DENISE DUPRAS: Good afternoon. My name is Dr. Denise Dupras, 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, Dr. Peter Marks.

Dr. Marks 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 Dr. Peter Marks.

PETER MARKS: Thanks very much for having me today. I'm just going to bring up my slides here. So thanks again. I would like to, as mentioned, talk about where we stand currently. In this area of gene therapy and where we are headed. Just for a moment, though, by way of background, gene therapy isn't something that has sprung up overnight. It's been something that has been almost half a century in the making.

It actually started with very early attempts at NIH and then has grown. There were kind of fits and starts and some setbacks at times. But over the past decade, there has been steady progress, and more recently, 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 familiar with the different methods of delivering gene therapy, gene therapies today, in the United States, are delivered essentially by 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 give them back to a person after the gene therapy has been conducted, essentially ex-vivo.

And that has the advantage of not exposing the entire person to the gene therapy vector. It also allows you to potentially characterize the cell population that you are transducing with the gene, and also allows you to potentially do that with reasonably high efficiency to a given cell population that you can measure. So the ex-vivo approach actually was the approach used for the initial products licensed in the United States, which were chimeric antigen receptor T cells.

But the other way of going about doing this is obviously to give the gene therapy vector directly, either locally, into an organ that is affected, or systemically. And that variety of vectors have been explored over the course of time, but most recently, the field has settled on adeno-associated viral vectors for that directly administered gene therapies. Now, there are others in development that we're going to talk about, so that is for the directly administered gene therapies.

And on the other hand for the gene therapies that are being handled in culture, ex-vivo, those are often being transformed with or transfected using lentiviral or retroviral vectors. So different vectors have predominated here. We've settled on these in part over time because of the safety profiles that have been demonstrated with each of these situations, the lentiviral vectors in the ex-vivo approach and the adeno-associated viral vectors in-vivo approach.

For those who aren't, again, familiar with AAV, AAV is a human virus, a virus that affects humans, that is generally non-pathogenic. It is something that most of us get exposed to at some point, but we don't have serious effects to it. Turns out to be a reasonable gene therapy vector, because you can take out a good part of its genome at roughly 3,500 to 4,000 base pairs and put in a gene of interest.

So that's helpful. The problem with that is that it is not the ideal gene therapy vector because you can't put in very large gene segments. And for certain gene applications, people have had to be creative and develop shortened proteins to be able to do gene therapy. An example of that, for instance, is what's done in hemophilia A, where the factor VIII molecule is just too big to put into an adeno-associated viral vector for expression.

So it turns out that there was a product developed previously, in which the B domain was deleted, and that particular construct can fit into a gene therapy vector. So this is the landscape of how we're doing this. Things are evolving because people are now starting to look at other methods for gene therapy delivery, including using lipid nanoparticles, or synthetic particles, either polymers, or what amounts to viral-like particles to do this. but those are still in development.

What has transformed this field, though, in the past several years has been the discovery that CRISPR/Cas9 genome editing could be applied to mammalian cells. It's essentially a bacterial protection system, almost like a bacterial immune system, that is able to be leveraged in the setting of gene therapy. The original CRISPR/Cas9 constructs on the left here cut both strands of DNA. Allowed one to then, potentially, have either incorporation of a segment of DNA at that locus, or essentially rejoining, and allowed one to knock out a gene or insert a gene.

But subsequently, through work that has evolved-- and it's quite elegant work-- we now have base editing genome editors, where you can fix. They've now come up with ones for all of the different possibilities. So you can take any nucleotide abnormality and fix a single nucleotide abnormality in DNA. And then finally, because there are many mutations where it's not a single base pair, it's a stretch of DNA that is improper, the prime editors, or the next generation, further even, of the CRISPR/Cas9 constructs, where these have a CRISPR, which is kind of an advanced CRISPR, the same one that's used, kind of the same type that's used, in the more advanced CRISPR constructs which does not cut both strands of DNA.

