Inovio Pharmaceuticals, Inc. (INO) Earnings Call Transcript

Thank you, Sabrina, as always, for making this so easy for all of us. And thank you, everyone, for joining in. We're going to have a pretty fast-paced call today with 3.5 people on this call. Of the 3 people are 2 people from Inovio. Dr. Simon Best from Johns Hopkins University and the half person is me, should be 1/10 actually of a person because that's the amount of talking I should be doing. And we're very lucky to have them to talk about recurrent respiratory papillomatosis. For me, reading up on this condition was very difficult, and I think we'll hear a lot about this condition. And hopefully, Inovio's pretty interesting approach to this condition. Dr. Simon Best is an otologist (sic) [ otolaryngologist ] at Johns Hopkins University, I apologize if I massacred that. And he's been a fellowship-trained laryngeal surgeon, whose clinical interest focused on voice and airway disorders. And really, really thoughtful gentlemen, we've talked to him before. It'd be great here -- to have him here on this call. And then we have Dr. Jacqueline Shea, the President and Chief Executive Officer of Inovio and Michael Sumner, who is the Chief Medical Officer of Inovio joining us. Again, really glad to have you all here. Thank you so much.

With that, we'll get it going here. Simon, with you, maybe just talk to us a little bit about RRP, how do these patients present? And I know there's children and adults. So maybe if you can address children first and adult second, and then we can go from there.

