Krystal Biotech, Inc. (KRYS) Earnings Call Transcript & Summary

Hello, everyone. Arslan Arif here with Endpoints News. And thanks for joining us today for Let's talk: Moving cell and gene therapy clinical development for 2023. We're sponsored by Precision ADVANCE and I'm excited to introduce today's expert panel. Joining us today, we have Dawn Buchanan, the VP of Clinical Operations at AffyImmune; Kinnari Patel, the President and COO of Rocket Pharmaceuticals. And also joining us is Ramona Repaczki-Jones, the Executive Director of Treatment Center Operations at Iovance Biotherapeutics; as well as Suma Krishnan, the President of Research and Development at Krystal Biotech. And moderating today's discussion is Teresa Pokladowski, the Regional VP of Clinical Business Solutions, North America at Precision for Medicine. If you have any questions during today's webinar, our panels have reserved some time for you for questions at the end. So just hit the Q&A button at the bottom of your screen as soon as you think of it. This webinar will be available on demand to rewatch or to share with your colleagues. And now I'm going to pass it up to Teresa to get it started. Teresa?

Thank you. Hi, everyone. My name is Teresa Pokladowski. I am the Regional VP Clinical Business Solutions here at Precision for Medicine part of Precision Medicine Group and part of the Precision ADVANCE Collective. It's my absolute pleasure to moderate today's panel discussion. To kick us off, the cell and gene therapy field is important to all of us here at Precision. Precision's interdisciplinary teams, including Precision for Medicine, Project Pharma and Precision Value and Health have been advancing clinical therapy development, manufacturing and commercialization for the cell and gene therapy sector. Having been a partner to over 100 advanced therapy organizations, we understand the complexities and hurdles to bring cell and gene therapies to market. Clinical trials are foundational to developing innovative life-saving treatments and cures for our patients. But for developers, the considerations for clinical trial success are vast and complex. During today's panel, we will be hearing from various experts on their respective complexities, their companies as well as their expert perspective on the current state and the future of clinical development in this space. Now before I get into introductions, I want to say how amazing it's been to prep with these ladies, and to be hosting and moderating an all-women panel discussion to kick off women's history month and the upcoming International Women's Day next week. In addition, it also happens to be employee appreciation week, of which none of this would be possible without the women here and their colleagues working to bring these innovative therapies to patients. That said, I'll briefly reintroduce these innovators and inspirators. Joining us today, Kinnari Patel, President and COO, I hope I pronounced that correct, but I'll get it. Suma Krishnan Founder and President of Krystal Biotech; Dawn Buchanan, VP, excuse me, Clinical Operations AffyImmune and Ramona Repaczki-Jones, Executive Director, Commercial Treatment Center Operations Cell Therapy at Iovance. Before we get started, it is important to remember that these views and opinions expressed during today's webinar are those of the panelists and do not necessarily reflect the official policy or position of their respective companies. With that, let's get started. I'd love to have the panelists describe their roles, their companies and the vision for driving cell and gene therapy clinical development forward in 2023. Kinnari, Rocket Pharma is focused on finding cures for genetic therapies by correcting the root cause of complex and rare life-threatening childhood disorders. The FDA recently granted regenerative medicine advanced therapy, RMAT designation to RP-A501, the company's -- excuse me, investigational AAV-based gene therapy for Danon disease. Can you tell us what that means for Rocket Pharma?

Certainly. And maybe I'll start off by just talking a little bit about Rocket Pharmaceuticals. So we have 6 programs in the clinic focused on heme indications as well as cardiovascular indication. And what's really exciting is 2 of our programs this year are heading towards BLA filings, and those are fanconi anemia and leukocyte adhesion deficiency. They both have had the pleasure of having designations with the health authority like the RMAT, PRIME, Fast Track, Orphan et cetera. So the Danon program, we are seeing the RMAT designation is a further validation that the promising data from the Phase I Danon disease is viewed to be efficacious and promising, not just to us and the patients and the investigators, but also to health authority. And what we think this means is we're going to have more collaborative discussions with FDA. So more frequent dialogue, more dialogue with the senior management at the agency and hopefully in an efficient path forward toward a Phase II pivotal study, which we anticipate to start in the second quarter to be a single-arm biomarker-driven strategy of a clinical design study that's going to be both conducted in the U.S. and Europe. And this just further derisk our ability to do that. So we're very excited to work with the agency and advance these amazing pipeline programs to patients with rare devastating diseases around the world.

Great. Thank you for that. And I know we'll get more into some thoughts around the single-arm versus control later on in this discussion. Suma, over to you. Krystal Biotech is focused on developing a topical gene therapy requiring multiple applications to treat serious rare diseases caused by the absence of, or a mutation in, a single gene. Can you tell us more about your proprietary platform.

