Hello, ladies and gentlemen, thank you for standing by. Welcome to the Travere Therapeutics Corporate Update Call. I would now like to turn the call over to your host, Naomi Eichenbaum, Vice President of Investor Relations. Ms. Eichenbaum, please go ahead.
Thank you, Melinda. Thank you all for joining us today. Earlier today, we issued a press release covering the positive top-line results from cohort 6 in the phase 1/2 COMPOSE study of pegtibatinase in classical homocystinuria. A copy of the release, along with the slides that we'll be reviewing on today's call, are available on our investor relations website. Today's call will be led by our Chief Executive Officer, Dr. Eric Dube. Joining Eric will be our SVP of Research and Development, Dr. William Rote, and Dr. Can Ficicioglu, MD, PhD, Clinical Director of the Metabolic Disease Program at Children's Hospital of Philadelphia. Our Chief Medical Officer, Dr. Jula Inrig, will also be available during the Q&A session.
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 future performance. They involve known and unknown risks, uncertainties, and assumptions that may cause our actual results, performance, and achievements to differ materially from those expressed or implied by such statements. Please refer to today's press release and accompanying slide deck, as well as risk factors in sections of our annual report or Form 10-K filed with the SEC. Any forward-looking statements represent our views as of today, May 31st, 2023, and we specifically disclaim any obligation to update such statements to reflect future information, events, or circumstances.
With that, let me now turn the call over to our Chief Executive Officer, Dr. Eric Dube.
Thank you, Naomi, and good morning, everyone. Earlier today, we were very pleased to share the next set of data from the ongoing phase 1/2 COMPOSE study of pegtibatinase in classical homocystinuria, or HCU. HCU is a devastating rare disease that can lead to serious complications. These include skeletal abnormalities, cognitive developmental delays, and intellectual disabilities, as well as the continuous risk of developing life-threatening thrombotic events such as heart attack and stroke. Patients have limited treatment options, and most must adhere to highly restrictive diets that are often inadequate and complex to follow, resulting in serious health risks. As such, we've advanced the phase 1/2 COMPOSE study in furtherance of our goal of enabling pegtibatinase to potentially become the first disease-modifying approach to HCU. In late 2021, we reported positive results from the first five cohorts of the COMPOSE study.
Specifically, in the highest dose cohorts tested at the time, we saw a dose-dependent reduction in total homocysteine levels, which served as a strong proof of concept. The new data from cohort 6 illustrates the potential for an even greater benefit in total homocysteine reduction and continues to show that pegtibatinase has a generally well-tolerated safety profile. Importantly, the results from cohort 6, which evaluated twice-weekly doses of 2.5 mg/kg lyophilized pegtibatinase, showed a continuous dose-dependent response, rapid and sustained reductions of total homocysteine beyond the previous highest dose, and resulted in patients achieving important clinical thresholds of total homocysteine below 100 micromolar and 50 micromolar. We are fortunate to have Dr. Can Ficicioglu with us today, an expert in the field of metabolic disease.
Dr. Ficicioglu is Director of the Newborn Metabolic Screening Program and the Lysosomal Storage Diseases Program and Clinical Director of the Metabolic Disease Program at Children's Hospital of Philadelphia, and an investigator in the COMPOSE study. He will discuss classical homocystinuria and the impact of the disease, the current treatment landscape, as well as clinical management and expert experience. Before turning the call over to Bill for a review of the cohort data, cohort 6 data. Before handing the call over to Dr. Ficicioglu, I would like to thank the patients, their families and caregivers, the investigators, and the site staff, all of whom continue to make great contributions to further our understanding of pegtibatinase and HCU. I'll now pass the call over to Dr. Ficicioglu.
Thank you, Eric. Homocystinuria is a rare inborn error of metabolism caused by the deficiency of the enzyme cystathionine beta-synthase, in short, CBS. Methionine, which is an essential amino acid, is converted to homocysteine. Homocysteine is broken down to cystathionine by the CBS enzyme. The deficiency of the CBS enzyme leads to toxic accumulation of homocysteine in the body, as well as a decrease in cystathionine and cysteine levels. Estimated incidence of HCU is about one in 100,000 to 200,000. It is more common in Qatar, one in 1,800, and Ireland, one in 65,000. This is due to founder effect. Certain mutations are common in those regions. Typically, the disease manifests in childhood and is characterized by involvement of the eye, skeletal system, vascular system, and central nervous system.
Patients are at risk of developing severe long-term complications like lens dislocation, severe myopia, skeletal issues such as osteoporosis, scoliosis, developmental delay, intellectual disability, and thromboembolism, which is the major cause of morbidity and early death associated with HCU. It is not unusual for a previously asymptomatic and undiagnosed individual to present in adult years with only a thromboembolic event that is often cerebrovascular. How do we make the diagnosis? How we identify these patients. In terms of patient identification, newborn screening is conducted in all states. It helps to have early identification, but many cases are missed because the screening is done measuring methionine levels, and not all patients have elevated methionine in the first three, four days of life that newborn screening is done.
We confirm the diagnosis by measuring total homocysteine level, plasma amino acids, and performing genetic testing of the cystathionine beta-synthase gene. Early diagnosis and treatment are crucial in managing homocystinuria and preventing complications. Cases detected through newborn screening and treated early have much better outcomes. The best results have been reported in those individuals identified by newborn screening and treated shortly after birth, in whom the plasma total homocysteine concentration is maintained below 100 micromole, which requires compliance with a very rigid, protein-restricted diet and medications such as betaine. What is the current management? The mainstay of treatment is methionine-restricted diet, betaine, pyridoxine, which is the cofactor of the enzyme. Sometimes we use vitamin B12 as well. Dietary treatment reduces methionine intake by restricting natural protein intake.
