Can Spark Phase III Results Ignite Gene Therapy?

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Jeffrey D. Marrazzo, Co-Founder and CEO of Spark Therapeutics, discusses the successful Phase III trial of its lead candidate, SPK-RPE65, was able to improve functional vision in patients with a rare form of a genetic disorder known as RPE65-mediated inherited retinal dystrophies. SPK-RPE65 is intended to treat rare blinding conditions caused by mutations in the RPE65 gene, which is linked to subtypes of Leber congenital amaurosis (LCA type 2) and retinitis pigmentosa (RP type 20). Wall St. approved as well–Spark shares rose almost 60% to $70 in trading before the market opened the day of the announcement. The study results represent the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease, Spark executives said.

Podcast Guest

Jeffrey D. Marrazzo

Jeffrey D. Marrazzo

Jeffrey D. Marrazzo is Co-Founder and CEO of Spark Therapeutics, Inc. (NASDAQ: ONCE), a gene therapy leader developing one-time, life-altering treatments to transform the lives of patients with debilitating diseases.

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Tom Salemi: Hi, everyone. This is Tom Salemi from the OIS Podcast. We have a great podcast for you today. Jeff Marrazzo, the CEO and cofounder of Spark Therapeutics joined us to discuss the company’s very successful phase 3 clinical trials of its SPK-RPE65 gene therapy. It’s intended to treat rare blinding conditions caused by mutations in the RPE65 gene, and is linked to subtypes of Leber congenital amaurosis and retinitis pigmentosa. The company’s successful clinical trials will lead to its plans to file for a BLA. So it’s a great win for gene therapy. This company is blazing trails not only in ophthalmology, but in all drug discovery. And Wall Street has certainly rewarded the stock this week. So Jeff joined us to talk about the clinical trials to talk about how the company will go forward with commercialization, and give us some insights on the very interesting origins of Spark. It actually came out of the Children’s Hospital of Philadelphia. So enjoy this Podcast. Very excited to bring this one to you.

TS: Hi, Jeff, welcome to the OIS Podcast.

Jeff Marrazzo: Thanks for having me. Look forward to talking.

TS: Well, you’ve got a lot to talk about. You delivered some great news. It was a nice way to start the week, a real positive punch on the clinical trial side. Had some positive phase 3 results for SPK-RPE65. What were the results, and can you talk a bit about the trial, the number of patients, the design, and just give us a rundown of where you are.

JM: Yeah. So earlier this week we announced positive top line results for or phase 3 pivotal trial of SPK-RPE65, which is for a form, various forms of genetic blindness caused by a gene, mutations in the gene called RPE65. That’s the name for the product candidate. What we reported out early this week was that we met the primary endpoint and the first 2 of three secondary endpoints, and we did so with high statistical significance. In fact, the primary endpoint hit with a P value of .001, and the first secondary hit with the P value of less than .001, and the second secondary hit with a P value of also .001. So highly statistical significance. And I think that’s particularly notable given the fact that this was a rare disease, so we conducted the trial with 31 subjects in a randomized 2 to 1. Two-thirds of the subjects, or 21 subjects received, were randomized to an intervention arm, and 20 of those 21 were exposed or received SPK-RPE65, and the other arm, the control arm, ten subjects, waited a year, received the same evaluations that those in the intervention arm, and then after one year they had the ability to cross over. All nine of the subjects that were followed during that year crossed over and subsequently received SPK-RPE65. But the analysis and what we reported out this week was on the one-year endpoint comparing the intervention group to the control group on a mobility test as well as on testing of retinal sensitivity.

TS: That’s terrific. And this gene therapy has had a bumpy road this year with clinical trials. What impact do you think these results will have on the field? It’s hard obviously to project the results from one trial over a whole field, but it is nice to get some positive news for this sector.

