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

My name is Mayur Kasetty. I'm Director of Business Development and Operations and Investor Relations Lead at Rocket Pharmaceuticals. Today, we are going to be discussing key updates from our ongoing clinical trials in three of our lentiviral programs, namely our registrational trial of RP-L102 in Fanconi Anemia, our Phase I trial of RP-L301 in Pyruvate Kinase Deficiency and our registrational trial of RP-L301 (sic) [ RP-L201 ] in Leukocyte Adhesion Deficiency-I. Updates from each of these trials were presented at various sessions during this year's American Society of Hematology Conference, and we would like to recap these updates and address any questions. I am required to note this is not an official program of the ASH Annual Meeting. Before we begin, I would like to briefly discuss the use of forward-looking statements during this presentation. Statements that we make may include statements which are not historical facts and are considered forward-looking within the meaning of the securities laws and which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will and other variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for the purposes of complying with those safe harbor provisions. These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control, including, without limitation, those set forth in Item 1A, Risk Factors, of our annual report on Form 10-K for the year ended December 31, 2020, as updated by our subsequently filed quarterly reports on Form 10-Q and other SEC filings. We assume no obligation to publicly update any forward-looking statements whether as a result of new information, future events or otherwise. We'll now begin the prepared portion of our presentation, which will be given by members of Rocket's executive team. As we have participants both here in person and participating virtually by our webcast, I would kindly ask that those here hold their questions to the end. We will have a Q&A session where our management team will participate. [Operator Instructions] You can enter your questions at any time, and we will address them during the Q&A. I will now turn the mic over to Rocket's Chief Executive Officer, Dr. Gaurav Shah. Gaurav?

Thank you, Mayur. Good to see everyone here today, and welcome to everybody on the webcast as well. So we have three key take-homes today relating to the data presented at ASH this year. These data represent, number one, two of the programs, Fanconi Anemia and LAD-I, potentially, we believe, moving toward top line results; secondly, they represent the Rocket team's consistent and reliable execution over the years; and thirdly, they represent the power and importance of the lentiviral platform in addressing rare bone marrow-derived diseases. And that's what you're going to see today. So I'll quickly move forward to introduce Dr. Jonathan Schwartz, our Chief Medical Officer, to discuss the results in Fanconi Anemia. Jonathan?

Thank you, Gaurav, and good morning. In Fanconi Anemia to date, we have treated 11 patients. You will note from the formal ASH presentations that this number was 10. But since the early November data cutoff for the ASH presentations, we treated an additional patient. We'll focus on the initial eight patients for whom there's at least 12 months of follow-up. And those patients are indicated on the left portion of this slide. As previously disclosed, one of these initial eight patients had progressive bone marrow failure subsequent to an influenza infection at 9 months after therapy and required an allogeneic metopoietic (sic) [ hematopoietic ] stem cell transplant, which was successful and received without undue complications. We will provide engraftment, phenotypic and blood count updates on the remaining seven, who remain on study. This is a very important slide with, I think, a lot of rich data. As indicated by the graph on the left panel of the slide, for the seven patients that remain on study, peripheral blood vector copy numbers has been detected in six of the initial seven patients. And four of these patients have a peripheral blood vector copy number that exceeds 0.1 at or after the 12-month time point. In the majority of these patients, the trajectory is consistently upward. A VCN of 0.05 is followed by 0.1. A VCN of 0.1 is followed by 0.2, et cetera, as the selective advantage of corrected hematopoietic stem cells manifests. This has not been seen in patients 2009 and 2014 to date. However, some of the patients with longer follow-up have had more pronounced VCN increases subsequent to the 12-month time point. These VCN increases are accompanied by evidence of bone marrow mitomycin-C resistance that's illustrated in the table on the right portion of the slide. Mitomycin-C resistance has been identified ranging from 6% to 63% and in six of the seven evaluable patients with a median MMC resistance for these six patients 29% to 31% -- I'm sorry, ranging from 16% to 63%, not 6%, 16% to 63%. Importantly, MMC resistance of at least 10% above baseline at, at least two time points in five patients is required for statistical significance as the primary endpoint of the study. This slide demonstrates blood counts in these six patients with -- in each patient's panel, white blood count in the upper left; neutrophil count in the upper right; hemoglobin, lower left; platelets, lower right. Peripheral blood count stabilization has been noted in five of the five patients who have had bone marrow MMC resistance at least 20%. And in the sixth patient, 1001, who has MMC resistance of 16% at 24 months, there's evidence of potential stabilization starting at around the 18-month time point. This slide is an advanced view of some of the correlative analyses that we'll be performing. The left panel indicates a very strong correlation between bone marrow and peripheral blood VCN at 12 months, indicating the corrections in bone marrow are highly likely to subsequently manifest in the blood and in the blood counts. The right panel indicates a potential correlation between bone marrow MMC resistance and peripheral blood VCN at 12 months, suggesting a correlation between the FA-specific endpoint, MMC resistance and the more universally recognized gene therapy endpoint, vector copy number. In summary, in eight patients with at least 12 months of follow-up, six show signs of engraftment and increasing MMC resistance. Bone marrow MMC resistance is correlated with peripheral blood genetic correction. And in the absence of cytotoxic conditioning, the safety profile continues to indicate very favorable. And we look forward to additional updates going forward. I would now like to introduce our President and Chief Operating Officer, Kinnari Patel, who will present updates regarding the red blood cell Pyruvate Kinase Deficiency program, PKD. Welcome, Kinnari.