However, to prevent protein malnutrition in methionine-free amino acid formula, plus the other amino acids is provided. The diet is very complex. To decrease homocysteine levels, patients must be on a very restricted low-protein diet and consume a methionine-free amino acid formula, which does not taste good. Since the disease is chronic, this treatment is lifelong. Compliance to management becomes a big issue, especially when patients get older. Once a patient tastes real food, they are even less compliant consuming the protein formulas. This condition poses significant challenges for patients, as the current available treatments have proven to be inadequate in managing the disease effects. Recent published European guidelines recommended maintaining total homocysteine levels below 100 micromole, which would help to decrease the risk of severe complications.
In the United States, metabolic experts recommend maintaining homocysteine levels 50 micromole or less. It is not easy to achieve this goal with the current therapies. Unfortunately, being on a special formula and a very low-protein diet for life is very difficult. Based on my 20-year experience in a center of excellence, following many new patients, about 70% of patients have levels more than 100 micromole. There is a huge unmet need to find therapies that will decrease homocysteine levels and relax protein restriction in diet. Let me highlight the unmet need by presenting two short cases from my practice. The first case is a 14-year-old boy with confirmed diagnosis of classical HCU. He was diagnosed through family screening at eight years of age.
His brother died of thromboembolic event at 12 years of age and diagnosed with classical HCU. Both brothers were screened for HCU as part of newborn screening and had normal results, they were missed by newborn screening. This patient was on a normal diet in the first eight years of life. At the time of diagnosis, we started him on a low-protein diet, supplemented with a special formula. He couldn't tolerate the special formula because of the taste. He used to eat everything all his life after the diagnosis of HCU and couldn't restrict his protein intake in the diet. His homocysteine levels are above 200 micromole, and it's very difficult to manage this case. The second case is a 17-year-old girl detected through newborn screening. Very compliant parents. They followed all our recommendations.
Her levels were kept at around 50 micromole through her childhood. Her levels went up to 80s when she started school. Now she's in her teen years in high school, and she struggles taking all her formula. She has more social life and wants to eat more protein like her peers. Her levels are above 100 micromole now. It is exciting to see that pegtibatinase significantly decreased total homocysteine levels.
Potentially allow patients to eat more protein while keeping their homocysteine levels as low as possible. Thank you, I will now hand the call to Bill.
Thank you, Dr. Ficicioglu. Good morning, everyone. I'd like to thank the patients, their families, caregivers, investigators, site staff, advocacy groups, and our Travere teams who have helped the advancement of pegtibatinase with the hope of it ultimately becoming the first disease-modifying therapy for patients with HCU. Pegtibatinase offers a promising approach to address the unmet need in HCU. As an investigational PEGylated, modified recombinant truncated human enzyme, pegtibatinase aims to introduce functional CBS enzyme activity into the bloodstream, addressing the underlying cause of the disease. By replacing the deficient CBS enzyme, pegtibatinase has the potential to significantly reduce the toxic buildup of homocysteine and restore metabolic balance. I'm pleased to share the positive results from the cohort 6 of the ongoing phase 1/2 COMPOSE study that build upon the proof of concept data previously announced from earlier cohorts of the COMPOSE study.
The study is a phase 1/2 multicenter, randomized, placebo-controlled, double-blind dose escalation trial to evaluate the safety, tolerability, and clinical effects of pegtibatinase in patients with classical homocystinuria, ages 12 to 65 years old. The primary and secondary outcomes are safety and efficacy, as measured by total homocysteine and methionine cycle metabolite levels. Overall, the COMPOSE study evaluated 24 patients across the six cohorts, including five patients in cohort 6. Cohort 6 evaluated four patients that were randomized to the highest dose of 2.5 mg/kg of lyophilized pegtibatinase twice weekly. Parent- patients were observed over a 12-week double-blind treatment period and then were eligible to enter into an open-label extension. The eligibility criteria for cohort 6 included confirmed diagnosis of homocystinuria based on genetic confirmation and plasma total homocysteine greater than 50 micromole, with documentation of a previous total homocysteine level greater than 80.
The total homocysteine entry criteria for cohort 6 was lower compared to the first five cohorts, so that the study could evaluate how a broader range of patients would respond to treatment with pegtibatinase. From a safety perspective, pegtibatinase has shown a generally well-tolerated profile throughout the study to date. In cohort 6, there have been no treatment-related serious adverse events, anaphylaxis, or discontinuations associated with the study drug. We've also not observed neutralizing antibody effects, as determined by pharmacokinetic and pharmacodynamic monitoring. In cohort 6, two participants experienced a moderate injection site reactions and urticaria, considered likely related to pegtibatinase. Both were resolved with a temporary dose interruption of 1-2 weeks and began up titration from a lower dose, ultimately achieving tolerability at the 2.5 mg/kg dose, either in the blinded portion of the open or in the open-label extension.
In cohort 6, treatment with 2.5 mg/kg of pegtibatinase, administered twice weekly, resulted in a 67.1% mean reduction in total homocysteine from baseline, compared to a 0.6% increase in relative change of total homocysteine levels from baseline for all patients receiving placebo in the study. For those treated with pegtibatinase in cohort 6, the effect of total homocysteine was rapid and sustained throughout the 12 weeks of treatment. Analysis of total homocysteine data differs slightly from what was used in cohorts 1 through 5 and was chosen for cohort 6 to provide a comprehensive analysis that incorporates the geometric mean total homocysteine reduction over weeks 6, 8, 10, and 12. This evolution in how we report changes in total homocysteine improves the precision for measurements that can be variable in patients with HCU.
