Below is the transcript from ACADIA Q4 Q&A regarding...

Below is the transcript from ACADIA Q4 Q&A regarding Trofinetide. Hope is can clear some

queries

Question

Ritu Baral(Analysts)

On trofinetide, canyou elaborate just a little bit more on the diarrhea management planthat you alluded to in the Acadia Connect program, I guess, is what the nursecare coordinators and on-call pharmacists will help manage? Can you describewhat you're going to recommend, the support? And then do you think that yourassumptions for diarrhea discontinuation rate will resemble what you featuredtoday in LILAC?

Answer

Brendan Teehan(Executives)

Sure. Thanks for thequestion. As we said in our prepared remarks, we are building our caregiver andpatient support around our hub, also known as Acadia Connect. This is intendedto provide comprehensive end-to-end support to both caregivers and patients.And it's critical to do that to help patients not only start, but stay ontherapy and ensure the optimal treatment experience. We will also have 24/7clinical pharmacists -- clinical nurse coordinators at the hub. And then in thefield, we are supplementing that with family access coordinators, family accessmanagers that are intended to be face-to-face with families as they start andthen begin to stay on trofinetide.

Answer

Stephen Davis (Executives)

Great. Thanks, Brendan. Ritu,in response to the last part of your question regarding diarrheadiscontinuation rates, I think with any drug, sometimes there can bedifferences between what you see in clinical studies and what you see inreal-world practice. And I think the way I would think about this, and as we'vesaid very consistently, with drugs that have symptomatic relief onsubjective endpoints, you will have a certain amount of discontinuations in theearly months of therapy. We see that in neuropsychiatry a lot. We see thatwith NUPLAZID. And so you'll see that.

I would think of thispopulation in 2 components. One is the prevalent population. So there's asizable prevalent population that we -- that will access the drug first. We'llwork through that population, and then there's an incident population beyondthat. And so as we think about the dynamics of this molecule, we recognize thatthere's -- it's a very, very highly debilitating disease. There's no approvedtherapy. The benefits that we see with trofinetide offer hope for the firsttime to these families. And so I think there'll be a high motivation to accessthe therapy. And then what we anticipate over time is as we work through theprevalent population, the -- in the early months of therapy where we have a lotof patients going through that simultaneously, then the discontinuation rateswill settle in -- will flatten out and settle into a much more normal cycle. SoI hope that's helpful. We'll go to the next question now.

Question

Charles Duncan(Analysts)

I guess I'mwondering if you had any, I guess, patterns that you recognize with regard todiscontinuations and/or diarrhea specifically with regard to timing andseverity. And do you anticipate actually formally engaging with the agencyregarding Rett?

Answer

Kathie Bishop (Executives)

All right, Charles, thanksfor the question. With regards to the pattern of discontinuation duetrofinetide -- due to diarrhea associated with trofinetide, I will say thatthe pattern discontinuations in LILAC was very similar to that in LAVENDER andthat we have a very similar discontinuation rate within about the first 3months and then a smaller rate after that.

And as I mentioned on thecall, in the subsequent study, LILAC-2, we have a very low discontinuationrate and none do the diarrhea to date. So one pattern that emerges fromthis is that the longer you are in trofinetide, longer you're able to stay onit.

As I mentioned, it is alsonotable, though, that in the early years of these trials, they did extend overseveral years, we did not have the diarrhea management plan in place. So as wethink ahead to launch, we are instituting that plan, and Brendan and his groupis there to provide many resources to caregivers and the patients to manage thediarrhea to be able to give them on drug.

Answer

Stephen Davis (Executives)

Yes. I think, Charles, ourstandard response when we're in registration is not to comment on back andforth we have with the agency, but I just simply say that they've been veryengaged. We're eager to [indiscernible] to our PDUFA day, but we don't commenton things otherwise.

Just one important contextualpoint, I just want to mention in terms of diarrhea. I know we've said itbefore, it's a really important point, though. Rett patients, on average, haveabout -- about 80% of them have significant constipation, and it can get quitesevere. It can lead to impaction, hospitalization. They've even a few reportedcases of death due to sepsis associated with constipation and infection. Sothis is very top of mind in the right community with physicians as well ascaregivers. And so in some respects, the diarrhea effect that we see withtrofinetide can be somewhat of a trade-off.

And you also have a situationwhere almost all of these Rett patients were diaper type garments sertraline.And so just some additional context around that. And as Kathie mentioned, a lotof diarrhea management mitigation regimen steps that we took late in -- or thatwe developed late in the LAVENDER study that time, significant majority ofpatients in LILAC had already been completed that 40-week program as well.

So we're very eager to get tothe finish line here. And as Brendan described earlier, we have a lot ofresources that will put -- that will bring to bear to help families manage thetolerability of trofinetide, which we think is significantly outweighed by thesignificant benefits that we see, which we see continuing sustained andcontinuing to grow through the LILAC study.

