Abeona Therapeutics Inc. (ABEO) Earnings Call Transcript & Summary

At this time, I would like to welcome everyone to the Abeona Therapeutics WORLDSymposium Data Review Investor Webinar. As a reminder, today's conference is being recorded, and a replay will be made available on the Abeona website following the event. [Operator Instructions] I'll now turn the call over to Greg Gin, Vice President of Investor Relations and Corporate Communications at Abeona. You may begin your conference.

Thank you, Sarah. Good afternoon, and thank you for joining us as we review the new positive data from 2 ongoing Phase I/II clinical trials of Abeona's AAV-based gene therapies, ABO-102 and ABO-101 being studied in MPS IIIA and MPS IIIB, respectively. These data were highlighted in late-breaking platform oral presentations at the Virtual 17th Annual WORLDSymposium on February 12. The presentation slides are available on Abeona's website at www.abeonatherapeutics.com and an archive of today's webinar will be available on our website after the conclusion of this event. Joining me for this event are Michael Amoroso, Principal Executive and Chief Operating Officer of Abeona; Dr. Juan Ruiz, Vice President of European Medical Affairs at Abeona and who heads up clinical development of our MPS program; Dr. Kevin Flanigan, Director of the Center for Gene Therapy at Abigail Wexner Research Institute at Nationwide Children's Hospital and Principal Investigator of the ABO-102 Transpher A study in MPS IIIA; and Dr. Maria Jose de Castro of the Hospital Clínico Universitario Santiago de Compostela and investigator of the ABO-101 Transpher B study in MPS IIIB. The agenda for today's call is as follows: first, Michael will make opening remarks and then turn the call over to Dr. Flanigan, who will review his presentation given at WORLDSymposium on ABO-102 and MPS IIIA. Next, Dr. de Castro will discuss our presentation at WORLDSymposium on ABO-101 and MPS IIIB. Michael will then complete our prepared remarks before opening up the call for Q&A, where we will be joined by Dr. Ruiz. I would like to remind everyone that during this investor webinar, we will be making forward-looking statements. Remarks made during today's call may contain projections and forward-looking statements regarding future events. Forward-looking statements are made pursuant to the safe harbor provisions of the federal securities laws. These forward-looking statements are based on current expectations and are subject to change, and actual results may differ materially from those expressed or implied in the forward-looking statements. Various factors that could cause actual results to differ include, but are not limited to, those identified under the section entitled Risk Factors in the company's annual report on Form 10-K and quarterly reports on Form 10-Q filed by the company with the SEC. These documents are available on our website at www.abeonatherapeutics.com. And with that said, I will now turn the call over to Michael Amoroso, our Chief Operating Officer, for opening remarks.

Thank you, Greg, and welcome to all of our investment community friends. We're delighted to have you with us today and even more delighted of the events and the data that we'll share with you today. Last Friday, we had the opportunity to present some very exciting clinical data that's providing hope for patients and families with Sanfilippo syndrome. On behalf of all the employees at Abeona, we are very pleased to have new interim data from the Transpher A study which evaluates ABO-102 in Sanfilippo syndrome Type A. I'll be using that interchangeably with MPS IIIA today for the presentation and from Transpher B study, evaluating ABO-101 in MPS IIIB or Sanfilippo syndrome type B. Both were featured as late-breaking oral presentations at the WORLDSymposium last Friday. During today's discussion, Dr. Kevin Flanigan, and Maria Jose de Castro, who will walk you through respective presentations from the WORLDSymposium. First, I wanted to take a few minutes and quickly touch on the highlights for each of the MPS IIIA and IIIB programs and presentations you'll see today. In MPS IIIA, you will see the 3 youngest patients treated with ABO-102 from cohort 3, 3x10 13 vector genomes per kilogram from whom we have follow that shows continuous ongoing development, gains and progress neurocognitive within normal range with the longest follow-up being 3 years post-treatment. These 3 patients were treated with ABO-102 at the respective ages of 27 months, 19 months and 12 months. And now as of the latest evaluation, they're between 3.5 to 5 years, between 2 and 3 years post treatment. This is a very important caveat of today's program because it's paramount to understand what the normal affected child without treatment looks like from the natural history of this disease. These 3 patients are now at the age range where children affected by MPS IIIA who go untreated with normal show of plateau and decline of cognitive abilities according to the natural history and what must be the historical control for MPS IIIA disease. In addition to the gold standard neurocognitive assessments, we have biomarker data. In both MPS IIIA and IIIB diseases, we continue to see dose-dependent and sustained reductions in disease-specific biomarkers, denoting clear biologic effect. Notably, in MPS IIIA, there are dose-dependent and statistically significant reductions in cerebrospinal heparan sulfate as well as the secondary substrates of GM2 and GM3, which Kevin and Juan will take you through 2 Years after administering ABO-102. This clearly denotes sustained enzyme activity in the central nervous system. We also see statistically significant reductions of systemic biomarkers, namely plasma and urine heparin sulfate as well as urine glycosaminoglycans, otherwise known as GAGs, and liver volume, all sustained for 2 years after treatment with ABO-102. These are the biologic effects we would want to see in these patients. But again, it would be surrogate markets for the gold standard, which must be the neurocognitive assessment of these children that Kevin will share. Next, Maria Jose will show you in the MPS IIIB presentation,that treatment with AB-101 was associated with the dose-dependent and sustained improvement in CNS and cerebral spinal fluid heparin sulfate as well as the systemic biomarkers of plasma and urine heparin sulfate and the urine GAGs. We look forward to continued follow-up to assess ABO-101's potential to preserve neurocognitive development in patients with MPS IIIB as these patients and their data post therapy matures more similarly to the IIIA program. Lastly, we are very proud that Abeona, with our study investigators around the world have continued to enroll both the Transpher A and Transpher B study patients and manage patient follow despite this worldwide pandemic that it remains for tremendous disruption for our health care environment. Being able to deliver these positive data to you today is a testament to the dedication of perseverance of our clinical and operational teams at Abeona in close collaboration with our partners like Kevin and Maria Jose, as well as equally important, our caregivers and our patients and their families. I will stop here and introduce Dr. Kevin Flanigan. He is the Director of the Center for Gene Therapy at the Abigail Wexner Research Institute at Nationwide Children's Hospital in Ohio, and Principal Investigator of the ABO-102 Transpher A study for MPS IIIA disease. Dr. Flanigan, thank you very much for being with us today. Please proceed with your exciting presentation.

