Capricor Therapeutics, Inc. (CAPR) Earnings Call Transcript & Summary

Good afternoon, and welcome to PPMDs webinar with Capricor Therapeutics. I'm Pat Furlong, and I'm going to be joining the webinar with Linda Marbán and Dr. Craig McDonald. We're here today to talk about CAP-1002 programs in HOPE-1 and HOPE-2 and bring you up to date on recruiting for this Phase 3 program. So with that, I'm going to turn the slides over to Linda and Dr. Craig McDonald. Please begin, and we'll go through the slides, and then we'll come back for Q&A. Should you have any questions, please put them in the chat, and we will respond during the webinar. Thank you for joining us.

Linda? Thank you, Pat, and thank you, PPMD for giving us this opportunity to provide this update to the community. This webinar is primarily focused on patients and their families to allow you to see the long-term benefits of CAP-1002 in those boys and young men that were in the HOPE-2 -- I know the HOPE-2 open-label extension trial. Next slide, please, Jane. We are a publicly traded company, our symbol is CAPR, and all of our filings are up to date with the SEC should you want to review. Next slide, please. Today, obviously, we are joined by Pat Furlong, I'm Head of PPMD and our webinar moderator. Thank you, Pat, for putting together PPMD, and I think we all realize that the world of Duchenne muscular dystrophy is a different and better place because of Pat. And we're also joined by our National Principal Investigator, Dr. Craig McDonald, who is the principal investigator on the HOPE-2 trial, the HOPE-2 open-label extension trial in our HOPE-3 trial, Dr. McDonald goes without any further introduction to this community as almost all of you have been touched either physically by him as his patient or by his abilities and activities in the space as an internationally recognized clinical trialist. So thank you, Dr. McDonald. And I, of course, I'm a familiar face to all of you. I'm Linda Marbán, the Chief Executive Officer of Capricor Therapeutics and a person who is wildly interested in seeing the progression of this disease halted so that the boys and young men can have normal life as possible. Next slide, please. Today, we're going to go through our agenda, which was the introduction by me. Dr. McDonald is going to take over now and he'll talk about CAP-1002 -- remind you of the results that were published in the Lancet of the HOPE-2 clinical trial, and then present to you today in the 18-month open-label extension data results. We will have 24-month data coming in the beginning of the second quarter, which will also include measurements of cardiac function. This has rarified and exciting data because it is one of the first time that there will be a long-term look at patients with DMD, especially the non-ambulant patients, and we'll have about 4 years of data at that point. So we're really excited to present this data to you today, and we'll be back in a few months with some more data. And then we're going to talk about HOPE-3, which is enrolling now. We need to continue enrolling that trial per FDA's mandate -- and finally, we'll take your questions. And with that, I will turn it over to Dr. McDonald's. Thank you so much, Craig, for joining us today.

