What changed in this filing

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Item 1. Business

2023-03-31 compared with 2022-03-29 · 69 added, 64 removed, 191 unchanged (41% of the section changed)

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Business Strategy

Our principal business objective is to identify, develop, and commercialize late-stage pharmaceutical therapeutic products for serious cardiovascular and pulmonary diseases with high unmet medical need.

Following a transformation of the Company in 2021 at the director and executive level, completion of the integration of a biotechnology company focused on PAH, the publication of the results of our HELP study (as described below), our Phase II TNX-103 (oral levosimendan) study, and formulation progress on a novel oral imatinib mesylate tablet, Tenax Therapeutics is committed to remaining operationally-efficient, scientifically-directed, and patient-centered in our effort to bring to market two potentially life-changing therapies to patients with two devastating forms of pulmonary hypertension.

The Company believes that through our proprietary formulation advances, advanced clinical trial design, and growing patent estate, it can bring these product candidates to an approved and commercial state.

The key elements of our business strategy are outlined below.

Having carefully considered alternatives within the ongoing strategic process announced in September 2022, and having raised capital to fund the Company through to the first quarter of 2024, the Company has recently elected to prioritize the Phase 3 testing of levosimendan, ahead of imatinib, with plans to commence a levosimendan Phase 3 study in 2023.

Supporting this strategic decision is a U.S.

Patent issued in March 2023, covering the use of IV levosimendan in patients with PH-HFpEF.

This patent is the second levosimendan patent granted to Tenax since the start of 2022, and Tenax believes it provides strong precedent for the ongoing review of a third patent which might be granted in 2023 or 2024.

This prioritization of the Phase 3 testing of levosimendan places the start of a Phase 3 imatinib trial likely outside the 2023 timeframe, pending fundraising to support that trial, as well as other strategic considerations.

The Company took steps to reduce its monthly operating expenses and conserve cash, as it commenced exploring strategic alternatives.

The Company has cancelled substantially all of its non-essential operating expenses such as consulting, its office lease, and dues and subscriptions and office supplies associated with that leased office.

Prior to announcing the strategic process, our principal business objective has been to identify, develop, and commercialize late-stage pharmaceutical therapeutic products for serious cardiovascular and pulmonary diseases with high unmet medical need.

The Company has been developing TNX-103 (oral levosimendan) for the treatment of Pulmonary Hypertension with Heart Failure with Preserved Ejection Fraction (PH-HFpEF) and TNX-201 (modified release imatinib) for the treatment of pulmonary arterial hypertension (PAH).

Both TNX-103 and TNX-201 are Phase 3-ready assets, each with the potential to meaningfully impact the quality and longevity of patient lives.

Pending the outcome of our strategic process, the key elements of our long-term business strategy are outlined below.

Efficiently conduct clinical development to establish clinical proof of principle in new indications, refine formulation, and commence Phase 3 testing of our current product candidates .

Levosimendan and imatinib have been approved and prescribed globally for more than 20 years, but we believe their mechanisms of action have not been fully exploited, despite promising evidence they may significantly improve the lives of patients with pulmonary hypertension.

Levosimendan and imatinib have been approved and prescribed around the world for more than 20 years, but we believe their mechanisms of action have not been fully exploited, despite promising evidence they may significantly improve the lives of patients with pulmonary hypertension.

We are conducting clinical development with the intent to establish proof of beneficial activity in cardiopulmonary diseases in which these therapeutics would be expected to have benefit for patients with diseases for which either no pharmaceutical therapies are approved at all, or in the case of PAH, where numerous expensive therapies generally offer a modest reduction of symptoms.

Our focus is primarily on designing and executing formulation improvements, protecting these innovations with patents and other forms of exclusivity, and employing innovative clinical trial science to establish a robust foundation for subsequent development, product approval, and commercialization.

We intend to submit marketing authorization applications following a single Phase 3 trial for each product.

We intend to submit marketing authorization applications following either one or two Phase 3 trials of levosimendan and, when appropriate, a single Phase 3 trial of imatinib.

Our trials are designed to incorporate and reflect advanced clinical trial design science and the regulatory and advisory experience of our team.