Thank you for the introduction, and I'm happy to present these updated results of the Transpher A study, which is a multi-center single dose Phase I/II clinical trial of AB-102 gene therapy for Sanfilippo syndrome Type A. This is a brief -- my other disclosures, and I'm going to just pause for a moment here, too, on the safe harbor statement to give you a moment to read that. I think most people here are familiar with Sanfilippo syndrome, the mucopolysaccharidosis type IIIA. MPS III is actually a group of 4 clinically indistinguishable lysosomal enzyme deficiencies that result in accumulation of glycosaminoglycan, or we refer to as GAGs, and specifically the glycosaminoglycan heparan sulfate. It is the most frequent subtype. It's caused by a deficiency in the SGSH gene and disease manifests as early as 12 to 24 months. We'll show you some natural history data in this in a moment, but really predominant features are central nervous system feature that includes slowing and then regression of development, affecting speech and cognition and then gross motor problems with later issues of impulsivity, hyperactivity, aggressive behavior, seizures, sleep disturbance and then this relentless loss of skills that progresses to dementia. In MPS III, the somatic features are milder than other MPS disorders, but they are present. These include facial features of hirsutism and coarse face, frequent otitis media, hepatosplenomegaly, heart valve thickening. It is important to note that no treatments are available. No approved treatments are available. 70% of children with MPS III do not reach the age of 18 years. This presents the design of the study. ABO-102 is a self-complementary AAV9 expressing a functional copy of sulfamidase under the control of the urine U1 promoter. It's administered IV. Cohort 1, 3 patients received 5x 8 to the 12 vector genomes per kilogram; cohort 2 received 1x 10 to the 13 vector genes per kilogram. And cohort 3, which is still enrolling, received 3x 10 to the 13 vector genomes per kilogram. Currently, children are enrolled from birth to 2 years of age or if they're older than 2 years, they have to have a developmental quotient of greater than or equal to 60 using Bayley scale and a confirmed diagnosis of MPS IIIA genetic and enzyme determinations. And I'll add, as it may come up later, that we have excluded -- in the inclusion criteria, we exclude those mutations, the genetic mutations associated with ameliorated or mild forms of MPS IIIA. The primary endpoint is comparison of the evolution of age equivalent neurodevelopmental scores in children, treated with the vector in comparison to natural history studies, and of course, product safety is an endpoint. There's a variety of secondary measures I'll share with you including baseline -- changes from baseline in biomarkers after treatment and changes from baseline in liver, particularly liver volume by MRI. So far -- I apologize for advancing accidentally, but we're happy to present data so far. 30 patients have been screened, 11 patients have failed screening, 19 patients have been treated. These are the numbers. Currently, 13 have been dosed in a cohort 3. And the mean follow-up as of January was in cohort 1, 55 months, 47 months to follow-up in cohort and mean follow-up at 24 months in cohort 3. Briefly, ABO-102 has been well tolerated with no deaths, no infusion-related adverse events, no drug-related serious adverse events. And drug-related adverse events have all been grade 1 or 2 and are resolved, including transient elevations in serum ALT and AST without accompanying changes in the GGT or bilirubin. There have been ELISpots that have been negative with the exception of low and transient positive responses to AAV9 capsid peptides in 8 out of 19 patients. And there's been mild and transient thrombocytopenia in 4 patients, none of which have been clinically significant with the lowest level being 69,000. This is an important slide. I want to take a minute to review this. This presents cognitive data from 92 patients enrolled in 4 different natural history studies. And these data together constitute the primary comparator group to assess efficacy in Transpher A. The horizontal access represents chronological age in months, and the vertical axis is the age equivalence in months using psychological tests, either the Mullen or the Bayley test. And in this case, these are calculated from empiric testing of the patient. Each purple dot here represents one measurement in the child, and each link dot represents changes over time from the 4 studies cited at the side here of the paper. The black line is really a mean of this data that shows a typical developmental pattern for children with MPS IIIA. The gray shaded area then represents a 95% credible interval accounting for variability from patient to patient and measurement errors. And then these 2 dotted lines are important as we look at the data from the study. This is the development quotient of 100. So a patient that's age 36 months, chronological age, who has 36 months of age equivalent on the appropriate test has a DQ of 100%. This is the DQ line of 60% then as another marker. What's quite clear is that we can see that no patients follow this DQ of 100% in any of the natural history studies to date. And over about 36 to 42 months, there is general slow decline in cognitive function by these measures.

Excuse me, Dr. Flanigan. This is Greg. If you don't mind, it appears your voice is kind of trailing off a little bit. So if you can just adjust your microphone. Thank you.

I'm sorry. Can I just confirm, is that better?

You sound more loud and clear. Thank you.

Okay. I apologize for that. Thank you for letting me know.

Yes, that's excellent, Kevin.

