Travere Therapeutics, Inc. (TVTX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Travere Therapeutics Inc. top line results from the ongoing Phase I/II COMPOSE Study. [Operator Instructions] I would now like to turn the call over to your host, Chris Cline. You may begin.

Thank you, Kevin. Good morning, and thank you all for joining us on short notice today to talk about the positive top line results from the ongoing COMPOSE Study of pegtibatinase in classical homocystinuria. A copy of the press release announcing the results is available on our website. Today's call will be led by our Chief Executive Officer, Dr. Eric Dube. Eric will be joined by Dr. Bill Rote, Senior Vice President of Research and Development. Before we begin, I'd 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 on forms 10-Q and 10-K filed with the SEC. In addition, any forward-looking statements represent our views only of the date such statements are made, December 15, 2021, and Travere 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 Eric. Eric?

Thank you, Chris, and good morning, everyone. Since we first learned about the pegtibatinase program, we've held the belief that it could become the first disease-modifying therapy for people living with classical homocystinuria, or HCU. This is critical because we conservatively believe that there are at least 7,000 patients with HCU in the U.S. and Europe that are not able to prevent a toxic buildup of homocysteine levels with current available treatments. The current standard of care aims to reduce home-assisting levels through a highly restrictive diet, combined with supplements, vitamin B6 and betaine. But many patients are nonresponsive to vitamin B6 or are unable to maintain a consistent or normalized level of homocysteine. Not only are the available treatments inadequate, but patients also face challenges with compliance and adhering to a difficult low protein diet, especially as they age. As a result, patients face serious complications like eye lens dislocation and extreme nearsightedness, skeletal complications including osteoporosis, developmental delay and thromboembolism, which can cause heart attack and stroke. Today, we are pleased to report positive top line data from the ongoing Phase I/II COMPOSE Study of pegtibatinase. This is a first-in-human study evaluating pegtibatinase in patients with HCU, and the results are compelling and consistent with our expectations given the promising preclinical work done earlier in the program. Let me turn the call over to Bill to walk through the data. Bill?

