In this Center for Individualized Medicine (CIM) Grand Rounds, Dr. Marks reviews the gene therapies that are approved in the United States. Dr. Marks describes the promise of genome editing technology applied to the treatment of rare disease and how platform technology provisions may apply to genome editing.
Center for Individualized (CIM) Medicine Grand Rounds
Main presenter
Peter Marks, M.D., Ph.D. Director, Center for Biologics Evaluation and Research (CBER)
Good afternoon. My name is Doctor Denise Dura. And I am the associate director of education for the Center for Individualized Medicine in Rochester. I would like to welcome you to the Center for Individualized Medicine grand rounds. The CIM Grand Rounds lecture series is designed to highlight the latest in scientific discovery and innovation. And demonstrate how individualized medicine is being translated into practice to meet our current and future patient needs. It is my great pleasure to introduce today's speaker, Doctor Peter Marks. Doctor Marx received his graduate degree in cell and molecular biology, and his medical degree at New York University, and completed internal medicine residency and hematology medical oncology training at Brigham and Women's Hospital in Boston. He has worked in academic settings, teaching and caring for patients, and in industry on drug development, and is an author or co-author of over 100 publications. He joined the FDA in 2012 as the deputy center director for the Center for Biologics Evaluation and Research, and became the center director in 2016. Over the past several years, he has been integrally involved in the response to various public health emergencies, and in 2022, he was elected a member of the National Academy of Medicine. The title of today's presentation is Advancing the Development of Gene Therapy for Rare Diseases. During his talk, Dr. Marks will review the gene therapies that are approved in the United States, describe the promise of genome editing technology applied to the treatment of rare diseases, and describe how platform technologies' provisions may apply to genome editing. Please join me in welcoming Doctor Peter Marks. Thanks very much for having me today. I'm just gonna bring up my slides here. So thanks again. Um, I, uh, would like to, uh, as mentioned, kind of talk about where we stand currently, um, in this area of gene therapy. Um, and where we are headed. Just for a moment though, by way of background, um, gene therapy isn't something that has sprung up overnight. Um, it's been something that has been, uh, almost half a century in the making. Um, uh, it, it, it actually started with very early attempts at NIH. Uh, and then, uh, has grown, uh, there were, uh, kind of fits and starts, uh, and, uh, some setbacks at times, um, but, uh, over the past A decade, um, there has been steady progress, and more recently, uh, there has been an acceleration of progress, and that's something I'd like to talk to you about today. So for those of you who are not, uh, uh, familiar with the different methods of delivering gene therapy. Gene therapies today in the United States are delivered essentially by uh essentially two major mechanisms. One is you take cells from the body, the cells that you're interested in altering, alter them in culture. And then uh give them back to a person after the gene therapy has been uh uh conducted essentially ex vivo, um, and, uh, that has the advantage of not exposing the entire person uh to the gene therapy vector. Um, it also allows you to potentially characterize the cell population, uh, that you are um uh uh transducing with the gene. And um also allows you to uh potentially do that with reasonably high efficiency to a given cell population uh that you can measure. Um, so, uh, the X vivo approach actually was the approach used for the initial products licensed in the United States which were uh chimeric antigen receptor T cells. But the other way of going about doing this is obviously to give the gene therapy vector. Uh, uh, directly, either locally, um, uh, into, uh, an organ that is affected, um, or systemically, um, and that, uh, a variety of vectors, uh, have been explored over the course of time, but, uh, most recently, um, uh, the field has settled on adeno associated viral vectors, um, uh, for that. Um, uh, directly administered, uh, gene therapies. Now there are others in development that we're gonna talk about, um, uh, so that, uh, is, uh, for the, uh, directly administered gene therapies often, um, and, uh, on the other hand, for the, uh, the gene therapies that are being, uh, handled in culture, ex vivo, uh, those are often being uh uh uh transformed with. Um, uh, are transfected using, uh, uh, lentivirral or retroviral vectors. So different uh vectors have predominated here. Um, we've settled on these, uh, in part over time because of the safety, um, uh, profiles that have been demonstrated with each of these, uh, situation, the lentiviral vectors in uh the X vivo approach and the I know, associated viral vectors in the in vivo approach, um. Uh, for those who aren't again familiar with AAV, um, AV is a, uh, human virus, a virus that affects humans, uh, that, um, uh, is generally. Uh, non, uh, pathogenic, um, it, it, uh, is something that most of us get exposed to, uh, at some point, but, uh, we, uh, uh, don't have a serious effects to it turns out to be a reasonable gene therapy, um, vector because you can take out, um, uh, a good part of his genome at roughly 3,500 4000 base pairs, uh, and put in a gene of interest. So, uh, that's uh helpful. The problem with that is that it is not the ideal gene therapy vector, uh, because you can't put in um very large uh gene segments and for certain uh uh gene applications people have had to be creative, uh, and, uh, develop shortened uh proteins. Uh, to be able to, um, uh, uh, do gene therapy. Um, an example of