5/29/2026
AMT
the entity in question today is Tenax Therapeutics TNX-103 (oral levosimendan)
- the co refers to it as “levo” which irks me because everyone knows that means levophed. whatever
Lets start with the basics – levo works on the ATP-sensitive potassium channels in smooth muscles as well as stabilizing actin-myosin cross-bridging in cardiac myositis which exerts a very minor inotropic effect that is considerably irrlevant.
Notably, its mechanism in vascular smooth muscle is ubiquitous across blood vessels in the entire human body. It does not, in any way, particulary effect the splanchnic vascular system despite what the management will have you believe. This will be relevant
Now, let’s discuss the entity being treated – Type II pulmonary arterial hypertension.
when it comes to PAH there are 5 distinct subtypes but type II is the one of particular interest here.
Type II PAH is attributable to left sided heart disease which back fills pressure into the post-capillary system of the lungs. This higher pressure leads to functional compromise and biologic derangement. Now TENX evaluates specifically HFpEF-related PAH.
Why you might ask? why specifically preserved EF? Surely this is a problem across both pEF and rEF disease spectrums.
I believe they are seeking a bastion of refuge in a more lenient disease state as the bar for HF with reduced EF has become so rigorous, they would stand no chance.
Lets look at Heart Failure broadly.
A paradigm shift occurred in treating heart failure in the early 1990s.
Before then, clinical treatment of heart failure was oriented around hemodynamics. If we lower blood pressure and vascular resistance, the failing heart can be off-loaded.
But what we found was that patients on some medications did better than others.
Enter Dr. Milton Packer, MD in 1992 who postulated the neuro-hormonal hypothesis of heart failure.
[https://www.jacc.org/doi/10.1016/0735-1097%2892%2990167-L]
This was a fundamental restructuring of how we understand and treat heart failure (be it preserved or reduced EF).
The basic principle is that neuro-hormonal bombardment of cardiac myocytes leads to irreversible necrosis, fibrosis, and apoptosis. The agents implicated are: Renin, Aldosterone, Angiotensin, Epinephrine, and Norepinephrine.
This brings us to modern-day GDMT, which targets these fundamental players in the pathogenic causation of heart failure.
Approved Medicines for HFpEF (and by virtue Type II PAH) are:
- Entresto (ARNI)
- Kerendia (MRA)
- SGLT2i
These are the same as HF with REDUCED EF, as they are spectral disease states rather than separate entities.
So now we know what works in heart failure, so what doesn’t work?
Vasodilators have a proclivity to fail in type II PAH due to the lack of specificity regarding the pulmonary territory and dilation of the pulmonary vasculature by the drug in question which leads to worse hemodynamics. Additionally they fail to address the underlying biological rationale for the issue in the first place (neuro-hormonal bombardment).
The graveyard of HFpEF-PAH is as follows:
- PDE5 inhibtors: SIESTA trial – no improvement in HFpEF
- ERAs – ENABLE trial – stopped early due to HF hospitalizations
- guanylate Cyclace stimulators – LEOPARD trial – no improvement
- Epoprostanel – FIRST trial – caused severe heart failure, terminated early
Now lets look at TENX data specifically
We’re discussing the Phase II HELP study primarily.
Firstly, for the PH2 study, they utilized an open-label run-in period to select only responders of the drug, which enriches the results dramatically, introduces expectation bias, and makes the phase III results likely to be worse. Despite this, they FAILED the primary objective endpoint.
- missed its primary endpoint, showing no significant reduction in exercise pulmonary capillary wedge pressure compared to placebo (p = 0.65)
- 6-minute walk distance showed a nominal benefit
The 6-Minute Walk Distance (6MWD) showed a nominal improvement (+29) meters, (p = 0.03)), yet the study completely missed its primary hemodynamic endpoint
The positive 6MWD result is highly vulnerable to alpha error via specific statistical and methodological factors. Small sample sizes dramatically increase the impact of individual data variations.
In the small sample size of the ph2 study it appears to me that few patients in the placebo group had an uncharacteristically bad day during their follow-up test (due to minor joint pain, poor sleep, or lack of motivation, etc), or if a few patients in the active group pushed exceptionally hard, the average scores shift dramatically.
2 patients in the placebo group had -90 and -120 meters lost
1 patient had 120 meters gained in levo group
This to me also reeks of data dredging – where in TENX by chance has found one notable signficant metric in a small study by virtue of testing for enough of them.
so what are we left with?
- a nonspecific vasodilator, of which 8 others have not only failed but shown often worse outcomes in type II HFpEF
- an unreliable, small, failed phase II trial with high expectation and survivor bias
- a drug that in no way addresses the underlying pathologic biology of HFpEF – in many ways is 40 years outdated – and flies in the face of proven modern GDMT.
- a Drug that was extensively studied in the early 2000s and did not improve HF patient outcomes [PMID: 18945637]
Readjudication 