levosimendan oral (TNX-103) / Orion Corp, Tenax Therap - LARVOL DELTA

Tenax Therapeutics Announces European Patent Office Intention to Grant Patent Covering Use of Levosimendan in PH-HFpEF (GlobeNewswire) - "In addition, this patent will include similar protection for the use of the active metabolites of levosimendan (OR1896 and OR1855) for the treatment of PH-HFpEF. This patent also will expressly provide protection in Europe for a wide range of doses of levosimendan, as well as for use of levosimendan in combination with various cardiovascular drugs, in PH-HFpEF. This new patent, once granted, will have a patent term until December 2040, and it may qualify for European patent supplementary protection certificates (SPC) that would extend the period of patent protection beyond 2040."

Patent • Heart Failure • Hypertension

LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF (clinicaltrials.gov) - P3 | N=230 | Recruiting | Sponsor: Tenax Therapeutics, Inc. | Trial completion date: May 2028 ➔ Oct 2028 | Trial primary completion date: May 2026 ➔ Oct 2026

Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Oral Levosimendan for the Treatment of Pulmonary Hypertension due to Heart Failure with Preserved Ejection Fraction: Rationale and Design of the LEVEL Trial: Rationale and Design of LEVEL. (PubMed, J Card Fail) - "LEVEL is the first phase 3 trial to investigate whether oral levosimendan can improve exercise capacity in patients with PH-HFpEF. The results may establish a new therapeutic approach and enhance understanding of the role of splanchnic vasoconstriction in PH-HFpEF pathophysiology."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Tenax Therapeutics Reports First Quarter 2025 Financial Results and Provides Corporate Update (GlobeNewswire) - "Patient enrollment in the Phase 3 LEVEL study of TNX-103 in PH-HFpEF continues, with high rates of study and therapy continuation during the blinded and open-label extension stages. Tenax anticipates completing enrollment of 230 patients in LEVEL around the end of 2025. LEVEL is being conducted in Canada and the U.S...Tenax remains on track to commence in 2025 a second registrational Phase 3 study of TNX-103, LEVEL-2, in patients with PH-HFpEF. This trial will have a global footprint...Research and development (R&D): R&D expenses for the first quarter of 2025 were $5.7 million, compared to $2.7 million for the first quarter of 2024. The increase was primarily attributable to increased expenses associated with the Company’s Phase 3 LEVEL study for TNX-103, as well as increased personnel costs (including $0.9 million of stock-based compensation) and regulatory consulting costs."

Commercial • Enrollment status • New P3 trial • CNS Disorders

Tenax Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "The past year has been transformational for Tenax Therapeutics in our quest to advance TNX-103, our oral levosimendan drug candidate, and bring meaningful clinical benefit to patients suffering from PH-HFpEF...We remain committed to a lean cost structure and responsible capital stewardship, ensuring our current funding sustains Tenax well beyond topline LEVEL data readout. We believe TNX-103 has the potential to improve the quality of life of patients living with PH-HFpEF, and expect to share topline data from LEVEL in the middle of 2026."

P3 data: top line • Cardiovascular • Heart Failure • Hypertension

LEVosimendan to Improve Exercise Limitation in Patients with PH-HFpEF (clinicaltrials.gov) - P3 | N=230 | Recruiting | Sponsor: Tenax Therapeutics, Inc. | N=152 ➔ 230 | Trial completion date: Jul 2027 ➔ May 2028 | Trial primary completion date: Mar 2027 ➔ May 2026

Enrollment change • Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

LEVEL Study Expansion Enhances Statistical Power (GlobeNewswire) - P3 | N=152 | LEVEL (NCT05983250) | Sponsor: Tenax Therapeutics, Inc. | "As of late February 2025, blinded LEVEL data reveal TNX-103 to be well-tolerated in patients with PH-HFpEF: >95% of patients who randomized have remained on therapy; >95% of patients who completed 12 weeks have elected to enter the OLE; and >95% of patients who entered the OLE have continued participation to this point."

