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

Hello, ladies and gentlemen, and 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, and 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 I/II 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. Bill Rote; and Dr. John 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. In addition, any forward-looking statements represent our views as of today, May 31, 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 I/II COMPOSE Study of pegtibatinase in classical homocystinuria, or HCU. HCU is a devastating rare disease that can lead to serious complications. This 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 have advanced the Phase I/II 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 illustrate 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 milligram per kilogram 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 threshold of total homocysteine below 100 micromolar and 50 micromolar. We are fortunate to have Dr. John 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 experience. Before turning the call over to Bill for a review of the Cohort data -- Cohort 6 data -- before handling 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, basically 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 a toxic accumulation of homocysteine in the body as well as a decrease in cystathionine and cysteine levels. Estimated incidents of HCU is about 1 equals 100,000 to 200,000. It is more common in Qatar 1 in 1,800; and Ireland, 1 in 65,000. This is due to founder effect. Certain mutations are common in those regions. Typically, the disease manifests in childhood, characterized by involvement of the 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 disabilities 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 individuals to present in adult years with only a thromboembolic event that is often cerebrovascular. And how we make the diagnosis or how we identify these patients? In terms of patient identification, a 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 level. And not all patients have elevated methionine in the first 3, 4 days of life the newborn screening is done. We confirm the diagnosis by measuring total homocysteine level plus amino acid and performing genetic testing of the cystathionine beta-synthase gene. Overall, early diagnosis treatment are crucial in managing homocystinuria in 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 does total homocysteine concentration is maintained below 100 micromolar, which requires compliance with a very rigid protein-restricted diet and medications such as Betaine. What is the current management? Mainstay of treatment is methionine-restricted diet, Betaine, pyridoxine, which is the cofactor of the enzyme. Sometimes, we use [ Vitamin B12 ]as well. The item treatments reduces methionine intake by restricting natural protein intake. However, to prevent protein malnutrition in methionine-free amino acid formula, plus 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 the 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 of cystine levels to about 100 micromole, which help to decrease the risk growth to the [indiscernible]. In the United States, metabolic experts recommend maintaining homocysteine levels of 50 micromole or less, but 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 [indiscernible] need to find therapies that will decrease homocysteine levels and realize protein restriction in diet. So let me highlight the unmet needs presenting to you short cases of -- from my practice. So the first case is a 14-year-old boy with confirmed diagnosis of classical HCU. He was diagnosed through family screening at 8 years of age. His brother died of thromboembolic event at 12 years of age and diagnosed with classical homocystinuria. Both brothers were screened for HCU as part of newborn screening and had normal results, so they were missed by newborn screening. This patient was on a normal diet in the first 8 years of life. At the time of diagnosis, we start the team on a low-protein diet, supplemented with a special formula. He couldn't tolerate a 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 about 200 micromole, and it's very difficult to manage this case. The second case is a 17-year-old girl detected through newborn screening. A very compliant parents, they followed all our recommendations. Her levels were kept at around 50 micromole through her childhood. Her levels went up to 80 when she started school. Now she is 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. So it is exciting to see that pegtibatinase significantly decreased total homocysteine levels and potentially allowed patients to eat more protein while keeping their homocysteine levels as low as possible. Thank you. And I will now hand the call to Bill.

Thank you, Dr. Ficicioglu, and 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 I/II COMPOSE Study that build upon the proof-of-concept data previously announced from earlier cohorts of the COMPOSE Study. The study is a Phase I/II 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 6 cohorts, including five patients in Cohort 6. Cohort 6 evaluated force patients that were randomized to the highest dose of 2.5 milligram per kilogram 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 homocystine level greater than 80. The total homocysteine entry criteria for Cohort 6 was lower compared to the first 5 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 one to two weeks and begin up-titration from a lower dose, ultimately achieving tolerability at the 2.5 mg per kg dose, either in the blinded portion or in the open-label expansion. In Cohort 6, treatment with 2.5 mgs per 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 effective 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 week 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 week 6 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 dose 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 milligram per kilogram 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 III 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 and 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 supported 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. [Operator Instructions] And our first question today comes to the line of -- comes from the line of Joseph Schwartz with SVB Securities.