JM: Well, what is notable is that this was, as far as we’re aware, this is the first randomized, controlled trial in gene therapy for a genetic disease, and was certainly the first one that had positive top line results. So that’s a big accomplishment. Certainly the field has gone through its ups and downs, and to have a positive top line results that are as significantly significant as we saw, we think is a major step forward for the field and for Spark. I will also add just as importantly we were really pleased with the safety data that we generated in this trial. We didn’t see – we saw no serious adverse events from SPK-RPE65. We didn’t see any deleterious [immune?] responses. And we also – the adverse events that we did see were consistent with adverse events that we saw in the earlier trials that were attributed to the procedure, and not to the product candidate. So all in all, from a safety and efficacy perspective, a real step forward. Really to some extent, a moment that I think the field has all been waiting for. And I think from our perspective in the company, I think it demonstrates the attention to detail that we put into developing these types of product candidates for gene therapy, focusing on all the little details from how we design the vectors, how we manufacture them, the formulation, the development of a novel endpoint and validation of a novel endpoint. All of those aspects together contributed to the success. And I think it speaks – I ‘m certainly very proud of the team that we have here at Spark who paid attention to all those details across a series of disciplines. And I think it sets us up well as we start to talk about the rest of our pipeline and introduce more of that pipeline, certainly both in the area of inherited retinal dystrophies in the eye, but also even outside that, the work we’re doing in hematologic disorders and hemophilia and neurodegenerative conditions as well. So we think it sets us up in a great position to not only bring this program, which we intend to do, intend to file next year for biologic licensing application in the US in 2016, but it sets us up equally nicely for the other programs we’re working on behind it.

TS: Jeff, what were your interactions with the FDA in putting together this trial? Was it any different than in other companies?

JM: Well, I think it’s different than many other companies in biopharma, just really which is a function of this stage of gene therapy. We ended up, and the FDA, to their credit, took an unusual step of calling an advisory committee meeting before we started our phase 3 trial. And they did that to gather a number of experts in the field of inherited retinal dystrophies together to really discuss what are the right endpoints for these types of diseases. I think it’s really important to remember that in addition to this potentially being the first approved gene therapy in the United States for genetic disease, equally as importantly, it is potentially the first approved pharmacologic treatment for any inherited retinal dystrophy. So the FDA was seeking advice and counsel through this advisory committee meeting from outside individuals. And we were interested in that thought process as well about what were the viable endpoints for this disease. And we can talk more about it, but what we heard throughout that dialog and what we’ve seen throughout this development program is that nyctalopia, or night blindness, is really one of the hallmarks of this disorder, and that the FDA and we were interested in looking at something that could measure clinical meaningfulness in that population. And so we developed this mobility test which I can talk in more detail, but we subsequently validated which measures the ability of someone’s functional vision, measures someone’s functional vision and their ability to navigate under different lighting conditions, which really gets at the, as I said, part of the pathophysiology of this disease. And then we also, secondly, as the first secondary endpoint in our trial, measured full field light sensitivity threshold testing, which is a measurement of light sensitivity across your field. And that is a nice demonstration of, again, the physiology being engaged in the context of this product candidate. And we saw, which was again why we were so pleased about these results, we saw that those that those 2 endpoints really supported each other in the context of the statistical significance.

TS: Was that advisory board, that committee’s, where their findings binding when they came up with the endpoints? Or did you sort of have some say in what the final endpoints would be?

JM: They weren’t necessarily binding. It was in June of 2011. We listened, participated in then listened to all the commentary, went back, put all of our thought together about what we heard and what we thought made sense. We then came back to them with a proposed phase 3 protocol. They actually asked us to hold off before we started, reviewed it, and didn’t just review it with individuals in the direct office that oversees gene therapy. They actually took it to a number of different offices and divisions throughout the FDA and got feedback from a number of parties that have expertise and knowledge in ophthalmology from across the FDA, and then came back to us with their feedback. And with that feedback, we then incorporated a couple of things and then got started. And then subsequently, we received breakthrough therapy designation for SPK-RPE65 and have used that to continue to have an active dialog with the FDA on a number of aspects of the development work.

TS: Excellent. And talk a but about the mobility part of the study you mentioned earlier.

