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

Welcome to the ASH 2020 Investor and Analyst Conference Call. My name is Sylvia, and I'll be operator for today's call. [Operator Instructions] Please note that this conference is being recorded. I will now turn the call over to Claudine Prowse. Claudine, you may begin.

Thank you, Sylvia. Good evening. I want to thank everyone for joining us for ASH 2020 Conference Call. We'll be focusing on our 3 lenti programs: Fanconi Anemia, Leukocyte Adhesion Deficiency-I and Pyruvate Kinase Deficiency. If you are not joining us live, the webcast will be available on our website at rocketpharma.com. My name is Claudine Prowse, I am Senior Vice President of Strategy and Corporate Development, and several participants from the Rocket executive leadership team are joining me on this call, including Dr. Gaurav Shah, our Chief Executive Officer and President; Dr. Jonathan Schwartz, our Chief Medical Officer; Kinnari Patel, our Chief Operating Officer; and Dr. Gayatri Rao, Vice President and Global Program Head of our LVV program. We're also very excited to be joined today by several experts and clinical collaborators. First is Dr. Maria Grazia Roncarlo, Professor of Pediatrics and of Medicine, Director of the Center for Definitive and Curative Medicine and Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine. She is a pioneer in cell and gene therapy for genetic diseases and has gotten 2 gene therapy products approved, including Strimvelis. Next is Dr. Agnieszka Czechowicz, Assistant Professor of Pediatrics at the Division of Stem Cell Transplantation and Regenerative Medicine at Stanford. Stanford is the lead clinical site for the Phase I/II trial in fanconi anemia for Process B, and Agnieszka is principal investigator. We are also joined by Dr. Rachael Grace, a Pediatric Hematologist and Clinical Researcher at the Dana-Farber Boston Children's Cancer and Blood Disorder Center. Dr. Grace is the lead investigator for the global PKD natural history study. Thank you all for joining us today, and we look forward to the discussion. In terms of today's agenda, Gaurav will begin with a review of the Phase I safety and preliminary efficacy data from our Process B study for our gene therapy program for fanconi anemia. Next, for the first time, Jonathan will be presenting exciting clinical proof-of-concept data for our gene therapy program for pyruvate kinase deficiency. Finally, Kinnari will then review our latest update on our gene therapy program for LAD-1. Following our prepared remarks, we will move to the Q&A in which all speakers will participate. We will end this call promptly at 7 p.m. or earlier if there are no further questions. But first, I'd like to remind you that the various remarks we will make today constitute forward-looking statements and are qualified by the cautionary statements shown in this slide. Please refer to our SEC filings if you have any questions. And now I will turn the call over to Gaurav.

