill (diastole) and pump (systole) blood effectively with each contraction. HCM is a chronic, progressive disease associated with significant impairment to patients’ overall quality of life, as well as an elevated risk of sudden cardiac death. Symptoms include chest pain, shortness of breath (dyspnea), fainting (syncope), fatigue and palpitations. As the disease progresses, patients may suffer premature death due to end-stage heart failure or malignant ventricular arrhythmia (VA) sometimes leading to sudden cardiac death or stroke. Disease onset can occur at any age, with HCM most frequently emerging in adults in their mid-40s. When HCM emerges in children and young adults, disease course is typically more aggressive and prognosis is worse than that observed in older patients. While a relatively rare occurrence, HCM is the leading cause of sudden cardiac death in young adults.

HCM is estimated to affect one in every 500 people, approximating more than 600,000 people in the U.S. A majority of HCM patients are currently undiagnosed, with diagnosis typically starting with the onset of symptoms,

family screening, or the discovery of an abnormal electrocardiogram (ECG) pattern. A clinical diagnosis of HCM in adults is defined as a left ventricular wall thickening of greater than 15mm. Patients with HCM can present with either the obstructive form (oHCM) or the nonobstructive form (nHCM) of the disease. Both forms of the disease involve significant LV hypertrophy; however, in oHCM, the thickening of the LV wall is such that the LV outflow tract (LVOT) narrows and “obstructs” the proper flow of blood to the rest of the body. Nonobstructive HCM is more frequently characterized by diastolic dysfunction resulting in increased LV filling pressures that leads to chest pain and dyspnea. The genetic causes of HCM may be diverse, but approximately 60% of patients with HCM have clearly identifiable familial disease with an autosomal dominant pattern of inheritance. Mutations in the MYBPC3 are estimated to represent approximately 20% of the overall HCM population and to affect approximately 115,000 patients in the U.S. MYBPC3 gene mutations result in both oHCM and nHCM, with one study involving a series of more than 1000 patients finding that 69% of patients with truncating MYBPC3 mutations had nHCM, while 31% presented with LVOT characteristic of oHCM.

Infants with homozygous MYBPC3 gene mutations represent a particularly severe patient group with high risk of death within a year after birth without heart transplantation. With no ability to produce MyBP-C protein and no available treatment to address the underlying genetic mutation, the only option for this young patient population is a heart transplant. HCM patients who are heterozygous for MYBPC3 gene mutations are typically diagnosed earlier in life and have more severe disease associated with increases in arrhythmia, sudden cardiac death and cardiovascular mortality as compared to genotype negative HCM patients.

The MYBPC3 gene encodes the MyBP-C protein, which forms a key component of the cardiac sarcomere, the fundamental contractile unit of the cardiomyocyte. MyBP-C protein is central to regulation of both contraction and relaxation of the cardiac muscle. Reduced MyBP-C protein levels associated with heterozygous mutations in the MYBPC3 gene result in increased activity of the myosin contractile machinery, which over time leads to LV muscle thickening, known as hypertrophy, excess deposition of extracellular matrix in the cardiac muscle, known as fibrosis, and disorganized muscle cells. As a result, the LV wall stiffens, and the chamber is reduced in size, decreasing the heart’s ability to pump. The contractile strength of the muscle declines in some cases, resulting in LV systolic dysfunction, which ultimately can necessitate advanced therapies, such as an LV assist device (LVAD) or transplantation, in the most severely affected patients. Fibrosis and muscle cell disarray may also lead to arrhythmias in some patients, including life-threatening VA and atrial fibrillation, which can lead to stroke.

Analysis of the hearts of patients who carry truncation mutations of the MYBPC3 gene show on average an approximately 40% reduction in the level of functional MyBP-C protein. In the most severe cases in which both copies of the gene are affected, there is a complete lack of functional MyBP-Cprotein expression. We believe these findings support the idea that mutations of the MYBPC3 gene cause human disease through haploinsufficiency, and also support the hypothesis that gene replacement may address the underlying cause of disease by increasing the levels of functional MyBP-C protein.

The current goal of HCM treatment is to relieve symptoms and prevent sudden cardiac death in people at high risk. In current guideline-directed care, patients are typically prescribed one or more symptomatic therapies, including beta-blockers, calcium channel blockers and antiarrhythmics. These therapies do not address the underlying genetic cause of HCM and do not appear to affect disease progression. No randomized clinical trials have assessed these therapies specifically in HCM. The standards of care are slightly different for patients with oHCM versus nHCM, but the unmet need is high in both forms of the disease. Cardioverter-defibrillators may be implanted for patients at high risk for malignant arrhythmias and sudden death. For a subset of oHCM patients with severe and disabling disease, invasive interventions, such as myectomy and septal ablation in which portions of the enlarged septum are removed, may be appropriate. For patients with severe nHCM implantation of an LVAD or a heart transplant may be the only options.

In recent years, a class of agents known as myosin inhibitors have emerged as potential treatments for oHCM and nHCM. One of these agents, mavacamten, was approved by the FDA in April 2022 for the treatment of oHCM. Other agents continue to be evaluated in clinical studies. However, there are no therapies approved specifically for HCM patients with MYBPC3 gene mutations that address the underlying cause of the disease.

Our Solution

We believe TN-201 has the potential to address the underlying biological basis of disease in adult and pediatric HCM patients with homozygous or heterozygous MYBPC3 gene mutations. Based on our preclinical data, TN-201 gene therapy has the potential to achieve highly selective and robust expression of the MYBPC3 gene and to

slow or even reverse the course of MYBPC3-associated HCM, including LV hypertrophy, outflow tract obstruction, heart failure, atrial fibrillation, and malignant arrhythmias. By improving upon these aspects of disease, TN-201 may improve heart functional capacity, stabilize or reverse disease symptoms, reduce the need for invasive treatments and improve survival. As with other AAV-based gene therapies, benefits are expected to be durable and a one-time dose may be sufficient to halt or even reverse disease.

TN-201 Clinical Development Plan

In October 2023, we dosed our first patient in MyPeak-1, our Phase 1b clinical trial of TN-201 in symptomatic adults with the nonobstructive form of MYBPC3-associated HCM. MyPeak-1 is a multi-center, open-label clinical trial designed to assess the safety, tolerability and efficacy of a one-time intravenous infusion of TN-201. The trial will seek to enroll up to fifteen symptomatic (New York Heart Association class II or III) adults (ages 18-65) with low titers of AAV9 neutralizing antibodies who have been diagnosed with MYBPC3-associated nHCM and have an implantable cardioverter defibrillator (ICD). Endpoints for the trial include safety and tolerability, pharmacokinetic (PK) (as measured by transgene and mRNA expression via cardiac biopsies), pharmacodynamic (PD) (as measured by imaging and plasma biomarkers), exercise capacity (as measured by a six-minute walk test and cardiopulmonary exercise testing (CPET)) and patient-reported outcomes (as measured by a Kansas City Cardiomyopathy Questionnaire). The trial will include a preventative immunosuppressive regimen and close safety monitoring, as well as a 5-year follow-up to evaluate long-term safety and efficacy. We plan to assess two dose levels of TN-201 in the trial, starting with 3×1013 vg/kg, a dose associated with near-maximal efficacy in preclinical studies. Three patients are expected to be enrolled in the first dose cohort and will be dosed sequentially, with a pause between patient doses to monitor for safety. An independent safety review following the initial cohort will inform plans for dose escalation to 6×1013 vg/kg, as needed, and/or enrollment of additional patients in the initial cohort. TN-201 has received orphan drug designation from the FDA and orphan medicinal product designation from the EC, as well as Fast Track Designation from the FDA. Initial data from the trial is anticipated in the second half of 2024.

In order to support our development efforts for TN-201, we have initiated two noninterventional studies: a study evaluating seroprevalence to AAV9 antibodies among adults with MYBPC3-associated HCM andMyClimb, a prospective and retrospective global natural history study focused on pediatric patients with MYBPC3 mutation-associated cardiomyopathy. The objective of the natural history study is to characterize the outcomes, burden of illness, risk factors, quality of life, and biomarkers associated with disease progression in pediatric patients with cardiomyopathy due to MYBPC3 gene mutations, as well as treatments and procedures. This study complements existing disease registries focused primarily on adult patient HCM populations and may support and expedite the development of TN-201 in the pediatric patient population. To date, we have activated more than 40 sites in the U.S. and Europe in connection with these noninterventional studies.

Preclinical Evidence Supporting TN-201 Clinical Development

In preclinical studies, we systemically administered a mouse surrogate of TN-201 (AAV:mMybpc3 or mTN-201) in two-week-old Mybpc3 knockout (KO) mice. The Mybpc3 KO model develops marked LV hypertrophy, poor cardiac function, and dilation at two-weeks of age, comparable to HCM patients with truncating or null mutations. Due to the severe phenotype of the Mybpc3 KO mice and the lack of any MyBP-C protein, this is considered a demanding model to demonstrate efficacy particularly for modeling heterozygous patients, who lack only 35% to 40% of normal sarcomeric MyBP-C protein levels. Treatment with mTN-201 improved LV hypertrophy and cardiac function compared to their pre-treatment baseline levels, indicating partial reversal of the disease and dramatically extended lifespan. Treated mice exhibited an absolute improvement of ejection fraction (EF) of more than 20% versus untreated controls that eventually increases to more than 30% at 13 months the last echocardiography measurement. EF and LV hypertrophy (LV mass normalized to body weight) improvements did not diminish over time, suggesting that a single systemic dose may be sufficient for a durable reversal of MYBPC3-associated HCM. Additionally, we observed improvements in LV diameter and ECG measurements. There is also a clear survival benefit with 100% survival in the mTN-201 arm and 100% mortality in the untreated control arm out to 18 months following dosing.