We intend to continue partnering with innovative companies, renowned medical and regulatory experts, and premier clinical testing organizations to help expedite development, and continue expanding into complementary areas when opportunities arise through our development, research, and discoveries.

We also intend to continue outsourcing to a limited number of premier clinical trial testing organizations, and seeking the advice of world-renowned biostatisticians, medical experts, and formulation and regulatory experts, in the design and execution of our research.

We intend to continue partnering with innovative companies, renowned biostatisticians and trialists, medical leaders, formulation and regulatory experts, and premier clinical testing organizations to help expedite development, and continue expanding into complementary areas when opportunities arise through our development, research, and discoveries.

We also intend to continue outsourcing when designing and executing our research.

Efficiently explore new high-potential therapeutic applications, in particular where expedited regulatory pathways are available, leveraging third-party research collaborations and our results from related areas.

Levosimendan has shown promise in multiple disease areas in its two decades of use following its approval.

Our own Phase 2 extension protocol research has demonstrated that a formerly under-appreciated mechanism of action of levosimendan, its property of relaxing the venous circulation, brings about a durable improvement in exercise capacity and quality of life, as well as other clinical assessments, in patients with heart failure with preserved ejection fraction and associated pulmonary hypertension (PH-HFpEF).

Levosimendan has shown promise in multiple disease areas in the two decades following its approval.

Our own Phase 2 study and open-label extension has demonstrated that a formerly under-appreciated mechanism of action of levosimendan, its property of relaxing the venous circulation, brings about durable improvements in exercise capacity and quality of life, as well as other clinical assessments, in patients with heart failure with preserved ejection fraction and associated pulmonary hypertension (PH-HFpEF).

We believe this patient population today has no pharmaceutical therapies available and we are committed to exploring potential clinical indications where our therapies may achieve best-in-class profile, and where we can address significant unmet medical needs.

We believe these factors will support approval by the United States Food and Drug Administration, or FDA, of these product candidates based on positive data from a single, rather than two, pivotal Phase 3 trials.

Through our agreement with our licensor, Orion Corporation, or Orion, the originator of levosimendan for acute decompensated heart failure, we have access to a library of ongoing and completed trials and research projects, including certain documentation, which we believe, in combination with positive Phase 3 data that we hope to generate in at least one indication, will support FDA approval of TNX-103.

We believe these factors will support approval by the United States Food and Drug Administration (the “FDA”) of these product candidates based on positive Phase 3 data.

Through our agreement with our licensor, Orion Corporation (“Orion”), the originator of levosimendan for acute decompensated heart failure, we have access to a library of ongoing and completed trials and research projects, including certain documentation, which we believe, in combination with positive Phase 3 data we hope to generate in at least one indication, will support FDA approval of levosimendan.

Likewise, the regulatory pathway for approval of imatinib for the treatment of PAH, as formulated by Tenax Therapeutics at the dose shown to be effective in a prior Phase 3 trial conducted by Novartis, allows Tenax to build on the dossier of research results already reviewed by the FDA.

In order to achieve our objectives of developing these medicines for new groups of patients, we have established collaborative research relationships with investigators from leading research and clinical institutions, and our strategic partners.

These collaborative relationships have enabled us to cost-effectively explore where our product candidates may have therapeutic relevance, gain the advice and support of key opinion leaders in medicine and clinical trial science, and invest in development efforts to exploit opportunities to advance beyond current clinical care.

These collaborative relationships have enabled us to explore where our product candidates may have therapeutic relevance, gain the advice and support of key opinion leaders in medicine and clinical trial science, and invest in development efforts to exploit opportunities to advance beyond current clinical care.

Additionally, we believe we will be able to leverage clinical safety data and preclinical results from some programs to support accelerated clinical development efforts in other areas, saving substantial development time and resources compared to traditional drug development.

Continue to expand our intellectual property portfolio .

Our intellectual property, and the confidentiality of all our company information, is important to our business and we take significant steps to protect its value.

We have ongoing research and development efforts, both through internal activities and through collaborative research activities with others, including an extension protocol to the Phase 2 TNX-103 trial referenced above, which aim to develop new intellectual property and enable us to file patent applications that cover new applications of our existing technologies, alone or in combination with existing therapies, as well as other product candidates.