that for, for instance, is what's done in hemophilia A, uh, where, uh, the factor 8 molecule is just too big to put into a nano associated viral vector uh for expression. So, uh, it turns out that there was a product developed previously, um, in which the B domain was deleted, uh, and that uh that particular uh construct can fit in to. Um, uh, a gene therapy vector. So this is kind of the landscape of how we're doing this. Things are evolving because people are now starting to look at Um, other methods for gene therapy, uh, delivery, uh, including, uh, using lipid nanoparticles or synthetic, um, uh, uh, uh, particles, um, uh, either polymers or, um, uh, what amounts to a viral like, uh, particles uh to do this, but, uh, those are still in development. What has transformed this field though in the past uh several years uh has been uh the discovery that uh CRISPR Cas9 genome editing could be applied uh to mammalian cells. This bacterial, uh, it's essentially a bacterial uh protection system, uh, almost like a bacterial immune system, uh, that uh is able to be leveraged. Uh, in the setting of, uh, gene therapy, um, and the original, uh, CRISPR Cas9 uh contract on the left here, uh, cut both strands of DNA, uh, allowed one. Uh, to then, uh, potentially, um, uh, have, uh, either, uh, incorporation of a segment of DNA at that locus or, um, uh, uh, essentially, uh. Rejoining, um, uh, and allowed one to knock out a gene uh or insert uh a gene, um, uh, but, uh, subsequently, um, uh, through work that has evolved, um, and it's quite elegant work, we now have, um, base editing, uh, genome editors where you can fix, um, at a, uh, they've now come up with ones for all of the different possibilities, uh, so you can uh take any nucleotide. Uh, abnormality, uh, and fix a single nucleotide abnormality, uh, in DNA. And then finally, um, because, uh, there are many, uh, uh, mutations where it's not a single base pair, it's a stretch of DNA that is, um, uh, improper, um, uh, the prime editors uh are the next generation. further even of uh the CRISPR Cas9 constructs where these have a CRISPR uh which uh is a a kind of an advanced CRISPR, the same one that's used kind of the same type, uh, that's used. Uh, in, in the more advanced CRISPR constructs, which does not cut both strands of DNA that is has its advantages, um, and it's hooked up to uh a uh uh a reverse transcriptase, uh, so it essentially can read right into DNA, uh, short segments, couple 100 base pairs, um, at this point, uh, and uh therefore correct. Um, uh, segments of DNA. It also can potentially put in a a a site into DNA which you can substantly come along. Uh, or simultaneously come along with, uh, and, uh, insert a longer stretch of, uh, uh, DNA segment that uh you're carrying along. So lots of, uh, innovation here. I, I'm not describing all of it, but just to try to give you a flavor, um, that, uh, CRISPR technology is really Uh, moving, uh, this field forward, particularly, uh, uh, as we'll come to, uh, because you can deliver these constructs as mRNAs into a cell, um, and, uh, uh, they will, uh, then, uh, much the same way as our vaccines work, uh, you will end up uh getting a, a, uh, an active construct, um uh with uh an mRNA delivery, um, so. The various products we have now in the United States, um, uh, depending on how you count them, it's either 19 or 20, um, or you could come up with 21 uh products because uh uh there is uh the it's, it's 19, probably, it's 19 unique products because two of the products. Um, uh, intelo and Lifgenia are, uh, the, the same basic product. It's just one is for sickle cell disease and one is for thalassemia and after, um, uh, we, we realized now we, we try to keep the products, uh, that are the same under the same names, um, uh, so it's, it's essentially 19 uh approved gene therapies, um. Uh, uh, uh, in terms of distinct entities, um, and the color code here is that the, the blue entities are, uh, chimeric antigen receptor T cells, um, or uh modified T cells in the case of uh tea, which is uh the first, um, uh, modified genetically modified T cell, um, uh, for a non hematology oncology indications for synovial cell sarcoma. um. Uh, the, uh, the ones in green are uh genetically modified stem cells, um, uh, in this case, uh, for, um, sickle cell disease, thalassemia, and adrenal leuko dystrophy, and the ones in uh purple, uh, are directly administered gene therapies, uh, which cover a range of both rare genetic diseases, uh, uh, uh, including. Uh, uh, hemophilia A and B and uh Duchenne's muscular dystrophy. So, um, we've come a a fair ways here, um, but there's a long way to go, in part because what uh the gene therapies that we have approved have covered are the more common, uh, uncommon diseases, um, uh, but, uh, there are a lot of very rare diseases for which gene therapy could be applicable, um, for which we still don't have, uh, products. So I just want to take a moment, uh, and kind of back up a little bit and say what, what is Um, uh, is, is, is car T cell, uh, where is it going? Um, uh, and, uh, then I'll go back and, uh, talk about where, um, uh, uh, gene therapy, uh, that's directly administered is going, um, uh, but I, I, I think when I think about where car T cell, uh, uh, development is going, um, it's largely driven by the developments that we've seen. Um, uh, in our ability to make molecular constructs. Just so that people know for autologous chimeric antigen receptor T cell production, um, uh, involves, uh, and this is, for instance, the, the licensed chimeric antigen receptor T cell products. Uh, there was a lot that had to be worked out. Um, they are made by uh uh doing an apheresis, um, uh, uh, after, uh, to mobilize uh cells which are then, um. Uh, the, the apheresis, uh, takes those mobilized cells, uh, and, uh, you then, uh, either isolate T cells or purify somewhat, and then, uh, transact, uh, formulate