In addition, a dose-response relationship has been demonstrated with mTN-201. Weight-based doses, 1×1013 vg/kg, 3×1013 vg/kg and 1×1014 vg/kg, all produced significant improvements in EF, LV hypertrophy, and measures of electrophysiological function (QT interval) at eight months post-injection in the Mybpc3 KO HCM mouse model. The 1×1013 vg/kg dose had the lowest levels of efficacy, while the 3×1013 vg/kg had high improvement with a mean

decrease of hypertrophy of more 5.3 mg/g LV Mass (± 1.3) and a mean improvement of EF of 26% (± 3.7%), similar to the 1×1014 vg/kg dose, suggesting a plateau in the dose-response curve.

In our preclinical studies with the Mybpc3 KO model, we have not observed MyBP-C protein levels substantially above normal levels, suggesting that protein accumulation does not occur and lowers the potential concern of overexpression-related toxicities. In addition, histological assessments of mTN-201 treated Mybpc3 KO model murine hearts support the uniform and robust distribution of expression following mTN-201 infusion, suggesting gene therapy may be able to replace the missing MYBPC3 gene uniformly across the heart. This observation is consistent with heart biopsy samples from patients treated with other AAV9-based gene therapies in development. Consistent with observed therapeutic benefit, treatment of the Mybpc3 KO mice with mTN-201 is also associated with a substantial reduction of expression of genes associated with fibrosis and B-type natriuretic peptide (BNP), a circulating factor associated with cardiac wall stress.

Differentiating Characteristics for TN-201

During optimization of our MYBPC3 gene therapies, we discovered a cardiomyocyte-specific promoter, TNP-CM1, with improved performance attributes as compared to the standard cardiac troponin T (cTnT) promoter. In vitro and in vivo analyses confirmed that TNP-CM1 significantly increased expression of the MYBPC3 gene compared to what can be achieved with the standard cTnT promoter.

TN-401: Gene Therapy for PKP2-associated ARVC

We are developing TN-401, an investigational and potential first-in-class and best-in-class AAV-based gene therapy for the potential treatment of ARVC, also known as arrhythmogenic cardiomyopathy or ACM, caused by mutations to the PKP2 gene. Such mutations are estimated to affect more than 70,000 patients in the U.S. PKP2 mutations result in insufficient expression of a protein needed for the proper functioning of the desmosomal complex that maintains physical connections and electrical signaling between heart muscle cells. As the desmosome structure is impaired, cardiac muscle cells are progressively replaced by fibrofatty tissue and electrical pulses in the heart become unstable, resulting in adverse remodeling and irregular heart rhythms. TN-401 is designed to deliver a working PKP2 gene to cardiomyocytes to restore function and reverse or slow progression of disease by addressing the genetic mutation most frequently underlying ARVC.

Overview of ARVC

ARVC is a chronic, progressive disease with an estimated prevalence in the general population of approximately 1:1000 to 1:5000. It occurs when the structure and electrical signals of cardiomyocytes are disrupted, resulting in irregular heart rhythms and a gradual replacement of heart muscle cells with fatty deposits and fibrotic tissue which can lead to heart failure over time.

Patients with ARVC most commonly present with symptoms related to VAs, particularly abnormally high heart rates known as ventricular tachycardia and premature ventricular contractions (PVCs). These dangerous rhythm abnormalities place patients at increased risk for sudden cardiac arrest or sudden cardiac death. In an effort to reduce the risk of sudden cardiac death, patients with ARVC are typically discouraged from competitive or endurance sports activities and physical exercise may be limited. The mean age of diagnosis in patients occurs before the age of 40. ARVC is a common cause of sudden cardiac arrest in young patients, and particularly in athletes. In an estimated 23% of ARVC cases, the first sign of disease is sudden cardiac death. ARVC patients may also grapple with additional symptoms, including palpitations, lightheadedness, dizziness, and fainting.

Mutations in the PKP2 gene are the most common genetic cause of ARVC, with more than 40% of ARVC patients carrying pathogenic variants. PKP2 protein is an integral component of cell adhesion protein complexes known as desmosomes which connect adjacent cardiomyocytes in the heart. Desmosomes are responsible for maintaining the heart tissue integrity and for stabilizing channels called gap junctions that allow for cellular communication among heart cells, which in turn is important to proper synchronization of cardiomyocyte contractions across the myocardium contributing to each heartbeat. When the PKP2 gene is mutated, reduction of PKP2 protein disrupts structure and function of desmosomes and gap junctions. As a result of these disruptions, cardiomyocytes become more sensitive to the normal mechanical stress of the beating heart, leading to progressive cell loss, inflammation, scar formation, and fat deposition, illustrating the crucial role the PKP2 protein plays in maintaining the structural and functional integrity of heart tissue.

Mutations in the PKP2 gene are commonly heterozygous and inherited in an autosomal dominant fashion, i.e., a mutation in one gene is sufficient to cause the disease. Most of these mutations lead to a reduction of wild-type protein level of less than or equal to 50%. We believe these findings support the idea that mutations of the PKP2 gene cause human disease through haploinsufficiency, and also support the hypothesis that gene replacement may address the underlying cause of disease by increasing the levels of functional PKP2 protein.

Following a diagnosis, ARVC patients are typically implanted with an ICD to control arrhythmias and prevent sudden cardiac death. ICD implantation is currently the only proven effective treatment for preventing sudden cardiac death in ARVC patients, but ICDs are also associated with complications, including inappropriate interventions. Patients may progress to catheter ablation procedures which have a high rate of recurrence of VA and have not been shown to reduce risk of sudden cardiac death or improve survival. ARVC treatment options may also include beta blockers and other anti-arrhythmic or heart failure medications, intended to reduce VAs. However, studies comparing the efficacy of such treatments have not been conducted. Despite the availability of these treatments, clinical heart failure has been documented in up to 40% of ARVC patients and there remains no approved therapies that address the underlying genetic causes of the disease.

Our Solution

We are developing a potential first-in-class and best-in-class AAV-based gene therapy to deliver a fully functional copy of the human PKP2 gene to the hearts of ARVC patients carrying PKP2 mutations. We believe that delivery of a working PKP2 gene to cardiomyocytes represents a promising treatment that can address the underlying genetic cause of this disease. As the disease is most often caused by haploinsufficiency, expression of a functional PKP2 gene to replace the missing PKP2 protein in cardiomyocytes is expected to restore proper structure and function of the desmosome. This in turn has the potential to slow and even reverse the progression of disease in patients. The PKP2 gene will be delivered using AAV9 capsid with well-established tropism for the heart and expression of the PKP2 protein will be targeted to the heart through use of a cardiomyocyte-specific promoter.

TN-401 Clinical Development Plan

In October 2023, we received clearance of our IND from the FDA to conduct a Phase 1b clinical trial of TN-401 in patients with PKP2 mutation-associated ARVC. We expect to commence patient dosing in RIDGE-1 in the second half of 2024 and have completed all necessary manufacturing of TN-401 to supply the clinical trial.

RIDGE-1 is a multi-center, open-label clinical trial designed to assess the safety, tolerability and efficacy of a one-time intravenous infusion of TN-401. The trial will seek to enroll at least six symptomatic (New York Heart Association class I, II or III) adults (ages 18-65) with low titers of AAV9 neutralizing antibodies who have been diagnosed with PKP2-associated ARVC and have an ICD. The primary endpoints for the trial include safety and tolerability, PK (as measured by transgene and mRNA expression via cardiac biopsies at 8 weeks and 52 weeks) and PD (as measured by changes in daily PVCs and non-sustained ventricular tachycardia).

Additional endpoints include frequency of ICD shocks or pacing, frequency of ventricular tachycardia, changes in premature ventricular contractions, imaging biomarkers by echo evaluating structural/hemodynamic changes, plasma biomarkers and patient-reported outcomes. The trial will include a preventative immunosuppressive regimen and close safety monitoring, as well as a 5-year follow-up on safety and efficacy. We expect to assess two dose levels of TN-401 in the trial, starting with 3×1013 vg/kg, a dose associated with near-maximal efficacy in preclinical studies. Three patients are expected to be enrolled in the first dose cohort and will be dosed sequentially, with a pause between patient doses to monitor for safety. An independent safety review following the initial cohort will inform plans for dose escalation to 6×1013 vg/kg, as needed, and/or enrollment of additional patients in the initial cohort. In order to support our development efforts for TN-401, we have initiated RIDGE-1 a global noninterventional study to collect treatment history and seroprevalence to AAV9 antibodies data among ARVC patients who carry pathogenic or likely pathogenic PKP2 gene mutations.

TN-401 has received orphan drug designation from the FDA and orphan medicinal product designation from the EC, and in November 2023, received Fast Track Designation from the FDA.