Great. Well, thank you all for having me. It's an honor to be here. And recurrent respiratory papillomatosis, or RRP is a disease that I care a lot about. I think, as you mentioned, if you see these patients and you deal with this patient population, you realize how much of the need there is for solutions for this problem. And so just some of the basics, RRP is a disease associated or caused by the HPV virus and very specifically, the HPV virus type 6 and 11, which in the medical literature, are called low-risk viruses, as opposed to high-risk HPV viruses, like 16 or 18, that cause cervical cancer or oropharyngeal cancer, like tonsil or base of tongue cancer. So there's always been a sense that this is the sort of the better version of the HPV to have. But that really obscures the fact that this is a very, very difficult problem for parents and for patients who are affected by it. Because recurrent, I mean, really tells you a lot about what these patients are dealing with. The disease is called recurrent respiratory papillomatosis. And it's characterized by wart-like growths, papillomas that occur specifically on the vocal cords, or the larynx would be the medical word for the vocal cords themselves, and the tissue around the vocal cords and then sometimes even in the trachea or in the lungs. And there's really been historically, essentially up until the current time, no treatment for this problem other than surgical debridement. Now the techniques have changed over the years. We used to use the sharp instruments and then there were lasers and all sorts of different types of treatments that you can imagine to remove the papilloma. But the disease is characterized by almost inevitable recurrence. Meaning you remove the papillomas from the vocal cords, the voice gets better, but then they grow back. And then the patient has those symptoms again. And then that necessitates essentially an endless cycle of surgeries and growth and surgery and growth. And so it's a very, very difficult problem to have. And I have patients who, by the time they're in their 20s or 30s, have no exaggeration, have had over 300 surgeries for this disorder. So you can imagine the impact on sort of patients, on caregivers of having a child or an adult undergoing a surgical debridement every month, every 2 months, every 3 months, basically indefinitely. So it's a horrible problem. As you alluded to, it affects both children and adults. And the mechanism of HPV virus acquisition is probably different between those 2 groups. So in children, generally, the disease presents quite young. So talking 1 year of age or 2 or 3 years old by the time the symptoms have sort of become apparent and they've worked their way through the medical system. Usually, the symptoms in a child are going to be a hoarse voice or sometimes even difficulty breathing or noisy breathing, while sleeping, for example, misdiagnosed as asthma, sleep apnea, et cetera, until they eventually find their way to an otolaryngologist, someone who does an examination of the vocal cords and sees these characteristic wart-like growths in the larynx. Then surgery, basically for diagnosis. We do HPV testing of the tissue to confirm the diagnosis, which is relevant for some of the treatments, I think, that we'll discuss coming up, but the virus is present in the tissue. It's a chronic viral infection, that's the way to think about it. It's a chronic viral infection that has not been recognized by the immune system and has not been cleared by the immune system. And so then, unfortunately, the children have surgery and then basically, it comes back, and they have more surgery until basically, they become adults, and then they have more surgery as adults. And for the most part, when children get the disease, the younger you get it, the worse it is. And the mechanism of infection is very likely maternal-child, maternal-fetal. It's a transmission from the mother who has this low-risk HPV virus infection either at the time of delivery or at the time of pregnancy. In adults, -- and so now we can characterize the disease either as juvenile onset, which is basically before age 12 or adult onset, after age 12. Using age 12 as, I suppose, a social surrogate for the potential onset of sexual activity because in adults, as in for many other types of HPV viruses, for example, cervical high-risk disease or genital warts or potentially even oropharyngeal cancer, there is definitely an association between sexual activity and acquisition of the HPV virus. So adults get this disease as well, presumably through contact with other adults, who have the disease. And as you may be aware, the HPV virus is extremely common in the population. There has been very good epidemiologic studies that show about 8% of the population at any given moment has HPV virus or HPV DNA that can be retrieved from an oral swish and spit. So when you're talking about 8% of the population at any given moment, I mean, that's a lot of people, obviously. And so these viruses are essentially ubiquitous in the population and being passed amongst people. And in the adult population, then again, there seems to be a small percentage of people, who have encountered the virus and for whatever reason, the typical mechanism of viral clearance doesn't take place and they end up with a persistent laryngeal infection of HPV, which manifests as these papillomas. Just one interesting side note that I'll flag here that the adult onset is much more common in men than women. And the reasons for that are entirely unclear. The same is true for oropharyngeal cancer, which is the high-risk HPV subtypes that affects men much more than women, about a ratio of 3:1, and the same is true for adult-onset HPV in the larynx, it's about men to women, 3:1, whereas as what you'd expect from a juvenile onset, if it's just maternal-fetal transmission, it affects boys and girls equally. There's no distinction. Again, though, then you run into the situation with recurrent surgeries. Generally speaking, in adults, it presents with voice changes. So what's the patient journey? The patient journey is basically to have some voice changes, impacts you personally and professionally. You end up seeing an otolaryngologist or ear, nose and throat doctor, who does a scope of the vocal cords and identifies these wart-like growths on the vocal cords. Again, biopsy, pathology, which confirms the presence of the chronic viral infection, HPV 6 or 11, and then we do surgery. And then we sort of have the discussion and the waiting game about how likely is this to come back? How quickly does it come back? And then that sort of spills over into discussion about adjuvant treatments and other things like that. I want to flag the one very important thing about the physiology of the vocal cords and sort of the impact of this disease, right? Because it's a disease for which patients undergo repeated surgeries, and there are a number of factors around that, that are very important and are actually very important when considering sort of what are the metrics of success in this disease. There's a -- thinking about like a cancer, right, which was like now, how many people have you cured, that's thinking about it like a cancer. But this disease is characterized by repeated surgeries, and surgeries are very difficult for patients. They are difficult financially, they're difficult psychosocially. For child, they're very difficult in terms of their schooling and their education. For an adult, they're very difficult in terms of their work life and time off of work. But I think really critically and what people, who deal with this disease, know and people who maybe don't, it would not be intuitively obvious to them, is that the more surgeries that you do for this problem, the more you create opportunities for permanent vocal cord injury. And so we have published some work on this, and we use the term iatrogenic laryngeal injury. Iatrogenic is just a word that basically means caused by physicians or caused by medicine, because these papillomas on the vocal cords are not destructive to the vocal cards. In fact, they grow away from or out of the local boards. They're not cancer, right? Cancer invades tissue, destroys tissue on its own, right? There's nothing about the physician doing something that destroys vocal cords if you have vocal cord cancer, the cancer is doing it. But in surgery for laryngeal papilloma, it is, in fact, our surgeries that cause the problem. Now our vocal cords are very, very special tissue. They are only about 1 centimeter, we have 2 vocal cords in our throat, in our larynx right here. And they open and close, they are like a V shape. They open when you take a breath and they close and they flutter and vibrate to make sound. So the best example on the analogy that we use when describing vocal cords to patients is the ability to flutter your lips. Imagine you can open your lips, you can take a breath, you can put your lips together, and you can flutter and vibrate your lips. Well, that's how the vocal cords work. They flutter and vibrate hundreds of times a second. That's the frequency of the human voice, 200 hertz, Hertz is vibrations per second. So imagine the softness and the pliability of the tissue that can flutter and vibrate 200 times per second for your entire life. Imagine the sort of the viscoelastic properties, the gelatinous nature. The characterizations of our vocal cords are just basically miraculous structures that can withstand those forces of vibration for your entire life. Well, all it takes is one surgery that goes slightly off track to destroy that tissue for the entirety of your life. It's never replaced again. It never grows back. We don't have stem cells that you can inject into the vocal cord to cause that sort of tissue to regenerate or to vibrate again. So I would say it's almost inevitable that as you accumulate surgeries for this disease, you end up at a point where that soft and pliable tissue of your vocal cords has been destroyed. And then you have essentially permanently lost the ability to use the vocal cord for the rest of your life, and there is no recovering. And we published research that shows that even if you had less than 5 surgeries for papilloma, you still have about a 50% chance of having permanent vocal cord damage. By the time you get to 10 or more surgeries, you have like a 98% chance of having permanent vocal cord damage. So the metric of success for this disease is avoiding surgeries, right? Because the surgical damage is not necessarily cumulative in the sense that the more surgeries you have, you sort of like accumulate scar tissue or damage. I mean, that's one way to think about it. But I think the more accurate way to think about it is that it's a stochastic process, meaning that, let's say, you have a 20% chance of having some sort of bad outcome from surgery. Well, if you just think about a dice that's got a 20% chance of coming up or a card deck or something like that, right, it's possible to hit that 20% on your first time, it's possible to roll the dice 15 times and never hit it, right? I mean, that's just sort of the nature of probability. So if you think about surgery that way and the vocal cords that way, you realize that avoiding even one surgery for a patient is a good in and of itself. That's a good -- that is very valuable, very valuable clinically, very valuable to patients. And so the metric by which we should be thinking about this disease is basically is there a treatment that allows us to avoid surgery.