Thanks, Teresa. Again, as just Kinnari mentioned, I'll give you a brief introduction about Krystal. Krystal was founded in 2016. I think the main reason Krystal was founded was to find a solution for a very ultra-rare disease called epidermolysis bullosa. Again, it is a gene defect and these patients are born with a missing, or a mutated gene, in collagen VII. Again, gene therapy was novel -- it's relatively novel, as you know. I mean it's basically gene therapy was more for one-and-done therapies with LUXTURNA with the RPE65 gene correction or for Zolgensma for SMN. But in case of epidermolysis bullosa, a one-and-done therapy was not feasible because again, the organ, the skin is because it turns over. So for this very reason, I mean we have to think out of the box to come up with a solution for these patients that would not involve grafting or that would not involve painful surgeries to correct the underlying issue. So this is where topical gene therapy came into being. And for us, it was very important that we selected a vector of virus that was redosable. That means it was not immune rejecting after it was applied for the very first time. So it was very important. So we embarked on such a vector that we engineered or designed it to make it immune invasive and we were fortunate enough to bring in -- again if it is novel to think about applying a topical gene onto an open wound. And we're very happy and proud that the concept and the idea we were able to take it, from concept to Phase I all the way very close to a BLA approval, fingers crossed shortly. And again, it's interesting, even though we found that a virus is very, I mean, our vector or our technology is applicable to skin along the way, as we said, what else can be fixed with this with our powerful platform and technology. And obviously, now we are going beyond skin into lung, we have a CFTR program and other lung programs, which we're very excited about.

That's great. Thanks, Suma. And I know that we're going to talk about some of the lessons learned later on with your experience running clinical studies on this. Dawn, over to you. Can you tell us a little bit more about AffyImmune and share any insights on how AffyImmune's proprietary Tune & Track technology is being applied to multiple target antigens for the treatment of various solid tumors.

Absolutely. Thanks, Teresa. So AffyImmune is developing autologous CAR T in solid tumors. We do have this Tune and Track technology. And I will actually walk it back a little bit and to talk a little bit about the history of autologous CAR T. Currently, I believe they're 6 marketed products, and as we all know, they're in heme malignancies. And the development of CAR T for these heme malignancies have been with a high affinity for the target. So it's kind of like a dog on a bone. Those T cells go after that target with vim and vigor, shall we say. And in solid tumor, that is a little different because our targets are also a healthy tissue that we don't necessarily want to have the T cells impacting. So we have affinity-tuned our CAR construct. In addition, we have this tracking technology, which is kind of interesting and very much -- I kind of think of like Osmosis Jones or other cartoons about like how we know the cells are going where they're going. And using dotatate scans and some additional engineering on our T cells, we're able to image with these dotatate scans where those engineered CAR T cells are in the body. So we know that they are getting to the tumor. The goal as well is also to help us with on-target off-tumor toxicity, potentially mitigating that or at least knowing that maybe the cells are going where they're not supposed to go and helping our PIs manage the toxicity for their patients. Our lead compound AIC100 is starting in advanced thyroid cancers, but we are working on indication expansion and preclinical to broaden that scope in the coming year or so as well.

Fantastic. Thanks, Dawn. Ramona, last but not least, can you provide some insights into how Iovance Biotherapeutics is using their T cell-based immunotherapy technology platforms to recognize, attack and kill cancer cells.

Thank you, Teresa. Thank everyone for joining. It's a pleasure being here. So tumor infiltrating lymphocyte TIL therapies are based -- is our T cell based immunotherapy platform. We are currently investigating TIL therapy in clinical trials of multiple advanced solid tumors, including melanoma, non-small cell lung cancer and cervical cancer. Our initial strategy is to deliver TIL as a single-agent therapy for patients with late-stage solid tumor cancers. It's an autologous cell therapy, which brings the treatment center and the manufacturer in a close collaboration. My team's role at Iovance is to prepare with treatment centers for TIL as standard of care instead of clinical trials, which means the focus is on scalability, leveraging the treatment centers, experience and capabilities to treat patients with TIL without the support of a protocol, which is fun, and aligning to the BLA.

Great. Thank you. So jumping right into it. I know in the prep discussion, we talked a lot about the regulatory components and the scrutiny around that and being inspection ready and the time lines around that. Peter Marks recently commented on the increase in clinical holds from CBER. He noted multiple causes, including an increase in clinical trial volume, less experience sponsors in the cell and gene therapy space amongst other factors. It'd be great to hear from all of you on some of the lessons that you've learned during your respective IND submissions and regulatory path. Dawn, do you mind if we start with you?

Absolutely. Happy to kick this one off. I think this will be a meaty discussion. I know that -- and this is something -- any of my former Celgene and junior colleagues on the phone, we're building the plan as we're applying it in cell and gene therapy. And there's a desire to look at the path of those who went before us to inform us of our own strategies and how we should be developing these compounds. And I think that there's aspects of that we can follow, but we should not be relying solely on looking in that rearview mirror to help inform us. And things like for example, Kinnari, the RMAT, that's a new pathway with the agency, not as rigorous as breakthrough designation as we now, and those are things that were -- for AffyImmune, we're building that into our strategy, how can we get more facetime, if you will, with the agency to help us with hearing from them what they're seeing and how can we build our path forward as quickly as possible. But at the same time, we have to be working with our CMC consultants. We all know that a lot of times, CMC unfortunately, can become that critical path for our filings. And when we hit the accelerator, we start to see good responses. We engage the agency, we have to make sure that our CMC colleagues are there with us and have that strategic line of sight to the horizon, would we have the accelerated that, they're ready and not having whiplash through the process, I guess, is a good way to describe it.

