The Winding Road of Science, Part 1 of 3
Tl;dr Science isn’t linear. It’s a log of our best mistakes & our best guesses on how to fix those mistakes.
Sit with me for part 1 of 3 of a story that encapsulates why and how Lylah Health came about.
On the silver screen, medical breakthroughs usually happen when a genius is sitting alone in an empty lab, finds a chemical that changes the landscape of medicine, and yells, “Eureka!” In reality, one of the most impactful cardiovascular medications, Entresto, came about after scientists spent 25 years failing in increasingly catastrophic ways.
Today, we’re talking about the sordid history of Entresto. For context, Entresto has the second lowest “number needed to treat” (NNT) to prevent one heart disease related death within heart failure and cardiology at large, second only to beta blockers, which came out three decades before Entresto did in 2014. The story starts back in the 1990s.
We knew about 2 natural peptides the body produces, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We knew they widened blood vessels and signaled to the kidneys to dump extra fluid, or volume, acting as natural diuretics.
The hypothesis was simple.
We knew an enzyme called neprilysin broke down ANP and BNP. If you block neprilysin, you can keep ANP & BNP hanging around and increase the natural diuretic effect, potentially curing heart failure. In real life, science doesn’t work that way.
As the saying goes, “the best laid plans of mice and men,” and we all know the rest. In clinical trials, pure neprilysin inhibitors, Candoxatril & Ecadotril, failed miserably. They barely affected blood pressure and did nothing for heart failure. Forget curing it altogether. The misstep was that neprilysin breaks down ANP & BNP, but it also breaks down Angiotensin II, one of the body’s most potent vasoconstricting chemicals. This just means Angiotensin II clamps down arteries, increasing how hard the heart has to work to pump blood through the body.
By blocking neprilysin, researchers kept around ANP & BNP, but they also kept around angiotensin II. The effects cancelled each other out. Like any good researcher should, they went back to the drawing board. They posited that blocking both neprilysin and the angiotensin pathway could fix the problem.
So, they came up with Omapatrilat. On paper it was flawless. So, they tested it in 25,000 patients in 2002 in the OCTAVE trial. The problem was that while blood pressure did decrease, it also caused an unexpected 3-fold increase in angioedema, or life threatening airway swelling.
Why?
Biologically, there are two “drains” that allow for clearance of the inflammatory peptide made by the body called bradykinin, which promotes the dangerous airway swelling (angioedema). Those drains are angiotensin converting enzyme (ACE) & neprilysin. When you block both drains, bradykinin has nowhere to go and builds up in the body.
The drug was dead on arrival.