Thank you, Claudine. It's great to be here. I believe that today is a great day for patients with rare disease and their families. Fanconi anemia needs no introduction. Basically, this is a disorder of DNA repair that affects all body organs, but especially the bone marrow, and the majority of patients unfortunately develop bone marrow failure by the age of 10 and also have increased risk of leukemia later in life. Now allogeneic transplant can be curative for the hematologic aspects of fanconi anemia, but majorly increases the risk of head and neck and other cancers later in life. The prevalence in the U.S. and EU is 4,000 patients. As you know, we focused our gene therapy efforts on FANCA, which is about 60% to 70% of the disorder, but we aim to address additional complementation groups over time that will cover the majority of FA patients. The Process A trial, which was called FANCOLEN-I, we wanted to update that enrollment is complete here and the study is ongoing for follow-up. We are not updating specific patient results during this ASH other than an update on integration site analyses, and there has been nothing significant or new to report. But I did want to remind people of the key take-home messages from FANCOLEN-I, which are twofold and very important. Number one, in fanconi anemia, we can engraft without any conditioning whatsoever. And that is because of the existence of a proliferative advantage of gene-corrected stem cells over diseased cells that are native to fanconi marrow. So engraftment can occur without conditioning. And number two, and this engraftment actually leads to clinical stabilization and even improvement in blood counts. So FANCOLEN-I clearly established the proof-of-concept of gene therapy in fanconi anemia in the absence of any conditioning. The hope of gene therapy in fanconi anemia is as prevention, potentially to eradicate the risk of bone marrow failure and leukemia and also to not worsen the baseline risk of head and neck cancer and other solid tumors that is often magnified, sometimes 30x or more, in fanconi patients, especially those who have GVHD as a result of bone marrow transplant. Hence, the ideal time for gene therapy treatment may be early in life, as shown on this graph. So we won't go through all the details of the inclusion and exclusion criteria for the pivotal Process B trial, which was covered today in -- at ASH by Dr. Czechowicz, but 2 key points that we want to underscore. Number one, we are trying to treat patients earlier in life for the reasons that I just mentioned, and most, but not all patients will have had a healthier marrow to begin with. And secondly, and this is a new point that we're going to reveal today, which is that of the 12 patients who are to be treated in the Phase I/II trial, in agreement with the FDA, only 5 of these 12 need to meet at least 10% mitomycin C resistance and have evidence of clinical stabilization between 1 and 3 years in order to reject the null hypothesis and have a statistically positive trial. We're very happy to say that we've now treated 9 of those 12 patients. Three were treated before the COVID pandemic and have at least 1 year of follow-up or more. Another 6 patients have had a follow-up out only to 2 months after treatment so far. Dr. Czechowicz went through the details of the drug product metrics brilliantly this afternoon. But suffice it for now to say that we have vector copy number and cell dose in 7 patients available. Certain parameters are still undergoing final validation and are thus listed as pending here. But in general, the vector copy numbers are higher than in FANCOLEN-I by about 2x; and the cell doses, especially in the recent Phase II patients, are now north of 1 million CD34+ cells per kilogram. We know that fanconi anemia stem cells are notoriously difficult to transduce. Since the beginning of the development of the program, we said that a cell dose of at least 1 million CD34+ cells per kilogram and a vector copy number of 1 would be ideal. And we're happy to say that with Process B, we are approaching or surpassing this metric in all patients that we are treating. So it's certainly been a journey here. 2 of the 3 patients who are followed for more than 1 year are clinically stable with regard to white counts, hemoglobin and platelets. I do want to take a minute to provide some details here on the third patient shown above. This is the patient, who was treated at Stanford that we had mentioned previously, who developed influenza B and required multiple blood -- red blood cell transfusions. This patient did end up undergoing a successful bone marrow transplant due to progressive bone marrow failure. And there are 3 points that we want to make with regard to this patient. Number one, their baseline bone marrow was borderline to begin with. She did meet the entry criteria, but overall was at higher risk for progression to marrow failure right from the beginning, but we had -- we decided to treat anyway in order to offer hope. Secondly, infections are known to accelerate bone marrow failure in fanconi anemia patients. And thirdly, there was evidence of mitomycin C resistance at the last follow-up. So this was the case where the repetitive engrafting could not catch up with the inexorable bone marrow failure. Nonetheless, what this case does demonstrate that in the infrequent case where gene therapy does not work, salvage bone marrow transplant can be successful as a backup option. Peripheral and bone marrow vector copy numbers from these 3 patients are shown here. All 3 had evidence of mitomycin C resistance, and I'll come back to this in a second. The peripheral vector copy numbers and the bone marrow vector copy numbers for the 2 optimized patients follow similar, or in fact, better courses than the best and most optimally treated FANCOLEN-I patients. So this slide is the most direct comparison we have between Process A and B. Bone marrow vector copy number is a great surrogate marker for engraftment. And you can see that with Process B here in red, at 1 year, the bone marrow vector copy numbers are as good or better than the best Process A patients. Historically, we've referred to patient 2002 and 2006 as the index cases and the optimally treated FANCOLEN-I patients. Mitomycin C resistance is available at this time point only using the original CMAT assay in 3 patients, and each 1 correlates closely with the bone marrow vector copy number. For 2004, I'm going to share a new data point today, as it has just emerged, that wasn't in the press release or presented at ASH because it's in real-time. The mitomycin C resistance for patient 2004 at the top is 31%. This is the highest we've seen at 1 year for any patient. For patient 2002, in the blue, the mitomycin C resistance at 1 year was approximately 20%. And for 2006, in the lower blue, upside down triangle, it was 8%. Again, the mitomycin C resistance values correlate closely with the bone marrow vector copy number. It's not available yet for 1001 because of assay development delays in recent months due to shipping issues and travel restrictions, but this is anticipated to similarly mimic bone marrow vector copy number and will be updated when available. FANCOLEN-I experience demonstrated that when gene-corrected mononuclear cells in the green, catch up to the gene-uncorrected cells in red, we start seeing evidence of clinical stabilization or blood count improvements. This usually happens after year 2, and we're still early but on track, as you can see here. Now on to the follow-up for the new patients who are out only 2 months from treatment. I want to note that 3 of 4 of these Process B patients are showing peripheral vector copy number of 0.01 to 0.02 at 2 months post treatment. These are VCN ranges that we have not seen in prior patients in Process A, FANCOLEN-I, including the most optimally treated patients, 2002 and 2006. In fact, the only other patient with positive VCN at 2 months was the Process B patient, 2004, who I just mentioned. So while early, we do believe that these positive vector copy numbers of 2 months are encouraging. Our fourth patient is out only 2 months, and in general, I would say this is too early to call. So to date, at least 5 of 7 of these patients with any follow-up are tracking for engraftment, and we cannot yet rule out a 6th. The bottom line from the current update for Process B: Number one, Process B appears to be an improvement over Process A, and this pivotal trial is on track as planned for potential registration. Number two, 9 of the 12 planned patients have been treated, 7 of these patients have follow-up, and at least 5 of these 7 are showing evidence of engraftment so far. And number three, 5 of 12 patients only need to be followed for 1 to 3 years and demonstrate engraftment in order to declare a positive benefit risk and a statistically positive trial. We will provide further updates in the first half of 2021. Thank you for your interest in Fanconi Anemia program. And I will now pass on the baton to our very dear Jonathan Schwartz.

