Travere Therapeutics Inc (TVTX) 2018 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Retrophin Third Quarter 2018 Financial Results and Corporate Update Conference Call.

(Operator Instructions) As a reminder, this conference call is being recorded.

I would like to turn the conference to your host, Mr. Chris Cline.

Please go ahead.

Great.

Thank you, Rusty.

Good afternoon, everyone, and welcome to Retrophin's third quarter financial results and corporate update call.

Joining me on the call today are Steve Aselage, Chief Executive Officer; Neil McFarlane, Chief Operating Officer; Laura Clague, Chief Financial Officer; Dr. Noah Rosenberg, Chief Medical Officer; and Dr. Bill Rote, Senior Vice President of Research and Development.

Before we begin, I would like to remind everyone that statements made during this call regarding matters that are not historical facts are forward-looking statements within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Forward-looking statements are not guarantees of performance.

They involve known and unknown risks, uncertainties and assumptions that may cause actual results, performance and achievements to differ materially from those expressed or implied by the statement.

Please see the forward-looking statement disclaimer on the company's press release issued earlier today as well as the Risk Factors section in our Forms 10-Q and 10-K filed with the SEC.

In addition, any forward-looking statements represent our views only as of the date such statements are made, November 1, 2018, and Retrophin specifically disclaims any obligation to update such statements to reflect future information, events or circumstances.

With that, let me now turn the call over to Steve.

Steve?

Thanks, Chris.

Good afternoon, everyone, and thank you for joining us today.

During the third quarter, we advanced our pivotal fosmetpantotenate and sparsentan programs, and our partner made good progress with the Phase II proof-of-concept study of CNSA-001.

These programs represent a potentially transformational opportunity to deliver therapies to patients with significant unmet needs and drive significant growth for our organization.

We expect the first pivotal data to come from the Phase III FORT Study of fosmetpantotenate for the treatment of PKAN.

Our clinical team continues to focus on execution, and we now have line of sight to the patients that will complete enrollment in that study.

Importantly, we remain on track for top line readout in the second half of 2019.

I'm also pleased with the progress we've made with the sparsentan programs for FSGS and IgA nephropathy.

We recently had positive interactions at the international IgA nephropathy symposia and at the ASN Kidney Week meeting.

At these 2 meetings, we leveraged the growing enthusiasm for sparsentan on an international stage to generate excitement for both the DUPLEX and PROTECT studies.

Notably at ASN, we presented the longest period of follow-up data thus far from the Phase II DUET open-label extension.

The data following FSGS patients out to 84 weeks suggested a progressive reduction in proteinuria and a stabilization of eGFR.

These findings give us growing confidence that the design of our Phase III DUPLEX Study is well positioned to show a clinically meaningful benefit with sparsentan and ultimately support approval in the U.S. and Europe.

The DUPLEX Study continues to open sites for screening and enrollment activities moving ahead in both the U.S. and Europe.

Our team remains focused on reaching our goal of getting the 190th FSGS patient into the study to enable a readout of the interim analysis in the second half of 2020.

In IgA nephropathy, we were pleased to present the design of the Phase III PROTECT Study at the International IgA Nephropathy Symposium.

As a result of our team's efforts, there is a growing enthusiasm for sparsentan within the IgA nephropathy community, and we're looking forward to dosing the first patient in that study before year-end.

At the end of the day, our goal is for sparsentan to become the first approved therapy for both FSGS and IgA nephropathy, and we are making great progress in this effort.

Additionally, our partner, Censa Pharmaceuticals, has initiated dosing in the CNSA-001 Phase II proof-of-concept study in phenylketonuria or PKU.

The team at Censa has done an exceptional job developing that program, and we are looking forward to the top line data readout expected in the first half of next year.

This will help inform our decision on the option to acquire Censa and potentially move the program directly into a Phase III study.

Overall, I'm proud of the advancements across our clinical programs.

We are in the fortunate position of having multiple opportunities to positively impact people living with rare disease in the near future.

Operationally, we maintained year-over-year growth on revenues but fell short of our projections for the quarter.

There were a few factors that led to net revenue coming in below our forecast, but the most significant one was lower-than-anticipated revenue from the bile acid products.

Neil will provide some additional color on that shortly.

The underperformance in the third quarter means we will likely end 2018 moderately below the low end of our net revenue guidance of $170 million for the year.