Thank you, Eric, and good morning, everyone. Classical HCU is caused by a genetic defect, resulting in the loss of function of the enzyme cystathionine beta-synthase, or CBS, leading primarily to a toxic buildup of its normal cellular substrate homocysteine. Secondarily, there's also a buildup of methionine and a reduction of the downstream products, cystathionine and cystine. The disease usually manifests in childhood with ocular, vascular, neurologic and connective tissue abnormalities. As Eric mentioned, it can lead to severe long-term complications. Pegtibatinase is an investigational, pegylated, modified, recombinant truncated human enzyme designed to address these underlying genetic cause of HCU by introducing a functional CBS enzyme into circulation. Replacement of the CBS enzyme is a highly rational approach for this disease, and the therapeutic potential of enzyme replacement in similar metabolic indications has been well established. It's important to note that native CBS enzyme normally resides in tissues while pegtibatinase remains predominantly in the circulation of plasma. However, pegtibatinase is intended to safely reduce both intracellular and plasma homocysteine levels. This effect is believed to occur by decreasing extracellular homocysteine levels, and creating what's referred to as a metabolic sink. The metabolic sink outlines that by lowering the homocysteine levels in the blood, and given the ability of homocysteine to move across cell membranes and the blood-brain barrier, treatment with pegtibatinase lowers plasma homocysteine and creates a concentration gradient that drives homocysteine movement from areas of high concentration, specifically in the tissues to the circulation where it's then metabolized by pegtibatinase. In short, our goal is to safely replace the missing CBS enzyme activity and meaningfully reduce total homocysteine levels. While the preclinical evidence generated to date has been striking, the ongoing Phase I/II COMPOSE study gave us the first opportunity to evaluate the effects of pegtibatinase in people living with HCU. COMPOSE is a Phase I/II randomized, multicenter, placebo-controlled, double-blind dose escalation trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects of pegtibatinase in patients with HCU. COMPOSE utilizes an adaptive design that allows for the addition of cohorts and extensions to enroll up to 40 patients in total. Thus far, patients in COMPOSE have been randomized 3:1 to receive subcutaneous doses ranging from 0.33 milligrams per kilogram once weekly to 1.5 milligrams per kilogram twice weekly of either pegtibatinase or placebo. And patients are eligible to enter into an open-label extension and receive the 1.5 milligram per kilogram dose of pegtibatinase. To date, we have enrolled a total of 19 patients across 5 dose cohorts. Today, I'm very pleased to report that top line data from the study demonstrate pegtibatinase's improved overall markers of metabolic function, and they provide clear proof of concept for pegtibatinase as the potential first therapy targeting the underlying cause of HCU. From a safety perspective, pegtibatinase has been generally well tolerated to date, and is advanced through 5 data monitoring committee assessments. Overall, the median duration of exposure in the study is just under 2 years with the longest patient approaching almost 3 years in the study. This provides valuable insight into pegtibatinase's safety profile. There have been no discontinuations due to treatment-related adverse events, and no reports of anaphylaxis or severe immune reactions related to study drug. To date in the study, there's been 1 serious adverse event considered by the treating physician to be likely related to pegtibatinase treatment, and that was a case of moderate acute urticaria or hives. Case occurred in the third dose cohort and resolved shortly after a single dose interruption. The patient resumed dosing pegtibatinase 1 week later at the original dose with no reoccurrence of the urticaria and remains in the study to date. From a pharmacokinetic perspective, plasma exposures of pegtibatinase observed in the patients in the study correlate with the previously reported range in preclinical work, and were sufficient to drive rapid and sustained reductions in homocysteine at the highest dose study. Through the ascending cohorts, we also evaluated dosing frequency. And the data has established that twice-weekly dosing of the current formulation provides adequate exposure to sustain homocysteine lowering. As for initial efficacy findings, I'm very pleased with the overall activity, which appears to be consistent with our approach to targeting the underlying CBS defect, and the encouraging preclinical package supporting this program. Pegtibatinase demonstrated dose-dependent reductions in homocysteine during the 12 weeks of treatment. And at the 2 highest doses -- dose cohorts to date, pegtibatinase appeared to reduce homocysteine regardless of starting baseline homocysteine levels or background therapy, including vitamin B6 and betaine. I'm very pleased to report that in the highest dose cohort to date of 1.5 milligram dose twice weekly, treatment with pegtibatinase resulted in rapid and sustained reductions in homocysteine, beginning at week 2 and continuing through 12 weeks of treatment, resulting in a maintenance of homocysteine below a clinically meaningful threshold of 100 micromolar. Historical data in the literature suggests that positive outcomes can be achieved if homocysteine concentrations can be maintained below approximately 120 micromolar. And as a result, the treatment guidelines recommend keeping homocysteine levels below 100 because of the complications associated with high homocysteine levels are very serious. Specifically, in the 1.5 milligram per kilogram dose cohort, treatment with pegtibatinase resulted in a mean reduction from baseline of 55.1% compared with a mean reduction from baseline of 4.8% for all patients receiving placebo in this study. This is especially encouraging given the median baseline homocysteine, and the pegtibatinase-treated group in this cohort was 187 micromole. This means that on average, treatment with pegtibatinase in this cohort resulted in reductions greater than 100 micromolar, and patients at high risk at baseline were able to achieve and sustain a clinically meaningful homocysteine level below the guided threshold. To assess other biomarker activity related to our mechanistic approach, we also looked at methionine and cystathionine. As expected, the data demonstrated a substantial reduction in methionine and increase in cystathionine in a dose-dependent manner following treatment with pegtibatinase. These results, especially for the 1.5 milligram per kilogram twice weekly cohort are highly clinically significant and give us great confidence in the potential for pegtibatinase to become the first disease-modifying treatment for HCU. We believe that these data support moving pegtibatinase to a pivotal development program, and we will be engaging with regulators in '22 to establish next steps. We will also, in parallel, enroll 1 additional cohort to explore formulation enhancements and the full dose response curve to evaluate the potential for additional total homocysteine reductions. We will take this opportunity to efficiently gain a bit deeper understanding while engaging with regulators and moving towards a potential pivotal development program. In the background, we'll also be working to scale manufacturing for a pivotal phase of development and commercial access. Lastly, and importantly, I'd like to thank the patients and investigators who are making the COMPOSE study possible, and contributing greatly to the advancement of potential therapies for the HCU community. Let me turn the call back to Eric for his closing comments. Eric?

