Sarepta Therapeutics, Inc. (NASDAQ:SRPT) Bank of America Napa Healthcare Convention June 24, 2020 12:30 PM ET
Doug Ingram – President & Chief Govt Officer
Convention Name Contributors
Tazeen Ahmad – Bank of America
Okay, everyone. Good morning or relatively good afternoon now. Thanks for becoming a member of us. I’m Tazeen Ahmad. I’m one of many senior biotech analyst right here at Bank of America. It’s my pleasure to have our subsequent presenting firm with us, Sarepta. We’ll be spending the following 50 minutes speaking about loads of thrilling issues which are taking place on the firm. Becoming a member of us from Sarepta are a number of members of administration, together with Doug Ingram, Sandy Mahatme; and Ian Estepan. Gents, good afternoon. Thanks for becoming a member of us.
Q – Tazeen Ahmad
So — however often actually to attempt to begin these conversations off with a fast recap for perhaps Doug, I do know there’s been tons of issues taking place on the firm, however perhaps you possibly can spend the primary couple of minutes speaking to us about what you suppose probably the most significant updates have been up to now this yr?
Positive. Thanks quite a bit, Tazeen, and thanks for having us right now. I am going to give a broad snapshot of the corporate after which we are able to go into a few of the milestones we have had this yr in addition to what we’ll have over the remainder of the yr and into subsequent yr. So for many who don’t know and I really feel everybody does, Sarepta is a precision genetic drugs firm and we’re centered on uncommon illness, and now we have a really massive ambition which is to change into the world’s premier uncommon illness firm, centered on genetic drugs.
However I feel what I am enthusiastic about is that our ambition has been largely being realized during the last three years. And I exploit that marker solely, as a result of I feel actually as of this or a few days from now can be my precise three-year anniversary on the firm. So I am very enthusiastic about that.
We now have two improvement stage platforms, RNA and gene remedy. And throughout these, now we have over 40 applications, and I feel it is pretty undisputed that now we have at the moment the broadest and, I imagine, probably the most promising gene remedy portfolio that no less than right now at the moment exists.
On the R&D facet, now we have two permitted therapies, EXONDYS and VYONDYS, each deal with totally different populations of the Duchenne Muscular Dystrophy neighborhood. And we can be finishing our rolling submission for our subsequent RNA remedy, which known as Casimersen this month. And so, if we’re profitable and we are able to receive an approval for Casimersen, we can be amongst that very uncommon membership of biotechs which have three or extra internally found, developed and permitted therapies, treating affected person communities.
Staying with RNA for a second, now we have a next-generation model of our RNA expertise that we name the PPMO, or peptide conjugated PMO, and we’ll have a proof-of-concept readout on that later this yr. I am positive we’ll contact on that right now.
After which shifting over to gene remedy, it is tough to break down gene remedy into just some sentences, however let me attempt my finest. We now have what’s approaching 30 gene remedy applications in numerous levels of analysis. In improvement, now we have a lot of them which are already in human scientific trials and pretty superior.
Our lead program, I feel, everybody is aware of is SRP-9001, that’s our microdystrophin gene remedy for Duchenne. And we have had very spectacular security expression and purposeful leads to the primary 4 affected person cohort examine that we had. In reality, we simply up to date with the one-year information on that examine.
We then, based mostly on these outcomes, commenced the massive placebo-controlled — a bigger, I should not say, massive, however a bigger placebo-controlled and blinded examine, which can full on the finish of this yr and browse out early subsequent yr. We have constructed alongside the way in which an infinite quantity of producing experience, and we’re constructing capability to start our subsequent trial with business course of materials. We’ll speak about that, however that can start later this yr. And our aspiration no less than is to hunt an approval subsequent yr, if we’re profitable in these numerous applications — numerous trials that we’re within the midst of proper now, or simply about to begin.
We now have six limb-girdle applications as properly. We have reported out earlier this yr, the second of our two cohorts of three sufferers, every from our program for 2E, LGMD2E. And so we did a decrease dose and a better dose cohort. And we noticed a constant security, strong expression and purposeful outcomes there, each within the decrease dose and the upper dose as properly. I am positive we’ll get into a few of the element there.
The one factor I’ll say, when you concentrate on the decrease dose cohort of 2E, the upper dose cohort of 2E, we take into consideration the one-year information on 2E, the one-year information on SRP-9001 for DMD, the expression and security outcomes from the primary four-patient cohort after which what we’re seeing to this point and what’s blinded, however placebo-controlled trial for SRP-9001, is that we’re constructing important confidence across the method that we’re taking, which is pretty distinctive to Sarepta, as a result of all of those applications share an identical design characteristic, related capsid, rh74, similar promoter, our MHCK7 and within the case of each the excessive dose after which SRP-9001, the identical dosing degree. After which behind all of that, now we have a lot of extra applications that we’re advancing, we are able to contact on.
So issues are going properly. Even within the midst of this pandemic, we proceed to make important progress. And I am proud to say that we’re largely on observe, however the truth that we have had this exterior discontinuous occasion, and I do not suppose anybody had anticipated in January.
And with that, we most likely ought to soar to questions.
Yeah. Thanks for that intro. So perhaps we might begin with a few of your current bulletins because it pertains to partnerships. Simply since your final earnings name, you have introduced new collaborations with Dyno, Selecta, Kodiac. Are you able to speak about how these partnerships are enhancing your present portfolio? And perhaps on the similar time, give us an perception as as to if there might be some synergy with present applications?
