***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)

$vera ***deep dive long*** as promised, deep dive before open tomorrow. I like this setup, with a PT of $90 , not many 100% + setups in this tape. So you’re welcome. Atacicept’s AA PDUFA coming up Monday or Tuesday this week. $vera is trading at $41 (~$3B cap, ~$2.4B EV), and btw Otsuka headline is what caused the sell off on Friday. I think people are trading the competitive optics and ignoring how big the TAM is getting. In fact the market is bigger than the Street models and KDIGO 2025 is why. The lazy version is treat obvious high risk ≥1 g/day proteinuria, everyone else stays on Gx + SGLT2. But get with the times bro. KDIGO 2025 moved the goalposts… biopsy is now recommended at possible IgAN with proteinuria >0.5 g/day or reduced eGFR and the treatment target dropped to <0.5 g/day, ideally <0.3. That pulls a materially larger pop into an active treat/escalate pathway and pushes disease modifying therapy toward any pt with disease because even a hemodynamically stable pt on ACE/ARB + SGLT2 with low proteinuria is still accruing slow tissue damage. Add an APRIL or APRIL/BAFF early enough and you can potentially arrest that before proteinuria even starts (and proteinuria itself damages the kidney over time). This is why I think the whole category has been under modeled, not just $vera ~100k US pts is the number people anchor to, but there are ~50k across just 10 European countries before you count the rest of Europe and China/Asia carries the highest IgAN burden on earth. Now the revenue math only ~2,500 treated patients gets you to ~$1B at current pricing. For context Otsuka added ~880 patients in Q1 alone. Run it forward… at ~$300k net off ~$390k gross (23% GTN … baking in real competitive friction), 15k active patients 1/10 of the US population alone is $4.5B in revenue. Sensitize net down to $250k (36% GTN) and 20k patients still does $5B. At a ~$2.4B EV, $vera only needs a fraction of IgAN to drive real upside. I think TAM $20–30B once you account for the KDIGO shift and ex US. A recent KOL survey points to heavy branded uptake… docs expect to put ~75% of their IgAN patients on new agents, including combos. ERAs and B cell agents are each projected to reach 35–40% of pts within 5 years two large categories stacking on top of each other consistent with a >$10B class. B cell uptake specifically is fast: ~17% penetration by 6 months, ~30% within a year. On the H2H stuff the survey says atacicept is not at a disadvantage. Nephrologists view the three lead B cell agents (atacicept, povetacicept, sibeprenlimab) as comparable on efficacy. Where they split them is marginal: povetacicept is seen as weaker on safety, atacicept slightly weaker on dosing i.e. the weekly cadence, which is precisely the gap that monthly dosing data would close. Survey implied intra class penetration lands around sibeprenlimab ~19%, atacicept ~12%, povetacicept ~12% , atacicept at parity with pove and within a few points of the first mover... The real gating factor is access and it’s class wide. The docs surveys dominant hurdle isn’t efficacy differentiation, it’s payer friction.. prior auths, SOC step throughs, sometimes proteinuria thresholds (typically 1–1.5 g). That’s a category dynamic every entrant shares not a $vera specific prob, and it argues the bear narrative is aimed at the wrong variable. Meanwhile about half of docs would consider combo use, most commonly B cell + ERA, which validates the stacking to UPCR<0.3 thesis and grows the treated base rather than forcing a 0 sum share fight.