Thank you, Jonathan. We'll provide a brief overview of our Phase I PKD program that has treated two patients to date. These patients have been followed for greater than 12 months. The first patient, as you see the data on the left, has shown a dramatic and sustained increase in hemoglobin. The range went from 7.4 to normalization and has been sustained for greater than 12 months. Both bone marrow and the peripheral blood VCN also remained stable through 1-year time point. Furthermore, we see decreases in key measures of hemolysis. As a reminder, PKD is a disease that causes hemolysis of the red blood cells. Between the increase in hemoglobin and the changes in hemolytic markers, it is clear that we're addressing the underlying genetic root cause of the disease. The second patient, this patient treated also more than 12 months ago, has shown a dramatic increase in hemoglobin from the baseline. Importantly, the degree of improvement is remarkable and distinct from the incremental improvement that you would see in other therapies. Of note, for those of you that have attended or listened to the PKD webcast, this is the one patient that had actually received AG-348 prior to receiving gene therapy. And this patient received that therapy without any substantive increase in hemoglobin, therefore, was enrolled in this gene therapy program. In addition to the bone marrow and the peripheral blood VCN activities, this patient had also seen similar efficacy at 9-month time frame and beyond. Preliminary results of these patients, in addition to the laboratory parameters, show the quality of life -- yes, quality of life represent an important efficacy parameter. We are not only scientifically looking at the measurements that are objective but also patient-reported outcomes through the Functional Assessment of Cancer Therapy-Anemia. This is a validated tool for assessing patients' physical, social, emotional and functional well-being. Both of these patients have sustained FACT-An scores of 1 year out in comparison to pretreatment, screening and preconditioning visits. Specifically, to just share a few anecdotes, the first patient that received gene therapy is transfusion-free and is also searching for a job and living a stable, normal life. The second patient received incredible feedback on social media because the PKD community found his pictures where he was no longer yellow, which is a sign of somebody with severe PKD disease. Both of these patients are doing incredibly well. To move on to the safety profile for this patient, in addition to the strong efficacy, as you see, for doubling of the hemoglobin sustained over 1-year time frame and being transfusion independent, the safety profile has been favorable. There have been no RP-L301-related SAE and transfusions -- or infusions were well tolerated. Only substantive lab abnormality was transaminase elevation, which resolved and were not accompanied by any clinical signs of liver injury. These were actually related to the conditioning regimen the patient received in the underlying iron overload. The hematopoietic reconstitution occurred within 2 weeks post therapy as these patients receive conditioning regimen unlike the Fanconi Anemia program, and the patient went home 1 month after treatment. Initial ISA results have been also reassuring for this program, along with all three of our lenti programs. We look forward to providing more granular data for these patients and their ISA results in the future meetings. With this, I would like to turn the mic over to Dr. Gaurav Shah to review our results from LAD-I program, which is a Phase I/II adaptive study design.