your product, uh, oftentimes after it's grown some in culture, uh, and then, uh, get back to the same person, uh, having introduced uh the uh chemeric anti receptor which is noted, uh. Uh, in schematic form in the uh upper left hand corner of the slide. Um But those autologous car T cells suffer from the fact that um each person who uh is a donor of those is generally the patient who's been treated with various amounts of chemotherapy, has a variable amount of uh background disease, uh, still circulating often, um, uh, and, uh, so it, it is not. Uh, an exact process and the response rates, um, though good are not perfect. And is there a way to improve upon that? Well, one way that that might be able to improve upon that in terms of both cost, availability. Uh, uh, for, uh, when somebody has relapsed, uh, without having to, uh, uh, wait a long time, uh, and, and to have a very consistent product would be to make allogeneic car T cells, take a healthy donor, uh, where you can potentially make 100 doses um of a product from one individual, um, uh, and that can potentially give you this idea of an off the shelf product. Now, The other beautiful thing about this is by using genome editing, we can start to make uh a number of cuts. Uh, and a number of changes, uh, into, uh, uh, the cells, um, uh, to, uh, introduce, uh, uh, multiple constructs while getting rid of, uh, the MHC class one molecules, um, and therefore have a, a potentially an allogenetic RT, uh, that can uh look at multiple, um, antigens. Now that's important, uh, because Um, uh, as we think, uh, uh, uh, about, um, uh, addressing solid tumors, um, being able to address multiple antigens, um, is really important, unlike in hematologic malignancies where we're lucky enough to have a single target like CD-19 or CD22 in the case of Um, uh, some pediatric acute lymphoid leukemias, um, where we can go after with the CAR T cell. Um, if you did that for, uh, some of the uh antigens and cancer cells, uh, that are solid tumors, there are too many, uh, that's too much overlap with normal tissue. However, if you can go after multiple antigens, um, you can hopefully find a unique, uh, composition, uh, uh, on the tumor that is not present. Uh, on normal tissue that you can then have the CAT recognized and people are working on that. But the other piece that Uh, that we might see in the future, um, is, uh, it may be that we'll see car T cells produced using mRNA technology, um, uh, and that's because uh you can take an MRNA, uh, uh, targeting approach, uh, potentially using CRISPR if you need to, um, and, uh, put that into a lipid nanoparticle or other, um, uh, uh delivery vehicle. Uh, potentially give that, um, uh, in uh in uh in intravenously, uh, rather than taking the cells out, uh, and then have, uh, the population of T cells, um, uh, altered with the construct. The advantage here is obviously you could significantly reduce the complexity and cost associated with the therapy. Um, which is something that we would like to help facilitate because these are very expensive therapies at the moment. Um, also make life a lot easier, um, uh, in, in, in, in, in practical, uh, sense of things, um, uh, but, um, this, uh, this kind of an approach potentially using CRISPR even. Uh, is exciting in part because uh when using CRISPR as a uh as a way to to uh make a site uh for the uh the insertion of a construct, you know where you're inserting in the genome whereas right now, when we make car T cells, we often don't know, uh where uh the uh uh the uh retroviral sequence is inserting the. Uh, uh, the, the chimeric antigen receptor construct, and that means that sometimes, um, it probably is going into a less than optimal place that could be associated with, uh, on rare occasion with secondary cancer. So lots of exciting, uh, going on here. We'll see how long it takes to get there, um, but I think this is uh over the horizon. And uh, for CAT, where we will for the next probably decade, we're probably in the business still of autologous car T cells and, um, uh, potentially allergenic uh car T cells coming online in the next 5 years or so. But my guess is that 10 years down the line, we may well see. Uh, these, uh, in vivo modifications in part because, um, the ability to potentially target, uh, to, uh, T cells, uh, using. Uh, uh, uh, started, uh, Lipizone technology or other technologies, and in part, um, uh, because it turns out you don't need to get um an incredibly high efficiency um of of T cells, uh, transducs your uh construct to still have efficacy. So now I'm gonna turn to a gene therapy for rare diseases. Um, uh, gene therapy for rare diseases, is, uh, there is just such an exciting area, and it's, it's really been moving ahead rapidly. Um, uh, I, I've talked about CRISPR Cas 9 genome editing, well, Um, for something that was described to be a utility potentially in humans in about 2012, to see an approved product, um, about a decade and a little bit later, um, is that uses that is is impressive. Um, and Casevvi is just that, it's a, it's a genome edited hematophoric stem cell based therapy, um, which can be used either for uh beta thalassemia major or for uh sickle cell disease, uh, that it essentially. Uh, uh, shuts off a repressor, uh, knocks out a repressor of, uh, fetal hemoglobin production. Um, uh, and fetal hemoglobin is a perfectly reasonable hemoglobin to have if you have beta thalassemia. There is actually a natural, uh, situation where that can occur, um, uh, and, uh, we also see a similar, uh, situation in sickle cell disease, uh, where people with uh hereditary persistence fetal hemoglobin don't have the same manifestations of sickle cell disease, uh, that those who um are are homozygous for. Uh, as hemoglobin. So here, again, uh, quite an impressive development. Um, that said, um, as I, I already alluded to, um, uh, gene therapy, um, is not