Thanks, Linda, and thanks, Pat. And it's really my pleasure to be able to share our experience with this cell-based therapy. This is really one of several really exciting therapeutic approaches to the treatment of Duchenne muscular dystrophy that are currently being investigated. And we've made great progress with regard to this mechanism of using cardiosphere-derived cells, a cell-based therapy. I'll -- if we could get to the next slide. So just to give you some background here. CAP-1002 is a biologic therapy. It consists of what I referred to as allogeneic cardiosphere-derived cells. And these are endogenous populations of stromal cells that are harvested from healthy human hearts. So these are hearts that were essentially destined to be donated and transplanted. But for whatever reason, they weren't perhaps an optimal match. And so the hearts were not dispensed with, but the hearts were still used to actually grow out these allogeneic Cardiosphere -derived cells. And there's really, I think, the exciting thing about these cells, the cells are actually infused by IV. They actually have a systemic effect really throughout the body. The cells actually will hone to the pulmonary vasculature or the pulmonary blood vessels, and they'll actually tend to reside for a period of time, and they'll actually secrete what are called exosomes. And the exosomes are really probably the mechanism by way -- by which the Cardiosphere-derived cells actually work. And these exosomes, they're essentially membrane laden packages or vesicles that actually have really important components within them. Some of them are actually -- some of the components are microRNAs, which have been shown to have positive effects on the progression of Duchenne muscular dystrophy in animal models. And these exosomes actually and their components actually have properties of stimulating muscle tissue growth. They actually help the muscle fibers retain more optimal muscle function. They decreased inflammation, and they also prevent scarring and enhance regeneration. And so the product, CAP-1002 is actually an investigational product currently in Phase 3 development. The FDA has granted a number of designations for more accelerated drug development and evaluation of this particular product just because of the exciting data that has been developed to date. If we go to the next slide. So the infusion protocol here is fairly simple. The CAP-1002 studies on Duchenne patients have actually utilized the highest dose yet that has been used in humans, 150 million cells are infused intravenously -- and this occurs every 3 months. There essentially, it takes about 45 minutes for the actual infusion to occur. And generally, patients, there's some preparation time. They received some oral pre-medications, a slightly higher dose of steroids than Duchenne patients are typically on essentially beginning the day of the infusion. There's also some other medications that are provided to try to prevent any allergic reactions. And that, to date, has been really quite effective. And the cells themselves are infused every 3 months. So far, the over 100 infusions have occurred in Duchenne patients. There's been no treatment-related severe SAEs reported to date in the ongoing HOPE-2 open-label extension study. And I think it's important to note that CAP-1002 has actually been previously used in other studies focused on diseases such as myocardio infarction. So there's really -- there's actually over 200 subjects to date that have received multiple infusions of the CAP-1002 preparation. So far, we believe that it's well tolerated and appears to be quite safe. Just as a note, this is probably not something that would ultimately be like exon skipping IV therapies where you would actually get home infusions every 3 months. I think because of the pretreatment regimen that is required and the monitoring that needs to take place to ensure that if there were some sort of reaction that it could be treated quickly. My guess is this will -- these infusions moving forward will probably occur in either an infusion center or some sort of hospital environment as opposed to a home infusion. If we go to the next slide. So what population had we initially addressed in the HOPE-1, the HOPE-2 and the HOPE-3 studies. And it's largely been the nonambulatory population with Duchenne dystrophy. That's been the target population 10 years and older. We've also treated some patients in the late ambulatory phases of the disease. It's estimated that upwards of 50% to 60% of all Duchenne patients in the U.S. are nonambulatory. And so therefore, the endpoints that we use have focused largely on upper limb function, cardiac function, we've also evaluated pulmonary function. But that isn't to say if this therapy ultimately was extended and applied to younger populations. I think this could potentially have benefits as well. But right now, we're focused on the patients in the late stages of ambulation and predominantly the nonambulatory population. Next slide, please. So the performance of upper limb is an emerging clinical outcome measure that has been developed specifically for Duchenne muscular dystrophy to assess upper limb function. And there's a number of items that focus on shoulder level function middle level or elbow level function and also distal hand function. And this is actually emerged as, I think, the key clinical endpoint in all nonambulatory Duchenne muscular dystrophy trials, including gene therapy trials as well as some of the antifibrotic trials that have been focused on the nonambulatory population. And I think this is -- this endpoint has actually performed very well. The patients that we have targeted the CAP-1002 treatments for the clinical trials have been those patients that actually show at least some degree of shoulder level difficulties or impairment. And that's just because we want to be able to have room to actually show improvement or maintenance preservation of function. The key primary endpoint has been focused on the middle level of the pole. And then obviously, these patients have actually relatively well-preserved distal hand function going into the trial. So while we measure distal hand function, we wouldn't necessarily expect to see a drug effect on distal hand function in comparison to placebo until many, many years of follow-up. So much of the data that you will see with CAP 1002 really focuses on the shoulder level item and the middle level item. But we look at the total pull score knowing that the treatment probably has the greatest effect at least over the course of the first year on shoulder level function and middle-level function. Next slide, please. Also now I'd like to review the results, the exciting results of the Phase 2 HOPE-2 trial. These results were actually published in the Lancet, which is really one of the highest impact in preeminent medical journals in the world. Next slide. And these were the results of the patients treated with CAP-1002 versus placebo from the HOPE-2 trial, the Phase 2 results, looking at the total pull 2.0 score. There was actually a relative preservation of function in the upper limb in the CAP-1002 patients. This was statistically significant over that seen in placebo and an ultimate change of almost 2 points over the course of 12 months and those that were treated with CAP-1002 versus placebo. This was not an actual improvement in function, but it was relative more stabilization of function versus the placebo group that actually had more significant decline over 12 months, but it was a clinically meaningful preservation of upper limb function. Next slide. So if we look at actually the slope of change, the blue are the CAP-1002-treated patients showing their -- essentially their mean change in their performance upper limb score. The red is the placebo group, the placebo group actually had a pretty predictable linear decline over the course of 12 months. The treated patients had a relative slowing of their disease progression by about 70% of their baseline