Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Microdystrophin Gene Therapy Update Conference Call. As a reminder, today's program is being recorded. I'll now turn the call over to Doug Ingram, President and CEO of Sarepta Therapeutics. Please go
ahead. Good
morning and thank you all for joining us for an update on the clinical data from our 4 patient Phase 1 microdystrophin gene therapy program. On this call, we may provide forward looking statements. I would refer you all to our public filings for the risks and precautions associated with our forward looking statements. Now before I turn the discussion over to Doctor. Luis Medina Klapac, let me put this update in context and explain why we are making it.
As you will recall, the World Muscle Conference in Mendoza, Argentina in the fall of 20 16, we provided an update on our 4 patient Phase 1 trial for gene therapy. We provided functional and biomarker results in the last day we had for each patient. You will also remember that those patients were treated in a staggered fashion. The earliest treated patients had 9 months data and the other patients had earlier last measures consistent with the date on which the patient could get in therapy. We are this morning presenting updated 9 month functional and CK related results for all four patients.
Many investors will also recall that I have repeatedly stated that as we are in the midst of a blinded placebo controlled study verifying the results we have seen in our 1st cohort, we do not believe it appropriate to provide ongoing updates on the first four patient cohort. So why there are we updating? We have also said repeatedly that while we do not intend to update, it is possible that the principal investigator, Doctor. Jerry Mendel, may decide to publish or otherwise present updated results in a medical meeting. We have been informed that in a recent medical meeting, Doctor.
Mendel updated the data to include 9 month results for all patients. Accordingly, in the interest of full transparency, we think it only appropriate to provide an update consistent with Doctor. Mendell's presentation. As you will see, the data remains very encouraging with continuing improvement on functional endpoints, unprecedented biomarker results and on safety as well. But finally, I do want to reiterate that we cannot intend to continue to update the first of our patients so we can focus on completing our placebo controlled trial.
And with that, I will turn the presentation over to Doctor. Rodino Klapac.
Thank you, Doug, and good morning, everyone. I'm pleased to present the updated results from our first four patients in our micro dystrophin trial, our 101 study. Just to remind you, this study was in DMD boys between the ages of 4 to 7 and we enrolled 4 patients. Inclusion included confirmed DMD mutations as well as the subject has to be negative for antibodies to rh74. This was a Phase 1 safety study, so the primary endpoint is safety, but there are various secondary endpoints, which included microdystrophin expression, decrease in creatine kinase, the 100 meter time test, NorthStar ambulatory assessment as well as stair climbing and time to rise.
So just to orient you on the demographics at baseline for our 4 subjects, They range between the ages of 4 to 6 at baseline and their creatine kinase or CK levels range between 20,035,000. And this is right in line what we would expect for DMD boys, which typically range between 200,401,000 at this age range for CK. So we previously presented the biopsy data at rheumelosin society in Mendoza and we'll just go through that today as well, but this is the same biopsy data that was previously reported. We had biopsies at baseline as well as at day 90. And these are the results of those biopsies.
So we quantified the amount of microdystrophin and here we're looking at immunofluorescence staining. As you can see, widespread microdystrophin expression is correctly localized to the sarcolemma or the muscle membrane. And we quantified this by looking at both intensity. So this is the amount of microdystrophin present at the membrane, and we see that it is 96% compared to normal, which you can see a comparative normal control in upper left hand corner. We also quantified it by looking at the number of fibers.
And here we see a mean of 81.2 percent of muscle fibers expressing microdystrophin across our 4 patients at 90 days post treatment. We further quantified the amount of microdystrophin by western blot. So this is looking at the total amount of microdystrophin protein. As you can see, we've shown gels for all 4 patients and you see robust microdystrophin levels and we quantified this by adjusting for fat and fibrosis and we get a mean of 95.8% expression compared to normal. If you don't adjust for fat and fibrosis, it's at 74.3% of normal.
This next slide is just a summary of the results I've shown you so far in terms of the amount of the seropant positive fibers at 81.2 Western blot and also vector genome copy number. So we see as a mean across the 4 patients greater than 10 to 5 copies per microgram of DNA. And to put that another way, that's greater than 3 copies per nucleus, so 3 copies per cell. So all of this biopsy data taken together is very consistent in terms of the number of copies we see and the amount of the dystrophin present. So we see high level widespread microdystrophin expression 90 days post biopsy.
So now I will summarize the clinical data. And just to remind you, previously disclosed 9 month data for patient 1. And today, we're updating you with 9 month data on patients 2, 34. So I'll start out with the NorthStar ambulatory assessment. To remind you, this is a functional scale looking at milestones that CMD Boys will achieve.
This is a 34 point scale, and so we're looking for increase that shows improvements over time. We're showing here is baseline out to on the left all the way out to 9 months or day 270 on the right. And what you'll see is a consistent increase in the NorthStar ambulatory assessment score in all four patients. Now to look at it more closely, we focus on patients 1, 2 and 4. These patients are the 4 to 5 year olds.
And we know from natural history that 4 to 5 year olds do see an increase over this time when they're on steroids of about 2 points. But if you look at our patients, they're increasing to 8 points over the course of just 9 months. So well beyond what we would predict from natural history. Now looking at patient 3, which was who was 6 years old at baseline, he was already doing quite well at the baseline of 26. He still improved with an increase of 2 points.