Okay. I'm going to go back one slide here to say that this is the -- looking at cohort 1, who were enrolled relatively late, the youngest in cohort 1 was enrolled at about 64 months. We can see that they followed a course that's really typical of patients with MPS IIIA as judged by the natural history studies. In contrast -- well, actually in cohort #2, the youngest enrolled is about 30 months, and one sees, again, no significant change in the slope of these patients in comparison to what was expected or what falls within expected from the natural history studies. This is the data from cohort #3. And we can see -- we can differentiate 2 groups here really by use of this DQ 60 line. Those on the right side of the line were treated when they were older and [indiscernible] this with more advanced disease. And their evolutionary of the disease is really not different from the natural history study. However, the children on the left side of the line really show a different evolution and diverge from what we would expect according to this black line. I've highlighted here just those patients, and we can see really the critical data from here. So this is -- we really see the youngest children track really along the normal range. Here, a patient treated at 12 months is following at really a DQ of 100% throughout. You can see that other patients treated in this range also show -- they maintain continued development. They have curves already that really don't represent -- they're distinct from the natural history data that we've seen in any other patients. So this is direct evidence in still a limited number of patients, but a direct evidence of cognitive outcomes that clearly differentiate from the natural history of disease in this patient population. There is also a dose-dependent and sustained at 2 years post treatment a statistically significant reduction in CSF heparan sulfate, a direct measure of activity then on glycosaminoglycan content in the central nervous system. And we can see that this decrease is present here in a dose-dependent fashion and in a sustained fashion at 2 years follow-up in these patients. We also look at GM1 -- I'm sorry, the gangly sized GM2 and GM3. These are markers of neuronal injury in -- we can detect in the CSF. We can see a similar sustained reduction in these in GM2 and GM3 over time. Again, dose-dependent reduction, in fact, below the upper limits of normal at the highest dose for both measures. So together with the decrease in heparin sulfate to indicate a reversal of pathology associated with disease or at least a stabilization of pathology associated with the disease. There is a dose-dependent and statistically significant reduction in plasma heparin sulfate and in urinary output of glycosaminoglycans that's sustained through 24 months observation in all groups, but most significantly in the high dose group. And then liver volume. So there is, again, a dose-dependent reduction and sustained reduction in liver volume. Patients go from hepatomegaly on the order of 1.5 to 2x normal size. This is diminished over time, consistent with the fact that -- consistent with activity in the liver, even though our primary target is in the CNS. So to summarize, this is quite well-tolerated treatment with no deaths, no treatment-related SAEs, no clinically significant AEs ranging from 24 to 55 months post dosing observation. There is evidence of clinical benefit. Those children treated before 2 years of age or with a DQ of higher than 60 in cohort #3 show continuous developmental progress 30 to 36 months post administration, a time when the natural history data clearly leads us to expect that they should be experienced cognitive decline. And quite strikingly, the child treated at 1 year of age continues to track on the DQ 100 line, 2.5 years after treatment really showing normal development. And this is the cognitive data we -- I consider most striking. Correlate to that is that there are dose-related sustained and statistically significant reduction in disease-specific biomarkers 2 years out, including CSF levels of heparan sulfate, normalization of GM2 and GM3 levels and reduction of plasma heparin sulfate and urinary GAGs, along with decrease in liver volume. So with that, I'll close. I just want to thank our team at Nationwide Children's Hospital as well as the teams in Australia. And of course, the team in Santiago de Compostela. And I want to especially thank parents for participating in these studies.

Kevin, thank you very much for the exciting presentation. Look forward to discussing it during the Q&A some of the questions that have been coming in for our investors. So thank you for the energy. Before we go there, we are going to move forward with Dr. Maria Jose de Castro for MPS IIIB presentation. Dr. de Castro is from the Hospital Clínico Universitario Santiago de Compostela, and she is the key investigator of the ABO-101 Transpher B study in the IIIB. Dr. de Castro, a special thank you to you because I know it's been a long day for you, and you're up a bit late here in your day in Spain. So thank you so much for bearing with us and being with us. And I turn it over to you now to talk to us about some of the exciting data in IIIB.