Notably, we anticipate an improvement in net revenue performance in the fourth quarter and to extend our trend of year-over-year growth.

We are already seeing signs of that rebound with the strong first month of Q4.

A highlight from operations in the quarter was the completion of a successful convertible debt financing, which provided us with resources to execute our ongoing and anticipated clinical activity to support our programs.

The additional capital also will allow us to proactively plan for upcoming product launches and give us some added flexibility when looking for new products or candidates to in-license.

Last but not least, we made a key new hire during the quarter with the addition of Dr. Noah Rosenberg as our Chief Medical Officer.

You'll hear directly from Noah next, but we are very pleased to have him join the team and focus on clinical execution.

His track record of advancing therapies for the clinic to approval further strengthens the team here, and he will play an important role in shaping our clinical activity.

Let me now turn the call over to Noah for the trial updates.

Noah?

Thanks, Steve, and good afternoon to everyone.

I'm honored to be here and to partner with Bill on our exciting efforts to deliver first-in-class therapies to patients in the near future.

One of the main reasons I was so motivated to join the Retrophin team was the opportunity to help lead the clinical activity that can potentially shape the treatment paradigm for thousands of people living with rare diseases like PKAN, FSGS and IgA nephropathy.

We had a very productive last few months that have built upon the momentum from the first half of the year.

The pace of enrollment in the pivotal FORT Study of fosmetpantotenate and PKAN is highly encouraging.

As Steve mentioned earlier, we have the privilege of being able to share with you today that we now have line of sight to completion of enrollment in the study, which should occur around year-end.

The FORT Study is being conducted under a special protocol assessment agreement with the FDA that provides assurance that the trial will support registration if we see clinically significant response on the PKAN activities of daily living scale after 24 weeks of treatment with fosmetpantotenate.

With the FORT Study, we have a great opportunity to help patients with PKAN, and we are eager to see the top line data readout in the second half of 2019.

We also continue to make progress with our sparsentan programs in both FSGS and IgA nephropathy.

Our pivotal Phase III DUPLEX Study continues enrollment efforts for approximately 300 patients with FSGS.

The majority of U.S. sites are now open.

Over the last month, we've been visiting these sites and the engagement with investigators has been encouraging.

We also recently completed our European investigator meeting and had the first EU sites opened during the quarter.

So far, we have been pleased with the protocol's design, ensuring that we have a population in the study that closely aligns with that of the Phase II DUET study.

As many of you will recall, our interim analysis in the DUPLEX Study will be looking at the FSGS partial remission of proteinuria endpoint in approximately 190 patients after 36 weeks of treatment with either sparsentan or the active control, irbesartan.

Right now the teams are working hard on enrollment to enable the top line readout in the second half of 2020.

If positive, interim analysis is expected to support Subpart H accelerated approval of sparsentan in the U.S. and conditional marketing authorization consideration in Europe.

We'll be evaluating change in slope of eGFR in all 300 patients after 108 weeks of treatment.

A positive outcome on this endpoint would support full approval in the U.S. and Europe.

We also reached a key milestone during the quarter for our IgA nephropathy development program.

At the 15th International Symposium on IgA nephropathy, we presented the design of our upcoming pivotal PROTECT Study.

This was well received by investigators and key opinion leaders in attendance.

The pivotal PROTECT Study is a global randomized multi-center double-blind parallel arm active control Phase III clinical trial evaluating the safety and efficacy of sparsentan for the treatment of IgA nephropathy.

This Phase III trial is similar in many ways to the DUPLEX Study.

One of the key shared features is a proteinuria based endpoint to support Subpart H approval in the U.S. and conditional marketing authorization in Europe.

The PROTECT Study's primary endpoint will evaluate reduction of proteinuria from baseline after 36 weeks of treatment with either sparsentan or irbesartan in approximately 280 patients with IgA nephropathy.

The link between reduction in proteinuria and renal survival has been well documented in IgA nephropathy, and our independent assessment here has given us confidence in the design of the PROTECT Study and its potential to generate a positive outcome for sparsentan.

Importantly, we anticipate dosing the first patient before year-end, and at that point, we expect to provide time lines for enrollment milestones and data readout.

In my first 3 months, it has become clear that we have an extremely talented organization dedicated to advancing life-changing therapies and collectively keeping patients' needs at the center of everything we do.

We have made some great recent accomplishments, and I am looking forward to helping build upon the team's success.