And we know that 67 year olds from natural history data are actually declining over the course of the year by 4 points. So we would expect that it would be declining. So really the net delta in all of these patients reports to a mean of 6.5 points from baseline. So very consistent results. So just to put this in some perspective, since this is a milestone scale, this is actually telling us that these patients can do 3 activities that other DMD boys in this age range can no longer do.
Or put another way, they can do 6 activities independently that another DMD boy that's untreated cannot do. So very consistent and encouraging results, which gives us great confidence as we enroll our 102 study or our placebo controlled trial of 24 patients. Now on this next slide, we're showing additional functional measurements. So we're showing time to rise, 4 stair climb and the 100 meter test. So just to give you some perspective on the slide, we're showing baseline measurement.
We're showing the previous time point disclosed as designated with the asterisk as well as day 270 or 9 month data. And so for all of the time tests, we're actually looking for a steep same amount of time to do that activity. So if you look across every single measure, we're seeing an improvement. So for time to rise, it's a mean of 0.8 seconds improvement for 4 stairs, 1.2 seconds improvement and 100 meter, almost 8 seconds improvement. So we're seeing consistent results across every single functional outcome measure that we've looked at.
We've also continued to look at the biomarker CK. And what we see is a continued trend for a drop in CK over time. As CK can be variable and we know that it can vary within a day and it varies with activity. And so as we look at the data here across 9 months, you'll see that we've seen a few spikes. For example, day 90 for patient 2, we know that this patient was doing activity prior to getting the measurement.
For our protocol, we asked that the patients do resting CK, but we know that we've had protocol violations where this has not occurred and we had several spikes. We can also see that for patient 1 at day 180 and patient 3 at day 270. So there is some variability, but these kids are doing very well and they're active and we're, know that this is an inherent variability due to CK. However, we're seeing an overall trend in the downward direction for CK, which is encouraging. So if we look at in graphical form, I think this makes the point that we're seeing still a drastic decrease in CK over time and this is still very unprecedented.
If you remember, we said that CK for VMD boys in this age range are between 2,040,000. And if you look at this graph, the only point that we're looking at in that range is at the baseline. So we're consistently seeing a drop in CK over time. And what's important is when we look at the function, so we've overlaid the Northstar ambulatory assessment here just to make the point that we'd consistent improvement in Northstar over the 9 months and we see a consistent decline in PK. So really unprecedented results in terms of function.
We're seeing durable improvement in function and we're extremely encouraged as we enroll our placebo controlled study. As far as safety, we've had no updates from our last report. The patients continue to do very well. Just to remind you, we've had no serious adverse investment study. 3 patients did have elevated GGP and they all resolved with steroids within 1 week.
There were no other clinically significant laboratory findings. The subjects had transient nausea within the 1st week, but that was when the steroids were increased and that did not correlate with liver enzyme elevations or any other abnormality. So just to summarize, all 4 of our open label patients are doing extremely well. The biomarkers, including CK and microdystrophin, have shown large magnitude effects within 3 months, and we're seeing continued functional improvement from baseline now to 9 months. All these results are showing that these patients are performing better than we would predict by natural history and there continues to be a favorable safety profile.
And all of this is supportive of our current enrollment in our Study 102 or our 24 patient placebo controlled study. With that, we will be happy to open up the call for questions.
Thank you. And our first question comes from Martin Auster from Credit Suisse. Your line is open.
Hi, everyone. This is Mark on for Marty. Thanks for taking my questions and for all the color that you guys provided today. I guess my first question is, big picture, what's a good way to monitor durability longer term? And then my second question is, I realize you don't plan to provide an update on this trial while the Phase 3 is ongoing.
That said, I was just looking for a clarification on the protocol design of that study of the Phase I site. Specifically, will there be 12 month biopsies taken? Thank you.
Thanks a lot for the question. This is Doug. So a couple of things on durability. So first of all, let me say I'm going
to answer the last question first.
So there is not currently a planned 12 month biopsy for these children. And one of the reasons for that kind of relates to your initial question, which is how do we look at durability. The preclinical work, the animal models, and we're talking across our programs, mouse models, the gold retriever model and also the nitrogen primate, there is no basis to believe that there would be durability issues in this kind of timeframe. In fact, for the mouse durability for as long as the mouse lives, normal age raising mouse. In the goal of retriever models with our partner Genaside, we've seen that out 7, 8 years, not even Primates has been out for years.
As long as we've looked, we've seen durability. So the problem with having a biopsy at the end of 1 year is it's a very invasive procedure for these children without any real justification because one would see at this point, the evolution in durability. And certainly given the level of expression that we're seeing in these firstborn children, there would be no reason to modify that. We would assume significant durability. The way we have a lot of work to do is just think about the how to measure long term durability in a way that's not overly invasive.
It's still because we're going to need to be monitoring this at least in 5 years and the like. And we have more work to do there, I think the coming weeks. I think function is so certainly payers would like to see function. If you want to know what payers want, they would love to see function. And that might very well be a measure of legal care for guidance to make sure that it's objective, but not over the long term, so we don't find ourselves in disputes with payers over accessing reimbursement related issues in the long term.