Yes, that's great. And I think it kind of dovetails into a conversation that we were having as a group around. CMC and the clinical development and really the trifecta being FDA manufacturing and treatment centers. And I know Ramona, we got into a pretty healthy discussion around that. Any thoughts on that trifecta and why that synergy is so important.

Yes. I like as you call it the trifecta. That's definitely a new term, I think you should coin it, right? To be honest when I joined the industry from the academic side, I remember being in a meeting. We are at treatment centers to identify that third-party vendors for procuring the raw material, right? It's really not a vendor relationship. And I think the mentality is shifting to understanding the need for a close partnership between the manufacturer and the treatment center. Because ultimately, both parties are impacting the patient outcome and are overseen by the FDA. So the trifecta that you mentioned, I'd like to call it the circle trust among the manufacturer, the treatment setting in the FDA. And as Dawn mentioned earlier, until you get to the FDA, you really have to have that solid CMC to be able to cross, right, into the FDA part. The partnership between the treatment centers and the manufacturer starts from the time the clinical trials begin. I think it's important to note that the transition from clinical trials to commercial product, the challenges that we encounter right with scalability, logistics, gaps and capabilities are encountered by both manufacturer and the treatment center. So recognizing these early on, starting to work on scaling the workflows, the capabilities, education to build on the partnership that got started in a clinical trial, it's critical when planning to advance clinical therapy development, manufacturing and commercialization for the cell and gene therapy sector.

Yes, that's a great -- that's a great point. And I love that. We'll make a note to coin the trifecta coming out of this. Suma, anything that you might want to add on this, have you really lived and breathed that with your current therapy?

Sure. I mean, Ramona mentioned about building the relationship with the vendor. It's much harder than said. So if people are fortunate enough, like we realized that very early in our Phase I study, we did have an external manufacturing. We very quickly realized that if we had to rely on a vendor, we couldn't get where we are today. So we focused all our energy considering CMC was the key for gene and cell therapy, we started bringing that in-house. So we build expertise in-house manufacturing, it's not just manufacturing, hand-in-hand goes assay development, potent assay development, releasing the materials. So we built analytical development group, our QC group -- our quality group. These are very, very critical for a successful filing, not only filing but going through the inspection and getting a drug approved. And I think the more controllable if you have it in-house as we saw the better the chances of success. So again, it's very important for us. I mean, as Kinnari said we have the RMAT status. So I can tell you a little bit because we've been through it for 5 years, it helps. But again, the agency is very, very overwhelmed. They are very busy. They have a lot of INDs. I think they need to help you, but it gets difficult. So you have to be very well organized. You cannot expect them to be consultants. You can't say, I'm going to go ask a question and they're going to give you an answer. A, they don't understand your process, they're learning themselves; B, they don't have the answers to all your questions. So I think you have to do the work and then present it to them and get their buy-in. So it's a little bit of -- even if you have the RMAT status, you are not going to -- it's a lot of effort is put on your end. So that's what we learned. And the other thing I would also advise is as we think about making batches for Phase III material, you have to also start thinking commercial very early. If you're thinking of accelerated approval, priority review then you're looking at an 8-month review cycle. And then you could get stuck in the very end because you've not thought about a commercial plan, how are you going to distribute the material? How are you going to package it? Do you have shipping studies, validation studies. So those are being sometimes we have learned the hardway, and I think there's a lot of thought and discussions you push out. I think, oh, you don't have to think about packaging. You don't think about cold-chain control. But again, being here at the very end, I mean, some of these things, we were by -- it's like rush, rush, rush. We have to get those done. But again, now going through the process and understanding, I think we have learned so much that hopefully for our next product the next cycle, you can -- I think we'll be better prepared. Again I think consultants are good, but even they don't think about it from beginning to end. So the onus and burden lies on the company, and I think it's very important to the internal team that you build with experience to make sure that you build for success.

And I think something Dawn said earlier about painting the plane will it's flying really comes in. It's -- you're constantly having to think about that next move and the impact that it's going to have and also advocating for yourself, for your company along the way. Kinnari, any kind of insight having had the recent RMAT designation.

I love what our panelists have said. CMC and clinical integration is so critical. I think when we're looking at cell and gene therapy, drug development and clinical trials, optimizing operational aspects as well as the quality of the product and finalizing what your final product commercially will look like it's early as possible in development. It's really, really critical. So I absolutely echo Suma's sentiment there. And I think for me, what I've learned is for Rocket, our Phase II products have all been RMAT designated, PRIME designated, et cetera, are single-arm studies, right? What happened is we do a Phase I study for AAV, it's dose escalation. So we're focusing on risk management safety with the promise of an efficacy, right? And Phase II tends to be the pivotal study that you are leading to go to BLA and MAA. So I think when you think about drug development efficiencies and effectiveness, consolidating what you would normally see in 12 to 15 years in from a Phase I to BLA into 5, 6 years because of the urgency of the unmet medical need, the severe life-threatening disease, many of us are treating. I think it becomes that much of a challenge. So knowing your product, knowing your knowledge, but also working with patients, scientists around the world that have the expertise in gene therapy platform manufacturing, but also the health authorities go transparently sharing your data and why you're recommending, what you're recommending, I think it really becomes a key to success. But I think for Rocket, our key to success is, we have a team that really whether we were a team of 20 or 250 now, everyone wants to know the data and knows the data and integrate everything as if this was their own child, what would they do, what kind of quality of product do they want to give them and how quickly can this efficiently and effectively get to the patients and make this experience as positive as possible for the patient, right? So I think that's kind of been our focus on there, making some of the challenges be overcome because of that urgency and the care that personalized care that the team members have.