Let me turn it over to Bill for additional updates in research and development.

Bill?

Thanks, Noah.

As you can tell from Noah's comments, we continue to build support and momentum for our programs.

This was evident at the recent ASN Kidney Week meeting held last week in San Diego.

It was great to have exciting new data from the DUET open-label extension and growing enthusiasm for the sparsentan programs at this year's premier nephrology meeting in our own backyard.

Notably, in the open-label extension, we saw durable reductions in proteinuria and an increasing proportion of patients achieving FPRE.

Treatment with sparsentan was also associated with the stabilization of eGFR out to 84 weeks.

The fact that 62 patients, about 2/3 of those who completed the double-blind portion of DUET, remain in the open-label extension of the study today is also very encouraging.

Some of these patients have been receiving sparsentan for nearly 4 years and continue to see benefit.

These foundational data from the DUET study give us increased confidence that the DUPLEX Study design has the potential to ultimately support approval of sparsentan.

We were also pleased to announce the publication of the Phase II DUET manuscript in JASN and have it featured as part of the Best of JASN (sic) [ASN] Journals session at the meeting.

The publication of our data helps bolster our position as leaders in the field of developing therapies for FSGS.

As Noah mentioned, our fosmetpantotenate program continues to make strides with enrollment in the FORT Study.

We're also doing considerable work beyond the FORT Study to support the eventual NDA submission for fosmetpantotenate.

Now having line of sight to the last patients to enroll allows us to start the NDA planning process, and we look forward to advancing that effort in parallel with the study conduct.

Additionally, the 4 patients receiving therapy through physician-initiated treatment protocols continue to remain stable on therapy now for up to 4 years.

Lastly, I'll touch briefly on CNSA-001, which is being developed for the treatment of PKU under a joint development program and option agreement with Censa Pharmaceuticals.

The team at Censa has been an excellent partner to work with, and we remain encouraged by their progress in advancing the PKU program.

During the third quarter, Censa initiated sites and recently commenced dosing in the Phase II proof-of-concept study.

We continue to expect the results from that study to be available in the first half of 2019.

Let me turn the call over now to Neil for the operational update.

Neil?

Thanks, Bill.

From a top line perspective, we continue to see year-over-year organic revenue growth in the third quarter, which resulted in $40.7 million net product sales for the period.

Our Thiola team's efforts to identify diagnosed patients remains effective in reaching more patients with cystinuria.

Also of note for Thiola during the quarter, our partners submitted an NDA to the FDA for approval of the new more patient-friendly formulation of Thiola.

We anticipate acceptance of the NDA submission for filing this quarter and a PDUFA date in the second half of 2019, which will keep us on track to launch a new formulation before year-end 2019.

We continue to be excited about the potential for this new product to improve the treatment experience for cystinuria patients, and we're making solid progress with our launch preparations.

During the quarter, we saw fewer-than-expected new patient additions with the bile acid products, which led to revenue coming in below our expectations.

As we've talked about in the past, we often see an uneven nature in patient identification and patient staying on therapy with the ultra-rare indications that our bile acid therapies treat.

In the third quarter, the uneven nature was more impactful than in previous quarters.

As a result, we will likely end 2018 moderately below the low end of our net revenue guidance of $170 million.

The commercial team at Retrophin has a deep collective expertise in delivering rare disease treatments.

Uneven periods are not new territory for us, and this is why we have a high degree of confidence in our team's ability to create further growth.

To that end, we are already seeing a stronger start to the fourth quarter, and we anticipate continuing the trend of year-over-year growth to end 2018 and in the years ahead.

Finally, we're pleased to have some added flexibility in our business development activities after the recent convertible notes offering.

Our disciplined approach to layer in additional assets into the pipeline and commercial portfolio continues in earnest.

Now let me turn the call over to Laura to walk through the financials.

Laura?

Thanks, Neil.

During the third quarter, net product sales from our commercial portfolio grew to $40.7 million.

We reported a GAAP net loss of $54.5 million for the third quarter of 2018.

After adjusting for noncash expenses and income tax benefit of $26.7 million, we reported a non-GAAP net loss of $27.8 million.

During the third quarter, we incurred a $17 million loss on extinguishment of debt.

This is related to the early repurchase of approximately $23 million in principle or approximately half of our outstanding 2019 convertible notes in September.