CK is not. CK is a great marker of the functional the benefits of the therapy because of course CK is associated with muscle memory. So when we see these significant drops like we see here, we can see that the therapy looks like it's working and the functional results confirm that. The issue with CK, as you can see it here, is there's a number of confounding variables. The first confounding variable is that CK moves around too much.
It moves around intraday. So it's a good marker of durability. That alone is going to be a problem. The second thing we see in these kids at least, the first four kids is that they do not act like you would expect in their age range for Duchenne muscular dystrophy kids. They appear to be significantly more active.
I think you're hearing something about one of those cases talking to their parents, who the day before he had a spike in his CK was at the park doing things like handstands and somersaults. It's not surprising. They're going to get spikes simply associated with the fact that the therapy is very appears to be at least in this early study, very functional. And then the third issue we have right here is you get protocol violations. It's very difficult to have these children assiduously abide by the resting CK protocol.
And we've seen that a couple of times now, probably now three times in this scenario where the families haven't been able to follow the strict rescue CK protocol, there was a spike. And as soon as they're reminded to go back on the resting protocol, then they come back down and then the CK drops to below what would be DMD like in both of the two cases that we've seen and then we'll see in the 3rd case I suspect it will be very similar to that. So CK is that CK will be a template for durability, but certainly it's a good marketer So we have a lot of the short answer is we have a lot of work to do to see if we can find a good either a good non invasive marker for durability for the long term or failing that on a good functional endpoint that payers and immediately is a good long term marker as well.
Great. Thank you.
Thank you. Our next question comes from Alethia Young from Cantor Fitzgerald. Your line is open.
Hi, this is Eileen on for Alethia. Thanks so much for taking the question. So as
we think about the different components of the NSIA,
clinically meaningful? Can you just help us think about the main drivers of this score between patients and over time? Thanks.
Sure. Thank you very much for that. I'm going to turn that question over to Louise from pricing.
Sure. I can say, as we mentioned, the scale is of 17 different measures on 2 points per measure. And we're currently evaluating the sub components of the NSCA to look just at that to see which are more responsive. So maybe we could use that going forward. But right now, we don't have any sub analysis to be able to speak to in terms of what's if there is response in some areas versus others.
Okay. Thanks.
Thank you. Our next question comes from Debjit Chattopay from H. C. Wainwright. Your line is open.
Hey, good morning. And so just a follow-up, the NorthStar ambulatory assessment compares obviously very favorably to age adjusted DMD patients. Wondering if you have insights on what is the norm as far as the interesting 20% decline in time to rise, the 29% decline in the forced air climb and I believe a 13% decrease in 100 meters to a similar age adjusted cohort. So what should the expectations be for those three markers? Thank you so much.
I'm going to turn this over to Luis and maybe additional as I remember as Luis said during your presentation, in the age range of the 4 to 5 year olds' total words, any benefit that they might see in development over that course of that time would be a fraction of what we're seeing in the NSA score here. And likewise, in the 5 to 6 year old range, you would see the office, I just 6 to 7 year old range, you would see the opposite, you would actually see these kids beginning to significantly decline over that period of time. And of course, in the 16 year old, we haven't received the opposite, We see a gain in function in NSNA. But Luis, do you have any other insight into the natural history regarding some of the subparts of the or the time here, particularly the one that Benjie referenced.
Just the natural entry data that we have for the time test, which isn't as extensive as Northstar, what we're seeing is improvement beyond what we would expect for natural history with the contests as well. But we'll certainly doing all of these detailed analysis in preparation for our future studies.
And just a follow-up on the CK. Does at any point these patients go off steroids post gene therapy?
They have all been tapered off their they went on daily steroids for the 1st 30 days, but then they go to paper down to their standard of care dose. So they're always on some level of steroids.
Okay. Thank you so much.
Thank you. Our next question comes from Christopher Marai from Nomura. Your line is open.
Hi, good morning. I have a question on Patient 2 specifically. Just noting that CK spike and then having the CK level come down, I guess it was the day 90 measure was quite high, 40,000 plots and you came down to sort of that 6,000 number. I was wondering if you could comment on how that might look for an untreated Duchenne patient. I suppose relative to how we might expect the microdystrophin to impart mechanistically benefit protective benefit to the muscles?
Is it something you would have expected, obviously, with the micro dystrophin there? And then secondarily, on the safety front, have you looked at any immune responses against the micro dystrophin construct? I didn't know any of that in the safety update.
Thanks a lot for that. So a couple of things. Remember, for that kid so these kids would never be in the 6,000 range. So the question is what would you expect to see the Duchenne kid similar to this, you would never see a drop in 6,000. These kids are in the 20,000 and above range.
So that isn't this is just they don't assuming they're told to rest and they take a resting CK, in both of the two instances we've seen, they've immediately dropped down to the 6,000 range, below what we would see in the MD patients. So this is not what I'm not this is not what I would see in DMD patients and then the second part part of your question was?
I guess, any immune response against the microstrophin construct? Have you guys measured that or looked at that out to date to 270?
