Good morning, everyone, and thank you for joining H.C. Wainwright 28th Annual Global Investment Conference. I'm Luis Santos, a senior associate in Patrick Trucchio's team in healthcare, and it is my pleasure to welcome CFO of Pharvaris, David Nassif, and Head of IR, Maggie Beller. Welcome, it's a pleasure to have you today.
Thanks. Pleasure to be here.
Pharvaris is a late-stage biopharmaceutical company that is developing oral bradykinin B2 receptor antagonist for hereditary angioedema, we're going to go with HAE, and the lead candidate, deucrictibant, is under FDA review as an immediate- release capsule for on-demand treatment of HAE attacks with a PDUFA date of April 23 next year. For those less familiar with the name, can you give us an overview of Pharvaris' focus and deucrictibant?
Sure. Pharvaris has been around 11 years, and it was founded by the founders of the icatibant molecule, even a decade before that. We are obviously publicly held with a $2.5 billion, nearly $3 billion market cap. Our goal ultimately, by the time we have our major products approved, is to have a label that says we are all about bradykinin-mediated disorders. We're starting with type 1 and 2 HAE, but as you'll hear in this conversation, there will also be normal C1 brought into the mix, there'll be acquired angioedema brought into the mix, and then we're looking at peripheral bradykinin-mediated disorders early on in the pipeline, possible sNDA candidates. We will have ultimately, if all goes well, the broadest label in this industry.
Can you tell us more about the unmet need in HAE and what is deucrictibant addressing specifically here?
Hereditary angioedema is a genetic disorder in which people have a mutation in their SERPING1 gene that results in either dysfunction or disorder of the C1 inhibitor. This is within the contact pathway in the kallikrein system, resulting in excess bradykinin. When that bradykinin binds with the B2 receptor, it causes vasodilation or leakage of fluid into the intracellular space. You end up resulting in swelling attacks that are unpredictable, they are extremely painful. They can be throughout the body, so in the hands, the face, the GI tract, sometimes in the throat, which results in swelling that can lead to asphyxiation and potentially death. These are unpredictable, painful, potentially fatal swelling events that occur in the U.S., it is in about 8,000 people, so it is a rare disorder.
Our drug, deucrictibant, is an antagonist of the B2 receptor, so that means that it blocks bradykinin from binding with the B2 receptor, thereby stopping the cascade of excess bradykinin at the very bottom of the cascade. We essentially plug the sink at the bottom of the cascade. As David alluded to, this enables us to not only address excess bradykinin from the kallikrein system that I talked about before, but also address other sources of excess bradykinin, including through mutations outside SERPING1, such as plasminogen, kininogen, factor XII. There are about eight common other genetic mutations that lead to excess bradykinin. That is where our drug acts, and we have, as you mentioned before, we have two settings for deucrictibant. We have an immediate release capsule that enables rapid uptick of the therapeutic exposure that is best suited for treating acute attacks.
If and when somebody is experiencing an HAE attack, they are able to take a single pill, and that rapidly and completely treats their attacks. In that setting, we are under review by the FDA.
Our MAA is also validated in Europe, and we hope to have that approved potentially on the market in April of next year. In a second setting, we have an extended- release tablet that is best suited for a slower, more progressive uptake, so it's extended release. Deucrictibant is absorbed in the gut. That is best for a once-daily prophylactic treatment, so we prevent attacks from happening. We reported phase III results of that just last week, and I think we're going to talk about that a little bit more in the future.
Yes. We'll get there in a minute. Also in July, the FDA accepted your NDA for the immediate- release capsule, the 20 mg. The EMA, as you said, validated the MAA the same month. How is the review progressing and what are the key next steps?
Great question. We've been answering questions. We've also been hosting various inspections, and a mid-cycle review is coming up, which we won't be giving guidance on as to when that is, but things are going well.
Great. Thinking about the April PDUFA, how should we think about axes of manufacturing, axes and positioning ahead? How are you building up toward that decision?