Preclinical Evidence Supporting TN-401 Clinical Development Plan

We developed a Pkp2 cardiac conditional knockout (Pkp2-cKO) mouse model that simulates key aspects of ARVC including dilation of the right ventricle (RV) and LV, decline in LV heart function, severe ventricular

arrhythmia, and early mortality. The onset of symptoms in this model is very rapid and occurs within three weeks after induction of the gene deletion. It is important to note that this Pkp2-cKO model is homozygous with no production of PKP2 protein in cardiomyocytes, resulting in a severity of disease and rate of disease progression that is greater than what is normally observed in most PKP2 patients who are almost all heterozygous for PKP2 gene mutations, and produce less than or equal to 50% of the necessary PKP2 protein. The Pkp2-cKO model is nonetheless useful as it provides important proof of concept for the potentially beneficial in vivo effect of the PKP2 protein replacement via a gene therapy approach.

In preclinical studies, we systemically administered either TN-401 or a mouse surrogate (referred to interchangeably as a “PKP2 gene therapy”) in Pkp2-cKO mice across a range of dose levels from 1×1013 vg/kg to 1×1014 vg/kg and observed similar efficacy utilizing either intervention. The severity and rapid progression of this disease model, combined with the homozygous gene knockout (KO) and near complete loss of PKP2 protein in cardiac tissue, resulted in 100% mortality within 4-6 weeks post induction of KO. This model represents a high bar for demonstration of efficacy with gene therapy, particularly given the slow kinetics (weeks) of AAV-based gene expression and protein production. Nevertheless, whether administered prior to or following disease onset, PKP2 gene therapy demonstrated prevention of disease progression, ultimately culminating in improved survival in both modes of treatment. These improvements in disease state were accompanied by restoration of desmosomes and gap junctions at the molecular and cellular level. All dose levels were well-tolerated.

Specifically, when administered prior to disease onset, PKP2 gene therapy prevented all ARVC disease characteristics in Pkp2-cKO mice including RV enlargement, LVEF decline, ventricular arrhythmias, and adverse fibrotic remodeling. Even when administered after disease onset in this rapidly progressing model, PKP2 gene therapy attenuated LVEF decline with an average 15% (+/- 5.6%) increase in EF versus the vehicle-treated group and attenuated worsening of VA event frequency and severity. Administration of PKP2 gene therapy also supported a near-complete reversal of RV enlargement leading to a restoration of the wild-type level. In either intervention, the beneficial effects of PKP2 gene therapy have been shown to be dose dependent and durable following a single dose lasting the remainder of the Pkp2-cKO mouse model’s natural life span. Survival was also improved in a dose-dependent manner and the effect was sustained for the duration of study; PKP2 gene therapy extended median lifespan from 4.7 weeks to ≥ 50 weeks, regardless of preventative or post-onset dosing.

Our Clinical-Stage Small Molecule Program

While much of our research, development and manufacturing focus is on cardiac conditions for which genetic medicines can address the underlying cause of disease, our target discovery and validation capabilities allow us to pursue modality-agnostic drug discovery efforts.

TN-301: HDAC6 Inhibitor Program for HFpEF

Using our proprietary modality-agnostic drug discovery capabilities, we discovered an HDAC6 small molecule inhibitor for the potential treatment of HFpEF. HFpEF is one of the greatest areas of unmet need in heart disease with more than three million patients in the U.S. for which there are few approved disease-specific treatment options.A complex syndrome, the causes of HFpEF are diverse, but result in a shared pathophysiology with systemic inflammation and metabolic dysfunction leading to hypertrophy, fibrosis, and diastolic dysfunction among other characteristic consequences. The result is high morbidity and mortality in affected individuals. Our product candidate, TN-301, is a differentiated compound with unique chemical structure and high specificity for HDAC6. In 2023 we completed a Phase 1 clinical trial in which TN-301 demonstrated safety and tolerability in healthy participants with dose-proportional pharmacokinetics and robust target engagement. We have also generated robust preclinical evidence of improving many of the hallmarks of HFpEF when utilized alone or in combination with sodium-glucose cotransporter-2 (SGLT2) inhibitors, a relatively new class of medicines that have shown some efficacy in HFpEF. Based on the large HFpEF patient population, we believe that TN-301’s late-stage development and commercialization would best be led by a strategic pharmaceutical partner with the global resources to explore the full potential of the molecule in HFpEF and other indications.

Overview of HFpEF

HFpEF is generally defined as heart failure with an EF greater than or equal to 50%. In patients with HFpEF, the LV is stiffened and does not adequately relax, and increased pressure is needed for the ventricle to properly fill. As a result, blood begins to build up inside the left atrium of the heart and eventually swells into the lungs, veins and

tissues of the body. HFpEF is a progressive disease in many patients. Symptoms initially include fatigue, shortness of breath, and edema, resulting in reduced physical activity. Over time, this results in a substantial limitation in activities and impact on quality of life, and patients are at risk of premature death.

Patients with HFpEF represent approximately half of heart failure patients, with prevalence of the disease anticipated to increase by more than 45% by 2030. The increase in HFpEF prevalence is at least in part due to the high overlap of this condition with diabetes and obesity which are also on the rise in the U.S. and globally. At least half of all hospital admissions for heart failure are related to HFpEF and approximately 24% of the HFpEF population is considered to have New York Heart Association Class III or Class IV disease, representing a disease burden that markedly impacts quality of life and limits physical activity. Among patients hospitalized for HFpEF, readmission for heart failure and mortality rates over a five-year period are as high as 40% and 75%, respectively. Historically, HFpEF patients have generally been prescribed therapies for HFrEF, including diuretics, beta-blockers, and ACE inhibitors, in spite of a limited data demonstrating efficacy or improved outcomes. Recently, a class of glucose lowering drugs known SGLT2 inhibitors have demonstrated encouraging evidence of reducing hospitalizations and mortality versus placebo in HFpEF patients, with one such agent approved by the FDA for the treatment of HFpEF. In spite of this recent progress, HFpEF remains one of the greatest unmet needs in cardiovascular medicine.

Our Solution

TN-301 is a small molecule inhibitor of HDAC6 intended for the potential treatment of HFpEF. TN-301 has demonstrated up to 2500-fold preferential selectivity for HDAC6 in contrast to pan HDACs which have been utilized in oncology. We believe that TN-301’s selectivity may reduce the risk of off target effects observed with less selective HDAC6 inhibitors or pan-HDAC inhibition.

Key aspects of HFpEF disease biology include oxidative stress and inflammation, cardiac fibrosis, cardiac hypertrophy, cardiac stiffness, which all result in diastolic dysfunction, and decreased ability of the heart to fill its chambers during contraction. Defects in glucose tolerance and insulin sensitivity and overall defective metabolism have also been proposed to play a role in HFpEF onset and progression due to high overlap between patients with HFpEF population and those suffering from diabetes and obesity.

Our preclinical data is suggestive of a multi-modal mechanism of action that may address these multiple aspects of HFpEF disease. In the preclinical setting, TN-301 was shown to reverse measures of HFpEF, including restoration of LV wall thickness, LV end diastolic pressure, LV relaxation and filling, and LV mass. Treatment with TN-301 also resulted in a trend of decreased lung weight, indicative of improvement in pulmonary congestion consistent with the reduction of filling pressure. In addition, we observed an improvement in glucose tolerance, suggesting that treatment with a selective HDAC6i may have a positive impact on glucose metabolism, as well as reductions of key biomarkers of fibrosis, hypertrophy and cardiac damage, and inflammation.

TN-301 Clinical Development Plan

Building on our preclinical data, we initiated a randomized (3:1), double-blind, placebo-controlled Phase 1 clinical trial to assess the safety and tolerability of escalating oral doses of TN-301 in healthy adult participants. Secondary objectives of the clinical trial included assessment of PK and PD measures. In October 2023, we shared positive data from our Phase 1 clinical trial of TN-301 in healthy participants at the 2023 Heart Failure Society of America (HFSA) Annual Scientific Meeting. The Phase 1 trial enrolled participants in two stages. In Stage 1, participants received single ascending doses (SAD) (1mg – 700mg) and in Stage 2, participants received multiple ascending doses (MAD) (25mg, 100mg and 300mg once daily for 14 days). TN-301 was generally well tolerated across the broad range of doses studied.

PK results showed dose proportional increase in plasma exposure in the SAD and MAD stages of the study with a half-life supportive of once-daily dosing. Increasing TN-301 doses and exposures in both stages of the clinical trial also resulted in corresponding increases in PD effect (as measured by acetylated tubulin). HDAC6 is localized to the cell cytoplasm where it interacts with multiple proteins to coordinate cellular processes and one of its main substrates is tubulin. Inhibition of HDAC6 therefore, results in an increase in acetylated tubulin over baseline. In the Phase 1 clinical trial, acetylated tubulin was evaluated in circulating cells in a robust and reproducible manner. There were no corresponding changes in histone acetylation with TN-301, underscoring the selectivity of TN-301 for HDAC6 and potentially reducing the risk of off target effects observed with less selective

HDAC6 inhibitors or pan-HDAC inhibition. Most adverse events were gastro-intestinal related, occurred with similar frequency in the placebo group and did not increase as doses of TN-301 increased.

Given the encouraging safety profile, potential for once-daily dosing and robust target engagement observed, we believe the results from the Phase 1 clinical trial of TN-301 provide early evidence of a suitable profile for the treatment of HFpEF and warrant further testing in HFpEF patients.

