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***Blockbuster binary, long idea*** It’s almost $TENX time, which to me is the cleanest shot at the 1st win in PH HFpEF. Oral levosimendan (Levo) in PH-HFpEF. Topline Aug (should be before the ESC abstracts drop imho) Pure binary +300% / -80% FDOS ~$750m. My base case: LEVEL hits primary >60%. Consensus sits ~40%. PH-HFpEF is the most common form of pulmonary hypertension. Multibillion market, ~2M+ US pts, zero approved therapies, high mortality. $INSM $ABVX $MDGL and a host of other binaries in the recent past where consensus said the drug wouldn’t work for various reasons. $TENX going into this feels like a similar setup, but with huge upside. So getting into it. First it’s important to note that the defining lesion is NOT the pulmonary artery. It’s the exercise induced spike in wedge pressure. On exertion splanchnic vasoconstriction auto transfuses blood from the abdomen into the chest. Lungs flood. Wedge, PA and RA pressure surge. As a result the pt can’t walk. ^the disease in short (Borlaug Circ HF 2010; Yaku/Fudim/Shah J Cardiol 2024) One fact to hold onto, it decides everything below. HFpEF pts still recruit cardiac output on exercise. They are NOT flow limited. Their limiter is the congestion, so the job is to decongest, not to pump harder. Every drug that failed here fixed the wrong node. Riociguat, macitentan, sildenafil: lowered PVR/PA pressure, never touched the wedge, no 6mwd benefit. Some risked pulmonary edema pushing more flow into a stiff LV. Relaxin: dropped MAP. Wrong prong. Milrinone, dobutamine: raised output via cAMP with an O2/arrhythmia/mortality tax. Wrong lever in a preserved EF heart. So what does a real 6mwd win actually need in preserved EF disease? •↓ wedge/RAP (decongest) •preserved CO reserve (not augmented) •stable MAP •no O2/arrhythmia tax Every failure violated a prong. Levo is the only agent that checks all four, and here’s the part almost nobody gets right… Levo isn’t one mechanism, it’s 2, and only one of them matters here. Vascular effect: K-ATP venodilation → less blood volume in the chest → lower wedge. This is a property of the vessels not the ventricle, so it’s EF independent. It ports from HFrEF to HFpEF unchanged. It is the effect the disease needs. Inotropic effect: Ca sensitization → more output. Shows up in low output HFrEF because those hearts are flow starved. In HFpEF it didn’t show. CO was flat in HELP at rest and exercise, and that is fine because HFpEF doesn’t need it as I mentioned above. So when you read “levo is a dangerous inodilator flogging a stiff heart” know it’s dead on arrival. There was zero inotropy in HELP. No extra squeeze. No O2 demand spike. The benefit came from decongestion (Burkhoff ESC HF 2021: mechanism is stressed blood volume reduction, no inotropy). The vascular effect also has a second arm. K-ATP opening drives pulmonary vasodilation AND antiproliferation. Glibenclamide blocked in the monocrotaline model (Intensive Care Med 2011). It replaces the K-ATP downregulation seen in PH remodeling. And Ca sensitization does earn its keep in one spot: RV support, no calcium overload no O2 cost. The target also has drug independent human proof of concept. SVC balloon occlusion and acute splanchnic nerve block both drop filling pressures with preserved output (Fudim/Burkhoff JACC HF 2020/2021). HELP’s levo curves are near superimposable on the nerve block curves. Same signature, different tool. Now HELP honestly, because the bears live here. The hemodynamic primary (exercise wedge at 6 weeks) missed. p=0.65… they stop there. They shouldn’t. READ the paper. The 6 week cath was done a full week after the last weekly infusion, at OR-1896 (the active metabolite) trough. Drug basically gone. The authors say so directly and say greater effects would show with drug on board. (Burkhoff JACC HF 2021; restated in the LEVEL design paper J Card Fail 2025)