Advicenne S.A. (ALDVI) Earnings Call Transcript & Summary

Sorry. Sorry, Adrian.

Thank you. Before. We do that, let's have an overview of the disease. Distal renal tubular acidosis is a disease that you may not hear about before. It's a rare, it's chronic and, on top of that, it's a very serious renal disorder. Has 2 forms as Didier was saying, one is genetic, usually, patients starts very early in life, and then an acquired form that is usually secondary to other diseases or to some drugs that patients might be taking. The real thing about this disease is that these patients suffer even started in the kidney, but suffered a systemic problem, which is metabolic acidosis. Their whole body, especially their blood, becomes acidic, below the pH of 7.4. And this leads to lots of issues short term and very long term. The disease, because of its rareness, sometimes, it's undiagnosed or misdiagnosed, confused with something else. But in my experience, usually, a disease gets better diagnosed and, of course, better treated when the product is approved for that because at this point in the United States, there is nothing approved for the treatment of dRTA in any way, genetic form or the acquired form secondary to other diseases like lupus, for example. But it's a relatively frequent disease in the United States and other drugs like some antibiotics. But talking about the disease, this is what usually kids experience. Basically, they do not grow as expected. They become very weak. Many kids also have deafness, have hearing problems associated with the disease, which is a genetic mutation. Cardiac problems, also associated to that. Nephrocalcinosis, which is very difficult to treat and sometimes almost impossible to treat, very spread out deposit of calcium in this kidney. Some of these patients where you see the kidneys in surgery or postmortem becomes like porcelain because of the amount of calcium that is deposited. As a result of that, they also have kidney stones. And above all, they have basically kidney failure set by a progressive chronic kidney disease. So as you can see, a very unpleasant disease that basically set the future for these patients if they are poorly treated, untreated and, of course, not diagnosed.

Adrian?

Yes, I cannot -- yes, it's not changing here, the slide. The next slide, please, when you can. Okay. Thank you. So -- and basically, there is one thing and one thing only above all that needs to be done to avoid everything I showed you before because it's basically the correction of this metabolic acidosis, restore a pH -- a blood pH in these patients, which is normal with the number 7.4. So anywhere between 7.4, 7.41 is normal, and this is what basically 7103 does when administered twice a day and very rapidly. I'm not going to describe the table in detail. It could be very boring, but what I can tell you what happened a few days after initiation of treatment, and these data from study B21, the pivotal study that led to the approval in Europe and in the United Kingdom is basically, as you can see, across different age groups, from adults to very little children with basically 2 years of age in the case of the study, but it was set for 6 months of age up to 3 years, the younger cohort. As you can see, cohort-by-cohort and overall, what you can see here, the largest number of patients, all of them restored normal bicarbonate values in blood after a few days of treatment. In this case, only 4 days of treatment with twice a day, they had a 24-hour control of that. And why we did bicarbonate? Because bicarbonate, which is a gas in blood after being administered is the best representation of normal pH that we can get in a clinical study. So basically, this was approved based on a value marker, which is very well-characterized, very objective, and there is no way to have a misunderstanding of that. In contrast, the patients that were treated prior to entering the study using the available standard of care, again, none of them approved, just being used by practice combination of liquids, powders, solid, et cetera, the patients require 3 to 6 times administrations per day, most of them 4 to 5. And they are very short acting as the DSL. The problem with this is that these patients over the course of the night, their pH -- or their bicarbonate levels goes down one more time or a couple of times until they wake up and they get their dose, et cetera, et cetera. And we also note that with adolescent, which are highly impacted by this disease, especially in the genetic form, keeping them taking a drug 4, 5, 6 times per day is not easy, especially if they're at school or something like that. So this becomes a problem. So very easy value proposition here, twice a day administration of a well-characterized and safe product restores pH throughout the day. The next one. And here are the results of the study based on statistics. As you can see, the study was first set to show non-inferiority versus multiple times per day administration of standard of care. That was highly statistically significant, you can see 0.0001. But then following the EU regulations of directives that EMA is governed by, what we did is a superiority assessment. Again, we showed clear statistical superiority compared to any standard of care taking up to 6 times per day. You can see that the ITT sets, which is all the patients randomized in the study, the value also highly statistically significant, very similar to the prior one, 0.0008. That means that the risk of this being by chance is 8 in 10,000, meaning there's no chance, this is treatment effect. And again, if you do the per protocol set with those patients without any deviation, et cetera, et cetera, also highly statistically significant. In summary, clear value proposition, clear efficacy, no safety issues. I will talk about the safety at the end. So one more slide, please. Thank