Yes. I think it's so important what you said, Kinnari. It's the idea of imagine if it was a loved one that was the patient on the other side of that treatment. And as an organization like Precision for Medicine, we're oftentimes thinking about that, if this was our study, if it was our loved ones going into it, what would we want. And I think that comes to the next question for the panel and maybe Kinnari, we can start with you is thinking about, how do we think about the changes in the clinical study design for these types of therapies going forward? I know you mentioned about the single-arm versus controlled arm. But moving that needle forward in a way as the innovations move forward, driving that process forward along with it.

Yes. And that's a great question because I've done about nearly 20 years of drug development. And I would say gold-standard is still randomized controlled arm study. However, the most therapies in cell and gene are being developed for, it's not ethical to have a placebo-controlled arm, right? So considering the ethics of it, considering the devastation, considering the unmet medical need where most of these therapies or diseases do not have therapies available if -- or any symptomatic treatment or anything available. So in that case, how do you have a single-arm study but still be able to stand behind the benefit risk data that you get at the end of the day. I think what we've learned as the best practice for us is where possible, we try to centralize our testing and analytics and validate as many assays potency and others as early as possible, right? We try to decrease any product changes. So that's one less variable, but you have to question if the data is not what you're expecting. And the third thing that we've done is we try to understand the disease from the patient's perspective and the treating physicians perspective even before designing the IND protocol. And what that means is you have to understand the disease, and in rare diseases, one of the biggest challenges that we face at the end when we get to the BLA, you've learned so much on your drug development and that might actually change the benefit risk or the paradigm of what was the secondary endpoint, was the primary point, the right one. So I think to answer that question, proactively, in a controlled environment as much as possible, doing a natural history, that's robust. You understand if the patient did not have an intervention, how would the disease progress and how does that compare to the patients you've treated and actually seen an improvement on, right? So being able to contrast and compare the natural evolution of the disease, the challenges of knowing the disease and being able to articulate all of that in a robust way. It's not easy to design a clinical study, but I think it's okay as much as possible that we want to lock it down from the beginning. It's okay to learn and develop it and evolve it if need be. I think our philosophy is, let the data speak for itself and let the data drive the decision if we need to change something in the middle of drug development. And that's kind of how we've approached the things as the best practices and work with the health authorities to make sure that they are aligned with the every step of the way. So you're not going back and rinsing and repeating again.

Yes. That's great and really insightful. I know Dawn, I'll kind of pass it over to you. I know that you've had a unique approach to your clinical trial and maybe you can share some insights into what you've seen in working through those hurdles and challenges.

Yes. So certainly, we're just in the clinic in a Phase I dose escalation and Kinnari a lot of what you spoke about are all the things were kind of trying to face down, including those locking in the commercial process. But again, it's for an initial small patient population. We do have Orphan drug designation for our product as well. And it's balancing that getting the best data, meeting those unmet needs, not leaving CMC in the dust. And I think that risk benefit also goes into CMC and what are we okay -- what could we take commercially for this first indication, and maybe those process improvements come with expand to a bigger indication and we tweak it at that point. But there's a lot of moving parts. And as we all know, you moved 2 things and then you go to do root cause and you have no idea what you affected. So I think in that sense, we're in early days, and I really appreciate hearing from the other panelists because I think some of you are a little further along in the places we want to go, like maybe snagging an RMAT designation, all these things we need to be thinking about as well.

Thank you, Dawn. Ramona, anything that you'd like to add having been further along in the development?

Honestly, I couldn't agree more. It's -- it takes a village. And what we like to say Iovance, it takes a tillage to get all of this -- all the pieces and parts aligned. And I think this whole -- it's quite a regimented mindset, right? Transitioning from clinical trials to really buttoning up all the loose ends to put it on to a BLA and get that going. And like I said, everything depends on the trifecta. Everything depends on that circle of trust. We have to be aware of the environment where the drug would be delivered in. We have to be aware of manufacturing constraints and all the validations and I just think that it's definitely a journey. I also think that it takes a special phenotype to be in this environment. And I think being on this panel just shows how much in common all of us have for doing what we're doing.

No. Thank you for that, Ramona. Suma, let's talk about any additional strategies or technologies that you think are poised to disrupt the clinical research space in 2023, again, having some experience working through that clinical continuum.