Our intellectual property, and the confidentiality of all our Company information, is important to our business and we take significant steps to help protect its value.

Our research and development efforts, both through internal activities and through collaborative research activities with others, aim to develop new intellectual property and enable us to file patent applications that cover new applications of our existing technologies, alone or in combination with existing therapies, as well as other product candidates.

We received in 2022 a patent covering the subcutaneous administration of levosimendan (TNX-102) in humans for any medical condition, through 2039.

At present, we have three patents pending, with some decisions expected as early as late 2022.

On March 21, 2023, we received our second patent for this product, covering the IV formulation of levosimendan (TENX-101) tested in the Phase II HELP trial in patients with PH-HFpEF.

At present, we have two patents pending, with additional decisions expected in 2023.

Enter into licensing or product co-development arrangements .

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Our Current Programs

TNX-103 and TNX-102 (levosimendan) Background

TNX-101 (IV), TNX-102 (subcutaneous) and TNX-103 (oral) ( (levosimendan) Background

Levosimendan was discovered and developed by Orion.

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Several studies have demonstrated that levosimendan protects the heart and improves tissue perfusion while minimizing tissue damage during cardiac surgery.

In 2013, we acquired certain assets of Phyxius Pharma, Inc., or Phyxius, including its North American rights to develop and commercialize intravenous levosimendan for any indication in the United States and Canada.

In 2013, we acquired certain assets of Phyxius Pharma, Inc.

(“Phyxius”), including its North American rights to develop and commercialize intravenous levosimendan for any indication in the United States and Canada.

The license was subsequently amended in 2020 to include the rights to develop and commercialize oral and subcutaneous formulations of levosimendan.

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In acute decompensated heart failure patients, levosimendan has been shown to significantly improve patients’ symptoms as well as acute hemodynamic measurements such as increased cardiac output, reduced preload and reduced afterload.

TNX-103 and TNX-102 (levosimendan) Development for Pulmonary Hypertension Patients

In 2020, we completed a Phase 2 clinical trial of intravenous levosimendan in North America for the treatment of patients with pulmonary hypertension associated with heart failure with PH-HFpEF, a disease defined hemodynamically by a mean pulmonary artery pressure, or mPAP, ≥25 mmHg, and a pulmonary capillary wedge pressure, or PCWP, >15 mmHg.

TNX-101 (IV), TNX-102 (subcutaneous) and TNX-103 (oral) (levosimendan) Development for Pulmonary Hypertension Patients

In 2020, we completed a Phase 2 clinical trial of intravenous levosimendan in North America for the treatment of patients with pulmonary hypertension associated with heart failure with PH-HFpEF, a disease defined hemodynamically by a mean pulmonary artery pressure (“mPAP”) of ≥25 mmHg, and a pulmonary capillary wedge pressure “(PCWP”) of >15 mmHg.

Pulmonary hypertension in these patients is believed to arise from a passive backward transmission of elevated filling pressures from left-sided heart failure.

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While none of these studies have focused specifically on PH-HFpEF patients, the general hemodynamic improvements in these published studies of various types of pulmonary hypertension provide a basis for further research into the potential beneficial impact of levosimendan in PH-HFpEF patients.

Several published studies provide evidence that levosimendan may improve right ventricular dysfunction which is a common comorbidity in patients with pulmonary hypertension.

In March 2018, we met with the FDA to discuss development of levosimendan in these patients.

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The FDA recognized there were no approved drug therapies to treat PH-HFpEF patients and acknowledged this provided an opportunity for a limited Phase 3 clinical program.

This topic was discussed further at the End-of-Phase 2 Meeting following completion of the Phase 2 study in PH-HFpEF patients, which is known as the HELP Study – H emodynamic E valuation of L evosimendan in P H-HFpEF.

We initiated the first of our expected 10-12 HELP Study clinical sites in November 2018 and the first of 37 patients was enrolled in the HELP Study in March 2019.

This topic was discussed further at the End-of-Phase 2 Meeting following completion of the Phase 2 study in PH-HFpEF patients, which is known as the HELP Study - Hemodynamic Evaluation of Levosimendan in PH-HFpEF.