Thank you, Bill. We've now generated 3 positive outcomes from our clinical programs this year, and this is what drives our organization. In addition to the excellent opportunities that we have ahead with regulatory submissions and the first potential launch for sparsentan next year, we also now have clear proof of concept for a program that has the potential to be the first therapy targeting the underlying cause of HCU, a rare and devastating disorder. We are excited about the work ahead, and about drawing upon our late-stage development and rare disease commercialization experience to advance this program with the goal of ultimately delivering pegtibatinase to more than 7,000 people in the U.S. and Europe who are not able to adequately control their HCU with the available treatment options today. Let me now turn the call over to Chris for Q&A. Chris?

Thanks, Eric. Kevin, can we please go ahead and open the lines for Q&A?

[Operator Instructions] Our first question comes from Joseph Schwartz with SVB Leerink.

Congratulations on the results. I was wondering if you could provide some more color on the additional cohort that you've added to COMPOSE with respect to the dose response and the formulation work that you're doing? And can you characterize the dose response curve over time for us in terms of the trajectory, and whether you're seeing it -- the effect continue to build over time? Or did you notice any leaning? And have you looked at whether there's any antibodies to the drug that could be neutralizing the effect over time due to immunogenicity?

Bill, would you like to take those questions?

Sure. The -- I think there were several in there. Let's start with the cohort 6, the next cohort that was just now opening up for enrollment. We're going to an additional higher dose. It is really an opportunity for us to ensure that we're exploring the entire dose response curve. We've developed a pretty good PK/PD model through the course of this study, and this will expand that and round that out. The formulation that we referenced in the call, the prior cohorts were all dosed with a liquid formulation, and this is our first opportunity to evaluate a lyophilized formulation that has cleared comparability, but it will be our first opportunity to confirm that in humans, and evaluate the PK of that as well. So it's a twofer in that respect. The -- with respect to the trajectory of response, what we saw was a rapid decrease in homocysteine that was apparent at the first measured time point after baseline, which was week 2. And it was really sustained in a pretty flat range across that 12-week observation period. We did look to see if we saw any one that went down, and then drifted up as you implied as potential neutralizing the antibody, and haven't seen that to date. We're looking at anti-CBS antibodies generation over time as well as looking at anti-peg antibodies. The -- but we haven't seen neutralizing antibody evidence based on the PD measurements to date. And I can say that the immunogenicity profile thus far has been very favorable.

The only other thing that I would add, Joe, is that the work that we are doing with the sixth cohort be conducted in parallel with the work that we will be doing with regulators to understand next steps. So we do see this as an opportunity to really optimize the program but not change time lines based on the strong data that we're announcing this morning.

That's really encouraging, and you kind of gave me a segue. First of all, I appreciate you taking off all those responses to me. But then I was curious about what is the range of clinical endpoints that would be relevant for this patient population, and also capturable in a reasonable time frame? If biomarkers weren't sufficient, could you talk a little bit about the event rates that you'd expect for various clinical endpoints for patients?

