Jennifer Good: So David, I’ll let you answer both of those.
David Clark: Yes. So with the SSRE we are utilizing, it is not acceptable with regulators, particularly the FDA to use the success criteria, such as you’ve outlined. So you’ve got 80 subjects completed the primary time point and you’ve separated with several doses from placebo. The FDA will not allow you to build that sort of success criteria into this sort of a standard SSRE. So there’s the answer to the first question. It really just in a closed loop system, you say is your variance and your effect size sufficient for your assumptions going in. So your sample size cannot fall below 160. And what was your second question? I’m sorry.
Jennifer Good: The second question, I can jump in, David, and then you can add color. He wanted to know if the magnitude of effect is strong. Can we go straight from POC to pivotals? And I think in IPF, we’re doing a Phase IIb to select dose and the intent is to roll into our pivotal program. I think with RIVER, the Phase 2a, the internal consensus is, and David, this is where you can add some color, is we are planning for a Phase 2b that is structured to look like a pivotal. So we still are probably going to need to do some dose ranging work to make sure we’re clear in that patient group, but we will try to structure it to look like a pivotal study and then depending on the data, can hopefully have discussions. But David, any color you want to add on that?
David Clark: No, I think that addresses it very well. Thanks, Jennifer.
Jack Padovano: Great, thank you.
Jennifer Good: Thank you, Jack.
Operator: The next question comes from Tom Smith from Leerink Partners. Please go ahead.
Nathanael Charoensook: Hi, this is a Nat Charoensook on for Thomas Smith. We have a couple of questions on the RIVER study. So first, what’s the rationale for choosing 21-day duration while the other late-phase trials look at endpoint at 12 or 24 weeks? And I have a follow-up.
Jennifer Good: Yes. I mean the rationale is all Phase 2as — I mean for the compounds you currently see in development, they all ran this Phase 2a crossover design as a proof-of-concept sort of to show that your drug is working, it takes away some variability. As you exit the proof-of-concept, that’s when you get into the longer trials.
Nathanael Charoensook: Got it. And what’s your expectation on the data expected in 2024? Do you anticipate to see a different level of efficacy in patients with moderate versus severe cough frequency, as you look at what change in cough frequency rather than the absolute changes.
Jennifer Good: Yes, David, do you want to talk a little bit about sort of the hypothesis around the study and what we’re trying to show with the different cough levels and things?
David Clark: I’d be happy to do that, Jennifer. So the information we have so far, and it is, as you know, it’s only from the CANAL study in IPF chronic cough population is that baseline cough frequency did not influence the efficacy signal. It was as robust in the subjects independent of that cough frequency. So that’s the only information we have going into this. And as you’re aware, there has been difficulty with peripheral-based mechanisms of action, getting the signal in that moderate population. But our information going into the study is that based on the IPF chronic cough, we didn’t see any evidence of the difference — a change based on baseline cough frequency.
Nathanael Charoensook: Got it. And do you plan to include efficacy endpoints that can capture, for example, like cough cluster or cough episodes appear to burden patients with RCC.
David Clark: I’m sorry, can you repeat that question?
Jennifer Good: Is that the cough clustering you’re asking about? And are we capturing some of that data?
Nathanael Charoensook: Yes.
Jennifer Good: Yes. And David, I think we have an ability to go back and do that analysis correct?
David Clark: We do — absolutely, we have that prespecified as analysis, which we will be conducting because as we have mentioned before, we believe — we think the primary end point for cough programs, we believe, will stay the same as it is right now, using 24-hour cough frequency, but there’s clinical relevance to these cough bouts by these different definitions. So we really want to study them in all of our studies moving forward. So we understand what sort of effects we’re having there, in addition to what we believe will be the registration endpoint.
Nathanael Charoensook: Alright. Thank you so much.
Jennifer Good: Thank you.
Operator: [Operator Instructions] The next question comes from Mayank Mamtani from B. Riley Securities. Please go ahead.
Mayank Mamtani: Good afternoon, team. Thanks for taking our questions, and congrats on the progress. So just maybe on the SSRE for the CORAL trial. If you could just maybe clarify the statistical assumption for placebo as well as, I guess, the top dose you’re looking to show separation against. Just maybe how many patients, what sort of effect size and p-value. And also, are there any baseline characteristics that could be different between CORAL than CANAL that we should be aware of? And then I have a quick follow-up.
Jennifer Good: David, do you want to take that?
David Clark: I’m happy to do that, Jennifer. So in terms of the inclusion criteria, we did not change them. So the way we are selecting the IPF chronic cough population is the same as we utilized in CANAL. I mean the main difference, as you know, is it’s a global program. So the — there is the potential for some differences there. We will see in the study. So the assumptions we made for the SSRE, the end of 160, so that’s 40 per group. That is based on an effect size of active drug above placebo on top of the placebo effect. So the separation on top of placebo effect of 36%. We’ve got more than 80% power going into the study with the end of 160, 40 per group. The top end of the sample size that we are allowed to go to, we said at 160, we can go up to 400.