Congrats on this data. I was wondering patients in Cohort 6 able to liberalize their diets at all? And looking to the Phase III, are you planning to include the ability for patients to do this? And then I think as a follow-up, there's some secondary endpoints that are being evaluated in COMPOSE. So I'm wondering if you've seen any changes on any of those fronts.

Sure. Thanks much for the questions. And Bill, maybe you can take the question about what we saw in Cohort 6 liberalizing the diet as well as the endpoints. And then -- and Jula, maybe you can talk a bit about how we're thinking about that in Phase III.

Certainly. Thanks for the questions. In Cohort 6 and throughout the COMPOSE Study, we've instructed the patients to maintain a consistent diet. So 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. So 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. So what I want to do is hold those data for that presentation.

And with regards to our Phase III study design, of course, you want to show efficacy. So the primary study will maintain patients on a stable diet to demonstrate efficacy on total homocysteine. But of course, to your point, liberation of a diet is clinically meaningful for patients. So over the long term, we're having conversations with 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 -- but we are thinking about that and engaging about how we can demonstrate that.

Okay. Great. And is there an OLE for the COMPOSE Study?

Yes, there is.

There is.

Next, we go to the line of Tyler Van Buren with TD Cowen.

Congratulations on the data. It looks great. I wanted to ask on two topics. The first one is just a clarification on the data. So is there any reason to believe that a higher percent reduction in HCY, not absolute, but percent reduction would be easier to achieve with lower baseline HCY levels? And then 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? So on that topic, are you able to discuss the potential size of the Phase III? How long it will 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. And maybe, Jula, then you can speak to where we are on Phase III design.

Certainly. It's a good question, and it's one of the questions we wanted to explore when we broaden 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 percent reduction? Or is there a floor effect that you see with pegtibatinase? And 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. So across a broad range, we see a generally consistent percent reduction independent of where the individual starts at treatment. As far as time to approval, we guided that we're working with regulatory agencies to align on the study design for Phase III. That's both the FDA as well as EMA. I think we'll be in line size-wise with other enzyme replacement studies. But until we have those specifics aligned, it's tough for me to give you 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 will be expressed as percent reductions as well as threshold percentage of patients getting below 100, percentage of patients getting below 50, for example.

Yes. I'll add that we are working to get our Phase III design finalized with the agency, as Bill mentioned, with the goal of having our Phase III started by the end of this year. And 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 III.

And maybe Dr. Ficicioglu, would you like to provide your comments on the question around baseline levels and thoughts on level of reduction?

I think percentage decrease is important. And of course, if patients start with a lower levels and the percentage decrease probably will bring patients, the sustained levels to much lower levels. But it is siting meaningful if a patient has 300 micromole, and decreasing 50% or more will decrease patient's homocysteine meaningfully and results in -- will put patients at much less risk for thromboembolic events. I don't know if I answered the question. But the decrease -- the baseline is important. Of course, the percentage decrease will definitely bring patients to different levels, depending level.

Yes. And I think that is helpful. And 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 studied with pegtibatinase in cohorts 5 and 6, which we believe are effective doses, have had a substantial and consistent reduction in their level. So regardless of where patients start out, all patients we've seen thus far in the Phase I/II have benefited from pegtibatinase.

Next, we go to the line of Greg Harrison with Bank of America.

Congrats on the data. On the baseline levels, which are already below what you've pointed out as clinically meaningful, the fact that those have declined below 50 micromolar, which you pointed out, is there an additional clinical benefit that you would expect below that threshold? And 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?

I think bringing homocysteine levels as low as possible is the case. So 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. So we want to keep homocysteine levels as low as possible to prevent complications. As I mentioned -- and I presented a study from Ireland clearly showed that if patients are detected through a newborn screening and their levels are kept below 100, the 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. So we don't have that knowledge. But of course, so lowering homocysteine levels will allow patients more protein. If They 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 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 milligrams per kilogram, 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 mgs per 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. So 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 will be the dose we'll carry forward into Phase III.