Thank you. So we'll start with a brief overview of the trial design. This is an adaptive Phase I/II global study in both the U.S. and EU intended to enroll nine patients, all nine of whom have been enrolled now. The primary endpoint of the Phase II part is overall survival. And there are also additional outcomes that we're looking at including CD18 expression and severity of infections. As of this month, dosing is complete. And all nine patients have actually engrafted after their autologous transplant. For the most part, patients were very young, between 5 months and 4 years of age. There was one outlier. The first patient treated was 9 years of age. Several years ago, we had talked about how -- when using lentiviral ex vivo platform, you want to target a drug product vector copy number ideally in the 2 to 4 range. And you want to get CD34 cell counts in the several million range per kilogram. And that's exactly what you see here. The DP, the drug product VCN, ranges from 2 to 4. Cell doses range from 3 to 10. We presented most of this at ESGCT with some incremental data here. Three months up to 24 months after infusion of the gene therapy, we're seeing CD18 reconstitution from between 26% to 87%. And the first patient now is actually out to 2 years, and another patient is out to 18 months. This is accompanied by sustained and consistent peripheral blood vector copy numbers. And you also see a concomitant drop in white cells, which -- white cells, the WC count is high in this disease because the CD18 is not expressed in neutrophils. So you have a high circulating white count because the body is trying to fight infections inefficient. So white count has gone down. You see this increase in CD18 count on average about 50% over time. The trial is complete with regard to enrollment. We've seen no drug product-related SAEs. CD18 expression is sustained. All patients before this therapy had at least one serious infection leading to hospitalization per year. And we've now seen a reduction in those infections. In fact, there are no LAD-specific infections in any patients who have been treated to date in all nine. We'll have more data on the reduction infections in the future. I'm going to end this with a story. Patient #2008 was a 5-month-old who was born with a double aortic arch and was unable to undergo surgery in the absence of neutrophils. Without neutrophils, you get wound dehiscence and other complications. 6 months after gene therapy, the CD18 count was 52%. Patient underwent successful and uncomplicated life-saving surgery. We are amazed by the potential of lentiviral gene therapy. This is the sort of bone marrow-derived disease, LAD-I, for which we believe lentiviral therapy was invented and intended. I'll turn it back now to Mayur, who will direct the Q&A session.

Great. Thank you. Thank you, Gaurav. So we'll now enter our Q&A portion of the presentation. We'll first take questions from here in the room. If you would like to ask a question, I kindly ask that you use the mic here just so that our webcast participants can hear.

Greg Harrison from Bank of America. When it comes to the PKD program, how should we be thinking about enrollment at this point now that you've had two of the adults with a fair amount of follow-up? How fast can you progress into the younger populations?

That's a great question. The PKD program, based on the data that we're seeing, we did go to the FDA and are in discussion with the agency to accelerate the study in order to move into pediatric cohort. So as you may recall, the design of the study was you start in older adults and then move to adolescents and then move to pediatrics. But based on the first two patients' treatment, we would like to move into the most severe population that has really the true unmet medical need, which is the pediatric patients. So we look forward to having that engagement with the agency. And if aligned, we'll move forward with the pediatric patient population, which means about two to three additional patients will be treated in our Phase I PKD program prior to starting a potential Phase II pivotal study.

Great. And then just one follow-up on the other two programs. Where are you at with patient identification as you get closer to a potential approval? And what can be done to improve diagnosis and identification of those patients?

So I'll start with Fanconi Anemia and then if Jonathan would like to comment. For Fanconi Anemia, fortunately, there have been great patient advocacy work that has been in place in U.S. with the FARF organization, Fanconi Anemia Research Foundation. And there are similar organizations that we partnered with across Europe and different parts of the world. And Fanconi Anemia, there are lots of patients waiting for treatment. And at this point, we're getting quite a bit of inbound interest already. Our goal is to work with the KOL communities, key opinion leaders and experts in Fanconi Anemia, the transplant centers as well as the patient advocacy groups to identify these patients. And for the LAD patients, Jonathan, would you like to comment?