For our setup in the commercial side of things, we are building out our team. We expect to have about 70 to 80 people in total in the commercial function. By the end of the year, we will have about 95% of that workforce hired. Within that, we are going to have about 30 to 40 sales reps. That is in line with other HAE companies that launch drugs here. We are in line with that. We are expecting our manufacturing to be ready for launch. Hopefully, the day that we get approval, we should be able to launch the drug. We are well set up and well capitalized to be able to successfully launch deucrictibant IR potentially in April of next year upon approval.
Excellent. As you are saying, [inaudible] with extended- release formulation for the prophylaxis setting met its primary endpoints and efficacy secondary endpoints from the CHAPTER-3 trial data that you announced last week. Can you tell us more about the actual study, how it was designed, and again, what were the key achievements that we are looking for here?
Absolutely. Pharvaris is the first and only company to date that has run pivotal phase III studies, not only in HAE types 1 and 2, but also in normal C1. A RAPIDe-3 study that is the on-demand study also included normal C1 patients. In CHAPTER-3, we enrolled 85 participants with HAE types 1 and 2 and normal C1. We randomized that study in a two-to-one fashion, so there were 55 participants in the deucrictibant arm. There were 30 participants in the placebo arm. That completed, we ended up finishing with 83 participants in total.
We were able to demonstrate across HAE type 1, 2, and 3 that deucrictibant resulted in an 83% attack reduction, and showed statistically significant decreases in severe and moderate attacks in use of rescue medication when an attack did occur. We showed significant reduction in the 50%, 70%, and 90%, as well as attack-free participants, and we showed statistically significant improvements in angioedema quality of life measures. That is through the AE-QoL and the AECT. Deucrictibant was well-tolerated and we anticipate, along with our open- label extension data and potentially the CREAATE data that I will talk about in a bit, that we will submit that NDA to the FDA in the first half of 2027. Importantly, within the CHAPTER-3 study, within the HAE type 1 and 2 participants, which is the majority of HAE.
We demonstrated an 87% attack reduction. That is the number that is most easily comparable to other HAE studies. I think you'll see across the board, you've got 87% in TAKHZYRO and in ANDEMBRY, and we were really pleased to demonstrate injectable efficacy in that type 1 and 2 patient population.
That is a good point because the alternative competitors are injectables, and with an oral, you're getting a similar efficacy. Can you tell us how that gives you a competitive edge?
Absolutely. As we read out our data, we realized that deucrictibant doesn't have the potential just to be a best-in-class oral. It has the potential to be a best-in-class prophylactic. As we think about the approach for our penetration in the commercial setting, we think of it in three/four settings. Number one, we've heard from physicians that based off of our 87% attack reduction, deucrictibant and its oral route of administration, which is the least invasive of all of them, deucrictibant should be the first therapy for any new starter on prophylaxis. In the U.S., that's about 150 to 250 new patients each year. Right now, there's an oral that's approved that has about 44% attack reduction. They tend to get new starters on prophylaxis as well. However, that oral medicine has about a 40% attrition.
Instead of having those patients start on deucrictibant and drop off, we would expect to have maybe a 3% to 5% attrition. That stacks over time. Next, we would be able to compete with the existing oral that's on the market. As I mentioned in a phase III study, they demonstrated 44% attack reduction. We demonstrated 87% attack reduction. We also had a well-tolerated profile with respect to GI side effects and cardiovascular side effects. So we believe that that could become the preferred oral therapy. In the U.S., that's about 1,600 patients who are on the existing oral. Next are people who have tried that oral but have come off of it for whatever reason. Either the efficacy wasn't meeting their expectations or the tolerability and side effects were untenable. That's about 1,900 patients in the U.S.
We know that these are people who desire an oral. They've already tried one once, and we believe with our clinical profile that we may be able to convert those patients from injectables back to an oral that works well for them. Lastly, and the largest target for us are going to be people who are on injectables right now, but who have never tried an oral because they didn't want to forego their efficacy. They're used to having 87% attack reduction, and we believe that with the availability of an oral that has the efficacy and tolerability that they're used to, we may be able to switch some of those patients from injectables to orals. That's sort of our four-pronged approach to the commercial penetration.
