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Dürfte, aber es wird eh drauf geprügelt

HERMES wurde scheinbar pausiert, aber Ziltivekimab dürfte nach ZEUS sowieso mit 0,0 im Kurs stehen. Medizinisch aber sicher bitter, dass ein Medikament die definierten Marker erreicht, diese Marker aber in der Realität/Kontext wertlos sind.

Another major shock for cardiovascular research. HERMES: one of the largest and most ambitious HFpEF trials ever undertaken, testing IL-6 inhibition has just been terminated. This is more than another negative trial. After the failures of Cardio-TTR transform and HORIZON all occuring this week, It raises fundamental questions about how we discover and develop Cardiovascular drugs. How we select biological targets, and translate mechanistic signals into therapeutic strategies. I’ll share more soon on what I think this means and most importantly what may need to change in the field.

I’m a cardiologist. Today cardiologists everywhere were humbled by this trial. The trial is Lp(a)HORIZON. Pelacarsen, a monthly antisense injection from Novartis and Ionis, was given to 8,323 patients who already had heart disease plus genetically high lipoprotein(a). These were not untreated people. They were on modern guideline therapy—high-intensity statins, blood-pressure control, antiplatelets. The drug did its job: it slashed Lp(a) levels by roughly 70–80%, the same drop we saw in earlier studies. The thing it was supposed to prevent did not move. Cardiovascular death, heart attack, stroke, and urgent stents or bypasses were no lower than placebo. The miss held even in the sicker subgroup whose Lp(a) started above 90 mg/dL. That is why the field is in shock. For a decade we treated this as settled biology. Lp(a) is 80–90% genetic. One in five adults carry high levels. Diet and gym do almost nothing. Observational studies and Mendelian randomization kept saying the same thing: higher lifetime Lp(a) means more heart attacks, more strokes, more aortic stenosis. Phase 2 looked like a home run—an 80% reduction with a simple monthly shot. We told ourselves this was the missing piece for the patient who already has perfect LDL, perfect blood pressure, doesn’t smoke, and still has events. Many of us expected it to be as important as the arrival of statins. Companies spent years educating the entire cardiology community that we finally had a target we could actually hit. We were wrong about the simple version of the story. A lifetime of high Lp(a) from birth is not the same experiment as turning the number down for a few years after the arteries are already damaged and every other risk factor is already optimized. Residual risk from Lp(a) may simply be smaller once LDL is already in the 40s. Eighty percent lower may still leave too much particle in people who started very high. The next drugs (siRNAs) go deeper and last longer; this was the first-generation ASO. Benefit, if it exists, might live in younger patients, primary prevention, or extreme levels rather than this secondary-prevention population. Or the effect on existing plaque and thrombosis is slower and smaller than the genetics made us believe. We will get the full event curves, actual achieved levels, and every subgroup later this year. Other outcome trials with more potent agents are still running. The Lp(a) chapter is not closed. But the version we all believed—“lower this inherited number and events will follow in already-treated patients”—just failed its first large, hard test. Measure Lp(a) once. Treat everything else we can actually change as if it still matters. Because today we learned, again, that a beautiful lab change is not the same thing as fewer funerals. Science is supposed to surprise us. This one did.

Wenn man mal überlegt was die Analysten in ihren Modellen hatten, niemand hat damit gerechnet und der weltweite Rollout ist gerade erst in den Kinderschuhen

Wer auf andere hört, der sollte in erster Linie sich selbst hinterfragen und nicht die Schuld bei anderen suchen…

Bei 50€+ werde ich dich wieder daran erinnern.😉