We initiated the first of our HELP Study clinical sites in November 2018 and the first of 37 patients was enrolled in the HELP Study in March 2019.

Enrollment in the HELP Study was completed about one year later, in March 2020.

The primary endpoint of the HELP Study was based on the change in PCWP during exercise versus baseline compared to placebo.

The primary endpoint of the HELP Study was based on the change in pulmonary capillary wedge pressure (“PCWP”) during exercise versus baseline compared to placebo.

The HELP Study utilized a double-blind randomized design following five weekly outpatient infusions of levosimendan.

On June 2, 2020, we announced preliminary, top-line data from the study.

The primary efficacy analysis, pulmonary capillary wedge pressure (PCWP) during exercise did not demonstrate a statistically significant reduction from baseline.

The primary efficacy analysis, PCWP during exercise did not demonstrate a statistically significant reduction from baseline.

Levosimendan did demonstrate a statistically significant reduction in PCWP compared to baseline (p=<0.0017) and placebo (p=<0.0475) when the measurements at rest, with legs up, and on exercise were combined.

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Hemodynamic Results

Hemodynamic measurements were made at rest (supine), after leg raise on a supine bicycle (a test of rapid increase in ventricular filling) and during exercise (25 watts for 3 minutes or until the patient tired).

In the initial open-label phase, 84% of the patients had a significant reduction in right atrial pressure, or RAP, pulmonary artery pressure, or PAP, and PCWP at rest and during exercise.

Hemodynamic measurements were made at rest (supine), after leg raise on a supine bicycle (a test of rapid increase in ventricular filling) and during exercise (25 watts for three minutes or until the patient tired).

In the initial open-label phase, 84% of the patients had a significant reduction in right atrial pressure (“RAP”), pulmonary artery pressure, (“PAP”), and PCWP at rest and during exercise.

In the randomized double-blinded 6-week trial, levosimendan demonstrated a statistically significant reduction in PCWP compared to baseline (p=<0.0017) and placebo (p=<0.0475) when these three measurements were combined:

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11,213,524, entitled PHARMACEUTICAL COMPOSITIONS FOR SUBCUTANEOUS ADMINISTRATION OF LEVOSIMENDAN.

We are currently studying the safety and efficacy of TNX-103 in all patients participating in the open-label extension of the HELP Study, all of whom previously received weekly infusions of intravenous levosimendan.

These patients were safely transitioned from the intravenous to the oral formulation in late 2021, with positive signs of efficacy observed across all measured parameters during the transition study phase of the open-label extension study, or OLE.

Following their completion of the randomized treatment phase of the HELP trial, patients were able to enter a study extension.

For over two years, Tenax and our HELP investigators continued studying the safety and efficacy of TNX-103 in all patients participating in the open-label extension of the HELP Study, all of whom previously received weekly infusions of intravenous levosimendan.

We expect the OLE to come to a conclusion in the first half of 2023.

In October 2020, we met with the FDA for an End-of-Phase 2 Meeting to discuss the Phase 2 clinical data and further development of levosimendan in PH-HFpEF patients.

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A proposed Phase 3 study design was provided in late 2021 for FDA review and comment on the safety database requirements at filing.

In February 2022, the FDA advised in a written response that the safety database at NDA filing should meet the minimum International Clinical Harmonization (ICH) standards for a chronic medication.

In February 2022, the FDA advised in a written response that the safety database at NDA filing only need meet the minimum International Clinical Harmonization (ICH) standards for a chronic medication.

The HELP Study design was novel in several respects.

To date, no other multi-center study has evaluated levosimendan in heart failure patients with preserved ejection fraction, or HFpEF, patients or PH-HFpEF patients.

Instead, all previous levosimendan heart failure studies have enrolled heart failure patients with reduced ejection fraction, or HFrEF, which specifically excluded HFpEF patients.

To date, no other multi-center study has evaluated levosimendan in heart failure patients with preserved ejection fraction (“HFpEF”) patients or PH-HFpEF patients.

Instead, all previous levosimendan heart failure studies have enrolled heart failure patients with reduced ejection fraction (“HFrEF”), therefore specifically excluding HFpEF patients.