values. So this did not completely arrest the disease progression, but it had a significant clinically meaningful slowing in the rate of decline in the CAP-1002 patients versus the placebo patients over the course of 12 months. Next slide. I think what was particularly exciting about the HOPE-2 results were the effects that we also saw in the heart. And this is really quite a unique therapy in that the cardiosphere-derived cells, they appear to have a systemic effect on both skeletal muscle and cardiac muscle through the secretion of these exosomes. And so when we actually saw a relative preservation of cardiac MRI function, let ejection fraction actually showed really stable measures over the course of 12 months and the hope in the CAP-1002-treated patients whereas again, these were patients that were more advanced in their disease progression. Many of them actually had abnormal cardiac MRI leaner ejection fractions at baseline below 55%. And they actually showed about a 4% decline in their ventricular ejection fraction over the course of the 12 months. And this was statistically significant. And there were a number of other structural measures on the cardiac MRI that also showed a relative stabilization and improvement in the CAP-1002 treated patients versus worsening seen in the placebo-treated patients. If we go to the next slide, I'd like to now present the data from the 18-month open-label extension experience treating these patients from the CAP-1002 clinical trial for a longer period of time. And this is new data that has been recently presented by Capricor if we go to the next slide. So as mentioned previously, the HOPE-2 trial was a 1-year trial was placebo-controlled, randomized clinical trials for patients were annomized to either placebo or control. There was a period of time, a so-called gap phase where patients were actually -- all patients were actually off treatment for periods an average of 392 days for periods of over a year -- and then all the patients, both the placebo and the treated patients went on to open-label extension, and they continue to be on open-label extension and Capricor has been committed to continuing to treat patients with CAP-1002 until we hopefully down the road can collect enough data to be able to submit for consideration of FDA approval. So in the original -- this actually provided a rather unusual or unique opportunity to essentially evaluate the impact of actually going off treatment for the patients who were originally on CAP-1002 in the HOPE-2 trial. And then being off treatment for a year and then going back on treatment and seeing what impact that had on their disease progression. And in addition, the placebo patients actually were not providing treatment for the year during the trial, we continue to follow those patients until we were able to arrange for the open-label extension. So many of those patients were off treatment for periods of up to 2 years, and we were able to look at the effect of those patients actually going on to the CAP-1002 treatment. So we have 13 patients that have been part of the open-label extension, the mean age of these patients were 13. All these patients were nonambulatory and all these patients remained on a stable regime of corticosteroids and they were on steroids for at least 12 months going into the HOPE-2 trial. Next slide. So here's the data. I think this data shows over on the left, the solid blue line and the solid red line to the left is the -- what their change in their pulse score was during the actual clinical trial. We then see the -- what happened to the patients when they were off CAP-1002 during the gap phase. And then we've been able to see what's happened to the patients in terms of upper limb function when they went back on to open-label extension and then continuing on that open-label extension for a period of 18 months. And so just to walk you through this data, it's complex, but we'll take you through this carefully. Originally, in the HOPE-2 trial, we saw the published results of the patients on CAP-1002, actually having relatively more slow disease progression and loss of upper limb function versus the placebo-treated patients. That's the solid blue line, the solar red line shown on the left. And then what you can see is during that gap phase, the placebo patients that transition from the solid red line to the solid -- to the red dashed line actually continued in that linear decline that they experienced for essentially a 2-year period of time, they continue to lose muscle function. And generally, that loss is irreversible. And then when you look at the placebo patients, even though they've shown a significant decline in upper limb function, when they finally were able to get on to the open-label extension of CAP-1002, you can see the relative slowing of progression that occurs as you transition from that red dash line to the blue solid line. And there was a statistically significant improvement in upper limb function in those patients in the placebo group that were off treatment for 2 years. And then finally, despite having a loss of 10 points in their pull function, they actually had some really nice stabilization where they only lost 2 points on their performance of upper limb function thereafter where they lost 10 points in the preceding 2 years of time. And I think what we also see is in the treated patients originally from CAP-1002 that go from the solid blue line to that red dash line, they actually show an acceleration in their disease progression when they're off treatment. And so they lost an additional 2 points over that period of time of treatment. But then actually, once they go back on treatment, there's again a relative slowing and that relative slowing of disease progression was very similar to the preservation of function they experienced when they were originally in the HOPE-2 trial. So in the upper curve, the blue solid line on the right was very similar to the blue sell line on the left. And so again, I think what this actually shows again is that we have these patients, I think, been on CAP-1002 for the entire period of time, they probably would have experienced even a greater degree of preservation of function. And you can see that, that -- the fact that they were on CAP-1002 for 2.5 years, actually, they're at a much higher level of function versus those placebo patients that were on CAP-1002 for a much shorter period of time. This really provides evidence for the potential for long-term disease modification of the CAP-1002 patients because those patients that were originally treated in the HOPE-2 trial and subsequently on open-label extension, we're much better off than the patients that only had cap later as part of the open-label extension. So they've been able to maintain their treatment benefit for a long period of time, upwards of 3.5 years, really suggesting long-term disease modification. I go to the next slide. All right. And this is actually some model data that I'll walk you through. If we look on the curves on the left, these are the original HOPE-2 patients in the clinical trial. So again, you see the blue solid line on the left is the CAP-1002-treated patients as part of the clinical trial. And the red is the placebo patients from that trial. And then if we go to those 2 curves on the right, those 2 solid curves, those are the 2 patient groups that were actually started on open-label extension on CAP-1002. And the good news is really the placebo patients in the previously treated CAP-1002 patients actually had very similar rates of decline. So both groups, even though the red group had declined to a lower degree of function. Both groups actually show the ability to respond to the CAP-1002 medication. And in fact, both those groups, if you actually compare their treatment effect over that 18 months of open-label extension, if you compare those to the blue curve over on the left and you model the data to predict where they would have been if you would have followed that group for 18 months, you see