Editas Medicine, Inc. (EDIT) Earnings Call Transcript & Summary

Good morning, everyone. Thank you for joining today's webinar. Today, we plan to review clinical data from Editas Medicine EDIT-101 program, which is currently being used in the Phase 1/2 BRILLIANCE trial for the treatment of CEP290-related retinal degeneration. As a formality, there may be some forward-looking statements during this webinar. Various remarks that we make about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigations Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factor section of our most recent Annual Report on Form 10-K and our subsequent filings with the SEC. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change. With that, I'd like to hand it over to our Chief Executive Officer, Jim Mullen. Jim, please go ahead.

Thank you, Ron, and good morning, everyone. Thank you all for joining us. I'm thrilled to be speaking to everyone today for Editas Medicine review of the clinical data from our ongoing BRILLIANCE trial. For those of you who do not know me, I'm Jim Mullen, Chairman and CEO Editas Medicine. I'm joined today by our company's Chief Medical Officer, Dr. Lisa Michaels; our Chief Scientific Officer, Dr. Mark Shearman; and Senior Principal Investigator of the BRILLIANCE clinical trial, Dr. Eric Pierce. During the next hour, we plan on reviewing our EDIT-101 program and initial findings from this trial. Today marks one of hopefully many more important milestones in Editas' journey. Early today, one of the principal investigators of BRILLIANCE trial presented initial clinical trial data at the International Symposium on Retinal Degeneration. These initial results demonstrate a tremendous step forward for patients with Leber congenital amaurosis type 10 and a glimpse into what we believe is possible for many other inherited diseases. The foundational science behind CRISPR-based gene editing is changing how medicines are developed and applications using this technology are steadily creating scientific and medical breakthroughs. Editas continues to be at the forefront of these next-generation medicines, and today's results demonstrates an important achievement for patients and the broader medical and scientific communities. Specifically, early results from our dose-finding safety trials show evidence of gene editing, resulting in clinical improvement and an absence of serious safety concerns. We believe these findings validate the fundamental notion that we can safely deliver a clinically effective gene editing medicine directly to patients in order to treat their ocular disease, an important advance that helps derisk our subsequent ophthalmology programs. Before I turn it over to Lisa, I want to acknowledge and thank the patients enrolled in this trial as well as the participating practitioners who witnessed firsthand how this technology can improve patients' quality of lives. This progress would not have been possible without your involvement and support. Editas' mission has always been to discover and develop a novel class of genome editing therapeutics, and today's event brings us one major step closer to achieving that goal. With that, I'd like to hand it over to Lisa Michaels.