Sure. I can take that. The challenge with homocystinuria from a clinical development perspective is that the endpoints, while severe and certainly significant to this patient population, they occur at sparse intervals, and they have a heterogeneous presentation. So that -- the group of endpoints would be assessing cognitive function and behavioral testing, ocular assessments, bone mineral density and quality of life scores. The study design that we envision going forward will be predominantly based on a metabolic endpoint, a biomarker of total homocysteine reduction. We know that the agency has approved one other drug based on homocysteine lowering. It was a long time ago, so it was prior to their biomarker guidance. But I think conceptually, the decision is rational to do it that way going forward because it would be intractable to hold sponsors or anyone to the criteria of clinical endpoints that may take decades to accumulate.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the update. I was wondering if you can say what the higher dose is going to be for this additional cohort? And now that the study is complete, can you talk more about how enrollment for the study went? And next -- I'll stop there.

Thanks, Maury. Bill?

Yes. At this point, we're not releasing the upper dose. We're looking toward a publication at a meeting, hopefully, in the spring, but that's to be determined. We're trying to preserve as much of this data set for that publication, and release as possible. The second part of your question was around enrollment. The study was underway when we acquired the program. And following the transition from Orphan Technologies into Travere and our team, that was kind of coincident with COVID, which certainly provided headwinds, but we never stopped the study. We made adjustments to allow the study to continue. That said, it wasn't a rapidly enrolling study, but I think we were comfortable with the pace, and it met our expectations. But it's rare disease, and it's always challenging, but it's also an area that we focus on, and have developed a fair degree of competency in. So we're comfortable that this next cohort, we will enroll in a reasonable time. And the team is already focused on looking at pivotal study, designs. And with those larger studies, what are the strategies that will help provide reasonable enrollment times and pace to facilitate that in a reasonable way.

Got it. And for this additional cohort, are you saying how many patients are going to be in that?

Yes. There will be 4 more patients.

And for the 19 patients, did they come from multiple sites? Can you comment on that?

Yes. It was 6 sites in the U.S.

Got it. And so basically, you're getting patients from all 6 of those sites?

Yes.

Okay. I was going to ask one more question just for the pivotal discussions. At this point, do you think you'll be able to leverage Orphan's natural history study as a comparator arm or will you have to run a placebo control?

Yes. It's a fascinating question, and it's one that I can argue both sides of. Regardless of where the position is, that natural history study is very valuable to the discussion, partially from an endpoint standpoint. It gives us prospective data in looking at the impact of differing levels of homocysteine control on clinical outcomes in a patient population over time. There are precedents where natural history cohorts are used as essentially an external control group. It's early days, but that's certainly something that is on our radar.

Our next question comes from Greg Harrison with Bank of America.

Congrats on the data. Can you give any additional details on the patient who experienced the hives? And if any other patients had any, maybe less severe infusion-related reactions?

Sure. Bill, would you like to take that?

Yes. Yes. I -- the patient that had the hives, it was early in the study, and it was characterized as acute moderate urticaria. It resolved pretty quickly. So within the patient stopped study drug -- within 10 days, it had resolved, and the patient resumed. And it wasn't -- and it has not reoccurred. So it's very possible that it was due to something else, but it was classified as likely related by the study investigator. So that's where that classification rests. From an adverse event perspective, injection site reactions we're seeing in the study, and that was probably the most common AE. And it was -- but they're mild and not anything that got in the way of dosing or study continuation. There were a couple of other patients that had hives, but it was transient and wasn't dose-dependent. So overall, from a safety perspective, it has been really quite a clean study.

Okay. Great. And then I also wanted to ask about compliance with the low protein diet during the trial. If you have any information on that? And would you expect patients in the future to be able to eat a normal diet, if they're on drug? I can imagine that'd be a pretty attractive attribute for patients and their families.

Yes. Maybe I can take that -- sorry, go ahead, Bill. I was going to give you a bit of rest, but go ahead.