Simon, I mean, that's just amazing explanation and also talks a little bit about the huge unmet need in this area. I actually think that you've pretty much exhausted all the questions I had for now, as I've said before in this call. No, I'm just kidding. We've got a lot we can go into. Before we kind of pull Jacqui and Mike in here, just a couple of specific questions I have, Simon. One is, how good are -- well, a couple of questions here. One is, can -- is there a possibility to catch this disease ahead of time? Meaning like do HPV vaccines help, right, with, for example, women and boys getting that to them. Can you actually try to -- I mean, I know there's some correlation with, for example, women that have genital warts might have a slight -- their infants -- their children might have a slightly increased ability. So is there any way to catch it more upstream or not really, that's very difficult?

Yes. I mean, eventually with GARDASIL, right, which is the preventative vaccine, or I should -- to endorse any particular brand, [ CERVAVAC ] or any of the preventative vaccines for HPV. Yes, I mean, eventually, this disease will go away. What's the time line though? Well, the time line is unfortunately long into the horizon, I think, right? Because now you're dealing with issues of vaccine uptake, you're dealing with not just the national, but the international community, where, of course, there are major problems in terms of vaccine access. I would say that the -- in countries where they have instituted very rigorous GARDASIL vaccination in young adults, below age 12, that they have seen a decrease in the juvenile onset form of laryngeal papilloma, Australia and Canada are good examples of that, and there's published research on those countries. But in terms of adult onset and just to say the general population, yes, I think we're quite a long way away, unfortunately, from eradicating HPV, many decades.

No, that makes complete sense. And by the way, we've seen this. Vaccines are always -- you're not just going to get 100% penetration. I think even if you get 50%, 60% penetration, a lot of times, you're very lucky. Another question I would have is the biopsy that you do on the vocal cords to confirm the diagnosis, how difficult or easy is that?

Easy. We can do biopsies on the vocal cords both in the office and in the operating room. Generally speaking, when you're making a diagnosis, you're taking the patient to the operating room, particularly in adults. Papillomatous lesions of the vocal cord could masquerade as other things, whether it's a papillary vocal cord cancer or so, we're always doing a very general and careful examination of the vocal cords under anesthesia. And in that perspective, it's very easy to take samples for biopsy.

And Simon, last question for me before just kind of before going over to Jacqui and Mike. I guess that -- the question is that as you're thinking sort of about the unmet need from surgery, there's also in academic literature of this malignant transformation that happens in 3% to 7% of the patient population. For -- I mean how big of an issue is that also? And how bad does it get for these patients, if there is a malignant transformation of these lesion?