That has its advantages. And it's hooked up to a reverse transcriptase. So it essentially can read right into DNA short segments, a couple hundred base pairs, at this point, and therefore correct segments of DNA. It also can, potentially, put in a site into DNA, which you can subsequently come along, or simultaneously come along with, and insert a longer stretch of DNA segment that you're carrying along.

So lots of innovation here. I'm not describing all of it, but just to try to give you a flavor that CRISPR technology is really moving this field forward, particularly, as we'll come to, because you can deliver these constructs as mRNAs into a cell. In much the same way as our vaccines work, you will end up getting an active construct with an mRNA delivery.

So the various products we have now in the United States, depending on how you count them-- it's either 19 or 20, or you could come up with 21 products. It's 19 unique products because two of the products, Zynteglo and Lyfgenia, are the same basic product. It's just one is for sickle cell disease and one is for thalassemia. Now we try to keep the products that are under the same names. So it's essentially 19 approved gene therapies, in terms of distinct entities.

And the color code here is that the blue entities are chimeric antigen receptor T cells, or modified T cells in the case of Tecelera, which is the first genetically modified T cell for non-hematology oncology indications for synovial cell sarcoma. The ones in green are genetically modified stem cells, in this case for sickle cell disease, thalassemia, and adrenoleukodystrophy. And the ones in purple are directly administered gene therapies, which cover a range of both rare genetic diseases, including hemophilia A and B and Duchenne muscular dystrophy.

So we've come a fair ways here, but there's a long way to go, in part because the gene therapies that we have approved, have covered, are the more uncommon diseases, but there are a lot of very rare diseases for which gene therapy could be applicable for which we still don't have products. So I just want to take a moment and back up a little bit and say, what is CAR-T cell? Where is it going? And then I'll go back and talk about where gene therapy that's directly administered is going. But when I think about where CAR-T cell development is going, it's largely driven by the developments that we've seen in our ability to make molecular constructs.

Just so that people know for autologous chimeric antigen receptor T cell production involves-- and this is, for instance, the licensed chimeric antigen receptor T cell products. There was a lot that had to be worked out. They are made by doing an apheresis after to mobilize cells. The apheresis takes those mobilized cells and you then either isolate T cells, or purify somewhat, and then transfect, formulate your product, oftentimes after it's grown some in culture. Then get back to the same person, having introduced the chimeric antigen receptor, which is noted in schematic form in the upper left-hand corner of the slide.

But those autologous CAR-T cells suffer from the fact that each person who is a donor of those is generally the patient who's been treated with various amounts of chemotherapy, has a variable amount of background disease still circulating often, and so it is not an exact process. And the response rates, though good, are not perfect. And is there a way to improve upon that?

Well, one way that might be able to improve upon that, in terms of both cost, availability for when somebody has relapsed, without having to wait a long time and to have a very consistent product, would be to make allogeneic CAR-T cells. Take a healthy donor, where you can potentially make 100 doses of a product from one individual, 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 a number of cuts and a number of changes into the cells to introduce multiple constructs while getting rid of the MHC class I molecules, and therefore have, potentially, an allogeneic CAR-T that can look at multiple antigens. Now, that's important because as we think about addressing solid tumors, being able to address multiple antigens is really important.

Unlike in hematologic malignancies, where we're lucky enough to have a single target like CD19 or CD22, in the case of some pediatric acute lymphoid leukemias, where we can go after with a CAR-T cell, if you did that for some of the antigens on cancer cells that are solid tumors, there is too much overlap with normal tissue. However, if you can go after multiple antigens, you can hopefully find a unique composition on the tumor that is not present on normal tissue, that you can then have the CAR-T recognized, and people are working on that.