We plan to implement this method of analyzing total homocysteine moving forward. Importantly, in cohort 6, all patients achieved a mean total homocysteine level below the clinically meaningful threshold of 100 micromolar, and some patients achieved below 50 micromolar over weeks six to 12 of treatment. This includes one patient with a lower total homocysteine level at baseline, who achieved normalization of total homocysteine, or less than 15 micromolar. These findings illustrate a continued dose-dependent reduction in total homocysteine levels, as previously observed in the highest twice-weekly dosed cohorts. Furthermore, in cohort 6, pegtibatinase treatment demonstrated favorable effects on other biomarkers related to its mechanism of action in HCU. A substantial reduction in methionine levels were observed, suggesting that pegtibatinase can restore the metabolic dysregulation associated with HCU.
Additionally, pegtibatinase treatment demonstrated an increase in cystathionine levels, a downstream product of the mutated CBS enzyme in HCU patients and signifies restoration of the deficient enzyme and improved metabolic regulation in patients with HCU. These favorable effects on methionine and cystathionine are consistent with our findings in cohort 5 and provide us with further confidence in the multifaceted therapeutic potential of pegtibatinase in addressing the underlying biochemical abnormalities in HCU. Overall, pegtibatinase has shown sustained reductions in total homocysteine and supports our confidence in the potential for a broader range of patients to respond well to treatment. We also believe that the 2.5 mg/kg twice weekly dose could provide the greatest opportunity for patients to reach safe levels of total homocysteine, thereby providing the potential to further prevent disease progression. With that, I'll turn it back to Eric.
Thank you, Bill. The diagnosis of HCU for patients and their caregivers can be overwhelming and dire, and the need for new effective treatment options remains high. The cohort 6 data shared today build upon the strong proof of concept data that was previously reported from the pegtibatinase program and further strengthen our optimism that pegtibatinase has the potential to become the first disease-modifying therapy for patients living with HCU. Looking ahead, these data will enable us to further our discussions with regulators with the goal of initiating a phase 3 program by the end of this year. We expect to provide a subsequent update with details on a potential pivotal program once those discussions have been completed and a plan to present additional results from the COMPOSE study at an upcoming medical meeting or in a peer-reviewed publication.
I'd like to close by thanking Dr. Ficicioglu for his sharing his insightful experience in treating people living with HCU and support of the rare disease community as we continue to advance the exciting pegtibatinase program. Now let me turn the call back over to Naomi for Q&A. Naomi?
Thanks, Eric. Operator, can we now open the line for Q&A?
Certainly. If you'd like to ask a question, please signal by pressing star and one on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Once again, that is star and one to signal for a question, and we'll pause just briefly to assemble our queue. And our first question today comes to the line of, comes from the line of Joseph Schwartz with SVB Securities. Please go ahead.
Great. Thanks so much. Congrats on these data. I was wondering, were patients in cohort 6 able to liberalize their diets at all? Looking to the phase 3, are you planning to include the ability for patients to do this? I think as a follow-up, there's some secondary endpoints that are being evaluated in COMPOSE. I'm wondering, if you've seen any changes on any of those fronts. Thank you.
Joe, thanks so much for the questions. Bill, maybe you can take the question about what we saw in cohort 6, liberalizing the diet as well as the endpoints. Jula, maybe you can talk a bit about how we're thinking about that in phase 3.
Certainly. Good morning, Joseph. Thanks for the questions. In cohort 6 and throughout the COMPOSE study, we've instructed the patients to maintain a consistent diet. We are not using diet liberalization at this stage, but I think that it's important to realize that when we get down into levels that we're seeing now with this degree of reduction in homocystinuria or homocysteine, sorry, it certainly is something that becomes possible, and there we do have the potential for that. That's something we look forward to in the future. With respect to secondary endpoints, most of the data from the study is going to be presented at a future scientific meeting. What I want to do is hold those data for that presentation.
Yeah-
With to our phase 3 study design, of course, you want to show efficacy, the primary study will maintain patients on a stable diet to demonstrate efficacy on total homocysteine. Of course, to your point, liberalization of the diet is clinically meaningful for patients. Over the long term, we're having conversations with the FDA with regards to how we would be able to demonstrate more of a liberalization within our more of an open-label extension type of study. We are thinking about that and engaging about how we can demonstrate that.
Okay, great. Thanks. Is there an OLE for the COMPOSE study?
Yes, there is.
There is, yes.
Great. Thanks for taking my questions.
Thanks, Joe.
Next. Next, we go to the line of Tyler Van Buren with TD Cowen. Please go ahead.
Hey, guys. Good morning. Congratulations on the data. Looks great. Wanted to ask on two topics. The first one is just a clarification on the data. Is there any reason to believe that a higher % reduction in HCY, not absolute, but % reduction, would be easier to achieve with lower baseline HCY levels? The second one is, given the strength of the data, the main question that comes to mind is, how quickly can you guys get approved? On that topic, are you able to discuss the potential size of the phase 3, how long it'll take to get in to enroll potentially, and when you might have top-line HCY biomarker results that you could file for accelerated approval?
All right, Tyler, thanks so much for the questions. Bill, why don't you take the first question on baseline levels and percentage, as well as our thoughts on regulatory approval? Maybe Jula, then you can speak to where we are on phase 3 design.