Sure. Louise?
Sure. So part of our protocol is to look for immune responses to micro dystrophin and we have not seen any immune response to micro dystrophin throughout the course of the trial.
Okay, great. And then just lastly, maybe any rough timing on the potential subpart and SAA update? Obviously, that could be pretty interesting. So thank you. That's all.
On the first four patients, our goal on the first four patients is not to continue to update. In fact, this is be honest, because the data looks so good here, it's kind of what I was concerned about initially. We don't want to look like we're hiding the first four patients as we're in the middle of a placebo controlled clinical trial. Our goal right now is to take what we see as very exciting results from the first four patients and to confirm them in our trials, the placebo controlled blinded trial and then we want to get started on a commercial supply trial as well. So that is successful.
We can hustle this therapy out to the community as fast as is reasonably possible. So it is not our goal to continue to
update. Got it. Thank you.
Thank you. Our next question comes from Brian Skorney from Baird. Your line is open.
Hey, good morning guys. Thanks for taking the question. Most of them on the updated data have been answered already, but I'm wondering the other news last night was that Brammer Bio is getting acquired by Thermo. And just wondering if you had looked at acquiring Brammer outright at all going to be capability to this program? And do you have any perspective yet on whether or not you expect an impact to your time lines from the Thermo Brammer deal?
Sure. So first of all, there's nothing in the Thermo acquisition of Brammer that puts any of my timelines at risk. We were so there's no issues there at all. We are very pleased as it stands right now with our the hybrid model that we have. We have a very, very good relationship with Brammer, working very closely with them.
We're late in process development and yield optimization. We need to get that completed and along with them getting all of our assays done so we can commence our commercial trial, our commercial process trial. So we're working on that. And of course, we have a relationship with Paragon as well, both for our micro dystrophin program as a secondary supplier for our micro dystrophin program and the primary supplier for our micro dystrophin program. So we feel very good about things.
We're nothing about the program acquisition of Brammer that puts anything in place.
Our
next question comes from Brian Abrahams from RBC Capital Markets. Your line is open.
Good morning. This is Bert on for Brian. Congratulations on the updated results and thanks for taking our question.
Can you give us a
sense of what kind of deltas and the functional measures you think you'll need to see in the 24 patient crossover study in order to show STAT SIG on some of the functional measures?
Well, I think the short answer based on the power that we've done is, if we see results like we're seeing in these first four patients, even over a longer period of time, frankly, we would hit Sac State function. And that's one of the reasons that we're so focused on moving as fast as possible to get our placebo controlled trial enrolled. These results are giving us a lot of confidence that we're on the 4% interval cohort in our placebo controlled trial, although we'll be doing some additional work in our commercial process trial. But our calorie analysis tells us that we would get to vaccinate at this or even modestly less than these results. These are I just want to it's easy to forget because this all becomes background and we've seen some of these functional results before not out to this level.
But just so we're all on the same page, these kinds of functional results are completely unprecedented for AEGSEN trial. So again, we want to be careful about over analyzing 4 patients' preliminary results, and it certainly gives us some confidence that we're on the right track.
Excellent. Thank you.
Thank you. Our next question comes from Ritu Baral from Cowen. Your line is open.
Good morning, guys. Thanks for taking the question. My first question is on the I guess, the takeaways from the extended functional data, especially NFAA on who you should enroll in the 102 study? I know we discussed the age range, but just given the improvement and the variable baseline NSAA from 18 to about 26, I believe. What does this tell you about who you should enroll to show the maximum benefit and who you probably don't want to enroll to basically avoid any sort of ceiling effect?
We have some external guidelines around enrollment to ensure that we don't end up with any kind of ceiling effects with a patient that might be unusual for his age range. So we're already sort of dealing with that issue. One of the things that it tells us that we're doing the right thing in enrolling 4 to 7 year olds in our placebo controlled trial, because what we're seeing is a very consistent benefit against natural history across all of these ages in the younger kids because they are greatly outperforming any functional benefit they would see in natural history for that age matched room. And if the older kid, he's gaining function, but he should be losing function. At least based on the natural history we have at patient level natural history, it's about the same.
So we are seeing at least 4 to 7 year olds again. I'll give you a cautious note that these are early days only for patients, but with that cautious note in place, we are seeing a pretty consistent and significant benefit functionally versus natural history that tells us we're on the right track for our placebo trial.
And do you think you have more confidence in the natural history on the increase in the older patients or in the I'm sorry, the increase in the younger patients or more confidence in the decline of the older patients in that range? Where is the national history more robust?
It's consistently robust across all of it. And it's an interesting question to ask, which of those 2 subgroups we think is we have more confidence about showing differences. The truth is, it's about balance. So on the latter the 6 and 7 year olds, they show function while others decline, they're going to see a big gap. So they can say, well, what about the earlier kids?
They could actually gain some of the natural history. But remember, they have a lot more headroom to ever need to a ceiling effect as well. And our goal is not to simply and we're seeing at least, this does not just moderate the decline in the disease. It appears at least early days to be getting significant gains in function. And I'd say our actual discrete gains in function.