Yes, malignant transformation is possible. It is certainly a rare event. I mean, it's a rare complication of an already rare disease. And generally speaking, occurs when the papilloma has moved from the vocal cords, into the trachea and then actually into the lungs as well. And why that progression happens in some patients and what the factors are that make it so that it's likely to transform into cancer, obviously, are sort of scientific questions that are not fully elucidated. But it is definitely true that the papillomas can extend into the trachea and then you start to have very bad issues in terms of breathing issues and by the time it gets to the lungs, then there is the possibility of transformation and basically transformation into lung cancer and patients do die from this when it has kind of reached that stage.

And sorry, one other question for you before I just go over to Mike and Jacqui. And before I ask the question, I just want to tell the audience, if you got us a question, you can always hit it through the chat function. You can send it directly to me. I can ask that question or send it to me on hartaj.singh@opco.com. Again, that's hartaj.singh@opco.com. But Simon, can you just tell us how many juvenile and adult patients you have right now, the numbers roughly that you see? And then how many new patients do you see per month, both with children and adults roughly?

So at Hopkins, I would say I probably have about 100 patients with papilloma. 95% of those are adults because I'm an adult otolaryngologist, so I mainly see adults. We do see new patients. I mean new patients come in not infrequently. I mean obviously, patients with papilloma find me because they know I have an interest and expertise in it. But we do make the new diagnosis and people who just have a symptom of voice changes, right? I mean sort of the American Academy Otolaryngology is very clear that if you have voice changes that persist for longer than 4 weeks, the best practice guideline is to have someone look at your vocal cords. And so a lot of people have voice changes. It's a common symptom of many different disorders. And among those is laryngeal papilloma. So we definitely do see every year -- I would say, every month or so, we're getting new patients that come in. That's a new diagnosis. They've been either scoped by me or by a colleague or an otolaryngologist in the Maryland, Virginia area, and so yes, there are people newly diagnosed all the time.

And Simon, roughly over the country about how many centers are there that specialize in this that patients could go to once a general practitioner would want to refer them?

I mean you're basically talking about voice centers, right? So people who have specialized expertise in vocal cord surgery. And so yes, you're talking probably the number of centers across the country where they would have substantial numbers of papilloma patients is probably, I would say, somewhere between 30% and 50%.

Got it. So maybe here -- and thank you so much. That was a lot of information in a very concise way. Maybe just go over to Jacqui and Mike. And maybe here, if we can just talk a little bit about 3107 and what was the sort of like the scientific approach, the science behind what got this product into the clinic, maybe even the [indiscernible] moment, Jacqui and Mike, if you can address with this product before we actually go over the data that we've seen in the clinic.

Yes, that's a really important question, Hartaj. So Inovio has been working in the HPV space for quite a while. We started off working in the high-risk HPV types, particularly HPV 16 and 18 looking at cervical dysplasia or anal dysplasia, which are really the precancerous changes ahead of those progression to potentially cancer, both cervical cancer and anal cancer. And what we found with our DNA medicines technology is that we were able to generate antigen-specific T cells and in particular, a kind of T cell cytotoxic CD8 T cells, which were really good at targeting cells that have been infected by the HPV virus and eradicating those cells. And we were able to demonstrate in cervical dysplasia or in anal dysplasia that we were able to eradicate those lesions in a certain proportion of patients, and we were even able to eradicate the detection of virus in those tissues, detection of the HPV virus. And once we became aware of RRP, it became very clear to us that our DNA medicines platform would be really applicable to this really terrible disease, and we developed a new product focused on HPV 6 and 11 called 3107, which is our product [ candidate ] that we're developing as a therapeutic alternative to surgery for treatment of RRP. So that was how we started out. We went from cervical dysplasia and working on 16 and 18, which we're still doing, by the way, also still working on anal dysplasia and really developed a product candidate that was focused on 6 and 11. And that was the start of our journey. And Mike, maybe you can talk a bit about our Phase I/II clinical trial and how we started really approaching RRP.