Yes. For diet compliance, the patients were instructed to have -- to maintain the diet that they were used to adhering to. They also met with a metabolic dietician with each site visit and had counseling around that and guidance. We have diet diaries which have -- are 1 tool that allows you to assess how well those patients are adherent to a consistency of diet. The other thing we can look at is that we can look at the placebo group and the variability in their data. And as a crude measure, the consistency there suggests that we had good compliance with that throughout the study. So very impressed with the work of the patients, and I think they were quite compliant and engaged in this setting. Your second question is an excellent one, and I don't have a substantive answer at this stage of the game. It will be an area of focus and study for us. The data does not exist yet on what's the level of liberalization that can be permitted in these patients given reductions like we've seen in the current COMPOSE study. We're encouraged by the magnitude of that reduction. And we think that, that opens the door to possibilities, but it's something that we need to study in a prospective situation because it may be that it's not complete normalization of diet, but it may be something intermediate anything for these patients that would allow some of the along that axis would be certainly very attractive to that patient population because they tell us that's really important.

Our next question comes from Liisa Bayko with Evercore ISI.

For the 1.5 mg dose, can you talk about like the sort of the range? I know that the average, the mean was 55% reduction with only 3 patients. I'm curious if all of them get below the 100%. What was the range? Just trying to understand your thoughts.

That level of detail is probably beyond what we want to get into today. We want to preserve the package for publication, and we hope to get that out into the public domain quickly. Let me try and answer it this way though. We saw a consistency in response. At that dose, we saw everyone reducing homocysteine. We saw everyone reducing it significantly, and we saw a consistent suppression across that 12-week window. With any metabolic study, there is variability. When you get to a 3-patient subset, there's certainly variability within that. One of the things that's important to note is that as the patients reduce their homocysteine, variability also reduces, which makes sense because you're moving toward the lower end of the scale. But it's just compression of the noise. But it was a consistent response across the group.

And just for baseline, was there a big range there, too? So I'm just looking at your baseline for the placebo, it was materially lower. It's like 131 versus 187 for the 1.5 mg dose. Just curious on like what -- how variable the baseline levels were.

Yes. Yes, the baseline levels. I mean if we look at the mean across the entire study, it's about 160 micromolar at baseline when we look at all cohorts. Placebo was the lowest, the 1.5 milligram per kilogram was just barely the highest, but there were others that were right -- there were 3 others that were right in there with it. So it was a mix, and it's something that is a byproduct of small numbers.

Do you see like a bigger, I guess, reduction with higher levels to start? I'm just kind of curious about like how much we can kind of compare placebo to kind of the higher dose, just given the differences in baseline. Like would you expect like are you at a little bit of an advantage if you start with a higher level? Or how should we think about kind of that dynamic?

Yes. Yes. No, it's a great question. We've looked at the data to see if there's evidence of what you suggest that with -- as you lower in starting points, you get a lower impact. If you -- when we look at it on a percent reduction, we see consistency of percent reduction relative to starting homocysteine values. And while there's a range here, it's not a huge range. We expect that even those patients that have lower starting values will see comparable percentage reductions going forward. We're in small numbers. We need to repeat these studies in a pivotal study -- repeat these results and confirm them in a larger data set, but that's what we're observing at this point in the study. Additionally, because this study has an open-label extension, the remaining patients that were on lower doses will now shift as they move into the open-label extension, the 1.5 milligrams per kilogram twice a week, and we'll be able to expand the data set beyond the 3 in this cohort to a much larger set. So that should grow to something greater than 10 -- somewhere between 10 and 14, depending on who rolls over. So we'll be able to have a better view of that and give you a more substantive answer when we have those data.

Yes. And I think while there is a range, it does -- for all patients, it does represent a moderate to high risk of these complications. And I think that really -- that and the consistency of response that Bill mentioned really gives us great confidence in the results that we've seen thus far.

Okay. And then any difference with like if patients were B6 responsive or not? Did you see any differences on that attribute?