Thank you, Jim, and thank you, everyone, for joining us this morning. As Jim mentioned, today marks an important landmark for the company. Editas Medicine was the first company to ever administer in an in vivo gene editing medicine in humans. So it's exciting to be able to share the company's first clinical data from the Phase 1/2 BRILLIANCE study. The ongoing trial is currently evaluating the safety of EDIT-101 as well as potential clinical benefit in the treatment of blindness lines to CEP290 retinal degeneration, which is also known as Leber congenital amaurosis type 10 or LCA10. CEP290 associated retinal degeneration is a rare inheritive disorder, affecting about 3 out of every 100,000 children [indiscernible]. It is Autosomal recessive, which means that to be effective, the person has to inherit 2 copies of the defective gene, one from each parent. If you can repair at least one of these copies, you can potentially reverse the disease. Despite being rare, it is the most common cause of early onset inherited retinal degeneration. The loss of vision is caused by early loss photoreceptors in the eye. However, even in delayed adult there remains a small area of normal anatomy in the central part of the retina, and this provides the opportunity for gene correction. Now diagnosis is usually made in the first years of life, a severe vision loss occurs in childhood, and the loss of vision is multifold. In addition to loss of visual acuity, the type of vision measured by reading the letters or shapes on the line chart, there is also a loss of critical vision and night blindness, which is an inability to see in dim light. So even people with some visual acuity, see the world through this narrow aperture and only in bright light, even then the world can be fuzzy. And because the vision loss occurs early in life, most individuals have nystagmus, uncontrollable eye movements that make it difficult to fix on logic. Some affected individuals are fully blind, but can only discern light and dark. All consequences of blindness go beyond just vision, it may impact mobility. Individuals are at much greater risk for falls and injury. And people with vision loss duty mutations such as CEP290 gene cannot drive, and then you're not able to independently use public transportation. Further, there is real and typically adverse impact on social function, school performance and employability. So a treatment that can stop further vision loss or even better correct permanently and permanently reduce the vision -- reverse the vision loss is greatly needed. Small improvements such as being able to see obstacles better and see the face of family member or even get around in the dark, can have a real positive impact on a person's life. Now blindness can result from the mutation in the CEP290 gene. Loss of vision results from disruptive production of the CEP290 protein, resulting in a protein deficiency. In the eye, the CEP290 protein plays a very important role in the ability of photoreceptors to convert light into signals that the brain translates into sights. It's got 290 genes to be delivered or as established methods of gene delivery including the adeno-associated virus vector or AAV. This means it cannot be treated with a similar approach as a gene therapy drug Luxturna, which is approved for the treatment of retinal degeneration due to mutations in the RPE65 gene. However, the gene editing apparatus that can surgically remove the mutation from CEP290 does fit in the AAV vector. So it's an ideal application for the use of gene editing. EDIT-101 calls for 2 guide RNAs that specifically frame the targeted IVS26 mutation and clinically remove it. In nonclinical work, we have demonstrated that by cutting out the mutation in CEP290, it's possible to restore gene function and restore normal production of the protein. Therefore, one specifically delivers the gene editing apparatus to the photoreceptors in the central retina and corrects the mutated CEP290 gene in those cells, it should be possible to restore photoreceptor function, improve retinal sensitivity light and hopefully improve functional vision. CRISPR/Cas9 gene editing puts CEP290 associated retinal degeneration is a highly innovative method, and preclinical data supports the high specificity and the fidelity of the approach. EDIT-101 was therefore designed to target the specific part of the retina where the reliable photoreceptors remain in limiting potential interactions with other structures in the eye. It was also designed to be a onetime treatment, resulting in permanent correction and avoiding need for repeated or recurrent injections. To do this, EDIT-101 was developed using the AAV5 vector with high trophism to retinal receptors, and it's delivered locally to the specific part of the retina with a targeted [indiscernible]. For those interested in the detail of the science, the vector comprises of DNA encoding Cas9 expressed under photoreceptor specific GRK1 promoter and also for 2 highly specific guide RNAs that ensure site-specific delivery to the mutation site. Our nonclinical data support the specificity of the approach and the lack of off-target effects. Now before I hand off the presentation to Dr. Pierce, who will give you more detail based on his personal experience treating these patients, I like to share a little more backdrop. Now when Editas embarked on the BRILLIANCE study, no one had previously attempted gene editing in the human body. It was not known how humans would react to the CRISPR/Cas enzymes when delivered to the eye using AAV as a delivery system. And there was a lot of concern about the potential of immune responses. For this reason, the study is primarily designed as the safety study. Today, we shared the collected safety data on the first 6 subjects treated, 2 subjects in the central low-dose cohort, and 4 subjects that have been treated in the mid-dose group. The observations we have collected to date support the safety of using CRISPR/Cas9 in this clinical setting and for the treatment of human disease. Importantly, we have not observed any serious adverse events associated with treatment, including observations for more than a year in the first 2 patients treated. Most encouraging is that we have monitored any dose-limiting inflammatory reactions, the most adverse events have been mild, with the majority related to the surgery required to perform the subretinal injection. Now the safety observed to date has allowed us to move to the next phase of the study, which includes treatment of adult patients at the highest planned dose and also the start of enrollment of children. Additionally, we present early top line data on the subjects who, as of the August 4 date cutoff date, had at least 3 months follow-up after treatment. Now why is this? A question I've received frequently is when is the earliest timeframe, we would expect to see a clinical benefit from editing. We know from the nonclinical data that it may take 6 weeks or even longer for the effects of editing to occur in the eye. Additionally, time is required for the treated eyes to heal following the subretinal injection surgery. Consequently, although the effects of editing might be observed earlier, we believe that the 3-month time point is the first where we can collect consistent and reliable observations for comparison to both baseline and subsequent patient visits. This decision is supported by the data we shared in which we were able to detect measurable changes in BCVA or FST by this time point. More importantly, for some of the patients, we have evidence that these changes are sustained on more than 1 measurement. And at the time of the data cut off, the fourth patient in the adult mid-dose cohort did not yet have a 3-month follow up visit. An unanswered question is whether 3 months after treatment is only the earliest time point in which a change in function can be measured. And it is possible that benefits may continue to accumulate over time as the photoreceptor function improves. And to answer this question, we continue to follow these subjects, respectively, and for now, continue to collect clinical measures to observe for additional changes over time. Finally, one of the challenges of this study is how do we identify efficacy, which depends on using measurements of vision rather than a simple assay such as a blood test, which would let us know, if we have corrected the CEP290 protein deficiency. Because EDIT-101 is being used to treat a small and important macular region of retina. There's no easy test durability or biopsy in the eye to confirm that effective editing has occurred. Consequently, an important secondary outcome of the BRILLIANCE study is the collection of multiple exploratory endpoints that can be used in the clinic to capture changes in retinal function as well as functional vision. Now many of these are difficult to collect in people with restricted vision or with an inability to fix their age on an object. There is also a lot of intrapatient variability in some of these measures. Complying to the BRILLIANCE study, Editas is also collecting prospective natural history data that explores which measures are reproducible on repeated measurements and thus best in capturing the effects of editing in the eye of this patient population. From this unpublished data, the FST appears to be a sensitive measure of [indiscernible] function. And we have also observed that individuals with CEP290 retinal degeneration of consistent measurements for BCVA and their performance on our version of the visual function navigation doesn't meaningfully change from repeated over multiple measurements over a year. Pupillometry is also repriceable, but it may not be a sensitive measure of potential effect. So for today's summary, we have focused primarily on FST, BCVA and VNC, the navigation phase, as they show the best consistency on repeated measures. So to summarize, no DLTs or serious adverse events have been reported in our ongoing BRILLIANCE study. And most excitingly, we do see early signs that indicating the productive edits have occurred and potential signs of clinical benefits for the patients treated. As safety has been supported, we are now taking a study to the next step and treating patients with the next planned higher dose. And as our preclinical data supports an expected dose response, we're hopeful that more edits resulting from administration of higher doses will translate into a stronger clinical effect. Additionally, safety has also supported moving in a number of patients until we believe that there is the strongest potential for benefit, and we have started enrollment in the first of 2 plans pediatric cohorts. Finally, this first gene holding trial in humans, reflects the results of years of hard work, and I'm very proud of the progress that Editas has made in advancing our programs into clinical development. The results shared today support our ongoing clinical and development efforts, and I'm very grateful to the scientists and the clinicians and our collaborating institutions that made this possible, especially to the patients and their families who have participated in the research. And I think that -- that's when we transition over to Eric, who has been a long-standing partner with Editas. Dr. Eric Pierce, William F. Chatlos Professor of Ophthalmology at Harvard University, with clinical appointments, both at the Harvard Medical School and the Mass Eye and Ear. And he's well-known for his clinical research contributions to operator genomics of retinal diseases. And not only has the increased the public's awareness of inherited retinal diseases, such as LCA10, but he's also helps potential patient participation in other gene editing and gene therapy trials, which undoubtedly helps bringing CRISPR mediated and medications closer to patients. We're very lucky to have Eric as the senior PI in the BRILLIANCE trial. His history of the study goes back way further. And his enthusiasm and support for the technology and the program has been incredible. And so Eric, I want to thank you for being a great partner in this trial, and please go ahead.

