Founder Stories: Krish Krishnan, CEO of Krystal Biotech

I'm Krish Krishnan, Chairman and CEO of Crystal Biotech. Our mission is to bring transformative, redosable genetic medicines to underserved patient populations and bring a meaningful change in their lives. Before I get started, please take a moment to look at the forward-looking statements. They are also available in our corporate deck, which is in the investor section of our website. You know, the founding principle or the founding mission of this company was to find a patient-friendly, molecularly corrective treatment for a debilitating disease called dystrophic EB, which is caused by a missing or a mutated gene in the patient's skin cells. We were technology agnostic when we started, um, but we knew that in order to provide another copy of the missing gene to the patient's skin cells, the delivery vector had to have certain properties. We were technology agnostic, so we were truly a company that had a specific problem to solve when we started, And we're looking for the right technology and the right people to help solve that problem. We settled on a vector that is a modified herpes simplex virus 1 vector that has many favorable properties to delivering genes to skin cells. It has the ability to transfect skin cells easily. It has an ability to avoid the immune system through a combination of innate capabilities and some of the modifications we have made. That allow us to redose. It has a carrying capacity of taking, of carrying these large skin genes to skin cells, and it's an episomal virus, which means it does not integrate or cause any kind of disruption to your existing DNA. And that's particularly important because vectors that have, that integrate or have the potential to integrate in certain circumstances result in oncological situations, and a truly episomal virus avoids those, the risk of oncogenicity. Most importantly, we realize that this is a vector that does well in titer, and we are able to scale it because after all, we're going to be treating a global population. So the first indication, just let me tell you a little bit about the disease we are going after, or the first disease we wanted to go after. It's a disease called dystrophic EB, or DEB, where essentially the two layers of your skin, the epidermis and the dermis, are not held together by anchoring fibrils. And because of the missing anchoring fibrils, even a minor contact or friction can tear the skin or form blisters. And, and the reason the patients do not have anchoring fibrils is because of a missing gene called COL7A1. And the goal of CRISPR is to find a simple, convenient, patient-friendly way to provide the missing gene to these patients. As you can see from the picture, the burden of life on both the patient and the caregiver is really very high. There is a high risk of these patients developing a form of skin cancer called squamous cell carcinoma of the skin. And to prolong the onset of that cancer, patients spend in the U.S. between $200,000 and $400,000 every year to simply prolong it, because once that cancer sets in, in most cases, mortality is inevitable. We estimate there are about 3,000 patients in the U.S. with this disease based on epidemiology data and maybe about 10,000 patients worldwide. The way we've designed VVEC is that the vector that's carrying the gene is formulated into a topical gel and applied directly on the patient's wounds, and when the gel is applied, it transfects the cells, the keratinocytes and the fibroblasts with the vector. The vector then faithfully delivers the gene to the patient's nucleus in these cells, and then the cell machinery does its job of producing the required protein, in this case which is collagen VII, that, that is the basis of the anchoring fibril formation and eventually holds the epidermis and dermis together. But remember, Skin cells do turn over. And so once the protein's half-life, or once the protein turns over, we have to redose to continue to supply the missing protein to these patients. So after 4 and 5 years of working with this disease and with this drug, we're happy to report that late last year, we announced results from a Phase 3 pivotal study of BVAC for the treatment of dystrophic EB. We enrolled 31 patients, randomized them into a double-blinded 6-month study, and looked for complete wound healing at the 6-month time point as the primary endpoint. In addition, the secondary efficacy endpoint was to look for complete wound healing at the 3-month time point, and also look for change in pain, in the severity of pain associated with wound dressing changes. The patients varied in age from 1 to 44 years old. 61% of the patients were pediatric patients in this study. So what we found was that BVAC was well tolerated in the study with a safety profile that was consistent with our prior studies. There was one mild drug-related AE was reported in the trial. And the immunogenicity profile was also consistent. And that's important because it informs us that yes, it is possible to redose the drug and continue to show efficacy. From an efficacy perspective, we found that the drug met its primary endpoint. There was a statistical difference between the active and the placebo at the 6-month time period. The p-value was less than 0.005, and there was a significant difference in response rate between the active and the placebo. In addition, we also met the secondary endpoint measured at the 3-month time point of complete wound healing. That too showed statistical significance and a difference in response rate. We also