How should Cirque Nation think about interpreting those results? Let's start there, and then let's get into actually what you found.

Well, first of all, it's a great question.

And Eugene Bromwald once said to me, there's no such thing as a failed trial, because you learn something from every trial that you ever do.

And we tend to think very black and white when it comes to trials, but we know that the Level of significance sometimes is arbitrary, and we've seen cases where you just miss clinical statistical significance, but you have important information, and sometimes you can see important heterogeneity in a study.

Not all drugs work in everybody the same way, but you have to be fairly rigorous, obviously, about it.

Now, in this trial, this was clearly a negative primary endpoint.

And part of the reason for that is because roughly 80% of the patients in this study were of the lambda isotype.

What do you think lies ahead for this program?

So Scott, give us, give us your view as you've looked over, uh, uh, the history of development that you've been so deeply involved in over the last, uh, twenty, thirty years.

Yeah.

So, um, you know, I think you, you set up the question very well, Chris, because, uh, ideally we would have surrogate endpoints that we could use to guide us, um, uh, with respect to, uh, both determining if a therapy is going to work when you do a proper outcomes trial, but also, you know, whether there are any potential surrogates that might be used, um, for, uh, registration, for example.

And, and, and it-- You know, we-- I think we might be joined in the next few minutes by, um, Maury Krantz from FDA, um, who, uh, can speak to this issue.

But so far, the, the, um, regulatory agencies have not accepted surrogates per se as, um, uh, for, for registration, uh, a-and, and approvability.

And, and instead, what they've said is that, you know, you either have to, um, demonstrate that you can keep people alive longer, keep them out of the hospital longer, or, um, you can make them feel better or function better.

So it's feel and function or survival or survival free of heart failure in the case of the, the heart failure studies.

Mm-hmm

Do you think we can put some standardization, some guidance, two investigators, two developers, two companies around the construct of phase two studies, let's say for heart failure development.

Sure, but I think it's worth taking a step back and thinking, what are you really trying to do with phase two? And we talked about de-risking phase two, but in fact, we're not really de-risking phase two.

What we want to de-risk is the whole program, the development of a therapy.

In fact, you know, phase two is a whole lot less expensive.

I'm sure there are people on this call who can vouch for that better than I can.

A whole lot less expensive than phase three.

So spending the money in phase two is not unreasonable if you get an answer that will lead you to either move forward in a way that will allow you to claim success ultimately or to stop a program.

What's the one most important bit of advice you'd give me as I think about designing my phase two study?