Regarding adolescents aged 12 and older, also could you think about a label that I think encompasses the patients that you designed the study for, also in adolescents, also the three types of HAE and maybe the transitional use of the immediate- release capsule with the XR?
Yes. I'll start off with our expectations around a label, and then I'll talk about combination use. In both the RAPIDe-3 and the CHAPTER-3 study, we included adolescents and adults, so 12 and older in HAE types 1, 2 and 3. Current HAE therapies are also labeled for HAE broadly. They're not prohibited to just HAE type 1 and 2. However, in actual clinical practice, physicians understand that HAE therapies that work higher up in the cascade may not be effective in HAE with normal C1 because if you obviously work in the kallikrein system, but you have some sort of mutation that's outside, that's kallikrein independent, such as a plasminogen mutation or a kininogen mutation, it's not going to be effective. By working at the bottom of the cascade, we believe that we will have an effective therapy for normal C1 patients.
We would still expect a label that's similar to what's existing and on the market right now. But we believe based off of our clinical data and feedback from actual clinical practice, that deucrictibant would be effective in the normal C1 patients. And of course, we have consistent efficacy that we've seen in adolescents and adults. So really pleased to see that across that entire patient population, we believe that deucrictibant could be successful. The second part of this question is really interesting and very important to our commercial positioning. Deucrictibant, as I mentioned, is one molecule with two different formulations, and HAE is a threshold-driven disease. That means that we have the potential to use deucrictibant XR in a once- daily fashion. If and when a breakthrough attack occurs, we believe that that's just because excess bradykinin has been able to accumulate.
Whether that's because the therapeutic exposure of drug in the system has dropped below this EC85, which is the measure of the effective concentration that 85% of the B2 receptor is blocked. We believe that you could add in an immediate- release capsule and bump yourself back up over therapeutic threshold to address that breakthrough therapy. We're 2/3 of the way through creating the data set to be able to support that. First and foremost is supporting that mechanism on mechanism is an appropriate way to address breakthrough therapies. We have data from our CHAPTER-1 study that demonstrates that if somebody had a breakthrough attack on deucrictibant and they treated with icatibant, which is the same mechanism as deucrictibant, that it was as effective as if they were on placebo and had a breakthrough attack. That's step number one, mechanism on mechanism.
We also see this in clinical practice. Right now, if somebody is taking TAKHZYRO or ORLADEYO, those are kallikrein inhibitors, and they treat with ecallantide, also a kallikrein inhibitor, that it effectively addresses their breakthrough attack. Second has been the safety margins that we're focused on. We have non-clinical models around a exposure profile of non-clinically of XR exposure plus two IR exposures at the highest rates that they could be. We intentionally held so that you're at the peak of your XR and the peak of both IRs. That was shown to be safe and well-tolerated in a non-clinical model. Lastly, and we're waiting on the approval of deucrictibant IR for this because you can't ethically evaluate two investigational drugs in a person at one time.
We believe that if in the CHAPTER-4 study there are breakthrough attacks and people are able to treat with approved deucrictibant IR, that we would be able to show that deucrictibant plus deucrictibant is safe and effective. That's really important because we are the only company that's able to utilize the same mechanism in two different treatment settings to be able to have what we consider a portfolio patient.
This is an off-script question, but it was occurring to me. What are the chances that there's over time some patients will build insensitivity to the drug. You can use that immediate release, but is there any history in your data that gives you confidence that this won't happen or that this will be controlled?
Of course, long-term data is going to provide more information there.
From CHAPTER-4.
From all deucrictibant use.
From the real world. From hopefully the real world.
Yeah, exactly. From all deucrictibant use. We do not believe scientifically that that should be the case, especially because deucrictibant is a small molecule. We've seen some cases of anti-drug antibodies in biologics, but we do not believe medically or scientifically that that should be the case for a small molecule like deucrictibant.