Sure. We certainly, for LAD, have a number of relationships with immunodeficiency advocacy groups, including Jeffrey Modell and Immunodeficiency Foundation (sic) [ Immune Deficiency Foundation ], and also, very importantly, the clinician and scientist groups, such as the Primary Immunodeficiency Treatment Consortium here in the States and the Inborn Errors Working Party Group of the EBMT over in Europe, to really hopefully accelerate means of recognition for the program and also strategize with respect to diagnostics. Over the years, I've created sort of a very handy one-pager that would enable even a very rudimentary pediatric primary care practitioner to identify and test for an LAD-I patient without a lot of real sophisticated bells and whistles, just a really basic sort of paradigm. Obviously, we'll also be doing work to make sure that LAD-I, specifically the ITGB2 gene, is on appropriate screening panels. And those efforts will definitely ramp up as we get closer to health authority approval.

And I also want to add that in Fanconi Anemia, the estimated prevalence in the U.S. plus EU is 4,000, at least. 2,000 of these patients have already been identified and are known. And for the remaining, we are working closely with FARF in patient-finding efforts based on screening the most likely patients genetically and education as well. So by the time we're in our peak year, we think we'll be able to address that full population of 4,000.

This is Gil Blum from Needham & Company. So maybe a first one on that patient with influenza, any mechanistic insights how to -- how does bone marrow failure happen in a patient with influenza? And is there any way to mitigate this in patients coming in on study?

Jonathan?

The first portion of the question, I think there is definitely -- there's experience just anecdotally within the Fanconi caregiver community that, oftentimes in these patients, say, prior to an allo transplant, if they get any number of infections, they can decrease their counts. Sometimes that happens transiently, and sometimes that happens without a recovery. And we know that the stem cell compartment in Fanconi Anemia is particularly susceptible to a lot of these -- to any number of childhood insults that would, in most other immunocompetent and nonaffected, non-Fanconi patients, be relatively straightforward and easy to recover from. There's also, I think, a lot of literature that in any number of infectious situations, including relatively modest viral infections, you will have an inflammatory cytokine milieu that affects the bone marrow compartment and can actually affect either stem cells or the supporting cast of cells that enable stem cells to engraft. All Fanconi patients are monitored carefully for infections or at least the ones that have carrying parents, which is the overwhelming majority. And they try to minimize a lot of -- trying to minimize a lot of compromising situations. The pandemic has been particularly hard for a lot of these Fanconi families. And they don't come to in-person meetings the way they had been, which has been very sad for them. I think the most important take-home is probably for us, try to really catch the kids early, early diagnosis and early attempt at a definitive correction via gene therapy so that there's just fewer time for different insults to transpire. And additionally, the younger the patients are, the more likely they are to have a meaningful contingent of bone marrow hematopoietic stem cells that will be the vehicle for the gene therapy to sustain them without bone marrow failure, hopefully, well into adulthood. So it's start early. It's early diagnosis. Again, it's the panels. And fortunately, Fanconi Anemia -- the FARF, the Fanconi Anemia Research Fund, is probably the model for a rare disease advocacy organization that pulls together scientists, clinicians, patients, families and enables several-times-a-year touchpoints with all of those people to track progress and develop a global community dedicated to this disorder.

Excellent. As for the PKD program, the emerging risk benefit in -- to adult patients is looking pretty good overall. Do you guys feel that this is maybe shifting the focus maybe on expanding outside of the super high-risk pediatric population or is just really good results? So...