Thank you very much, Lisa, and thanks to you and your colleagues at Editas for inviting me to speak in this webinar. As you indicated, I've been enthusiastic about CRISPR mediated gene editing since it was initially reported. And that's one of the reasons why Mass Eye and Ear is delighted to partner with Editas on the clinical studies of CEP290 associated treatments for CEP290 associated retinal degeneration. And in addition, the discovery work, as you've indicated on therapies for other genetic forms of inherited retinal degeneration. As you can imagine, the opportunity to help develop site preserving or restoring therapy for patients with CEP290 associated retinal degeneration is really exciting and rewarding. So if we could move on to the next slide. I'm going to talk about the trial design and some of the results that we've been observing. As Lisa described, the design of the BRILLIANCE trial is a standard dose escalation study with 3 cohorts of treatment for adults at low, medium and high doses as indicated. As Lisa described, that adult subjects in cohorts 1 and 2 have been treated and the first subject in cohort 3 at the high dose has also been treated. Based on the safety data, which we'll describe the independent Data Safety Monitoring committee has approved enrollment of subject from the first pediatric cohort. All subjects in the study are monitored closely following the surgical treatment to deliver the genetic gene therapy and then followed every 3 months in the first year and then less frequently thereafter for 2 more years to fully assess safety and efficacy. Next slide, please. In order to participate in the study that subject up to meet key inclusion criteria for adults. Obviously, this is to be 18 or older for cohorts 1 and 3; for pediatric subjects need to be between ages 3 and 17, and they all need to have a clear genetic diagnosis of CEP290-associated retinal degeneration and be at least heterozygous for the intron 26 mutation, which is the target of the therapy as we have described. The subjects in cohort 1, the simpler cohort treated with low dose had impaired vision in the light reception or black white discrimination level. The sentinel subjects in cohorts 2 to 5, also need to have more impaired vision in the range of light perception to about 20/800 on the Snellen chart or logMAR of 1.6. The following subjects in cohorts 2 to 5 can have better vision up to 20/50 Snellen equivalent. Subjects will be excluded from the study, if they don't have a clear genetic diagnosis [indiscernible] generation, as you can imagine. If they're able to pass the Visual Navigation challenge course at the most difficult level, and I'll describe that in more detail shortly. If they had recent surgery or infection or inflammation in their eyes. If they have a history of steroid-glaucoma or increased pressure inside their eyes, if they aren't willing to take oral prednisone or if they've had and participated in other studies of other therapeutic modalities such as other gene therapies or oligonucleotide. To move on to the safety data in the next slide -- sorry, baseline characteristics, subjects on the next slide. As you can see, this slide describes the baseline characteristics of the first 6 subjects treated in the trial. Ages range from 9 to 63. The subjects in cohort 1, had more impaired vision as indicated, Sentinel subjects in cohort 2 also had relatively impaired vision -- visual function and acuity has the subjects enrolled later has been better as planned. All the subjects are at least heterozygous for the intron 26 mutation of CEP290, the sentinel subject in cohort 2 is homozygous for this mutation. Now if we can move on to the next slide for the safety data. In order to assess safety in the BRILLIANCE study, we're evaluating -- presence for dose limiting toxicities and adverse events related to both the editing therapy and also the surgery required to deliver it. The graphic here depicts how dose-limiting toxicity is defined, and that is decreased vision of at least 0.6 logMAR units that was sustained or loss of light perception in patients with more poor vision that was sustained or corticosteroid-unresponsive inflammation in response to the therapy, or severe non-ocular adverse events. A summary of the safety data to date is shown on the next slide. As we have described, we're thrilled, there have been no dose-limiting toxicity for serious adverse events that are subjects in the first 2 cohorts. There have been no -- to date no treatment-related cataracts, edema or retinal thinning observed. As indicated in the table below, the majority of adverse events identified have been mild and must have been related to the surgical procedure to do the subretinal injection to deliver the gene editing drug. For example, eye pain was the most common reported and is resolved as typically dose following the surgical procedure. Only mild cases -- mild treatment-related inflammation has been reported and it all been responsible to therapy, no Cas9 specific antibodies have been detected. And all of the adverse events listed on the table have resolved at this point. Based on those data, the IDMC now has supported enrollment of pediatric subjects into mid-dose cohort, which has begun, as Lisa indicated. Moving on to the next slide. I'm now going to focus on the data we've -- sorry, related to efficacy in the study. As Lisa described, this is focused on using 3 primary measurements, of vision that were observed to be the most reliable and consistent in the natural history study of CEP290 [indiscernible] retinal degeneration that's in progress. This includes visual acuity, full field light sensitivity threshold and the visual navigation challenge, and I'm going to describe all 3 of these in a little more detail so you can understand how efficacy is being assessed. For example, visual acuity on the next slide. Subjects who can read, have a standard test using letters on an eye chart, which is a standard early treatment diabetic retinopathy study or ETDRS chart, which provides logMAR acuity for meeting small and smaller size letters. For pediatric subjects who are unable to read letters, it's the same kind of chart using pictograph. And for subjects with more impaired vision, using the Berkeley rudimentary vision test, which measures vision using other kinds of stimuli such as the grading acuities shown here. In the next slide, we can get a brief description of the full field light sensitivity threshold test or FST. This is a measure of how sensitive someone is to light, how good their retina is at detecting the levels of light. In order to perform the test, [indiscernible] as shown on the slide, and light stimuli are presented in order to do this test, there's sound tone emitted by the dome, and then the light is presented. If the subject can detect the light, they press the green button. If they can't, they press the red button. And in this way, we can measure the threshold at which the lowest level of light that is needed for them to perceive it where their sensitivity threshold. We use red, white and blue lights in order to distinguish between rod and cone responses. The navigation course is shown on the next slide. This is a multi-luminance