Rocket Pharmaceuticals, Inc. (RCKT) Earnings Call Transcript & Summary

Welcome to the Phase I data for RP-A501 gene therapy for Danon Disease conference call. My name is Adrian, and I'll be your operator for today's call. [Operator Instructions] I'll now turn the call over to Claudine Prowse, Senior Vice President of Strategy and Corporate Development. You may begin.

Thank you so much. Good evening, everyone, and thanks for joining us as we provide, for the first time, clinical results from our Phase I trial from our gene therapy program for Danon Disease. This is Claudine Prowse. I'm Senior Vice President of Strategy and Corporate Development at Rocket. And I'm joined by several members of the Rocket leadership team today, including CEO and President, Dr. Gaurav Shah; Kinnari Patel, our Chief Operating Officer; Dr. Jonathan Schwartz, our Chief Medical Officer; Dr. Jose Trevejo, Senior Vice President and Global Program Head of our AAV Program; and Dr. Brian Beard, Associate Vice President of CMC. We're also very excited to be joined today by Dr. Eric Adler, Professor of Medicine at the UC San Diego School of Medicine. Dr. Adler is widely recognized as an expert in Danon Disease and is the lead innovator of a gene therapy approach for heart failure. In terms of today's agenda, Gaurav will be taking us through the clinical updates, and then we will open it up to Q&A. We will end the call in just under an hour or earlier, if there are no further questions. I'd like to remind you that various remarks we will make today constitute forward-looking statements that are qualified by the cautionary statements shown on this slide. Please refer to our SEC filings if you have any questions. And now I will turn it over to Gaurav.