And so there is a lot of headroom in the older kids to gain and gap away from DMD toward more non DMD and SAH scores. So if you sort of think of that panically results, we feel pretty comfortable right now in the entire 4 to 7 year old range, both from an absolute history perspective, we've looked at patient level balance across that. I think we have more information about that than just anybody who would on the sham dystrophy, and then we feel very good about the results across these age ranges for the cell.
Got it. My last quick question was just on the protocol violation that you mentioned on patient 2, the increase in CKs. And I was noticing that patient 2 also was the patient that had a while a good increase in NSAA, also an increase in time to rise. Can you give any more detail on what the protocol violation was or how that might impact this patient's functional measures?
Yes. The preclinical patient population is straightforward. Look, again, the parent is not that surprising. These kids are very active in ways that are at least anecdotally, they have been you see in VMD patients. The kids are often, I think, maybe consistently in the first four cases, where kind of a C case taken on a Monday is the most convenient time for them.
It's also a problem because it's right after a weekend. So there's a real probability that we can do something on the weekend that's inconsistent with the protocol that's supposed to be resting for the 2 days beforehand. On this particular case, I think you have a part, if I'm not mistaken, anecdotally. I can tell you, very, very active on input. We came in from the UK, parents, they've been very active the day before, literally been to our handstands and curtails and the line.
So we had a higher CK. Parents were reliving for the next to come back in and do a ranking CK. And as you can see, when they did that, it immediately dropped down to 6,000 units. So that's what happened there. I think the other kids that had a spike within the zoo, Ohio Zoo is a big zoo.
So it's very simple. The struggle is, I mean, I can tell you, my semi tonnagee have seen the bother of patients who at a conference right around the same time that this decay was being taken. The father was talking to me about how active this child was. And we're actually tried to convince him that maybe he could be so active in the middle of the trial. He respectfully told me that that wasn't going to change.
It's very difficult to get these kids to not act like children.
Thank you. Our next question comes from Salveen Richter from Goldman Sachs. Your line is open.
Hi, this is Andrea on for Salveen. Thanks for taking our question.
As a follow-up to one of
the initial questions, you mentioned that the preclinical data showed durability lasting years in a number of different animal models. But how should we be thinking about trends over time? Can we expect the functional improvement in the CK levels to continue as we've seen in the initial 9 months or is it more likely that we'll see some leveling off? Thanks.
Louise, you have some thoughts on that?
So in the mouse, we've looked in primates as well. We can look at expression there, but in the mouse, it's the best we can do as far as function. So over the time points that we've looked at, we've seen a continued improvement in function over the lifespan of mouse, not the mouse. And I also know some other work in the Golden Retriever, they have durability out to, I think, almost 8 years now showing still sustained functional improvement. So those are the collective data that we have to rely on that basically shows that there's durability of functional benefit over that time point.
Thank you. Our next question comes from Joseph Schwartz from SVB Leerink. Your line is open.
Hi, good morning. Thanks for taking the question. This is Dae Gon dialing in for Joe. And congrats on the update. I understand that it's still early days, but great progress so far.
So Doug, two questions for you. First one with regards to, I guess, your prepared remarks, you were talking about discussions with the payers and how they want to look for some durability measures. Just wanted to get your take on since you mentioned functional measurements on one aspect as an indicator of long term durability and on the other hand potentially looking at CK, I guess there were a lot of questions during the Q and A talking about the variability aspect and protocol violation. Which of those two aspects do you think is gaining a little more traction in terms of progressing on the dialogue? And I guess the second question is, when we look at the improvements here, is it safe to assume that these treated patients should at some point reach normalcy, given that in the 4 to 7 year olds you're seeing such dramatic effect if you were to take these patients out for a longer period of time that it's no longer a natural history that you should compare it to but the normal bole?
On the last question, I don't we don't know where how well they'll do over the long term. We certainly have as our goal and as our belief that this therapy is going to be truly transformative for these children. That's our goal. The children have had Duchenne muscular dystrophy since they were born. So they've had the effects of Duchenne muscular dystrophy from birth.
And so that may be some sort of later and I don't want to hold a promise. But it is our goal and certainly it is our subjective belief nowadays and everything we've seen that we have a therapy that could truly transform the lives, extend the lives and improve the quality of the lives of these children in ways that has never been seen before in the share. If we look to the discussions of payers, I'll think I was 1, there's no way payers would ever take CK as a measure of durability. So to us, it's really 2 issues. There are couple issues.
One is, I think the gold standard for payments is going to function. They want to see function durability versus natural history over time. And so long as we can come up with effective standards for natural history and the like, that might very well be the thing we end up with. There's another alternative, but you can see the issues associated with it. The other one would be just the expression level.
The issue with looking at expression levels is that they require invasive biopsies over the long term and that there probably are significant practical and ethical issues associated with asking children to come in for regular biopsies or post therapy once the therapy is the market. So we're looking at other things as well. One of the things we're looking at right now is, are there other biomarkers that we can find in the congestive basis that would be directly correlated with expression levels. We don't have an answer to that yet, but we'll be working that through. We are in ongoing dialogue with payers even as we speak.
And I think we'll have a better understanding about what those measures would look like as we track into the Q1 of 2020.