mobility test, which in some ways is similar to the kind of course we've seen and the results from the RPE65 gene therapy studies sponsored by Spark, which like to be approval of the drug, which is now called Luxturna. In this navigation, of course, there are 4 types of courses. The most difficult one is a low contrast course due to the low contrast path, subjects to follow has multiple objects and has performed at 8 different levels of illumination. If the subject can pass this test at the most difficult -- lowest level of illumination, which is 0.3 lux, we're like walking outside on a partially moon light night, they get a score of 21. Many of the subjects in our study can't perform the test at all. So there are additional navigation courses to address different visual function. The high contrast course us is with the same kind of path, there is the low contrast one that has performed with higher contrast paths, as you can see on the slide, also with multiple obstacles and also 8 levels of light and subject can get a score of 16 to 13, depending upon which the level of light they pass the test out. Subjects who are not able to perform that also can you use the high contrast to room exit course, with a simpler test with a straight path leading, for example, to a room exit, a high contrast test -- has high contrast path, a contrast obstacles and has performed at 3 levels of illumination scores of 3 to 5. The easiest course is the backlit room exit course where the path is illuminated as shown and the obstacles are illuminated. This has performed at 2 levels of light giving scores of 1 to 2. So you can imagine a subject -- and for example the Sentinel subject in any of the cohorts might be able only to do the backlit room exit course but what we're hoping to observe is if their vision improves, they might be able to perform, of course, it's more difficult or perform the same course at a lower level of illumination as we will describe. Next slide please. So to get to the subject data, this is the data for the central subject in cohort One. For all the 5 data sites related for subjects, the data is presented so that it present tangent baseline showing change in baseline and an improvement is shown by downward deflection of the curve over time. So it's a little counterintuitive. For example, this subject appeared to have an improvement, right, a downward reflection of the vision for their treated eye at 6 months. Unfortunately, due to the COVID pandemic, we haven't been able to return to the treatment center for further evaluation, and we're really looking forward to seeing if this improvement is sustained at further follow-ups. The subject did not have consistent improvement in their sensitivity for light or their ability to do the navigation course. Next slide, please. With the second subject in Cohort 1, this subject also had poor vision starting at light perception. It appeared they might have had improvement again a downward reflection in their acuity of 3 months, but this was not sustained at follow up visits. They appear to have improvement in their ability to do the navigation course, again, with a downward deflection of the curve, although this was [ done ] with both eyes or uncertain because of treatment effect. I will say this subject very clearly described subjectively improvements in their vision. For example, they now describe that they can see where food is on their plate, which they couldn't do before, and they're starting to be able to perceive colors. So we're looking forward to further follow-up with this subject. For subject 1 in Cohort 2, we're very excited to share these data. The subject started with impaired vision in the confiners and motions range and at 1.5 months following treatment demonstrated a significant improvement in acuity of 0.6 logMAR units, as shown with the downward deflection of the acuity graph of BCVA. They've also demonstrated consistent increased sensitivity to different levels of light as shown in the FST graph and improved performance on the visual navigation challenge course and the treated eye showing improvement again in the downward direction. And we're excited about these data, if they show sustained improvement and why don't we show you what the change in individual navigation course look like on the next slide. So as you can see on the baseline video here, this is a subject performing high contrast course at the highest level of like 500 lux, which is like being in a very bright-lit room. And as you're about to see here, they fail in this test because they step outside the course right there. In contrast, in the month 6, is that they're performing the same course, but at a much lower level of light, like walking in a dim corridor, and they're able to follow the course effectively and avoid the obstacles and they don't step out of the pathway. So this is a clear improvement and the subject describes these improvements in their vision. This way they can see lines, better, they can find objects we drop on the floor and they kind of navigate better at work, or just by detecting doorways more usually. So we're very excited about these results. Let's go on to the next subject, please. Next slide. Subject 2 in cohort 2 started out with a vision in about the 2,500 range. They have experienced consistent improvement in their ability to detect lower levels of light as shown in the middle graph or FST. This would be consistent with seeing better when it's dimmer or darker. We've also had improvement in -- a little improvement in their navigation performance. Although today, no measurable change in visual acuity, we're looking forward to continued follow-up and help with the changes in FST results appreciate additional improvements in vision. Subject 3 on the next slide, had the best vision so far, enrolled in the study at about 20/80 to start with. As you can see, they have not shown consistent improvement in any of these three measurements at a three-month time point, although the recent follow-up is that Subject 3 describe that they feel -- objectively, the vision in their treated eye is now clearer than it used to be. So again, we're looking forward to further follow-up with this and other subjects going forward. Next slide, please. So in summary, we're very excited that early analyses in the mid-dose cohort show signs of efficacy. We think this is a very important result. As Lisa described, it's our way of telling if editing of the CEP290 gene is occurring in these subjects' retinas in their light-sensitive cells, which is then restoring light-sensitive cell function, which underlies their improvements in the metrics we described. We're thrilled to look forward to continuing this study and really excited about the possibility of developing an effective treatment alternative for patients with CEP290-associated retinal degeneration. And really, I think, as Lisa described, these first-in-human data demonstrate the potential of biological effects of gene editing, which to me supports further development of genetic editing therapies for other forms of inherited retinal degeneration and potentially other inherited diseases going forward as well. Thank you very much. Lisa, back to you.

