The Winding Road of Science, Part 2 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 2 of 3 of a story that encapsulates why and how Lylah Health came about.

Why Scientific Breakthroughs Take Time

Imagine yourself at work or doing something that you’re passionate about. Let’s say you have a thought: “If I do X, Y will happen.” How long are you willing to spend failing repeatedly before you decide this is no longer worthwhile?

That’s exactly the question that Entresto poses. Entresto, for the uninitiated, is a landmark heart failure drug with the second lowest number needed to treat (NNT) to prevent one heart disease related death in the entire arsenal of therapies we have in cardiology. The magic number for the researchers behind it was 25 years, 25 years of repeated failure.

They failed over and over again before finally finding success in a trial after repurposing the drug itself. They encountered failures, went back to the drawing board, and came up with new ideas in response to the data that they saw.

This is a story about Entresto. This is a story about science. This is a story about passion.

From Failed Clinical Trials to Entresto

So, let’s pick up where we left off.

The OCTAVE trial was tested in 25,000 patients, a massive number. The researchers thought they had it with Omapatrilat. However, there were unexpected side effects. Accumulation of bradykinin, a pro-inflammatory peptide, increased the risk of angioedema, or life-threatening airway swelling, by 3-fold. Fast forward to 2014, and the PARADIGM-HF trial came out, testing Entresto.

This time, they paired the neprilysin inhibitor, sacubitril, with an angiotensin receptor blocker (ARB), Valsartan. This combination was pitted against standard of care Enalapril, an ACE (angiotensin converting enzyme) inhibitor, on the same pathway as ARBs like Valsartan.