Yes. Great question. So we always want to start in the most severe population and really understand the effect of the gene therapy, and that's why we started where we did. But certainly over time, as we get more comfortable and further into potentially Phase II and even postlaunch, we may move into more moderate patients. We think that gene therapy is applicable not just to the most severe post-splenectomy, transfusion-dependent patients, which is the current trial, but pre-splenectomy, transfusion-dependent, pre-splenectomy, highly transfused, so more moderate patients as well. At some point, we will also introduce nongenotoxic conditioning. So we could cover a much larger spectrum of the patient population with nongenotoxic conditioning where the benefit/risk may be more palatable for patients with milder symptoms. So we're starting in severe, going to eventually move to severe to moderate and potentially even more moderate to mild.

Dae Gon from Stifel. Three questions, I'm hoping I can remember all of them. One is on PKD. So Kinnari, you mentioned and Dr. Shah presented about or commented about the Agios compound experience before coming in. So wondering if you can remind us what your inclusion-exclusion criteria is on the prior therapy. And understanding that you guys are currently working with the FDA to open it up for pediatric patients and also understanding the biological rationale that efficacy could be better for those patients, how are you thinking about perhaps opening up perhaps even a compassionate use basis such that more adults can give you more data points to beef up your data package, if you will, before you even go into the pediatric patients? And I'm going to see if I can remember my questions, and I'll let you answer.

Sure. So the key eligibility criteria for the Phase I study was that patients have had to have a splenectomy and have either a fairly extensive transfusion burden or a very low hemoglobin in the absence of transfusions, specifically, I think, a hemoglobin less than or equal to 8 grams per deciliter or either six transfusion episodes during a prior 12-month period or three transfusion episodes per 12-month period over 2 prior years. And we did not stipulate a prior therapy being contingent in part because most of the patients with the most severe hemolytic anemia are probably going to have non-missense, non-missense mutations. They're unlikely to derive a tremendous benefit from the allosteric enzyme activators. And we didn't want to create additional impediments to enrollment. There were going to be some cases like the first patient on the study who came from Spain. This is a woman who lived in the Canary Islands, who didn't have access to such a clinical trial and wasn't really interested in one. And we were able to help her. Patient 2 was treated at Stanford, and this is an older gentleman -- well, not older, 47. That's -- for me, that's young but relatively older, who had been part of that study and didn't benefit. So -- and additionally, to require another investigational therapy before somebody can come on a clinical trial, I think I would get a failing grade from our Board of Directors and probably from you guys if I wrote that in as an eligibility criteria. So I think we felt that it was better to be left to clinician preference and, obviously, investigator thought with respect to the -- that aspect of eligibility. In terms of the other question, the option to expand adults is definitely one that's on the table to be considered. We know of some fairly young adult patients who are interested in coming on. I would prefer to treat them in a Phase II so they can count for registration, and hopefully, we can help them sooner than later. But if we need to treat them in an expansion in Phase I, then that's something that we'll proceed to do sooner than later especially if we think that, that would subsequently facilitate more vigorous pediatric enrollment. Kinnari, did you want to add anything on that? Okay. And the third question?

No, that was actually question number one. Question two was on the FA program. The -- actually, it's a two-part question. If you look at patient 1, you had the cross marking, which denotes that it wasn't conducted -- the MMC resistance was not conducted in a centralized lab, 16%. So I'm wondering if you were to run that in a centralized lab -- I think Dr. Czechowicz yesterday was saying that she runs her local assay as well as essential. What does that 16% give you? Or at least extrapolation-wise, what does that give you? And then for patient 8, I know you followed to 12 months, but the MMC resistance was still 0. So can you maybe talk a little bit about what we can expect in terms of kinetics? Is there a chance to go higher? And if so, what gives you confidence that we can get above the 10% threshold?