Question

NeenaBitritto-Garg (Analysts)

Just a follow-up onthe last question on the impact of diarrhea and discontinuation. Just curiousif you can comment on what happened when you did implement the diarrheamanagement program in the LILAC open-label extension study. Did you see thatpatients who were maybe earlier in the OLE did have a lower discontinuationrate? I'm just trying to contextualize how to think about the impact of thediarrhea management on the discontinuation rate.

Answer

Kathie Bishop (Executives)

Yes. Thanks for the question.So as we implemented the diarrhea management plan, which, as Steve mentioned, it'sreally important to keep into context that 80% of these patients haveconstipation, which can be very severe, the first step in the plan is to stoptaking your anti-constipation medications, and many of these patients are on 2or 3 of those, and then to implement anti-diarrhea over-the-counter measuressuch as increase in fiber in the diet and over-the-counter loperamide. Soas that plan rolled out and then became implemented by the caregivers and thephysicians in the trial, we certainly hear feedback that those steps arehelping to control the diarrhea and later on in the trial keep patientstrofinetide.

I should also add, as we'retalking about diarrhea, remember that the diarrhea is almost all mild ormoderate in nature, and it's not a safety concern. It does notlead to dehydration, does not lead to weight loss, does not lead tohospitalization. So this is really a management issue and through thetrials and working with some of the study nurses and clinicians, I think we putin place steps to help [ parents ] better manage it, and that's what we intendto do as we move towards hopeful commercialization.

Question

Eddie Hickman(Analysts)

This is Eddie onfor Yatin. Congrats on the quarter. Do you expect any impact on the trofinetidefiling or review now that [ Billy Dunn ] has departed? And do you expectto have any restrictions or limitations on the label or have to complete anypost-marketing studies after potential approval?

Answer

Stephen Davis (Executives)

Yes. Yes, I'll take the firstpart of that. We don't anticipate any any impact from [ Billy Dunn ] leavingFDA. We -- as you might expect, we reached out the FDA today, heard back,and they expressly confirmed that we should not -- this should not have anyimpact on our application. [indiscernible] has been acting Deputy Directorof the Office of Neuroscience for some time and will continue with that role aswell as the Director of the Neurology One division. So I understand thereason for asking the question, but we don't think it will have any impact onour application.

Question

Lee Hung(Analysts)

Can you share withus some of the recent feedback you've been hearing from your conversations withpayers of trofinetide? Is there anything that you found surprising?

Answer

Stephen Davis (Executives)

Yes. Thanks much for thequestion. Brendan, do you want to take that?

Answer

Brendan Teehan(Executives)

Sure. Yes. Thanks for thequestion. Just in context, we have had discussions with payers really since weacquired the program dating back over a year at this point. But even morerecent conversations, I would say that payers have very logical questions thatwe're able to address. The first is many payers simply don't know what Rettsyndrome is. We have to describe this as a devastating disease, the fact thatit requires a round-the-clock support and dimensionalize it for them from theoutset. They are very well aware that trofinetide would be the onlyFDA-approved drug for treating the core symptoms of Rett in that it isdifferent than some of the individual symptomatic types of medications that mayhave proceeded it. They're aware of now from our education trofinetide, thatpositive benefit risk profile and understand that this is a rare disease spacewith a pricing model for products like this that they've come to expect andthat this is a very rare and difficult population.

So given that, we feelconfident that we're going to be able to ensure access to patients -- toappropriate patients and their families if we are lucky enough to have anapproval in the near term

Question

Kathryn Smith(Analysts)

This is Kathryn onfor Paul. Just on trofinetide on the regulatory side. What do you see as thegreatest risk to [indiscernible] at this point, if any? And then on thelaunch, how are you thinking about the cadence post approval and how soon afteryou can expect to start treating patients?

Answer

Stephen Davis (Executives)

Yes. Thanks much for the --for 2 questions. Brendan, do you want to take the second question first? .

Answer

Brendan Teehan(Executives)

Sure. Thanks for thequestion. As you would expect, we're doing everything that you would expect ofa company getting ready to launch a first-in-class product in a rare disease,and we will be ready to go pretty quickly after approval.

There are really just a fewthings from a logistical perspective that takes some time. One is thefinalization of a label, obviously, because it has lots of implications aboutproduct drug availability, also training our field force to make sure that theyare 100% prepared to support the physicians that want to prescribe and thefamilies that want to get started. But other than those simple logistics,we see no other reasons for delay, and we know that the community is[indiscernible].

Answer

Stephen Davis (Executives)

Thanks, Brendan. I'll takethe second part of the question. I think in terms of risk to an approval, I'llstart just repeating what we said before, and that is we just don't comment onback and forth with the agency. And when under review, it's just always beenour standing policy. Having said that, as we've said, we're eager to get toMarch 12. The FDA -- we're very happy with the level of engagement we've hadwith FDA. And as noted a second ago, they just confirmed this recently as thismorning that [ Billy Dunn's ] departure will not have any impact. And so we'reeager to get to March 12. Everything appears to be on track at this point.