Yeah. So let me clarify the method that we’re taking, as a result of to your excellent level, we have Dyno, Selecta, Kodiac, we have completed StrideBio earlier than that as properly. And we even have a relationship with Dr. Guangping Gao at UMass for some humanized capsid expertise as properly. And it is broadly in overarching technique to construct a permanent gene remedy engine.
There are three large pillars to this enduring gene remedy engine, one is manufacturing. Experience in capability, and I feel we have made important strides during the last 24 months on that, constructing monumental quantities of capability with companions of Catalent and Thermo Fisher and constructing monumental quantities of experience throughout Sarepta, each in Berlin and Aldevron [ph] over in Ohio and our gene remedy heart of excellence in course of improvement, analytical improvement alike. In order that’s one pillar.
The second pillar, in fact, is our portfolio. And as you recognize, I — now we have a really deep portfolio of gene remedy candidates. And we have talked about a few them right here. And, in fact, now we have a lot of different ones deeper into the portfolio as properly.
After which the third one, which will get these current collaborations, is the idea of constructing instruments that can advance the science of genetic drugs is thrilling as gene remedy is right now. There are methods to proceed to enhance it and due to this fact, convey a greater life to sufferers. Issues like higher supply, re-dosing, and invasion and the like, flattening pre-existing neutralizing antibodies and all of those applications look in numerous methods to convey these instruments to the crew and to our gene remedy heart of excellence, in order that if we’re certainly going to fulfill our aspiration of being the chief within the premier gene remedy firm in genetic drugs give attention to illness, now we have to advance the science as properly. And I feel that is what these do.
After which in your latter query, it is too early to know the place these instruments will fall within the present applications that now we have. However actually, there can be parts of value between many of those numerous applications. Some are new capsids, which might be next-generation alternatives even for present applications. Some are literally mixture therapies the place you’d use the remedy together with an present expertise to do issues like empower future redosing, or knockdown neutralizing antibodies to permit present dosing of both sufferers who’ve pre-existing neutralizing antibodies or who’ve gene remedy induced titers of neutralizing antibodies. So nonetheless analysis proper now, however there’s a risk that it’s going to improve our portfolio and assist sufferers even with the present therapies that we’re growing.
Okay. Now with reference to Selecta particularly, when do you suppose we might see any updates from this collaboration? You talked about the neutralizing antibodies. And is it your plan to see potential combo use with gene remedy?
So sure, it will be too early to present timelines. This can be a analysis program proper now. Clearly, as we advance this, we’ll come again with some views on timelines after we might get to sufferers with this remedy. The remedy itself is — we’re very, very enthusiastic about this relationship with Selecta. That is some fascinating expertise. That is the so-called mTOR platform that they use profitable.
The usage of the mTOR platform with the gene remedy might empower two issues. You could possibly empower redosing and it might probably even enhance expression within the first on the spot. And so we’ll do extra work with Selecta after which come to some views on that. And if we see issues which are thrilling, clearly, we’ll begin constructing out some gantt charts and begin offering some element on what we expect the timelines are. It is a bit of early, sadly, for that proper now.
Okay. However it’s your purpose, although, presumably to attempt to improve your gene remedy utilizing that expertise?
That might be the purpose. The purpose is both to boost expertise or empower redosing. One of many – one of many issues that is thrilling about gene remedy, in fact, it is one-time remedy. And if we’re profitable within the issues that we’re all attempting to do throughout the biotech business with gene remedy, we might have profound, practically healing kind of impacts on sufferers. That is the hope of one-time remedy.
It is also one-time remedy as a result of it should be at the moment with the present state of the science, it should be one-time remedy as a result of, as you recognize, you’ll construct to AAV-mediated gene remedy, you’ll construct up a secondary immune response of the time to capsid. And due to this fact, whereas it is going to work the primary time, the second time round, your physique can be prepared for the capsid and the potential for safely with the ability to get expression and transduction is low.
And so here is a possibility. If we are able to resolve that, we might take away the type of unforgiving nature of gene remedy and permit for the idea of with the ability to redose sooner or later or pop up sooner or later.
So I feel in loads of you in gene remedy actually might create extra utility with our applications. And that is whilst in our present applications, we’re seeing some fairly extraordinary ranges of expression and a few very thrilling outcomes to this point.
Okay. So we’re wanting ahead to seeing updates from that, for positive. This week Sanofi had its R&D Day and gene remedy was one thing clearly that they wish to make a spotlight for themselves. They particularly talked about establishing infrastructure to make their very own AAV product. And I needed to get your ideas, Doug, on what you suppose the long-term purpose of Sarepta is on manufacturing as properly?
Sure. So let’s begin with the technique that we took. And we took this technique actually now – now we’re turning about nearly two years in the past, and I feel it is actually stood us in good stead proper now. It is actually served us. And that was this hybrid manufacturing model.
What we realized earlier was that on this nation discipline of gene remedy manufacturing, if we actually wish to transfer quick, and now we have to maneuver quick, by the way in which, proper as a result of now we have therapies that may save lives, and we have to get these therapies to children.
We might both slowly construct up experience and manufacturing capability. Or we might affiliate ourselves with those that have already got some experience, enable them to be the owner, construct out the type of the brick-and-mortar of this for us, whereas we construct the experience internally. And that is what makes it hybrid.
And in order we sit right here right now, what was two years in the past, a imaginative and prescient and a story, right now is a actuality, which is we sit right here right now with a freestanding facility in Lexington, Massachusetts for SRP-9001, single-use facility with Thermo Fisher, and we have much more important numbers of suites in capability at Catalent there.
