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. At this time, all participants are on a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you need to press star one on your telephone. If you require any further assistance, please press star zero. 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 in 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, 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 homocysteine levels through a highly restrictive diet combined with supplements, vitamin B6, and betaine. Many patients are non-responsive 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 cysteine. 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 the 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 mg/kg once weekly to 1.5 mg/kg twice weekly of either pegtibatinase or placebo. Patients are eligible to enter into an open-label extension and receive the 1.5 mg/kg dose of pegtibatinase.
To date, we have enrolled a total of 19 patients across five dose cohorts. Today, I'm very pleased to report that top-line data from the study demonstrate pegtibatinase 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 has advanced through five data monitoring committee assessments. Overall, the median duration of exposure in the study is just under two years, with the longest patient approaching almost three 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 one 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. The case occurred in the third dose cohort and resolved shortly after a single dose interruption. The patient resumed dosing of pegtibatinase one 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 have 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. At the two highest dose cohorts to date, pegtibatinase appeared to reduce homocysteine regardless of starting baseline homocysteine levels or background therapy, including vitamin B6 and B12. I'm very pleased to report that in the highest dose cohort to date of 1.5 mg dose twice weekly, treatment with pegtibatinase resulted in rapid and sustained reductions in homocysteine beginning at week two 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 micromolar 'cause of the complications associated with high homocysteine levels are very serious. Specifically, in the 1.5 mg/kg 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 in the pegtibatinase-treated group in this cohort was 187 micromolar.
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 mg/kg 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 2022 to establish next steps.
We will also, in parallel, enroll one 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 three 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 the 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 up the lines for Q&A?
Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touch-tone telephone. If your question has been answered and you wish to move yourself from the queue, please press the pound key. Our first question comes from Joseph Schwartz with SVB Leerink.
Great. Thanks so much. 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. 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 waning? 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. I think there were several in there. Let's start with the Cohort 6, the next cohort that is 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'll be our first opportunity to confirm that in humans and evaluate the PK of that as well. It's a twofer in that respect.
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 two. It was really sustained in a pretty flat range across that 12-week observation period. We did look to see if we saw anyone that went down and then drifted up as you implied, you know, potential neutralizing 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. We haven't seen neutralizing antibody evidence based on the PD measurements to date. I can say that the immunogenicity profile thus far has been very favorable.
Great. That's really—
I think the only other thing that I would add, Joe, is that the work that we are doing with the sixth cohort will be conducted in parallel with the work that we will be doing with regulators to understand next steps. You know, we do see this as an opportunity to really optimize the program, but not change timelines 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. 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 timeframe if biomarkers weren't sufficient. You know, could you talk a little bit about, you know, 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. 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.
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.
Super helpful. Thanks for taking all my questions.
Thank you, Joe.
Our next question comes from Maury Raycroft with Jefferies.
Hi. Good morning. Congrats on the update, and thanks for taking my questions. I was wondering if you can say what the higher dose is gonna be for this additional cohort. Now that the study is complete, can you talk more about how enrollment for the study went? I'll stop there.
Thanks, Maury. Bill?
Yeah. At this point, we're not releasing the upper dose. We're looking toward a publication at a meeting, hopefully in the spring. 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 studies was underway when we acquired the program, and following the transition from Orphan Technologies into Travere and our team, that was kinda coincident with COVID, which certainly provided headwinds. 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. It met our expectations.
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. We're comfortable that, you know, this next cohort will enroll in a reasonable time. The team is already focused on looking at pivotal study designs. With those larger studies, what are the strategies that will help provide, you know, reasonable enrollment times and pace to facilitate that in a reasonable way.
Got it. For this additional cohort, are you saying how many patients are gonna be in that?
Yeah, there'll be four more patients.
Okay.
So-
For the 19 patients, did they come from multiple sites? Can you comment on that?
Yeah. It was six sites in the U.S.
Got it. Basically you're getting patients from all six of those sites.
Yes.
Okay. I was gonna 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?
You know, 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.
Got it. Okay. Congrats and thanks again.
Thank you, Maury.
Thanks, Maury.
Our next question comes from Greg Harrison with Bank of America.
Good morning. Congrats on the data, thanks for taking our questions. 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?
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. It wasn't, and it's not reoccurred, so it's very possible that it was due to something else. 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 were seen in the study, and that was probably the most common AE. But they're mild, and not anything that got in the way of dosing or study continuation.
There were a couple other patients that had hives, but it was transient and wasn't dose dependent. Overall, from a safety perspective, it's been really quite a clean study.
Okay. Great. Then I also wanted to ask about compliance with the low protein diet during the trial, if you have any information on that. 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.
Yeah, maybe I can take—
Yeah, sure.
Oh, sorry. Go ahead, Bill. I was going to give you a bit. Sorry. Go ahead.