Also, the HELP Study utilized a unique 24-hour weekly infusion regimen of 0.075- 0.1µm/kg/min.

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The transition of patients in the OLE from intravenous to oral therapy was encouraging.

PH-HFpEF has an approximate 50% rate of survival of 5 years.

PH-HFpEF has an approximate 50% rate of survival of five years.

The patients who enrolled in the HELP study had very advanced disease, with 87% Functional Class III at enrollment.

At the time of the transition these patients had already been on levosimendan for 2 years or longer.

At the time of the transition these patients had already been on levosimendan for two years or longer.

The fact that there was an improvement in all measures of efficacy on oral therapy beyond what had been achieved on intravenous therapy speaks to the remarkable durability of the treatment effect.

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Imatinib (marketed in the U.S.

as Gleevec®) is a tyrosine kinase inhibitor, which changed the treatment of chronic myeloid leukemia, or CML, following its approval over 20 years ago, as the first curative treatment of chronic leukemia.

as Gleevec®) is a tyrosine kinase inhibitor, which changed the treatment of chronic myeloid leukemia (“CML”) following its approval over 20 years ago, as the first curative treatment of chronic leukemia.

The first clinical trial of imatinib took place in 1998 and the drug received FDA approval in May 2001.

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Serious side effects may include myelosuppression, heart failure, and liver function abnormalities.

Novartis manufactures of Gleevec.

Novartis manufactures Gleevec.

Previous Imatinib Development for Pulmonary Arterial Hypertension Patients

In PAH, a rare disease, patients who remain symptomatic despite available therapies have a high morbidity and mortality.

Though several therapies are now available, there is no cure for the disease, and there is no data supporting that the existing therapies, all of which are pulmonary vasodilators, halt progression or induce regression of the disease.

Imatinib has been shown in animal models of pulmonary hypertension to induce disease reversal by an effect on platelet derived growth factor, or PDGF, which appears to be causal in the disease.

Though several therapies are now available, there is no cure for the disease, and there is no data supporting that the existing approved therapies, all of which are pulmonary vasodilators, halt progression or induce regression of the disease.

Imatinib has been shown in animal models of pulmonary hypertension to induce disease reversal by an effect on platelet derived growth factor (“PDGF”), which appears to be causal in the disease.

After that discovery was made, several case reports and small case series of patients with advanced PAH failing combination pulmonary vasodilator therapy were published showing a dramatic effect of imatinib on stabilizing and improving these patients.

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Current TNX-201 Development for Pulmonary Arterial Hypertension Patients

On May 30, 2019, PHPM, which was acquired by Tenax Therapeutics in January 2021, met with the FDA to discuss a proposal for a Phase 3 trial of imatinib for PAH.

On May 30, 2019, PHPrecisionMed Inc., a Delaware corporation (“PHPM”), which was to be acquired by Tenax Therapeutics in January 2021, met with the FDA to discuss a proposal for a Phase 3 trial of imatinib for PAH.

At that meeting, PHPM discussed a single Phase 3 trial using change in 6-minute walk distance as the primary endpoint (p<0.05).

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We recruited 16 volunteers, who received a single dose of the modified release formulation and a single dose of the existing immediate release formulation.

The formulation has been optimized in preparation for a second Phase 1 study to be completed in the second quarter of 2022.

A Phase 3 study is planned with TNX-201, the modified release formulation of imatinib, and is expected to be initiated in the second half of 2022.

This formulation was later optimized in preparation for a second Phase 1 study, completed in the second quarter of 2022.

A Phase 3 study of TNX-201, this optimized modified release formulation of imatinib, would be the next clinical trial to commence in Tenax’ development planning, pending the outcome of our strategic process and funding of the trial costs.

Manufacturing and Supply

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We may engage other third-party suppliers and CMOs for the supply and manufacture of TNX-102, or other formulations we may develop.

We have engaged various third-party suppliers and CMOs for the supply and manufacture of imatinib for planned, upcoming clinical trials, and relied on such contractors for material contributing to TNX-201, for testing in our completed Phase 1 trial, a second Phase 1 trial scheduled for the first half of 2022, and our planned Phase 3 trial, planned to start in the second half of 2022.