However equally vital – no less than equally vital, now we have constructed internally – now we have a whole lot of staff centered on Tech Ops at Sarepta now. And now we have experience in course of improvement and analytical improvement for gene remedy that I feel is second to none already after two years.
We introduced in monumental quantity of expertise. And certainly, all the actual course of improvement and analytical improvement developments that we made during the last 15 months, and we type of talked – everybody type of lived that with us that just about totally got here out of our personal experience. So the hybrid model is serving us properly.
The following query then is, do you wish to construct your personal facility as properly? And the brief reply to that’s, whereas it is not obligatory, it will probably be a part of the flight path ahead. One of many values of getting our personal facility from a pure manufacturing perspective is it most likely would supply us extra flexibility in instances of crunch instances, pace of motion. However it won’t change the present model as a result of we’ll nonetheless want this hybrid model with companions as properly as a result of we’d like a voracious quantity – now we have a voracious urge for food for manufacturing capability.
So whereas I actually might envision us having a standalone facility alongside the way in which, it’s only a – it is a tactical subject, greater than a large strategic subject, the actual intellectually differentiating features of producing. The components of producing which are going to be essential to the enduring nature of a gene remedy engine, that is truly the method improvement and analytical improvement. And that experience we have inbuilt.
The place there have been the brick-and-mortar homeowners, the place there have been the tenants or the landlords of the power is actually as a lot a financing query as it’s a strategic subject. However I might envision that we might have a standalone facility as properly alongside the way in which, and we’re doing the feasibility evaluation on that as we communicate.
Okay. So, whereas we’re on this specific matter, because it pertains to gene remedy program for DMD, are you able to speak about the place you are actually on business provide readiness? Are you on observe for GMP manufacturing subsequent month?
Sure. Effectively, we’re in GMP manufacturing now. So now we have a number of GMP runs. This — so truly for 2 applications for SRP-9001, our microdystrophin program, that is our most superior program, in fact, now we have a number of GMP runs there. And now we have GMP runs ongoing for SRP-9003, which is our limb-girdle program, 2E program as properly.
Our purpose is to have the fabric by July, so one month from now, and we’re on observe for that. Issues — one of many issues that’s so happy about proper now’s due to all the development that we made working into 2020, this pandemic has not impacted our timelines from a producing perspective.
Now, it might have — if we hadn’t gotten to the method developed — we had made the method improvement progress that we made earlier than 2020. If we hadn’t gotten our analytical improvement so as earlier than 2020, there might have been an actual threat that we might have been slowed down on this. However we’re not.
So, the excellent news is we can have GMP materials in July. We now have a number of runs occurring as we communicate. We’ll have GMP materials, hopefully, by the again half of the yr to the tip of the yr for 2E. So, we’re in good condition proper now.
Okay. So, it has been — I imply, you’ve got talked concerning the July purpose for a while and it is nice to listen to that you will be assembly that concentrate on. So, now as examine 301 is meant to begin within the second half of the yr, are you able to speak about what the gating components are actually for that to begin? Assuming that all the pieces goes properly in July, what are you searching for now to really feel snug to begin the beginning enrolling sufferers?
Sure. So, there are three — broadly talking, there are three large moments in time for us that get us to our purpose. Primary, GMP materials by July — in July. And in order I stated, we’re on observe there.
Quantity two, important company. So, we’re going to meet with the FDA. We do not have the date for that but, however we’ll meet with the FDA as we’ll work from their perspective to substantiate our method, manufacturing, protocol, all of that after which based mostly on that, we simply must start these trials.
We’re doing a bunch of labor whilst we communicate on-site readiness and getting these trials up and working across the globe. That is going to be a multinational examine. And so these are the three large gates. And as I stated, we — our purpose is to have that examine up and working within the second half of this yr.
Okay. So, I do know this can be a query that you simply get on a regular basis and I am sorry to ask you once more, however can you give a bit of bit extra granularity on when within the second half of the yr you count on to begin this examine?
No, I actually do not wish to give extra granularity than to say second half for a easy motive that a few of that is choiceful. So, we had been speaking type of a bit of bit extra in direction of the center of the yr earlier than we observe into 2020. And also you may have a look at it and say, properly, why are you pushing into this to say extra second half once you’ve simply advised us that manufacturing is coming alongside high-quality and web site readiness is working? And the reply for that’s, in fact, now we have a pandemic.
And one of many issues we wish to be a bit of considerate about is ensuring that we’re watching the exterior surroundings and thoroughly every of those particular person websites to make it possible for they don’t seem to be solely that we’re — we are able to get in there, that we are able to have stay coaching that we are able to guarantee prime quality as the location is initiated.
I do know we will be assured that, that web site goes to stay open and proceed to dose sufferers in direction of — within the again half of the yr as we observe into subsequent yr. And so we push that ahead a bit of bit.
So, I do not wish to give loads of — I do not wish to give loads of extra shade on that as a result of it truly is a reality and circumstances associated as we take into consideration initiation, aside from to say, we’re very dedicated to commencing the trial within the second half of this yr. And if we do this, it won’t.
Whereas it is going to have then a delay from our begin time that we type of talked about late final yr, it actually will not delay this system as a complete in any respect, if we’re profitable in that regard.
Okay. You’ve got beforehand said that so long as you begin by October, you would not want to alter any of your plans, submitting timelines for the product. Does that also holds?