P3 data • Cardiovascular

Tenax Therapeutics Expands Phase 3 LEVEL Program, Advancing Two TNX-103 (Oral Levosimendan) Registrational Studies for the Treatment of PH-HFpEF (GlobeNewswire) - "Tenax Therapeutics, Inc...today announced the U.S. Food and Drug Administration (FDA) has completed their review of Tenax Therapeutics’ updated Phase 3 development plan for TNX-103 (oral levosimendan), including an Amendment to expand enrolment and increase the power of the ongoing Phase 3 LEVEL study, and the protocol for LEVEL-2, Tenax Therapeutics’ second registrational Phase 3 study. The Company today announced it expects to enroll 230 patients in the LEVEL study, increasing the statistical powering of the study to over 95%. LEVEL-2, a global study, is expected to commence in 2025...The Company is on track to enroll the first 150 subjects in the first half of 2025, expects to complete enrollment by around the end of 2025, and expects to present topline data from the LEVEL study in the middle of 2026."

Clinical protocol • Enrollment status • New P3 trial • P3 data: top line • Cardiovascular

Tenax Therapeutics LEVEL Setting: The Scientific Rationale for Levosimendan as the First Treatment for PH-HFpEF and the Ongoing Phase 3 LEVEL Study (Tenax Therapeutics Press Release) - "Join Tenax Therapeutics for LEVEL Setting, a panel of globally-recognized thought leaders in the field of heart failure, exploring the potential of TNX-103 (oral levosimendan) to treat patients with pulmonary hypertension from heart failure with preserved ejection fraction (PH-HFpEF)....Expert panelists will review emerging science, clinical experience with TNX-103, and the evolving heart failure landscape: Understanding the setting of PH-HFpEF."

Live event

Tenax Therapeutics Announces Oral Presentation of Levosimendan for the Treatment of PH-HFpEF at THT 2024 (GlobeNewswire) - "Tenax Therapeutics, Inc...today announced Dr. Sanjiv Shah, Stone Endowed Professor of Medicine, Director of Research for the Bluhm Cardiovascular Institute, and Director of the HFpEF Program at Northwestern University Feinberg School of Medicine, will present data and review the scientific basis for the use of levosimendan in PH-HFpEF. Dr Shah’s presentation will occur during a scientific session focused on the treatment of pulmonary hypertension in patients with heart failure at the upcoming Cardiovascular Research Foundation’s Technology and Heart Failure Therapeutics (THT) Conference in Boston....'Our Phase 3 LEVEL study is on the cutting edge of PH-HFpEF drug development, and Tenax is privileged Dr. Shah has chosen to review the scientific rationale for levosimendan use in these patients with the many international heart failure experts attending THT 2024.'"

Clinical • Trial status • Cardiovascular • Heart Failure

Tenax Therapeutics Announces Pricing of Approximately $9 Million Public Offering (GlobeNewswire) - "Tenax Therapeutics, Inc...announced today the pricing of a public offering of (i) 1,600,000 shares of its common stock (or pre-funded warrants in lieu thereof) and (ii) warrants to purchase up to 3,200,000 shares of its common stock (the 'Common Warrants') at a purchase price of $5.65 per share and associated Common Warrant....The Company intends to use the net proceeds from the offering to advance the initiation of sites and the enrollment and treatment of patients in its LEVEL trial, a Phase 3 trial of oral levosimendan, as well as for working capital, capital expenditures, and other general corporate purposes."

Financing • Cardiovascular

LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF (clinicaltrials.gov) - P3 | N=152 | Recruiting | Sponsor: Tenax Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Levosimendan in Pulmonary Hypertension Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction (clinicaltrials.gov) - P3 | N=152 | Not yet recruiting | Sponsor: Tenax Therapeutics, Inc.

New P3 trial • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Tenax Therapeutics Achieves Major Milestone as USPTO Grants Notice of Allowance for U.S. Patent Application Covering Use of Oral Levosimendan (TNX-103) in Pulmonary Hypertension with Heart Failure with Preserved Ejection Fraction (PH-HFpEF) (GlobeNewswire) - "Tenax Therapeutics...announced today that it has received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for its patent application with claims covering the use of TNX-103, oral levosimendan, titled: 'LEVOSIMENDAN FOR TREATING PULMONARY HYPERTENSION WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION (PH-HFpEF).' The patent, once granted, will have a patent term through December 2040....'With this Notice of Allowance, Tenax is now exceptionally well-positioned to realize the significant commercial potential of oral levosimendan, based on this new IP protection that will last until at least the end of 2040. Advancing this daily, oral formulation into Phase 3 studies for the treatment of PH-HFpEF, a heart condition affecting millions of people in the United States with no FDA approved treatments, is our next step.'"