We have engaged various third-party suppliers and CMOs for the supply and manufacture of imatinib for potential future clinical trials, and relied on such contractors for material contributing to TNX-201, for testing in our two completed Phase 1 trials.

As we further develop our product pipeline, we expect to consider secondary or back-up manufacturers for both active pharmaceutical ingredient and drug product manufacturing.

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We expect third-party manufacturers to be capable of providing sufficient quantities of our product candidates to meet anticipated full-scale commercial demands, but we have not assessed these capabilities beyond the supply of clinical materials to date.

We believe alternate sources of manufacturing will be available to satisfy our clinical and future commercial requirements;

however, we cannot guarantee that identifying and establishing alternative relationships with such sources will be successful, cost effective, or completed on a timely basis without significant delay in the development or commercialization of our product candidates.

All of the vendors we use are required to conduct their operations under current Good Manufacturing Practices, or cGMP, a regulatory standard for the manufacture of pharmaceuticals.

We believe alternate sources of manufacturing will be available to satisfy our clinical and future commercial requirements; however, we cannot guarantee that identifying and establishing alternative relationships with such sources will be successful, cost effective, or completed on a timely basis without significant delay in the development or commercialization of our product candidates.

All of the vendors we use are required to conduct their operations under current Good Manufacturing Practices (“cGMP”), a regulatory standard for the manufacture of pharmaceuticals.

Intellectual Property

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Currently, we require our officers, employees, consultants, contractors, manufacturers, outside scientific collaborators and sponsored researchers, and other advisors to execute confidentiality agreements in connection with their employment, consulting, or advisory relationships with us, where appropriate.

We also require our employees, consultants, and advisors whom we expect to work on our products to agree to disclose and assign to us all inventions conceived during the workday, developed using our property, or which relate to our business.

We have one granted patent, and three U.S.

We also require employees, consultants, and advisors whom we expect to work on our products to agree to disclose and assign to us all inventions conceived during the workday, developed using our property, or which relate to our business.

We have two granted patents, and two U.S.

patent applications pending, related to product candidates and proprietary process, method and technology.

Our issued patent expires in 2039.

On January 4, 2022, we filed and received a patent application for the subcutaneous administration of levosimendan, whether through the formulation we have developed in collaboration with a formulation development partner, or other subcutaneous formulations meeting certain broad characteristics defined in the patent.

In addition, we have filed a patent application for the use of levosimendan in the treatment of PH-HFpEF patients, based on several discoveries that have emerged from the HELP Study and the OLE.

Our issued levosimendan patents expire in 2039 and late 2040.

On January 4, 2022, we received a patent for the subcutaneous administration of levosimendan, whether through the formulation we have developed in collaboration with a formulation development partner, or other subcutaneous formulations meeting certain broad characteristics defined in the patent.

In addition, we received on March 21, 2023 a patent for the use of IV levosimendan in the treatment of PH-HFpEF patients, based on several discoveries that have emerged from the HELP Study and the OLE.

trademark registration for Simdax® is owned by Orion and is licensed to us for sales and marketing purposes for any intravenous pharmaceutical products containing levosimendan that are commercialized in the United States and Canada.

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We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be sure that any of our existing patents or any patents we may own or license in the future will be useful in protecting our technology and products.

For this and more comprehensive risks related to our intellectual property, please see “Risk Factors - Risks Related to Our Intellectual Property”.

Licensing Agreement

Comprehensive risks related to our intellectual property are described under the heading “Risk Factors - Risks Related to Our Intellectual Property” included elsewhere in this Annual Report on Form 10-K.

Simdax License Agreement

On November 13, 2013, we acquired, through our wholly-owned subsidiary, a license agreement between Phyxius and Orion, which was later amended on October 9, 2020 and January 25, 2022 (as amended, the “License”).

The License grants us an exclusive, sublicenseable right to develop and commercialize pharmaceutical products containing levosimendan in the United States and Canada and, pursuant to the October 9, 2020 amendment to the License, also includes two product dose forms containing levosimendan, in capsule and solid dosage form, and a subcutaneously administered product containing levosimendan, subject to specified limitations.