Sure, that is precisely proper. So we began – we begin in — someday in October, it is going to be zero efficient delay on the again finish. And naturally, we’re month delayed from there, we’ll have a 30-day delay on the opposite facet.
Okay. So sufficient about these timelines, I did wish to ask you concerning the 1-year information out of your Part II examine for the microdystrophin program that was just lately revealed in JAMA Neurology. Are you able to spend perhaps a minute speaking concerning the significance of that information and what the read-through needs to be for us?
Sure. The beauty of the 1-year information, its publication and the depth of knowledge in there’s that, this could proceed to construct confidence within the method that we’re taking very cautious program general in addition to SRP-9001. And it supplies extra affirmation of this design characteristic.
What we’re seeing constantly is a really constant view on security, on expression and now as you noticed it 1-year on operate. So we had the unique information from the examine 101, these first Four children, which I feel everybody may be very enthusiastic about. The at the beginning, from a security perspective, it was properly tolerated. There have been elevations in liver enzymes, however very properly managed by means of will increase in steroid use. And in order that seemed to be fairly manageable. And so they nice – we acquired nice 9-month information on these children from a purposeful perspective, we have extraordinary expression outcomes.
I feel you had been – from a genome copy per nucleus, you will recall, we had been 3.Three genome copies per nucleus. After which we get the 12 month information, we begin seeing the identical factor. We see — persistently, these children are all – each single baby at each single purposeful measure is considerably bettering on the 1-year mark, which is actually thrilling for us. And clearly, security nonetheless appears nice.
To remind you, we by no means noticed the sorts of security considerations which are plaguing different AAV8-mediated full-body infusion gene therapies. We’re not seeing complement activated aHUS or kidney injury or worse but, which others have seen kidney failure within the scenario. I see no indicators of that in any respect.
After which that simply builds on. It builds on that, then you definately go construct a low dose. Limb-girdle 2E, similar reply on expression and performance and security. And then you definately go to the excessive dose on 2E, which is actually reads over strongly on SRP-9001 as a result of now we’re speaking about precisely the identical caps at rh74, precisely the identical promoter, MHCK7.
And within the excessive dose, precisely the identical dose, however at – however in bigger and heavier youngsters and once more, you see over there, you do not see the security considerations which have plagued others. You see this monumental expression – these expression outcomes, which I am positive we’ll speak about.
After which once you have a look at the purposeful outcomes from the low dose of 2E, you see children at 1-year once more; all not slowing degradation, not secure, however all bettering considerably. And even on that low dose, keep in mind, a type of children truly acquired excellent rating. So there’s no one on this webcast that would do higher than that child in his latter scores. I imply he replicated that a few instances.
So all of that is triangulating that actually, you have a look at that 1-year information on microdystrophin SRP-9001 in JAMA Neurology, and it’s simply a part of the bigger bundle of the constructing and triangulating expertise round this distinctive method that we have taken and that Louise Rodino-Klapac and her crew have taken to constructing out these constructs for uncommon illness. So we’re very enthusiastic about it.
Okay. And needed to the touch upon one factor specifically you simply talked about. Because it pertains to security, clearly, you guys haven’t seen something of substance that might trigger concern for traders. And after we evaluate your product to Pfizer’s, everyone has completed doc checks at this level and medical doctors are actually pointing to the foremost distinction between the two therapies, no less than of their thoughts proper now as a security profile on your merchandise being cleaner.
And so based mostly on what you have seen from the admittedly small group of sufferers which have been on remedy now for fairly a while, how ought to we take into consideration the affect to count on within the 102 examine that you simply’re working because it pertains to the potential for any sort of negative effects? Ought to we really feel higher about that that it ought to proceed to remain clear?
I might solely — it is a blinded examine. So, everybody has to take what I say with the caveat that this can be a blinded examine. However with that blinded examine, in fact, that examine has stopping guidelines. And so, clearly, critical sudden end result would very probably set off a stopping rule. And I might contemplate aHUS or kidney indicators or the like, actually inside that realm. And we’re not seeing that. We’re not hitting any stopping rule.
So, sure, you need to be — not solely ought to we get growing confidence from what we’re seeing from SRP-9001, 101, SRP-9003 low dose and SRP-9003 excessive dose. However now in the primary examine, 102, the truth that, that examine is shifting ahead, shifting nice, no impediments, not interrupted in any manner, ought to begin giving some — constructing confidence, no less than on the identical.
Issues to recollect, all the children, the primary evaluation had been dosed had been the pandemic children. So we did not have any points with delays related to the dosing for the primary examine. And we’re dosing children on crossover now as properly. So greater than anybody else — simply to be very direct about this. Nobody has dosed on this microdystrophin area. No person has dosed practically the variety of children with energetic remedy on the presumed business dose that now we have throughout the 2E and DMD.
I imply, the DMD alone, we have dosed now most likely — and I say most likely, as a result of keep in mind, it is placebo management, and I have not checked on the crossovers within the final couple of weeks. However we’re most likely no less than within the 35-patient vary of sufferers which have been dosed with 2×10/14 on rh74.
So, sure, we’re getting increasingly assured that the method that we’re taking is very differentiated. And I feel it is extremely differentiated in two, however most likely in a associated methods, it appears to be extremely differentiated on the security facet. Once more, I used to be simply merely saying, focusing solely on ours and never on others.
We don’t see this complement-mediated aHUS subject, which is, I feel, everyone is aware of, very, very critical and life threatening. We do not see kidney injury. We do not see kidney failures. We’re not seeing these sorts of issues. After which additionally, we’re seeing actually strong expression.