Yes, absolutely, happy to. So our Phase I/II study looked at administration of INO-3107 over 8 weeks, 0, 3, 6 and 9. And at its basic principle, it was comparing the number of surgical interventions in the previous year to that day 0 administration, to the number of surgical administrations following day 0. And the reason we did that -- I mean, obviously, from a vaccine technology, it takes time to build up the immune response. But as you heard from Dr. Best, from a patient perspective, any surgery matters. So recording the number of surgeries following day 1 and looking at that 52-week period was very important to us. So obviously, with a Phase I/II study, we recruited the 32 patients and the primary objective in an early phase research is to look at the safety of the product. And what we saw from a safety perspective that we saw no grade 3 or above treatment-emergent related adverse events. And in fact, the most common reported treatment-related adverse events was related to treatment administration. And we saw 10 of the 32 patients report injection site pain, and then following that, the next most frequent adverse event was actually fatigue in just 16% of patients. When I look at safety and this sort of leads into a regulatory filing. I mean, at the end of the day, a regulatory filing is all about establishing the risk-benefit profile of the product. So I do just want to sort of go slightly off track and talk about the data we have for our safety profile. We're a combination product. So we administer the product through intramuscular electroporation. And then we obviously have our plasmid, which targets HPV 6 and 11. When we look at the data set we have for our intramuscular electroporation, we actually have 6,000 administrations with over 1,000 of them with the 5PSP device, which is our commercial device, which really targets the user to make the administration easier. It's a one press of the button to administer the plasmid and the electroporation. So we have considerable safety data on electroporation. And as you heard Jacqui just talk about, we -- this is an evolution of our HPV-related research. And so we have considerable data from our 16, 18 plasmids, which I think is all highly relevant when we are presenting a safety profile to the FDA because obviously, that safety profile is built up from your initial Phase I/II data and culminate in continuous post-market collection of data. So having that wealth of data, I think, really characterizes the product. And then moving on to the efficacy. Obviously, we were delighted with the efficacy we saw in our trial, 81% of patients saw a reduction of greater than one surgery again, linking back to sort of how Dr. Best talked about the impact to these patients and 28% saw no requirement for surgeries whatsoever in that following year. And then I'd also just like to have a brief mention about sort of our mechanism of action as Jacqui mentioned, is really, we believe, is all about our CD8 T cell response. And we presented in our last earnings call, a representative patient, who had, in the prior year, required 6 surgeries. And then following day 0 and the 52-week subsequent required no surgeries. And what we saw in that patient was the most highly-activated T cells, which showed expression of 3 activation markers. We saw an almost tenfold increase in that patient. And all the T cells were positive for both granzymes and perforin, which are key mediators of eliminating virally-infected cells. So as we put together our efficacy package, I think the immunology aspects is really going to make a very convincing argument to the agency. Hartaj, you are on mute.

Mike, before going over to back to Simon, and his thoughts on the data, I would just want to just touch on one thing. You just recently had an FDA interaction. I think at meetings in San Francisco a week or 2 weeks ago, we all met, also you gave kind of a rough update. We'll probably expect the full update at your earnings call. But maybe if you could just kind of give us a broad overview of what the interactions were. And I believe you put out a press release also indicating what the next steps would be from -- that came from that interaction.

Yes. One of the real advantages, I think, for the breakthrough designation is the ability to interact with the FDA in a more meaningful manner and in a more frequent manner. So this was really our initial comprehensive multidisciplinary meeting with them. And the goal from our perspective was really to gain alignment on our registration strategy. And when we look at the elements of the registration strategy, obviously, we have CMC, the manufacturing of the product. And so gaining alignment on our process performance qualification, or PPQ strategy was vital. And I would say, we actually did that previously with 3100. So we had a lot of internal information to draw on. We also obviously want to make sure that our nonclinical submission is in alignment with the expectations of the agency, again with the devices when you think of them are moving pieces of regulatory perspective. So a good example of that is the recent cybersecurity guidelines, making sure that we were going to put in the required data to meet those guidelines. So just alignment on the device strategy. And then finally, the clinical was actually one of the smaller parts of our interaction because as you've heard me say previously, we've had many interactions and discussions with the agency on Phase III confirmatory study design. So really, we just had 1 or 2 questions before submitting our confirmatory study for alignment with the FDA. And as soon as we have that full alignment, we'll obviously share the design of the study and our strategy behind that.

And actually, before going back to Simon, Jacqui, just one question here, what Mike has talked about on the strategy. I just want to be clear like your device -- and I believe you have a partnership with contract manufacturers. Those are ready to go, right, on the manufacturing side. I mean, those are essentially, I guess, for lack of better commercial ready in terms of the application.