JM: Yeah. So we had used this assay in the earlier phase 1 trial, specifically, the second phase 1 trial. And what the test, in essence, it tries to capture a number of aspects of vision, and specifically tries to get at really right at the heart of visually dependent activities of daily living, like for example, stepping up onto a sidewalk or walking around an obstacle, or identifying something that might be in your home, and having the ability to navigate around it. And so this course is basically set up in the ophthalmology suite that looked at, has a number of obstacles and turns. There’s actually 12 different courses. They’re randomly presented to subjects so that they can’t remember them. And then we test the subjects’ ability to navigate the course successfully, which is measured by the number of obstacles that they don’t hit, essentially for accuracy, if you will. And we also measure it for speed. And that gives them an ultimate pass/fail. And we measure them at various lighting conditions, from the brightest light being the brightly lit office, all the way down to one lux, which is the darkness of a moon on a summer night or you’re walking around your hallway in the middle of the night with just the nightlight on. And so we measure them at 7 different levels across 7 different lighting conditions across that scale. And at baseline before they’re receiving the SPK-REP65 product, we see where they are able to function at, and then we looked a number of time points later, but the measurement was when we looked one year later, where were they able to now function at. And what we saw actually, we shared this earlier this week in addition to some of the other data, we saw that approximately two-thirds of the subjects in the intervention arm could actually perform, no matter where they started out beforehand, could actually improve to the maximal point on the assay, going all the way down to one lux. So two out of every three people, approximately, in the study can basically now perform in what is nearly the darkest condition, which going back to this hallmark of this disease being night blindness, we really are opening up potentially a number of visually dependent activities of daily living that previously the subjects weren’t able to do with the same amount of independence.

TS: We’re going to take a quick break from this conversation, this great story in ophthalmology and drug development to remind you to go to to register for the upcoming OIS@AAO Conference. We’ve got a number of new features, including one that Spark will be part of. Our Public Company Showcase features presentations from publicly traded leaders like Spark, and we’ll also have an excellent panel discussion led by co-chair Emmitt Cunningham about where ophthalmology fits into Wall Street. It’ll be a panel of analysts who will be bringing their insights on the field. So this isn’t something you want to miss. Go to to register. Now let’s hop back into this conversation with Jeff Marrazzo of Spark.

TS: How big of a population are we talking about? And what sort of durability data did you see in the study?

JM: So we estimate, based on existing epidemiology research, we estimate that there’s about 3500 people in the United States and the 5 largest European markets with mutations in RPE65. We are in a process of doing a fair amount of market research and work on a go around in a number of markets outside of those 6 markets, including in South America, as well as in Pan Asia. And so we’re going to continue to provide more visibility over time on what those opportunities look like in other markets, as well as, I should say, outside of the 5 European markets and other European markets and countries. And so we think the opportunity is larger than 3500 as we think about a global opportunity here, which is what we’re planning for and are investing towards. And in terms of your question about durability, we have really 2 data sets that we think are particularly useful. Obviously the phase 3 trial, we measured it at one-year time point. But in two of our earlier phase 1 trials, in the second of those trials, the subjects who received SPK-RPE65 got the high does and high volume, which was the volume that we used in the phase 3 study. And the 8 subjects that were in that trial that would have qualified for phase 3, we now have – those patients are now have been followed out anywhere from 3 to 4 years. And the effect that we see, that we saw within the first year, whether you measure through mobility testing or full field light sensitivity threshold testing, whether you measure instant measurements, you see that whatever effect that they got within one year is stable out at those marks, whether it’s 3 years or 4 years, depending on the subject’s last follow up. So that’s a really good start, we think. And then when you tie that together with the subjects that participated in the first of our phase 1 studies, who admittedly were a part of a dose escalation study, where we were using various endpoints at the time, nonetheless, those subjects are also coming back in every year. And they report through our clinical team that they are seeing a durable effect. Now we have less data on that, but the data I think in the second phase 1 study and then the experience that we’re hearing reported through the clinical teams in the first phase 1 study really provide a nice beginning picture for durability for us to move forward with.