It is tough to check and distinction for hosts of causes, together with titering, however greater than that, as a result of others have been much less prepared to reveal data than us, however simply specializing in ours. You have a look at our excessive dose for SRP-9001, and we’re seeing 3.Three genome copies per nucleus.
I imply the largest query, I feel, that all of us had earlier than we began this path was, might you actually do full-body infusions and get strong transduction and strong expression? And we’re getting 3.Three genome copies for nucleus in SRP-9001 correlated with up within the 90% vary of dystrophin manufacturing.
And then you definately go stroll that over to SRP-9003 for LGMD2E, similar capsid, similar promoter, so clearly very related. In lo and behold, we’re getting 4.2 genome copies per nucleus after which, in fact, terribly strong expression, had been within the 70 percentile vary. So, I feel, we have quite a bit nonetheless left to do. And I do not wish to — delcaring victory too early is inappropriate.
We have to get 102 completed. We have to get our subsequent examine with business course of materials up and working. However actually, the constructing proof that we have seen during the last 18 months, as much as the latest proof, each within the one-year information on SRP-9001 within the excessive dose on SRP-9003 continues to present us constructing confidence that the method that we have taken from the start is the correct method with respect to gene remedy. And I am going to inform you, kudos and hats off to Dr. Rodino-Klapac, M.D. Gene Remedy Heart of Excellence in Columbus, Ohio for all of that.
Okay. So you probably did point out the following upcoming examine 301, when it does begin later this yr. Are you able to speak concerning the trial design for that one, Doug? And what the important thing variations are between that and the continued 102 examine?
Sure. The largest distinction between — so there’s loads of similarity. And the explanation for the needing to be loads of similarity, in fact, is that we wish to replicate 102. We wish to have a look at expression throughout these two, one with business materials, one with scientific materials. And so, initially, probably the most important distinction between the 2 is, one makes use of the scientific materials, the method for making scientific materials at nationwide, which is hyperstacks, and the second goes to be utilizing our business scale course of. Apart from that, it is the identical, similar promoter, similar capsid, similar gene, as a result of clearly however utilizing iCELLis items to make it.
After which on the protocols themselves, this can be a multi-center, multi-country trial. It is over 60 sufferers. There can be a one to at least one placebo. The age vary can be 4 to seven. So in loads of regards, it is similar to one and two in that regards. In order that’s the place we’re with that.
Okay. And what’s your technique to maneuver past the 4 to seven-year-old sufferers into youthful sufferers and likewise probably nonambulatory?
So let’s actually give attention to the nonambulatory facet as a result of that is the massive group of — now we have plans throughout the complete scope. However the actual large one we should always give attention to is the older — nonambulatory sufferers as a result of we’re learning for seven-year olds. And one ought to be aware that actually 21st Century Cures Act and the FDA steerage and the like, they do wish to imagine that you may and infrequently ought to, DMD is a traditional instance, examine a slender affected person inhabitants for displaying the impact of a remedy and with the ability to use a constant purposeful endpoint, however then you need to get a broader label for all the presumed affected person inhabitants that might profit from the remedy, given its mechanism of motion.
However past simply that, individually from that, we’re beginning an older nonambulatory examine, and we’ll do it as — on the similar time or as quickly as attainable after the graduation of our primary examine, what we name 301. So now we have a separate examine for older nonambulatory sufferers. It is going to require, in fact, a distinct purposeful endpoint, as a result of these nonambulatory sufferers, NSAA, which is except for one measure is all require sure presumes ambulation, they may require one other purposeful endpoint.
However we’ll begin that trial as quickly after the beginning of the following trial as is feasible and it is near concurrent as is feasible. And that can present data. That can be good for — I am going to present security within the older sufferers, in fact, we have already seen indicators on that with SRP-9003, so security. It is going to — so purposeful outputs can be nice from a payer perspective and entry reimbursement, it is going to assist us ex-U.S.
Okay. What % of the inhabitants proper now’s nonambulatory?
I haven’t got the quantity in entrance of me, however a big share of the inhabitants is, in fact, nonambulatory as a result of I haven’t got the precise information in entrance of me. However keep in mind, with Duchenne muscular dystrophy, the massive majority of those youngsters are in a wheelchair by the point they’re 15 years previous. So it’s a important variety of sufferers.
And the very fact is that this remedy will profit nonambulatory sufferers considerably. And the mere reality that you’re in a wheelchair does not imply that you simply should not profit from a remedy like SRP-9001 that may restore dystrophin manufacturing and the protecting qualities of dystrophin if it is profitable.
So there are a big variety of nonambulatory sufferers that can be ready for this remedy, and we have to do the correct factor by them by getting aesthetic the one as quickly as attainable.
Okay. Is it your present plan to attempt to embrace that information along with your utility for approval? Or would that occur later?
I do not suppose it has to. Let me say this. I feel that now we have them that information in for the primary approval in the USA. In some locations all over the world, which we wish a broad label, we must. However in the USA, I feel the 21st Century Cures Act would say we would not should. I believe we can have a few of that information, no less than on the security facet, on the time that we’re prosecuting the appliance. And so actually, we would supply that degree of knowledge within the utility.
Okay. So I suppose if we quick ahead to subsequent yr, are you able to give us a little bit of a timeline on what we should always count on by way of sequencing? When the Research 102 readout, what — assuming that that information is optimistic, when would you wish to go speak to FDA? And what’s your plan for submitting?