Well, thank you, Eric, and thank you for explaining -- helping to explain the trial and the clinical findings, and I really appreciate some of the insights of the conversations that you had with the patients regarding their subjective feelings that they have had some benefit from the treatment. Well, we believe here at Editas that the findings discussed today do provide initial proof-of-concept for our ocular portfolio as well as our broader in vivo gene editing platform. And these results reinforce our confidence in advancing our other ocular programs, such as those for Usher syndrome and Autosomal Dominant Retinitis Pigmentosa, which impact even larger patient populations than the CEP290-related diseases. We're excited to continue the trial and enroll additional patients, and I look forward to sharing additional progress to you on this program next year. And with that, I'll hand it back to Jim.

Thank you, Lisa, and thank you all for joining us today. As Lisa mentioned, we believe these early data validate our in vivo's platform proof of concept. As we think about our long-term strategy, today's findings help strengthen our foundational technology and provide us with the clinical evidence to progress our pipeline. There are hundreds of conditions that could potentially be addressed with this technology, and we are actively exploring a number of them in our preclinical and discovery work. Again, we want to acknowledge all current and future patients of the study. We understand the commitment this means for you and your families, and we owe you a great deal of gratitude. And thank you once again to Dr. Eric Pierce and the rest of the principal investigators for partnering with Editas. And for everyone joining us with today's -- on today's webinar, we thank you all for your interest and support. And with that, we're happy to answer questions with the time we have remaining.

[Operator Instructions] The first question comes from Joon Lee.

Can you guys hear me? Great. So with the data that you have to date, what do you envision could be an approvable endpoint for a pivotal trial? Is that still BCVA or something more innovative? And the second part of the question is, given the better efficacy in the homozygous that you're getting at the interim data, do you think getting it approved first in homozygous only and then potentially expanding that into heterozygous could be a strategy that you may consider? And the last part of the question is, if it is BCVA that you ultimately need to pursue for approval, what do you think is the hurdle -- a clinically meaningful hurdle for that?

All right. Joon, that's an awful lot of questions and one hell of swoop. I'm going to start with the first one and how do I think of approvable endpoints. At the moment, the clinical data is at least suggesting -- and again, it's a very small number of patients, and we haven't even established the dose that we will be moving forward. But -- so the first thing I want to emphasize is that the nonclinical data does support that we should see improvement with -- with moving up to the next dose cohort. That data would suggest that we would be achieving editing efficiency somewhere around 50%, which we -- as long as we don't consider -- as long as we continue to not see any safety concerns, that's really our next obvious step for evaluating effectiveness. So far, the data, at least in a very small number of patients, does suggest that we can see meaningful changes in BCVA or in functional navigation. We know those are both approvable endpoints. We also know the potential of being able to use FST in combination with that to support meaningful changes in the patient. So it's a little premature for me to identify specific endpoints. But if Eric wants to jump into that, I certainly welcome him because the second part of that question, I think, is where we actually see the meaningful benefits.