But the other piece that we might see in the future, it may be that we'll see CAR-T cells produced using mRNA technology. And that's because you can take an mRNA targeting approach, potentially using CRISPR, if you need to, and put that into a lipid nanoparticle, or other delivery vehicle. Potentially give that in intravenously, rather than taking the cells out, and then have the population of T cells altered with the construct. The advantage here is, obviously, you could significantly reduce the complexity and cost associated with the therapy, which is something that we would like to help facilitate because these are very expensive therapies at the moment. Also make life a lot easier in practical sense of things.

But this kind of an approach, potentially using CRISPR even, is exciting, in part because when using CRISPR as a way to make a site for 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 where the retroviral sequences inserting the chimeric antigen receptor construct. And that means that sometimes it probably is going into a less than optimal place that could be associated with, on rare occasion, with secondary cancer.

So lots of exciting going on here. We'll see how long it takes to get there. But I think this is over the horizon for CAR-T, where, for the next decade, we're probably in the business still of autologous CAR-T cells and, potentially, allogeneic CAR-T cells coming online in the next five years or so. But my guess is that 10 years down the line, we may well see these in-vivo modifications, in part because of the ability to potentially target to T cells using studied liposome technology or other technologies, and in part because it turns out you don't need to get an incredibly high efficiency of T cells transduced with your construct to still have efficacy.

So now I'm going to turn to gene therapy for rare diseases. Gene therapy for rare diseases is just such an exciting area and it's really been moving ahead rapidly. I've talked about CRISPR/Cas9 genome editing. Well, for something that was described to be of utility, potentially, in humans in about 2012, to see an approved product about a decade and a little bit later that uses that is impressive. And CASGEVY is just that. It's a genome-edited hematopoietic stem cell-based therapy, which can be used either for beta thalassemia major or for sickle cell disease.

It essentially shuts off a repressor, knocks out a repressor of fetal hemoglobin production. And fetal hemoglobin is a perfectly reasonable hemoglobin to have. If you have beta thalassemia, there is actually a natural situation where that can occur. And we also see a similar situation in sickle cell disease, where people with hereditary persistence of fetal hemoglobin don't have the same manifestations of sickle cell disease that those who are homozygous for S hemoglobin.

So here, again, quite an impressive development. That said, as I already alluded to, gene therapy is not proliferating at a rate in which we think it probably should. There are many reasonable targets that exist. And gene therapies that have made it partway through development that have dropped out, not because they have failed clinically, but they have failed because of a combination of challenges with their manufacturing.

The fact that, with venture capital funding, a lot of this work, the clinical development timelines are critical. If they get too drawn out, people lose interest or they run out of cash, so that's been a problem. And the other piece is that when you're dealing with very small populations in one country, like the United States, the different global regulatory requirements, where someone then has to go and redo studies, reformat submissions for other regulatory authorities, becomes a disincentive to going into those markets, which means that the commercial market is left being the United States, and sometimes that's just not a large enough to sustain commercial viability.

So I'm going to quickly tell you a little bit about what we're doing at the Center for each of them, which is we're trying to help move forward manufacturing of gene therapies, particularly because the manufacturing of adeno-associated viral gene therapy vectors has been quite challenging, despite a decade of work on it. The application of our platform technologies provision is a way that we're hoping to advance more products coming through the system. We'll talk a little bit of how we are using accelerated approval to help shorten development timelines, and then talk about 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. I'm just putting it to remind me to tell you that although 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 various labs trying to automate this process-- if not the cell culture production for adeno-associated viral vectors, the downstream process and the viral vectors.

Something I haven't said-- part of the issue is they have to be produced in a producer cell line. So you have a nucleated cell line that has to be producing these. Oftentimes, they're HEK cells. Obviously, the viruses-produced cells die. You have to purify away the virus from the cells, and then you have to hope that the process you've used has led to a product in which the virus is very filled, the capsids are very filled with your construct and DNA, and not empty of that.

And so have to deal with this, and this has been a very, very challenging thing. Every time we see people trying to do this, they oftentimes run into challenges. Sorry, too fast. We're trying to help people here by both fostering research in this area, as well as working with our colleagues at the Foundation for NIH and National Center for Advancing Translational Sciences, who are working on the bespoke gene therapy consortium to try to develop standard procedures for making these.