TS: And can you talk a bit about your vector and what other diseases it allows you to target? I know you’ve got some other retinal products in your pipeline. Are they using the same technology or something different? And what are you looking at outside of ophthalmology?

JM: Yeah. So the vector technology that we use is something called adeno-associated virus, or AAV vectors. And it has the potential to be used in a number of cells that don’t divide a lot. Cells like those in the back of your eye in the retina, cells like those in your liver, as well as cells in your central nervous system. So we actually focus as a company on 3 different areas to begin with, with the retina being one of them, hematologic disorders, specifically hemophilia being a second area, and the third area being neurodegenerative diseases. And so the vector technology that we’re using, which incorporates everything from the way we design it, the way we manufacture it, that is all used across those 3 areas. And so we have programs in each of those 3 areas. And what we’ve done in each of those 3 is to have a lead program and then candidates that follow them. And the concept is that as we work out and solve whatever challenges may be in front of us in that therapeutic area or in that target tissue, once we start to do that and solve those, as we now demonstrate in the context of the eye and the retina, it opens up the ability to go after other diseases and to leverage a lot of our experience from the first program with the second program.

TS: And moving forward toward filing for the BLA, what are the challenges that are unique in filing for a BLA? I know it’s often been talked about as an issue of contention in the negotiation of the ACA as to the 12-year exclusivity period that you have with a BLA. As a company going forward, what are the challenges unique to filing for a BLA from the FDA? It’s a lot of letters.

JM: Well, in this context, I think for us, because we may be the first BLA that the FDA may be taking up and considering for approval in the United States for gene therapy, for genetic disease, we’re going to be ultimately blazing some new ground in the context of establishing precedents and things like specifications around manufacturing, considerations around the module that you put forth around your preclinical testing. And so there’s a lot of things that we’re going to be establishing the standards on, which we see as actually a real advantage for the company because the more we set those standards at a bar that we believe we’re uniquely capable to meet, it gives us a real competitive advantage. So that’s – separate from that, and in the context of things like the Trans-Pacific Partnership and ACA, admittedly, I’m not up to speed on all the specific details and how they’re being negotiated and the current status of all of them, I will say at a high level that the ability for us to be first to market for patients with RPE65 mediated diseases and bring a solution that may be a potential one-time treatment, it really – it’s a different dynamic than going into a marketplace with a therapy that you have to take on a chronic basis. Because you can be a second or third mover, theoretically, into those markets where it’s a chronic therapy, where you’re going into a market as a second or third player where someone else has come in and treated a large portion, if not all the prevalent population with a potentially one-time treatment is a very competitive dynamic. You can see how that becomes a real advantage for us as we get out to the market certainly sooner than anyone else has the potential to do so.

TS: It’s almost a device, a medtech sort of sale. So how do you – what will your commercial strategy be moving forward? Have you figured out whether you’ll be selling it yourself? Or are you looking to partner? What’s your plan?

JM: Yeah, we’ve determined that at least for the foreseeable future, the way we think about it is we’ve been able to build a leadership team in the commercial and medical and patient advocacy arena already within the organization. We’ve have many leaders in the rare disease and orphan products space coming from places like Genzyme and Shire that we’ve been able to recruit. And our goal is to bring this to the market globally with internal resources. And as I said, we’ve already begun the process of working with potential centers of excellence that will provide this product to patients if it’s approved. And then we’ll be moving forward, looking not only at the US and the European markets, but as I said earlier, we’re going to be looking more broadly than that with internal resources that we’ve brought on.

TS: And finally, it must be very exciting to be the first, you’re right, to create the criteria and just sort of set the standard that everyone else has to follow. What are the origins, through, of the company? Because you’ve got a unique history as well. I know the Children’s Hospital of Philadelphia is an investor. How did the company come about, and how did that relationship with Children’s Hospital as their being an investor in the company, how did that come together?