Yes. Yes, in this study, there really weren't any what were classically defined as B6-responsive patients because of the cutoff for the homocysteine value at screening required to get into the study. But I think that if you -- that's an old definition, and that's evolving in the space. I think that B6 responsiveness is probably a gradient across patients, and it relates to where the mutation is and how badly damaged the enzyme is. That said, about half the patients in the study were on B6, about 80% were on background betaine therapy. And that was consistent, and it was maintained through the study. When we look at those patients, who are on B6 or not on B6, we don't see a separation in the response. There's no difference.

Meaning there's consistency of response.

Yes.

Okay. And then just final question from me. As you think about you're moving up to a higher dose and kind of what you're seeing with the dose response curve, are you expecting that you might, I guess, increase the amount of reduction -- I guess have a greater reduction is what I mean, at a higher dose, the way you're looking -- from what you can see of the dose response curve?

Yes. As we increase the dose, there's an expectation that there should be a concomitant increase in effect, that is a greater reduction in plasma homocysteine. We need to run that cohort and see what that is. But additionally, we're really rounding out the overall dose response curve and broadening the data that goes into the PK/PD model that will be used to select a pivotal dose. We have what is now a very effective dose in hand, and we'll further understand what pegtibatinase can do. And then as Eric noted, it's important to -- that we're not waiting for that cohort to complete. We think we have everything we need right now to engage with regulators and begin that discussion and determine and start to define that path to the pivotal work.

Our next question comes from Tim Lugo with William Blair.

Congratulations on the data. Can you discuss if there was any of the PRO findings that came out of the patients that saw declines under 100 micromole versus placebo?

At this point, we have not analyzed the patient-reported outcome data, yet. This was an interim data cut, and very fresh for us. We will be analyzing those data going forward, but we don't have those results today.

Okay. And maybe it sounds like the highest dose explored so far, 100% kind of response rate, I'd say. Is that relatively -- as you look across the study, could you say that there was a relatively well-defined dose response or some of it being just so variable in these patients across baseline and week to week? But there's a trend but maybe not completely clear.

Well, the study started at a very low dose, which is customary for a first-in-human study with a recombinant protein. So as you can imagine, starting dose was -- didn't emerge with dramatic results. As we went up in dose, and especially when we hit the twice-a-week dosing, that's where we saw the dose response really start to begin. And the clearest results were, as you note, at the highest dose level with -- you're correct in assuming a 100% response rate. Yes.

Okay. Great. And maybe one last one. As you explore a higher dose, is there any risk of kind of overcorrecting maybe too quickly? Is -- I'm just not familiar with the disease as much as homocysteine drops within a week kind of too rapidly. Is there any maybe adverse event risk?

We -- there's none that I've seen reported. These values are so high above background in normal homocysteine. So it's unlikely that there would be an issue of hypo-homocystinuria as -- would be what you're describing. So we don't see that as a problem. We haven't seen that in animal studies either when we've pushed to much higher, 10x this in nonhuman primates. So we think that the safety margins that we have are pretty good.

Our next question comes from Michelle Gilson with Canaccord.

Congrats on the data. Maybe just following up on some of the questions around the long-term extension. How many patients have rolled into the long-term extension? And then have you dose escalated within the long-term extension as you've gone up cohorts? I guess I'm wondering if you see any deepening of the, I guess, intra-patient homocysteine reductions as you escalate the dose? And also, are you seeing an effect as placebo patients roll over?

Thanks for the question, Michelle. The study that we inherited from Orphan Technologies didn't have an open-label extension. So we've amended the protocol to add that, and we're just now getting through IRB approvals of that protocol amendment. So the open-label extension is just opening now at sites. As such, we have 1 patient that's rolled into the open-label extension. And with the holidays, we don't have patients scheduling visits between now and the end of the year. So we expect that in January, that process will accelerate and those patients will roll in. So what we haven't seen is, as you asked, the impact of the placebo patients rolling in, which should replicate the start of the study for the patients in the cohort that we're talking about this morning. As well as we're very interested to see that dose escalation of those patients into the 1.5-milligram group as they roll in. So that will further expand and strengthen the data set. But it's a -- from a timing perspective, that's just starting.