So that is all — so I am going to provide the aspirational reply. And I feel folks did not know me know that I’m pretty aspirational. We can have — Research 102 will full by the tip of this yr. They may, in fact, have the QC, can get the highest line. And so we can have high line of Research 102 within the first quarter of 2021. Which suggests, if we’re profitable, we can have proven the security of and – examine of the SRP-9001 in a bigger cohort of 41 youngsters along with the kids we have already dosed, and now we have proven the purposeful advantages of this microdystrophin in it, in reality, does profit youngsters on this 48-week examine.
So additionally some operate, and we’ll have additionally profit was on security. After which Research 301 properly, by the primary quarter — it is actually our purpose that by the primary quarter of subsequent yr, we’ll — we’ll have the power to do an interim minimize on examine 301 for expression in a subset of 301. We do not contain the kids, however a related subset of examine 301 can have the expression degree information.
We’ll have CMC displaying the comparability of the business provide and the scientific provide. We’ll have expression information, it exhibits the comparability and expression between the essential provide and the business stride. We’ll have purposeful outcomes, we’ll have security outcomes.
And it is going to be in that foundation, by the tip of the primary quarter, we would not wish to meet the company, have delayed assembly with the company and never disclosing something that I have not stated many instances, it will be – if we’re profitable, once more, and all of that with the correct manner, it will be our place at that time that we ought to have the ability to submit for an approval then versus ready for the completion of 301.
And if we’re profitable in that regard, our purpose is to be able to submit. We’ll do loads of the work in danger prematurely of the info. If the bundle able to go after we begin placing the items collectively as quickly as now we have the info, and I would like to have the ability to submit by the center of 2021. After which aspirationally we might have an approval by the tip of 2021.
I see. Okay. I suppose, earlier than we depart this matter, I needed to get your newest considering on price. So for some time now, you had been speaking about Novartis sort of pegging the place gene remedy of this kind needs to be priced. You do have – we do have another corporations now which are considering, no less than speaking about perhaps breaking out from that – from that 2.15 million quantity, how are you fascinated with it now? Do you’re feeling like there could be a motive to price increased than Zelgens was priced for SMA?
Sure. So we nonetheless do not have loads of work but to do earlier than we are able to actually have an affordable dialogue of pricing. I can provide you some broad ideas on it. I do know, as an illustration, Biomarin has instructed price factors as much as $5 million for some gene therapies they’re engaged on. And I do not suppose Biomarin is unreasonable in that method.
I feel these gene therapies, if they’re profoundly impactful, might be justified from a price effectiveness perspective. Keep in mind, a few of these costs sound — they sound monumental within the widespread press, nevertheless it’s a deceptive, in fact. As a result of this can be a onetime occasion that basically continues to create remedy in situ, in vivo for, hopefully a long time and a long time later.
So what — metaphorically, it is the distinction between shopping for the home and renting the home. So if I purchase a home for $200,000 that seems like much more cash than renting a home for $5,000. However all of us perceive if we did the maths, and it is not, and that is the distinction between gene remedy and power remedy. And I do suppose all of us wish to sort of get that understood.
So we price therapies for gene remedy, to illustrate, that make them so aggressive towards power illnesses by means of power therapies that — the dispassionate investor desires to proceed to spend money on gene therapies and make them profitable as a result of society will win and sufferers will win, if that is the case.
So I do not suppose these are insane. If we have a look at the SMA pricing of Novartis, I feel it was affordable within the low finish or perhaps direct. And I feel there’s a motive for us, I feel it is going to tether us to some extent in our aspirations for pricing, however I do suppose now we have the correct to count on to premium price to it for no different motive that the fixed items can be extra just because the kits are greater, extra remedy.
So if we’re within the cost of — it will be a onetime fastened charge price, it most likely goes to be increased than Novartis’s price. However we do not have the precise price but.
Okay. All proper. I do wish to speak about your subsequent upcoming catalysts, which is on your PPMO program. You are planning to report some early outcomes from SRP-5051, I imagine, within the second half of this yr. I simply needed to test if that is nonetheless the plan. In that case, what sort of information ought to we count on from the readout?
Sure, it actually nonetheless is the plan. We can have an replace within the second half of this yr on the PPMO program. I am going to simply step again for only a second to verify we’re on the identical web page. We now have an RNA expertise to the PMO, which is in some ways, it is simply wonderful expertise. It is exact. It creates glorious skipping and dystrophin and it’s totally secure. And it has been the one there could be the PMO that is ever been capable of reliably present the creation of dystrophin, the very factor that these youngsters are lacking.
It has a limitation related to it, which is that it’s a impartial cost molecule, it would not get into the cell extraordinarily effectively and it not solely passively, and it clears quantity about 4 hours. So, if we might discover a option to get it into the cell extra aggressively, we’re fairly assured based mostly on animal models that we might have a lot higher exon skipping and a profound enchancment within the quantity of dystrophin that we make and the profit to those youngsters. That is what the PPMO does. It is a peptide conjugated PMO. The peptide is positively charged. The animal models inform us it drags the PMO into the cell a lot higher bond and create important extra.
The 2 fronts is cannot — keep in mind, I stated it is — PMO is secure and efficient — secure and exact. And the query for the following manner is we all know — we strongly imagine what’s going to occur if we are able to get extra remedy into the cell. What we — the massive open query for the peptide conjugated PMO is that if we are able to do it safely.