Thank you, Claudine. Thanks, everyone, for joining. So in my time at Rocket, I've had the privilege to meet several Danon Disease patients and their families. And I can tell you this is really a devastating disease. And I really am proud today to share for the first time ever what we think are very exciting preliminary clinical data in Danon Disease. A little bit of background. So Danon Disease is an X-linked dominant disorder of autophagy, resulting from mutations in LAMP2. Autophagy is like the vacuum cleaner of cells. The main mortality in Danon Disease is cardiac, but it also does affect skeletal muscle and CNS. Now Danon Disease almost invariably leads to cardiomyopathy and death, unfortunately, in boys and girls. Cardiomyopathy tends to be more severe in boys who, unfortunately, pass away by the age of 20 or need a cardiac transplant. In our gene therapy program, per agreement with the agency, we started our Phase I in adolescent males 15 years of age or more, with the goal of ultimately moving earlier in a patient's life for potentially a true cure and a true preventative approach. Now while cardiomyopathy causes mortality, it is the primary cause of mortality in Danon Disease patients. Cognitive issues are often the first manifestation early in age, followed by skeletal muscle weakness and then followed by cardiomyopathy. So this sequence of manifestations historically has led to massive misdiagnosis or more commonly nondiagnosis of Danon Disease. But these days with increased genetic testing, these points and these developments are now starting to change and Danon Disease is becoming much more commonly diagnosed. Our program begins in males in our current Phase I, but we intend to open the program up to females a bit further down the road. Females also pass away, unfortunately, of cardiomyopathy, but it is delayed by 2 to 3 decades on average. Now just a word on prevalence. I wanted to announce today that our estimate of 15,000 to 30,000 prevalence U.S. plus EU, which was based on literature review, has now been fully validated by a third party, namely IQVIA, through comprehensive global hospital and KOL surveys, along with a genomics database deep dive as well as supporting literature. On natural history, we are now putting together a comprehensive 3-pronged natural history strategy: one, a literature review; two, a retrospect chart review; and three, a prospective natural history program to better understand what our control arm will look like in our gene therapy trial. However, while patients eligible for Phase I often have normal ejection fraction, patients also have elevated transaminases CK-MB and BNP as well as mildly impaired cardiac output and global longitudinal strain despite the normal ejection fraction. What we're discovering firsthand in our natural history efforts is that these markers are all emerging as early harbingers of disease progression toward the inexorable march to heart failure. A snapshot of what we're uncovering in the natural history efforts. This is anecdotal. But as you can see here, on the EF, when it does start declining eventually, it tends to be rapid over the course of 2 to 3 years. In 1 year, it can drop as much as 10% or more, as you can see in both teenagers as well as older patients. Anecdotally, we have been stating and we are continuing to state that female Danon patients, who are heterozygotes, theoretically have up to 50% of normal LAMP2, but specific expert experience based on a few female Danon heart specimens demonstrate that it is likely less than 50% as shown here. The exact percent LAMP2 expression in females will be further evaluated with female biopsies as our program develops. Now we know also that heterozygote females live 2 to 3 decades longer. This observation, combined with our preclinical experience in our gene therapy program, based on these combination of factors, we estimate a minimum of 10% to 20% expression to confer a stable phenotype that could provide some clinical benefit and potentially halt the course of disease. Currently, we have about 5 biopsies of female Danon patients. And what these demonstrate, as you see here, is patchy areas of expression with large areas of absent LAMP2. Based on these combinations of observations, our thesis remains stronger than ever that destroying homogeneous and widespread LAMP2 expression, even at a low dose, could be the key to long-term benefit for both males who have no expression and females who have patchy expression at baseline. In other words, low level homogeneous distribution of LAMP2, even 10%, 20%, 30%, may be far better than low level patchy distribution. A couple of words on the clinical trial design for a current Phase I trial. First of all, we have a low dose and a high dose, the low dose is 6.7e13 vector genomes per kilogram. The high dose is 1.1e14 vector genomes per kilogram. The trial enrolls male patients with a pathogenic LAMP2 mutation and some evidence of cardiac involvement. I do want to note one additional point. A lot of Danon patients have elevated transaminases at baseline, which likely represents muscle. We specifically exclude patients with preexisting liver disease. So here are the demographics on the 5 patients that we've treated to date. The first 3 are at the low dose. The second is -- the last 2 are at the high dose. Each patient here was a journey, and we learned as we progressed the trial, from these particular patients and also alongside others who are in the AAV field, many of our colleagues. Let me take you through what we learned with each patient. Patient #1, 1001, was suspected to be noncompliant with steroids. I think it's pretty well established now that early immunosuppression is likely necessary for appropriate tissue transduction and translation across multiple organs and based on results from multiple AAV serotypes. This patient likely did not receive the intended full spectrum of therapy because of potential noncompliance with steroids, and thus likely had muted retention of gene therapy long term. So learning from patient #1, with patient #2, we instituted a more stringent immunosuppression monitoring regimen to ensure the patient actually received gene therapy as intended. This is the first patient treated with what we would consider an adequate total product and gene therapy. With patient #3, who is labeled as 1005, we've added tacrolimus in order to reduce the total steroid exposure. We then had an IDMC meeting, and together, we agreed to move to a higher dose with some further refinements to the immunosuppression. Patient 4 tolerated the higher dose with no issue. Patient 4 is 1006. Patient 5, who is 1007, was a very heavy patient, 96.7 kilograms, also had a high level of preexisting immunity, although within acceptable range. We'll come back to that in a second. So today, I'll be presenting the efficacy data for the low-dose cohort. And for completeness, we're also providing all up-to-date safety data for both the low and high dose. Let's start with the low dose, again, for which I'll be presenting efficacy data in a little bit. Low dose was well tolerated. Platelet declines were seen in 2 out of 3 patients. They dipped just below the lower limited normal transiently and self-resolved without the need for Soliris or any other intervention. In the low dose, transaminase elevations were also seen but were most pronounced in the patient who is likely noncompliant. These were mitigated substantively in patient number 2 and 3 who had confirmed immunosuppression use. And overall, in the low dose, we found a very manageable safety profile. In the higher dose, the first patient dosed tolerated the treatment with no issue. The second patient experienced a drug-related serious adverse event that was