proliferating at a rate which we think, uh, it probably should. There are many very Um, reasonable targets that exist and gene therapies that have made it partway through development that have dropped out, not because they have failed clinically, uh, but they have failed because of a combination of challenges uh with their manufacturing. Uh, the fact that, um, with venture capital funding a lot of this work, uh, the clinical development timelines are critical. If they get too drawn out, um, uh, people lose interest, uh, and, or, or they run out of cash, um, uh, and, uh. So, uh, that's been a problem. And the other piece is that when you're dealing with very small populations uh in one country like the United States, um, uh, the different global regulatory requirements where someone then has to go and redo studies, uh, reformat. Uh, submissions for other, uh, regulatory authorities becomes a disincentive to going into those markets, uh, which means that the commercial market is left being the United States and sometimes that's just not large enough to uh sustain um a commercial viability. So I'm gonna quickly tell you a little bit about what we're doing at the Center for each, um, uh, which is we're trying to help move forward manufacturing of gene therapies, particularly because the manufacturing of an associated viral gene therapy vectors has been quite challenging, um, uh, despite a decade of work on it. Um, uh, the application of our platform technologies provision is a way that we're hoping to, um, uh, advance more products coming through the system. Um, talk a little bit of how we are, are using accelerated approval to help shorten development timelines, um, and then, uh, talk about, um, some of our learning from the pandemic and how we're applying it to rare disease development. So I'm not putting this schematic up here to make anyone have a headache at this hour, um. I'm just putting it to remind me to tell you that um uh although uh gene therapy vector is a complex process, it is one that can be broken down into steps and can potentially be automated, and there are um uh various labs trying to automate. This process, if not the cell culture production for an associated viral vectors, the downstream process, and the viral vectors, um, something I haven't said, part of the issue is they have to be produced in, uh, in, in a producer cell line, um, uh, so you have a nucleated cell line that has to be producing these, uh, oftentimes they're heck cells, um. Uh, uh, those then, uh, uh, obviously the virus is produced, cells die, you have to purify away the virus from the cells, um, and then you have to hope that the, uh, the process you've used has led to um a product in which the virus, uh, is very filled, um, the capsids are very filled with your Uh, construct, um, and, uh, DNA and not um empty, um, of that, and so, uh. Uh, have to deal with this and, and, and this has been a very Very challenging thing. People every time uh we uh see people trying to do this, they oftentimes run into challenges. Uh, so, uh, we're, we're, uh, sorry, to mean to advance. We're trying to help people here, uh, by, uh, both fostering research in this area, um, as well as, uh, working with our colleagues at the Foundation for NIH and National Center for Advancing Translational Sciences, um, who are working on the bespoke Gene therapy Consortium, uh, to try to develop standard procedures, uh, for making these. Another way though, we can, we can try to help here um is by uh leveraging what we know about manufacturing uh for one product that works uh to another uh and uh because gene therapies that use a vector like a associated viral vector on vectors, um, the different stereotypes, because they, uh, oftentimes use the very same, uh, or similar manufacturing process. Um, and they have very similar toxicology. It is can we leverage that information from uh one vector to another, and, uh, toward that end, uh, Congress gave us. The ability to do so for approved products, um, and so if one has an approved product and comes along with another gene therapy product that uses that same vector backbone, um, but a different insert, uh, and one has this uh platform technology designation, one can Uh, uh, leverage the, uh, uh, initial, uh, uh, toxicology and manufacturing and control information, so it streamlines things. Again, this is helps reducing burden, hopefully moving forward development. Importantly though, this platform technology guidance is very relevant for CRISPR Cas9 because if you look at the genome editing construct on the right, the prime editor, you can use a prime editor to uh correct mutations that might be present, for instance, in hemophilia B factor 9 deficiency. You can use that same. General construct 99.5% of it, except for changing out uh the uh uh the RNA guide segment of 100, 200 nucleotides. Um, uh, and, uh, then correct, uh, hereditary hypercholesterolemia by knocking out uh PCSK9, um, and so very different diseases, um, with a construct that's 99%. Uh, uh, the identical, um, this is really very much a platform, uh, and we're working through what we need to, uh, be able to regulate this most efficiently. Stay tuned because it's not all worked out yet. It's also very promising, uh, because you can deliver CRISPR, uh uh genome editors uh as uh uh lipid nanoparticles, and I shouldn't say just lipid nanoparticles. You can also deliver them uh on uh uh on essentially uh polymer scaffolds, uh, or in synthetic capsids. So lots of ways uh to do this. And the beautiful thing about this is as opposed to needing. These uh uh producer cell lines, which are often mammalian cells here, uh, the mRNA is made oftentimes using uh E. coli, uh, to make a DNA which you then, uh, make RNA off of, uh, uh, the DNA template from. uh, and, uh, so the, the device on the right here is a prototype showing that you could actually make