Yes, that's an important question, Hartaj. So in terms of the plasmid, we have our plasmids manufactured by a contract manufacturer that we've worked with for a number of years, and that's already at commercial scale. And as Mike has mentioned, we've already gone through PPQ for another product candidate previously with that manufacturer. So we're comfortable with where we are with our CMC package, and we have a great CMO partner there. In terms of the device, we manufacture our devices in-house. So we have complete control of that process. As Mike says, devices are constantly evolving landscape. So it's been very important to get alignment with the FDA as to what their expectations are around the device both for the confirmatory study and also for launch. And I think following those discussions with the FDA, we're very comfortable with where we've ended up. I think it's important to note that the device is proprietary to Inovio. This is our [ selector ] device. And the purpose of the device is really to deliver the plasmids to the patient cells and then provide brief electrical pulses, which enable improved uptake of the plasmids to the patient cells and better immune responses. So the device is a necessary part of our combination product.

Yes. Fantastic, Jacqui. Yes, a lot of like the work the company has done over the last 2, 3, 4 years on the device side, DNA plasmids, your partnership with really good manufacturers that are now coming to fruition, right? So knock on wood. Going back to Simon. Simon, maybe if you can just kind of talk to us all about the Phase I/II data and your thoughts on it, both from a safety and then an efficacy perspective?

Sure. Yes. I mean I think as has already been stated, right, safety is a very important component here. And I think the safety data is obviously very encouraging, and I can speak from experience in terms of being a participant in the Inovio based earlier phase trials that patients tolerate the medication, and there's been no concern from anyone's perspective about sort of the device, the electroporation, the medication or side effects. So that obviously changes the calculation dramatically, right? Because when we talk about sort of splitting patients into cohorts in terms of disease severity, which is one of the things that I think is relevant for this discussion. The reason why we do that as physicians, as surgeons in sort of classifying patients into mild disease severity or moderate or severe disease severity, is because if you're considering an adjuvant treatment for this population, adjuvant meaning different than surgery, which is the current standard of care, it's always a balance between what is the potential benefit and what is the side effects, what are the side effects. Some of the older treatments for laryngeal papilloma that people tried as adjuvant therapy, interferon infusions have horrible side effects. And so as a field, we sort of classified patients into these categories in order to sort of see who would potentially be worth it to deal with the side effects versus the benefits. Now if you have a treatment that has potential upside, which I think is clearly DNA vaccination does. And as far as we can see, no downside, then obviously, that's something that's very attractive to patients and physicians alike because the purpose of classification in terms of this disease severity is one of weighing the risks and benefits. And so if we can see a reduction in surgery and even a portion of patients and there's no downside, then, I mean, the potential patient population that would receive this vaccine is obviously going to be excited about it as would be physicians.

And Simon, I guess one of the things -- and we are -- I mean, I'm also one of those people that kind of fell for this a little bit. When we originally saw the data in, I guess, middle part of last year or I forget when exactly my. But I remember, I was like, okay, 1 surgery decrease. On paper, it doesn't sound like a lot. But your -- Simon, what you've talked about is many surgeries and then by the time patients get to their 20s and 30s, they've had potentially hundreds of surgeries. So can you just talk a little bit how about even like that decrease of something like 1 for a majority of the patients that it just adds up over time. What does that mean for potential for damage, et cetera, et cetera, those kind of side effects of surgery, so to speak?

Yes. I mean it's what we were saying before, right? A reduction in one surgery is a meaningful reduction, right? And if you don't believe so, then you volunteer to have the surgery, right? I mean it's that obvious, right? I mean -- and it should be that obvious to the FDA and to anyone else who looks at this sort of disease, right? If you think that reduction in one surgery is not a meaningful outcome, then, I mean, I don't know what to say because you're not going to volunteer to have that surgery in place of that person, right? I mean -- and so particularly when you combine the fact that these surgeries accumulate damage over time, and they have a huge impact on patients' lives. And so the reduction in surgery is an extremely meaningful clinical outcome. And anyone who deals with this problem as a surgeon or as a patient understands that, that's an extremely meaningful outcome. And I think the FDA, over the past 2 years has sort of clearly moved in that direction. And I have to give a lot of sort of credit to the patient organizations, who have pushed them in this direction, right? I mean this is so important to realize that the patients are advocates themselves for this disease, right? Then they can speak for themselves, and they can tell the FDA what matters to them as patients. And I can tell you with 100% certainty, what matters to patients is less surgeries.

And to that point, Simon, I mean, just going over Mike and Jacqui, I think in our conversations in San Francisco, you had mentioned that the FDA had met with the patient organization, right, and the RRP Foundation, and they had even put out some thoughts on their meeting with the FDA, I believe.