Certainly. It's a good question. It's one of the questions we wanted to explore when we broadened the inclusion criteria in COMPOSE. Because these patients present over a very broad range of baseline total homocysteine, one of the questions was actually the inverse of what yours was: If you have a lower baseline, do you have a lower % reduction, or is there a floor effect that you see with pegtibatinase? What we saw was the answer was no to both questions. There isn't a greater effect at lower total homocysteine values at baseline, nor is there a floor effect that we can observe in these patients that have the lower baseline. Across a broad range, we see a generally consistent % reduction independent of where the individual starts at treatment.
As far as time to approval, we've guided that we're working with regulatory agencies to align on the study design for phase 3. That's both the FDA as well as EMA. I think we'll be in line size-wise with other enzyme replacement studies. Until we have those specifics aligned, it's tough for me to give you know, any kind of clarity around size, duration, et cetera. From an endpoint standpoint, we know that we'll be using reductions in total homocysteine for the primary endpoint in the study, and that'll be expressed as % reductions as well as threshold, percentage of patients getting below 100, percentage of patients getting below 50, for example.
Yeah, I'll add that we are working to get our phase 3 design finalized with the agency, as Bill mentioned, with the goal of having our phase 3 started by the end of this year. The other thing I do want to clarify is we have agreement on total homocysteine as our endpoint, and so we're seeking full approval, not accelerated approval for our phase 3.
And maybe, Dr. Ficicioglu…
Thanks so much.
would you like to provide your comments on the question around baseline levels and thoughts on level of reduction?
I think, you know, you know, percentage decrease is important. Of course, your patient starts with the lower levels, and that percentage decrease probably will bring patients' homocysteine levels to much lower levels. It is, I think, meaningful if a patient has 300 micromole and decreasing 50% or more will decrease patients' homocysteine meaningfully and results in if to put patients at much less risk for thromboembolic events. I don't know if I answered the question, but, you know, the decrease, the baseline is important. Of course, the percentage decrease will definitely bring patients to a different levels, depending on their-
Yes, I think that is helpful. Tyler, maybe just to round it out, I think one of the important observations that we've seen thus far is that all patients that we've studied with pegtibatinase in cohorts 5 and 6, which we believe are effective doses, have had a substantial and consistent reduction in their levels. Regardless of where patients start out, all patients we've seen thus far in the phase 1/2 have benefited from pegtibatinase.
Next, we go to the line of Greg Harrison with Bank of America. Please go ahead. Your line is open.
Hey, good morning. Congrats on the data and thanks for taking the question. On the baseline levels, which are already below, you know, what you've pointed out as clinically meaningful, the fact that those have declined below 50 micromolar, which you've pointed out, is there an additional clinical benefit that you would expect below that threshold? Then, given the increasing reduction in total homocysteine, is there an opportunity or would it make sense to explore an even higher dose?
Thanks for the questions, Greg. I'll turn Dr. Ficicioglu, to you to really provide a view of what would be important, particularly for those patients that may be at or around 100 micromolar. What's the benefit of getting below 50 or lower?
Right. I think, bringing homocysteine levels as low as possible is the key. We do not know what the toxic level of homocysteine is or what is the safest level of homocysteine is. Normal homocysteine is 15, 1, 5. We want to keep homocysteine levels as low as possible to prevent, you know, complications. As I mentioned, when I presented a study from Ireland, clearly showed that if patients are detected through newborn screening and their levels are kept below 100, their outcomes are acceptable. They do not have lens dislocation, they do not have learning disabilities. The lower the level, the better, but we don't know what level is the best, we don't have that knowledge. Of course, the lowering homocysteine levels will allow patients more protein.
If you can keep homocysteine levels as low as possible and increase their protein intake, it will be extremely important and will be a game changer for these patients and improve quality of life and decrease complications of the disease.
Thank you for that perspective. I think that certainly is our goal as we think about, really trying to strike that balance of keeping those levels low enough to prevent clinical sequelae, but also allowing patients to be able to have, more protein in their diet. That really is what we're, what we're aiming for. Bill, maybe you can take Greg's, last question around the potential for exploring a higher dose.
Certainly. We believe that at 2.5 mg/kg, we've reached the upper end of what we'd want to use for the clinical development of pegtibatinase. We've seen dramatic reductions at 1.5 mg/kg, and now a further reduction at 2.5, with one of the four patients getting to a normal value, something that's just never been heard of in this population of patients. We feel that we've reached the upper end of the safe end of the dose response curve, and that's where we're going to stop, and that'll be the dose we'll carry forward into phase 3.
Got it. That's helpful. Thanks.
We go to the line of Maury Raycroft with Jefferies. Please go ahead. Your line is open.
Hi. Good morning. Congrats on the updates, and thanks for taking my questions. I was wondering how many patients have enrolled into the open-label extension, and are you providing an update on how those patients are performing at the higher, 1.5 mg twice weekly dosing, or will you have an OLE update at the upcoming medical conference?
Thanks, Maury. Jula, would you like to take this?
Yeah. We've had a significant proportion of the patients roll over and realize that we've got patients that are now out to nearly four years in this study. We do plan to give an update at the upcoming medical conference, so more to come, and/or, we're going to publish some of this data in peer-reviewed literature is our other plan as well.
I think the other aspect, Maury, is that we are going to be increasing patients now that we've reported the efficacy and safety of 2.5 mg, increasing those patients in the open-label extension to the 2.5 mg, which again, as Bill mentioned, really would be, you know, the optimal dose at this point.