related to complement activation, specifically atypical hemolytic uremic syndrome, resulting in reversible acute kidney injury and requiring transient hemodialysis with complete resolution of renal function within 2 to 3 weeks. In fact, the patient's current creatinine is actually better than baseline. Of note, rescue Soliris was instituted during the course, and the patient did not require blood or platelet transfusions. This patient has recovered fully from this event, and now, almost 2 months out, has also not experienced any further unexpected transaminase elevations. The complement related issues just mentioned were exacerbated by 2 things: one, the high total dose, the high total vector load given the patient's weight; and number two, importantly, a relatively high level of preexisting AAV immunity. I also want to note that this was an advanced and especially advanced heart failure patient and a very high-risk patient. Before starting treatment, we weighed the benefit-risk very carefully together with the principal investigator, Dr. Barry Greenberg, and we decided to move forward given that the only other option in a patient like this is transplant or death. Moving forward, we believe complement risk mitigation can and will occur in this program through: number one, an earlier trigger for complement inhibition and similar measures; and two, I cannot overemphasize that our ultimate target population will have lower rates. Remember, the ultimate study population is pediatrics age 8 to 14. This is a gene therapy company where we started in adults, but that is not the ultimate target population. In general, overall, the safety profile is manageable and any toxicities observed have been fully reversible and nonpersistent. We've learned from other programs now who have faced aHUS as a short-term challenge and successfully pushed through higher vector doses in Duchenne and other diseases. We believe that we similarly will be able to do so with some refined supportive care guidelines, especially with those with preexisting immunity as we continue forward with a higher dose. I will now review the low-dose efficacy results. Specifically, you'll see VCNs, immunohistochemistry, Western blot, electromicrography, lab measures of cardiac function and cardiac output. Again, these are the 3 patients who were dosed at the low dose. Again, number one, 1001, was likely noncompliant with immunosuppression. I believe this is the first time we're revealing vector copy number in heart tissue for any gene therapy. As you can see at baseline, the vector copy numbers are 0. At long term, which is between 9 and 12 months, VCNs range from 1 in the first patient that was likely noncompliant to 3.5 or higher in the most recently treated patients. So this, is the one slide to really pay attention to. Immunohistochemistry measures LAMP2B in our patients versus normal patients -- normal people. This immunohistochemistry measure is much like transduction efficiency in the lentiviral world. What we see here is increases in IHC over time from week 8 to long term, which again is from month 9 to 12. This is way better than expected based on the mouse model data at similar doses. In patient number two, long term, we have 68% immunohistochemistry. And in patient number three, it's 92%. Picture is certainly worth a thousand words here. You can see at baseline, there's no LAMP2 at month 12 in patient #2 and 3. There is a lot of LAMP2, and in fact, patient #3 almost looks like a normal heart control on the far right. Western blot, a different measure of protein expression, is more of a bulk measure of intensity. I compare this like vector copy numbers in the lentiviral world. Even patient 1001, who is likely noncompliant, shows a stable about 20% expression over time. I also want to note that this patient #1 had a milder manifestation of Danon Disease than patient #2 and 3. And per our previous guidance of 10% to 20%, even this range could be beneficial in stabilizing disease. For patient #3, 1005, we see 61% on Western blot at 9 months. And this is comparable to the 92% that we saw on immunohistochemistry, which represents the -- how widespread the distribution of LAMP2 is. In patient #2, 1002, we were unable to process a long-term sample due to travel and shipping restrictions during this era of COVID, unfortunately. We will update at a later point. But given the near doubling for patient 1002 on IHC from week 8 to 12 on the previous slide, we may expect similar increase from week 8 Western blot of 20 -- upward from 27%, but we'll update when available. This is another key slide. BNP, which is known to worsen during the course of Danon Disease based on our emerging natural history analyses, as mentioned earlier, stabilized for patient #1 in the red at the bottom and improved substantially for patient 2 and 3, as you can see here. For patient 2 in the maroon, it dropped from more than 900 to just over 200. And for patient #3 in the gray, it dropped from just under 200 to normal range well below 100, and these are measures between 9 and 12 months. This slide stopped me in my tracks. About 2 years ago, when we presented preclinical mouse data, we never expected that a human outcome, looking at electromicrography, would ever look similar. On the baseline on the left, you can see extensive vacuoles and no muscle architecture. Even at week 8, but certainly long term, you see markedly fewer vacuoles and excitingly the revelation of intact restored muscle architecture. The vacuum cleaner seems to be working. And finally, perhaps the most exciting biomarker in this presentation is cardiac output. Cardiac output dropped a bit in patient #1 who had lower expression, but that patient was more normal to begin with, as I mentioned, and the cardiac output remains in the normal range of 4 to 6. For the confirmed immunosuppression compliant patients, we see significant improvements in cardiac output. This was based on invasive hemodynamics of between 1.35x higher to 1.62x higher. Most importantly, this is consistent with the BNP decreases as well as the high levels of protein expression. Notably, the stroke volume in patient #2 increased by 40% and in patient #3 by 31%, and there were also respective reductions in pulmonary vascular resistance. So in summary, for the low dose, the low dose was well tolerated with a manageable safety profile in all patients. LAMP2B gene expression was demonstrated in cardiac biopsies from all patients. In the case of IHC, cardiac expression was between 60% and 90% in the patients who were compliant -- known to be compliant with immunosuppression. The Western blot was 60% in the 1 patient where it is available. Also, increases in percentages and levels of IHC as well as Western blot were seen over time. Positive trends were seen in key biomarkers and efficacy endpoints, including qualitative improvements in vacuolar pathology; lab marker improvements, notably BNP; and improvements in cardiac output, as I just mentioned. So overall, the low dose in our estimation demonstrated benefit in all 3 patients and serves as a clinical proof-of-concept as Danon Disease patients generally do not improve on their own, especially older patients like this who are progressing pretty rapidly to heart failure. In terms of next steps, we plan to treat additional patients with a higher dose, going to continue data collection from patients in both cohorts. And we will also initiate a pediatric cohort, which is the ultimate target patient population between 8 and 14 years old. We'll be engaging with global regulatory agency discussions to discuss the registration trial design once we figured out the exact Phase II dose. Stop there. Thank you for your time, and we will turn it over to Q&A now.