Lisa, I think you're correct with your assessment in terms of potential approval endpoints. And to address the question about what's a significant level of improvement, 0.3 logMAR improvement is considered clinically significant. So we're definitely achieving that range.

And I think that's only really on one patient so far. As we move forward, we're hopeful that we'll be able to see a range of improvements across multiple different patients as they move in. The second one is resulting to the homozygous. We've only had one patient so far enrolled to homozygous, okay? Again, it's a very small number of patients. I think at this point in time, I'm not writing off homozygous versus heterozygous. The way this works is this is an autosomal recessive disorder. And as a consequence, we only need to repair one allele in the cell. So it really shouldn't make a difference if the patient is homozygous or heterozygous. So we've only had one homozygous patient in the study. She's actually one of the patients with the worst seeing eyes. We have the opportunity moving forward to evaluate a wider range of patients, and that will be considered as part of the development program.

We will now take a question from Philip Nadeau.

Two form us, so first on the efficacy. I guess we were a bit surprised that the older patient had benefit while the younger ones, at least thus far, didn't seem like they did. So curious to hear your potential explanations for why that is the case. And does it at all make you question whether the 20/50 Snellen criteria that you've instituted for patients beyond the first patient in each cohort is reasonable? It does seem like maybe efficacy is inversely correlated to the initial BCVA that the patients have. And then second question is on inflammation. Can you give a little bit more information on the duration of the inflammation and whether you think it's through the Capsid or the procedure itself?

Eric, I'm happy to let you jump in on that because you're the one who had the hand-on experience on both of those.

Sure. So with regard to inflammation, to take the second part of your question to start with, most of the inflammation that we've observed has been pretty mild and quite steroid-responsive. It's certainly within the range of what we have expected following an intraocular surgical procedure. In terms of the relationship between acuity or age and potential response, I just don't think we have enough patients yet to know for sure. There is a challenge with treating subjects of better vision with subretinal injections and that they have to recover from surgery before we can observe potential improvements. And I think in the two subjects with better acuity, who are the 34 subjects in cohort 2, we're really just getting to the point in postoperative care and follow-up that we can detail if they have a response to the therapy or not. So I just -- I think we need more data to know whether -- which subjects are going to be potential responders and which might be best suited for treatment with this modality.

So Eric, I have to admit, I'm quite impressed that the worsening eye in that cohort has so far to date shown the best benefit. And I think my other question is in patients who have at least some better visual acuity, are we looking for more subtle changes related to improvement in vision and how we would actually capture those?

So I think the improvement observed in the first subject, I think, cohort 2 reflects this issue of structure function depreciation that's come up as you described in your comments on the webinar. I think the improvement that patients experienced reflects their intact structure observable on ocular imaging studies and correction of the genetic defect in the observable cells, which then restores their structuring function. So to me, that's very optimistic finding. It implies that for any subject with intact retinal structure, meaning intact outer retinal cells, photoreceptor cells observable by imaging techniques, that there's the potential for improvement. And I think we're just going to have to have more experience with subjects across the different severity spectrum of disease to know how much improvement could be expected, for example, in someone starting with better vision. I don't know whether they're going to have improvement in acuity or whether their improvement might be more subtle as you suggest, perhaps with FST responses or navigating the visual navigation challenge at lower levels of illumination. But I think the early findings is just all of that's possible, and we're just going to have to see what we've learned from further study.

So that validates us continuing to follow them with both FST and visual navigation means as we move forward prospectively. And I think the other part of the question I want to come back to is there's a lot of concern about inflammation in the treatment and whether or not that's dose-limiting or might potentially is clinically relevant. Are there any concerns that you've had in your hands related to inflammation? And what are you seeing? Is it beyond just what you normally would expect with this type of surgical procedure?

We're really pleased with the lack of information that we're observing in the treated subjects, for example, as was mentioned, the first subject in the adult high-dose cohort has been enrolled. They're early in their follow up. But even at the higher dose, we have not observed significant inflammation in the first six weeks post-treatment. So I think it's a very promising sign.

I stole the questions for a bit, but I'll hand it back.

We will now take a question from Liisa Bayko.

Thanks for asking the question about the patients with better eyesight. I was a little curious about that Lisa. So that was my first question, which we can check the box on. My second question is, so in some patients, we've seen a change in BCVA and some we've seen FST and some maze. Like would you expect some sort of like correlation of these things or to see improvement on multiple metrics? Like why do you seem to see some sort of like, within these different parameters, changes on one but not the other and it kind of varies from patient to patient? I was curious about that.

Well, I think the first thing I'll interject is that the maze is actually sort of measuring two different things. We are evaluating the ability of patients to function in increasingly complex mazes and obstacles at different levels of light. So we know and then most of these patients, they have significant impairment of being able to see in low lights, they do much better. Those who have the better vision, do much better at higher light. So every one of these configurations of the maze -- some basically follows. Can you do the maze at high light? Can you do it at dim lights? The other one is also the complexity of the path that the patients have to follow, which would actually require them to be able to see those obstacles. So I think we're measuring two different things in our current version of the maze, and we are seeing changes in both of those -- both the ability to maneuver much more complex mazes as well at different levels of light.