New P3 trial • Patent • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Heart Failure

Tenax Therapeutics Provides 2023 Business Update (GlobeNewswire) - "Based on an end-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA), the FDA agreed that one or two Phase 3 clinical studies (depending on the size) with a primary endpoint of change in 6-minute walk distance over 12 weeks, or a single Phase 3 trial with clinical worsening (e.g., death, hospitalization for heart failure, or decline in exercise capacity) over 24 weeks would be sufficient to demonstrate the effectiveness of levosimendan in PH-HFpEF. The FDA also agreed to a plan to replace weekly intravenous levosimendan dosing with daily TNX-103 (oral) doses in a Phase 3 clinical study."

FDA event • Cardiovascular • Heart Failure

REFALS-ES: Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension (clinicaltrials.gov) - P3 | N=227 | Terminated | Sponsor: Orion Corporation, Orion Pharma | Completed ➔ Terminated; This was an open label extension for patients completing the REFALS study (3119002; NCT03505021). Study 3119002 showed lack of efficacy of ODM109 so the sponsor decided to terminate this study

Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

The Transition From Chronic Intravenous To Oral Levosimendan Is Safe And Effective In Patients With Pulmonary Hypertension With Heart Failure And Preserved Ejection Fraction (HFSA 2022) - No abstract available

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. (PubMed, Lancet Neurol) - P3 | "Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation."

Clinical • Journal • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Pain • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Determinants of clinical response to levosimendan in the REFALS phase 3 study in people with ALS (AAN 2021) - P3 | "The REFALS study explored the clinical effects of oral levosimendan during prolonged treatment in people with ALS...83% and 17.5% patients were taking riluzole and edaravone, respectively... Although the REFALS study of levosimendan was not positive, subgroup analyses may be of value in identifying patient groups with a stronger treatment effect and inform future trial design."

Clinical • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

[VIRTUAL] Correlation of laboratory safety variables with disease course in the REFALS phase 3 study of levosimendan in people with ALS (AAN 2021) - P3 | "Participants were randomized (2:1 allocation) to oral levosimendan 1-2mg daily or placebo for 48 weeks in a double-blind, parallel group design... The REFALS trial has provided a unique opportunity to study the potential of routine clinical chemistry measurements as markers to follow ALS disease pathology, which could be useful for managing patients in future clinical trials."

Clinical • P3 data • CNS Disorders

REFALS-ES: Effects of Oral Levosimendan on Respiratory Function in Patients With ALS: Open-Label Extension (clinicaltrials.gov) - P3; N=227; Completed; Sponsor: Orion Corporation, Orion Pharma; Active, not recruiting ➔ Completed; N=450 ➔ 227; Trial completion date: Mar 2021 ➔ Nov 2020; Trial primary completion date: Mar 2021 ➔ Nov 2020

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

REFALS: Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS (clinicaltrials.gov) - P3; N=496; Completed; Sponsor: Orion Corporation, Orion Pharma; Active, not recruiting ➔ Completed; Trial completion date: Oct 2020 ➔ Jul 2020

Clinical • Trial completion • Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

REFALS-ES: Effects of Oral Levosimendan on Respiratory Function in Patients With ALS: Open-Label Extension (clinicaltrials.gov) - P3; N=450; Active, not recruiting; Sponsor: Orion Corporation, Orion Pharma; Recruiting ➔ Active, not recruiting; Trial completion date: Jul 2022 ➔ Mar 2021; Trial primary completion date: Jul 2022 ➔ Mar 2021

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

Orion’s phase 3 REFALS trial evaluating the efficacy of oral levosimendan in treatment of ALS patients did not reach its pre-specified endpoints (GlobeNewswire) - P3, N=450; REFALS (NCT03505021); Sponsor: Orion Corporation; "The primary endpoint of the trial was to show a statistically significant difference between levosimendan and placebo in slow vital capacity (SVC) in supine position at 12 weeks compared to the baseline. An important secondary endpoint was to show a statistically significant difference between levosimendan and placebo in patient functionality measured by ALSFRS-R Scale (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) in combination with survival at 48 weeks compared to the baseline. These pre-specified endpoints were not met in the trial. No new safety concerns were identified for levosimendan in this study. The REFALS phase 3 trial data will be presented at a future scientific meeting."

P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use. (PubMed, Card Fail Rev) - "A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years."

Clinical • Journal • Review • Amyotrophic Lateral Sclerosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Congestive Heart Failure • Critical care • Heart Failure • Hypertension • Pulmonary Arterial Hypertension