Levosimendan

Nearly three decades after its failed bid for FDA approval, the cardiovascular drug levosimendan is still struggling to secure a decisive clinical win to enter the U.S. market. In the latest chapter of the drug’s U.S. odyssey, Tenax Therapeutics reported that an oral version of levosimendan missed the primary endpoint of a phase 3 trial, leaving the biotech to rely on subgroup data to chart a narrow path forward with the FDA. In the phase 3 Level trial, Tenax’s oral levosimendan, coded TNX-103, failed to outperform placebo in improving 6-minute walk distance in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF), the company said Monday. The least-squares mean difference between the levosimendan group and the control arm was merely 3.5 meters, with a p-value of 0.63. The key secondary endpoint, improvement in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), also returned negative, with a least-squares mean difference of 0.1 points. Despite the flop, Tenax has zeroed in on a prespecified subgroup of patients with greater disease burden and plans to request a meeting with the FDA to discuss a path forward for TNX-103. Specifically, among 119 patients who walked less than the trial median of 333 meters (about 1,093 feet) at baseline, levosimendan demonstrated an improvement of 26.3 meters versus placebo on the 6-minute walk test, with a nominal p-value of 0.0112. On average, patients on Tenax's drug improved by 26.7 meters, while those on placebo declined by 2.6 meters. In an Aug. 10 statement, Tenax’s chief medical officer, Stuart Rich, M.D., called this finding “a strong result in a more characteristic HFpEF population that needs this therapy.” The increase in walking distance was accompanied by a 49% decrease in a heart failure protein biomarker, NT-proBNP, and a reduction in right ventricular systolic pressure by 3.5 mmHg, compared to placebo. According to the Level trial’s principal investigator, Sanjiv Shah, M.D., from Northwestern University, the 49% NT-proBNP reduction versus placebo is larger than any prior HFpEF trial. “Taken together, these data support TNX-103’s substantial cardiovascular and pulmonary biologic effects on reducing the severity of disease in patients with pulmonary hypertension due to HFpEF,” Rich said. “In my opinion, a drug that lowers wall stress and modifies cardiac structure and function this robustly is likely to be disease-modifying,” Shah said. “The improvement in exercise capacity was concentrated in patients with lower baseline walk distance and more advanced disease, which is consistent with a therapy that may improve long-term outcomes in those patients who need it most.” Originally developed by Orion Pharma, levosimendan got its initial European approval in 2000 under the brand name Simdax, an intravenous infusion for treating acutely decompensated chronic heart failure. But the drug has a difficult clinical and regulatory past in the U.S. In 1999, Orion withdrew its application with the FDA after the agency requested larger phase 3 outcome trials to support levosimendan’s case. Later, the phase 3 Revive II trial of 600 patients showed some short-term symptomatic improvement with the inodilator on top of standard therapy, but more deaths were recorded in the levosimendan arm at 90 days, along with higher rates of certain adverse events, such as hypotension, raising safety concerns. In 2007, Abbott terminated its U.S. development efforts for the drug after the large-scale Survive trial of more than 1,300 patients, which compared levosimendan with dobutamine, failed to meet its primary endpoint of a statistically significant reduction in 180-day all-cause mortality. At the time, Abbott concluded that conducting additional phase 3 studies would not be commercially reasonable. U.S. rights to levosimendan then landed at Tenax. But in 2017, the drug again failed in the phase 3 Levo-CTS trial in patients with left ventricular dysfunction undergoing cardiac surgery. Prophylactic levosimendan did not result in any significant improvement versus placebo on a composite endpoint of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device. Tenax licensed North American rights to oral levosimendan from Orion in 2020, then expanded the deal in 2024 to cover oral and subcutaneous levosimendan globally for PH-HFpEF. Compared with the original intravenous version, a daily oral formulation could offer “an advantage of stable dosing and eliminate the risk of line infections and thrombosis,” a team of researchers, including Shah, wrote in 2023.

Tenax Therapeutics is pinning its hopes for TNX-103 on a subset of sicker patients with pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) after its experimental treatment failed to significantly improve exercise capacity in a Phase III trial.The company still believes the results point to a potential path forward for the drug, though that didn't seem to resonate with investors, who sent Tenax shares down close to 90% on Monday.TNX-103 is an oral tablet form of levosimendan, an intravenously administered drug that acts as a calcium sensitiser and potassium-ATP channel activator. The LEVEL study enrolled 241 patients who were randomised to TNX-103 or placebo. Those in the treatment group took 1 mg twice daily, with the dose increased to 1 mg three times daily from week five, if tolerated.Walk test falls shortThe primary endpoint looked at whether the drug could improve how far patients could walk in six minutes (6MWD) after 12 weeks. TNX-103 fell short, according to topline results, with patients walking an average of 14 metres farther than at baseline, compared to 10.4 metres for those on placebo. The resulting 3.5-metre difference wasn't statistically significant (p=0.63).The drug also failed to separate from placebo on the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), a key secondary endpoint, with improvements of 6.6 and 6.5 points, respectively.However, Tenax is zeroing in on prespecified subgroup analyses suggesting TNX-103 could have greater activity in patients who started the LEVEL study with more severe disease.Among those whose baseline 6MWD was below the trial median of 333 metres, the treatment difference was 26.3 meters (nominal p=0.0112), with patients receiving TNX-103 improving by 26.7 metres while those on placebo declined by 2.6 metres. A similar pattern emerged among older patients, with those aged 71 and above showing a 27.1-metre treatment difference (nominal p=0.0021).Subgroup lifeline"I am encouraged we have a clear path forward," stated Chief Medical Officer Stuart Rich in a company release. "Our entry criteria enrolled a broad population, including too many patients with less severe disease," he added, whereas the subgroup of patients who couldn't walk as far at the start of the study disease demonstrated "a strong result in a more characteristic HFpEF population that needs this therapy."The company also highlighted exploratory biomarker and haemodynamic findings across the overall study population. TNX-103 reduced NT-proBNP, a marker of cardiac wall stress, by 49% versus placebo (nominal p<0.0001) and lowered right ventricular systolic pressure by 3.5 mmHg (nominal p=0.0045). The latter reduction reached 4.9 mmHg in patients with baseline 6MWD below 333 metres (nominal p=0.009)."The treatment effect on NT-proBNP is larger than any prior HFpEF trial, and it was accompanied by improvements in multiple echocardiographic measures of cardiac structure and function, spanning right ventricular systolic function, left atrial function, left ventricular mass and diastolic filling, and pulmonary pressure," noted lead investigator Sanjiv Shah. "In my opinion, a drug that lowers wall stress and modifies cardiac structure and function this robustly is likely to be disease-modifying."FDA meetingTNX-103 was generally well tolerated in the study, with serious adverse events occurring at similar rates between treatment and placebo groups, at slightly under 11%. However, overall treatment-related adverse events were more frequent with TNX-103 at 38.3% versus 17.4% with placebo. Full results will be presented at the European Society of Cardiology (ESC) meeting later this month.Tenax plans to request a Type C meeting with the FDA to discuss revising the registrational development programme, including an enrichment strategy focused on patients with greater disease burden. The company said the FDA had previously agreed that a single Phase III trial with a p-value of 0.01 could support an NDA submission. It also plans to seek scientific consultation with the EMA.