you. Didier also mentioned long-term 6 years, which is very important because, as I show you when describing the disease, the metabolic acidosis when it's chronically established gets too many issues, including height, bone growth, bone quality, especially calcification. These patients suffer from fractures. And then some of these bones in these patients, especially the long bones in arms and legs, become very fragile and they have deformities. But here is what we have up to 4 years, what you see in adults and in children, where you see this, the change in their spine bone mineral density. Here, we have BMD compared to the moment they started the study, all these were sick at that time, and treated anywhere with some of the non-approved products, all these patients have a statistically significant change in bone mineral density, meaning bone mineral density was restored, increased. These patients become healthier for their bone quality. Why? Only one thing, as we said before, because the metabolic acidosis was controlled with the BID administration. So this is not, of course, what you're going to see in 4 or 5 days. But because what you see in 4 or 5 days after treatment and remain sustained, this is what you get over time. Clearly, children have been going back to a normal bone health, meaning all the things are getting away. And in adults, also, some of them have an increase in mineralization. Can we go to the next slide, please? Thank you. As I said, this is the safety summary that we've seen. Basically, in B21, the short-term pivotal study, all the adverse events we've seen were mild to moderate, and all of them resolved over the course of the study. The most frequent were abdominal pain, mild to moderate, and in some patients, headaches. SP3, what we thought here was the third period of the study compared to the first period of the study where the patients took standard-of-care product. The number of treatment-related, according to investigator, adverse events was smaller with 7103 compared to standard of care. Only one patient had a serious adverse event not assessed as related to the study drug, gastroenteritis. Patient ate something that shouldn't be eaten, so resolved very quickly. And then in the long-term study, up to 6 years, then on adverse events, the majority, I would say, were mild in nature and the most frequent, again, were GI, gastrointestinal, basically abdominal pain. Nothing else. Everything resolved over time. All patients remain in the study. No study drug discontinuation because of AEs, and nothing that changed the very well-known profile of the drug. So no unexpected adverse events. We can really say, and EMA and MHRA agree with this, that 7103, or Sibnayal, when it's approved is well-tolerated, and the safety profile is very clear without any surprises. If we go to the next one. Here is something what I call the validation of the treatment of dRTA by 7103. You may know that GOSH Hospital in London is one of the best and most prestigious institutions for children care. Because the product is approved in the United Kingdom, they did their own study on their own. Basically, they had a group of 10 pediatric patients. As you can see, the median age was around 10 years. The oldest patient was less than 14. And they have genetic dRTA, and they were treated for a year. Basically, as you can see, when these patients were evaluated at diagnosis, their median bicarbonate level was very abnormal. In this patient population, the normal values are between 19 and 29. These patients had between 13 and 15, so clearly abnormal. And you can see this when you see the box in the diagnosis column. After they treated the patients for a year, twice a day, what they found is exactly what you see here. All these patients, without exception, regain normal values that were sustained over the 12-month treatment. And this was just even in this very small number of patients, just 10, highly statistically significant. So again, 0.007, basically replicating what we saw in study B21. You remember the p-values I showed you before, and this was done just using the commercial product understanding that also GOSH is a reference center, but they see patients that have problems when treated elsewhere, maybe in primary care centers or no centers with this complexity. Again, I believe this is a very good and totally independent external validation of the safety and efficacy of 7103 for this rare disease in these little children. The next one, please. You can skip that. So let's talk about cystinuria now. Another rare disease -- thank you, Didier . Another very rare disease that, again, similar to dRTA has short-term and long-term morbidities associated to this. This is a genetic disorder affecting children and adults. Usually, patients start very early life because of the genetic nature. The key issue with this disease is that these patients have a problem reabsorbing cystine in their kidneys. Because of a genetic mutation, one of the transporters is not working, and cystine is highly insoluble at common or normal physiologic urinary pH. In most people, urinary pH is between 5 and 6, including people with cystinuria because pH is not impacted. This becomes very insoluble. Because of this, cystine starts touching each other, aggregating. The aggregation forms crystals, and these crystals over time form stones that affect the whole renal system, the kidney, the bladder and, of course, the whole urinary tract. The stones short term produce very, very severe pain. Patient starts bleeding through their urinary system. Nausea and vomiting as a result of this very acute pain. Infections become very common because their urine flow is not working. People feel very, very tired. And because of the nature of these stones, which are usually not regular, surgery is highly common to remove it. So over time, these patients have multiple number