So on the lab question, we've done some analyses comparing local values for MMC resistance with our centralized lab. Our centralized lab is out of University of Minnesota, which has probably the most experienced in the world when it comes to Fanconi Anemia, somatic mosaicism. So we've done comparisons, and they're pretty close, so pretty consistent across a wide range of MMC resistance is they're pretty close. So although it is local, we do feel confident that it's going to represent the real number at the end of the day when we do the submission. On the patient who is still 0 at 12 months, first of all, not everyone has to engraft, right? The statistical design is such that only 5 out of 12 need to show that 10% MMC resistance at two time points to be a positive trial. Obviously, the stronger the data set, the better. That's number one. Number two -- especially, by the way, in the absence of conditioning, because even patients like the second Stanford patient who did not engraft, what we learned from that patient is that in case this doesn't quite engraft in time, you can still go to transplant successfully, right? So that's number one. Secondly, some patients do take more time. And the patient that you mentioned was an older one, a 6-year-old. And it could be that the therapy is better intended for earlier in life, right? So as -- the median age of transplant in these patients is around 7 or 8. So it could be that as you move toward that median transplant age, it's a little bit more difficult. However, we have seen in FANCOLEN-I that even after 1 year, patients can turn positive at the 18-month time point. So we're not taking off that off the table yet. So [indiscernible].

And then last question on LAD-I. Recognizing your enrollment is now complete, and I can respect if you don't want to comment on the regulatory discussions, but when was sort of your most recent discussions? And I'm just wondering, how appreciative are they of the Almarza natural history paper that 10% or above is really clinically meaningful since that seems to be sort of a moving bogey here?

So I'll address the first question and pass it to Jonathan for the second question. In terms of having all patients treated, we're really excited about the data of consistency we're seeing on the CD18 as well as survival for those patients that have been more than 1 year. So one of the discussions we've had is because this is a global study intended to be filed in Europe, U.S. and now, of course, MHRA with the Brexit happening, our discussions are ongoing with health authorities. Every step of the way for LAD program, similar to our other programs, we're always unofficially engaged with health authority, and they know the data that we present before we present it publicly. So the data they find very compelling and exciting. What we have decided to do at this point is while we could do an accelerated approval of one of the questions we received earlier this week based on CD18, getting a full approval may be the best way to go because it's just a 6 months lag time from the top line. So once we have a full approval of overall survival, the three components really benefit. One, it gives it easier submission to approval time frame so we can get a more accelerated approval with the broader label. And that would actually help us with the pricing point, which has been a recent challenge in the lenti field. So if we can get the overall survival, we can really have all of the data needed to support a stronger pricing, which is absolutely needed for a disease like this where most patients unfortunately pass away by the age of 2. So that's our thinking of the long-term success. We might lose the 6 months initially. But I think it's worth it compared to doing an initial accelerated filing and then a repeat filing 6 months later for full approval. So we figured we'll just do everything together. And that will be happening essentially in parallel in Europe and U.S.

And with respect to the CD18 component, the natural history publication that we did, the Almarza 2018 paper looking at really every published case of LAD-I in the literature from the '70s all the way through 2017, what we were able to show was that, by and large, the survival to age 2 for kids with less than 2% CD18 expression was 39% in the absence of the transplant, which was very similar to the 25% value that Alain Fischer had published back in 1988 when the disease was diagnosed. And we also saw that, that value was similar even when we looked at it for patients that had been treated or evaluated in the -- in a more modern time frame since year 2000. And what we also saw was that patients who had even 4% or greater CD18 expression had survival through childhood. Most of them seem to survive at least into adulthood. And then -- and obviously, the patients who had at least 10% also seem to survive into adulthood. Bear in mind that those patients all in the literature, even though they had this modest expression, it was still abnormal protein. It wasn't a completely normal functional integrin that lets these neutrophils land on an endothelial surface and then extravasate to go find infections or clear wounds. It's all abnormal. So the numbers that you see on our graph, that's normal CD18. We picked 10% based on some of that and some other findings from the transplant literature in patients with incomplete chimerism and also based on some experiments that Hickstein and Bauer did with an LAD dog model, where anything above about 5% seem to be effective at arresting that model. As it turns out, we've exceeded 10% for all patients. We have exceeded probably 20% for all patients. And very importantly, as part of the data package, we'll also show information about CD11a and CD11b expression because the functional integrin is a dimer between a CD18 and a CD11a or CD11b. In these patients, CD11 was uniformly low, less than 2% prior to therapy and is also above 10% in the time points that we're looking at as well. So we're not only going to show the FDA that we've restored CD18 expression, we'll show them that, that CD18 is highly likely to be functional because it's now accompanied by CD11 that was absent prior to gene therapy. We've initiated that discussion, and that's, I think, something that will be an ongoing discussion on our part to emphasize the clinical relevance of this flow cytometry-derived marker.