Thank you. Our next question comes from Gena Wang from Barclays. Your line is open.
Thank you for taking my questions. Maybe first question also follow-up with 2 questions regarding the CP. So I remember back at the work, Maso, also there is variability on CK and then there is a discussion on follow closely monitoring a patient's activity. So you also mentioned patient 2 was some violation of protocol. What about patient 3?
And do you have any what kind of pre testing monitoring? And then after test, if you see the high score, do you have a follow-up score? And can you share that score with us?
So the answer to Patient 3's high score appears to also relate to activities. So every time we see spikes, they're consistent and a clear pattern associated with it. And then when they so far, they're like, they basically have a follow-up yet. So far, when they've been reminded to do a resting TK, at least 2 of the 3 now, drop below what would be DMD like 2K levels.
Thank you. Our next question comes from Joel Beatty from Citi. Your line is open.
Good morning. This is John Yeegan on for Joel. Thank you for the update this morning. My question is also on CK. Could you remind us at what point patients were tapered back from the daily steroid regimen back to standard of care steroids?
And what trial design protocols are built into your studies to kind of control for this? And also as a brief follow-up, are you looking at any other muscle damage biomarkers besides CK, such as like lactate dehydrogenase or alanine aminotransferase?
I'll give the second question to Louise. The first question is the children in the first four patient cohorts were on 30 days of steroid. 30 days of increase in steroid and tapered back if there was a signal of increase in liver enzymes, they were tapered back, they were put back on the steroid additional 30 days and tapered back down to normal steroids. I will say, still we're absolutely clear on this point, there is no correlate between the use of steroids and any drop in PK. We've shown that repeatedly.
Recently, you may recall that we had some results on our limb girdle 2 d and we had there are only two times that we're aware of in studies where there's been any correlate between significant cost of TK and therapy. And the one is our micro dystrophin program and the second is our 2D program with the girdle. And in connection with that, we showed we actually had an interesting this is all of the literature that shows that steroid use does not correlate with ROS and CK. We also showed in that study that using the same protocol for a different amount of limb girdles to be but at a much lower level of non with a non systemic gene therapy, it was either limb at a much lower dose, but we did systemic steroid use with the same protocols we're talking about both in that program as well as in our microdystrophin program. What we showed there was there was 0 impact on CK.
So even with isolated red gene therapy, but at low doses, the systemic CK did not have any impact at all. In fact, CK went up over the course of the study, not down. So the current protocol was for these kids was 30 days, 3 days of the increase in steroids, taper back down to baseline steroids unless they saw elevated liver enzyme, in which case they would be put back on steroids and allow that liver enzymes to go back to baseline as they always did in all those kids. And likewise, same thing with Limb girdle, except Limb girdle because standard of care is not steroids. They were treated all the way off, no steroids at all.
So that's the protocol. So for the avoidance of any doubt, there's no evidence whatsoever that CK level drops correlated anyway with steroids. So it seems pretty clearly related to the use of the gene therapy itself.
Thank you. Our next question comes from Yun Zhong from Janney. Your line is open.
Hi. Excuse me. Thank you for taking my questions. And the first question is sorry, also on CK and just noticed that all the variability happened after day 60 and wonder is physical activity the only reason that affects CK level? Or can potentially anything else affect it?
And any reason why nothing happened before day 60?
Well, we would be we might be speculating to suggest that they might have better followed it might be just coincidence they didn't follow the breast and protocol a little bit later and they assiduously followed immediately after the therapy. But beyond that, do we still have any other speculation about why they would have been these protocol violations later but not earlier?
No. Just I mean, it would be anecdotal or speculation that they're just as they're feeling better and getting more comfortable with the way they feel that they had an increase in activity later on versus early on in the trial. So we don't have any specifics.
Thank you. Our next question comes from Tim Lugo from William Blair. Your line is open.
Hi. This is Miles Winter on for Tim. Thanks for taking the questions. Mine just revolves around patients 1, 2 and 4. The improvement in the NSAA is pretty similar amongst those patients.
And I know patient 4 has considerably higher mark of tissue and expression of 3 month biopsy. So my question is, is there a roofing effect on microducifin expression that could confer functional benefit? Or is there milestones that are acquired by patient 4 in those 9 months that we're not seeing reflected in those numbers that are in patient 12? And the second, just an enrollment update, if you could, on the placebo controlled trial, that
would be great. Thank you.
Yes. I mean, I think the answer on I don't think we can take from this data that there's a feeling effect on the functional benefits, but we can take from the data potentially that there is a ceiling effect on the NFAA. These kids at 27, 27, 26, these numbers are getting close to the top end of NFAA. We can't do better than the top of the NFAA and we can't do better than an age matched non DMD child at this age. So that's the ceiling impact.
These kids have had such a profound impact. If you look at these kids, they were baselines as one would expect of 2018 2019 2019 and now they're getting up to nearly 30 points on what is a theoretical 34 point scale. So there is that potential ceiling effect that occurs. They're getting very close to what a aged NASH non DMD child would perform on this therapy. And then I think you asked about enrollment, if I'm not mistaken, on the current placebo controlled trial, these are going very well.