Comparison with SGLT2 Inhibitors

In order to test our selective HDAC6 inhibitor, we conducted a comparison study with empagliflozin, an SGLT2 inhibitor approved for HFpEF in a proprietary mouse model of disease using a combination of high fat diet (60%) and Nω-nitrol-arginine methyl ester (L-NAME, 0.5 g/L) to recapitulate systemic and cardiovascular features of HFpEF in humans. In the study, empagliflozin behaved as anticipated based on the data generated from large clinical trials providing validation of our mouse model. TYA-018, a structurally and functionally equivalent compound to TN-301 used for preclinical testing, improved glucose tolerance, reduced LV mass and diastolic pressure, and increased diastolic function with comparable efficacy, suggesting that preclinical results may translate to the clinic. More recently, using a validated mouse model of disease, we demonstrated that HDAC6 inhibition co-administered with empagliflozin demonstrated additive benefit compared to either agent alone improving several measures of heart function. Taken together, these data support the potential for TN-301 to be used either alone or in combination with SGLT2 inhibitors, as a potential treatment for patients with HFpEF.

Potential Indications for HDAC6 Inhibitors Beyond HFpEF

Data from preclinical studies evaluating TN-301 as a treatment for HFpEF suggest that there may also be a role for TN-301 in the treatment of sub-populations of patients with obesity, diabetes or metabolic syndrome, as well as potentially in sub-populations of patients with dilated cardiomyopathy (DCM) where there is strong alignment between the multi-modal mechanism of action of TN-301 with the pathophysiology of the HFpEF disease.

In addition to improvements in glucose metabolism associated with TN-301 treatment in HFpEF mouse models, treatment with TN-301 also led to improvements in glucose tolerance (after a single dose) and insulin sensitivity (after once daily dosing for four weeks) in a diet-induced obesity (DIO) mouse model. A single dose of TN-301 in the DIO model was also associated with a significant reduction in inflammatory markers in adipose tissue, which are thought to be linked to glucose tolerance and insulin sensitivity.

Our small molecule HDAC6 inhibitors were initially discovered and validated as having cardioprotective qualities in preclinical studies of a rapidly worsening mouse model of BAG3 mutant DCM. In this model, treatment resulted in a greater than 20% improvement in EF after eight weeks of treatment relative to controls. These initial data support the potential of TN-301 as a potential treatment for DCM, a form of cardiomyopathy characterized by an enlarged and weakened left ventricle. Collectively, these data are supportive of a role for HDAC6 inhibition in multiple indications beyond HFpEF.

Next Steps in TN-301’s Development

Given the extensive preclinical data generated and the positive Phase 1 clinical trial results, we are encouraged by TN-301’s emerging therapeutic profile as a potential differentiated treatment for HFpEF. We believe that TN-301 will best be advanced into efficacy studies by a well-resourced partner.

Our Integrated Capabilities

Foundational to our research and drug discovery efforts are our proprietary integrated capabilities that collectively support discovery of novel targets, in vitro optimization and lead validation, in vivo characterization, rapid product development, precise product delivery, and efficient production.

We believe integration of these in-house capabilities provides us with several advantages and differentiates our efforts relative to other drug discovery companies, especially for gene therapy drug development. For example, we believe the application of our capsid engineering and promoter design and delivery expertise may enable us to overcome the limitations faced by prior cardiac gene therapy approaches by enabling more precise delivery and more robust gene expression and lowering the risk of off-target effects. Leveraging our extensive in-house capabilities, we are able to take a competitively advantageous approach to target identification and validation and preclinical characterization of each of our prospective candidates, which we believe provides us with deeper

insights, shortened product development cycles, reduced scientific risks and improved probability of technical and regulatory success for our product candidates. Ultimately, we believe our differentiated capabilities can support development of product candidates that, if approved, could address the high unmet need of patients with heart diseases. Our core internal capabilities include disease models, capsid engineering, promoters and regulatory elements, drug delivery and manufacturing, each described in more detail below:

Disease Models

We have internalized the ability to create and integrate proprietary in vitro and in vivo models within our research organization, which allows us to simulate human heart disease phenotypes. This creates significant value to the organization, as existing models of human heart disease may not be adequate to assess the efficacy or safety of novel therapies. Our disease modelling capabilities serve to facilitate the discovery of new leads and to characterize the activity of existing leads as we move through preclinical development.

In Vitro: For our in vitro human iPSC-cardiomyocyte (iPSC-CM) disease models, we use multiple methods to induce phenotypes within cell lines that simulate human diseases and then use these models for high throughput target identification and drug discovery. Specifically, we have implemented three primary approaches to model human heart disease: (i) short interfering ribonucleic acid (siRNA) constructs to silence specific genes of interest in human iPSC-CMs; (ii) CRISPR-based gene editing approaches to create isogenic human iPSC-cell lines where specific genes have been altered; and (iii) iPSCs derived from patients with severe heart disease. We have developed our own high throughput imaging analyses technologies, known as TAMARACK and PORCUPINE, to characterize the impact of drug leads directly on cardiomyocytes and cardiac fibroblasts. Taken together, our advancements in disease modeling, including our practice of characterizing targets using three-dimensional human engineering heart tissues, our ability to produce human iPSC-CM’s reliably and at an increasing scale, our use of immunostaining, high-resolution imaging and our application of imaging and machine learning algorithms to support high-throughput phenotypic screening, enhance our ability to both identify and characterize potential product candidates early in the discovery process.

In Vivo: For our in vivo disease models, we have a dedicated onsite in vivo pharmacology group and vivarium, where we have established approximately 20 rodent heart disease models. We can dose with gene therapies as well as small molecules or biologics. We also have the ability to perform heart surgeries on these rodent models and use blinded echocardiography-based imaging techniques to assess the impact of our therapies under development. The internalization of these capabilities greatly reduces our reliance on external CROs and academic organizations and significantly increases the speed and consistency with which we can iterate on product prototypes, generate data and formulate insights on our product candidates. We also work with established CROs for research efforts involving large animal models, including for efficacy studies and evaluation of drug delivery methods. Through these efforts we have developed important insights into the advantages and limitations of specific models and have learned how to optimize the design of our experiments. This insight influences our preclinical drug development strategies and our discussions with regulatory agencies.

We believe our success will be supported by the know-how we are developing and the proprietary integration of these disease models across our programs.

Capsid Engineering

We believe selection of the right capsid for optimal delivery and safety of genetic medicines can make a profound difference in patient safety, therapeutic efficacy, manufacturing productivity and cost of goods. For our initial pipeline programs, we elected to use AAV9 as the capsid due to its clinically established safety and cardiac tropism and proven manufacturability. As part of our early product design efforts, we tested AAV9 alongside several other capsids for tropism to cardiomyocytes and for resulting mRNA and protein expression, and in our hands AAV9 proved to be superior to other available capsids. This work contributed to the selection of AAV9 for use with TN-201 and TN-401, and also contributed to the foundations of our novel capsid engineering efforts.

Our goal is to discover, design, and develop novel cardiac-tropic AAV capsids with superior attributes in order to enable more precise targeting of heart cells and to improve the safety profile of our product candidates by reducing tropism for other organs, particularly the liver. We also believe that using capsids that more specifically target one cell type over another can also help lower cost of goods for our future product candidates by lowering doses while increasing efficacy. To achieve our goals related to capsid engineering, we have established in-house

AAV capsid engineering capabilities and have designed and screened over one billion variants from diverse, proprietary libraries to discover, design, and develop novel capsids to support our programs.

Our approach includes the use of diverse screening methods across a variety of in vitro, in vivo, and in silico libraries to enable our ability to identify novel capsids, followed by the application of broad criteria for the selection of novel capsids, including improved tropism for the heart compared to other organs, with a particular interest in de-targeting the liver; improved transduction of specific heart cell types; lower susceptibility to neutralizing antibodies; and comparable manufacturing in both HEK293- and Sf9/rBV-based manufacturing systems. We then evaluate these novel capsids to identify ones that can outperform the relevant parental capsids, which may vary depending on the intended use.

Through these efforts, we have discovered proprietary capsids with superior performance over parental variants across multiple species. These next-generation capsids have improved tropism for the heart compared to other organs and even for specific cells within the heart; improved transduction and expression within the heart cells; and lower susceptibility to neutralizing antibodies. In fact, as compared to AAV9, several novel capsids identified have equivalent transduction in the heart and lower transduction of the liver and a better ability to evade human neutralizing antibodies We have also generated additional data that demonstrate that certain of these capsids have a greater ability to improve heart function compared to AAV9 in specific disease models.

Overall, these data provide important proof of concept of the potential utility of capsid engineering. We believe our capsid engineering efforts will be critical in supporting the successful clinical development of future product candidates and enabling those product candidates, if approved, to reach more patients.

Promoters and Regulatory Elements

We have created novel promoters and regulatory elements that support our gene therapy and cellular regeneration programs by controlling the expression of genes within the cells. We use these innovations, which are essential to the success of gene therapy, to help ensure more precise and more robust expression of therapeutic payloads in the different cell types of the heart as compared to what can be achieved with currently available methods. We believe our innovations can support successful clinical development in part by improving the efficacy and safety profile of our product candidates.

Illustrative examples of our innovations in this area include:

•

Heart specificity:We have developed cardiac-specific promoters that enable more selective and robust expression in the heart as compared to other organs. For example, during optimization of TN-201, we developed a cardiomyocyte-specific promoter, TNP-CM1, with improved performance attributes as compared to the standard cTnT promoter. In vitro and in vivo analyses confirmed that TNP-CM1 significantly increased expression of the MYBPC3 gene compared to what can be achieved with the standard cTnT promoter. In addition, in a mouse model we observed 1000-fold selectivity of expression in cardiac tissue relative to other tissues, including skeletal muscle, brain and liver.