Got it.
More to come from the OLE beyond the 1.5 mg.
Got it. Okay. One other question. At the ACMG meeting earlier this year, you talked about the E72 ICD-10 code data suggesting there could be a higher prevalence of patients in the U.S. at about 17,000 patients, which is much higher than the approximate 3,500 from the literature. Do you have an updated update on this data, and what are your latest thoughts on prevalence and incidence for this opportunity?
Yeah, it's a great question, Maury. We're continuing the work to better refine estimates of prevalence as well as, you know, whether the addressable population is higher. I mean, certainly we've been conservative in the, our estimates of addressable population, including those patients that are not able to, you know, maintain their levels with diet and betaine. With the additional ICD-10 code, as well as further, you know, work that we're doing, we'll be in a position perhaps later this year to provide, you know, further updates on the addressable population. Again, I think that is probably on the conservative side, but it is one that we have a high level of confidence in at this point.
As you know well from other rare diseases, once there's greater awareness, the potential for an additional treatment option, that oftentimes the diagnosis rate increases. Importantly, as Dr. Ficicioglu also mentions, we see an exceedingly high false negative rate from newborn screening, and it's also our goal to help in identifying earlier diagnosis for patients with known HCU.
Got it. Okay. Thanks for taking my questions.
Thank you.
We go next to the line of Liisa Bayko with Evercore ISI. Please go ahead.
Hi. I was just chatting to my associate here, and we're trying to figure out what's the B6 background of these patients and actually the response, whether or not the patients were on a background of B6 or not.
Thanks, Liisa, for the question. Bill, would you like to take that?
I, it's my understanding that most of the patients are supplemented with B6, but what I don't know are the specific details. You know, what dose, and what's also more important is what percent. You know, are they responders to B6, and that B6 has a positive effect on their overall total homocysteine. I think qualitatively, because we have a lower baseline in this cohort, it suggests that we're more likely to have some B6 responders in that group and potentially better compliance with diet in this group of patients. Those are just inferences. The other con med that's utilized in this population, betaine?
Yeah.
Two of the four patients, two of the four were on betaine, and two were not.
Okay. I guess across the board, do you see any, you know, differences in patients that are on any of these background meds, either B6 or betaine, as you look through the cohort?
Well, yeah, as we've looked through the data to date, we don't see an interaction between B6 or betaine. Where it impacts is the, you know, the entry total homocysteine value when they enter into the study. The other area where we see an impact is if a patient stops taking betaine, we can see that impact in the metabolic data when we look at less the total homocysteine, but more the total methionine, because betaine pushes total homocysteine up to methionine. We see a greater reduction in methionine when they stop taking betaine. We don't see an interaction between the agents, so it doesn't present any type of complication for clinical development or clinical usage in the future.
I think, Liisa, the other aspect that maybe to answer your question is just from the natural history study that we have. You know, we know that these patients oftentimes will be, you know, will try B6 and betaine, but we do know that it's very challenging for patients to maintain control of their homocysteine levels with that and with diet. I think that the case study that Dr. Ficicioglu is a very relevant and common one, where as patients age, you know, they lose control of their homocysteine levels because of the difficulty of diet.
I think if we take a step back and look at the data from cohorts 5 and 6, we're very encouraged by the fact that across a broad range of baseline levels and treatment regimens, that you see a very consistent and profound reduction in total homocysteine that is sustained over the 12 weeks. That's what is encouraging us as we move forward. Maybe we'll Dr. Ficicioglu, we'll invite you to share your clinical experience and how you think about the addition of pegtibatinase potentially to patients that are on the other treatments.
Right. I just want to clarify Vitamin B6 response in homocystinuria. The definition of Vitamin B6 responsive is they should be able to maintain good metabolic control on Vitamin B6 only. This is the definition of Vitamin B6 responsive Homocystinuria. If patients need diet therapy or other medications, it means that they are not really responsive to Vitamin B6. I think it's important to clarify the what it means or what we mean with Vitamin B6-responsive Homocystinuria. The other question, I think, Eric, was the. Can you repeat the question?
Yeah, just your clinical experience in the potential addition of pegtibatinase to patients on, and vitamin B6.
Right. Most patients are on vitamin B6. Even if they are not, we keep B6 to just to prevent the deficiency of vitamin B6. Vitamin B12 is important because vitamin B12 should be within normal range. If there is deficiency, vitamin B12 is an important vitamin for remethylation of homocysteine, so it should be kept within normal range. Sometimes we use folate as well, just to prevent the deficiency of folate. Of course, betaine basically converts homocysteine back to methionine, so it's an important medication in the management of this disease. I should emphasize that if patients cannot be on a very, very low protein diet and take their medications every day, it is very difficult to achieve good metabolic control in those cases. It's
Can you just remind-
A therapy, so it doesn't work well.
Got it. Can you just remind us what it means to be with B6 responsive?
Well, vitamin B6 is a cofactor for the CBS enzyme. It means that those patients are milder, you know, cases, and there should be some residual enzyme activity. Vitamin B6, if high doses, can make the enzyme more stable and break down more homocysteine. Vitamin B6-responsive cases have a residual enzyme activity, and they have much milder phenotypes.
Is responsive mean any change when you start B6, or is there some level? Like, what's the criteria for B6?
I think it's a good question. When we diagnose a patient, we test first if they are vitamin B6 responsive or not. We start them on a high dose of vitamin B6. In newborns, we do 300 mg. In older patients, 500 mg. We test the responsiveness to vitamin B6, a week or so, and we measure homocysteine, plasma amino acid levels and see if vitamin B6 will decrease methionine and homocysteine level. If there is biochemical response, we call those cases, vitamin responsive.