[Operator Instructions] And we have a question from Mani Foroohar from SVB Leerink.

Congrats on really great data. You talked -- I mean, we discussed before and you mentioned briefly the importance of how much native distribution of LAMP2B expression potentially being important to function. How do you -- is there any evidence of difference in distribution in terms of homogeneity between the higher and lower dose? Or is there anything you've learned from a high-dose experience that could be applied to the low dose to produce sort of the most homogeneous and effective gene replacement throughout the patient hearts in later-stage studies?

Mani, so great question. We don't have any biopsy results to show for the high dose. And we will next year, so we'll obviously explore more. In terms of homogeneity across the heart compartments, the only data we have so far is from our NHP study that we presented last year, where we did see increased protein expression in both ventricles and both atria. Obviously, we'll probably never be able to do that in humans. But as we move for the higher dose, we'll certainly get a better understanding of answer to the question you're asking.

Great. That makes sense to me. And as a quick follow-up. So how do you think about the path forward across doses? Looking at this data, there's a lot of compelling evidence that even the low dose could replicate perhaps the female Danon women phenotypes, which could potentially be approvable in Danon boys. How do you think about moving forward with the higher dose versus staying where you are? And does that answer vary for Danon women versus Danon boys? And what is your development path for women, broadly speaking? And how is that informed by the data? I know that's 4 question all at once, so I'll hop off after this.

Well, no problem. So one, we are feeling good about the current results from the low dose. Obviously, we need to see them over time, and we'll also, at some point, evaluate pediatrics. Now our philosophy has always been to provide the highest safe dose to patients. While the agency has said very clearly that approvability can be based on cardiac improvement. As I mentioned in the beginning, and as folks on the call here know, Danon is a multiorgan disease. We also want to ultimately be able to address skeletal muscle and CNS issues, if possible. So I think the final dose will be -- we'll push and find the most safe dose where we see efficacy. For the cardiac, we're happy with what we see at the low dose. So I don't know the answer to your question at the moment. And I think the discovery of patchy expression in female Danon patients certainly helps inform how we move forward in the female population. It may be that it's the same dose for males and females, but it may be slightly different. All to be determined, don't want to speculate, but how about we talk again in a year?