it's almost spot on. They're about -- they have a change in upper limb function, right where you would expect them to be looking at the original CAP-1002 data from that original treatment group with their projected levels of decline. But I think what's important to note is looking at where those patients are, they've lost a little more than 2 points on their performance of upper limb measure on the right, if you actually compare them to a model projection of the placebo group and where the placebo group would be after 18 months, the placebo group continuing on with their linear decline would be projected to have lost about 7 points on the performance of upper limb whereas the treatment group, both the red and the blue treatment groups of the open-label extension have lost just a little more than 2 points on their performance of upper limb function. So that's a big difference over 18 months of being on CAP-1002. So again, the good news is that, again, that those placebo patients, once they began the CAP-1002 treatment, there's no longer a difference in disease progression versus those patients that have been on CAP-1002 from the beginning. If we could go to the next slide, I just wanted to show you some just video examples. Time is muscle in a Duchenne population. And I think preservation of function sometimes can be captured better with some of our newer emerging clinical outcome measures. And one of those is actually the Duchenne Video assessment, which is actually a home cell phone-based assessment that we've used during the open-label extension of the CAP-1002 trial and is being incorporated into an increasing number of Duchenne trials. And this gets it functions that are really very unusual and not typically captured. A.J., if we could just show the video, the first video, this is a patient of baseline. And the instructions here essentially actually, if we go to get back to that slide. So he's reaching below the armrest to the side as far as he can reach using both this trunk and his arm. So that was pretreatment at baseline with that patient. And then next. So this is 3 months after -- essentially after his first infusion. And you can see there's a slight increase in trunk motion there, a little bit of greater ease in terms of the upper land being brought back to the armrest, but that's after only one treatment. But this is the patient after 9 months of treatment in the open-label extension. So here, you can see much greater ability to actually utilize the trunk as well as the upper limb to reach down to pep the dog or feed the dog. And so that actually, those trunk movements are not captured with our typical Duchenne outcome assessments. So if we can go to the next slide. This is actually, again, looking at some truck movement and open-label extension patient. If we could show the first video on the left. The participant actually is trying to do a dressing maneuver. He's instructed to lean forward. You can see the degree of strain that he has really strains the head and neck and cannot maintain the position without holding on with his arms. If we show again the patient after 9 months of treatment in the open-label extension, you go ahead and show this video -- and see, I think you can see there, no longer these hands to pull forward has a minimal strain in the head and neck and is doing those trunk movements with much more ease. If we could go to the next slide, this is a 21-year-old patient that I've been following who's now been on CAP-1002 for 3.5 years. He's 21 years of age. And what's really been impressive to me, he was essentially barely able to get his hand to his mouth at when he originally entered the study, he was -- had the hand-to-mouth function to be able to get into the study. But I here show the video on the left. This is after 3.5 years of treatment. What's been impressive is just he has maintained the ability to get the hands to the mouth in really a quite nice fashion for 3.5 years since starting CAP 1002. If we go to the next slide, this is something that he was really unable to do prior to starting the CAP-1002 therapy. And this is really leaning forward. He's at 21 years of age leaning forward in his wheelchair to actually reach to the floor and then get himself back to a ceded position in a relatively easy manner. And that's actually a new function that's emerged for him that I think has been pretty impressive to see. If we go to the next slide. So again, I think time is muscle for Duchenne patients. CAP-1002 demonstrates the potential to slow disease progression in more severely advanced Duchenne patients in the nonambulatory phase. They experienced lower progression of their loss of upper limb function and cardiac function. I think there's -- I would argue that there's really an urgency to initiate therapies such as this as the loss of the upper limb function and the loss of the performance of upper limb points are never recovered once they're lost. And then also, I think what's exciting is the preservation of cardiac function and specifically MRI left injection fraction shown in the HOPE-2 trial. And the safety profile of CAP-1002 has been reinforced in over 20 projects to date. And the HOPE-2 open-label extension patients continue to receive CAP-1002 treatment as Capricor has been great about being committed to continuing those patients on therapy. We've now had patients entering into their third year of treatment on the open-label extension. If we go to the next slide, I think it's important to note that I think this is one of those in terms of a cocktail approach to targeting multiple mechanisms. This could be one of those backbone therapies in addition to exon skipping gene therapy steroids. And I think this -- there's no reason to believe that this treatment could not have synergistic effects with an exon skipping approach or with a gene therapy approach, there's no reason why patients couldn't receive this subsequent to gene therapy or receive gene therapy subsequent to receiving CAP-1002. And in addition, we've seen effects of this therapy on top of steroids, so we think it would have a complementary effects to perhaps using a steroid regimen as well. And I think many of the other therapeutics that are under clinical investigation now similarly, I think could be used synergistically with CAP-1002. Next slide. And then just a couple of quick comments about the HOPE-3 trial, which we have launched at many of the study sites. We're actively enrolling patients. We go to the next slide. The -- we're looking at a target enrollment of 70 patients. And so because of the treatment effect, we're anticipating, we think we can show statistically significant results with a trial of 70 patients. Patients will be initially on steroids, 10 years of age or older with the pole entry score of 2 to 5 or looking at an essentially late ambulatory and nonambulatory patients, previous treatment with steroids for at least 12 months with a stable dose for 6 months before randomization. The primary endpoint will be the PULL 2.0 12 months. We're also looking at cardiac endpoints, quality life managers as well as the Duchenne video assessment. And then at the end of 12 months, patients will then transition to the open-label extension, where both groups will continue to receive CAP-1002. Next slide. We've now activated 10 sites that are actively recruiting patients in California in Sacramento. UC Davis in Utah, University of Utah, University of Colorado, Cincinnati Children's Hospital, Children's Hospital Wisconsin, Washington University, St. Louis, Boston Children's Hospital, University of Iowa, Children's Hospital, Artic Children's Hospital and then the rare disease clinical trials center in Atlanta. And then the whole test you add 5 additional sites very soon. But hopefully, people can contact one of these sites. I think we have a contact number next slide. There's our contact person in their phone number for if you want to get any more information about this clinical trial. And with that, I'll transition back to you, Linda.