these um uh essentially without needing uh huge facilities. Um, I'm just gonna move on to the last couple of things. Um, we're trying to leverage the parts of gene therapy that we can help. Use to make products get across the finish line to be approved products more rapidly uh to try to keep things from falling out of development. And so one of the things we're doing is uh leveraging um our accelerated approval provisions. Accelerated approval is a regulatory program that FDA has which allows us to use a biomarker or intermediate endpoint that's reasonably likely to predict clinical outcome, that is how someone feels functions or survives. Um, uh, by looking at things like enzyme activities or structural protein levels, and if you think about it, for gene therapies, we often will have an animal model or human observation where we know that a certain reduced percentage uh of a protein um is associated with no observable effect, um, uh, and obviously if you have an even lower level, you'd get the effect. So if you can ring. Uh, a, uh, a protein level back up to that no observable effect level, uh, you have something that's reasonably likely to predict, and, and then you can come back later on with a clinical endpoint, and so that's one of the things we're encouraging. Um, but we're also trying to help move this field forward by eliminating unnecessary regulatory barriers both globally. And uh here in the United States, one of them is we're collaborating right now with our European colleagues to try to be able to eliminate some of our regulatory differences so that uh the same regulatory filing could serve uh both in the US and the EU, um, and then be potentially even reviewed by the regulatory agencies together. Um, obviously the ultimate decisions are made by the respective. Uh, sovereign entities, but, um, this might help speed things up and make things a lot simpler for sponsors. So if this works with uh European Medicines Agency, we'll probably expand it to other regulators as well. And finally, one of the things we learned during Um, uh, the several years of the pandemic, um, was that, uh, one of the most valuable things we have to offer, uh, at FDA for developers is very timely feedback, um, during the Operation Warp speed for developing the mRNA vaccines and other vaccines. Um, the MRNA vaccines were developed so rapidly, in part because we took risks and we condenses clinical trials times, but in large part, um, a fair amount of time was saved because rather than having formal regulatory meetings, which can take a month or two or even 3 to schedule. Um, uh, we simply had an ongoing dialogue by email and teleconference, Zoom conference, um, uh, to, uh, resolve problems in manufacturing, clinical development, or etc. um, as they came up, um, usually helpful there, very labor intensive, uh, rather expensive in terms of needing additional. Our resources to make it happen, but, um, the cost is actually negligible when you uh think about the potential benefits, um, if you're saving many lives doing so. So the idea of uh trying a pilot of this in the rare disease area. Uh, was very logical and so we're doing just that now, uh, where we have 4 products, um, that are having enhanced communication, um, as part of this pilot, uh, they're all for pediatric in in our center, uh, they're all for pediatric, uh, rare diseases that tend to, uh, cause severe disability or death early in life. Um, and you can see there, uh, the, the SAT program, a pilot is one that will uh try to give this kind of warp speed like. Communication, uh, to these and see if we can get them across the finish line faster, um, you know, 25% would be great, faster than they would otherwise, even faster would be even better. But, um, uh, you can see NGLY 1 RET, Canavan, methamloic acidemia, various, uh, uh. Rare genetic diseases that cause um great harm to children. So we are um really trying to advance our uh uh abilities in this area of uh gene therapies. I think genome editing holds tremendous promise, likely um to become an ever greater part of of what we're doing. My guess is that as genome editing takes off, some of our use Of adeno associated viral vectors, at least traditional adeno associated viral vectors will tend to fall off, um, uh, but, uh, hopefully this will bring a tremendous benefit across a wide spectrum of diseases and thanks for your attention and I'll look forward to questions. Thank you, Doctor Marks. Um, there are some questions that have come in through Q&A. I don't know if I need to put my face on here or not, but, um, anyway, the first question that came in is the following. After recently reported pediatric cancers, can you comment on the next steps with regards to, is its schisona for AML by Bluebird? Yeah, so this is, this is was a known issue with the product. It was talked about an advisory committee. Um, uh, of, uh, the, the issue that, uh, there seem to be, uh, blood cancers, mylodysplastic syndromes, or acute myeloid leukemias that seemed to develop in a, uh, portion, roughly 10% of kids who are treated with this, uh, product, um, uh, as reported in a series in the New England Journal from, I think it's from yesterday's New England Journal online, um, uh. I, I suspect I, I, I can't say, uh, because, because it's an active issue, I can't say a ton, but I can tell you we're gonna look at this very carefully, in part, uh, because, uh, people may also be aware that, uh, there were some cases of acute myeloid leukemia MDS in the their sickle cell disease product as well. And overall, I think. Um, it, it, it leads us to have to think through this, um, for adrenal leukodystrophy, it's such a terrible disease. I mean, there's the benefit risk there was felt to be acceptable at the time it was approved, um, because the alternative, uh, was so terrible, um, but Uh, I think we do have to be cautious here as we move