of surgeries, again, chronic kidney disease as a result of the impact of these multiple stones over time, in some cases, may lead to removing one of the kidneys. And then hypertension as a result of kidney damage, and frequent, sometimes, never ending urinary tract infections. Rare disease, as we said. Number of patients in the whole Europe, about 40,000. In the United States, about 30,000. That's why orphan drug designation was granted. Clearly, rare disease. As well as it is, cystinuria accounts for up to 7% of kidney stones in children and up to 2% in adults, especially in children because they start with this. And then similar to dRTA, there is nothing approved in the United States as an alkalizing drug for this treatment. And while we're talking about an alkalizing drug for cystinuria, because cystine in the next slide, increase its solubility with higher pH. The first-line therapy for cystinuria is very well established. Medical guidelines, even the most recent from '24 or '23 in the United States and in Europe, have the same exact recommendations, and the recommendations are illustrated here. The 3-fold increase the amount of water that these patients take trying to make the concentration in the urine lower. So that may lead to less precipitation, basically try to avoid excess animal protein and sodium chloride, table salt, because this may also lower the production of cystine, but above all is how to make this cystine in urine soluble. Meaning if it's solubilized in urine, does not precipitate, does not form crystals, therefore, does not form stones because the solubility of cystine increases almost logarithmically with higher pH. As we said before, pH 5 to 6, highly insoluble, precipitates and the whole process starts leading to stones. When you increase pH to 7 or higher, the solubility increases multiple folds, meaning the risk of everything else that happened, the whole cascade goes away or minimizes dramatically. If patients need a second-line therapy, basically Thios these days, Thios should be also administered in addition to the first-line therapy. It is well-described actually in the FDA approved prescribing information for Thiola to say, add this Thiola on top of urine alkalinization, diet restrictions and increasing fluid intake. Let me show you another data that shows that all this is possible with 7103. The next slide, please. One of the first studies Advicenne did was to demonstrate the ability of 7103 to be -- to alkalize urine in healthy volunteers. As I told you a few minutes ago, normal pH in humans is between 5 and 6, and that also applies to patients with cystinuria. This study was a double-blind study in healthy volunteers, 3 dose levels of 7103 that were administered over 5 days, twice a day as recommended. The main assessment was the pH over 24 hours in days 4 or 5. Again, very rapid onset of action. And of course, evaluate the safety. You can see in the graph on your left the 3 dose levels in red, green, and I believe the top one is brownish or black. In all cases, at day 4, the pH was much higher than the subjects taking placebo, which is the blue line at the bottom. And what you see with the mid-dose or with a higher dose, in all cases, over 24 hours, the values were 7 or higher. Clearly, what we want to achieve. And then to basically validate what we saw in the first 5 days, when you stop the drug on day 6, you see all patients going -- all subjects in this case, healthy subjects, going back to baseline, meaning the drug works very rapidly and provides 24-hour control with twice a day administration. In general, patients need to take similar to dRTA 4, 5, 6 times per day drug and a combination of different things. It was the first proof that 7103 clearly is an effective agent for increasing the pH of the urine. Then we have data in patients. The next one, please, which is here. This study was originally planned to be much larger, also double-blind, placebo-controlled study in patients with cystinuria. Unfortunately, like many other companies, we were impacted by the COVID-19 pandemic and recruitment was terminated early as a result of that. Only 6 patients were enrolled at that time, but it was well randomized. So it was 2 patients per dose group, 2 in the low dose, 2 in the medium dose and 2 in the high dose. And you can see here that the proportion of patients with urinary pH 7 or higher on day 7, that was the primary endpoint, was very high with almost 92% proportion of subjects having that in the high dose. You will see that only 75% with the low, and the medium dose has 100%. That is why one patient missed a dose in the evening, so this morning time sampling get this. But let me show you the actual pH values on the table on the right side of your screen. You see that in all cases, people that had pH values below 7 at baseline, in all cases, on day 7 and over a 24-hour sampling, the pH was greater than 7 to the point that, in some cases, it was above 8. And then in the high dose, even with the patient that missed the dose was almost 8. Basically, in all cases, the prespecified trigger for efficacy was achieved, greater than 7. So 6 patients only, very clear demonstration of efficacy that, in addition to the data we have in healthy volunteers, plus the restoration of normal bicarbonate in dRTA, all of them together provide a clear proof of efficacy and what we are trying to accomplish, which has basically been an easy to use alkalizing agent. The next one, please. What is coming next? We are working with the FDA. Robbie is going to tell us a lot about this. Things are moving very nicely. Things we have established, very constructive and 2-way relationship. Meeting is planned before the end of this year. And then we plan to initiate a study in cystinuria before the end of the second quarter next year. So with that, I will turn it to you, Robbie. Robbie, this is -- thank you.