On a GAAP basis, R&D expenses were $32.4 million for the third quarter of 2018.

The increase over the same period in 2017 is largely due to the higher expenses to support our pivotal fosmetpantotenate and sparsentan programs as well as development funding for CNSA-001.

On an adjusted basis, R&D expenses were $30.6 million for the third quarter.

Relevant noncash expenses for the third quarter included $1.9 million of stock-based compensation and amortization.

Selling, general and administrative expenses were $26.1 million in the third quarter of 2018.

The increase compared to the same period last year is primarily due to increased initiatives to support our commercial products.

On an adjusted basis, non-GAAP SG&A expenses were $18.3 million for the third quarter.

Significant noncash adjustments for the quarter consisted of $7.8 million related to stock-based compensation and depreciation and amortization.

As of September 30, 2018, we had $478.8 million in cash and cash equivalents and marketable securities.

This reflects the net proceeds from our successful convertible notes offering in September.

Looking ahead, we expect our operating expense level to remain in line to marginally higher than the current quarter.

With 3 Phase III programs advancing at various stages, from site initiation to near full enrollment, our R&D expenses may vary by quarter, but we are likely to moderately trend upwards.

I'll now turn the call back over to Steve for his closing comments.

Steve?

Thanks, Laura.

Across the organization, we continue to get stronger and make considerable progress towards our goal of becoming a preeminent rare disease company.

Our 3 pivotal programs have the potential to transform how we treat PKAN, FSGS and IgAN and at the same time, create substantial value for our organization.

As we close 2018, we have never been in a better position to execute, and we look forward to reaching key upcoming data readouts starting in 2019.

Let me now turn the call over to Chris for questions.

Chris?

Thanks, Steve.

Rusty, can we go ahead and open the line for Q&A, please?

(Operator Instructions) The first question comes from the line of Joseph Schwartz.

So just a couple questions on sparsentan.

I see that you have some DUET open-label extension study data at ASN and you're reporting the FSGS partial remission endpoint for 45 patients on drug out to 84 weeks.

Since the endpoint in the Phase III DUPLEX is being evaluated at 36 weeks and I think the last data that you reported was on 29 patients achieving this endpoint well over a year ago, I'm just wondering how the FPRE data at 36 weeks has been evolving as more patients are included in the analysis given FSGS can be fairly heterogeneous.

I think there are around 64 patients now that are evaluable up to this point, which are using the Phase -- in Phase III.

Are you seeing that the primary endpoint data is fairly stable as you include more people in that analysis?

I'm just wondering why that hasn't been updated.

So the - thanks for the question.

Yes, it's -- with a year's later and it's almost 1.5 years later since the prior data cut.

The ends have increased.

So you're -- in the spar:spar group, you're at 62 and 30 in the irb:spar group.

So you're almost -- you're 90 in 90-something patients.

And they're in the, right around 40% FPRE, a little higher in the spar:spar group, a little lower in the irb:spar group.

As we increase the ends, the data becomes more solid.

And confidence is there that this is a good representative set for what we're going to see in DUPLEX.

And then regarding IgA nephropathy, I'm curious why the PROTECT Study is only evaluating 400 milligrams of sparsentan without the option to titrate up to 800 like there is in the DUPLEX Study -- in the DUET study.

Yes.

I think I'm going to ask Noah to field that, or I can the take that either way.

Yes.

So great question.

Sparsentan is highly protein bound, so exposure was positively correlated with serum albumin indicating that when albumin levels are low, drug exposure, in other words, AUC, is lower.

So just important to make it clear that patients with lower serum albumin and higher levels of proteinuria may benefit from higher doses of sparsentan in order to achieve [easy] levels of drug exposure.

Patients at risk for progression with FSGS, in other words DUPLEX, generally have higher levels of proteinuria, in some cases, up to 20 grams per day than those with IgAN between 1 to 3 grams per day.

Therefore, it was our contention that patients with FSGS may benefit from the 800-milligram dose to ensure an adequate dose.

In contrast, the IgAN patients who have lower levels of proteinuria, the 400-milligram dosage is the preferable dose.

That makes sense?

Yes, that's helpful.

Next question comes from the line of Maury Raycroft.

This is David for Maury.

So just regarding the general thoughts and generic competition for Thiola, how confident are you guys on the IP for the new formulation that's going to keep out the generic competition?

And then can you just comment on Retrophin's entrenchment, how this maybe function as a competitive barrier to entry for the generics?