The License grants us an exclusive, sublicenseable right to develop and commercialize pharmaceutical products containing levosimendan in the United States and Canada (the “Territory”) and, pursuant to the October 9, 2020 amendment to the License, also includes two product dose forms containing levosimendan, in capsule and solid dosage form, and a subcutaneously administered product containing levosimendan, subject to specified limitations (together, the “Product”).

Pursuant to the License, Tenax and Orion will agree to a new trademark when commercializing levosimendan in either of these forms.

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The pharmaceutical and biotechnology industries are intensely competitive.

Many companies, including biotechnology, chemical, and pharmaceutical companies, are actively engaged in activities similar to ours, including research and development of drugs for the treatment of rare medical conditions.

Many of these companies have substantially greater financial and other resources, larger research and development staffs, and more extensive marketing and manufacturing organizations than we do.

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Our success will be based in part on our ability to identify, develop and manage a portfolio of product candidates that are safer and more effective than any competing products.

We believe the concept of using TNX-102/103 (levosimendan) to treat patients with PH-HFpEF is novel.

We believe the concept of using TNX-101/102/103 (levosimendan) to treat patients with PH-HFpEF is novel, and the patent granted for this use in March 2023 demonstrates USPTO’s concurrence.

Because no therapies are approved to treat PH-HFpEF, we believe our ability to succeed in the market is primarily dependent on our ability to change the established practice paradigm, which could be difficult.

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Furthermore, while we believe the mechanism of action of levosimendan is novel, other low-priced, generically available products possess some similar qualities, which could present competition in the form of therapeutic substitution.

TNX-201 has the potential to be the first disease-modifying treatment of PAH, a fatal orphan disease.

TNX-201 (imatinib) has the potential to be the first disease-modifying treatment of PAH, a fatal orphan disease.

Pulmonary vasodilators, the only approved medications for PAH, do not have disease modifying properties.

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We believe that our development plan has advantages in that we already know the effective dose of imatinib administered orally, and the systemic exposure from an inhaled route remains uncertain, and costly to determine.

Since only the first FDA approved formulation of imatinib to treat PAH will qualify for the 7 years of Orphan Drug exclusivity in the U.S., these alternative formulations of imatinib represent potential competitive threats.

In order to compete successfully in this and other therapeutic areas, we must develop proprietary positions in patented drugs for therapeutic markets that have not been satisfactorily addressed by conventional research strategies.

Since only the first FDA approved formulation of imatinib to treat PAH will qualify for the seven years of Orphan Drug exclusivity in the U.S., these alternative formulations of imatinib represent potential competitive threats.

In order to compete successfully, we must develop proprietary positions in patented drugs for therapeutic markets that have not been satisfactorily addressed by conventional research strategies.

Our product candidates, even if successfully tested and developed, may not be adopted by physicians over other products and may not offer economically feasible alternatives to other therapies.

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The FDA may also require post-marketing testing, which can involve significant expense, to monitor for adverse effects.

The effects of government regulations on our business are discussed in “ Item 1A — Risk Factors — Risks Relating to Regulatory Matters ”.

The effects of government regulations on our business are discussed under the heading “Risk Factors - Risks Relating to Regulatory Matters” included elsewhere in this Annual Report on Form 10-K.

Employees and Human Capital

We have assembled a high-quality team of clinical development managers and executives with significant experience in the biotechnology and pharmaceutical industries.

As of December 31, 2021, we had eight full-time employees and one part-time employee.

In addition to our employees, we also use the service and support of outside consultants and advisors.

As of December 31, 2022, we had seven full-time employees and one part-time employee.

In addition to our employees, we also rely on the service and support of outside consultants and advisors.

None of our employees are represented by a union, and we believe relationships with our employees are good.

In response to the COVID-19 pandemic, we put in place several safety measures for our employees.

These measures included, but were not limited to, substantially restricting travel, limiting access to our corporate office, including allowing employees to work remotely, providing personal protective equipment to employees, investigator sites and third-party vendors, implementing social distancing protocols, and coordinating safety protocols with our investigator sites.

Available Information

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

What changed 10-K

Item 1. Business