Thank you very much, Adrian. Let's past the -- let's go to Robbie. It's you now.

Thank you. Yes. Next slide, please. Thanks, Adrian, and thanks, Didier. So yes, we're going to talk a little bit about the regulatory situation in the U.S. and the strategy that we developed and have put into action and the results of that. I'm also going to talk about the time lines now through to approval for the 2 indications, a little bit about the support we have from the expert community, which I think has been really critical. We can tell you -- or we'd like to tell you about the efficacy of our own drug, but I think critical to the success has been the support of the expert community. And then we're going to talk a little bit about the market situation on launch in the U.S. in terms of the value of the product. So our regulatory strategy has really accelerated the NDA filing opportunity in distal renal tubular acidosis. We were actually engaged in running a Phase III study here in the U.S. in order to generate data for the U.S. submission. That study was put on hold due to COVID as so many were, and we looked at the opportunities of relaunching that study. And as time moved on, the long-term data from Europe was presented and looked extremely strong. And so we had a review of the strategy and decided that a better approach may be to go back and enter into discussions with the cardiorenal division and look at the data we have and suggest that maybe a long-term safety study in the U.S. would not be necessary because we could maybe present them with the data from Europe, which had really, really strong results. So the long-term safety and efficacy data from Europe really referred to the 2 studies that Adrian has outlined, B21 and the real-world data we have from GOSH, which have demonstrated this rapid and sustained 24-hour control with great safety and tolerability program -- profiles. And the real-world data is very helpful in confirming the results of B21, something specifically the FDA had asked for. And then the B21 long-term follow-up with those 27 patients followed up out to 72 months really shows what a safe and easy to live with drug this is. And the vast 27 of the 32 patients still on a drug at 6 years is an extraordinary result. So with the idea that we would go back to the FDA, we entered discussions and gained agreement that the B22 would suffice for the long-term data in terms of an NDA submission in the U.S. And then we decided, "Well, let's be more aggressive. Let's go back and let's look at B21. And with the support of the experts around the world and the team at Great Ormond Street, let's see whether European data, plus that real-world data would be sufficient." And we organized a Type C meeting. They agreed to an in-person meeting, a virtual in-person meeting, live meeting. And our team with the experts were able to have a very balanced discussion with the cardiorenal division at FDA, which resulted in them agreeing that the European data, as long as it meets their expected criteria, would be sufficient for an NDA filing. It's been a huge win for Advicenne because no further U.S. clinical study is therefore required and saving clinical costs estimated easily at $20 million. So it's certainly been an extremely valuable approach. Next slide, please. In terms of the regulatory strategy for cystinuria, I can't stress enough the importance of achieving orphan drug designation, and that is actually true for cystinuria and for distal renal tubular acidosis. We had 2 denial letters initially for orphan drug designation in both those conditions. And again, working with experts, we restructured our arguments. We went back, and we won in both cases, obtaining orphan drug designation for cystinuria and for dRTA. And I do believe that, that has opened up real opportunities for balanced discussion about how we can find a pathway to approval when we're talking to the FDA because they want to make sure that drugs are made available to underserved populations, especially those with rare diseases and have been, I believe, very flexible and very balanced in their discussions with us. They want to find a way to make this work. So in terms of the strategy in cystinuria, we've been working with key opinion leaders, and we have a new study design for a Phase III study in cystinuria. It's been developed, it's been reviewed and supported by the experts in the field and submitted for discussion with FDA. We expect to have a face-to-face virtual Type C meeting with the cardiorenal team at FDA before the year-end. And the objective is to gain agreement for that Phase III registration study design, and we are leveraging the KOL and patient advocacy group who are aligned to support. I'll tell you a little bit about those as we move forward. Next slide, please. So