Alnylam Pharmaceuticals

It failed despite showing the same, uh, reduction in TTR as siRNA showed in the past.

The reason it failed is because now in the current populations, they are a lot earlier, they're a lot either healthier or frankly more advanced, and they actually went on top of the stabilizer, the oral drugs, which Alnylam back in the day didn't have to do because they weren't around.

And it turns out that adding an ASO to a stabilizer doesn't work.

We've covered that many times.

You were the pioneer that is credited with discovering RNA splicing and how critical that is for expression of the genome to what we were talking about earlier on.

And this is a critical piece of foundational biology that has led to companies like Alnylam, and we've previously had John Maragonori on the podcast.

So I'm curious if there were, if you can

walk us through some critical moments, I'm sure like this could be, you know, it is like the heart of your documentary, so it could be quite lengthy, but I'd say for this audience knowing, what were the key moments for you? What were the aha moments, if there were any, or, you know, what were the series of smaller moments that led to this critical discovery?

And there's a couple of good examples, some in the past, some in the present.

Our deal with Alnylam.

Yeah, well, this

is a great segue because that's what I wanted to go to.

Now, a few people would argue that it's paid off with Lekvio.

Now it's a blockbuster.

But I think the point of the deal from Alnylam's point of view was to bring them to profitability.

So in the context of what you talked about before, and I know you know John Maragonor, former CEO, chairman of Alnylam.

Of course.

So I mean, I cover Dyne too, like, like, uh, like Brian, and, um, I've covered Alnylam and Ionis for a really long time.

And, you know, as Brian sort of alluded to, like a big question with the Avidity approach in DM one was that they use siRNA, and Dyne uses an antisense oligonucleotide.

And I think we've seen in most all readouts, right, where the two are head to head, siRNA has outperformed, right? We just saw this in, in the TTR space.

It's still about who wasn't at the White House rather than who was.

Administration sources and pharma lobbyists tell me that companies like Vertex, Biogen, Alnylam are under pressure to do MFN deals.

So far, there's no indication that they're gonna succumb to that pressure, and we can circle back to that.

But first, a couple of other things that we learned since last week's podcast.

For starters, Jeffries said that the new data mean oral stabilizers from Bridge Bio and Pfizer will likely remain the preferred first-line option for ATTR-CM.

Alnylam, on the other hand, also has an ATTR-CM drug on the market, and it's a TTR silencer like Wynua.

But Stifel said they don't see a commercial impact for this drug.

Rather, they pointed to potential shifts in Alnylam's ongoing Phase 3 program for its next-gen RNAi therapy.

For this one, Steifel said the company could direct further enrollment toward monotherapy and make results from that group the primary outcome.

Yeah, I mean, certainly learn from others' failures if you can and improve the outcomes for patients.

So let's talk more about Inceptive.

And you recently partnered with Alnylam Pharmaceuticals.

From your perspective, just what makes this partnership and this collaboration so powerful? And how will it help unlock future medical breakthroughs?

So...

That's the whole fight.

Eighty-one percent of this trial was already on stabilizers against fifty-three percent in Alnylam's HELIOS-B.

So a contemporary population is exactly what AstraZeneca and Ionis enrolled, and it may be what buried eplenercin.

The reading amplifying pressure on Alnylam is that the additive benefit of stacking a silencer on top of a stabilizer is smaller than HELIOS-B implied rather than the study having been designed badly.

Alnylam is down around thirty percent since the top line landed in July.

Anucrasiran is now the referendum.

Its pivotal allows stabilizers with enrollees on them.