Great. You talked about the safety margin. Can you tell us a little bit about the safety profile, cardiovascular, hepatic, ECG findings? How should we think about, yeah, that cardiovascular safety evaluation that you've presented at the symposium recently?
Mm-hmm. The biggest question in the scientific field is if you are impacting the contact system, which is where kallikrein sits, and bradykinin as well, how does that impact other organ systems? Bradykinin is highly involved in other organ systems, specifically within cardioprotective.
Activities. We've put out a ton of data around the cardiovascular safety of deucrictibant, and most recently we and that's both clinical and non-clinical. We most recently read out our CHAPTER-3 study. We were pleased to see that there were balanced cardio findings in placebo and deucrictibant, no additional risk of cardio safety challenges. That for us is really important because across the entire class of HAE, if management of kallikrein or, and therefore bradykinin, was impacting other organ systems, we as a class of drugs, of all HAE drugs, would need to obviously evaluate that more stringently. Additionally, I think I alluded to this, we were really pleased to see in our CHAPTER-3 data that there was balanced findings between the placebo and deucrictibant arm for GI side effects.
The approved oral right now has some GI side effects between vomiting and diarrhea that we were very pleased to see did not occur in our oral therapy.
have GI side effects, we were happy to address that.
To debunk that.
Yes.
That's great. David, given your plan to unite the on-demand and the prophylaxis franchises, what is the strategy of intent to treat population initially at your launch? So which patients will you target at launch?
Our first launch will be the immediate- release.
Acute setting. There, the market leader is generic icatibant and FIRAZYR.
57%, I think, of the total market. Again, I started off this presentation by saying our inventors were icatibant's inventors, so it's, we hope, a very easy conversation to say, "How would you like something that has icatibant-like safety and efficacy, but is oral?" We think we should do very well at that.
After that would be ecallantide, and it's well documented which aspects of our drug or why our drug is superior to ecallantide. We think this will be a very smooth, very successful transition into deucrictibant.
Excellent. Very briefly on your pipeline expansion, the CREAATE trial is the first phase III focused on acquired angioedema, like you were saying earlier. C1 inhibitor deficiency, and there is no approved therapies here. What are the drivers that made you pursue this opportunity, besides obviously there is no other approved therapies?
Our ability to address acquired angioedema is twofold. Number one, we believe that deucrictibant mechanistically is the most inclusive of all of the bradykinin-mediated angioedema drugs due to the fact that we are at the bottom of the mechanism. AAE, because it is due to C1 inhibitor deficiency, this clinically operates most similarly to HAE types 1 and 2.
We heard feedback from physicians that they were desiring having an approved therapy for AAE. These are patients who have underlying disease, whether it is lymphoma or myeloma or lupus. These are sick patients, and unfortunately, what we have heard from a recent paper, is that they struggle with diagnosis because there is not necessarily the awareness from their primary physician, whether that is a rheumatologist or an oncologist, around their angioedema. Our ability to include AAE in our label enables us to conduct medical education at meetings like in ASCO and bring awareness of this.
Smaller disease to a broader physician population.
It also enables us to apply for bradykinin-mediated angioedema in our label. That, as a broader label, could also open us up to priority review in the prophylactic setting.
Interesting. For our investors listening to this discussion, your cash runway into 2028, so how should we think about covers both launches, and what other catalysts should investors be focusing in the next year?
We publicly guided to cash through the middle of 2028. The commercial team for both products will be built out by the end of 2027, therefore, that is all currently funded. As to catalysts, I would say we have a first half 2028 NDA filing for prophy. We have an April 23rd PDUFA date for the IR product. We intend to launch immediately after that, the next day if possible. Then we will be publishing or presenting one way or another more of the data coming out of the CHAPTER-3 trial.
Excellent. Maggie and David, it was a pleasure to have you. Thank you so much for everybody for attending, and have a great rest of your conference.
Thanks, Luis.
Thank you.
Thanks, H.C. Wainwright.
Okay