in terms of the time lines, 2024, Type C meeting has clarified the data needs for filing on the dRTA pathway, which was above the line. We are on track to submit the NDA file in the middle of next year. It gives us a projected PDUFA date out into 2026 and a U.S. launch potentially by the end of 2026 in that initial lead indication. We will have -- at quarter 4, we'll have a Type C meeting to clarify the Phase III design in cystinuria. And once we have that, it is all action to run that Phase III study with what we think would be a very manageable number of patients, around 50 patients, with an endpoint of urine pH as the primary endpoint of the study. And as you can recall from hearing Adrian talk about the guidelines, that's extremely consistent with the way alkalinizing therapies used in this population. Run the study and look to submit a file for an NDA the end of '26 with a PDUFA date kind of 9 to 12 months later. So they are our projected pathways, and we have been working with the orphan drug designation obtaining that. We have been working with all of the regulatory strategy to really derisk those pathways and make sure that we have a very clear route towards approval and, therefore, generating revenue. This has been critical. We have developed great relationships with, really, the leading physicians in the world for dRTA and cystinuria. Doctor -- Professor Bockenhauer, David Goldfarb, NYCU (sic) [ NYU ] is really what we would call Mr. Cystinuria. He's a part of every piece of clinical work. He's linked to the advocacy groups. He's the author of guidelines. He is absolutely fundamental. David Sas at the Mayo, Larry Greenbaum at Emory, who has been an absolute -- a wonderful person to work with and has been incredibly helpful in the FDA meetings, has a great reputation with those guys. Paul Goodyear from McGill, Aurelia Bertholet-Thomas, who is an incredible supporter and, really, the primary person behind the B21 and B22 studies; and Bertrand Knebelmann from Necker in Paris. So we really believe that these excellent relationships have been fundamental to our success. They really support the recognition of true clinical unmet need and support the concept that ADV7103 in both conditions is really going to make a significant difference to patient care. And we have used those both in terms of generating support letters that go with our submissions to FDA and also in the meetings themselves. For -- next slide, please. For cystinuria, we have another element that we can bring in, and that is support from the patient group. Now in rare diseases -- in many diseases, but certainly in rare diseases, FDA, very sensitive to the patient voice and understanding what the patient experience is and wanting to make sure that drugs are anticipated, are going to be helpful, are necessary, are needed. And we have great support from the International Cystinuria Foundation, who again have agreed to support us in providing support letters for the meeting that is upcoming with the FDA about the unmet need and the need for this drug, ADV7103, and also making themselves available to give that patient voice in the meeting we have with FDA, making it very clear that this is really something that the patient group are excited about and will really benefit from. So next slide. So all of this is great, but at the end of the day, we are a commercial organization, and we need to make a profit from all of the activities that we are investing in upfront prior to gaining approval. And we have run 2 very significant pieces of market access research in the U.S. with 2 different highly respected providers, and I will give you the highlights here. The sweet spot for coverage and price, there's always this balance and a tipping point, and you identify what is your optimal price in terms of coverage and in terms of profitability per patient. The wholesale acquisition cost or the list price for that sweet spot is about $45,000 per patient per year. Now patient financial assistance will be required for a physician prescribing to remain unhindered. That's all factored into this. We expect the prior authorization will be needed. And a step edit will be put in place, basically, meaning that physicians will need to, one, attest to the fact that patients have already been treated and they're not doing as well as they could be. Now we know our populations are already -- 99% of those are already pretreated who will be going on to this drug once we launch. So we're not concerned around that. And that prior authorization, i.e., a letter that it comes from the physician saying, "I would like to use this drug in this patient," will be required. Most payers will implement a prior auth to restrict the use to primary dRTA. And we have based all our projections on that smaller