So can I actually ask one more question? On that point, I guess gene therapy now seems to be this growing concern or question mark around CMC because that's the real black box until the filing comes in. To your point about LAD-I, this integrin identification, I guess you can do maybe an ELISA or a facts-based assay to demonstrate it is there, but to your earlier point about extravasation, do you need to show, in addition to the presence of the integrin, that it does properly extravasate to, I guess, fulfill that CMC component at all? Or is integrin presence kind of sufficient?

Yes, we don't think we need to show a more -- anything more mechanistic. We will have -- we do have potency assay in place that demonstrates that the drug product that we release is adequate. We think that combined with the CD18 biomarker and clinical outcomes should be sufficient for a filing. We don't think we need to do any more specific neutral migration assay or something like that. We did do neutral migration assays in preclinical models. We don't think we need to repeat that in adults at this point.

Just on the CMC component, the one thing I wanted to share is our LAD-PKD programs. The good thing we've done is learn from others as well as our Fanconi program. So since the first patient that was treated on these clinical programs, we actually have a commercial-grade vector plasmid provider in cell-processing as well as centralized analytics. We believe that investment that we had made about 3 years ago, a little over 3 years ago, will help us in decreasing the CMC challenges that others may face in doing a comparability or tech transfer, et cetera. So I think a lot of the bulk of the work there was done previously and that should help us with the CMC package because I do realize the regulations and things are changing quite a bit.

Great. Thank you all for your questions. We'll now move to questions from the webcast. The first question is from Patrick Dolezal at LifeSci Capital. Can you provide a little more color on the primary endpoint in FA? What time course is required for clinical stabilization? Is that just through the attainment of two time points with 10% MMC resistance or longer? And what is the current thinking as it relates to the timing of BLA filing?

So the endpoint in Fanconi Anemia, which we've discussed with both FDA and EMA, is 10% increase in mitomycin-C resistance from baseline at two time points if one has to be at 12 months, so at 12 months and then following that, in conjunction with at 12 months or after 12 months, right? So MMC resistance of 10% or greater at or after 12 months with one follow-up confirmatory value. So in conjunction with clinical stabilization based on some predefined measures that has to be seen in at least 5 patients out of the 12 enrolled patients to have the ability to reject the null hypothesis. That's the bottom line in FA primary endpoint. Sorry, Mayur, the second? Timing of registration, we have not given guidance on this. As we complete the trial, we'll and get closer to top line, we will provide additional guidance. We haven't given guidance on exact timing of BLA filing yet. Jonathan wanted to add one word on the neutrophil migration assay, the question from the first.

Very importantly, the -- there is a window to recognize the efficacy in the Fanconi trial between 1 and 3 years. And that's because we're not using cytotoxic conditioning. So unlike PKD or LAD-I, where we pretty much think we see with the results that are going to hopefully be lifelong by 3 or definitely 6 months, in Fanconi, it takes time for the replicative advantage of the corrected stem cells to manifest. And the agency was very receptive to being able to identify that primary endpoint over that window, which could be recognized as quickly as 1 year but might take something more like 2 to 3 if needed.

And did you want to follow up on the LAD question?

Yes. And then one final note regarding to Dae Gon, Gaurav already indicated in terms of the potency assay that doesn't require demonstration of migration. It's a simpler assay that we have buying for. I think additionally, in the patients that we've treated, there's very compelling evidence of neutrophil migration. The very first patient on the trial had had really multiple severe infections every year of her life, including ones that required prolonged hospitalizations and IV antibiotic courses, surgical debridements, partial lung resection for an aspergillus pneumonia. And in the 2 years since her therapy, she's not had any infection requiring any sort of hospitalization. So many of the other patients have a similar story, but since they were treated younger, there weren't as many infections, but we're still talking about, across the cohort of nine patients, dozens of infections and hospitalizations over the course of the months and years that they were live, and we'll be able to present their posttreatment course with a vastly reduced fraction of hospitalizations. The kid that got the aortic arch repaired, that's evidence that the neutrophils can extravasate and clear debris and do what they need to do. And if they can't, then you're going to have that aorta dehisce in the days and weeks following a cardiothoracic surgical procedure.