Yes. I mean, again, we talk about clinical standards within the OTP division. I mean there is no real standards, right? I mean it's not like for one particular therapy, you have a controlled blind of study, and there are examples where you have a single-arm, non-randomized natural history. So again, there is no standard. I can -- all I can urge is, I mean, every disease is different. There are 5,000 different diseases. Some diseases you are lucky because they are very organized patient advocacy groups. For example, the CF Foundation, where they have genotyped every patient. They follow the patients, so you have a lot of natural history data on the patients that you can really reliably use to make the case of your design with the agency. In some other case instances for the disease that we worked on, yes, there is some organization, but there is no structured collection. So that's where it becomes very difficult. And we were not successful arguing an open label single arm. We have to do the placebo-controlled study. So again, I think that we need to challenge the FDA and have these panel discussions for these ultra-rare diseases, where you're looking at patient populations of 1,000 patients, that doing a placebo-controlled study is as Kinnari just mentioned is unethical because these patients have nothing. And you know the conditions of these patients deteriorate very rapidly. So every month that they go without a treatment, you are basically depriving them of a quality of life that could have been improved. So we cannot -- it's just not right. So I just wanted to point that out. The second question you asked is about the disrupting technology. I mean, look at where we have come in the last decade. It's amazing. I think we had small molecules, we had mAbs, then we have the protein therapies. And now we are in a completely new era with gene and cellular therapies. And I look forward in the future, you look at cutting-edge CRISPR/Cas9 where you can correct the defect of the defective gene in vivo. I mean it's, again, early phases, but it's very exciting to see these kinds of technology. But again, the regulatory path is not caught up with the science and technology that's moving much faster than the regulations that can catch up with these kind of technologies. So -- but I'm hopeful and I think we have gotten here for us to see for us, for especially seeing a topical redosable gene therapy in it's final phase of a biological application, again, it's the grit and the determination to work and help with these patients and again, without the big team around, I cannot -- we cannot be here. I mean, as somebody mentioned here, it's your team that holds you and they all care for these rare diseases. And it's these patients, and we all are committed to the same to find a solution for these patients. And we pave the wave and we have to keep fighting. So -- and I think it's exciting times, and I think the future ahead is some of the things we can't even fathom, but it's there. Because 20 years ago, I would not have thought of a topical gene therapy, and we're here. So it's very exciting times.

Yes. No. And I think that you hit on a really critical point that kind of moves us into the next point of discussion for this webinar and really thinking about the patients. The reason that we do this is there is a passion to bring hope to patients that are suffering from an unmet need. I know patient access continues to be a major bottleneck for industry. We're seeing right now patient waitlist with commercial CAR T-cell therapy, and expected demand to increase as demand will potentially double following CAR T approvals this year. I think as a group, we must figure out a way to relieve these bottlenecks to successfully bring these drugs to the patients, some of that being from a manufacturing. Again, going back to that trifecta, the manufacturing, the regulatory and advocating for ourselves and ultimately, the patients. So through the panel here, how is your perspective or your respective organization approach patient access and clinical trial, diversity challenges to alleviate this aforementioned bottleneck? And how can we best implement practices and establish an industry-wide efficiencies? I know that we spoke about different various groups that have committee meetings and such. Is that the way? Is there something else that's out there. Ramona, if you don't mind, let's start with you.

Of course. Well, first of all, I want to echo Kinnari's point earlier. We're developing this great therapies, and we have to think about the patient is our family member, right? It puts everything in a different perspective. I come from an academic center. I count from seeing patients make it, not make it. And it was very important for me to build a team that has the patient -- direct patient experience because of this. I think being proactive about understanding the environment to drive product would be delivered in and starting to make logistical quality operational adjustments in the clinical trials to overcome some of these burdens and honestly get those aha! movements earlier on. It helps prepare for commercializing the drug product. If best practices exist, why we invent the wheel. So for example, product labeling is a critical path item for both clinical trials and commercial products. There are best practices for labeling cell therapy products. They're called ISBT 128. Why not start to align to these international guidelines for cell therapy products during clinical trials and empower scalability during BLA and commercialization phase. Another thought for patient access is building a patient and order registration, scheduling and the whole chain of identity, chain of custody on one platform instead of multiple platforms or perhaps a variety of spreadsheets and phone calls may actually create efficiencies in the clinical trials and prepare again for the scalability, quality and CMC readiness long term. Going back to this chain of identity and chain of custody, another critical path item for an autologous therapy. This is an area needing both the treatment center and the manufacturer in lockstep during the development as well as post launch as both are active participants in any deviation of both tune of identity, tune of custody item because it has the potential to cost lives. So in my opinion, the sooner the manufacturer starts thinking about building an efficient platform for patient access and encompass all these areas are must haves for clinical and commercial products are better off in the long term. And if you start building this platform, I believe it actually is going to help identify potential scalability gaps in patient access when it comes to a user-friendly platform to register or order the drug product. It would offer an opportunity to review how standardizing approach to raw material intake is. Scheduling plays a huge role if you depend on manufacturing and the whole logistics piece and drug distribution.

Right. Yes. Kinnari, I'll pass it to you to add to what Ramona said and knowing that we're really trying to get these into the hands of the patients that need them the most, anything that you'd like to add?