And our next question comes from Tyler Van Buren from Piper Sandler.

A couple of busy days for you guys, and I too was really shocked when I saw the electron microscopy slide. I have a question on the cardiac output data and stroke volume. So it's 1.62, 1.35 increase in patients 2 and 5 and then the 40% and 31% increase in calculated stroke volume. Can you just, for those of us who aren't experts in cardiac output, those endpoints, can you help us put those -- the magnitude of those improvements into context? And then secondarily to that, I guess, is there a way to tie improvements or is there some correlation of improvement in cardiac output with, I guess, more functional endpoints such as exercise test or peak VO2?

I can take...

Great question. Yes, Eric. Yes, please go ahead, Eric.

I can take this one. So I think to keep in mind that just to review, cardiac output is the stroke volume, which is the amount ejected during 1 cardiac cycle multiplied by the heart rate. And then these patients to confirm that the improvement in cardiac output was due to the improvement in stroke volume, we look back. We saw the heart rates at normal. So this is indeed -- and obviously, everything has to be taken with a grain of salt, only 3 patients and 2 where we saw this. But nonetheless, we saw it was not due to heart rate. So it wasn't just like the patient's hearts were beating faster. This was a result of either improved filling or improved contraction of the heart, which are the 2 kind of pathognomonic findings in heart failure. The heart can either not fill well or contract well. And the ultimate barometer of how the heart is functioning is -- there are 4 cardiac outlets that it can fill and contract. And if you look back all the way to kind of transplant, to that world, cardiac output is kind of the sine qua non of what we look for to help us determine transplantation status. And you mentioned -- and the reason I say that is that if you look at exercise test and the genesis of why we use 6-minute walk, why we use cardiopulmonary exercise testing, initially, that was really to estimate what a cardiac output is like. So when we talk of VO2 max and when we look at some of the parameters of exercise testing, and you look back, that was really the best estimate of cardiac output because you didn't want to do invasive testing in every patient. Here, we're actually doing the invasive testing, and we're showing the cardiac output goes up. Now the 2 patients. The numbers are, at least I'm looking at it right in front of me, in 1002, that's an abnormal number. 3.58 is abnormal to begin with. In 1005, it's 4.5. It's still low normal, I would say, or on a normal side. But in both, it goes up significantly. And that increased to -- from abnormal 3.58 to normal, so it's totally normal, if not at 5.8. I'd say that normal is a really good sign, but it's still just 2 patients. We still have a lot to say, but we'd be happy if any medicine we use did that in our clinical practice. I hope that -- that's a kind of a long answer to that question, but I hope that helps.

That does. At what cardiac output level would you consider like heart failure, recommend transplant?

So it depends on the body surface area. But usually -- and it also depends obviously on the symptoms, but below 3, that's when you're starting to worry. With a cardiac index below 2. So the index of the body surface area goes below 3 with symptoms, that starts to make you worried depending on the size of the patient. There's no absolute indication for transplant. It's really a clinical indication more than anything. I will say that.

So in your mind, you don't need to see exercise test data if patients start getting cardiac output in the level of approaching 6?

Well, this is a little -- I think you can't look at 1 piece of data, especially when you have limited numbers of patients. So when you look at that and you look at the BNPs and one thing that's on the -- the BNPs were very abnormal in 102 (sic) [ 1002 ] and 105 (sic) [ 1005 ], and they went to nearly normal. And BNP is maybe the best prognostic blood test that we have in cardiology. And again, I will say it's only 2 patients, but the fact that you see BNPs go down, something like 70% in the normal range. In 101 (sic) [ 1001 ], it was normal to begin with and stayed normal. In 102 (sic) [ 1002 ] and 105 (sic) [ 1005 ] because it presented as relative numbers. But in reality, these numbers are quite high from 102 (sic) [ 1002 ] and 105 (sic) [ 1005 ], and they went down to near normal. And BNP is probably as prognostic as anything that we do, exercise test, cardiac output, et cetera. But if you look at both the BNP and the cardiac output, and then you look at electron microscopy, the sum total is exciting. I think I temper it because it's only a couple of patients. And I want to see this be consistent, but it's exciting. There's not many medications that I know of as a heart failure cardiologist that lower BNP that much.