Another way, though, that we can try to help here is by leveraging what we know about manufacturing for one product that works to another. And because gene therapies that use a vector-like adeno-associated viral vectors-- the different serotypes-- because they oftentimes use the very same or similar manufacturing process and they have very similar toxicology, can we leverage that information from one vector to another? And toward that end, Congress gave us the ability to do so for approved products.

So if one has an approved product and comes along with another gene therapy product that uses that same vector backbone, but a different insert, and one has this platform technology designation, one can leverage the initial toxicology and manufacturing and control information. So it streamlines things. Again, this 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 correct mutations that might be present. For instance, in hemophilia B factor IX deficiency, you can use that same general construct, 99.5% of it, except for changing out the RNA guide segment of 100 to 200 nucleotides, then correct hereditary hypercholesterolemia by knocking out PCSK9.

And so very different diseases with a construct that's 99 plus percent the identical. This is really very much a platform, and we're working through what we need to be able to regulate this most efficiently. Stay tuned because it's not all worked out yet. It's also very promising because you can deliver CRISPR genome editors as lipid nanoparticles. And I shouldn't say just lipid nanoparticles. You can also deliver them on, essentially, polymer scaffolds or in synthetic capsids. So lots of ways to do this.

And the beautiful thing about this is as opposed to needing these producer cell lines, which are often mammalian cells, here, the mRNA is made oftentimes using E. coli to make DNA, which you then make RNA off of the DNA template from. So the device on the right here is just a prototype, showing that you could actually make these, essentially, without needing huge facilities.

I'm just going to move on to the last couple of things. 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, to try to keep things from falling out of development. And so one of the things we're doing is leveraging our accelerated approval provisions. Accelerated approval is a regulatory program that FDA has, which allows us to use a biomarker or intermediate endpoint that is reasonably likely to predict clinical outcome-- that is, how someone feels, functions, or survives-- 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 a human observation, where we know that a certain reduced percentage of a protein is associated with no observable effect. And obviously, if you have an even lower level, you'd get the effect. So if you can bring a protein level back up to that no observable effect level, you have something that's reasonably likely to predict, and then you can come back later on with a clinical endpoint. So that's one of the things we're encouraging.

But we're also trying to help move this field forward by eliminating unnecessary regulatory barriers, both globally and 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 the same regulatory filing could serve both in the US and the EU, and then be potentially even reviewed by the regulatory agencies together. Obviously, the ultimate decisions are made by the respective sovereign entities, but this might help speed things up and make things a lot simpler for sponsors. So if this works with European Medicines Agency, we'll probably expand it to other regulators as well.

And finally, one of the things we learned during the several years of the pandemic was that one of the most valuable things we have to offer at FDA for developers is very timely feedback. During the Operation Warp Speed for developing the mRNA vaccines and other vaccines, the mRNA vaccines were developed so rapidly, in part because we took risks and we condensed clinical trials times. But in large part, a fair amount of time was saved because rather than having formal regulatory meetings, which can take a month or two or even three to schedule, we simply had an ongoing dialogue by email and teleconference, Zoom conference, to resolve problems in manufacturing, clinical development, or etc, as they came up.

Usually helpful. They're very labor-intensive, rather expensive in terms of needing additional resources to make it happen. But the cost is actually negligible when you think about the potential benefits, if you're saving many lives doing so. So the idea of trying a pilot of this in the rare disease area was very logical, and so we're doing just that now, where we have four products that are having enhanced communication as part of this pilot. in our center, they're all for pediatric rare diseases that tend to cause severe disability or death early in life.

You can see there the START program pilot is one that will try to give this warp speed-like communication to these and see if we can get them across the finish line faster. 25% would be great. Faster than they would otherwise. Even faster would be even better. But you can see NGLY1, Rett, Canavan, methylmalonic acidemia, various rare genetic diseases that cause great harm to children. So we are really trying to advance our abilities in this area of gene therapies.