Our next question is from Raju Prasad, William Blair. Any thoughts on targeted preconditioning regimens as it relates to the PKD therapy?

A couple of years ago, we announced a collaboration with Forty Seven to look at nongenotoxic conditioning. The regional application is Fanconi Anemia. However, as we think long term about the lenti platform, we think the greatest application may in fact be PKD, especially in more mild patients for whom chemotherapy may be somewhat burdensome but for whom a non-genotoxic regimen may be more palatable. So we have thought about this, and it's something we will plan as part of the life cycle of PKD postlaunch.

Our next question is from David Hoang, SMBC. Is there a potential to treat more mild to moderate patients in LAD-I? And what CD18 expression is needed to achieve a fully normal phenotype?

There is some interest from both the community and physicians and from us in addressing moderate LAD-I. In fact, when we expand the population into moderate because most severe LAD-I patients die early in life, there are a lot more moderate LAD-I patients out there. In fact, I visited a hospital in India a couple of years ago in Bombay. And it turns out that at just one center, a single center, the physician had seen 70 LAD-I patients in the prior year, 7-0, right? So it's much -- we think that the numbers of LAD patients may actually a lot more than what's reported in the severe cases, especially if we include moderate.

What level of CD18 expression be needed to see [indiscernible] phenotype?

That's going to be a function of the normal -- the fact that the CD18 that we're going to confer if we treat moderate patients is going to be normal CD18 versus a dysfunctional CD18. Typically, most moderate patients have between 2% and 30%. Likely, I think even a 5% to 10% increase over their baseline is going to be adequate because that 5% to 10% increase is going to be normal CD18. But for any moderate study, we'll also build in, as a critical endpoint, a resolution of existing inflammatory or infectious lesions, and many of these moderate patients have ongoing nonhealing ulcers, gingivitis and all sorts of other skin or subcutaneous festering abnormalities that never resolve. So we'll be able to do a very nice before, after with pictures as -- in addition to that relatively modest CD18 increase that will be needed. Hopefully, we'll confirm more than a modest increase like we've done for the severe patients. But I don't think -- I think a little will go a long way here for this group of people that live with a very chronic disorder that puts them in constant contact with the healthcare system.

We have a question from Mani Foroohar, SVB Leerink. Manufacturing and scale-up have proven a meaningful challenge for other companies in the space. Where is your current infrastructure in terms of annual volume of patients treatable, assuming one of your lenti programs is approved -- one or more of your lenti programs is approved? How should we think about incremental CapEx to further scale your manufacturing footprint ahead of launch?

Great question and a relevant one in the current lentiviral landscape. We've been working and partnering with CDMOs, as Kinnari mentioned, across plasmid vector and cell processing in the lenti space. And we have negotiated agreements to ensure that the patient demand meets capacity out to several years through peak. This is something that doesn't happen overnight. It's been a focus of Rocket from day #1 when, in my second or third week, we signed an agreement with MolMed, which is now part of AGC. And so we've had this put in place for some time, and we're confident that with the CDMO model in the lenti space, we have adequate capacity to serve all the patients at the peak year. In terms of CapEx, most of the investment for lenti is behind us. And as we've figured out over time how to reduce cost of goods leading into launch, we're confident that the new capital, the new CapEx is going to be dedicated toward ensuring ongoing capacity, cell processing vector and plasmid to some extent, but also we'll be able to focus to new pipeline assets and moving them into clinic. So most of this is behind at this point.

Great. I see no further questions from our webcast participants. That concludes our Q&A session. I'll now turn the mic back to Gaurav for our closing statements.

Great. Well, this was -- it's great to talk to everybody who are virtual and also great to see several people live as the world returns to normal slowly. Thank you for coming.