Thank you so much, Mike. I'm really happy to be here and join you today. So good afternoon. In this presentation, I'm going to provide you an update on the progress made in the program for MPS IIIB, a devastating disease, similar in many aspects to MPS IIIA. Dr. Flanigan has done a nice introduction to IPS III or Sanfilippo syndrome. And I would like to stress the fact that both diseases can only differentiated by enzyme activity and genetic testing. Please, next slide. I have nothing to disclose, and this is the safe harbor statement. Next? As I mentioned before, MPS IIIB is also devastating disease, and this is manifest theory, MPS IIIA and involve central nervous system features like the neural degeneration and also impulsivity, hyperactivity, sleep disturbances and aggressive behavior. As I mentioned before, the MPS IIIB and MPS IIIA can only be differentiated by enzyme activity and genetic testing. The frequency of the disease is 1/3 of that of MPS IIIA, but there are regions in the world where it can be as frequent or even more frequent than MPS IIIA such as some regions in Asia. Again, there are no approved treatments. And currently, the program from Abeona is the only going us in gene therapy to treat the disease. Next? This slide present the design of Transpher B trial, which is very similar to the trial design of Transpher A explained by Dr. Kevin Flanigan. ABO-101 is a single stranded AAV9 expressing a functional copy of NAGLU under the control of a CMV promoter. There is a single dose administered intravenous in 3 different cohorts. And I would like to highlight that the highest cohort is just in 1x 10 to the 14 vector genomes per kilo, which is quite a high dose. Children can be enrolled from birth to 2 years of age or older than 2 years, but with the developmental quotient equal or above 60. For us, it's very important to treat the children as early as possible, and this is related to the DQ a child have at that moment. As higher is the DQ, we think that the disease is less advanced. So that is a very important window of opportunity to treat and to try to reverse or try to maintain the DQ. They need a confirmed diagnosis of MPS IIIB by genetic and somatic determinations, and the primary endpoint is the same that in Transpher A, the comparison of the age equivalent neurodevelopment score evolution in children treated compared with natural history data. There are several secondary endpoints, some of them listed in the slide, including biomarkers, liver and brain volumes and additional cognitive and behavioral assessments, quality of life. Further details about the trial can be found at clinicaltrials.gov. Next? You can see here, more details on the trial. The study duration is 24 months with more frequent visits around and after treatment and then visits every 6 months. At the end of the follow-up, patients are following a long-term follow-up study for 3 additional years. And we think that this is very important because, as I mentioned before, we are recruiting very young children. The product is administered intravenous and children stay at the hospital for 2 days. And steroids are used for the first 2 months. Next, please? As of January 2021, a total of 19 patients have been screened with 4 patients not meeting inclusion or exclusion criteria. 11 patients have been treated, 4 of them in cohort 3 with a higher dose. Interestingly, 2 pairs of siblings have been enrolled and treated with one child treated with -- in cohort 1 and had a 4 months old sister in cohort 2 under political waiver and 3.7-year-old male and his 1.74 -- 1.75-year-old sister in cohort 2. This is very interesting because we can compare the similar genetic background with different doses and with different times of treating the patients. Next, please. Regarding safety. Children enrolled in cohort 1 had been followed for 31 months, children in cohort 2 for 17 months and in cohort 3 for 7 months. ABO-101 has been very well tolerated so far with no deaths, no infusion-related adverse event and just 1 drug-related serious adverse event. An episode of prolonged hospitalization more than 2 days established per protocol due to Grade 2 diarrhea and vomiting. Drug-related adverse events include liver function test elevations, subclinical and transient and without changes in bilirubin, mild and transient changes in red blood cells, absolute lymphocyte counts and platelets; and finally, vomiting, diarrhea and other general symptoms 1 or 2 days after administration of the product. No cellularly more response against the AAV9 capsid have been detected as that for 2 patients, 1 in cohort 1 and 1 in cohort 2 at month 12, but they were negative again at month 18. Next, please. This slide presents cognitive evolution of patients enrolling the trial represented by age equivalent in months on the Y-axis versus chronological age in the X-axis. This is the same graph that Dr. Flanigan has presented for the Transpher A trial. Again, we're presenting great data from natural history studies conducted at Nationwide Children Hospital and at the University of Minnesota. There are less patients than MPS IIIA. But the recent release of information from another natural history studies will help us populate the comparator group. In purple, it is a data from the 2 children treated in cohort 1 with 2 years of follow-up, showing no treatment effect. [Audio Gap] that need to be confirmed at later visits. Remember that after completing the 3 years follow up in Transpher B, patient will continue to be monitoring a long-term follow-up study for 3 additional years. Finally, results of children treated in cohort 3 in blue are very limited with only 6 months follow-up in 2 out of 4 children. This is still too early, and additional follow-up from all patients in cohort 3 is needed to evaluate the effect of the investigational product. Next. Regarding biomarkers, children treated with ABO-101 experienced a rapid decrease in CSF heparan sulfate in all cohorts. That is sustained over time up to 24 months in the patient in cohort 1 that has reached that time point. This is very important because we are cleaning the storage material that is affecting the CNS. The table below present a number of observations included in the graph per cohort and time point. Next, please? This graph is the only one in which an increase over baseline levels is expected positive results. We present here enzyme activity in plasma after treatment, and we see, as it should be expected, are those dependent increase in plasma naval activity, reaching higher and more sustained levels in cohort 3 with normalization of enzyme activity at 6 months after treatment. Next. The increase in plasma naval activity -- please remember that [indiscernible] that was deficient in these children. The increase in plasma naval activities correlated with a rapid and dose-dependent reduction of plasma heparan sulfate that in cohort 3, the blue line, has been normalized up to 6 months. Although the number of patients and follow-up is still limited. Next. Results of urinary heparan sulfate and urinary GAGs are similar to those of plasma heparan sulphate with a rapid reduction after treatment that rebounds slightly after months 2, 3 and stabilized below baseline values. Next. Finally, liver volume is enlarged in children with MPS IIIB at baseline, around 2x the volume of a liver of a normal child of the same physical characteristics and there is a rapid reduction 1-month after treatment. That decreases for the as 6 months. Additional follow-up on patients are needed to confirm this observation, but this observation is similar to those described in Abeona trial from MPS IIIA. Next. In summary, the use of ABO-101 has been well tolerated with no infusion-related or any acute reactions and no clinical significant adverse events or laboratory abnormalities. Treatment with ABO-101 is associated with a dose-dependent and sustained improvement in CNS and systemic biomarkers, indicating a potent biological effect for treatment. Decreased CSF heparin sulfate levels sustains up to 2 years, dose-dependent normalization of plasma naval activity up to month 6 in cohort 3, dose-dependent reduction of plasma and urine heparin sulfate and urinary GAGs and reduction in liver volume. Right now, committed valuation requires a longer follow-up to in children treated in cohort 2 and cohort 3. Next. And of course, I would like to thank all the patients, all the families that are devoted to these children because this is the devastating disease, and they are caring for their childs 24 hours per day, 7 days per week. And I think that they are truly amazing. And thank you again to Abeona Therapeutics that made this possible and to Kevin Flanigan and, of course, and the other investigators around the globe. Thank you for your attention.