forward because, um, I, I think, uh, especially when there are now potentially alternatives that we're starting to see, um, in, in some of these areas, um, uh, that, uh, we're we're very cognizant of what toxicity. So more to come on this, um, uh, and uh it it is a it is a complicated area. It's, it's one of the issues that can be, it's obviously why. Um, knowing where something goes into the genome is, uh, more satisfying than random integration into the genome, um, because when things tend to randomly integrate into the genome, they tend to go to active regions of the genome, and active regions of the genome tend to be where you tend to see oncogenes in regulators, uh, so, um. Uh, I, I think this is, I think we'll probably, um, If nothing else, I think it will make the field kind of reconsider uh the kinds of vectors that we're using and the approaches we're taking. That's a great question and I more unfortunately the answer is more to come and stay tuned about that specific product and um and its sister products uh because I think we'll be we'll be having to have another look at those. It would seem from your discussion and presentation that that may be a potential benefit of CRISPR technologies because of just the comment you made with the ability to know where things are happening within the genome versus a little bit perhaps not a buckshot of, but the ability to further be precise. That may be less of an issue when CRISPR can be used. Yeah, well, see, this is what's such an interesting, it's so interesting to me because the first generation CRISPR, the biggest thing that we were all panicked about were off target effects. Um, but this shows you the power of molecular biology because um uh a number of uh investigators working in this area. We're able to advance the CRISPR molecule, uh such that they uh they they they're now we're now using longer guides. We're not, uh, we have CRISPRs that don't cut both strands of DNA floppy DNA is not a good thing, um, right, um, uh, and so, um, by, uh by having this, I think we've we've got a more precise genometer and there's been a fair amount of nonhuman primate uh work done to support. Uh, the, uh, reduction and off target effects such that indeed, uh, what was originally something we were worried about now is turning out to be its strength, the idea to know, hey, this is gonna put something at a given location, you can direct something uh to a given place and, and in particularly for things like chimeric antigen receptor T cells, it may turn out that using that in and Uh, even in the, in the X vivo approach may help uh reduce some of these concerns, especially as we're starting to think about using these, uh, CAR T cells in non uh hemalog malignancies and and non-malignant diseases. For those of you who may be interested, um, uh, you know, these, uh, potentially have great applicability in uh inflammatory diseases like lupus, systemic. Uh, sclerosis, etc. uh, and there again, you want the safety margin, even though they're bad diseases, you want the, the safety margin to be as great as you can have it. Great. Uh, next question. For the platform designation program, how might an existing platform technology, for instance, AAV 9 made by a company that isn't the manufacturer and isn't owned by an applicant company, acquire the designation? Is it possible to get a platform designation without applying for an NDA? Yeah, it's, it's, it's not at this point, um, and that may change in the future, but the, the problem is right now the, the manufacturing is such that any one manufacturer, even if they follow somebody else's cookbook. Ends up with a product that's not exactly the same because of differences perhaps in reagents, differences um in other factors that we can't always quantify. And so until we can get a better handle on this, um, we have to take an approach that's much like the approach we take in cell therapies, which is that each, you you you have to be manufacturing it, um, in order to actually get a a a designation. Right. So a very pragmatic question. Are there differences in gene editing outcomes between sexes? Uh, really good question and, and to, you know, in, in, in to, to my knowledge, I don't know this, but I, I, I, someone may, it also may be that we haven't had, uh, an I mean the number of genome editing, uh, the, the number of sickle cell, uh, patients who have seen it the gene edit, those that's an in an in vitro edit, uh, so it's uh it's hard to Uh, no, whereas the, um, directly administered genome editors have not been given to tremendous numbers of people yet. Be interested, great, great question. I just don't know the answer to it. I don't know that anyone knows it just yet. More numbers, more to come, more, more to come. Yeah, yeah. Are the, are the four-star pilots all CRISPR technology based? No, they're all they're, uh, 3 of them are AAV vectored and one is an MRNA technology uh based. So, um, it turns out they are, they are not uh the the part of the reason why that, you might say, well, why, why aren't you leaning in. We wanted to take products that were probably closer to the market today, and the market today is um for, for, you know, for better or worse, our workhorse gene therapy vector, uh, that's most advanced right now is an associated viral vector for directly administered gene therapies uh or uh potentially. Not using something like an mRNA based technology, um, CRISPR directly administered CRISPR is just, it's a little bit uh uh less uh far advanced right now. So, uh, we wanted to have things that we knew that in the next potentially in the next year or two, could make it over the finish line. Given the report, reported deaths of patients receiving systemic infusion AAV encoding the truncated dystrophy, dystrophin gene for muscular dystrophy, are their concerns for the future of AAV as the as a gene therapy vector. Uh, you