Yes. Maybe -- I think Ramona covered so many topics, maybe I'll come up from a different perspective, right? For Rocket, our values are really about trust, generosity and curiosity. And if we do that, we can elevate the industry. And why do I raise that in and bring this up right now? I think the component of sharing your best practices and what works, whether you create a white paper or work with the organizations like Alliance for Regenerative Medicine, [indiscernible] et cetera, helping and create white papers of guidance documents to help health authorities really come up to speed when they honestly are under research just like many of us are in the company, right, to make our best practice is what works and doesn't work. Spreading that knowledge is so valuable. So then we make newer mistakes or figuring new things up, but not spend the time in efficient and doing things that others have already figured out. And then being curious. I think we have to be open to knowing what we don't know and asking for help, right? So I love the fact that in this panel, just in the pre-discussion to today, I feel like I'm learning so much from different places and different experiences that all of you have, right? So being curious about what we know, showing that launch, we're also curious about asking the questions and seeing when you need the help. I think in this industry with ex vivo Lenti and AAV and so many different technologies, right? We're on the forefront of innovation. And sometimes we forget that or in the day-to-day lives that we do, but there's so much we need to learn. And to me, I think if we can do that more efficiently, then we can have perhaps more therapies approved and into the market. I think ARM had presented a data in -- at the JPMorgan conference, about 13 therapies have been approved in this space to date, right, in the U.S. How wonderful would it be that in the next 1 to 2 to 3 years, we have 13 per year being approved, so we can actually do those. And I think the more therapies we're going to bring to market, more scalability and efficiencies come into play, the price of these therapies also come down. And the risk of these therapies also come down. And that could increase the accessibility to the therapies that patients absolutely need. And I kind of say that for us, we think about patient as a whole. And as you see a picture behind me, when you walk into our headquarters at Rocket, we have a wall of stars. Patients are north star. And so every patient that's been treated in our clinical study, we put a star with their -- remembering how we treated them and in what we learned and how they've helped advance the knowledge of the disease that they're on, they have been investigated for right, and the therapy that can help bring to the market. So for us it's always about the drug, the patient in mind and trying to learn in a collaborative fashion with everybody, how to do this better and better.

Yes. I think it's great talking about keeping that trust, that curiosity and continuing to learn. But all the meanwhile, keeping that patient and every patient matters. We're bringing hope to every patient, every mother, father, daughter, that's out there that's dealing with this with a loved one. And something that I wanted to bring up with you, Suma, is thinking about that racial and ethnic diversity in clinical research, again, thinking about every patient mattering for clinical research. It's the key to advancing health equity. We've seen a lot of discussions around that diversity and inclusion. How can our industry and organizations work to better ensure racial and ethnic minorities are not underrepresented in the clinical research sector. I think we've seen -- I mean, just thinking this week or the past week alone with some of the sickle cell therapies that have gone on with Intellian, Novartis and Pfizer. And I think Sangamo was another one that was recently in the news, where you're really thinking about that diverse patient population. Would you care to elaborate on that and how you're dealing with that?

I mean this is a tricky question because, again, when you say rare diseases, they can range from a population of as small as 100 people to as high as 200,000. So it's a very tricky situation to say we can have racial diversity in all of these studies. Because when you have a smaller subpopulation, unfortunately, some of these diseases are more focused or more prevalent in a subset of population, maybe because of the generic predisposition or because of consensual marriages and children being born out of it. Sometimes these diseases itself are not fair. They don't have racial diversity. So in those situations, you truly cannot comply or require that you want to know. So the hope is every patient matters. I mean I know race and sex and everything matters, but these are ultra-rare patients, every patient matters. So I understand the regulators think about it as a typical study. They want data in ages, black, whites, age groups is very, very different. For example, even when you break down into age categories, we struggle with the agency they say -- if you -- I know you want to include babies from 0 -- from birth to 3, 5 years, but you may not find that a baby, but then they limit you to those age groups. And even though you've established safety and efficacy, so there needs to be some sort of -- even with the agency expansion to say in what, we truly cannot study all of these patient populations. Age, it's ideal, but not feasible, so they have to be more flexible. So again, my thinking, my position is every patient matters. I mean -- and I think it's more understanding the disease. I mean, we all think that we have book knowledge about the disease. We know what the imitations are. If you look at the limitations and say, oh, yes, this is the limitation. We know what kind of severity of the disease they have and we are wrong because many of these patients know their disease much more than we do. So I think getting to know the patients, working with the patient advocacy group, really understanding what are the manifestations of the disease. So even if you have a solution, is it fixing all of their issues? And how else can you substitute or help them with maybe your product may not completely fixed. I can speak in my case, for example, EEB is a skin disease because it's very visible. But they have additional manifestation, for example. It's the eye because Collagen VII holds the cornea together. So you have blistering in the eye, some of these kids go blind. They have malnutrition because they cannot absorb the food -- so you have to -- even though you fix some of them, you cannot forget to help them with all the other manifestations so that you can overall improve their quality. And I think you as an organization saying that their disease matters, and as all the guys on the panel if we support you, I think we can never forget these patients, and we need to continue to be there for them and help them in the full blown solution so that can see overall improvement in these patients.

I love how you touched on the fact of knowing the patients and really getting to know them and understand what they're going to from a day-to-day basis because they oftentimes know more about their disease than we even do. And I think that's such a critical factor, especially in rare diseases, is thinking about not only the impact it has on that patient, but their family, their caretakers that are along the way the treatment centers, again, we go back to that trifecta and really advocating for the regulatory changes that need to happen. So really appreciate you positioning it that way, Suma. I know that we've got about 15 minutes left. So I want to make sure we try and cruise through a few more questions and have some time for some Q&A. I know that Kinnari, you had mentioned the kind of idea of bringing more approvals into 2023 and beyond and going from 13, I think we were talking in our prep, it was 3 to 5 a year, how do we double that or triple that in the coming years. How -- what are your thoughts on doing that? And how do we move that needle again?