I think genome editing holds tremendous promise, likely to become an ever greater part 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. But hopefully, this will bring tremendous benefit across a wide spectrum of diseases. Thanks for your attention, and I'll look forward to questions.

DENISE DUPRAS: Thank you, Dr. Marks. 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 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 it Skysona for AML by bluebird?

PETER MARKS: Yeah, so this was a known issue with the product. It was talked about in an advisory committee, of the issue that there seemed to be blood cancers, myelodysplastic syndromes, or acute myeloid leukemias that seem to develop in a portion, roughly 10% of kids who are treated with this product, as reported in a series in The New England Journal. I think it's from yesterday's New England Journal online.

Because it's an active issue, I can't say a ton, but I can tell you we're going to look at this very carefully, in part because people may also be aware that there were some cases of acute myeloid leukemia, MDS, in their sickle cell disease product as well. And overall, I think it leads us to have to think through this. For adrenoleukodystrophy, it's such a terrible disease. The benefit risk there was felt to be acceptable, at the time it was approved, because the alternative was so terrible.

But I think we do have to be cautious here as we move forward because, especially when there are now, potentially, alternatives that we're starting to see in some of these areas that we're very cognizant of toxicity. So more to come on this. It is a complicated area.

Knowing where something goes into the genome is more satisfying than random integration into the genome. 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 and regulators. If nothing else, I think it will make the field reconsider the kinds of vectors that we're using and the approaches we're taking. But it's a great question. Unfortunately, the answer is more to come and stay tuned about that specific product and its sister products, because I think we'll be having to have another look at those.

DENISE DUPRAS: It would seem, from your discussion and presentation, 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, but the ability to further to be precise. That may be less of an issue when CRISPR can be used.

PETER MARKS: Yeah. Well, see, it's so interesting to me because the first generation CRISPR, the biggest thing that we were all panicked about were off-target effects. But this shows you the power of molecular biology, because a number of investigators working in this area were able to advance the CRISPR molecule, such that we're now using longer guides. We have CRISPRs that don't cut both strands of DNA. Floppy DNA is not a good thing.

[LAUGHS]

Right? So by having this, I think we've got a more precise genome editor. And there's been a fair amount of nonhuman primate work done to support the reduction in off-target effects, such that, indeed, what was originally something we were worried about now is turning out to be its strength, the idea to know, hey, this is going to put something at a given location. You can direct something to a given place.

And particularly, for things like chimeric antigen receptor T cells, it may turn out that using that, even in the ex-vivo approach, may help reduce some of these concerns, especially as we're starting to think about using these CAR-T cells in non-hematologic malignancies and non-malignant diseases. For those of you who may be interested, these, potentially, have great applicability in inflammatory diseases, like lupus, systemic sclerosis, etc. And there, again, you want the safety margin. Even though they're bad diseases, you want the safety margin to be as great as you can have it.

DENISE DUPRAS: Great. Next question. For the platform designation program, how might an existing platform technology-- for instance AAV9-- 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?

PETER MARKS: Yeah, it's not at this point. And that may change in the future. But the problem is right now, 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 in other factors that we can't always quantify. And so until we can get a better handle on this, we have to take an approach that's much like the approach we take in cell therapies, which is that you have to be manufacturing it in order to actually get a designation.

DENISE DUPRAS: Great. So a very pragmatic question. Are there differences in gene editing outcomes between sexes?

PETER MARKS: A really good question. To my knowledge-- I don't know this, but someone may. It also may be that we haven't had-- I mean, the number of genome editing-- the number of sickle cell patients who have received the gene edit-- that's an in-vitro edit, so it's hard to know, whereas the directly administered genome editors have not been given to tremendous numbers of people yet. Be interested. Great question, I just don't know the answer to it. I don't know that anyone knows it just yet.

DENISE DUPRAS: More numbers. More to come. More to come.