Thank you, Gaurav. We'll talk about RP-L301, the lentiviral gene therapy program for red blood cell pyruvate kinase deficiency. Pyruvate kinase deficiency is a hemolytic anemia that results from mutations in the PKLR gene, a gene that encodes for a key glycolytic enzyme. Because red blood cells lack mitochondria, they are heavily dependent on glycolysis for their metabolic needs and ATP generation. There exists a spectrum of severity for clinical PKD, ranging from mild to extremely severe, with the more severely afflicted patients experiencing anemia, jaundice, splenomegaly and iron overload. Available therapies include chronic red cell transfusions, iron chelation and splenectomy. Of note, splenectomy on average concurs a 1.5 gram per deciliter increase in hemoglobin, but does not improve iron overload. And it's associated with lifelong immunocompromised and thromboembolic risk. The therapeutic lentiviral vector employed in the RP-L301-0119 clinical trial has been evaluated extensively in preclinical studies, including those in the PKD murine model or transduction of murine in hematopoietic stem and progenitor cells and further reversal of the PKB phenotypes, including increases in hemoglobin and normalization of organomegaly with an unremarkable safety profile. These preclinical efficacy and toxicology evaluations enable the activation of the current first-in-human global gene therapy study. In addition to the primary endpoint of assessment of safety and toxicity, key secondary endpoints on this clinical trial include assessment of RP-L301's impact on anemia and ability to confer decreased transfusion dependence, including transfusion independence. Eligibility criteria include confirmed [ bio-mutations ] in the PKLR gene, severe PKD, defined as either extensive red blood cell transfusion dependence or hemoglobin consistently below 8 grams per deciliter. Patients are to be enrolled in sequential age-defined cohorts, starting with severely afflicted adults, followed by adolescents and then followed by children age 11 and under. And this global study is taking place at 2 centers in Madrid as well as Stanford in California. Demographic and disease characteristics of the 2 patients comprising the adult cohort are depicted on this slide. These adult patients have, on average, pretreatment hemoglobin levels in the 7 to 7.5 gram per deciliter range and markedly increased bilirubin and erythropoietin levels. Both had required multiple red blood cell transfusions in the 2 years prior to study participation, including 14 distinct transfusion episodes for the first patient to come on the study, the 31-year-old woman, who was treated several months ago at Hospital Jiminez Diaz in Madrid. Product metrics on the bottom portion of the slide include CD34 cell doses ranging from 2.4 million to 3.9 million CD34 cells per kilogram of body weight and vector copy numbers in the 2 to 2.8 range. We will discuss the preliminary results of the first patient, the 31-year-old female, and only those results, because the second patient received investigational infusion at Stanford during the later part of November, and it's simply too early for us to have any results. I will now talk about the initial results. This graph depicts the patient's hemoglobin, which had been, on average, 7.4 grams per deciliter during the 2-plus years prior to study entry despite the 14 transfusion episodes. Do not attempt to adjust your computer screen. The numbers that you see on the right portion of the graph are accurate, bona fide and verified. At 3 months post-RP-L301 infusion, the patient's hemoglobin was 14.3 grams per deciliter. That's nearly 7 points higher of any average pretreatment level, vastly exceeding even our most salubrious expectations. She has not required any red blood cell transfusion subsequent to hematopoietic reconstitution. As indicated on the left panel of this slide, during the 3 months post therapy, there has also been concomitant normalization of reticulocyte count, bilirubin and erythropoietin levels and also LDH, which is not pictured here. Vector copy number at 3 months, indicated on the right portion of the slide, was 1.55 for peripheral blood nucleated cells and 2.72 for peripheral blood mononuclear cells -- I mean, for bone marrow mononuclear cells. Side effect profile was, by and large, very favorable. There were no RP-L301-related adverse events, hematopoietic reconstitution and neutrophil engraftment was identified by day 13 post infusion. She did experience transient neutropenias, dermatitis, transaminase and triglyceride increases, which were considered secondary to the conditioning of the cell path that's required for an autologous stem cell transplant. She also had a grade 2 transient event during apheresis collection, including some chest pain and dyspnea and nausea, and this all resolved very readily with supportive care medications. Our preliminary conclusions regarding this first patient's treatment are that it's one patient, and she's been followed for only 3 months. But nonetheless, it's an outstanding start. The safety profile has been favorable, her hemoglobin has nearly doubled, and that's been concomitant with normalization of multiple circulating markers of hemolysis. We look forward to additional adult results in 2021 as well as initial evaluation in initial pediatric cohorts in the beginning months of 2021. As is the case with other Rocket-sponsored lentiviral programs, commercial-grade drug product centralized evaluation is implemented for all patients treated and planned on the study. I will now turn things over to my colleague, the inimicable Kinnari Patel, the hardest working woman in biotech, who will present equally exciting results on an additional lentiviral program, RP-L201, in Leukocyte Adhesion Deficiency-I.