know, good question. Um, I think that it's less about AAV as a gene therapy vector and understanding, um, Uh, how we have to be careful about where we deploy via a gene therapy vector, um, uh, for instance, it, it's, it's because it does go to the liver, um, uh, at least in part, um, uh, in, in many cases, uh, you don't want to be, uh, giving a a large bolus of AV. Uh, to someone with impending liver failure, um, uh, as, as, as we've learned, um, and then there are also certain, certain mutations that are, are seem to be uh problematic. AAV is not the ideal gene therapy vector. And that's why people are trying to develop synthetic vectors that might look like AAV but um improve upon it. Um, one of the things I did not mention that I should have mentioned, um, is that AAV cannot be redosed. Once you see the large number of genome copies, usually on the order of 10 to 13th, 10 to 14th. Um, particle forming units per kilogram, uh, that are given, uh, as part of a systemic gene therapy, you get cross reactivity against uh all different AV serotypes and so you can't redose with an AAV. So there you can just see right, right off the bat that that's a problem with this vector, um, because you might think you Might want to redose because if you look at, for instance, the hemophilia gene therapies, they do wear off, uh, particularly the factor 8 gene therapies wear off with time. So redosing would be very helpful. Right now, if you want to redose, you have to do something heroic, which is, um, uh, try to, uh, uh, uh, essentially remove the antibodies or, uh, uh, uh, desensitize to them. That's just, it's just often it's probably a bridge too far. Um, so people are trying to develop synthetic capcids, um, that would also again get over some of the challenges of of AV um it's, it's, it's where we've come to. It turns out the previous generation of vector, which was adenovirus, was even a worse problem. Uh, and actually, uh, led to essentially the gene therapy field shutting down for several years. So, um, hopefully we'll continue to see advances. Um, I think. You know what we're seeing and that's why we have to be really careful here and why we'll look at each complication as it comes up, is we need the public to know that we care to look very carefully at these adverse effects that we're very much always looking at risk benefit and uncertainty in making these decisions um and that um we will take action to take something off the market when we're if we get overly concerned, but um. I think if we want the field of gene therapy to progress and bring benefit to um patients who have no other hope, we're probably gonna have to deal with some of the bumpiness that's gonna come as we explore and we learn about. Um, uh, AAV, uh, and then subsequently same thing will happen. I'm sure we're gonna find we've already learned some, uh, things about, uh, CRISPR, uh, that will, uh, tell us, um, uh, more of how it can be deployed. So it's, it's a really good question, um, not a straightforward answer, uh, but, um, I think we're, we'll we'll take it, each case as it comes, um, based on benefit risk uncertainty. Um, next question. Is the FDA considering any strategies or regulatory requirements that could encourage increased affordability for gene therapies, such as mandating cost transparency or implementing guidelines to promote more equitable pricing during the approval process. So, Well, this is one of these questions where I'm gonna say, I couldn't agree more with the questioner about the need to get down the price of gene therapy. It is one of the top things on my mind. But, uh, some of us have to, you know, if you work in government, you have to abide by the rules. Our statutory mandate at FDA does not include, um, Uh, uh, doing anything about price controls or mandating prices that falls in the hands of our sister agency, the Center for Medicare and Medicaid Services. That said, our goal is to try to do everything we can, uh, and to reduce the cost of Uh, that goes into this. So that includes everything from the manufacturing costs to the development costs to potentially having markets that are larger, uh, so that people can, uh, hopefully, uh not feel I need to charge as much. I do think that, um, ultimately the key here is going to be to moving to some type of vector production that can be much more automated, um, and, and that's why I'm, I, again, this is not. Not an official position, it's just a a a gut check to me. Um, I, I think that as we can move towards um lipid nanoparticle or other synthetic particle delivered gene therapies where you can make them without amalian producer cell line, um, uh, and, uh, so you don't have to go through all of the growing up and purification. Um, I think we will see the price of these come down by, uh, you know, half an order to an order of magnitude, um, and that'll make a huge difference. So I think advancing that science and then the technology of manufacturing will make a big difference, um, and we'll leave it in the meantime to our colleagues in Center for Medicare and Medicaid Services, uh, to try to get a handle on this. Um, uh, because I, I, I think I, I agree with the questioner that, uh, the problem is that if we, if we didn't, if something doesn't change, the ability to pay for gene therapy won't, it won't be sustainable. Yeah. There's a related comment in the Q&A that it basically said, you know, to approve a product and deliver it is a whole another issue because uh despite it being available, there is nobody in Minnesota who has received the sickle cell therapy, primarily as a result of uh. concerns regarding reimbursement. So uh to, to basically illustrate your point that, you know, costs should not be the limiting factor on the delivery of needed care, but that's, that's the reality of the world we face. Um, um, there's one other comment here before we, uh, close