Okay. So you mentioned that there's a patient that was dosed 3 years ago, I think in your opening remarks. So the patients -- so have patients not continued therapy, I guess, continuously since they enrolled in the study?

Yes. They have. They've continued in the study depending -- from start till now. Those that were in the study earlier were able to dose escalate to lower dose cohorts as the study progressed, and they will now be able to jump to the 1.5 milligram per kilogram. The data that we're talking about and analyzing right now is just a 0- to 12-week comparison across these groups.

Okay. And in those other dose cohorts, are you seeing that the reductions in homocysteine are sustained through the long term?

We'll be analyzing those data, and we'll be presenting that with a future publication. We don't have those data to discuss today.

Okay. And then you mentioned that about half of patients were on B6 when they entered the study. Did you see similarities in, I guess, the magnitude of response between patients that were on vitamin B6 and patients that were not on vitamin B6?

Yes. We saw a consistency of response that was independent of B6 status. We didn't see any difference whether they were on B6 or not, it was indistinguishable.

And then the high dose cohort that you are evaluating, just I guess a couple of clarifying questions. The first is that you will use the lyophilized formulation in that dose cohort. Am I hearing that correct? And then the other is -- are you evaluating a different dose frequency? Or is it just a higher dose? Do you think that -- I guess I'm wondering is like twice a week going to be the frequency going forward, do you think?

Yes. So for the latter question, yes, we think that twice a week, now that we have a better understanding of the human pharmacokinetics, that seems to be the sweet spot for pegtibatinase. So that will be the dose frequency going forward. And yes, we're going to be switching now from the liquid formulation to the Lyo formulation for this cohort 6.

Okay. If I can sneak one more in. Sorry. Do you have a plan for, I guess, a pivotal trial that you are planning to present to the FDA in your meetings -- in your end of Phase II meeting? Or are you having more general discussions? And I guess I'm wondering if you have an idea of what you're planning yet to bring to the FDA, or if you are just going to kind of have an initial discussion to discuss the data and get their feedback?

We're at a point now where we have some initial discussions that are already on the books for Q1 of next year, and that will be the beginning of those discussions. Now that we have these data in hand, we have what we need to really engage in a discussion that's much broader as you imply, and we'll be working with the regulators, both in the U.S. and Europe to get those on the books. They're not scheduled now, and we do have -- to your question, do we have a plan? Yes, there are study designs being developed. And they are, of course, being refined now that we have unblinded this study and have access to data that's certainly very informative. But that progress is just at its beginning stages.

Okay. Are you able to give us an idea of whether or not the study design that you're thinking of now is focused on a biomarker, and maybe if you have any idea of what the right duration might be for a pivotal design?

Well, we do believe that the pivotal study should be focused with the biomarker end point, but we need to achieve alignment with the regulatory agencies on that. Duration is something that we're going to have -- need to have conversations with the agencies, and I don't think I can give you guidance on that at this point.

Okay. Do you have any idea on like how big the study might be?

Again, that's something that's still to be determined. I think as you look across enzyme replacement therapy studies, you see a wide range of study size. A lot of that's going to be determined based on the overall variability in the numbers as well as exposure needs from the agencies. So there's different ways to calculate the needed sample size, and that's part of what we'll be engaging the regulators to discuss.

Thank you, Michelle. Appreciate the questions. And maybe the only other thing that I would add just based on the discussion of the open-label extension is that the patients that are in the study remain blinded through their up titration. So just another important part of the trial design.

Our next question comes from Carter Gould with Barclays.

This is Justin on for Carter. Congrats on the exciting data announced this morning. Wondering if you can comment at all on the age range of the 19 patients that you read out data for? And if any of them were asymptomatic at baseline?