looked at wounds that were closed at both the 3 and the 6-month time point. And even in that analysis, which was an ad hoc analysis, we demonstrated complete wound healing that was statistically significant at both the 3 and the 6-month time point. We had a concept in the study that a patient received a maximum dose per week. The patients were treated weekly until the wound closed over the 6-month study, and then if the wound reopened, they were dosed again.. And if there was any drug left after what was assigned to the primary wound pair, they were applied in an open-label setting to a bunch of secondary wounds in that patient. And I'm going to show you two examples if on the secondary wounds on how the drug behaved. Um, this is a patient who's had this large wound that's greater than 100 centimeters squared on their back for over 10 years. Causing a lot of discomfort and decrease in quality of life. After 6 weeks of treatment on BVAC, about 50% of this wound closed, and by the end of the study, as you can see from the picture, there was complete, almost complete, if not complete wound healing, uh, which was— made the patient excited and the physician was very happy to see this result. But the thing to remember is because collagen will turn over, some of the lesions will start to open, and that is why we're able to redose, which is really important, and bring the wound back to closure. So this is one example that dramatically improved the quality of life on this patient. Here is a second example, the foot of a 34-year-old patient. I show the foot because the ability to walk, the ability to put on shoes, simple things reduce their quality of life. And being able to take it to closure and heal the wound dramatically improves the quality of life in these patients. So what we did at the end of the study was to move all these patients into an open-label extension study, which is ongoing right now. The feedback from the OLE to date has been very positive. The patient experience and feedback has been positive. The physician feedback experience has been positive, um, and it provides an opportunity for them, um, in a patient-physician interaction basis to think about where to apply Bevac to, and also gives us some insight into how often, um, a drug needs to be applied over the course of the duration of the OLE. So that study is ongoing. And we expect to provide some kind of announcement, uh, some announcement on the summary of what happened in the OLE towards the end of the study. Um, so our next steps are to work with— to file a BLA with the agency, and we anticipate filing that in the first half of this year. Uh, we have— the drug has achieved a lot of regulatory designations like RMAT and Fast Track, and we're hoping to get fast-track or accelerated review of the BLA. Concurrently, we're also getting ready for launch. We have a commercial burgeoning team in Boston working towards an, you know, a potential anticipated launch following BVEC approval, following potential BVEC approval. And also in Europe, we've been in conversations with the EMA, and we expect to file a marketing authorization in the second half of this year. We're also in early conversations with Japan— with respect to the PMDA filing. With respect to the MA filing, we're also in early stages, starting to build out a commercial team in Europe. Once we started achieving proof of concepts in BBAC, we realized there are other debilitating diseases, other monogenic diseases that can be treated using the same approach. And as you can see from the slide, we have an active pipeline not only in skin, but also starting to make inroads in pulmonary indications where we would use a nebulizer to deliver the delivery vector to the pulmonary cells. A quick extension of the same concept can also be applied to treating simple skin conditions, improving skin quality and skin texture. Which are all associated with some cell that loses its ability to produce the required amount of protein as people age. So collagen III, elastin, collagen VII, as patients age, there's less and less of that being produced by skin cells. And being able to augment that, we believe, can improve the skin quality and the skin texture of many subjects. Our commitment to rare disease is, is very strong. We built out a GMP facility in the early stages of this company that's now fully functional and operational. Our second facility, Astra, which is about 150,000 square feet, is expected to be online in the second half of this year and would serve as a backup for not only our potential commercial products but also our pipeline drugs. So, to summarize, we are working to become a fully integrated gene therapy company to treat debilitating diseases and some skin conditions. We have a lead drug that is close to a BLA filing. We have a drug in Phase 2 for the treatment of lamellar ichthyosis. We're looking to file a third drug in skin, an IND filing towards the end of this year. We have an active pipeline in pulmonary indications and in aesthetics. As I mentioned earlier, we're building out our manufacturing capabilities. We already have one that's functional. We're building out our commercial team. So all the work being done in the company is towards a mission of building a fully integrated company that can serve patients with debilitating diseases. We continue to work with respect to research and platform Looking for other tissue tropism, um, that's ongoing. Um, we're fortunate to have a good balance sheet of $500 million that would allow us, um, to work to bring these medicines to market. Thank you.