Our goal is to complete the let me say let me make sure we're clear about this because people have asked how is enrollment going. In one sense, I'm going to be very clear. We don't have any issues with enrollment. There is a significant inventory of patients available for our 24 trial. So it's not really about enrollment like you would expect to see in some greater diseases.
What it does is simply workload. We have a single site, single principal investigator. Doctor. Mendell is our principal investigator. He is required to do much of all of the work, including all the initial analyses, the infusion, follow ups and the like.
And as productive as Doctor. Mendell is and as committed that he is, I think nobody knows him wouldn't expect him to be unbelievably committed, there's just a certain limit to his ability to get to do that. So as we stand right now, we are noticing just about 1 patient a week. We would love to improve that to you, but frankly, our current timeline would suggest it will be completed before the end of the second quarter, certainly only requiring us to dose once a week. So things are going great.
We are in dose. I think we are I'm not sure exactly, maybe 13 patients or so by now, so it's very variable.
Thank you. Our next question comes from Nirav Shlott from Piper Jaffray. Your line is open.
Hi. This is Nirav Shlott on for Danielle Brill. I just most of my questions have been asked. The only question that I had was, I know the subcomponent analysis hasn't been done yet on the North Star. Are there any expectations into which subcomponents will show greater or lower effects down the road as these patients get older?
Louise, do you have some thoughts on that?
Yes. I can't speculate now until we do that analysis on the different subparts in terms of which would respond. So I don't want to speak too soon on that right now, but we're certainly evaluating it.
Thank you. Our next question comes from Vincent Chen from Bernstein. Your line is open.
Good afternoon, David. And thanks for taking the questions. A couple of things that help us better understand the bumpiness in the CK levels. Could you help us dimensionalize the degree of variability in CK levels that one might see in untreated BMD or Becker patients with variation in activity? And then how much impact, if any, would you expect that the temporary increase in steroid dosing might have on CK levels?
And then finally, just a follow-up quickly on Gina's question. When there is a protocol violation related to activity, are patients simply told to rest before the next scheduled test 90 days or so later? Or are they actually receiving additional tests in the interim period after resting appropriately, whether it's part of the protocol or just other clinical care?
So going to the first one, Luis might have more detailed data on the fluctuations, but this is no, there are normal fluctuations. They're all above 20,000, but there are significant fluctuations in DMD children even in more advanced, in fact, it's not uncommon for DMD children to have the ramp up if they over exercise. And then on the dose violation, the answer is yes. They're just they remind the parents are reminded to have the kids rest in a few days preceding it and then they come back. At least so far that's worse.
I apologize for that. Can you repeat the second question,
And Mr. Chen, your line is back open.
Sorry about that. And sorry, the second question is how much impact, if any, would you expect that the temporary increase in steroid dosing might have on CK levels?
Okay. Thank you. The answer is done. The literature, this is going back all the way in the '80s. There was literature where there was early attempts to in the hope that steroid use could be correlated with Drozdzinski and notwithstanding the fact that steroid use has been shown at least temporarily to slow down the progress of the degenerative disease.
There's never been a correlate between the use of steroids and any profit CK. And in our studies, we used to be a clip. I can't tell you in our girdle studies, we actually had secondarily kind of an interesting experiment on this. We on the one hand, we did 2 d full infusion, 5 times liters, 13. And then we used the same protocol we're using here within 30 days and then pay for unless we saw an elevated liver enzyme.
And this is the same thing as the liver program 2E. And in 2E, you see these profound drops in TK. But we also indicated the lip girdle program did for our 2b program. We did a low dose lower glans perfusion study and we did the same exact steroid protocol and where you see where you saw real low dose and non systemic gene therapy, so obviously less effective than the higher dose, we looked at the actual steroid use and we looked at CK. In that instance, because you didn't have systemic gene therapy, you didn't have gene therapy and more robust doses, we saw no impact in CK.
So clearly, there was no CK related there was no CK related impact on the steroid. In fact, in the 2 d study, we showed this in connection with our webinar for the CD, the CK actually went up over time. So it seems pretty straightforward that once seeing this kind of profound PK drop is associated with the protective nature of the therapy itself. In this instance of the micro dystrophin and our prior instance, the use of the 51% protein positive fibers on the gene that codes for a big sarcoglycan in that case, TBE program.
Thank you. Our next question comes from Christopher Marai from Nomura. Your line is open.
Thanks for the follow-up. I was wondering if you could further clarify perhaps some of the increases in things like time to rise on patient 2. But perhaps could you, number 1, help us understand some of these are effort based outcome measures and how you are trying to control for that? Are there multiple measures in this study? And then secondarily, where should a patient like this, patient 2 and the others, sort of be on the time to rise in general?
And then finally, is there a cutoff level on measures like that, that you might think about with respect to, I guess, past the point of no return in a patient with Duchenne? And just specifically on that time to rise since there was a question on it earlier. Thank you.
Sure. Louise might ask the more specific Actually, hi. This is Phil Maromyr here. Let me address some of those questions. I think first of all, the most important thing to understand is that the function of how the function data is all moving in a very positive direction.