So the age range -- I'm searching for the numbers. Eric, do you have that?

So we know that the -- the mean was about 24 years. There were patients that were below 18, but I don't have the oldest range. But it was I think, representative of what we see in the natural history study. But again, small numbers, Carter (sic) [ Jason ]. And with regard to symptoms at baseline, I think that's something that we're going to continue to explore relative to what we see based on. But we do know that patients do have -- some patients did have a history of some of the complications that Bill outlined as representative of the disease.

And that -- yes, the mean was 24, and 6 of the patients were below 18.

Okay. And then I just want to confirm. It sounds like you're only going to be enrolling 4 more patients into the extension study and capping COMPOSE at 23 patients. Is that correct?

That's correct.

Our next question comes from Laura Chico with Wedbush Securities.

I just have 2 follow-ups here. So one, I'm wondering if you could just spend a moment back on market sizing, and how you're getting to your prevalence number. I think you mentioned, Eric, 7,000, I remember, in the opening remarks, I think that's higher from your prior estimates. And just looking back at a study from Orphan Technologies, that examined chart reviews, they projected at least 12,000 HCU patients by ICD-10 codes in the U.S. So just wondering if you can help walk me through how you're getting to that 7,000 number in the U.S. and EU? And perhaps what are some of the drivers that might influence that figure up or down?

Yes. Great question, Laura. And certainly, the work that you referenced is very much in line with our understanding. And part of the reason that disconnect between, let's say, 3,500 in the U.S. up to over 10,000 or 12,000, really is why reflected that our estimates may be conservative. That 7,000 patients equally split roughly around 3,500 between U.S. and Europe really reflect what we believe the addressable population is today. That is those patients who have been diagnosed and do have homocysteine levels that represent that they are not well controlled with diet, B6 and betaine. But we do -- as similar with many other rare diseases, the more we learn and the more information is gathered from clinical trials, et cetera, we do recognize that there may be more patients, and that's exactly what the study that Orphan Technologies did. They recognize, as we do, that about 50% of patients that have homocystinuria are missed at newborn screening. So homocystinuria is part of the panel for many states for newborn screening, but it measures methionine levels, not homocysteine levels. And those don't -- at birth, don't always move in the same direction until later. And so many of these patients are missed. And in exploring what might be the true prevalence, that's where we started -- or Orphan Technologies started to look at chart reviews in those patients that had consistently elevated home assisting levels upon routine lab draws. And that's where you started to see that there could be upwards of 12,000 patients that may have homocystinuria. So again, much like other rare diseases, there's a lot more work that we will be doing to help in more accurately estimating what the population is and what the addressable population would be at the time of launch. But we do believe that conservatively, there are 3,500 but certainly room to -- for that to be much higher as there's better recognition in earlier diagnosis. And I think a lot of the work will be improving the approach to newborn screening and really the accuracy of those efforts.

Okay. That's super helpful, Eric. And maybe one quick follow-up here. I apologize if I missed this, the gating factors on manufacturing. I believe you mentioned that you need to kind of start moving forward there, but still waiting on some of that formulation data. How does that impact the start timing for a pivotal study?

Yes. So I would say, at this point, those efforts are all going to be done in parallel. So the work that we're doing on PMC optimization, including the scale up and the investment now that we have proof of concept, we will be doing in parallel with engaging with regulators on biomarker and trial design as well as the work with the sixth cohort. So I'd say at this point, I wouldn't necessarily characterize it as gating, but we do think that we'll be in a better position to provide updates on timing once we've met with regulators next year. And as you can imagine, with the exciting data we're announcing, we're going to be moving as quickly as we can.

I'm not showing any further questions at this time. I'd like to turn the call back to Chris for any closing remarks.

Great. Thank you, Kevin. This concludes our call for today. Thank you again for joining us on short notice to talk about the promising results from the pegtibatinase program. We hope you all have a wonderful and safe year-end, and look forward to talking again soon.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.