Okay. Just like even a tiny decrease.
There's no response to vitamin. Yeah, yeah.
Okay. Okay. I don't know what the threshold is. Okay. Just for the one patient that was less than 15 micromolar achieved that level, where did they start? I know you said they were lower at baseline. Just curious.
Bill, would you like to take that?
Yeah, the that individual patient was right around 40 micromole at baseline. They were higher than 50 at screening. As you know, there's a certain amount of variability day to day and even within a day. That was the that's where they started the cohort.
Thanks.
Thanks, Liisa.
We go next to the line of Tim Lugo with William Blair. Please go ahead.
Hey, guys, this is Lachlan on for Tim. Thanks for taking the questions. I guess first for Dr. Ficicioglu, yeah, I think you mentioned about 70% of patients aren't really controlled at the moment. I'm just curious, does that translate into, you know, basically all those patients would be good candidates for pegtibatinase if it was approved, or would there be a subset where you see it being most valuable? For the Travere team, I know you were testing the lyophilized formulation in cohort 6, so just wondering if there were any learnings there on how that performed relative to your expectations.
Thanks, Lachlan, for the question. Dr. Ficicioglu, would you like to take the question on, you know, how you see appropriateness of pegtibatinase based on what we know to date?
Yeah. As I mentioned, you know, based on my experience, we have many patients with HCU. Over the years, I saw many patients with HCU. Majority of patients have levels more than what. It is extremely difficult to decrease homocysteine levels 50 or below, even patients are extremely compliant to diet and medication. All patients will be eligible. All patients with classical HCU will be eligible for pegtibatinase if it is, when it is available.
Thank you. Lachlan, I apologize, can you please repeat your second question?
Yeah. I was just... Yeah, I know you were testing the lyophilized formulation in cohort 6, which was new. I was just wondering if you could comment on how that performed relative to expectations and if there are any learnings from that.
Great. Thank you. Bill, would you like to take that?
Yeah. Thanks for the question. We were pleased with the utility of the lyophilized formulation. It reconstituted well, there were no apparent issues with it relative to the liquid. As you know, this provides a broader range of storage conditions, which will facilitate what patients are able to do. Our ability to ship and store the drug becomes much easier, and it was a key point of advancement of the program from a CMC side to enable a broad geographic footprint for the phase three study. We're very happy with how that's working to date. Obviously, this is 5 patients. We want to see more experience, and we'll have that expanded throughout the open-label extension as well.
Got it. Thanks.
We go to the line of Mohit Bansal with Wells Fargo. Please go ahead.
Great. Thank you for taking my question. Congrats on the data. I have two questions, one five- part and one seven- part. Sorry, just kidding. Maybe like, I mean, like, I just like beating down the same horse here, but talking about the levels, and from our reading, we are getting two different messages: that anything above 10-12 micromole is bad, and with vitamin C, the target is to bring this below 100. One, can you confirm that these numbers are correct? Number two, is there any analysis that is done to show that, I mean, if you are above 100 versus below 100, is there a benefit long term on accumulation or neurological deficits? This is the first question.
Second question is that there's another metabolic disease which looks very similar, PKU, and it kind of reminds me of early days of KUVAN. KUVAN was not particularly great drug, but it lowered it by 30%, the Phe levels. Is there similarity or differences between these two diseases in terms of manifestation, and seriousness of the disease? Could it become a more like a PKU-like disease as the development progresses? Thank you.
Mohit, thank you for the questions. I think there certainly are a number of parallels that we have been studying between HCU and PKU. You know, particularly given the similarity in how patients are treated with diet and the difficulty there, as well as the diverse constellation of symptoms and the time course of the disease. That said, you know, there are some differences as well, and we want to make sure that we're understanding this disease specifically. Maybe Dr. Ficicioglu, I'll ask you to give your thoughts, if you can, between HCU and PKU, as well as, you know, really a better understanding of those, the goal or threshold in HCU in getting below 100.
Right. I think it's a good question, and so there are two different diseases, but there are some similarities. One is, of course, in PKU, phenylalanine is toxic. We need to decrease Phe level, and in homocystinuria, homocysteine is toxic. We need to decrease homocysteine levels. Biomarkers are extremely important in both disorders. This is one thing. The second thing is, I think, as you know, PKU, what is the safest Phe level, right? We keep Phe levels less than 6 mg/dl , but it's also okay to keep it at around 10, and you can prevent mental retardation and learning disability if you keep it less than 10. You know, if you keep it in two or three, I think it will be great too. The same for homocystinuria.
We don't know exactly if 15 is better than 20 or 50, it is really not that clear, based on what we have at this point. The lower, the better. The lower the level, the better, probably. You know, there are many similarities with these disorders.
Thank you for that perspective, Dr. Ficicioglu. I think the other aspect, Mohit, of the question of patients above and below 100, one of the very consistent pieces of feedback we get, and this is anecdotal from experts that treat patients with HCU based on their clinical experience, it's not based on literature, because there's just been so little, is that really physicians-
Right.
... want to get closer to or below 50 before patients start to add additional protein in their diet. Doing so around 100 or greater could certainly increase the risk and the toxic levels based on as Dr. Ficicioglu mentioned, the Irish study. You know, I think it's really important as we continue to hear from this community, that getting lower is better, which is why we continue to increase to a higher dose in cohort 6 and why we increased the, or broadened the inclusion criteria to those patients above 50, because we know that there is still an unmet need for those patients that are between 50 and 100.