Thank you, Dr. de Castro, And thank you, Dr. Flanigan for the exciting presentations. So next, I think, just to summarize a bit. In summary, we remain extremely enthusiastic about these interim data. We believe the results from Transpher A show potential long-standing, durable neurocognitive improvements and the life-changing effects that ABO-102 may have on patients with MPS IIIA. We're pleased to see the promising early data of ABO-101's impact on disease-specific biomarkers from the Transpher B study. And we look forward to continued follow-up to assess, again, the gold standard, ABO-101's potential to preserve neurocognitive development in patients with MPS IIIB. So what's next for these programs? Let's talk a little bit about the milestones for the programs, and then we'll go a little wider about Abeona. First and foremost, regarding ABO-102 and MPS IIIA. We met target enrollment for the Transpher A study, as you might remember, in the fourth quarter of last year and decided to keep the study open to address the high unmet need and based on the backbone of the very exciting data we're seeing. That is still ongoing and accruing. In January, we requested a meeting with the FDA to discuss the updated data from Transpher A and to discuss our potential path to a BLA forward for ABO-102 and MPS IIIA. That meeting will be in quarter 2 of this year. Also throughout 2021, we expect additional follow-up visits and neurocognitive assessments of patients treated in the high-dose cohort 3, 3x 10 to the 13 vector genomes per kilogram in the Transpher A study. I'll remind you today, we looked at the children who are the 3 longest runners who had the most follow-up, but we are now up to 8 that have been treated in the pivotal cohort 3 that we believe is the backbone for efficacy of ABO-102. We anticipate sharing these data at future medical meetings to be determined as we're able to get these assessment in and see which congresses are available to us. Regarding ABO-101 and MPS IIIB, we plan to complete enrollment in Transpher B in Q1 of 2021. We will leverage the FDA feedback as well as the EMA feedback we've already received from the MPS IIIA program to help guide us with our path forward toward a BLA for ABO-101. The meeting in Q2 with the FDA will be very important for both programs. We also expect additional clinical updates from Transpher B later this year, and we will put them at the appropriate future medical meetings and letting you know as we get closer to those times. So that's obviously our focus from today, our MPS data, which is our clinical in-clinic programs 2 and 3. I'm now going to pivot to our lead pivotal clinical program, which is our first program, EB-101 in recessive dystrophic epidermolysis bullosa, our anticipated milestones for '21 that you should be looking for. First, in January, we announced that at the end of 2020, we had a successful Type B meeting with the FDA. We aligned on co-primary endpoints for the pivotal Phase III VIITAL study. We're proceeding to enroll between 10 to 15 patients with up to 35 chronic large wounds. These are specific types of wounds, the most problematic for patients with RDEB, the worst of epidermolysis bullosa. We anticipate dosing our fourth patient and are very excited about that later this month, and we plan to complete enrollment in the VIITAL study in 2021. As we pivot to our preclinical programs on the back of our AAV platform and success from our MPS programs, we're making progress on adding new clinical programs to our pipeline. We're conducting preclinical research today with novel AAV capsids in 6 undisclosed eye indications. And we're executing toward IND-enabling studies in 2 to 3 indications in early 2022. We'll provide more updates on this front in our future quarterly updates. I think you can expect in the first half of the year to see some nonhuman primate data for some of our novel capsids, and we'll take those into proof-of-concept in the second half of this year, taking us into toxicology studies in 2022. Before we open up to questions, I'd like to thank Dr. Kevin Flanigan and Dr. de Castro for their many contributions to the respect of ABO-102 and 101 clinical development programs and for their participation on today's call and sharing the results. I also want to take a minute and express my gratitude to patients and families who, without them, we could never have this data, this conversation and their bravery in participating in these clinical styles -- clinical trials is astounding, our Abeona employees who worked tirelessly through this pandemic to make sure we've met these milestones because these patients are counting on us as they have no approved treatments today. With that, I'm going to open up to the question-and-answer session. I know we have an extra slide. I think we'll bypass that for time today so that we can get to what's most paramount in the minds of our investors. Thank you. Operator, please open us up.

[Operator Instructions] The first question comes from Maury Raycroft at Jefferies.

This is Dr. Flanigan. I'm very sorry. It says the host is not letting me start my video. It stopped. I apologize to interrupt the question. But here we go. All right. Thank you.

Can you hear me okay?

Yes, we can.

Great. Congrats on the progress with these programs. I guess after one of the presentations on Friday, there was some discussion around the natural history data that's been compiled. And so generally, I think it looks consistent. And Abeona's neurocog divergent seems clear in the MPS IIIA patients with these severe mutations. And so my first question is how well-characterized are the mutations that these patients have? And how much weight will FDA put on the mutation?

Maury, good to hear your voice. Great question. I think that's probably most appropriate for Juan. I'm going to open that up to our Lead of Clinical Development, Juan. And then Kevin and team feel free to chime in. Go ahead, Juan.

Thank you, Michael. Yes, that's an important point. Because as we know, the age that we are enrolling our children, very gentle age. We have to find the predictors that these children are going to evolve in a severe way. And we are including those that are considered rapid progressors. So for including children in the trial, they have to be fully characterized from a genetic point of view. We conduct genetic testing in addition to [indiscernible] also. And the mutations that we are seeing are reviewed with the investigators in order to check that they belong to -- or they have been previously described in natural history and publications associated with our rapid progressor phenotype. So we are pretty sure that all the patients that we have enrolled are meeting this criteria. They have been shown to have -- and in fact, they are -- usually, they are very common mutations that are very well described. Unless a couple of patients with more rare mutations also describing the [indiscernible] associated with the rapid progressor phenotype, all children have been well characterized.

Got it. Very good. And second question is, just wondering if there are any variables that could contribute to sort of a placebo effect? Or has anything changed since the natural history studies were completed that could introduce some risk that what we're seeing on neurocog is not related to ABO-102?

Yes. Good question, Maury. Dr. Flanigan, I think that would be a great question for you as somebody who's seeing these patients day in and day out.

Sure. Well, I can say -- I can speak specifically to the patients who've been treated at our center, for example, who we know that the same investigators, including the same neurocognitive specialists who did -- oversaw the training for the natural history study or doing the performance of the same test in hand. And I -- during the trial. So I think that argues that there's not something different. There's not been a change in treatment protocols for patients, and we don't have -- there's nothing in the concomitant medication record or anything from these patients that would be suspicious for another effect besides treatment with the investigative agent.

Maury, the only thing I would add to your last half of your first question is, I think as we're waiting for our FDA meeting coming up, we've had correspondence with the teams through the years. And I think as often as we can have match comparisons, we've worked on a modality to try to look at that with natural history data. That is important to the FDA whenever we can show that similarity. So I think that's a fair question and a stout comment.

So the next question comes from Kristen Kluska at Cantor Fitzgerald.

Congrats on these data updates. So the first question I had is whether you saw any further benefits on the secondary outcome biomarker measures, specifically in cohort 3 when looking at the younger patients? So in other words, how correlated do you believe that all of these endpoints are?

Kristen, we lost you a little bit on the question there.

Can you hear me better now?

We got you now. Kristen, please repeat that. You faded out a bit.

Yes. Sorry about that. So the question was just on whether you saw any further benefits on the secondary outcome biomarker measures, specifically with the younger patients? I know -- you noted that there is a dose-escalating response. But how about, again, for these younger patients that seem to be doing much better? And then how correlated do you believe these endpoints are?