Thank you, Craig, and it's always nice for me to be able to hear this presentation and to actually look at the data. I didn't plan on any real extemporaneous comments today, but I just want to say that I'm a co-founder of Capricor and I'm a scientist by training and data is what has always driven my excitement. And when I look at those videos and I look at these full scores, I really have a sense that we have a real opportunity to make a difference for the Boys & young man with Duchenne. So as somebody who is involved on every level of this company, I'm excited for this data, and thank you, Craig, for that great presentation. Next slide, please. So I just want to remind everybody that we have a partnership with Nippon Shinyaku, better known in the United States NS Pharma for the distribution and commercialization of CAP-1002. Basically, that means we do everything up to and through approval. And then once it's ready to be sold NS Pharma will take over from there. We're very excited. They're great partners. And as you know, they have one of the Exxon Skippers, Viltepso, available for use and has been approved in the United States. So thank you to our colleagues at NS. And final slide, I want to leave time for questions. I can't say thank you enough to Craig to PPMD to all the organizations and people that are listed here, no small effort on the part of all of our investigators, Sishen at Cincinnati, Russ Butterfield Utah, Rich Finkel, who has moved on from [indiscernible], but was there originally, now at St. Jude's, Joanne Janus from Colorado; Matt Harmeling from Children's Hospital of Wisconsin, Dr. [ Braderchari ] in St. Louis, [indiscernible] University of [indiscernible], cousin Cathy Matthews at Iowa, then we'll be adding to that list. So thank you. But it goes without saying that the only way that these studies can be done and these products can be approved just by families taking the risk of putting their children or themselves in a clinical trial and hoping for the best. So thank you to everybody who is participating in the open-label extension study and in HOPE-2 and, of course, HOPE-3. Next slide, please. So I think we'll leave it open for questions then. And I think, Pat, you're probably going to moderate the question-and-answer.