If you actually take individual data points, data by data, you will actually see where very limited to payroll. And certainly, we know from our analyses of time function tests and the various types of tests in the public literature that you can get some more variability on some of the time functions tests. I think the other thing you asked about is the normal data, like what a normal boy would be doing at those different ages with those time functions test. We actually are collecting that information. We actually are working with a number of It hasn't been published yet, and I think it will be published soon by some of our academic collaborators, and we're actually doing But what I can tell you is that what we are seeing in the team in boys achieving outcomes that are in excess of the expected of their gate route with their disease and do approach or move them towards a more normal range.
I think the final thing you asked is about the ceiling effect. I think we will have you can certainly obviously anticipate feeling effects for certain even in normal boys for certain functions like going from supine to standing. And it's of the order of I'm just hope that's about 1 to 1.5 seconds. We obviously are doing those analyses and building that publication to answer issuing probably coming out based on scheduling of some of our academic collaborators. For other things like running, you're very well aware of the literacy because even Olympic acid cannot exceed certain caps for running at our 100 meter I think the optimal, I think, the unit capacity is capped at about 9 seconds per 100 meters.
So you are right that the hard caps there and stealing effect. However, they are much less restricted, if you will, than something like an NFAA, which is a functional modality at scale or the skin. Does that make sense? Do we have that to that?
Thank you. Our next question will come from Yun Zhong from Janney. Your line is open.
Hi. Thank you for taking the follow-up question. Can you remind us if you had any discussions with the FDA on the length of all on efficacy analysis and safety analysis for potential approval, please?
We haven't had detailed discussions yet. Certainly, we're in continuing dialogue with the agency as we complete our TUVOCROL trial and we plan our commercial supply trial.
Thank you. And our next question comes from Edward Nash from SunTrust Robinson Humphrey. Your line is open.
Hey, good morning. Thank you
for taking our questions. This is Fang Ke on for Edward. Could you remind us what's the rationale to conduct a 24 patient trial at a single site? Thank you.
1st of all, remember, this is very consistent with what AveXis Novartis did as well. It started with a single site study with Doctor. Mendell as well, ironically, very similar program to ours. We will be moving to a multi center trial for our commercial supply trial, which our goal is to start that before the end of 2019. We're in a single site right now for a couple of reasons.
One, because of the expertise of Doctor. Mendell himself and the consistency associated with the infusion of the like from Doctor. Mendell. And second, for SPEAKER to get going with the study and to get the functional data confirmed in a well controlled placebo controlled trial at the fastest possible pace required us to go with Doctor. Mendell, who had a spike that was out in writing and able to dose these kids.
It would have probably delayed us by at least 5 to 6 months if we had attempted to get additional sites up and running before we commenced this 1st test vivo control trial. But with that said, we have the time over the course of this year to get other sites up and running. It is inevitable to get at least 10 or more sites up and running in the U. S. And very likely ex U.
S. For our next trial, which
is our commercial supply trial.
Got it. That's very helpful. Thank you.
Thank you, Ben.
Thank you. Our next question comes from Tim Chiang from BTIG. Your line is open.
Hi. Thanks, Doug. Do you guys
have data for patient 1 all the way above and beyond 1 year at this point? And if you do, when do you think you'd be able to release that data?
I'm not sure if we have additional data. Obviously, my patient 1, I don't have it in front of me, but we were updating because Doctor. Mendel had updated. Again, I will say I am very concerned about continuing to update on the first four patients as we're literally in a placebo controlled trial right now. I think there is a real risk that it looks like we're inadvertently looks like we're overly promoting the first four patients while we're trying to confirm the results in a placebo controlled trial.
So I want to, to the extent possible, weigh additional updates to just really get this placebo trial completely dosed to get the functional results confirmed. Hopefully, if those functional results are consistent with what we're seeing so far, We'll have success in the trial. That's our goal certainly. And then to get our commercial supply ready to go and to get into our commercial supply trial and then get commercial supply available so that as early as the end of 2020, we would have commercial supply ready to go We have to get an approval and start serving as a community that is. So that's really a need for transformative therapy for Duchenne muscular dystrophy.
Thank you. And that does conclude our question and answer session for today's conference. I'd now like to turn the conference back over to Doug Ingram for any closing remarks.
Thank you very much. Well, presumably, you will understand ASEM's data, whether we are moving in such speed to confirm these results in our placebo controlled trial and get this therapy as successful to the community as quickly as possible. While preliminary, these functional results are better than anything that has ever been seen in Duchenne before and better even than we would have anticipated at the outset. The CK drops are unprecedented and while we see occasional spikes due in part to the variable nature of CK in part to the non DMD like activity in some of these children and from the occasionally consistent inconsistency with the rest of CK protocol. We also see that whenever they spike, we drop back down to below DMD like levels whenever that protocol is followed.
And of course, safety is extraordinarily important in these gene therapy trials and we are very encouraged by the safety profile that has been observed to date. With all of that said, we are moving as fast as it's reasonably possible to complete our placebo trial and to get our commercial material trial initiated, which we intend to do in 2019. And this will be the focus for the rest of 2019 for us as we feel an obligation of the families living with Duchenne to move at the pace that this degenerative disease demands. With that, I thank you all for joining us this morning.
Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone have a wonderful day.