And the next question comes from Eric Joseph from JPMorgan.

Congrats on the data, guys. The first I'll ask is in follow-up to patient 00 -- sorry, patient 101 (sic) [ 1001 ], who is noncompliant on corticosteroids. I'm just curious as to sort of how representative that may be. And whether supplementing -- if you were to move forward with the lower dose regimen, whether supplementing corticosteroids with other immunosuppressants might be part or a reasonable strategy? And secondly, just as a market-related question. If we look at underneath that prevalent estimate of 15,000 to 30,000 across the U.S. and EU, do you have a sense of the rate of -- the confirmed diagnosis rate? And how are you thinking about measures to sort of streamline the patient identification and diagnosis process?

Yes. So I don't -- it's hard to speculate on whether additional immunosuppression would have helped patient #1. Patient -- starting with patient #3, we are using the combination of steroids and tacrolimus, and that's when we start seeing really robust protein expression for sure. And I think it's pretty clearly established that immunosuppression is good, not just from a safety viewpoint, but likely reduces the immune response and helps with transduction and protein expression eventually. So moving forward, all patients will have an upgraded immunosuppression profile. So we don't anticipate facing these sorts of issues that we did in patient #1 again. And on the second point, okay, I answered so long, remind me that. Jonathan has got that question -- that answer.

Yes. This is Jonathan. With respect to the question regarding diagnosis and prevalence. I mean, obviously, we're still in the beginning stages of this aspect of the journey. I think the most relevant thing to remember is that the majority of patients who died of Danon Disease died without even knowing that they had Danon Disease. And that even at present, you're really talking about a 20% incidence of genetic testing for patients with hypertrophic cardiomyopathy in the United States. It's a bit higher in Europe. So the majority of patients who have hypertrophic cardiomyopathy, even adolescents and young adults, aren't getting genetic testing because I think there are a lot of individuals out there who don't believe it's going to be fruitful. But increasingly, there are actionable mutations that are being determined. And obviously, Danon is one of them, but not the only one. And that's an educational effort that we and others will undertake and already are, to some degree, but we'll continue to ramp that up as encouraging data accumulates. And for those of you who've heard me say this before, I apologize for the redundancy, but think of Danon Disease currently or hypertrophic cardiomyopathy currently as analogous to lung cancer some 15 or 20 years ago. In the old days, when we would diagnose somebody with lung cancer, it was basically parsed out into small cell and non-small cell. And every small cell -- every non-small cell lung cancer, patient got treated the same way. And then over time, while the whole people recognized that adenocarcinoma would respond differently than squamous carcinoma. And that within those categories, a number of critical mutations, including EGFR, varices and ALK mutations and others would also conceivably direct therapy. So in this day and age, just saying somebody has non-small cell lung cancer and trying to treat them based on that is substandard practice. And I think everyone recognizes that. And the same will happen over time for hypertrophic cardiomyopathy, especially in younger patients.

And the next question comes from Yaron Werber from Cowen.

Congrats on the data. So I have a couple of questions. Number one, just a little housekeeping. When you're talking about expression versus normal, is that actually based on with respect to sort of real biopsies in live tissue or is that from cadavers? And then secondly, did you have a chance to do any skeletal biopsies? And what does that show? And also, any data you can share with us on exercise physiology, 6-minute walk and some of the other clinical markers?

I'll pass this to Jose Trevejo, who, by the way, just recently joined us. Jose?

Great. Thank you. Yes. So yes, we actually used normal cadaveric hearts to compare. But I think during -- this very much mirrored the preclinical data where they compared it to live hearts and they saw similar ratios. So we would compare that. And I think the important thing to know is that LAMP2B is the predominant gene that's expressed in myocytes, and that's particularly what we compared to. And with your question with exercise test. We plan to do long-term exercise testing in all of these patients. We've actually seen some positive trends, but some of the patients are still recovering from their gene therapy. So we'll continue to update as we go. And yes, indeed, we did collect skeletal muscle, and we're going to continue to assess that, especially at the higher dose. At the low dose, we saw low levels of expression there, but we're going to continue to assess, and we'll update that at a later date.