JM: Yes. So the way this actually all started is actually a little bit less than 5 years ago I had the occasion to spend a little bit of time with the CEO of CHOP. And the CEO of CHOP was interested in – the then CEO of CHOP was interested in identifying potential ways to diversify revenue sources and think differently about how to commercialize research that was going on within the walls of the hospital. And so he and I agreed that I would spend a little bit of time sort of roaming the halls, if you will, and meeting with various scientists and researchers and clinicians that were doing some really interesting work. In all my travels, I met a woman named Kathy High, who was running what was effectively the gene therapy center at CHOP. And she had some interesting data around RPE65 mediated diseases. And she also had some interesting work going on in hemophilia and in some neurodegenerative diseases, as well as had built a really excellent group that had the ability to manufacture these viral vectors. And so we started to talk about potential to create a company based on that technology as opposed to out-licensing the IP or the program to a particular existing biopharma company. And then as we got into those discussions, my view was that CHOP had made a tremendous commitment and contributions to the field of gene therapy. About a decade ago, when the field had fallen on harder times, CHOP had basically stood up and doubled down and invested their resources in advancing the work of Kathy and her colleagues, and that they deserved to have the proper return on that contribution that they had made to the field. And I felt that the way that they were best set up to do so was to be a cofounder and a founding partner in creating the company, as well as have the opportunity to be a sole investor or an investor along the way. And we were able to do that, having them as the sole investor in our first financing round, participating substantially in our second round, and even participating in our IPO. And obviously, the way things have worked out, it’s worked out to a point where CHOP is in a great position, a position that frankly they deserved all along to be in from my perspective.

TS: Is that a model you think that can be replicated? Is this something that other hospitals might consider doing?

JM: I think it’s possible. There’s really a confluence of factors that made this potentially doable. We looked at other projects. I looked at other projects along the way there, and those didn’t have the same sort of unique attributes to make it achievable. So it is situation dependent, but I do think if you think about any hospital or frankly any organization with a large endowment, what you have to understand is that that large endowment does invest typically single digit percentages of that endowment into alternative investments. Most of those alternative investments, or some of them are private equity investments. In the case of CHOP, they were an investor in a number of venture capital firms, albeit as a limited partner. So if you think about and take a step back, they were exposed to that type of risk and reward that any – you know, that a venture investment exposes you to. And my pitch to them was this is a unique opportunity to expose yourself to it directly because you have unique insight and information about this potential opportunity. And if you do that, you’ll have the potential to benefit from that substantially. So I think it is possible to replicate, and I think it’s a unique model. It does take a unique leader like Steve Oesterle, who was an NCO of CHOP. And it takes a number of other factors that have to come together. But I think under the right conditions and the right situation, I think it’s possible to replicate it.

TS: This is a great story from start to – I don’t want to say finish, but from start to now, and really happy to have it within the ophthalmology field. And you’re going to be telling your story at OIS in Las Vegas, correct?

JM: Yeah. I’m really looking forward to that. We’ve obviously this has been an exciting opportunity this week to tell people about the top line results. We’re going to share some additional data about the trial this weekend at another ophthalmology meeting, and then we’re looking forward next month to share additional data around the next ophthalmology meeting, including at your meeting at OIS. And we’re looking forward to all those opportunities.

TS: Excellent. Well, I can’t wait to see you there. I think you for the time. I know you’ve got a busy week. And congratulations on such great news.

JM: Thanks for taking the time.

TS: Thank you, Jeff Marrazzo, for joining us on the OIS Podcast, for juggling your busy schedule of what’s really been a historic week for gene therapy. So great to have these insights presented to our OIS community. For those who want to hear more, Jeff will be at OIS@AAO on November 12 in Las Vegas. You should be there, too. Go to and register to attend. Jeff and Spark will be part of our new Public Company Showcase. We’ll have presentations by these leaders in ophthalmology as well as a great panel discussion involving the analysts covering the sector. So again, go to to sign up, and we’ll see you in Las Vegas.