Yes. Thank you, Linda. Thank you, Craig. That was really excellent. And a few sort of overarching questions first, and then we'll go back through the slides, if you don't mind. It was a great presentation. And certainly, we've all talked about combination therapies as it seems like forever. And the fact that this could be a backbone therapy with gene therapy with [ antisense ] with downstream with steroids is really where we need to go. And finally, time is everything. So one of the questions that has come in about joining this study, Linda and Craig is washout. So if he were in another study or what is the length of time for washout that's required to join the study.

Craig, you probably are familiar with that problem.

Generally, as with most clinical trials, there's generally about a 3-month period of time for watch out. This study incidentally is actually open to patients that are on FDA-approved commercial available exon skipping therapies. I believe the requirement is for patients to have been on an exon-skipping drug for about a year. At the time, they would be considered for this clinical trial. But generally, it's about a 3-month watch out if somebody has been in a recent clinical trial. And we are open to patients that are actively on other FDA-approved therapeutics such as exon skipping therapies.

Right. Thanks, Craig. But at the moment, it those people who've been in a gene therapy study, for example, at this moment.

Yes, that's correct. And so it's not open to patients that have recently been in a gene therapy trial. And most non-gene therapy trials would have that same exclusion at the moment.

And then just again, overarching questions, and then we'll go to specific to the slides. Linda, as you know, Becker muscular dystrophy is a very heterogenous and difficult disease to figure out. Are you planning or have you thought about Becker and doing a study in Becker muscular dystrophy?

Yes. I mean there's certain energy for indication expansion into any and all muscular dystrophies. Our focus right now is getting CAP-1002 approved for the patient population that we're currently targeting in HOPE-3 and the data shown today and HOPE-2, and we'll continue to be forward-looking with the therapy over time.

Great. And just for everyone on the phone, supply is not a problem at this moment, your manufacturing processes are up and running and you're good to go. And once there's approved, you'll have adequate supply for every single Duchenne Becker, [indiscernible] patient that is hopefully included in a broad table. FDA, you've been the FDA, you're going to wait for your next interaction or submitting the BLA until you complete the Phase 3? Is that the plan?

Look, we are open to continuing our dialogue with FDA in whatever form that takes. FDA told us on the review of the HOPE-2 data that they thought that the data was very exciting, specifically the cardiac implications as well as the skeletal muscle. There's very few if any studies that have shown similar efficacy in DMD. But they really wanted to see a Phase 3 trial. And their focus just so people understand, is that we need to accept the fact that the pull scores are very relevant, but now we have to tie them to clinical meaningfulness. What does it really mean? What does one pull point mean, 2 pool points. And fortunately, we think we're going to be able to demonstrate that very cleanly. Once they are comfortable with the fact that there's clinical meaningfulness, we feel that there's a very clear path to a BLA here.

Great. Thank you. So let's go back to Slide 6, A.J., if you don't mind. Okay. Craig, you explain these cardiosphere-derived cells, and you explained the dose of millions of cells in there. So how long do these -- and the protocol in this particular case in - the protocol in HOPE 1,2,3 has been quarterly infusions basically, of the cardiac cardiosphere-derived cells. It's hard to say. CDs will be easier for me. So tell me a little bit about how long do they stick around? How did you come up with this dose of quarterly -- and could you increase the dose? I had a father who said, the more the better. And sometimes, I think in Duchenne because time is everything we think, well, could you double that dose and have a greater effect or give it more frequently, have a greater effect. Could you comment?