Okay. And then as it pertains to BCVA, I know there's different ways to measure it, right? You discussed on one of your earlier slides, there was the kind of standard eye chart in a way and then there's -- the one -- the chart with the lines. Were all the patients using the same chart? Or if I'm understanding correctly, patient one was using the chart with the lines and maybe the others weren't? Or -- and I guess, is the threshold the same of minus 0.3 logMAR as being a clinical and meaningful change across all of those different methods?

Sure. So the clinical protocol includes the use of the Berkeley Rudimentary vision test, which is the one you're referring to with the grading acuities, the lines that were faced in different directions for subjects who can't do the ETDRS chart. The ETDRS chart is a well-used and understood tool in vision science. We know that a threshold, for example, of a change of 0.2 logMAR units for people who can read those letters is reliable. It's not noise. And we know the FDA requires a three-line change, it's an approvable endpoint. There's less experience with the Berkeley Rudimentary vision test, which is designed to detect or discriminate different levels of low vision. So that, I think, we would have to [ word ] about what would be an approvable endpoint from that test. But it works very well. Distinguishing between someone who, for example, might be able to see hand motions, that's the clinical description we would give if we were just examining them without that tool. But now we can break it down and see, well, what spies grading did they detect and find a logMAR start, too. So it gives us a chance to quantify vision in at the low end of the spectrum, which I think is very useful.

So Eric, I think one of the questions that I think will come up is how meaningful is 0.3. And I think the other one is understanding that ProQR and sepofarsen has actually reported 0.7 in, quite frankly, a different patient population we're exploring here. I think do we need to read that threshold? Or is 0.3 and better actually a really good achievement?

0.3 and better is a really good achievement. That's an approval endpoint. That's a good test. And that's -- you can validate that by hearing the patients reports, with the patient report outcomes are consistent with improved function and quality of life and have those kind of improvements on the ETDRS chart.

We will now take a question from Luca Issi.

Oh great. Can you guys hear me, okay?

Yes, sir.

Terrific. I have two questions, but they're all pretty quick. So the first one is a neutralizing antibody. I know you mentioned no neutralizing antibody to Cas9. I'm wondering if you've seen any neutralizing antibody to the actual vector, again just asking that in the context of potential redosing. Two, clarifying questions on the DLT. How long was the DLT assessment period? Was it just four weeks post-surgery? Or was it throughout the follow-up of the patients? And then three, maybe on sickle cell disease. Lisa, I think it looks from the 8-K that the dosing of the first patients was postponed from the second half of 2021 to the first half of 2022. So, wondering if you can elaborate on that.

Okay. So let's just dispense at the last one really quickly. We actually are moving forward very quickly with the clinical trial in terms of patient enrollment, patient selection and screening. We actually have a number of patients that are currently undergoing electrophoresis processes and having their cells. I think even today, we have [indiscernible] cells being delivered to our site. At the moment, it's -- each one of these patients is requiring more than one for [ resis ] event and then the cells are being edited, then we're getting ourselves into the holiday period. So we're just kind of looking at the crunch of timing at the moment as related to the event that has to take place in order to get the patients for [ resis ] as well as the timing of the holidays and being able to dose the first patient. So we're -- it's -- we would have liked to have gotten in at the end of the day, but I wasn't going to have a patient enter the hospital for probably a six-week hospitalization on Christmas Eve. As for the other two questions, I guess, real quickly, neutralizing antibody, not all of the patients have had antibody responses and the titers are very low. They may not even be clinically relevant. So at this point in time, there's nothing to suggest that we cannot dose the second eye. Mark, you're welcome to jump in if you want to add any more to that one?

No, I would agree. The levels are low. And actually, their preclinical data is suggesting that those neutralizing antibodies are not going to interfere with dosing the second eye. And in fact, redosing of the same eye could be possible, too, although that would -- we're predicting would not be necessary based on the mechanism of action.

And I guess the last question is related to the DLT. Quite frankly, as part of the safety trial, DLT can happen at any point of the clinical trial. But the primary evaluation period for safety related to the procedure and the injection is actually in the first 28 days.

We will now hear from Joel Beatty.

The first one is how confident are you that the currently planned high dose of 3x10^12 will be the highest dose that you'll need to test in this trial? And then the second question is that some of the patients had trends in improvement on certain measures in the contralateral eye in the data presented today. Any way that, that could be due to drug? Or is that just kind of some random noise?

I think I was writing down one of the questions, but I didn't get the second one. So the transient one is Legrand noise, I'll let Eric answer that one.

Sure. So subjects with CEP290-associated retinal degeneration have nystagmus, which means their eyes wobble back and forth, often due to poor vision in childhood. And what we've observed is that improvement in vision in one eye can reduce the degree of nystagmus, which kind of, in some cases, confer improvements in vision in the second eye. So I think there could be a little noise in some of the metrics, we're still collecting data, as we've been saying since early in the study. But some improvement in function with the non-treated eye would not surprise me, if the nystagmus is reduced, falling improvement in vision in the treated eye.

And fixing of days is one of the clinical endpoints that we're collecting, so we'll have an opportunity to be able to evaluate that moving forward. Yes, I think I missed the first part of the question, though.