Thank you, Jonathan, and we definitely have the hardest working and most passionate team at Rocket. Hi, attendees. It is my pleasure to provide an exciting clinical development update on the most advanced gene therapy program at Rocket Pharmaceuticals. Before I get started, let me acknowledge Generic Fund, which has made this clinical study possible by fund. So what is LAD-1? LAD-1 is a rare disease characterized by defects affecting how white blood cells respond and travel to the site of infection or a wound. Patients with this disease have an increased risk of bacterial and fungal infections, and unfortunately, those with severe disease with -- have high morbidity and mortality. Only treatment option available for the severe LAD-1 patient is an allogeneic hematopoietic stem cell transplant. But unfortunately, these patients do not have the luxury of time. By the time they're able to identify a potential match donor, it tends to be a little bit too late. And if they're fortunate enough to get a donor and get a transplant, the side effects associated with graft rejection tend to be quite severe. This disease is really in the 2 spectrums, moderate and severe. Patients with severe disease have a CD expression -- CD18 expression on neutrophils of less than 2%. 2/3 of these patients unfortunately pass away by the age of 2. The graph on the right shows data from a large retrospective literature study conducted by Rocket Pharmaceuticals. We looked at all patients in the literature for survival and found patients with CD18 expression of 4% or greater survived into adulthood. So 2% -- less than 2%, unfortunately, 2% of the patients passed away by the age of 2; 4%, they survived by -- survived to adulthood. Based on the promising preclinical data and high unmet medical need, an agreement was reached with global health authorities that Rocket was able to design an adaptive Phase I/II study in total of 9 patients in order to do registrational enabling. 2 of these patients out of the 9 were treated in the Phase I portion of the study, and 2 additional patients out of 7 were treated in the Phase II portion of the study. Despite the pandemic, I am excited to share with you that we have identified all patients needed to complete this clinical program, and we have manufactured 7 of the 9 patients' drug products to date. In subsequent slides, I will go through preliminary data available for 3 patients followed up to date. The first patient, as you may remember from ASH 2019 data, was treated over a year ago and received a drug product of 4.3 million cells with a VCN of 3.8. Her CD18 expression in a year out have stabilized to around 40% and her peripheral VCN is greater than 1. Most importantly, this patient is doing clinically well and has a good quality of life. Pre gene therapy treatment, unfortunately, she had severe infections, at least one per year, needed hospitalization, continuous need for prophylactic antibiotics and required home schooling. Luckily, post gene therapy, she had 0 infections, 0 need for hospitalization, is completely off antibiotics, and if it wasn't for COVID-19, she'd attending school currently. On the bottom, what you see are the pictures that was shared in 2019 ASH. On the left most, were before gene therapy treatment, she had spontaneous abdominal lesions. As you see the progression out to 12 months, this has fully recovered. The next patient treated on the Phase I study has been followed for more than 6 months. This patient is 1 of 3 siblings affected by severe LAD-1 disease. All 3 siblings have enrolled in our Phase I/II clinical study. This patient specifically had a cell dose of greater than 2.8 million cells, CD34+ per kilogram and a drug product of VCN of 2.5. Her CD18 expression has stabilized to approximately 25% and her peripheral VCN is approaching 1. Now remember, CD18 percent over 10% is the goal that we have for the study and greater than 4% means she could make it into adulthood. Next slide. Her younger brother, also diagnosed at birth with severe LAD-1, received a drug product of 4.3 million cells with a VCN of nearly 3. He has achieved CD18 expression of 76% at 2 months. Yes, 76%, and he is now clinically stable. In the spirit of the holidays, I'm happy to inform you that the third sibling has also been treated with the gene therapy product and is also clinically stable. This family temporarily had to relocate to California in early 2020 to avoid the risk associated with travels during COVID-19. And we're happy to say that they're able to return home to their family and friends for Christmas as all 3 siblings are now clinically stable and able to travel. In conclusion, the benefit-risk of this product in severe LAD-1 patients appears to be very favorable in all patients treated to date, all 4 patients, as I mentioned. 7 out of 9 patients needed to complete this adaptive Phase I/II study have a commercial-grade product produced, meaning each of these patients in the study has received a product produced by commercial-grade plasma, commercial grade vector, commercial-grade cell processing and centralized analytical testing. I'm also happy to announce today that we are going to be planning to complete enrollment in treatment of all patients by first half of 2021. So everything at Rocket that we do is really motivated by patients and bringing hope to patients with rare diseases. Our dedicated team has provided a creative way to overcome the pandemic and bring hope to these patients with rare diseases in fanconi anemia, in PKD-1, in PKD disease and LAD-1 disease. And next slide, what I wanted to highlight is a story from Rare Disease Day. This iconic image of the Empire State Building is the colors of the rare disease. Earlier this year, before the pandemic lockdown, we were fortunate enough to celebrate our annual Rare Disease Day with patients and families with rare diseases, and one of our key attendees was the first girl treated on the LAD-1 program. Joining this event, we were told about her 2 dreams. She had a dream that one day, she will get her ears pierced like any other girl will dream of. And two, that when she turns 16 -- if she turns 16, she can get a driver's license and do a road trip across the country. Well, I'm happy to say, she recently got her ears pierced without any complications, and now she's counting down to turning 16. At Rocket, we work really hard and are passionate about bringing hope to patients like her. One patient, one high-quality product at a time. With this, may I ask the operator to open up the forum for questions.