•

Cell specificity: We have also developed a proprietary combination of regulatory elements that enable more optimal and selective expression in one cell type in the heart compared to others. For example, we have discovered ways to optimize the robust co-expression of two protein-coding genes and one micro-RNA gene delivered within a single AAV in cardiac fibroblasts, as well as how to use specific micro-RNA binding sites to silence the translation of those same genes in both existing cardiomyocytes as well as newly created cardiomyocytes, which may support higher efficacy and provide a safety benefit and reduce the chance for off-target effects, respectively.

•

Tunable gene expression: We have also developed a spectrum of novel promoters to titer the expression of genes within cardiomyocytes, by combining various combinations of enhancer elements from different cardiomyocyte selective genes. These efforts have enabled us to achieve higher expression in certain disease models than what can be achieved with a standard cTnT promoter.

Drug Delivery

Delivery of drugs to the heart is widely considered to be an important challenge to successful translation of cardiac gene therapy and regenerative medicines into approved products. Delivery methods vary significantly in terms of degree of invasiveness, distribution of therapy around the heart, degree of therapy uptake into the heart,

technical difficulty of administration, and clinical relevance and experience. The diversity of programs in our current pipeline necessitates the use of different delivery methods. Therefore, we are actively exploring different routes of administration as well as different infusion- or injection-based catheters to support more targeted delivery and more efficient uptake of therapies based on viral vectors. We believe our discoveries in drug delivery can widen the therapeutic index of our product candidates by reducing the dose required for a therapeutic benefit.

For our gene therapy product candidates, including TN-201 and TN-401, we generally need broad distribution across the heart tissue that is more suited to infusion-based approaches. By contrast, for other gene therapy programs, we need more precise delivery into the heart tissue directly around a scar area of the LV in a way that is more suited to injection-based approaches. For example, to support our early-stage program focused on cardiac regeneration, we developed a novel transendocardial injection catheter for more precise delivery of therapeutic payloads around the scar area that is formed after heart attack, but in a way that is minimally invasive and would not require heart surgery.

We believe our capsid engineering efforts will be critical in supporting the successful clinical development of future product candidates and enabling those product candidates, if approved, to reach more patients.

Manufacturing

Our strategy is to have complete ownership of our process development, analytical development, manufacturing and quality control (QC). Maintaining internalized manufacturing increases our understanding of the attributes of our drug substance and drug product, enables continuous process improvement, consistency (quality and productivity) and supports manufacturing requirements for clinical development and commercialization. The resulting innovation and insights are expected to apply not only for rare populations, but also for more prevalent indications, and allows us to be a partner of choice in strategic drug development partnerships and with early-stage academic programs. Overall, the internalization of manufacturing efforts provides us with know-how that yields several advantages that allow us to be in a better position to support our future capacity expansion needs or swiftly transfer technology know-how to CDMOs to achieve sourcing for product candidates across multiple third parties for risk mitigation purposes.

•

Vector core:We have established vector production to support early research involving both parental and novel AAV capsids up to the 50L scale. We have also established the necessary process development expertise to support comparable product efficacy in both HEK293-based and Sf9/rBV-based manufacturing systems for both existing AAV serotypes as well as for novel capsids discovered from our capsid engineering efforts.

•

Manufacturing Technology Development Center (MTDC): Co-located with our research labs in the San Francisco Bay Area, we have established in-house operations at the 200L scale to support all non-clinical studies including those involving large animal models under Good Laboratory Practice (GLP) regulations. We rely on our MTDC for assay development and technology transfer to our dedicated cGMP facility. Our production at this scale has been at yields and with full/empty capsid ratios that compare favorably to industry standards.

•

Genetic Medicines Manufacturing Center (GMMC):Our GMMC is a dedicated cGMP facility for AAV drug product manufacturing that is strategically located in the San Francisco Bay Area. The facility operates at the 1000L scale to support all clinical development activities from first-in-human (FIH) clinical trials through to late-stage development, as well as initial commercialization, if regulatory approval is obtained. It uses a modular design that will support scale-out and/or scale-up of manufacturing capacity in response to evolving business needs.

Competition

The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on intellectual property. We believe our scientific know-how, core internal capabilities and experience provides us with competitive advantages. However, we face substantial competition from many different sources, including large and specialty pharmaceutical companies and biotechnology companies, academic research institutions and governmental agencies, and public and private research institutions. Any product candidate we develop and commercialize will have to compete with existing therapies, as well as therapies currently in development or that may be developed in the future.

Due to the depth and diversity of our pipeline, we may face competition from a variety of companies, including:

TN-201: We believe the principal competition for TN-201 will be programs that address the underlying genetic cause of MYBPC3-associated HCM. Based on publicly available data, we don’t believe any such treatments have received approval from a regulatory agency or reached clinical development. Notwithstanding, we believe BioMarin and DiNAQOR’s BMN-293 for treating the underlying cause of MYBPC3-associated HCM may initiate clinical development in the near term. We may also face competition from treatments for both nHCM and oHCM, including Bristol Myers Squibb’s myosin inhibitor Camzyos approved for oHCM. There are also several other programs in clinical development for HCM, including Cytokinetics’ Aficamten.

TN-301: We believe that the principal competition for TN-301 in HFpEF includes agents approved in the U.S. and/or Europe for the treatment of HFpEF, including Novartis’ Entresto and Eli Lilly and Boehringer Ingleheim’s SGLT2 inhibitor, Jardiance and Astra Zeneca’s SGLT2 inhibitor, Farxiga. While there are no approved HDAC6 inhibitors for cardiovascular indications, HFpEF clinical development is an area of robust investment and multiple additional agents for the treatment of HFpEF are in clinical development.

TN-401: We believe the principal competition for TN-401 will be programs that address the underlying genetic cause of PKP2-associated ARVC. Based on publicly available data, we don’t believe any such treatments have received approval from a regulatory agency. However, there are several programs in clinical development for treating the underlying cause of PKP2-associated ARVC, including Rocket Pharmaceutical’s RP-A601, Lexeo Therapeutics’ LX2020, and BioMarin’s BMN-365. We may also face competition from therapies and medical devices directed to treat the symptoms of ARVC.

For information regarding the risks related to competition, see “Risk Factors—Risks Related to the Discovery Development, Manufacturing and Commercialization of Our Product Candidates.”

Intellectual Property

Our success depends in part on our ability to obtain and maintain intellectual property protection for our product candidates, technology, manufacturing processes and know-how, to operate without infringing, misappropriating or otherwise violating the intellectual property or other proprietary rights of others and to prevent others from infringing, misappropriating or otherwise violating our intellectual property or other proprietary rights. To protect our intellectual property rights, we primarily rely on patent and trade secret laws, confidentiality procedures, and agreements, including employee disclosure and invention assignment agreements. Our policy is to seek to protect our proprietary position by, among other methods, pursuing patent applications in the U.S., European Union (EU) and other select jurisdictions related to our proprietary technology, inventions, improvements and product candidates that are important to our business. Our patent portfolio is intended to cover our product candidates and components thereof, their methods of use and processes for their manufacture, medical devices and systems for their administration, our proprietary reagents and assays and any other inventions that are commercially important to our business.

Each of our lead product candidates is covered by at least one or more issued U.S. patents, which are described below. We also have numerous pending patent applications, and will continue to file new patent applications, in the U.S., the EU and other select countries covering our lead product candidates, as well as our early-stage programs in preclinical development.Beyond these issued patents and pending patent applications, our owned and exclusively licensed patent portfolio also covers various aspects of our core capabilities, including our gene delivery expression cassettes and vectors, recombinant capsid proteins, gene editing technology, manufacturing processes and medical devices.

TN-201: With regard to TN-201, we own three issued U.S. patents covering a recombinant adeno-associated virus (rAAV) virion whose vector genome encodes MYBPC3 and methods of using the same for treating cardiomyopathy, one pending non-provisional U.S. patent application, and twenty-six pending foreign patent applications. Any U.S. or foreign patents issued from the pending patent applications are expected to expire in 2041, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. The issued U.S. patents and pending U.S. non-provisional patent applications are directed to various aspects of TN-201, including MYBPC3 gene expression cassettes, rAAV vectors, rAAV viral genomes and methods of using such compositions for therapeutic indications.

TN-301: With regard to TN-301, we own one issued U.S. patent, one allowed U.S. application, one pending non-provisional U.S. patent application and thirty pending foreign patent applications. Any U.S. or foreign patents issued from these pending patent applications are expected to expire in 2040, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. The pending patent applications cover TN-301 and various analogs. We also own two patent families that cover methods of treatment of various diseases and disorders with TN-301 and its analogs, with a total of three pending non-provisional U.S. patent applications and thirty-nine foreign patent applications. Any U.S. or foreign patents issued from the pending applications are expected to expire in 2042, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. We also own one patent family that covers additional HDAC6i compounds, with one pending non-provisional U.S. patent application and three pending foreign patent applications. Any U.S. or foreign patents issued from these pending patent applications are expected to expire in 2040, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account.