Yes.

I think the only thing I would say about the new formulation is that we have filed for IP.

We feel comfortable that we've made meaningful improvements in the product, and we're hopeful that, that IP issues.

Until it issues, can't really forecast odds of getting what we want.

But we feel good about what we've submitted.

In terms of generics, there is obviously a huge amount of noise around generics right now, some legislation pending that is probably going to get in front of Congress again in December.

So I think as far as the future goes, I think we should wait and see how things play out.

We feel good about the product we have on the market now.

We feel even better about the product that Mission filed for this quarter that we anticipate launching in the second half of next year, and we hope to grow the Thiola franchise for many years to come.

Okay, that's very helpful.

My second question is regarding the trials for PKAN.

Can you comment on the, now that you opened up more pediatric patients, are they -- how are they enrolling, what's severity level like?

And then can you just comment on the sites?

Are they contributing equally demographically?

Well, I don't think that we're in a position to comment on demographics in any level of detail, but I think that I can answer your question in this way.

We had a DMC, a data monitoring committee, that ran earlier in the year, and that was the gateway that we had to go through in order to open up to pediatric patients.

So their enrollment started after the enrollment of the adults.

From -- as far as distribution, it's been fairly diverse across the sites.

And from a total population, it's somewhere around 1/4 to 1/3 of patients, is probably where we expect to end up with pediatrics relative to adults.

Okay, that's very good.

So one last question.

Can you just give us some ideas in terms of your feedback from the Kidney Week?

Or is this sort of sentiment like regarding the sparsentan program?

Let me start, and then I'll ask either Bill or Noah to comment.

But I think it was the most positive experience we've ever had with the sparsentan unveiling of the long-term data in the open-label extension.

We could not have asked for a better data set.

We saw proteinuria reductions continue to improve over those 84 weeks.

We saw patients stay in remission over those 84 weeks.

We saw patients stay on therapy over those 84 weeks, which I think is a feat in and of itself in a study like this.

And the enthusiasm we got with the data, I think, portends well for our ability to enroll both the DUPLEX Study and FSGS.

And I think some of that, there's an overlap into the IgA nephropathy area as well in the PROTECT Study.

But I think Bill and Noah both had more interaction than I did, so maybe they could expand on that a little bit.

Yes, I would just -- just to amplify Steve's point, I completely agree.

I think that the DUET data presentation really gave the renal community at ASN, coordinators and investigators, patient advocacy groups, a lot of confidence in sparsentan and is really translated into being able to leverage that in terms of recruitment for DUPLEX, especially for FSGS.

The term that was used, and again, this was a term used by outside scientists, was that the DUPLEX Study is really now a landmark study.

It's a critical study that not only Retrophin gets done, but the renal community at large for this serious life-threatening disease needs to get this done.

So there's alignment on many fronts and some wind beneath our sails or under our wings, I should say, to help us rise up and get this done.

Bill, I don't know if you want to add to that at all.

Yes -- no, I think you've summed it up real well.

Your next question comes from the line of Michelle Gilson.

Congrats on the data last week at ASN.

It was a great presentation.

I just wanted to ask you guys more about what is your expectation for the first half '19 data for PKU, for CNSA-001.

What would signal to you that CNSA-001 would have -- would be a significant improvement over Kuvan?

And can you just kind of frame it in context of your trial design as well just kind of with the different arms and the different washout periods and treatment arms?

Certainly.

Thanks for the question, Michelle.

This is Bill.

The -- with the CNSA-001, it should be fundamentally superior when you look at the data relative to the current standard of care.

We're not looking for an incremental improvement.

We know that the compound has very significant increases in bioavailability as well as tissue availability, where the actual molecule is -- serves as a helper to the enzyme.

From a study standpoint, each patient serves as their own control.

So within an individual patient, we have a measurement of how they respond to the current standard of care and then on 2 different doses of the Censa compound.

So we have -- we should have very adequate data coming out of that to have a good characterization of just what the level of superiority is that exists between them, what the delta is between those 2 compounds.

And that's why the -- you see the study designed the way it is, to provide that robust comparison, both on an individual level as well as a group.

Is that helpful?

Yes, yes.

And then can I also ask one on fosmetpantotenate?

Can you just talk about the study design and how the PKAN-ADL might help to control for some of the intra-patient variability within these PKAN patients?