I think they are amazing like therapies out there. There's amazing work being done all the way from pre-IND to late-stage clinical. I've seen the data being presented at [ ASH ] in various other conference in the last few years. I think a couple of things that could help make this happen is, of course, FDA talks about the resources that they need to get in order to help expedite these therapies and have the interactions and the frequent dialogue that we need. I think the second component we can do together with the agencies around the world has helped develop policy papers and share our best practices that could be really standardize things. And maybe the third component that could help is Dr. Peter Marks, I do love his vision. And what he said is -- he's saying that we can make potential platform therapies and looking at data in a platform approach. If we can make that happen, I think that could really be so efficient and really help the patients around the world. For example, Fanconi anemia, we're studying Fanconi anemia FANCA gene but there is FANCA through 23 plus other genes, right? But if we get the FANCA approved and if we take FANCC and FANCD and FANCG through the clinical studies, can we just apply the paradigm of learning across the platform from a CMC vector plasma analytics clinical perspective. I think if we can do some of those more platform approaches, to the complexity -- if we can do those platform approaches, we can decrease the complexities, the cost and investment that we need because a lot of times, I know there were quite a bit of discussions before in the CMC panel. I was on some other form RCL testing, right? What is the value of that? And what's the value of data that we all know that exists? And could we get a waiver for that as an industry because there's enough known about it or only have it all when there is a risk. I think while people are thinking, hey, that's one test. If we think every step of the way, how do we do this more efficiently and share that knowledge of where we can do some optimization, I think that could really help expedite more therapies not only get into the clinic, but efficiently getting through the clinical development where we can understand the benefit risk and getting them even more readily approved to the market, so patients can have access to it.

Great point. Dawn, anything that you'd like to add, again, coming at it from a very early phase development perspective?

I think there's so much that -- and Kinnari, you hit on a lot of things, how can we standardize. And I think also going back to my original we're building the plane as we're flying it. And how do we move along and I'm thinking to our previous topic about getting to more patients, right? Right now, the cell and gene therapy is in certain institutions and getting it to a broader population is a struggle. And how can we bring up the next group of PIs who are comfortable with cell and gene therapy, right? Like in my space, like for autologous CAR T, it's a lot of BMT and heme docs who have been the pioneers here, right? But you go into solid tumor and the medical oncologists say, well, I've never touched a CAR T, I don't know anything about it. So I think there's opportunities for education, even within the treating physician population, how can -- and how can we get this into out of the big regional academic institutions into the smaller community settings. I think that's with education, it's with standardization. I think about -- from what I'm thinking about like in Europe, standard European code as for chain of identity, right, for privacy reasons. There's lots of opportunities, but it's a lot to try and tackle all at once. But I'm hearing lots of great ideas on how we can move the needle here. So that's just a couple of thoughts for me. I know we probably want to leave some time for a lot of question and answer.

So Yes. And I think if the panelists are okay. I think there's a couple of questions coming in, and then maybe we can pause and do just a rapid fire to wrap it up on what we think for kind of some thoughts and [ gems ] to leave the discussion with. I know Kinnari, there's been a couple of questions that came up around the single arm versus controlled arm in the chat, comparing and observing natural history untreated to placebo controlled arm, what's the ethical difference as well as thinking around the immune responses, excuse me, for rare diseases and how do you tackle that? Would you like to go ahead and answer that?

So natural history, when we talk about natural history. There's 3 ways that FDA health authorities and we can lean natural history, right? One -- the 2 of them are really retrospective. So one is literature search, doing literature search of case examples of rare diseases cases out there and learning from that. Second, that we've also taken into consideration and done a lot of work at Rocket for is retrospective chart review. So patients that have already been treated and seen how their data was collected over time. And each of these have a benefit and efficiencies, but they also have gaps and data challenges, et cetera. The third one that I think the question has been asked about is a prospective natural history. The reason it is still considered a much better option from an ethical perspective as you could imagine, whether it's AAV therapy or CAR T or ex vivo lenti, right? What happened is patients go through so many supportive care from Busulfan to Rituximab. So every care that you give in a controlled environment, you need to give them placebo like a water. And every time you do blood draws and things like that, you need to have a placebo control. So if you could imagine, some of our diseases like Danon disease, we do hard biopsy. If they're in a controlled arm to go through those types of invasive measures, whether to blood draw or biopsy of the bone or the heart, that is a lot and so that's where the ethical consideration of -- does it make sense, especially if they're not getting a potential for therapeutic benefit from an intervention therapy is the reason that we do a natural history separately and all we're doing is absorbing the patient in a normal way of life through their primary care or through registry and just seeing how they're evolving versus giving them state control liquids and blood draws and et cetera. So I think that's the one of the questions I just wanted to answer the high level. And the second question is, have we seen a shift because of safety challenges, right, in AAV form to a more controlled arm study, I've actually seen a shift the other way, especially with Dr. Peter Mark in the last few years, right? It's more how do we have surrogate endpoint at sort approval pathway, how do we have a Phase I/II single-arm studies that for certain diseases, FDA is becoming more and more open to that. And I think the body of knowledge and data that exists from a safety perspective for all the therapies that have been approved, but also a lot of them that are under BLA reviews or in clinical studies. We've learned how to risk mitigate this immunological responses. And at least for Rocket, we've used this successfully for 2 pediatric patients in our Danon program, and we are very transparently shared this with the entire industry, so they can use the same protocol if they think it's suitable for their therapies. And I think the data we've seen to date is it does help. And I think because of the concern of the risk or being able to manage the potential for risk and more proactively, I think FDA is become more open to actually a single-arm study versus having a Phase I, II, III controlled arm. Sorry, that was really fast. I apologize in trying to get through the response.