More to come there, but again, I think we're very encouraged by the profile we're seeing, emerge on pegtibatinase and really helping to address, these unmet needs.
Helpful. Thank you very much.
Thank you.
Next, we go to the line of Vamil Divan with Guggenheim. Please go ahead.
Great, thanks for taking the question. Just a couple to clarify things that have been discussed before. Sorry if I missed this. One, on the two of the four patients on the 2.5 dose that developed the moderate ISRs, can you just talk a little bit more about when they developed it? Was there any sort of dose titration up that you had in that cohort, or is there anything you're planning going forward to maybe minimize those ISRs? Sort of tied to that, are you planning on just going forward with the 2.5 dose, or at this point, are you thinking you may be moving forward with both the 1.5 and 2.5 doses? Lastly, just if you can comment on what you're seeing from a competitive dynamics perspective.
I think there are some other companies, you know, working in this space, but we haven't really seen much in terms of any data or progress. Curious what you've seen from your side.
Vamil, thanks so much for the questions. Bill, why don't we have you go through the ISRs, how we expect to manage it and our thoughts on dose going into phase 3?
Certainly. I think part of the question was timing. We saw the appearance of ISRs in these two patients at either week 2 or week 3, and it was urticaria or hives that caused the cessation of dosage for these individuals. The dosing was stopped for two weeks and then restarted at a lower dose. There was also premedication with that restart with H1, H2 blockers, over-the-counter, histamine blockers, which allowed them to tolerate the lower dose. After a period of a few weeks of dosing, they were then titrated back up to the 2.5 mg/kg dose and continue on that dose today.
In, you know, going forward, you know, this is a strategy that's been utilized with other enzyme replacements and other protein therapeutics. We haven't finalized the phase 3 protocol, but both titration and premedication are under consideration for the further development or the phase 3 study.
With regard to dose, I mean, certainly we're encouraged by what we saw in 2.5. I think that, you know, given the unmet need, it is likely the dose that we move forward in phase 3, but again, we'll provide those complete updates on phase 3 trial design once we've fully aligned with regulators. With regard to competition, maybe, you know, I would say, you know, perhaps it's early. We don't see anything in late stage development, so it's very difficult to comment. Dr. Ficicioglu, is there anything that you'd like to comment on the emerging landscape for other treatment options?
You know, As you said, I think, you know, I don't know anything in the phase 1, 2, or 3 clinical trials stage, so I think it is too early to talk about, but more therapies will probably come for many inborn errors of metabolism.
Okay, thank you.
Thank you.
We go next to the line of Laura Chico with Wedbush Securities. Please go ahead.
Thanks very much. I have one question for the Travere team, I'm sorry if I missed this, but could you just elaborate a little further as to why the 2.5 mg/kg twice-weekly dose, you think is the top end of the range? It looked like when you had the once-weekly versus the twice-weekly dose at 1 mg/kg, you had some benefit there. I'm just trying to understand, is there potential to increase the dose but decrease the frequency? Any other commentary? Then I have one follow-up.
Thanks, Laura. Bill, would you like to take that?
Yeah. No, it's a good question. The part of it is limitations based on the amount of protein being delivered. There's a limit to solubility, and so as you go up in dose, you also go up in volume. There's an injection burden that starts to create part of that equation. I think the other aspect that you mentioned, could you get to a once-weekly dose with a higher administration? It's less likely to get there when we look at the PK modeling. Theoretically, if you got high enough, you could cover the full week period, but you'd probably be pushing it with the amount of volume that you would need to inject to get there.
It's, in our eyes, the 2.5 mg/kg, administered twice a week, is probably the optimal, given the pharmacokinetics of the drug.
Okay, got it. Thanks, Bill. I guess one other question for Dr. Ficicioglu. Sorry, apologies on the pronunciation. I think I missed it, but how many patients with HCU do you currently manage? Thanks very much.
You know, in our center, we have 20 active patients with classical HCU.
Perfect. Thanks very much, guys.
Thank you.
My apologies. Our next question or comment comes from the line of Alex Thompson with Stifel. Please go ahead.
Great, thanks for taking our questions. I guess to sort of round out the discussion on dose response, could you maybe talk a little about some of the categorical endpoints between the 1.5 mg biweekly dose in this cohort 5 and cohort 6? Just how many patients were below 100, how many below 50, for each of those, just to sort of get a better understanding of that. And then in the prepared remarks, can you talk a little bit about sort of the reason why the U.S. versus EU guidelines have 50 versus 100, and if that might impact sort of the regulatory bar across those geographies? Thanks.
Thanks, Alex. Bill, why don't you take the question around the categorical response. Dr. Ficicioglu, perhaps you can give comment on treatment guidelines.
Right.
Dr. Ficicioglu, why don't we start with you.
Sorry, should I comment on treatment guidelines, Eric?
Yes. Why don't we start with you, Can?
Right. The treatment guidelines, we do not have treatment guidelines in the United States. One recent publication came from Europe, and the treatment guidelines are basically, as I mentioned before, recommend keeping homocysteine levels 100 or less. That number came from each individual expert's personal experience. As I said, you know, there was one paper published from Irish group on the cases detected through newborn screening, and they kept those patients' levels less than 100, and their outcomes were good. But the general, I think, guidelines is combination therapy with diet, amino acid formulas, betaine and vitamins are the current recommended therapy for these patients.
I guess, can you... did I miss something around the sort of the endpoint around 50 micromolar as to where that came from and whether that's different in the U.S. or EU?