[Operator Instructions] And our first question comes from Greg Harrison from Bank of America.

Congratulations on all the data. Very exciting update. Just wanted to ask one on the Fanconi Anemia program. How are you thinking about the path to approval at this point given that you've already seen at least some preliminary efficacy in the 5 patients that you would need? What's more to come? Is there anything you would point to as possibly a risk that could cause results in additional patients to differ from what you've seen so far? And just wanted to get your thoughts around on how that affects your view going into a potential filing?

Greg, Gaurav here. Thanks for the question. I'll let Kinnari answer, but I just want to say overall that the fanconi trial results that you saw are very much part of our anticipated registration plans without any change. We mentioned that a positive trial with regard to statistical significance would require about 5 of 12 patients engrafted between years 1 and 3. And we don't necessarily anticipate expanding the trial beyond that at the moment, but I'll let Kinnari chime in as well.

Thank you, Gaurav. So as Gaurav mentioned, this -- both of these studies in the Europe and U.S. are progressing along, and we are providing these products with commercial-grade products. So our path to approval for FA is really waiting and seeing how the patients do at least at 12 months and beyond. And as this is an open-label study, our plan is the minute we hit the 5 out of 12, given the fact that we have no conditioning being utilized on this product and the safety profile is quite manageable, we do anticipate a positive benefit risk profile to go to a prefiling discussions, both with the EMA and the FDA. As you also know, this program has received the RMAT designation and the pan-designation in Europe and U.S., so we are already engaging frequently with health authorities in both regions to accelerate this as quickly as possible.

Great, and congratulations again.

Your next question comes from Tyler Van Buren from Piper Sandler.