I'm sure we're looking at the time and the clock and we're getting a lot of really great questions. So thank you, Kinnari. Dawn, one of the questions that came up in the chat was how does the panel think about selecting their vendors to support clinical development, CMC support, lab support, anything along that line. And I know that you're eager to kind of when we talked about it in prep. What are some key attributes that you look for when you're partnering with external vendors.

Yes. And again, this is -- I forget if you said it, we're trailblazers and I think we have to remember, we're on the leading edge. We're the first ones out there. And with looking at cell and gene therapy vendors, for me, there is no goldilocks out there. I'm going to go back to my earlier comment about finding PIs who have all the experience, you're not going to find it. They don't exist yet. So for me, it's been very important to go in and work -- and evaluating vendors what are my must haves? What experience do I need them to have that it's going to be important for me to start the study, to start manufacturing, to do the assay development. Like if -- I know I'm going to need a companion diagnostic. I want to know that I'm going to be not maybe for developing the companion diagnostic, but working with a CRO or others who have familiarity with this, maybe that is going to be really important for me. And there's going to be things you're going to have to agree that you're okay climbing that learning curve with your vendor. You're not going to find everything. If you spend your time looking for everything, you're not going to move your programs forward.

Yes. I think it's really what I hear, and I know you and I have talked about this, trying to find a true partner that's going to go and trail blaze with you and be transparent. Suma, I know that you've been through this, and I know that we talked about kind of some of the educating of folks, whether it be vendors, ourselves, the regulatory industry, any gem that you could share with those of us who are on the service providers side as we think about moving forward and having these types of discussions.

I can tell you from our experience, having a strong agreement with the vendor, it's very critical. Because we'd be in [ bond ]. Again, when there's a rush between gene and cell therapy, you're so super excited. You want to get that product in. You don't worry about all of the legal aspects and the quality agreements and then you can be in a pickle because of that. So I think I would my advise it may be really pay attention to that because I think then you -- so that you are not surprised because you lose your [ slot out there ], they fail to meet specifications and the still stop with paying all the bills and more of it mean for us, startups in gene therapy. We are fiscally -- it's fiscally we need to be responsible. Otherwise, it's survival. So I think it's very important to be upfront, pay attention to that builder collaboration relationship because you can have a vendor saying, "I'm sorry, you're not allowed to come into clean rooms. You're not allowed to come into our labs and watch". As Dawn mentioned, the vendor is your second arm is like your organization. So you need to be very upfront in your collaboration agreements, build sort of a partnership relationship so that your team can freely walk in there, work with your scientist hand in hand. And then as you know, this is a very competitive space. If we as an industry, in spite of being the parent company, you can lose good talented people. You can imagine in a random setting, that turnover is pretty high. So again, these are the things you have to keep in mind, building the relationship, making sure it's a reliable vendor, they treat employees right, they're happy, and you can build a collaborative relationship for the success. I mean -- and also you maybe incentivize them, like your success is their success. So sometimes you have to think out of the box to be creative as you build relation if they are your bread and butter for our survival. So it's not like a standard 30 years ago, you go to manufacturing, you have the make and -- they're supposed to serve you and you're done. That -- those days are over with gene and cell therapy. So...

So I think it's such a critical point that you make about their success is your success. You're in it together. And if you're building your own organization, you're bringing in folks that you want to be successful because, again, their success is yours and vice versa. I'll do I know that we've got 2 minutes locked. There's a lot of really great questions, and I apologize we haven't gotten through them. We'll do our best to try and answer these in follow-up, hoping that we can invite these ladies back for another discussion. But quick kind of rapid fire in the last 2 minutes, and I'll give you 2 questions. If you could go back and inform your colleagues here on this webinar, a lesson that you've learned or alternatively, something you're excited to see in the field in 2023 and beyond. Ramona, let's start with you.

Well, I will start with the excitement of 2023. I am hoping to see more approved products on the market to offer life-saving treatment to the patients. I think that's important to every single treatment center, every single physician out there, that has patients that they don't have options. Overall, the experience in the industry, if I would go -- if I were to go back, I would say, leverage existing best practices. I expect in the future, the patients and the tumor centers to put pressure on us as manufacturers to come together and standardize some of the interactions with them.

Great. Suma?

I mean, hopefully, 2023, I look forward for the drug approval of the first topical gene therapy. So I mean, again, I think -- that's the biggest thing we are anticipating, and we're looking forward to, again, hopefully, we can add our names to the 2023 list of gene therapies that's approved.

Great. And Kinnari, Dawn, I'm so sorry. We're going to have to wrap this up. But I want to thank Endpoints News for inviting us the panelists here and all the amazing work that their organizations are doing. And huge thanks to everyone in cell and gene therapy space that continue to move the needle and bring hope to these patients, definitely be in touch and try and follow up on these questions. Thank you.

Thank you.

Thank you.