If we get to good doses of the peptide conjugated PMO with out placing a sign, the sign on this case that we might be looking out for is a renal sign, proper? We wish to cease in need of any important renal sign. And so we began a single ascending dose, this multi ascending dose. And I am happy to say — once more, I haven’t got the info. So, we depart this with a limitation that they do not have information, and I do not learn extra into it than is there. However our animal models advised us that we might be — we might begin getting happy with the dosing and we get the dosing above about six mg per kg in sufferers, and we actually begin getting excited if we are able to stand up to 12 mg per kg with out inducing any security indicators that might make us have to scale back the dose.
And we’re already at 20 mg per kg. So, we’re more than happy based mostly on what we all know up to now. And that is what the info will seem like in direction of the again half of this yr, which is we’ll have a look at dosing, what does it seem like at 20 mg per kg what we’ll have a look at?
And what the security profile seem like? What’s PKPD? What’s tissue publicity? What’s exon skipping? Now, the very fact is that we — issues look good, we’ll proceed to dose above 20 mg per kg, however now we’ll — however as a proof-of-concept, we’ll have a look at 20 mg per kg within the second half of this yr.
After which we are going to — we’ll be exon skipping, specifically. And exon skipping is a incredible surrogate for dystrophin manufacturing as a result of the exon skipping creates the dystrophin manufacturing and it occurs a lot sooner than dystrophin manufacturing. And we are going to, in fact, as we’re attempting to find out how important PPMO might be compared to our present PMO expertise. We can have some data that may present perception on the meaningfulness of this exon skipping versus what one would have seen or anticipated to see in a PMO at this timeframe.
Okay. So, we are going to see exon skipping information, however to be clear, we’re not going to see outcomes of dystrophin per se?
It was simply early. I imply it is 12-week information and dystrophin takes — dystrophin is, I feel, as you properly know, it is the longest gene within the physique. Simply to learn — the studying of the messenger RNA to make a single protein take 18 hours. And what we have seen over time is that tissue publicity will increase over time and dystrophin manufacturing will increase over time. And in Topricin, we noticed one degree of dystrophin manufacturing at one yr and a big enhance in that dystrophin at 4 years. So, simply 12 weeks, most likely for an RNA-based expertise, it is most likely too early to take a look at dystrophin.
However the excellent news is exon skipping can occur very quickly. So, we are going to get a correlate, after which we’ll get a core degree. This is what you’d count on from exon skipping within the PMO, here is what you count on from the exon skipping from dystrophin and in broad strokes, we’ll know the way — is that this extra profound than the PMO after which sort of what vary is it extra profound? And what we’re searching for? We’re not searching for a share enhance. We’re actually searching for a a number of elevated over the PMO and that is our purpose in any case.
Okay. So, what’s your anticipated subsequent step down for this program when you present this replace?
Effectively, now we have — we’re — we’re ready for this proof-of-concept, after which we’ll make some choices out the place we go. The excellent news is, now we have already formulated and constructed PPMOs that may deal with north of 50% of the Duchenne Muscular Dystrophy affected person inhabitants, and we are able to go even past that. And we are able to go even past DMD, the PPMO.
Our PMO is type of bespoke for DMD and match for goal there. PPMO is profoundly higher within the PMO, you possibly can take it to different therapeutic areas. So earlier than resist on DMD, we’re going to maneuver as quick as attainable to begin getting all – we’ll give you a achieve chart subsequent yr, if we’re optimistic with respect to this present learn up.
However our purpose can be to begin shifting these applications as quick as attainable. We have already got been formulated for 50% of DMD. And we imagine, based mostly on all the interactions we have had up to now with the company and definitely with the actions – with the interplay we had within the again half of 2019, that we might avail ourselves probably of the accelerated approval pathway for the PMO. It appears good, and that can be our purpose to maneuver as quick as attainable in that path, if the FDA agrees with us.
Okay. Then on the PMO facet, are you able to speak about the place you had been with Casimersen’s submitting? When ought to we count on an replace on that?
Sure. So we’ll have – so one factor we are saying, we’re within the rolling submission. We’ll end that submission within the second quarter for many who are counting. That is the final month of that quarter. And we are going to meet that timeline. So we can have Casimersen totally submitted this quarter. Then, in fact, the company opinions it and accepts it and we’ll get a PDUFA date. After which we’ll prosecute that NDA over the course of this yr.
Given – relying on when the FDA confirms the submission and accepted for submitting, we are going to probably get a PDUFA date within the first quarter of subsequent yr. So, one was going to be conservative, you’d say that we’ll get an approval for Casimersen in Q1 of 2021, as at all times, the chance that actually, the company has been recognized to do that previously.
And if we get far sufficient alongside in that NDA, the prosecution of that NDA, we are able to get an approval by the tip of this yr, however we’ll know what the PDUFA date is shortly after we submit and may very properly be a Q1 occasion.
And if we get that permitted, then I’m going repeat myself, I feel it is actually vital. To start with, Casimersen will deal with 8% or so of Duchenne Muscular Dystrophy sufferers. Casimersen and VYONDYS collectively, are symbolize extra sufferers than even than EXONDYS did by itself. So that is actually significant for the neighborhood that is ready for Exon 45 amenable youngsters, however it is going to additionally imply one thing about our method as a result of we can be one of many only a few biotech corporations which have internally researched and developed and gotten permitted three or extra therapies which are treating sufferers. So it has been an thrilling milestone for us.