In the United States, we try to get homocysteine levels less than 50. In the European guidelines came out, and then they recommend keeping homocysteine levels less than 100.
I guess for the company, is that something from a regulatory perspective in the U.S. or EU, that you would consider whether that differences in guidelines or clinical practice might impact approval?
Yeah, it's a great question, Alex. I think like so much else in rare disease, there's just very little clinical evidence upon which to go on. But certainly, as we continue to provide evidence that you can get numbers below, you know, number of patients below 50, I think that that is going to be really important. I'll just remind you that really the driver for us in looking at going below 50 is that that is oftentimes the trigger for clinicians to allow patients to liberalize their diet and add additional protein in. I think that really is the driver, less so guidelines, because again, as Dr. Ficicioglu mentioned, the guidelines are really based on anecdotal clinical experience, not on a wave of clinical trial evidence.
That certainly we expect to evolve with time and greater experience, but it's just such an emerging and inchoate area at this point. Bill, why don't you talk about the view of what regulators might be looking for, as well as that categorical response rates from cohorts 5 and 6?
Sure. The discussions we've had with regulators thus far, both U.S. and Europe, have not centered as much around threshold, but more around percent reduction. How do you characterize how best to analyze the response variable of percent reduction when you have a starting population that's going to range from somewhere around 50 micromolar up to 300 micromolar? What's the clinical relevance across those groups? Dr. Can mentioned that, you know, if you have somebody at 300 and you reduce them by 50%, that's a significant benefit. If you have somebody that's at less than 100 and you have that same 50% reduction, does it provide the same benefit?
That's been part of the discussion with the agency, but they are not, I guess, the heart of your question. The thresholds don't represent a regulatory challenge. It's most likely going to be some format of a % reduction. Now, with the categorical reductions, we do see a difference in the effect between cohort 6 and cohort 5, where in both groups, all patients were able to get below 100 micromolar as a mean post-treatment value. The difference is that when we go to cohort 6, we had half of them getting below 50, and one of those in that half getting down to normal levels.
We saw a difference in the categorical response, just by nature of the fact that you're driving the group lower on an overall percentage basis, that's gonna result in an overall benefit across those individuals.
Great. Thank you so much.
Thanks, Alex.
Next, we go to the line of Ed Arce with H.C. Wainwright & Co.. Please go ahead.
Hi, thanks for taking my questions and congrats on this latest data set. A few questions for me. First, I know we've talked about this in some other angles previously, but regarding the phase 3 dose that you expect, I know you mentioned the 2.5 mg/kg will be included, but just wondering if you've decided to also include the 1.5 mg/kg to not only allow for titration to optimize effects, but also to allow for, you know, minimizing the ISRs with urticaria. That's first. Second is, you could discuss the difference in the average diet compliance between sort of this study cohorts and sort of the real-world setting, and any implications you think, and sort of the differences there.
And then lastly, if you could, this is for the company, next steps from here and any potential gating factors between now and the end of the year when you expect to initiate the phase three study. Thanks so much.
Ed, thanks for the questions. I'll start with the last one. Really, the next steps are to meet with regulators, and while we've because of the Breakthrough Therapy designation, we've had regular engagements, we wanna make sure that we finalize those, particularly now that we have the data from the lyophilized formulation and from cohort 6. That really is the next step, and we also will be presenting these and additional data, or we're planning on at a medical meeting. Those are the next steps between now and end of year or between now and the start of a potential start of the phase 3.
You know, with regard to diet, what I would say is if we look at the placebo patients, and essentially the placebo cohort had little to no change, 0.6% increase. I think, you know, against the backdrop of variability, even within patients day to day, that is a very consistent kind of effect. You can see that, you know, they're gonna be stable or disciplined with whatever diet they had going into the trial, which was, I think, largely the goal. I'll ask Dr. Ficicioglu to give comments on what he sees in his clinical practice with regard to diet in the real world versus perhaps what we've seen thus far in the COMPOSE trial.
Right. I think, you know, the again, there are two groups of patients in the real world. Some patients, they try to be as compliant as possible. They take their formulas, they try to eat low protein. There are also, you know, patients that they eat more protein. I have patients with HCU, they eat meat, and they are not supposed to eat any high protein, but they do. Their diet really, they It doesn't change dramatically. If they are on stable diet and either on higher, you know, protein or they continue low protein, but the stability is, I think, there. We don't see any major flat ups and downs in their diet in real world when we follow these patients in the our clinic.
Many patients, as I said, they are eating much than what they can tolerate, but their diet, you know, protein intake doesn't really change too much.
Thank you for that. Jula, maybe you can comment on the phase 3 dose and what we're thinking about with regard to titration and the use of 1.5.
Yeah, certainly. As Bill said earlier, we're considering two options with regards to tolerability. This is what's been done in other programs. There's one as a premedication, which is what we did with those patients who had injection site reactions with H1, H2 antagonists. The other is a titration. That's what's done with other enzyme replacement. To your point, that is something we're discussing and considering moving into for phase 3.
Great. That's very helpful. Thank you so much.
Thanks, Ed.
This does conclude today's question and answer session. I'd like to turn the call back over to Ms. Eichenbaum. Please go ahead.
Thank you, everyone, for joining us this morning for our top-line results update on the phase 1/2 COMPOSE study of pegtibatinase in classical homocystinuria. We look forward to sharing additional updates on the progress. Have a great day, and thank you. Goodbye.
Thank you. Ladies and gentlemen, this does conclude today's teleconference. We appreciate your participation. Have a great day.