Biotech Values

[poorgradstudent]

Cardioxyl:

This is yet another attempt to promote vasodilation and relieve stress on the heart. One of the founders, Kass, has long been beating the drum that the viagra target PDE5 is present in the heart and through its inhibition could mediate beneficial effects. As brief background, NO donors work to increase intracellular cGMP (via guanylate cyclase activation) and this is a primary mechanism of blood vessel relaxation. Viagra (sildenafil) induces relaxation by inhibiting PDE5, the enzyme responsible for breaking down cGMP.

Most people accept that the NO effect is directed at the vasculature; Kass insists that the heart is also major direct target. He has published multiple papers showing that "PDE5" inhibition in the heart is beneficial in animal models*.

This HNO approach seems to come at it from another way: to increase guanylate cyclase activity via HNO in order to increase cGMP production rather than decrease its breakdown via PDE5 inhibition. I don't see why this would be anything meaningful. They make a fuss that HNO is not just simply NO, but then show that the HNO effect in relaxing the vasculature is dependent on guanylate cyclase activity just like NO. So really, the only thing left is the magic that they claim for this compound once it enters the heart. They note that it may also react with some redox sensitive amino acids (like cysteine) to impact intracellular signaling. Not exactly a targeted approach, and definitely ill-defined. All in all, it's a compound that, despite their protests, seems to act a lot like NO; I'm unconvinced that there is any special sauce here.

They also claim that:

Experimental HNO prodrug CXL-1020 improved ventricular relaxation and systolic function in two different preclinical models of chronic diastolic dysfunction, a disease that has so far eluded effective clinical therapy.

Well, that may be interesting if not for the fact that a Kass collaborator ran with his idea and tried sildenafil (PDE5 inhibitor) in a large population of heart failure with preserved ejection fraction (HFpEF, annoyingly pronounced heff-peff!), which is basically synonymous with "diastolic dysfunction." Bottom line: zero benefit whatsoever. In fact, many of the results were actually numerically better for placebo.

I honestly have no idea what BMY is doing. It's their dime. But I'll be very surprised if this goes anywhere.


* Multiple papers by many strong scientists have shown that the PDE5 enzyme is not present in the heart to any certain relevant degree. Kass continues to insist that it is, and shows blots with antibodies that have been shown to be nonspecific. Despite his funding and publication background, I wouldn't base any of my work on his prior publications. That's just me.