And did you do cardiac testing in the meantime? And you're just waiting to kind of release the 12 months' data or you didn't do any yet?

We did 6-minute walk tests on the patients. And so we're going to continue to collect that. A couple -- one of the patients had some myopathy that is from their Danon Disease, and it exacerbated a little bit from the steroids, I think, as Gaurav has talked about. So we're going to wait for them to be fully strong because the 6-minute walk test can be affected by many different parameters. And then we'll release the data once all of the patients are back to their full strength and be able to give kind of a real go at it.

Yes, Yaron, I think for the -- for exercise testing, et cetera, it's really 1-year mark or more. Some of the patients just weren't able to make those visits because of travel restrictions at the moment. So we'll update all of those next year.

And maybe just a final question. Were...

Sorry. The trends we see where it is available have been positive.

Great. And is the thought that the high dose will be the 1.1? Or are you considering even sort of a third higher dose level or a third sort of in between dose level? I promise that's my last question.

No, it's a good question. So with the FDA, we have clearance to go up to 2e14 vector genomes per kilogram. So -- however, given what we've seen at the low dose and we'll see what we see at the high dose, where we call the high dose, 1.1e14, we may not go any higher. We may. We just don't know yet. But I think we have the range to go up to 2e14. So I think the jury is out on that still.

And our next question comes from Greg Harrison from Bank of America.

Congratulations on the data. Just to dig a little more into diagnosis. What have you learned throughout identifying patients to enroll the trial that would inform the effort that you'll need ahead of a potential commercial launch as far as increasing awareness and diagnosis? It seems like some of the patients don't have the ideal profile in terms of baseline characteristics you want. So just wanted to see how you're thinking about what we should expect in terms of enrollment pace and the trend of diagnosis rates in the future?

So I'll ask Eric also to weigh in on personal experience with patients. I would just say that enrollment has certainly been -- has not been an issue. There are a lot of Danon patients who are progressing pretty rapidly. And there's also -- in the pediatric cohort, which we haven't started yet, there's definitely a large pool of patients there who are interested. In terms of the -- how we're going to ultimately discover and sort of close the gap between known Danon cases and the 15,000 to 30,000 number, which we're confident about. Over time, first of all, there's a lot of family sort of related diagnosis of Danon. For example, there was a family where 1 person was the index case and then decided to test other family members, and it ended up that 14 patients in that patient's family -- or 14 people in that patient's family had Danon Disease. Half of them ended up passing away or needing a transplant. So there's a lot of family associated diagnosis that's just now emerging. Secondly, there's a lot of de novo Danon Disease as well. It's not fully genetically inherited. And then thirdly, we ultimately aim to bring this as a diagnostic assay for any patients suspected of early heart failure and through genetic testing, whether it's soon after birth or even neonatally. And that's a pathway that we're embarking on already. We didn't want to move too fast in some ways. We wanted definitive proof of concept. But in the last several months, we've been moving down that path pretty rapidly now. Eric, maybe you have something to add on recruitment of patients as well?

Yes. Well, I will give some context on that. I've been running a natural history study for Danon for several years and then been in close contact with Danon patients for 9 or 10 years. And I can say that from kind of a rare disease community perspective, these patients and their families are extremely eager to participate because they know this is an extremely morbid disease that without intervention that there -- you see moms and dads kind of watching their kids get worse and predictably either die of heart transplant by their 20s, if they're lucky. So because of that, we know that the community is very eager to enroll and we've had patients begging how can I get this trial, et cetera, for a long time. So I think the community is going to be strong. I think there's a bit of a nihilist perspective about gene testing in the heart. And that maybe I'm kind of forward-thinking here, but it's partially because we didn't have a ton of specific therapeutic options for patients despite the result of gene testing. Now that we have something, I'm hoping this is going to encourage more screenings that includes gene testing for more patients because there may be a gene test, specific gene therapy. So even if it's relatively rare, you have the therapy for patients. So I think that's going to increase. With the right outreach and the right messaging, it will -- this will get to cardiologists who will know that even just ordering the gene panels, which have also gotten cheaper, almost all the commercially available gene panels have LAMP2 on them, and that's really what we need. So I think those things combine and eagerness from family plus awareness of providers will result in identification of patients and enrollment in the trial.