Obviously, in the -- there were these 2 siblings that had these episodes of distress in ISTs.

And can you just talk about, yes, the way that you're controlling for that intra-patient variability in your study?

Sure.

The PKAN-ADL is a patient-reported outcome measure or caregiver-reported outcome measure, and they're assessed through the mechanism of an interview process across how they feel or how they function in different domains.

How well do you get out of a chair?

When you speak, do people understand you?

How well do you write?

Can people understand your writing?

So they're very common-sense-based types of questionaries, and they're assessed by a trained interviewer, in this case -- in each case, the PI.

The fact that, that's done repeatedly over periods throughout the trial goes a long way toward some of that variability.

With that said, in any measure like this, there's always going to be a significant amount of variability partially in the measurement, but partially in the change that you're going to see day to day with the patient population that's suffering from a disease like this.

So I don't want to leave you with the impression that I think that we're going to tamp out all the noise.

But I think with a patient population of 82 patients, the trial size is sufficient there to accommodate the inherent variability that we're going to see in this population with this type of measure.

Okay.

And then you had some natural history data at MDS recently.

Can you just talk a little bit about how it can get a -- help us get comfortable with the trial design and what you saw in that in terms of baseline characteristics and age of onset of symptoms and how this kind of informed your trial design and how we should look at that data?

Sure.

Those data stemmed from the effort that was conducted or extended to develop the PKAN-ADL scale.

So it was an effort to interviewing patients and caregivers around the different domains they were going to be evaluated on.

I think as you look at those data, you do see divergence in severity but a pretty good spread across the scale that is that there's plenty of room in that scale to see improvement should improvement occur.

I think that you -- with many genetic diseases, there's a fair degree of heterogeneity, and PKAN is no different from that.

And that comes out in those scales.

It's part of the reason the clinical trial is 82 patients.

You'll see a lot of rare disease studies that are a dozen or 2 dozen patients in a Phase III study.

This is 82 to -- And part of that is to manage those levels of variability.

Next question comes from the line of Liisa Bayko.

This is Jon on for Liisa.

Just a couple on the new patient trends that you're seeing you said.

For the bile acid products, they're a little bit lower than expected.

I was hoping you could speak a little bit about what you're seeing for both CHOLBAM and CHENODAL.

If it's both products or if there is one that was lagging behind?

Jon, it's Neil.

Thanks for the question.

Whenever you operate in this ultra-rare disease space, you see uneven sales.

Patients don't usually have consistent starts, and how they stay on therapy also is not in a consistent manner.

We had some troughs in patients adds this quarter.

It resulted in lower revenues, particularly in September, but we actually see an increase in patient starts moving into already this fourth quarter, specifically in the -- with the closeout of the month of October.

Great.

And then one just kind of piggyback on the previous questions on the PKU program.

We saw some early-stage data recently from a gene therapy candidate, and I was wondering if you could speak kind of how you view competitive gene therapy programs in PKU and if that affects -- will affect your decision at all when you have the option coming up.

Well, we certainly monitor gene therapy programs.

I mean, we're a rare disease company.

85% of rare diseases are genetic in origin, and gene therapy is getting obviously increasingly visible, more and more programs.

PKU gene therapy, like most gene therapies, is early, and I think it remains to be seen if it's going to be the answer in PKU.

And we'll see.

It's too early to say it's going to be a major competitor, and it's too early to say it's not.

I think we're just going to have to see how things evolve.

What we know is that the standard of care out there right now is commercially available product from another company, which is tetrahydrobiopterin, and we want to know if we can improve therapy for patients by giving a CNSA-001.

We think its pharmacokinetic characteristics, its tissue distribution, its ability to cross the blood-brain barrier give it the potential to be a better product, and we want to do that head to head.

We want to see if it is as good as we think it may be.

And if it is, then we'll move forward.

If it is not, then we'll walk away.

But we're very optimistic about the program.

Next question comes from the line of Tim Lugo.

It's Myles on for Tim from William Blair.

I'm just wondering about the PROTECT Study and the rationale behind why you'd perform a GFR rate out at 52 weeks and 104 weeks as opposed as to in the DUPLEX Study, where you're just doing it at the longer-term time point.

Am I thinking about it right that could just be an expedited therapeutic concept because of severity of the proteinuria in IgA patients is not as much?

Or is there something else I'm missing here?

So this is Bill.