Sure. Yes, I'll open that up to Juan and Kevin as well as Maria Jose on this because I think the biomarker and how much of a surrogate marker endpoint this is for neurocognitive development and at what age the importance of getting to them early before the damage is done. I think these are some good questions, Kristen. So opening it up to the team, please feel free to my physicians to jump in.

Yes. Let me start. I think that like Dr. Flanigan has presented some of the most recent data on relevant biomarkers that are associated with the pathology of the disease. And those are the data related with the ganglioside, GM2 and GM3. We don't have yet analyzed the full set of patients because we have started with patients that have been followed from the beginning to the end, 2 years data. And in those patients, and we don't see differences between age as we don't see difference in the response of biomarkers according to the different age of children. We see the same type of reductions of heparin sulfate or urinary GAGs in children treated at 8 months or children treated at 8 years of age. So we expect to see the similar changes in GM2 and GM3, and this is very relevant because GM2 and GM3 have been related with the pathology of the disease. They are secondary substrates that accumulate as a consequence of the initial accumulation of heparin sulfate, and they are related with the brain damage.

Got it. And then my second question here is given the evidence from both Abeona and other companies in the gene therapy space, that early intervention may lead to more robust benefits. What work do you anticipate needs to be done in the MPS III landscape to ensure that patients are getting diagnosed at an earlier age?

Yes. Kristen, you were nice enough to prep me on that one. So yes, the neonatal screening is super important. Juan, why don't you talk a little bit about some of the programs that we have across the nation at some of our sites. I know Maria Jose has programs at her site. Why don't we give some clarity on some of the programs and the work going on right now for the early screening in order to have the recommended uniform screening panel representative of MPS IIIA and IIIB?

Yes. Thank you, Michael. Yes, this is one of the very, very important activities that Abeona is conducting with tech providers all around the world. And in particularly, people within Abeona is in constant contact with patient groups and their foundations and looking at different countries and identifying those who have newer screening programs. For example, in Taiwan, there was a newborn screening program that identified several patients with Sanfilippo MPS IIIB. And we contacted the FDA of this study, and some of these patients have already been considered for our trials. This is something we are doing in other countries. In Spain, for example, there is a product that is called the find program, where there is some early diagnosis where a particular site, in fact, is, because I gave the [indiscernible] where Dr. de Castro is an investigator. They are receiving samples from all around Spain, from patients that suspect the diagnosis of the child, they send the sample, and this is confirmed, whatnot. We are also working in the U.S. supporting and helping through MPS -- National MPS Society, supporting the [indiscernible] we want to screen in New York, led by [ Dr. Melissa Warstein ]. This is an important program who's testing children with -- for several different MPS diseases, including Sanfilippo. We would like to promote and in the inclusion of Sanfilippo on this panel also. The method is ready, developed by Dr. Michael Gale at the University of Washington, and it could be implemented very quickly in order to identify a year on these children. I'd like Dr. de Castro Maria can tell us something about this 5 initiative in the hospital in Spain.

Thank you, Juan. But regarding the 5 initiative, we have been carrying -- conducting that program for 5 or 7 years, and we are going to publish the results for -- in the next months. And we are -- that program is supported by the MPS societies and by patients and families. And in fact, we have achieved the goal to diagnose children in an early stage compared to the -- to when we started with the find program. So I think that is a very meaningful impact. We are now diagnosing childrens in Spain that are younger with MPS younger than 5 years before, for example. And also, this program is being implemented in another countries in Europe, for example, in Germany. Regarding West, like Michael mentioned before, the recommended uniform newer screening panel in the U.S. MPS that really, really affect cognition, MPS I is already included in that panel because the treatment is there and it's very important to treat a child in the 2 first years of age. So I think that the Sanfilippo disease is going to follow the same path as soon as we have an available treatment.

Thank you, Maria Jose. And Kristen, just concluding, maybe Jodie Gillon with us on the phone. She was recently appointed in the beginning of this year as a Chief Patient Officer. For reasons exactly like you're talking about, Kristen, to make sure as we're operationalizing, we are fastidious on programs around the world in the world's major markets on neonatal, also for some of our accrual efforts in RDEB, the EB trial. Jodie, anything else you might want to comment on?

Sure. I think Juan and Maria covered quite a bit when it came to newborn screening. We do partner with patient groups all around the world on their efforts. So Juan mentioned the screen plus program in partnership with Kirsten Filippo. And then actually, the National MPS Society was working on MPS I rough panel, and we already are supporting a grant writer from test 3. So even though this will happen when there's an approved treatment, there is a long runway and work is already underway, not just in the U.S., but most countries. The other thing that I'll add is that there's newborn screening, but there's also early diagnosis. So we're doing quite a bit in the HCT engagement sector. So we're working in different specialties. We had a campaign actually to ENTs because they see a lot of early ear infections and issues in children. We supported a booth at the American Academy of Pediatrics. And then we're working even with geneticist, making sure we get a lot of education to neurologists and have supported different CME events globally.

So this concludes the first section of the Q&A session. I would now like to turn it over to Greg Gin to see if any questions may have come in over the web.

Thanks, Sarah. Yes, we've got quite a few questions coming in. So hopefully, we'll -- and we'll address as many as we can in the time that we have left. The first question is, what does the FDA consider clinically meaningful in terms of the length of time over which treatment like ABO-102 would need to demonstrate impact on neurocognitive development and performance?

Yes. I'll start that one, and then I'll ask Juan to chime in. So I think that's a great question. And I think the answer on that is to be determined. That's paramount for our dialogue here coming up shortly. We're going to have our meeting in Q2. I know we thought it'd be at the end of Q1. The FDA has worked with us hard during the tough time, where they're a bit delayed by COVID. So our meetings pushed into Q2. Changes nothing about our course of action, but the exact magnitude needs to be agreed upon. But Juan, maybe you can give an idea of 2, 3, 4 fold, 300% deltas here, we're seeing with some of these children, we think the magnitude of benefit is substantial. But we do not have a defined cut off yet. That will be important for our dialogue with the agency in quarter 2. Juan?