And one more thing, this is Kinnari Patel, to add. In the 15 years I've been working in rare disease and rare disease products, every time there's a first-in-class therapy available, it really changes people's awareness of the disease, especially as what Eric said. Echoing that effort is genetic testing and having a therapy allows cardiologists and at least cardiologists we've talked and the patients we've talked to. They've mutually said, what's the benefit of getting a genetic testing and getting the diagnosis if the outcome is the same. So having therapies over time, as we've seen this in studies, does increase patient awareness, physician awareness, and hopefully, this will help patients get earlier diagnosis and greater patient population to be recognized for Danon Disease and hopefully have a treatment option where they can have a potential cure for it.

That's very helpful.

And let's say, technologies might be amyloid, whereas before we had therapies, no one was really talking about amyloid. And as soon as you have potential therapies, everyone is screening everyone for amyloid.

And our next question comes from Raju Prasad from William Blair.

Congrats on the data. I just had a quick question on kind of expression. So it looks like in 1001, you had a decent amount of expression as well by Western blot. Is there anything you can say between kind of that 10% to 20% expression, which you're kind of going for initially and some of the higher expression that you're seeing with regards to histology?

Yes. I mean I think this is a disease that -- it's not a structural fix we're looking for. It's basically enabling an enzyme pathway to degrade existing cellular degree. So we've always thought that even low levels could have benefits on histology. Actually, you know what, we might switch to Slide 32 for a second, which is in a backup. So in our mouse data, right, and this is -- this was part of our rationale for why a low dose might work. You can see that even at 5e13, the immunofluorescence maybe a surrogate of immunohistochemistry here, on 5e13 in the mouse is not that great. It's -- we can estimate what that number is, but it's certainly pretty low. Yet, on -- at the same dose on the prior slide, the histology change is pretty remarkable, right? So I think how this translates into human is a little bit unpredictable, but even 10% to 20% could have a physiologic effect and stabilize disease. So I would say that all 3 patients treated here could have some clinical benefit long term. Obviously, we need to see what happens over time. And I think the higher, the better, as you see with the improvements in BNP and cardiac output. I don't want to sort of draw a dose response with 2 or 3 patients, but we'll find out over time.

Great. And maybe just a quick follow-up. Is there any concern about over-expression or a super expression of LAMP2B in these patients with some of the higher dose?

Jonathan?

Well, certainly, that's something we'll be looking out for. I think that probably a modest amount of LAMP2 over-expression is not likely to be deleterious. There is a bit of literature on this that suggests that, in many respects, if you do over-express LAMP, there's some cancer protection associated with that. But I don't think anyone's tested really extensive super physiologic activities. The real issue, I think, with LAMP2 expression and over-expression would be potentially in liver tissue. And that's obviously something that we're keeping an eye on, although I doubt we'll be doing a lot of extensive liver biopsies. But part of this study is maintaining assessment of liver enzymes and other parameters of liver injury. And the most important thing to note to date is that these patients, by and large, have transaminase levels and other liver markers like GGT, which is more liver specific, that are lower at months 9 and 12 than they were before they started the treatment. So, so far, no evidence of harmful over-expression. And I think it's unlikely that we'll have over-expression of levels that would be detrimental to patients.

And this concludes our question-and-answer session. I'll turn the call back over to Claudine Prowse for final remarks.

Thank you all for joining us this evening, particularly given the very busy week. We'd like to acknowledge our dedicated employees, our partners and the physicians and patients participating in our trials. We look forward to providing additional updates as we continue to move forward -- our gene therapy programs forward. And with that, we will now end the call.

Thank you, ladies and gentlemen. This concludes today's conference call. Thank you for participating, and you may now disconnect.