All the results are very heartening. I guess the first question -- I have 2 questions, actually, related to PKD. The hemoglobin improvement in that patient is striking, clearly. And I guess my question is, do you worry about hemoglobin overload potentially in some of these patients and increasing their levels too high? Or is there a way -- is that managed kind of mechanistically? Or do you manage that with cell dose? And then the second question is just related to the conditioning. My understanding from the LAD-1 presentation from Dr. Kohn earlier today is that it's a busulfan-light conditioning. So are you guys using busulfan-light conditioning for PKD as well? And could that allow you maybe to treat more patients then with a harsher conditioning regimen?

This is Jonathan. So I'll start with the second question with respect to the busulfan conditioning. The conditioning level that we have for busulfan in the LAD-1 study was 65,000 nanograms per milliliter an hour, which is still -- it's on the lower end of the myeloablative conditioning spectrum. And it's -- some people would consider it on the lower end, but it's nonetheless myeloablative. We've actually decided to increase it up to a target of 75,000, which we did for -- will be implemented for the patients on the latter half of the trial with the intent of really optimizing your potential for comprehensive and sustained benefit. I should point out that I think much of the consensus is that things in that 75,000 to 80,000 range are considered a standard for myeloablative conditioning in nonmalignant inherited hematopoietic disorders. Obviously, people do go higher and there are some settings where people will go higher. We did not feel that was necessary. The target level for the PKD study has been and likely will continue to be 73,000, which is also myeloablative, but on the lower end of the range. We do believe that for a red blood cell disorder, we definitely need to give myeloablative conditioning, and we absolutely need to -- we need to give myeloablative conditioning. We need to really affect 20% to 30% correction in hematopoietic cells. This is not reduced intensity conditioning. With respect to the initial question, please remember that this is a red blood cell enzymatic disorder. It's not a hemoglobinopathy. So correcting the disorder -- correcting the enzyme that promotes glycolysis in red blood cells is really unlikely to result in sustained abnormally high hemoglobin levels. Obviously, it's still really early in the game. We'll need to keep our eyes and ears open. But I think that the enzyme correction is unlikely to cause that overcorrection. It's not like we're pumping up globin. I don't know if Dr. Grace is available, but perhaps she could provide an even more informed assessment of that.

I agree, that I wouldn't expect the hemoglobin value to supersede normal in these individuals. If you have normal gene expression and pyruvate kinase production, it should be that it's equivalent to healthy individuals. And I think what we're seeing in this patient, that she has resolution of hemolysis and normalization of the hemoglobin in the normal range for an adult female. So I also wouldn't [indiscernible] to supersede normal.

Our next question comes from [ Eric Withall ] from JPMorgan.

Can you hear me?

Yes.

Okay. Great. Just a couple of questions -- or a question on fanconi anemia and potential delays to registration requirements. Can you just clarify how engraftment is specifically defined in the eyes of regulators? And what, if any part, the use of potential grafting interventions to these transfusions might count in [indiscernible] of engraftment repetitive failure? And then just a second question as it relates to LAD-1. Just curious to get a sense from you sort of what accounts for the dramatic difference in CD18 positivity in the third case of patient. Is that of expected based on age and sort of would you get a similar level of correction in additional subjects, also looking, I guess, to other years of age?

So for the first question, the agreement with agencies, both FDA and EMA, is a primary endpoint of 10% mitomycin C resistance between 1 and 3 years after treatment in at least 5 of 12 patients. That's the basic agreement. And it needs to be seen, however, in conjunction with evidence of clinical stabilization. In other words, we can't just have great engraftment, but then patients continue to be highly transfusion-dependent or even move to bone marrow transplant for bone marrow failure, right? So there's some combination of this MMC resistance plus clinical stabilization that is required. There's no specific guidelines with regard to transfusion requirements. Please note that in the first year or two after therapy, as we saw in FANCOLEN-I, blood counts can continue to decline until there's adequate engraftment to take over the process. So just because there's some transfusion in the year or two after, it does not mean that those patients will not reach the appropriate endpoint. And then the second question with regard to -- I think you were asking generally about a dose response or other predictors of response in LAD-1. As Don Kohn mentioned earlier today, the numbers are too small to make any definitive conclusions. Certainly, patient #2 had a lower drug product metrics versus patient #1 and the CD18 is lower. Patient #3 seems to have similar drug product metrics as #1 and the CD18 is higher, but remember, this is 2 months out only. We'll see what happens over time, but that will be certainly an important correlation to follow over time, Eric.