For diet compliance, the patients were instructed to maintain the diet that they were used to adhering to. They also met with a metabolic dietitian with each site visit and had counseling around that and guidance. We have diet diaries which are one tool that allows you to assess how well those patients are adhering to a consistency of diet. The other thing we can look at is the placebo group and the variability in their data and, you know, as a crude measure, the consistency there suggests that we had good compliance with that, throughout the study. 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. 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 relief along that axis would be certainly very attractive to that patient population because they tell us that's really important.
Okay. Very helpful. Thanks again and congrats.
Thank you.
Thank you, Greg.
Our next question comes from Liisa Bayko with Evercore ISI.
Hi. Thanks for taking my question. For the 1.5 mg dose, can you talk about like the range? I know that the average, the mean was 55% reduction. There's only three patients. I'm curious, did all of them get below the 100 micromolar? What was the range? I'm just trying to understand the response.
Yeah.
Sure thing.
That level of detail is probably beyond what we want to get into today. We want to preserve the package for publication. We hope to get that out into the public domain quickly. Let me try and answer it this way, though. We saw consistency in response. At that dose we saw everyone reducing homocysteine. We saw everyone reducing it significantly, and we saw consistent suppression across that 12-week window. With any metabolic study, there is variability. When you get to a three-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.
It was a consistent response across the group.
Just for baseline, was there a big range there too? Because I'm just looking at your baseline for the placebo is materially lower. It's like, you know, 131 micromolar versus 187 micromolar for the 1.5 mg dose. I'm just curious on like what, how variable the baseline levels were.
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.
Okay.
Placebo was the lowest. The 1.5 mg/kg was just barely the highest, but there were three others that were right in there with it. It was a mix and it's something that is a byproduct of small numbers.
Do you see like a bigger, I guess, reduction, you know, with higher levels to start? I'm curious about like how much we can kind of compare, placebo to, you know, kind of the higher dose just given the differences in baseline. Like, would you expect like, are you a little bit at an advantage if you start with a higher level or, you know, how should we think about kind of the, you know, that dynamic?
Yep. Yep. 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. When we look at it on a percent reduction, we see consistency of percent reduction relative to starting homocysteine values. 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. 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 mg/kg twice a week. We'll be able to expand the data set beyond the three in this cohort, it's a much larger set, so that should grow to something greater than 10, somewhere between 10 and 14, depending on who rolls over.
Yeah.
We'll be able to have a better view of that and give you a more substantive answer when we have those data.
I think while there is a range, you know, it does, for all patients, represent, you know, a moderate to high risk of these complications. I think that and the consistency of response that Bill mentioned really gives us great confidence in the results that we've seen thus far.
Okay. Any difference, like, if patients were B6 responsive or not? Did you see any differences on that attribute?
Yeah. 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—
Right.
— get into the study. I think that—
Okay.
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—
Okay.
— of response.
Yes.
Okay. Just final question for 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, you know, I guess, increase, you know, the amount of reduction, I guess, have a greater reduction is what I mean at—
Yeah.
— at a higher dose, the way you're looking from what you can see of the dose response curve?
Yeah. 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, you know, we need to run that cohort and see what that is. Additionally, we're really rounding out the overall dose response curve and broadening the data that goes into the PK/PD model that'll 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. As Eric noted, it's important 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.
Okay. Great. Thank you so much for answering the question.
Thank you.
Sure thing.
Our next question comes from Tim Lugo with William Blair.
Thanks for the question, and 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 micromolar versus placebo?
At this point.
Yeah.
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. Maybe, you know, it sounds like the highest dose explored so far saw a 100% kind of, you know, 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 is homocysteine just so variable in these patients across baseline and week to week that, you know, 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. As you can imagine, the starting dose 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. The clearest results were, as you note, at the highest dose level. You're correct in assuming 100% response rate. Yes.
Okay, great. Thanks. Maybe one last one. As you explore a higher dose, is there any risk of kind of overcorrecting maybe too quickly? You know, I'm just not familiar with the disease as much. If homocysteine drops within a week, you know, kind of too rapidly, is there any maybe adverse event risk?
There's none that I've seen reported. These values are so high above background and normal homocysteine. It's unlikely that there would be an issue of homocystinuria as would be what you're describing. We don't see that as a problem. We haven't seen that in animal studies either when we've pushed to much higher, you know, 10x this in non-human primates. We think that the safety margins that we have are pretty good.
Great. Thank you for the question.
Mm-hmm.
The next question comes from Michelle Gilson with Canaccord.