TN-401: With regard to TN-401, we own one issued U.S. patent, four pending U.S. non-provisional patent applications, one issued foreign patent, and twenty six foreign patent applications. Any U.S. or foreign patents issued from the pending patent applications are expected to expire by 2041, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees and without taking potential patent term extensions or adjustments into account. These patent applications are related to proprietary PKP2 gene expression vectors and methods of use. We own one pending PCT patent application and two foreign patent applications related to PKP2 therapeutic treatment methods. Any U.S. or foreign patents issued from national stage filings of this PCT patent application or the pending foreign patent applications are expected to expire in 2043, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. We own one pending PCT patent application and two foreign patent applications related to capsids for PKP2 therapy and methods of use. Any U.S. or foreign patents issued from national stage filings of this PCT patent application or the pending foreign patent applications are expected to expire in 2043, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. We own two pending U.S. provisional patent applications related to methods for modulating gene expression. Patents claiming priority to these U.S. provisional patent applications are expected to expire in 2044, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account. We own one pending non-provisional U.S. patent application related to methods for treating arrhythmogenic right ventricular cardiomyopathy. A U.S. patent issuing from this patent application is expected to expire in 2040, assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and without taking potential patent term extensions or adjustments into account.

Trade Secrets

In addition to our reliance on patent protection for our technology and product candidates, we also rely on trade secret protection of our confidential information and know-how relating to our proprietary technology, product platforms and product candidates. Through development of internal manufacturing capabilities for AAV-based gene vectors, we have secured proprietary know-how and trade secrets related to our most-advanced programs as well as vector technologies widely applicable to potential AAV therapies. However, trade secrets can be difficult to protect. We seek to protect our trade secrets, proprietary technology and processes, in part, by entering into confidentiality and invention assignment agreements with our employees, consultants, scientific advisors, contractors and other third parties. 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.

For information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing

We rely on a combination of our internal manufacturing capabilities as well as on external CDMOs for the manufacture of the drug substance and/or drug product of our portfolio programs and intend to continue to utilize this strategy as our programs progress through various stages of clinical development and eventually to commercialization, if approved.

AAV Manufacturing

Supported by in-licensed and internally developed manufacturing technologies, we have fully integrated and internalized AAV manufacturing capabilities to support product candidates emerging from our product pipeline that utilize AAV for delivery. In addition, we have established a Quality Management System to oversee our GxP operations, including cGMP, GLP and Good Clinical Practice (GCP).

Our Manufacturing Technology Development Center, or MTDC, includes a Vector Core, upstream and downstream process development labs, as well as assay development and QC capabilities, and is co-located with our research labs in the San Francisco Bay Area. The MTDC does non-GMP work and operates at the shake flask, 50L, and 200L scales to support all non-clinical studies including, IND-enabling efficacy, pharmacology, toxicology, and biodistribution studies involving both small and large animal models. We also rely on the MTDC for technology transfer of our proprietary processes to our GMMC, a dedicated cGMP facility for AAV drug substance and drug product manufacturing strategically located in the San Francisco Bay Area.

Our Genetic Medicines Manufacturing Center, or GMMC, facility has the ability to operate at the 200L and 1000L scales to support clinical development activities from FIH clinical trials through to late-stage development, as well as initial commercialization, if regulatory approval is obtained. We utilized the GMMC to produce drug product for our FIH clinical trials for both TN-201 and TN-401.We customized approximately half of the 94,000 square foot GMMC facility using a modular design that could support our ability to scale-out and/or scale-up of manufacturing capacity in response to evolving needs, including future potential clinical and commercial production needs.

In addition to our internal cGMP manufacturing capabilities, we have also negotiated and entered into master service agreements with multiple CDMOs for additional AAV manufacturing and filling capacity and related risk mitigation.Additionally, we will rely on third parties for certain manufacturing of ancillary materials and release assays, for which we have already secured or intend to secure dual-sourced capacity.

Small Molecule Manufacturing

To optimize our use of resources, we work with CDMOs for our small molecule programs.

Government Regulation

Government authorities in the U.S. at the federal, state and local level and in other countries regulate, among other things, the research, development, testing, manufacture, QC, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of biologic and small molecule therapeutic products. Generally, before a new therapeutic product can be marketed, considerable data demonstrating a biologic candidate’s quality, safety, purity and potency, or a small molecule candidate’s quality, safety and efficacy, must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority. For biologic candidates, potency is similar to efficacy and is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.

U.S. Biologic and Small Molecule Drug Product Development

In the U.S., the FDA regulates small molecule and biologic therapeutic products under the Food, Drug and Cosmetic Act (FDCA) and the Public Health Service Act (PHSA). Biopharmaceuticals, including both small molecule and biologic products, also are subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

Biologics must be licensed by the FDA through a biologics license application (BLA), and small molecule products must be approved by the FDA through a new drug application (NDA), before they may be legally marketed in the United States. The process generally involves the following:

•

Completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP requirements;

•

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

•

Approval by an independent institutional review board (IRB), or ethics committee at each clinical trial site before each trial may be initiated;

•

Performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, GCP requirements and other clinical trial-related regulations to establish the safety and potency or efficacy of the investigational product for each proposed indication;

•

Submission to the FDA of a BLA or NDA;

•

A determination by the FDA within 60 days of its receipt of a BLA or NDA to accept the filing for review;

•

Satisfactory completion of a FDA pre-approval inspection of the manufacturing facility or facilities where biologic or small molecule product will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the biologic’s identity, strength, purity, potency, and QCs, or the small molecule product’s identity, chemistry, and QCs;

•

Potential FDA audit of the preclinical study and/or clinical trial sites that generated the data in support of the BLA or NDA;

•

Satisfactory completion of other studies required by the FDA, including immunogenicity, carcinogenicity, genotoxicity, and stability studies;

•

FDA review and approval of the BLA or NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the biologic or small molecule therapeutic in the United States; and

•

Compliance with any post-approval requirements, including the potential requirement to implement risk evaluation and mitigation strategies (REMS), and the potential requirement to conduct post-approval studies.

The data required to support a BLA or NDA are generated in two distinct developmental stages: preclinical and clinical. The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for any future product candidates will be granted on a timely basis, or at all.

Preclinical Studies and IND

Preclinical studies include laboratory evaluation of product biochemistry, formulation and stability, as well as in vitro and animal studies to assess the potential for toxicity and to establish a rationale for therapeutic use for supporting subsequent clinical testing. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, among other things, to the FDA as part of an IND. An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before human clinical trials may begin. Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

Clinical Trials

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all

research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of a BLA or NDA. The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under an IND if the trial was conducted in accordance with GCP requirements and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials in the United States generally are conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap.

•

Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, tolerability and safety of the drug.

•

Phase 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified and a preliminary evaluation of efficacy is conducted.

•

Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments. The duration of treatment is often extended to mimic the actual use of a product during marketing.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of a BLA or NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected adverse events, findings from other studies suggesting a significant risk to humans exposed to the investigational product, findings from animal or in vitro testing that suggest a significant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk or non-compliance with GCP requirements. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the investigational product has been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether a trial may move forward at designated check-points based on access to certain data from the trial. Concurrent with clinical trials, companies usually complete

additional animal studies and also must develop additional information about the biochemical and physical characteristics of the investigational product as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, companies must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidates do not undergo unacceptable deterioration over their shelf life.

NDA and BLA Review Process

Following completion of the clinical trials, data is analyzed to assess whether the investigational product is safe and effective for the proposed indicated use or uses. The results of preclinical studies and clinical trials are then submitted to the FDA as part of a BLA for a biologic product or an NDA for a small molecule drug product, along with proposed labeling, biochemistry and manufacturing information to ensure product quality, identity, purity and other relevant data. In short, the BLA or NDA is a request for approval to market the biologic or drug product for one or more specified indications and must contain proof of safety, purity and potency for a biologic, or safety and efficacy for a small molecule drug product. The application may include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA. FDA approval of a BLA or NDA must be obtained before the product may be marketed in the United States.

Under the Prescription Drug User Fee Act (PDUFA), as amended, each BLA or NDA must be accompanied by a user fee. FDA adjusts the PDUFA user fees on an annual basis. According to the FDA’s FY 2024 fee schedule, effective through September 30, 2024, the user fee for an application requiring clinical data, such as a BLA or NDA, is approximately $4 million. PDUFA also imposes an annual program fee for each marketed human prescription drug product ($416,734 in 2024) and an annual establishment fee on facilities used to manufacture prescription biologics or small molecular drug products. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on BLAs or NDA for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA reviews all submitted BLAs and NDAs before it accepts them for filing and may request additional information rather than accepting the BLA or NDA for filing. The FDA must make a decision on accepting a BLA or NDA for filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth review of the BLA or NDA. Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months, from the filing date, in which to complete its initial review of an original BLA or NDA and respond to the applicant, and six months from the filing date of an original BLA or NDA designated for priority review. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs or NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Before approving a BLA or NDA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. The FDA also may audit data from clinical trials to ensure compliance with GCP requirements. Additionally, the FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes physicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when making decisions on approval. The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process. After the FDA evaluates a BLA or NDA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug product with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the BLA or NDA identified by the FDA. The Complete Response Letter may require additional clinical data, additional pivotal Phase

3 clinical trial(s) and/ or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the BLA or NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the BLA or NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

Orphan Drugs

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the product available in the United States for this type of disease or condition will be recovered from sales of the product.

For biologic or small molecule drug products, an orphan drug designation must be requested before submitting a BLA or NDA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a major contribution to patient care or in instances of drug supply issues. However, competitors may receive approval of either a different product for the same indication or the same product for a different indication but that could be used off-label in the orphan indication. Orphan drug exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or if a product candidate is determined to be contained within the scope of the competitor’s product for the same indication or disease. If one of our products designated as an orphan drug receives marketing approval for an indication broader than the indication for which it is designated, it may not be entitled to orphan drug exclusivity. Orphan drug status in the European Union has similar, but not identical, requirements and benefits.