The first part of the question was about the potential to dose that might be used in the study was the current high-dose -- definitively the highest dose that will be used.

No, thank you, Eric. So at the moment, we're pretty much extracting latent dosing based upon the nonclinical studies that were collected. It appears that if we really want to try to get to that threshold of at least 40%, 50% or higher editing, that higher dose is kind of the sweet spot, whether that's the final dose will be largely predicated on safety and what we see from clinical findings.

We will now take a question from Gena Wang.

So, I have two sets of questions. So the first one...

Hey, Gena, we can't hear you very clearly.

Okay. Can you hear me now?

Very softly.

Can you hear me now?

Yes.

Okay. Perfect. Sorry about technical difficulties. So yes, so I have two sets of questions. The first one is regarding the measurement. I think on more the BCVA logMAR, I think as some already touched upon, but wanted to ask a little bit specifically. So when we look at the cohort 1 Subject 2, the patient drop -- if we're only focusing on the study eye, so the patient dropped by 0.9, which Dr. Pierce you said 0.3 will be very meaningful. But then the next visit come back all the way to the baseline, and then we saw also similar cohort 2 Subject 2 dropped by 0.2 roughly and then come back to baseline. So just wondering how much measurement error in general for logMAR? And how much is the intrapatient variability and that is normally will be seen? So that's the first question. And then similar question for FST and the navigation, we saw also some kind of bouncing back there. And then my second question is related to the inflammation. I know we discussed a little bit, but do wanted to ask again. I think all these patients, if I understand correctly, they were already on oral prednisone for six weeks. So at what point was the onset of the inflammation? And how long does it last? And how was that resolved? And regarding those patients have inflammation, what are the status of AAV antibody?

So I think starting with the inflammation one. First of all, we're not seeing a dose-related response in inflammation. Most of the events of inflammation actually were reported in only one patient, and it was the first patient in the study. That's also the patient where we did have some truncated efficacy follow-up and data on her because of the problems related to COVID from all patients in a relatively conservative fashion where prophylactic prednisone at the beginning of treatment, which they received for about a month and then it taper. What I will share with you is that there was no need for additional therapy in most of those patients. The only one who received additional treatment, again, was that very first patient in the very first cohort. So, that dose effect has not been seen. It is not dose limiting, and it does not persist beyond the period of time that we would expect it based upon both the surgical procedure as well as also -- have not required any patients to require further duration of treatment as part of the study. Eric, would you agree to that?

Yes, absolutely.

I guess the other one is it still sort of that question about the noise in the data. I will throw in at least that our unpublished data so far from a non -- from a natural history study. What we chose to share this time is the data that seems to be the most reproducible on follow-up on repeated measurements. At least in our hands, to date, the BCVA is relatively stable as well as the oral [ PNC ] maze. That still is yet to be further evaluated. But I guess in terms of just some of the normal clinical variation that takes place, I'd ask Eric to just sort of let us know what that tends to be in the clinic.

So as I mentioned, there's a lot of good data over many, many years regarding the reliability and retest -- test/retest reliability or accuracy of the ETDRS chart. There's less information available about the reproducibility of measurements taken with the Berkeley Rudimentary vision test. As Lisa said in the natural history study, most patients are pretty steady in the measurements we got from the Berkeley Rudimentary vision test experience. But we do see, from time to time, changes in patients acuity as measured with the BRVT, even not associated with treatment just within the natural history study. So the Subject 2 in cohort 1 had, as you said, a 0.9 change in logMAR acuity as measured with the Berkeley Rudimentary vision test, but the amount -- that was not sustained at subsequent visits. I think we have described that as some noise. Patients with inherited retinal diseases will tell you that they have good vision days and bad vision days. And perhaps that was a good vision day, and we'd love to see that recur, but I think we all have to be watching for consistent changes that are reproducible over time in order to ascribe them to a treatment effect.

I think my usual example has always been what your eyesight is like at the beginning of a long Zoom day and what it is at the end of a long Zoom day. But I think, again, this has always been one of the things that I've reiterated and emphasized over and over again is we really want to see reproducible responses and we begin to see that, not only are we starting to see reproducible responses in at least one or two patients, but we're also beginning to see consistent changes in more than one patient. For me, that's a very valid signal that we're starting to see effective editing.

Thank you. As we are coming up to an hour, we have only time for one more question. The next question comes from Steve Seedhouse. Please have in mind that we only have two minutes remaining.

I'll be quick then. Can you comment if you had any positive anatomic improvement by OCT in any patients?

Eric is welcome to jump in, but I think that was actually answered beautifully at the seminar earlier today by Mark Pennesi. One of the challenges with imaging these patients is that nystagmus and the ability to get very good imaging on the back of the eye. It's a very important endpoint for us for safety because we're not seeing degeneration or changes in the back of the retina that would suggest that we're actually inheriting the anatomy by treatment. But the ability to be able to demonstrate in a sensitive manner restoration of the outer nuclear layer is still something I think we're evaluating, but it's difficult to obtain at this time.

Thank you. That was the last question. And this now concludes today's session. Thank you for joining the webinar, and we hope you have a great day. You may now disconnect.