Great. Maybe just a follow-up on, fanconi, if I could. Very forward-looking question. If you are achieving -- do achieve engraftment, say, 1 to 2 years out and that potentially starts to wane, is there an opportunity here for retreatments? The generation of sort of new product and retreatment considering the alternative of bone marrow transplant does carry some pretty significant adverse risks?

I'll ask Dr. Roncarlo to weigh in given her experience in the past. I will say that Dr. Johnson Liu, quite -- about a decade ago did achieve validation of reinfusion, the second gene therapy with fanconi, but that was in FANC using a gamma retrovirus a while ago. So it is feasible, but I will let Dr. Roncarlo to weigh in on retreatments.

Thank you for the question. And thank you, Gaurav, for giving me the opportunity to answer. I think that specifically for fanconi anemia, it's a possibility to have a second intervention with the retreatment, because we don't condition the patients. Of course, the biggest challenge is for the treatment is when you give a myeloablative conditioning prior to the gene therapy. Although, as we know, in myeloablative allogeneic stem cells transplantation, unfortunately, sometimes, we won't do a second transplant, and we do condition the patient the second time. But specifically for the fanconi anemia, the possibility of retreatment is there, because we don't need to condition the patient.

Our next question comes from Wangzhi Li from Landenburg.

Starting with the fanconi anemia program. Just further clarification on the approval criteria. You mentioned in combination with the clinical stabilization, when do you see -- is there a time frame for that, a parameter? Is it stabilization in the first year, second year, third year or any time during the 3 years?

Kinnari will answer.

Based on discussions we've had with the treating physician in Madrid, Dr. Julian Sevilla, as well as the treating physicians around the 3 clinical sites, what we have seen is patient quality of life tends to improve within -- as early as 9 months to within 3 years. So we have seen stories and then heard about anecdotes on the FANCOLEN-I patients, where they felt like they were -- they had Superman cells and they were running around and doing normal things. So the totality of the clinical data is not just stabilization of the blood count, but really how the patient's quality of life had changed in comparison to prior to gene therapy treatment.

Got it. That's helpful. And then related to the one case of -- in the end, I'm just wondering if you have any thoughts on how to prevent such cases going forward, and specifically follow the patient for some years, and these patients are highly increased for infection? So how -- do you have any plans or strategies to mitigate such potential infections?

Sorry, are you referring -- you're still referring to fanconi anemia, right? Perhaps we can...

Yes.

Yes. Okay. Great. Jonathan first, and then maybe Dr. Czechowicz can weigh in as well.

Yes. I think, I mean, obviously, most fanconi parents are extremely protective of their kids. They are doing their utmost really to decrease their exposure to anything. So compared to anything that we can do, the parents and the families themselves are already hypervigilant about trying to make sure that their kids are not exposed to issues. I think probably the most critical thing to emphasize is that although this -- the patient that did not have a successful engraftment met eligibility criteria for the study, her bone marrow, CD34 counts, her platelet counts were all in the sort of lower threshold -- lower end of the threshold that was permissible. The majority of patients who have been subsequently enrolled on the Phase II study, both in Europe as well as in the North America, have had considerably higher bone marrow CD34 counts, considerably higher overall peripheral blood CBCs relative to that patient. So in that respect, I think we've already -- based on just the patient's general statement, blood and bone marrow health at initial study entry and at the time of harvesting and treatment, that's already been sort of built-in just based on overall patient selection. But I'll ask Dr. Czechowicz, who is working with these patients week-in and week-out, if she has any further thoughts with respect to things that are being done to try to make sure that patients don't get into trouble, especially during those vulnerable early months.

Yes. I think what Jonathan mentioned is exactly right. This patient community and these families in particular are extremely cautious and aware that infections can cause issues, and so they really try to prevent them as much as possible. And we have been doing additional counseling and guidance and continue to further encourage that. And ironically, what we're finding is actually the COVID-19 pandemic has increased their safety as the rest of the world is paying more attention to reducing infectious complications. And a lot of kids are getting home schooled right now, and so these patients actually feel a more similar to their classmates than they used to. The other hope is that with time, and as these gene-corrected cells continue to increase, they should protect patients in the setting if they were to actually develop infectious complications, so that the gene-corrected cells will be resistant and -- whereas the uncorrected cells may still struggle.

Got it. Makes sense. So my last question if I can is, well, PKD, the hemoglobin level on this program looks quite struggling. I'm just wondering if you also look at the spleen volume and if -- do you see any structure change?