In Catalyst Pharms., Inc. v. Becerra, 14 F.4th 1299 (11th Cir. 2021), the court disagreed with the FDA’s longstanding position that the orphan drug exclusivity only applies to the approved use or indication within an eligible disease. In particular, the circuit court held that the orphan-drug exclusivity for Catalyst’s drug blocked FDA’s approval of another drug for all uses or indications within the same orphan-designated disease, or Lambert-Eaton myasthenic syndrome (LEMS), even though Catalyst’s drug was approved at that time only for use in the treatment of LEMS in adults. Accordingly, the court ordered the FDA to set aside the approval of a drug indicated for LEMS in children. This decision created uncertainty in the application of the orphan drug exclusivity. On January 24, 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst, the FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved. It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

Expedited Development and Review Programs

The FDA has a fast-track program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria. Specifically, new drug products are eligible for fast-track designation if they are intended to treat a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast track designation applies to both the product and the specific indication for which it is being studied. The sponsor can request the FDA to designate the product for fast-track status any time before receiving a BLA or NDA approval, but ideally no later than the pre-BLA or pre-NDA meeting.

Any product submitted to the FDA for marketing, including under a fast-track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. Any product is eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies.

A product may also be eligible for accelerated approval, if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM), which is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require that a sponsor of a drug product receiving accelerated approval to perform adequate and well-controlled post-marketing clinical trials. If the FDA concludes that a biologic or small molecule drug product shown to be potent or effective for the proposed indication can be safely used only if distribution or use is restricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the product. In some cases, FDA may limit the scope of the indication.

Additionally, a drug product may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination with one or more other drug products, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints. The benefits of breakthrough therapy designation include the same benefits as fast-track designation, plus intensive guidance from the FDA to ensure an efficient drug development program. Fast track designation, priority review, accelerated approval and breakthrough therapy designation do not change the standards for approval, but may expedite the development or approval process. Depending on other factors that impact clinical trial timelines and development, such as our ability to identify and onboard clinical sites and rates of study participant enrollment and drop-out, we may not realize all the benefits of these expedited or accelerated review programs. For accelerated approval, the FDA has the authority to specify conditions for post approval study requirements and can withdraw a product on an expedited basis for noncompliance with post-approval requirements.

Abbreviated Licensure Pathway of Biological Products as Biosimilars or Interchangeable Biosimilars

The Patient Protection and Affordable Care Act (Affordable Care Act or ACA), signed into law in 2010, includes the Biologics Price Competition and Innovation Act of 2009 (BPCIA), which created an abbreviated approval pathway for biological products shown to be highly similar to an FDA-licensed reference biological product. The BPCIA attempts to minimize duplicative testing, and thereby lower development costs and increase patient access to affordable treatments. An application for licensure of a biosimilar product must include information demonstrating biosimilarity based upon the following, unless the FDA determines otherwise:

•

Analytical studies demonstrating that the proposed biosimilar product is highly similar to the approved product notwithstanding minor differences in clinically inactive components;

•

Animal studies (including the assessment of toxicity); and

•

A clinical trial or trials (including the assessment of immunogenicity and pharmacokinetic or pharmacodynamic) sufficient to demonstrate safety, purity and potency in one or more conditions for which the reference product is licensed and intended to be used.

In addition, an application must include information demonstrating that:

•

The proposed biosimilar product and reference product utilize the same mechanism of action for the condition(s) of use prescribed, recommended or suggested in the proposed labeling, but only to the extent the mechanism(s) of action are known for the reference product;

•

The condition or conditions of use prescribed, recommended or suggested in the labeling for the proposed biosimilar product have been previously approved for the reference product;

•

The route of administration, the dosage form and the strength of the proposed biosimilar product are the same as those for the reference product; and

•

The facility in which the biological product is manufactured, processed, packed or held meets standards designed to assure that the biological product continues to be safe, pure and potent.

Biosimilarity means that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product. In addition, the law provides for a designation of “interchangeability” between the reference and biosimilar products, whereby the biosimilar may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. The higher standard of interchangeability must be demonstrated by information sufficient to show that:

•

The proposed product is biosimilar to the reference product;

•

The proposed product is expected to produce the same clinical result as the reference product in any given patient; and

•

For a product that is administered more than once to an individual, the risk to the patient in terms of safety or diminished efficacy of alternating or switching between the biosimilar and the reference product is no greater than the risk of using the reference product without such alternation or switch.

FDA approval is required before a biosimilar may be marketed in the United States. However, complexities associated with the large and intricate structures of biological products and the process by which such products are manufactured pose significant hurdles to the FDA’s implementation of the law that are still being worked out by the FDA. For example, the FDA has discretion over the kind and amount of scientific evidence—laboratory, preclinical and/or clinical—required to demonstrate biosimilarity to a licensed biological product.

The FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity and recommends that sponsors use a stepwise approach in the development of their biosimilar products. Biosimilar product applications thus may not be required to duplicate the entirety of preclinical and clinical testing used to establish the underlying safety and effectiveness of the reference product. However, the FDA may refuse to approve a biosimilar application if there is insufficient information to show that the active ingredients are the same or to demonstrate that any impurities or differences in active ingredients do not affect the safety, purity or potency of the biosimilar product. In addition, as with BLAs, biosimilar product applications will not be approved unless the product is manufactured in facilities designed to assure and preserve the biological product’s safety, purity and potency.

The submission of a biosimilar application does not guarantee that the FDA will accept the application for filing and review, as the FDA may refuse to accept applications that it finds are insufficiently complete. The FDA will treat a biosimilar application or supplement as incomplete if, among other reasons, any applicable user fees assessed under the Biosimilar User Fee Act of 2012 have not been paid. In addition, the FDA may accept an application for filing but deny approval on the basis that the sponsor has not demonstrated biosimilarity, in which case the sponsor may choose to conduct further analytical, preclinical or clinical studies and submit a BLA for licensure as a new biological product.

The timing of final FDA approval of a biosimilar for commercial distribution depends on a variety of factors, including whether the manufacturer of the branded product is entitled to one or more statutory exclusivity periods, during which time the FDA is prohibited from approving any products that are biosimilar to the branded product. The FDA cannot approve a biosimilar application for twelve years from the date of first licensure of the reference product.

Additionally, a biosimilar product sponsor may not submit an application for four years from the date of first licensure of the reference product. A reference product may also be entitled to exclusivity under other statutory provisions. For example, a reference product designated for a rare disease or condition (an orphan drug) may be entitled to seven years of exclusivity, in which case no product that is biosimilar to the reference product may be approved until either the end of the twelve-year period provided under the biosimilarity statute or the end of the seven-year orphan drug exclusivity period, whichever occurs later. In certain circumstances, a regulatory exclusivity period can extend beyond the life of a patent, and thus block biosimilarity applications from being approved on or after the patent expiration date. In addition, the FDA may under certain circumstances extend the exclusivity period for the reference product by an additional six months if the FDA requests, and the manufacturer undertakes, studies on the effect of its product in children, a so-called pediatric extension.

The first biological product determined to be interchangeable with a branded product for any condition of use is also entitled to a period of exclusivity, during which time the FDA may not determine that another product is

interchangeable with the reference product for any condition of use. This exclusivity period extends until the earlier of: one year after the first commercial marketing of the first interchangeable product; 18 months after resolution of a patent infringement suit against the applicant that submitted the application for the first interchangeable product, based on a final court decision regarding all of the patents in the litigation or dismissal of the litigation with or without prejudice; 42 months after approval of the first interchangeable product, if a patent infringement suit against the applicant that submitted the application for the first interchangeable product is still ongoing; or 18 months after approval of the first interchangeable product if the applicant that submitted the application for the first interchangeable product has not been sued.

Abbreviated NDA Pathway for Generic Drug Products

The Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as “the Hatch-Waxman Act,” established abbreviated FDA approval procedures for drugs that are shown to be bioequivalent to drugs previously approved by the FDA through its NDA process, which are commonly referred to as the “innovator” or “reference” drugs. Approval to market and to distribute these bioequivalent drugs is obtained by filing an abbreviated NDA (ANDA) with the FDA. An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredients (API), drug product formulation, specifications, stability, analytical methods, manufacturing process validation data, QC procedures and bioequivalence. Rather than demonstrating safety and effectiveness, an ANDA applicant must demonstrate that its product is bioequivalent to an approved reference drug. In certain situations, an applicant may submit an ANDA for a product with a strength or dosage form that differs from a reference drug based upon FDA approval of an ANDA Suitability Petition. The FDA will approve an ANDA Suitability Petition if it finds that the product does not raise questions of safety and efficacy requiring new clinical data. ANDAs generally cannot be submitted for products that are not bioequivalent to the referenced drug or that are labeled for a use that is not approved for the reference drug. Applicants seeking to market such products can submit an NDA under Section 505(b)(2) of the FDCA with supportive data from clinical trials.

Post-Approval Requirements

Following approval of a new product, the manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and record-keeping requirements, requirements to report adverse experiences and comply with promotion and advertising requirements, which include restrictions on promoting drugs for unapproved uses or patient populations, known as “off-label use,” and limitations on industry-sponsored scientific and educational activities. Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such uses. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use. Further, if there are any modifications to the drug product, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new application or supplement, which may require the development of additional data or preclinical studies and clinical trials.