Next, we go to the line of Maury Raycroft with Jefferies.

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 those?

Yes. We've had a significant proportion of the recent rollover and realize that we've got patients that are now out to nearly 4 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 the data and the peer review literature of 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 the optimal dose at this point. So more to come from the OLE beyond the 1.5 mg.

Got it. Okay. And one other question. At the ASMG 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. in 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 incidents for this opportunity?

Yes, it's a great question, Maury. We're continuing the work to better refine estimates of prevalence as well as whether the addressable population is higher. I mean certainly, we've been conservative in our estimates of addressable population, including those patients that are not able to maintain their levels with diet and betaine. With the additional ICD-10 code as well as further work that we're doing, we'll be in a position perhaps later this year to provide further update on the addressable population. But again, I think that our view is that, that is probably on the conservative side, but it is one that we have a high level of confidence in at this point. But 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 mentioned, 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.

And we go next to the line of Liisa Bayko with Evercore ISI.

I was just chatting my associate here, and we're kind of figure out what's the basic background of these patients? And [indiscernible] response, whether or not the patients were on a background of B6 or not.

Yes. Thanks, Liisa, for the question. Bill, would you like to take that?

It's my understanding that most of the patients are supplemented with B6. But what I don't know are the specific details, what dose. And what's also more important is what percent. Are they responders to B6, and that B6 has a positive effect on their overall total homocysteine. 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, but those are just influences. The other conmed that's utilized in this population, betaine, two of the four patients -- two of the four were on betaine and two were not.

Okay. And so I guess, across the board, do you see any differences in patients that are on any of these background meds either B6 or betaine as you look through the cohort?

Yes. As we've looked through the data to date, we don't see an interaction between B6 or betaine. Where it impacts is 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 homocystine up to methionine. We see a greater reduction in methionine when they stop taking betaine. But 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. We know that these patients oftentimes will be -- 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 the case study that Dr. Ficicioglu is a very relevant and common one where as patients age, 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. So that's what is encouraging us as we move forward, and maybe 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 [indiscernible] vitamin B6 responsive homocystinuria. The definition of vitamin B6 responsive is they should be able to maintain good metabolic control on vitamin B6 only. So this is the definition of vitamin B6 responsive to homocystinuria. Patients need diet therapy or other medications, it means that they are not really responsive to vitamin B6. So I think it's important to clarify what it means -- what we mean with vitamin B6 responsive homocystinuria. So the other question, I think, Eric, was the -- can you repeat the question?

Again, just your clinical experience in the potential addition of pegtibatinase to patients on [indiscernible] and vitamin B6.

Right. [indiscernible] are on vitamin B6. Even if they are not be keep in B6, so just to prevent the deficiency of vitamin B6. And in vitamin B12, it's important because vitamin B12 should be between normal range. If there is deficiency, vitamin B12 is an important vitamin for [ remediation ] of homocysteine. So it should be kept within normal range. And sometimes, we use folate as well, just to prevent the deficiency of folate. And of course, basically converts homocysteine back to methionine. So it's an important medication in the management of this disease. But I should emphasize that the patient 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. So it's a combination therapy that doesn't work well.

Got it. Can you just remind us what it means to be B -- [indiscernible] B6 responsive?

Well, vitamin B6 is a cofactor for the CBS enzyme. So it means that there should -- those patients are milder cases. And there should be some residual enzyme activity, so vitamin B6, in high doses, can make the enzyme more stable and breakdown more homocysteine. So vitamin B6 responsive cases has a residual enzyme activity, and they have much milder phenotypes.

So does 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. So when we diagnose the patient, we test first if they are vitamin B6 responsive or not. So we start them on a high dose of vitamin B6. In newborns, we do 300 milligrams; in older patients, 500 milligrams. We test the responsiveness to vitamin B6 a week or so. And we measure how much does amino-acid levels and see if vitamin B6 will decrease methionine and homocysteine level. If there is biochemical response, we call those cases vitamin b6 responsive.

Okay. So just like even as [indiscernible] decreases...