Hi. Congrats on the data. Maybe just following up on some of the questions around the long-term extension. You know, how many patients have rolled into the long-term extension? 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 intrapatient homocysteine reductions as you escalate the dose. 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. We've amended the protocol to add that, and we're just now getting through IRB approvals of that protocol amendment. The open- label extension is just opening now at sites. As such, we have one patient that's rolled into the open- label extension. With the holidays, we don't have patients scheduling visits between now and the end of the year. We expect that in January that process will accelerate and those patients will roll in. What we haven't seen is, as you asked, you know, 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 mg group, as they roll in. That will further expand and strengthen the data set. From a timing perspective, that's just starting.
Okay, you mentioned that there was a patient, you know, that was dosed three years ago, I think, in your opening remarks. 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 from lower dose cohorts as the study progressed, and they will now be able to jump to the 1.5 mg/kg. The data that we're talking about and analyzing right now is just the zero to 12-week comparison across these groups.
Okay. You know, in those other dose cohorts, are you seeing that the reductions in homocysteine are sustained, you know, 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. You mentioned that about half the patients were on B6 when they entered the study. You know, 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.
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? 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?
Yeah. 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. That will be the dose frequency going forward. 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'll 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 U.S. and Europe to get those on the books. They're not scheduled now. We do have to your question, do we have a plan? Yes. There are study designs being developed. They're 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 a biomarker endpoint, but we need to achieve alignment with the regulatory agencies on that. Duration is something that we're going to 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 a, you know, as you look across enzyme replacement therapy studies, you see a wide range of study size. A lot of that's gonna be determined based on the overall variability in the numbers as well as exposure needs from the agencies. There's different ways to calculate the needed sample size, and that's part of what we'll be engaging the regulators to discuss.
Okay. Thank you guys so much for taking all my questions.
Welcome.
Congratulations on the data again.
Thank you, Michelle.
Thank you.
Appreciate the questions. 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 uptitration. Just another important part of the trial design.
Our next question comes from Carter Gould with Barclays. One moment. Your line is open.
Hi, this is Justin on for Carter. Thanks for taking the question, and 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.
The age range, I'm searching for the numbers. Eric, do you have that?
We know that the mean was about 24 years. You know, there were patients that were below 18, but I don't have the oldest range. I think it was representative of what we see in the natural history study. Again, small numbers, Carter. With regard to symptoms at baseline, I think that's something that we're gonna continue to explore relative to what we see at baseline. We do know that some patients did have a history of some of the complications that Bill outlined as representative of the disease.
I've found the number. Yeah, the mean was 24, and six of the patients were below 18.
Okay. Thank you for that. I just wanna confirm, it sounds like you're only gonna be enrolling four more patients into the expansion study and capping COMPOSE at 23 patients. Is that correct?
That's correct.
Okay. Awesome. Thanks so much, and congrats again.
Thanks, Justin.
Thank you.
All right. Thanks, Justin.
The next question comes from Laura Chico with Wedbush Securities.
Hey, good morning, guys. Thanks for taking the questions. I just have two follow-ups here. One, I'm wondering if you could just spend a moment back on market sizing and how you're getting your prevalence number. I think you mentioned, Eric, 7,000 as a number 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. Just wondering if you can help walk me through how you're getting to that 7,000 number in the U.S. and E.U., and perhaps what are some of the drivers that might influence that figure up or down?
Yeah, great question, Laura. Certainly the work that you referenced is very much in line with our understanding. Part of the reason that disconnect between, let's say, you know, 3,500 in the U.S. up to over 10,000 or 12,000 really is why I reflected that our estimates may be conservative. That 7,000 patients, you know, equally split roughly around 3,500 between the 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.
We do, you know, as similar with many other rare diseases, the more we learn and the more information is gathered from, you know, clinical trials, et cetera, we do recognize that there may be more patients. 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. Homocystinuria is part of the panel for many states for newborn screening, but it measures methionine levels, not homocysteine levels. Those don't at birth always move in the same direction until later. Many of these patients are missed.
In exploring what might be the true prevalence, Orphan Technologies started to look at chart reviews in those patients that had consistently elevated homocysteine levels upon routine lab draws. That's where you started to see that there could be, you know, upwards of 12,000 patients that may have homocystinuria. You know, 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. We do believe that conservatively there are 3,500, but certainly room to, you know, for that to be much higher as there's better recognition and earlier diagnosis.
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. Maybe one quick follow-up here. I apologize if I missed this, but 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? Thanks very much.
Yeah. I would say at this point, you know, those efforts are all gonna be done in parallel. The work that we're doing on CMC optimization, including, you know, the scale-up and the investment now that we have, you know, 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 six cohorts. I'd say at this point, I wouldn't necessarily characterize it as gating, but we do, you know, think that we'll be in a better position to provide updates on timing once we've met with regulators next year. You know, as you could imagine, with the exciting data we're announcing, we're gonna be moving as quickly as we can.
Thanks very much, guys.
Thank you, Laura.
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 concludes today's presentation. You may now disconnect and have a wonderful day.