This is Jonathan. The -- please remember that these first cohorts of patients on the Phase I are all splenectomized patients, and I'm sorry if that wasn't clear in the presentation. So this is the absolute most severe end of the PKD spectrum. All the patients on this study already had, had a splenectomy and they're still requiring all these transfusions. They're still encountering severe anemia despite the splenectomy. So there's no spleen. The spleen is in the pathology lab, it has been for many years with respect to this patient, so we can't really follow the spleen volume. Now obviously, if we continue to see results like we're seeing, then we'll absolutely seek to investigate this therapy potentially in patients, who have not had splenectomy to see if we can provide this kind of benefit in the absence of splenectomy, so that they don't have to worry about a lifelong susceptibility to encapsulate bacterial organisms, and they don't have that 10% venous and arterial thromboembolic long-term risk that splenectomy and PKD is associated with.

Our next question comes from Mani Foroohar from SVB Leerink.

Congrats on the data and correct use of salubrious in a sentence. I guess that will make you the hardest looking vocabulary, too. So I want to add a couple of quick questions, maybe dancing around this 1 patient who had sort of a less-than-ideal outcome from the fanconi side in terms of infection, et cetera. But I want to -- maybe this is Dr. Czechowicz's question, around that patient with a relatively poor baseline sort of bone marrow characteristics, which happened over time with these patients, what proportion of the other patients in the study, if any? And what proportion of the fanconi population, which is large, fits that sort of poor bone marrow phenotype? I'll stop there before we get off-topic, and I'll follow-up.

I think, Dr. Czechowicz, you can -- if you want to go ahead.

Yes. So I think how we assess bone marrow failure in these fanconi patients is still something that as a community, we are working to clarify definitions around. Part of it is related to their cytopenia, and part of it is related to their bone marrow cellularity. And then what's really rather novel in this trial is that we're actually assessing patient's CD34 counts in their bone marrow prior to enrollment and treatment. And that's something that's not done as a standard of care for these patients. And so it's difficult to know exactly where our patients lie in terms of that parameter, and therefore, where they are in terms of how many [indiscernible] are still retained within their marrow. But in general, this patient has had the lowest cytopenias and the lowest bone marrow CD4 count of all of the other patients and is really at the edge of the inclusion criteria. That said, we generally did want to proceed because the treatment as a preventive way to potentially avoid the need for now to make simple transplant or potentially even just delay it. I'd say that where we are in terms of how make to [ thematic-like ] simple treatments. It's better today than where we were even 1.5 years ago, and then it's continuing to improve. And so this family is very happy and has decided to enroll, and her being treated in this treatment could potentially have been beneficial for her care. Again, in terms of where other patients are, as a community, we're trying to get better and better at screening and diagnosing patients earlier and earlier. And we're seeing much more of that now today other than where we previously were. I know that there are a lot of patients that are approaching us that are in very early stages, either diagnosed due to congenital abnormalities or family histories and/or screened in other ways or starting to show very just early signs of cytopenias, where, again, this patient in particular had pretty profound cytopenia and [indiscernible].

That's really helpful. And a follow-up around that sort of diagnosis screening effort, are there some reasons, where there's relatively limited therapeutic options as something approaches approval or a truly innovative option becomes approved, we'll see newborn screening and patient diagnosis efforts, et cetera, rapidly accelerate? Where are we in terms of the maturity of screening and early diagnosis of fanconi anemia when compared with some other well-understood, but not always universally well-diagnosed rare diseases in your view?

I will say that -- yes, sorry, you go ahead. Sorry.

No. I was going to personally say it's a little bit of a chicken-and-egg situation, where the diagnostics often come in when therapeutics are available. And I've personally had several conversations with entities interested in developing the types of diagnostics with the therapy side there.

Yes. I was just going to add also that the fanconi anemia community is very closely knit. And since a lot of diagnoses occur through family and family connections, there's -- we certainly have a head start on it in many ways. But this is a parallel effort that we'll update over time, Mani.

And then we are also seeing more and more carrier screening being done during pregnancy, both for pre-pregnancy and [indiscernible].

Ladies and gentlemen, this is all the time we have for questions. I will now turn the call back to Claudine Prowse for final remarks.

Thank you, Sylvia. I would like to extend a thank you to all of those who contribute to these programs, including the physicians involved in our trials and the patients they serve, academic collaborators, institutional support, and of course, our shareholders. We will now end this call. Thank you.

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