PETER MARKS: More to come.

DENISE DUPRAS: Yeah. Yeah.

PETER MARKS: It's a good question.

DENISE DUPRAS: Are the four star pilots all CRISPR technology-based?

PETER MARKS: No. Three of them are AAV vectored and one is an mRNA technology-based. So it turns out, a part of the reason why that-- you might say, well, why aren't you leaning in more? We wanted to take products that were probably closer to the market today. And the market today is-- for better or worse, our workhorse gene therapy vector that's most advanced right now is adeno-associated viral vector for directly administered gene therapies, or potentially using something like an mRNA-based technology. Directly administered CRISPR, it's a little bit less far advanced right now. So we wanted to have things that we knew that, potentially, in the next year or two, could make it over the finish line.

DENISE DUPRAS: Given the reported deaths of patients receiving systemic infusion of AAV encoding, the truncated dystrophin gene for muscular dystrophy, are there concerns for the future of AAV as a gene therapy vector?

PETER MARKS: You know, good question. I think that it's less about AAV as a gene therapy vector and understanding how we have to be careful about where we deploy AAV as a gene therapy vector. For instance, because it does go to the liver, at least in part in many cases, you don't want to be giving a large bolus of AAV to someone with impending liver failure, as we've learned. And then there are also certain mutations that seem to be 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 improve upon it. One of the things I did not mention, that I should have mentioned, is that AAV cannot be dosed. Once you see the large number of genome copies-- usually on the order of 10 to the 13th, 10 to the 14th particle forming units per kilogram that are given as part of a systemic gene therapy-- you get cross-reactivity against all different AAV serotypes, and so you can't dose with an AAV.

So you can just see, right off the bat, that that's a problem with this vector. Because you might think you might want to dose. Because if you look at, for instance, the hemophilia gene therapies, they do wear off. Particularly, the factor VIII gene therapies wear off with time, so dosing would be very helpful. Now if you want to dose you have to do something heroic, which is try to essentially remove the antibodies or desensitize to them. It's probably a bridge too far. So people are trying to develop synthetic capsids that would also, again, get over some of the challenges of AAV. It's where we've come to. It turns out the previous generation of vector, which was adenovirus, was even a worse problem, and actually led to essentially the gene therapy field shutting down for several years.

Hopefully, we'll continue to see advances. I think 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, and that we will take action to take something off the market if we get overly concerned.

I think if we want the field of gene therapy to progress and bring benefit to patients who have no other hope, we're probably going to have to deal with some of the bumpiness that's going to come as we explore and we learn about AAV. And then subsequently, the same thing will happen. We've already learned some things about CRISPR that will tell us more of how it can be deployed. So it's a really good question. It's not a straightforward answer, but I think we'll take it each case as it comes based on benefit risk uncertainty.

DENISE DUPRAS: 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?

PETER MARKS: So this is one of these questions where I'm going to 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 some of us have to-- if you work in government, you have to abide by the rules. Our statutory mandate at FDA does not include 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 and to reduce the cost that goes into this. So that includes everything from the manufacturing costs to the development costs to, potentially, having markets that are larger so that people can hopefully not feel, I need to charge as much. I do think that ultimately key here is going to be moving to some type of vector production that can be much more automated.

Again, this is not an official position. It's just a gut check to me. I think that as we can move towards a lipid nanoparticle or other synthetic particle-delivered gene therapies, where you can make them without a mammalian producer cell line so you don't have to go through all of the growing up and purification, I think we will see the price of these come down by half an order to an order of magnitude, and that'll make a huge difference.

So I think advancing that science and then the technology of manufacturing will make a big difference. And we'll leave it, in the meantime, to our colleagues in the Center for Medicare and Medicaid Services to try to get a handle on this. Because I agree with the questioner, that the problem is if something doesn't change, the ability to pay for gene therapy, it won't be sustainable.