up a little bit. Um, can you provide context to the FDA reviews and your input on the recent DMD gene prescription decision? Yeah, so, so really good question. Uh, I, I, I'm, I'm, I'm without going into incredible detail, um, you know, so Duchenne's muscular dystrophy, um, the first generation gene therapy that was studied, um, uh, uh, is somewhat controversial because, uh, we, the, the, the product when it was studied. Um, uh, in its phase 3 randomized clinical trial, it missed its primary endpoint at the end of the day. The primary endpoint was the North Star Ambulatory Assessment, which is composite of 17 different assessments rated on a scale from 0 to 2, um, uh, uh of uh of function. Uh, however, it it actually made, uh, nearly all of its secondary. Um, uh, end points, and it actually had very clear, um, uh, improvements in laboratory values that would be consistent with an improved effect on Um, muscles such as um major reductions in creatine kinase levels, major reductions in LDH, um, uh, levels, and so the totality of the evidence, um, here, uh, was compelling that the product did have a clinical benefit. Now, um, for those who are pure, you know, if, if you look at it from a purely statistical perspective, it failed its primary endpoint and FDA would be within its rights to um reject this. On the other hand, if you look at what else was in development at this time, uh, and when the next available therapy would potentially be able to come along, that would be bring benefit um to boys who might potentially not be able to. Um, uh, receive those therapies because after, uh, the, the, the, the problem is that once you lose function, giving a gene therapy is not gonna help you regain that. It just this is not how it's gonna work in in Duchennes. You're not gonna regain function. So the idea that we might have boys that could be walking for a longer period of time, and we might deprive them of that. Um, had to be had to be weighed against, um, well, could we get, you know, could we be feel better if 3 years from now we had data from another clinical trial, um, where people knew better than to Um, I, uh, use North Star angular to assessment. So at at FDA we are, we do have a little bit of latitude. Um, I think the controversial aspect of this was that there we had to, I, I ended up overruling some of our reviewers in this, but um I, I think when you step back and you can, and this has happened prior, uh, in prior. Uh, files at FDA and actually it even happened when I was in industry. If you can step back and you can understand why a trial failed, uh, because of an assessment, and you have very good evidence that the product has uh uh efficacy and that it essentially, um, uh, is foundationally effective, um, in some way. I think it it allows us to make uh the our statute allows us to make a judgment. So that's how we got there, um. Uh, it, it does, it, it, it, it actually, it's, it's very funny because back when I worked uh years ago in industry, um, I worked for a rare genetic disease company and we kind of all would we knew enough uh back then to try to avoid using composite endpoints for precisely this reason and just so, so that um that everyone understands what I'm talking about. The problem with North Star Ambulatory assessment is that many of the the tasks are rated. As uh on a 3 point or scale, the problem is that 0 is you can't do it at all, sorry, in this case, I, I, I just reversed it. 0 is you're not affected at all. 2 is you can't do it at all, and 1 is everything else. And the problem is that that means that there is the there's just so much uh uh vagueness in this middle category that it's hard to actually show differences. Um, in that area, so people are trying to use things like videography now to Uh, to, to get a better handle on this, and I think we've learned for future trials, um, uh, uh, but, um, long answer, uh, to say that, you know, I think we have to do the right thing, uh, by the totality of the evidence, um, uh, and it's very, I, I only like to overrule our reviewers very, very rarely, and I think there's a very uh a very uh specific special circumstance. Great. Um, that is the end of our questions, which brings us nearly up to one o'clock. I would give you the opportunity to, uh, are there any closing remarks? This has been just a fascinating presentation, and I can express to you how much I thank you for being here, um, for this wonderful summary of really where this started, now 50 years ago, uh, where we're at and, and the promise really of where we may go in the future. Uh, albeit with all the bumps and warts along the way because it's clear that there are things we are learning. It's not a perfect science, um, but there is clearly promise, um, not without expense, but it's clearly something that to look forward to for medicine. No, I, I, I think you've, you've summed it up really nicely and I think the only thing I will say is one of the things that this whole field has taught me. Um, it's although the, the science behind this is incredibly exciting, uh, the medicine is incredibly exciting. Um, at the end of the day, the affordability will largely depend on the technology, our ability to actually make the stuff, um, and, uh, that actually is something that we'll have to be focusing on, on if, if we're gonna actually have gene therapies get to. Um, the type of cost and availability that will allow them to be used to me, uh, in the most important way, which is globally with great equity, um, uh, and so we've got some work to do. Absolutely, absolutely. Again, Doctor, Doctor Mars, thank you so much for taking the time to join us today. Uh, we are so very appreciative of your time and your excellent presentation. Wish you all the best and uh thank you on behalf of the Center for Individualized Medicine, Mayo Clinic, Rochester. Have a great day. Bye-bye. Take care. Bye-bye.