Yes. I mean, addressing the question, I mean, what is the relevant length of follow-up in order to find that children are clearly showing a treatment effect. This has been previously discussed with the FDA. The FDA made clear that as we were reducing the type or the age of enrollment, the follow-up necessarily have to be prolonged because children treated at a regular rate, by the time we finish the follow-up within the trial, 2 years later, they are still 3 years of age. This is a time with natural history. It's still showing some gaming skills has reached a plateau that has not started yet to degenerate. So for younger children, the longer follow-up might be longer. In our trial, we are following actively 2 years with maybe 001 and then all children are transferred [Technical Difficulty], wherein in addition to following the safety, we are also looking at the same quality valuations that we have in ABT-001 prolonging up to 5 years, the level of [Technical Difficulty]. So this is variable depending on FDA [Technical Difficulty] which is a matter of discussion with the FDA. And currently, as Michael was mentioning, in the trial, we have seen clearly that children that have been -- that have us over 3 years, 4 years of ages have deviated significantly from the study [Technical Difficulty] and the gap between the committee rates that they have achieved versus what they expected in [Technical Difficulty] has been wider than 1-year, 2-year -- I mean, 1.5 years and this, we believe it's clinically significant.

And just to make sure we don't confuse Juan's talking about 1, 2-year difference gap of commit against neurocognitive age versus chronologic age, right? So that they don't have that plateau. Thank you, Juan. Next question, Greg?

Sure. Next question is in the MPS IIIA transfer a study or the younger patients in whom neurocognitive development preservation was seen, were they challenging to enroll? And what are some of the principal hurdles to getting these patients enrolled?

Yes, why don't we send it over to Kevin, and then Juan, you feel free to chime in.

Yes. I would say the -- it's the delay in diagnosis, typically. Many of these patients do go through a diagnostic odyssey, and it's not uncommon for diagnosis to be made after the age of 2, for example, as the trial begins to have some regression and everything kind of fits together. We've had good success, and we'll continue. I think they have success with siblings, newborn siblings of patients who are known. And to some extent, that also addresses an earlier question about how do we know the severity of the disease when we have a newborn, who is the younger sibling of a child who unfortunately has had significant progression of it. But that's the major challenge really to have this recognized early. We are fortunate that those physicians who geneticists, in particular, who've seen and enroll patients in the study, we are getting referrals earlier for the trial, but most of the youngest ones have, in fact, come from younger siblings or arriving from younger siblings.

Thank you, Kevin. And Greg, Greg to our life Sciences part, I'm okay, doing about 5 minutes over here. I want to make sure we get to everybody's questions. So [ with questions ], keep moving on.

Okay. Thank you. All right. So the next question is with respect to the biomarker data and liver size reduction data, are they considered particularly impactful by regulators? Or is neurocognitive performance, the be all and end all with regard to determining the provability?

Juan, maybe you could qualify a little bit what we see at any dose on biomarker. I think we talk a lot about a negative screen versus seeing a therapeutic effect seeing enzymatic activity. But how that would maybe correlate for the neurocognitive development being really the prime end one?

Yes. As both presentations have clearly shown, I mean, we see dose dependent relationship between the dose we administer and the level of reduction of biomarkers, both systemically and also on the CSF. So clearly, this is something that we have saw and have presented to the FDA previously. The FDA has released guidance on how to conduct trials on MPS and what is going to be reviewed by them regarding a potential BLA application. And currently, there is no data that support the use of biomarkers as sort of a [indiscernible] for efficacy. As we gather data on these trials, not only as other companies, this might be something possible. But so far, the FDA is focusing on clinical endpoints. And regarding clinical endpoints, neurocognitive endpoints are the most relevant. Because, as you know -- as we have described before, Sanfilippo mainly affect the brain and it's impacting mainly on the growing capabilities of children and secondarily in other aspects of the daily life.

Thank you, Juan. The only thing I would add, I would say is we've seen in early dose finding, which is what transfer A transfer B started as. We've seen in the cohorts, cohort 1, cohort 2 that are not the move forward cohorts an improvement in systemic biomarkers, dose-dependent to Juan's point, but the real hurdle has to be, what does that mean? You're seeing it going in the right direction. But that 2-year -- once you get past that chronologic 36 months, so we say 2 years for the patient treated at 12 months plus, what's the neurocognitive development look like? That really is important because we've seen some improvement in biomarkers where maybe the neurocognition testing, the Mullen scores weren't ideal in the subtherapeutic doses. 3x 10 to the 13th is why we're super excited about those is because of the neurocognitive data we're showing you today.

Yes. Biomarkers and liver sizes are very important indicators that the potency of the vector and the those relationship is having a higher impact. So they are necessary. So you need to have an enzyme experience, and this is shown by the reduction in the biomarkers, but this is not sufficient to get cognitive changes. Because if you don't treat early enough in order to correct the deficit of the disease at the time when the brain has not been generated to a certain level, this is not going to change the course of the disease.

Thank you, Juan. Greg?

Sure. Yes. So the next question we've received from a couple of different people. So I know people are interested in hearing about this. So with respect to the outcome measures or scales that we're using in terms of monitoring neurocognitive performance and development, what are the most appropriate that the FDA considers and -- in the young patients? And how amenable is the agency to company input with respect to these scales, these instruments?

Yes. I think -- maybe, Kevin, you could talk about the scales we use. And Juan, maybe you can speak about the importance of concordance with the FDA potential.

Yes. I would say the scales we have been validated in this age range as developmental scales and tested for their feasibility and sensitivity, I guess, in the natural history study. So we're confident that they are. I'm going to defer to one to really address questions of provability based on these scales.

Sure. Juan, talk a little bit about Mullen and Bayley some of the histories across the natural?