DENISE DUPRAS: Yeah. There's a related comment in the Q&A. It basically says, to approve a product and deliver it is a whole other issue because despite it being available, there is nobody in Minnesota who has received the sickle cell therapy primarily as a result of concerns regarding reimbursement. So to basically illustrate your point that cost should not be the limiting factor on the delivery of needed care, but that's the reality of the world we face.

PETER MARKS: Yeah.

DENISE DUPRAS: There's one other comment here before we close up a little bit. Can you provide context to the FDA reviews and your input on the recent DMD gene prescription decision?

PETER MARKS: Yeah. So really good question. Without going into incredible detail, Duchenne muscular dystrophy, the first generation gene therapy that was studied is somewhat controversial because the product, when it was studied in its phase III 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 a composite of 17 different assessments, rated on a scale from 0 to 2 of function.

However, it actually made nearly all of its secondary endpoints. And it actually had very clear improvements in laboratory values that would be consistent with an improved effect on muscles, such as major reductions in creatine kinase levels, major reductions in LDH levels. So the totality of the evidence here was compelling that the product did have a clinical benefit.

Now, if you look at it from a purely statistical perspective, it failed its primary endpoint and FDA would be within its rights to reject this. On the other hand, if you look at what else was in development at this time, and when the next available therapy would potentially be able to come along that would bring benefit to boys who might potentially not be able to receive those therapies-- the problem is that once you lose function, giving a gene therapy is not going to help you regain that. This is not how it's going to work in Duchenne. You're not going to 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 had to be weighed against, well, could we be feel better if three years from now we had data from another clinical trial, where people knew better than to use North Star Ambulatory Assessment?

So at FDA, we do have a little bit of latitude. I think the controversial aspect of this was that I ended up overruling some of our reviewers in this. I think when you step back-- and this has happened in prior 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 because of an assessment, and you have very good evidence that the product has efficacy, and that it, essentially, is foundationally effective in some way, our statute allows us to make a judgment. So that's how we got there.

It's actually very funny because back when I worked, years ago, in industry, I worked for a rare genetic disease company. We knew enough back then to try to avoid using composite endpoints for precisely this reason. And just so that everyone understands what I'm talking about, the problem with North Star Ambulatory Assessment is that many of the tasks are rated on a three-point org scale.

The problem is that 0 is you can't do it at all. Sorry. In this case, 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 means that there's just so much vagueness in this middle category that it's hard to actually show differences in that area.

So people are trying to use things like videography now to get a better handle on this, and I think we've learned for future trials. But long answer to say that I think we have to do the right thing by the totality of the evidence. I only like to overrule our reviewers very, very rarely, and I think this is a very specific special circumstance.

DENISE DUPRAS: Great. That is the end of our questions, which brings us nearly up to 1 o'clock. I would give you the opportunity, are there any closing remarks? This has been just a fascinating presentation, and I cannot express to you how much I thank you for being here for this wonderful summary of, really, where this started, now 50 years ago; where we're at; and the promise, really, of where we may go in the future, 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. But there is clearly promise. Not without expense, but it's clearly something to look forward to for medicine.

PETER MARKS: I think 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 is although the science behind this is incredibly exciting, the medicine is incredibly exciting, at the end of the day, the affordability will largely depend on the technology, our ability to actually make the stuff. And that, actually, is something that will have to be focusing on if we're going to actually have gene therapies get to the type of cost and availability that will allow them to be used, to me, in the most important way, which is globally with great equity. So we've got some work to do.

[LAUGHS]

DENISE DUPRAS: Absolutely. Absolutely.

PETER MARKS: Great. Thank you so much.

DENISE DUPRAS: Dr. Marks, thank you so much for taking the time to join us today. We are so very appreciative of your time and your excellent presentation. Wish you all the best. And thank you on behalf of the Center for Individualized Medicine, Mayo Clinic Rochester. Have a great day.

PETER MARKS: Thanks very much.

DENISE DUPRAS: Bye bye.

PETER MARKS: Take care. Bye bye.