Thanks for the question.

There's a chance that you've got enough effect at 1 year that you'd have a robust package and then you have to make the decision, do you go on file?

And if you're not prespecifying that as one of your endpoints, that's -- that becomes more of a challenge.

The -- if you compare it to the IgA nephropathy -- I mean, excuse me, if you compare that to the FSGS population, the IgA dataset that we look at as a whole and the progression over time, changes are slower, but the magnitude is not as great and the variability is a lot lower.

So there is a chance that you could hit it at 1 year.

I don't think that, that's the highest probability.

The study is really designed to be successful and that's around a 2-year endpoint, and we expect to run the study that long.

But should there be an opportunity for a win at 1 year, we don't want to leave that on the table.

So that data point is in there, and that's where we capture it.

So if you hit on the partial remission of proteinuria in the PROTECT Study but you're too early for the GFR, you'd still chase the accelerated approval pathway?

Or you're looking for a position where you'd need both to address that?

No, no, the primary thesis is to hit on proteinuria at 36 weeks in both studies and file for Subpart H accelerated approval or conditional marketing approval in the EMA.

And then the study runs to the eGFR endpoint as the confirmatory endpoint by which we can then file to convert it to a full approval.

Yes.

Okay, great.

And I'm just looking at the dropout rates for DUET, in particular.

Really nice data by the way.

But we had 96 patients originally, down to 71 and then 62 currently.

So 2/3 is still there.

But I'm thinking in the DUPLEX Study, where you've got to keep patients over that 100-week period, is it safe to assume that we're going to see a similar dropout rate?

Or is there going to be increased compliance in that trial?

Well, I wish I knew.

That's -- those crystal balls are always tough.

We do look at trials with an eye toward the patient experience because you want to keep them in and you want to keep them happy.

I'm quite impressed coming up on 4 years for some of the patients in DUPLEX that they are managing the rigors of continuing to participate in a clinical trial, the scheduled visits, the assessments, the extra blood draws, all of that.

And it's just leveled out, and they are just staying in there.

The other piece anecdotally that we get back from the physicians and the study coordinators is that these patients are very happy.

They have not seen stable proteinuria like this before in the course of their disease.

Their blood pressure's rock solid.

And it's not a difficult medicine for them to take.

It's a daily oral with a reasonable side effect profile, and it fits into their life.

And they're happy with it.

That gives me confidence, well, let's say, optimism that we'll be able to have a similar experience in DUPLEX because the study isn't written to be more arduous on the patients or on the investigators.

And knowing that the drug works and knowing that people long term enjoy being on it and see the benefits, that's really helpful.

Now the challenge is that what you're talking about in DUET is people seeing benefit in open label, and we've got to get to a certain point in both DUPLEX and PROTECT before they get to that open label.

And that's longer.

But with the overlap in PIs, that knowledge also flows forward into the current studies.

So I'm hopeful that it's not -- the dropouts aren't going to be an issue.

It is with every Phase III program, loss of patients HER2 and missing data HER2, these are all things we focus on every day.

I promise it's the last question.

Just heading over to CNSA-001, a differentiating factor I'd say is crossing the blood-brain barrier and potential cognitive benefiting in some PKU patients.

Wondering whether that trial that's conducted by Censa is actually looking at an endpoint to do with cognition.

And you talked about superiority that you're looking for.

Would the trial potentially be powered to detect any superiority in a central function?

So in the current study, they certainly will be evaluating patients for their cognitive function, but it's no way powered for -- to see a difference in cognition.

That's a much more difficult endpoint, and that would be something that would need to be in a much larger study.

This is really just looking at the change in phenylalanine plasma Phe levels between the different groups.

Yes.

Maybe I'd add also, any kind of neuro-cognitive study would have to have a much longer duration of treatment than we have in the study as -- than Censa has in the study as well.

This is simply a, can Censa at a couple different doses provide greater benefit in terms of blood Phe reduction than maximum dose Kuvan?

And I think we can get that answer reasonably quickly.

(Operator Instructions) I'm showing no further questions at this time.

I would now like to turn the conference back to Mr. Chris Cline.

Thank you, sir.

Great.

Thanks, Rusty.

Thank you, everybody.

This concludes our call.

We look forward to updating you on our progress in the near future.

Ladies and gentlemen, this concludes today's conference.

Thank you for your participation, and have a wonderful day.

You may all disconnect.