So we actually have done 15 years of bench research in the development of CAP-1002 the research version called CDCs cardiosphere-derived cells. We actually started off, and you may remember, Pat and HOPE, Duchenne our first trial, we were doing intracoronary infusion of the cells. This was back in the days when we thought we had to get the cells close to the sites of injury, and we were actually targeting the cardiomyopathy associated with Duchenne based on a significant number of studies that were done and now published, so happy to send to anybody that's interested. We came to understand exactly, as Craig so beautifully described that what happens to the cells is once they get into the vascular system, no matter how we get them there, they end up in the microvascular turbulence and don't worry, there's no evidence even in -- when we treated COVID patients of any type of respiratory complications associated with the infusion of these cells. And then they release the exosomes that travel to the sites of injury and seem to target specifically to muscle both skeletal and cardiac -- so once we understood that process from a preclinical perspective, we were able to back out of the coronary system and then just do straight IV delivery. Part of the work that we did at the bench also was dose escalation studies. And what we found is 150 million cells as a sweet spot. So sure, we might be able to go higher, but we felt that the benefits seen at least preclinically, would be incremental. And this is a way of keeping all of the metrics in terms of manufacturing, cost of goods and also infusion time points within reason as we built a drug for clinical and obviously market development. So that's sort of how that all happen. Does that answer all the questions?

Yes. No, just how long it sells to ground. So you're getting them quarterly. So how long do they stay in the system than what happens and more frequent is that resale or not needed and why?

So thanks for the note. Yes. So they don't stick on very long. We have seen, of course, not in human beings, but preclinically that the cells are completely gone with no evidence of a cell sometime within 1 week to 1 month. But what we know, and this is how we ended up discovering that the exosomes are meeting the mechanism of action is. And if you go back to our publication in neurology, which was the HOPE-Duchenne clinical trial, we saw benefit from one infusion, cardiac confusion of 75 million cells out to a year. It was kind of going downwards after 3 months, but we saw evidence that there was benefit. And that's where we came up with the quarterly infusion was because we knew that we had the best benefit between 6 weeks and 3 months and decided that rather than having people undergo an infusion protocol every 6 weeks, 3 months was good enough and we were still seeing tremendous benefit. So the cells don't stick around. But what we know, and this is sort of high-grade science is that the exosomes that are released travel, as I mentioned, to sites of injury, they're taken up by inflammatory cells called macrophages, which are angry. So remember, Duchenne is 2 sides of a coin. It is muscle degeneration for lack of dystrophin, but also tremendous amounts of inflammation from that chronic process of muscle breakdown. So we're targeting both. We're allowing the cells to reenter the cell cycle and actually create new healthy muscle, but we're also down regulating the inflammatory response. And so the exosomes are taken up by the macrophages. They're also taken up by the stem cells of the skeletal muscle. We've demonstrated that and published it, and we're able to see long-term efficacy that way. So the cells are a long time gone, but the work is still continuing.

Great. Thank you, Linda. I know we had previous discussions with regulatory folks to include [indiscernible] said if we could better manage the inflammation and get it into the satellite cells as well as get it into macrophages, we would have a better chance of moderating disease scores. So that is terrific. Let's go to Slide 7. So Craig, you talked about increasing the steroids a little bit prior to this -- the infusion of the CAP-1002. How long is that steroid increase? We're used to hearing in obviously in other gene therapy, specifically where steroids are increased for a period of time. So how long are the steroids increased and following when an individual receives CAP-1002, are they required to stay overnight in the hospital or for a period of hours, just to make sure that there aren't -- I know you haven't had any side effects, but what's the oversight?

Yes. Great questions, that. And essentially, these patients will take -- generally just 2 doses of higher dose steroids, and then they're back on their regular steroid regimen. So it's essentially only last for 1 day, the higher dose steroid regimen. So completely back to their baseline steroid regimen after that infusion day. And in terms of how long they stay in the hospital, generally, they come in the morning, they leave about mid-afternoon and go home. There's no long term or overnight oversight that's required.

And Craig, as you well know, some of the folks that are currently taking advantage of an antisense drug are often dosed at home on antisense using home health nurses. Do you foresee that this could get there as well?

Yes. I think that I think given just the theoretic risk of an allergic reaction to DMSO, which is the preservative in the therapeutic, the need for the need for the pretreatment regimen with H2 blockers, H1 blockers and with the steroids. I think we're a ways off before we feel comfortable enough for a patient to actually get home infusion. There's the -- usually from the DMSO patients will get a little bit of metallic taste in their mouth. The nurses are monitoring patients very carefully for any signs of an allergic reaction. And if you did have an allergic reaction, you may have to treat that with some degree of medical intervention, it's sort of like an allergy to a [indiscernible] or something like that. And so I don't necessarily foresee that we'd be able to rely completely on home infusions. But fortunately, this is only once every 3 months. So the burden on the families is not to the same degree as the currently FDA-approved exon skipping drugs.