The FDA may also place other conditions on approvals including the requirement for REMS, to assure the safe use of the product. A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products. Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

•

Restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market, or product recalls;

•

Warning letters, or holds on post-approval clinical studies;

•

Refusal of the FDA to approve pending applications or supplements to approved applications;

•

Applications, or suspension or revocation of product license approvals;

•

Product seizure or detention, or refusal to permit the import or export of products; or

•

Injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Drugs and biologics may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

FDA Regulation of Combination Biologic-Medical Device Products

Certain products may be comprised of components, such as biologic components and device components, that would normally be regulated under different types of regulatory authorities and frequently by different Centers at the FDA. These products are known as combination products. Under the FDCA and its implementing regulations, the FDA is charged with assigning a Center with primary jurisdiction, or a lead Center, for review of a combination product. The designation of a lead Center generally eliminates the need to receive approvals from more than one FDA component for combination products, although it does not preclude consultations by the lead Center with other components of the FDA. The determination of which Center will be the lead Center is based on the “primary mode of action” of the combination product. Thus, if the primary mode of action of a biologic-device combination product candidate is attributable to the biologic product candidate, the FDA Center responsible for premarket review of the drug product would have primary jurisdiction for the combination product. The FDA has also established an Office of Combination Products to address issues surrounding combination products and provide more certainty to the regulatory review process. That Office serves as a focal point for combination product issues for agency reviewers and industry. It is also responsible for developing guidance and regulations to clarify the regulation of combination products, and for assignment of the FDA Center that has primary jurisdiction for review of combination products where the jurisdiction is unclear or in dispute.

A combination product with a biologic product candidate as the primary mode of action generally would be reviewed and approved pursuant to the biologic approval processes under the FDCA. In reviewing the BLA application for such a product, however, FDA reviewers in the Center for Biologics Evaluation and Research could consult with their counterparts in the device center to ensure that the device component of the combination product meet applicable requirements regarding safety, effectiveness, durability and performance. In addition, under FDA regulations, combination products are subject to cGMP requirements applicable to both biologics and devices, including the Quality System Regulations (QSR) applicable to medical devices. Further, in February 2024, the FDA issued a final rule replacing the QSR with the Quality Management System Regulation (QMSR) which incorporates by reference the quality management system requirements of ISO 13485:2016. The FDA has stated that the standards contained in ISO 13485:216 are substantially similar to those set forth in the existing QSR. This final rule does not go into effect until February 2026.

We may develop one or more of our biologic product candidates in combination with a novel delivery medical device, such as an injection catheter device for more precise delivery of a biologic product candidate. Regulatory review of such combination product candidate will increase the timing, cost, and the complexity of the FDA review and approval process, and subject us to additional regulations and exposure to liability. Pending discussion with the FDA, if the medical device is considered a significant risk device under the FDA’s Investigational Device Exemption (IDE) regulations, then we may be required to comply with the IDE regulations for clinical studies in addition to the IND regulations and may be required to submit both an IDE and an IND before commencing clinical testing of the combination product. We cannot provide any assurance regarding how FDA will regulate our combination product, or if we will be successful in obtaining approval for any combination product.

510(k) clearance process

To obtain 510(k) clearance, a pre-market notification is submitted to the FDA demonstrating that the proposed device is substantially equivalent to a previously cleared 510(k) device or a device that was in commercial distribution before May 28, 1976, for which the FDA has not yet required the submission of a Premarket Approval

Application (PMA). The FDA’s 510(k) clearance process may take three to twelve months from the date the application is submitted and filed with the FDA, but may take longer if FDA requests additional information, among other reasons. In some cases, the FDA may require clinical data to support substantial equivalence. In reviewing a pre-market notification submission, the FDA may request additional information, which may significantly prolong the review process. Notwithstanding compliance with all these requirements, clearance is never assured.

After a device receives 510(k) clearance, any subsequent modification of the device that could significantly affect its safety or effectiveness, or that would constitute a major change in its intended use, will require a new 510(k) clearance or require a PMA. In addition, the FDA may make substantial changes to industry requirements, including which devices are eligible for 510(k) clearance, which may significantly affect the process.

De novo classification process

If a new medical device does not qualify for the 510(k) premarket notification process because no predicate device to which it is substantially equivalent can be identified, the device is automatically classified into Class III. The Food and Drug Administration Modernization Act of 1997 established a different route to market for low to moderate risk medical devices that are automatically placed into Class III due to the absence of a predicate device, called the “Request for Evaluation of Automatic Class III Designation,” or the de novo classification process. This process allows a manufacturer whose novel device is automatically classified into Class III to request down-classification of its medical device into Class I or Class II on the basis that the device presents low or moderate risk, rather than requiring the submission and approval of a PMA. If the manufacturer seeks reclassification into Class II, the manufacturer must include a draft proposal for special controls that are necessary to provide a reasonable assurance of the safety and effectiveness of the medical device. The FDA may reject the reclassification petition if it identifies a legally marketed predicate device that would be appropriate for a 510(k) or determines that the device is not low to moderate risk and requires PMA or that general controls would be inadequate to control the risks and special controls cannot be developed. Obtaining FDA marketing authorization, de novo down-classification, or approval for medical devices is expensive and uncertain, and may take several years, and generally requires significant scientific and clinical data.

PMA approval process

The PMA process, including the gathering of clinical and nonclinical data and the submission to and review by the FDA, can take several years or longer. The applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness, including information about the device and its components regarding, among other things, device design, manufacturing, and labeling. PMA applications are subject to an application fee. In addition, PMAs for medical devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought. As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the QSR, or QMSR when it comes into effect, which imposes extensive testing, control, documentation, and other Quality Assurance and GMP requirements.

Other U.S. Regulatory Matters

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, including the Centers for Medicare & Medicaid Services (CMS), other divisions of the Department of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, and state and local governments.

For example, in the United States, sales, marketing and scientific and educational programs must also comply with state and federal fraud and abuse laws. These laws include the federal Anti-Kickback Statute, which makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf), to knowingly and willfully solicit, receive, offer or pay any remuneration that is intended to induce or reward referrals, including the purchase, recommendation, order or prescription of a particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid. Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties and exclusion from participation in federal healthcare programs. Moreover, the ACA provides that the government may assert that a claim including items or services

resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act.

Pricing and rebate programs must comply with the Medicaid rebate requirements of the U.S. Omnibus Budget Reconciliation Act of 1990 and more recent requirements in the ACA. If products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply. Products must meet applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act. Manufacturing, sales, promotion and other activities also are potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of biologic and pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The failure to comply with any of these laws or regulatory requirements subjects firms to possible legal or regulatory action, including fines, penalties, injunctions, requests for recall, and exclusion from participating in government programs. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. Changes in regulations, statutes or the interpretation of existing regulations could impact our business and increase our exposure to additional liabilities. For more information, see “Risk Factors— Risks Related to Regulatory Approval and Other Legal Compliance Matters.”

U.S. Data Privacy and Security Laws

In the United States, a broad variety of laws, rules, regulations and standards relating to privacy, data protection and information security may apply to our activities, such as state data breach notification laws, state personal data privacy laws (for example, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act (CCPA)), state health information privacy laws, and federal and state consumer protection laws. The CCPA requires covered businesses that process personal information of California residents to disclose their data collection, use, sharing and retention practices, provides California residents with data privacy rights (including the ability to opt out of certain disclosures of personal information including for certain advertising purposes), imposes operational requirements for covered businesses, provides for significant civil penalties for violations as well as a private right of action for certain data breaches and statutory damages (that is expected to increase data breach class action litigation and result in significant exposure to costly legal judgements and settlements). Aspects of the CCPA and its interpretation and enforcement remain uncertain. Although there are limited exemptions for clinical trial data under the CCPA, the CCPA and other similar laws could impact our business activities, depending on their interpretation. Other states have enacted laws similar to the CCPA that are either in operation or slated to go into operation over the next three years, and other state legislatures are currently considering, and may pass, their own comprehensive data privacy and security laws, with potentially greater penalties and more rigorous compliance requirements, and laws in all 50 states require businesses to provide notice to customers whose personal data has been disclosed as a result of a data breach. We will continue to monitor and assess the impact of these state laws, which may impose substantial penalties for violations, impose significant costs for investigation and compliance, allow private class-action litigation and carry significant potential liability for our business. For more information, see “Risk Factors— Risks Related to Regulatory Approval and Other Legal Compliance Matters.” We are subject to stringent laws, rules, regulations, policies, industry standards and contractual obligations regarding data privacy and security and may be subject to additional laws and regulations in jurisdictions into which we expand. Many of these laws and regulations are subject to change and reinterpretation and could result in claims, changes to our business practices, monetary penalties, increased cost of operations or other harm to our business.

U.S. Patent-Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of FDA approval of any future product candidates, some of our U.S. patents may be eligible for limited patent term extension under the Hatch-Waxman Act. The Hatch-Waxman Act permits restoration of the patent term of up to five years as compensation for patent term lost during product development and FDA regulatory review process. Patent-term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent-term restoration period is generally one-half the time between the effective date of an IND and the submission date of a BLA or

NDA plus the time between the submission date of a BLA or NDA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The United States Patent and Trademark Office (USPTO), in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA or NDA. However, there can be no assurance that our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustments to the terms of any patents we may own or in-license in the future.

TNYA US Equity

TNYA · 10-K · period ended 2023-12-31

Item 1. Business.

TNYA US Equity☆

TNYA · 10-K · period ended 2023-12-31

Item 1. Business.

TNYA US Equity