Yes. We are included in our trials after recent amendments, both scales, Mullen and Bayley, in order to address the committed capabilities of children over time. Initially Mullen was the scale selected because as Dr. Flanigan was mentioning, [Technical Difficulty] scale used in the natural history study that used to inform the design of the clinical trial. Following recommendation by the FDA and some consensus conferences who recommended the use of Bayley we implemented [Technical Difficulty] And what we have seen so far is that in those that has been evaluated with Mullen and Bayley at the same time. And several different repeated administration of this case, we see a very, very high correlation in terms of results with Bayley and Mullen. In fact, the correlation is so hard that we've been able to put together natural histories of the data from studies using Bayley or Mullen because the description of the evolution of the disease, the changes that they described are exactly the same. This is something that we are going to discuss with the FDA in the meeting we are going to have with them. We've been in contact with key opinion leaders, experts on the use of scales from Maria's [indiscernible] at the University of Pittsburgh Medical Center, who's [indiscernible] in the trial [indiscernible] who conducted one of the natural history studies at the University of Minnesota. One of them using the Mullen and the other Bayley. At the end, in this discussion, we all agree that what is important is that the scale is able to capture the changes over time, both of them do. They are sensitive to change. At the end, the actual data we have got in the trial. So the correlation is very high, and this is what we are going to present to the FDA.

Thank you, Juan. Greg?

Sure. Do we have time for 1 or 2 questions?

Sure. Go ahead. Let's take 2 more.

Okay. Next question is when might we see impact on cognitive development in the Transfer B study of ABO-101?

Okay. So Juan, Maria Jose if you want to talk about when will we kind of hit the cutoff of our 2 years one post-treatment for Transfer B on our first patients at the higher dose.

Cohort 3 has started, obviously, the latest, I mean we were escalating. And the follow-up -- current follow-up in children in growing cohort 3 is only 6 months. So we still need a significant follow-up in order to reach the 2 years that we indicated that we are, I mean, modifying or deviating from what is expected because of the disease. Cohort 2, obviously, there are children more advanced, some of them are 18 months of follow-up. But this is information that we are -- I mean, we are following patients, and this is our schedule. Hopefully, with an improvement in the situation with COVID-19, it will be easier to schedule treatment on time and a on-site visit for the children. But this is something that, in collaboration with our investigators, we'll be able to do in due time.

Yes. Thank you, Juan. And the only thing I would add to that is, if you look at MPS IIIA and the high dose, where we expect you saw the first 3 children today, we really expect the eighth child to pass the 2-year cutoff estimate around Q3 of August '22, that's when we can Transfer B we'll have some of our first patients with 2 year data, about 18 months. So there's a nice overlap there of clinical program to MPS IIIA and IIIB clinical program 3. Maria Jose, anything you want to add there? Or is that okay?

I could only like to add that a recent presentation at world has released data from natural history study, including 62 patients with MPS IIIB. So I think that using that data together with a longer follow-up will give us the global view of how the children are really evolving compared to the natural history studies.

Thank you, Maria. Greg, how about one more?

Sure. So this last question is really about -- or is about a pivotal study in MPS IIIA, I presume. So we might be limited in terms of what we can say without a feedback. But it's a multipart question. So it's -- what are your thoughts on targeted enrollment for a pivotal study? In terms of timelines, when do you think you could potentially start a study? And also what are your thoughts on the duration of such a study?

Yes. I'll start and Juan can correct me like he usually does. But I think we're hopeful, and I think a conversation, a really constructive conversation with the FDA coming up in Q2. I think we believe that MPS IIIA, our most advanced MPS program Transfer A, that cohort 3, we believe, is potentially therapeutic. We know it's safe. We like what we're seeing from an efficacy standpoint. So we're hoping that could possibly be a backbone of a pivotal package. As far as whether we would need to start another trial, that's not in our plan right now. But that's possible, and that's a dialogue we'll have to have with the FDA. For me, it's probably somewhere more potentially in between. For example, is 8 patients at cohort 3 passed the 2-year neurocognition, someone before and 5 years at that point. Is that enough with continued follow-up? Those are dialogues -- those are questions I can't answer just yet. So we'll be able to check in on some of our next investor calls or earnings calls and give you updates on that. That's where the conversation in Q2 with the agency will be paramount. But we do believe the magnitude of the data will be the most important thing to guide the conversation with any regulatory agency. The data is safe. We believe we're seeing data that's very therapeutic. And we'll have to hope that the durability holds up, then we'll have to make sure we have that dialogue with the agency because these patients have tremendous unmet need and no options right now. And we've got to get to them as fast as possible. Juan, I don't know if you would add anything else there?

No, I never try to correct you, Michael. No, I just want to add, you're right. I mean the FDA agrees that a single trial so in an evident and significant treatment which has might be sufficient for a BLA in an ultrarare condition. And we believe that with the current dose, 3 x 13 in cohort 3, with a follow-up that by Q3 2022 will be 4 years in several patients and 2 years at the minimum in the other patients, there will be a significant treatment effect. So a clear variation from natural history that will be clinically meaningful and sufficient to support BLA at the time. If the trends that we see so far are reproducing the new children that we have treated, and we continue to see the evolution in those that were already passed the time that they should start losing cognitive correlatives.

Yes. Thank you, Juan. Just a reminder, we have treated 8 now in cohort 3, 3x 10 to the 13th with MPS IIIA disease. So the 3 of the longest runners you saw today between 2 and 3 years post treatment. And Juan is talking about around August and that 2022 time frame, where we'll have all 8 at a minimum of at least 2 years of data, some will be 4 and 5 years. So that will be a really important time point to have the maturity of the neurocognitive. I want to say thank you to our partners and peers on the phone today to our investors. Greg, maybe you can address any questions that came in. Maybe we can get some answers back in writing. We'll send up through Brendan, just to make sure all of our investors are getting their questions answered, so they can have all the facts about Abeona. And thank you again very much for our investment community to our KOLs. Maria Jose, thank you for the -- staying after here on the Madrid time. And I just want to say thank you to the team, and most importantly, our patients here. So we remain very, very hopeful about our MPS programs. Thank you for the level of attendance and your level of interest.

Thank you, everyone.