Yes. I totally agree. And the vehicle that are used to protect these cells going in is what could have potentially an allergic response, and that's why they need to stay in the hospital. So -- or the infusion center just to be ultimately safe, but we haven't seen that. But always better to be safe. So if we can go to number -- Slide #8. I'm always amazed by this. And while we have been able, certainly with other interventions to move out slow progression with steroids, et cetera, Oligonucleotide. I think what I wonder here is for Linda and Craig, Time is everything to patients with Duchenne Muscular dystrophy, as you know, and your cutoff ages early nonambulatory. Can you explain what late-nonambulatory is in terms of the definition? And can you talk to us about why if we're thinking about preservation, why we won't go younger and much younger. And so you -- and then finally, once this is approved, it would be applied to younger patients with a broad level. Is that your assumption?

Yes, that would certainly be, I think, a hope. I think that, first of all, the inclusion criteria, it doesn't really pertain to the potential effectiveness of the therapy. It really pertains to our ability to measure a treatment effect in the course of just 12 months or a clinical trial. And while this therapy would be -- right now, we are infusing patients that have at least retained hand-to-mouth function, there's no reason to believe that a patient that perhaps has lost hand to mouth function or a later nonambulatory patient might not benefit from this therapy in terms of preservation of distal arm function. We've even toyed the idea of a combination of some of the robotic approaches, upper limb function, perhaps this could even make your ability to access some of those engineering technologies more available. And then similarly, right now, we are including nonambulatory patients that have 10-meter walk run times of greater than 10 seconds as the inclusion criteria. And generally, that has been sort of predictive of loss of ambulation within the next 2 years. So I think that hopefully, we'll be pushing the envelope in treating some patients that are -- have more ambulatory function preserved and are younger in age over time.

Can we go on to Slide 9, please. First of all, I'd love to talk about natural history of the pool. But first question is, Craig, is it scored similar to the North Star 0, you cannot do the activity. One, you can do it with some assistance in terms of perhaps trunk function and then 2, you can do it independently. Is that how it's scored?

Yes. That's how the poll 2.0 has moved to that scoring paradigm, whereas the pull 1.2 version had a different scoring paradigm. But yes, it's very similar to the North Star in terms of how it's scored.

Yes. And I think in the videos, when -- just to comment on the videos, we won't go to those slides right now. But I think what is strike in the videos in terms of a hand-to-mouth function is, as you mentioned, the use of robotics often requires that you're able to lift that elbow off the armrest for a couple of inch distance or at least 1-inch distance. So I think to be able -- while for people who have good function to think about lifting your elbow 1 inch off of an arm rest, doesn't feel like much. It is stunning to be able to do that so that you can then use some of the robotics that you all are developing in others. So can you elaborate on the pool and what you're seeing in terms of you've listed all of these different hand-on-table Stackline cans, et cetera. What are -- can you get a little granular, Craig, in terms of what you're seeing specifically? And one other mention I want to say to the group that's listening. I think that the neck flexors are something that we really don't think about and these boys very often. And if you look at a baby with Duchenne muscular dystrophy, their Neck flexors, their ability to curb their head down when they're being pulled up is moving not very good. And to -- and what we see in these voices those next letters get weaker and weaker, which means they need for sure in their wheelchairs, they need some headrest and that means they can't go on very fancy big terrorizing rides a Disney World, for instance or Disneyland because of the Neck Flexors. So could you comment one on what you're seeing in mid-level and 2 on those Neck flexors and the weakness in what I saw in your video is strength gained in the neck flexors?

Yes. So again, if you -- let's just take the mid-level for example, we actually -- the first side in their hand to mouth with and without weights. And so that would really -- I think you can think of it in terms of bringing a glass of water to your mouth versus just being able to bring your hand to your mouth. And then it scored in such a way that you actually score perhaps unable to perform the task performing the task with compensation or really perform the task without compensation with without difficulty. And similarly, you have other items such as bringing the hands to the tabletop, which are essential for being able to perhaps access a computer keyboard or stacking light cans or heavy cans. That's really getting at some of the strength aspects to it. tabletop activities, moving weights on a table, removing a container led lifting -- heavy light cans a certain distance, being able to tear paper. Those are just some of the tasks of the mid-level pool, which as you can imagine, require more just beyond the biases or beyond the elbow muscles, but we call it the mid-level poll just because those items tend to be lost in similar stages of the disease after overhead reach and shoulder level function is lost. But those are just some examples. I think that some of the other endpoints are really quite exciting in getting at some of the aspects that the traditional endpoints such as the pull [ dunkin ] at such as some of the trunk motions and trunkability ahead positioning and so forth, which I think are really exciting aspects of some of the video assessments.