Sure. So we look ahead to that. We solely have a few minutes left, however I did not wish to depart with that no less than relating limb-girdle. So actually rapidly, you probably did just lately report updates from the high and low dose cohorts for the 2E examine. Are you able to give us a really fast replace on that? And any ideas you are having about what kind of inclusion standards you will have on your subsequent examine, resembling the best age vary and your ideas about what must be proven on the NSAD scale?
Sure. Simply to remind everybody the place we’re with the limb-girdle 2E. And once more, I’ll remind you that the end result that we see in 2E are significant for youngsters who’ve limb-girdle 2E. They’re significant for all the limb-girdle applications, and we cowl over 70% of kids with sturdy muscular dystrophy with the applications that we at the moment have. And so they’re significant for constructing proof and confidence on SRP-9001 for Duchenne as a result of these are all the identical capsule, these are all the identical promoter. And on the excessive dose, these are all the identical dosing ranges. So there is a gigantic quantity of read-through to all of our applications.
And what we have seen is that this, now we have two cohorts, a decrease dose and a better dose. Decrease doses final yr, and after we up to date with the purposeful outcomes. However what we noticed there, even at low dose, we noticed consistency. We noticed an amazing security profile, properly tolerated, some elevated liver enzymes however manageable with steroids. After which we noticed 51% protein optimistic fibers – protein optimistic fibers by itself isn’t sufficient, you must have a look at depth.
We noticed practically the identical, 47% depth after which Western blot, sensible, 36% on Western blot. After which at 9 months we noticed final yr, each baby and each purposeful measure was bettering in ways in which you would not have anticipated from pure business, so all sensible there.
Then we went to the excessive dose for SRP-9003, and that is what we have simply introduced very just lately. And once more, in vector promoter and similar doses 9001. And we acquired a big uptick even once more on expression. So broadly similar security profile. We had 1 baby so as to add dehydration – it was dehydration that was a results of nausea from the remedy, not totally sudden.
However I need — curiously and I do not wish to hammer this too exhausting, we’ll see later, however we modified the steroid protocol for the excessive dose, and we did not see the elevated liver enzymes even on this a lot increased dose and in heavier sufferers than we did both in a decrease dose or within the prior examine for SRP-9001. So there’s some probability that we may have partially solved or actually enormously mitigate, even the precise readout, however by way of — we’ll have to attend and see on examine 102.
However what we noticed right here was 72% protein optimistic fibers. Once more, you may’t have a look at protein optimistic fibers with out depth. It is deceptive to try this. I actually wish to strongly state that. And excellent news, 73% depth, 62% on Western blot. These children had a 90% discount in CK after which once more, actually vital, 4.2 genome copies per nucleus.
So there is a motive why we’re getting the expression we’re getting, getting an infinite quantity of gene nucleus to the correct place, and that compares to three.Three with DMD. After which its been a similar reply, no, we did not get any of the complement-mediated aHUS that individuals would fear about with different applications. We did not get kidney failure, kidney injury, any of these sorts of points in any respect of this remedy. So it was sensible.
And on the similar time, we up to date — I feel I stated this or outstand yet one more time, we up to date the low dose 1-year research. And even on the low dose, all of these children on each single purposeful measure was bettering. I feel I stated this earlier than, I am going to say it once more, a type of children acquired an ideal rating on the, so it is all sensible.
Then we stroll over to what we’re fascinated with with respect to the event for 2E and different limb-girdle as a result of they’re actually going to be associated to one another? And the brief reply is we do not know but. We’re working with the company, and we’ll work with the company over the course of this yr. We’ll come again early subsequent yr and speak about it.
However I’ll be aware a few issues. That is an especially uncommon affected person inhabitants 2E. This can be a gene that codes for the native protein. And so, if one that top expression, there’s not an apparent motive why you are not going to get a transformative impact. This can be a properly monogenic illness characterised by the lack of — full absence of a structural protein.
There can be a paper coming. I do not wish to talk about it in an excessive amount of element, however there can be a paper coming earlier than the tip of this yr, that correlates expression ranges and purposeful ranges. And it’ll counsel that the sort of expression we’re getting proper now could be correlated with a really profound affect on purposeful profit.
So when we’ll speak to the company, a few issues I — aspirationally, I don’t need – I need an all-comers truck for 2E. I feel attempting to go to a narrower set of sufferers to see an impact, I feel, is unlucky, given the scale of this affected person inhabitants and the rarity of this illness.
And second the directs, and I haven’t got a solution but. We now have to work with the company. However to our thoughts, no less than, that is the sort of space the place a really truncated improvement program assuming that product is secure could be acceptable. And I might argue that no less than on tempo, one thing like an accelerated approval is actually an space that we should always be capable of no less than have a productive dialogue with the company about given the very fact that is extraordinarily uncommon illness.
And it is characterised – monogenic illness characterised by a lacking protein and we’re capable of present, no less than within the present 2 cohorts of 6 children that we are able to considerably change the native protein in these children and it is a very native protein, the absence of which is comping there into era and demise.
So I do not know but what the trial appears like, however we’ll be aspirational in our method there, after which we’ll come again subsequent yr and inform you what the outcomes of these discussions with the company to seem like.
Okay. Cool. I might most likely speak to you for an additional 2 hours, however we’re out of time for right now. So thanks a lot for spending time with us. As typical, we realized quite a bit. There’s quite a bit occurring in Sarepta and we look ahead to seeing your whole updates for remainder of the yr and past.
Thanks very a lot. Thanks for having us. We actually respect the chance.
Thanks, guys. Have a superb day.
You as properly.