group of the dRTA community. The primary and secondary are the indications in Europe. And it's the primary genetic form that's the indication for the U.S. Most payers will require trial and failure, at least one, more than one generic alternative, physician attestation to that fact. So after we do the kind of list price to net bridge, once we factor in all of the things that will be needed to make this an attractive proposition, we end up with a weighted net price of around $26,500. Next slide. What does that look like in terms of projections for revenue stream? You can see the lighter blue is the dRTA, the darker blue is the cystinuria. And I think the obvious and initial takeaway is that you can see that cystinuria is a more valuable indication as the second indication and very much critical to our strategy for the overall asset that we gain both of these. We will be able to generate some revenue, start market penetration with the dRTA indication, build our familiarity and use with the drug and follow that up with a more valuable cystinuria indication approval. It's a larger, more clearly defined population. We know that ODD will protect our exclusivity on both of these for 7 years after the first NDA. And there's no doubt that the U.S. market will be the most significant contributor to global sales potential. So that's why the regulatory strategy has been so absolutely fundamental to getting us to a point where we have really derisked this asset. We know there's an unmet need. We have great support from everybody. We are generating really excellent data on this product. And the next step will be -- for cystinuria will be the Type C meeting we hold with the FDA at the end of this year, which will give us clarity on the study that's needed. And then we can move forward and execute against that. So with that, I'll hand back to you, Didier.

Thank you very much, Robbie. I think I stopped sharing the slide. So before we turn into the Q&A session, we will have a couple of minutes to answer some questions. I think it was very important for us with Adrian and Robbie to give you an update on where we are in the U.S. following the major news we issued about 2 weeks ago. I think it's rather exceptional that the FDA agrees on a direct filing with non-U.S. data. I think it shows the pragmatism of the cardiorenal division, and it's very important. Once again, this is a rare disease. And frankly, it makes no sense to redo the trial, which has been conducted once again for 6 years in Europe and to redo almost the same in the U.S. to in the end get exactly the same data. So it shows the pragmatism of the cardiorenal division. Now I think we have a product. The product is approved in Europe. It shows its efficacy, its safety. We manufacture the product, that is no issue. Second, we have a plan. In the U.S., first, is to work on the dossier, to file on -- for dRTA, to file this dossier mid-next year and to get -- and to expect an approval mid-2026 something and launch in the U.S. before the -- before 2026. We also have a plan in cystinuria, and I think this is very, very important. The data shown by Adrian are also very important. We are talking about a product, which is controlling urinary pH over 24 hours. So it makes a major difference to the standard of care in this indication. We have a plan. We are -- we have a meeting with FDA. And hopefully, this meeting will lead to starting a Phase III in the indication. I would say I'm cautiously optimistic on this. Finally, as Robbie shown you, we have a time line and a significant potential for this product. I think we are talking about EUR 40 million to EUR 50 million in dRTA and about EUR 400 million to EUR 450 million in cystinuria. That's EUR 0.5 billion in the end. So it's massive, it's significant, and you know we are a small company. It will -- it's not in our plan to market the product directly in the U.S. and standalone in the U.S. We are working on potential partnerships in the U.S., licensing the product in the U.S, that's where we are. But I'm very proud because with Robbie, with Adrian, with all the team, with our partners in the U.S. on the regulatory side, we have already achieved a great moment on dRTA. And I'm sure we will be able to have another touchdown in cystinuria. So let's see. Now if you have questions, Adrian, Robbie and myself will be happy to answer your questions. No questions? I think Adrian and Robbie were very clear. So I think -- if there is no question, we will be perfectly on time. Okay. So I hope we -- you learned a little bit more about Advicenne and more specifically on 7103 and even more specifically on what is the promising U.S. market and the promising U.S. project for ADV7103. Thank you very much. Have a good evening. Bye-bye.

Thank you. Bye-bye.

Thank you. Bye.