Good afternoon, and thank you for joining Guggenheim's 3rd Annual Healthcare Innovation Conference. I am Debjit, one of the therapeutic analysts, and joining me on stage are Peng Lu, president, and Maggie Beller, the head of IR from Pharvaris. Thank you both for making time for us.
Thanks for having us.
Who wants to take the first one? Maybe for people who have not heard the story, a very quick intro would be helpful, and then we can dive into Q&A.
Yeah, maybe I can start. I'm Peng Lu here. I'm the president of Pharvaris. Actually, I'm the physician scientist, have been working in HAE over a decade. Our motivation is how we can translate the novel science to really help the patients and really address what the patient need. That's exactly why we built up Pharvaris here. Pharvaris actually is a company really dedicated to developing oral treatments for HAE or maybe potentially bradykinin-mediated patients there. Currently, we have our leading compound, deucrictibant, and have one molecule with two different formulations. One formulation absorbed in upper GI and would be considered for on-demand treatment to help the HAE patients, and the other is the prophylactic formulation, and to be considered for the prevention of the attacks for the HAE or eventually for the bradykinin-mediated angioedema patients.
Currently, indeed, in the exciting moment for the company, and we are very close to bring deucrictibant for our patients to give them greater control and simplicity here.
Yep. Just a quick update across the business. We read out our pivotal phase III on-demand data in December of last year. We have a PDUFA date for that on April 23, 2027. That will be for deucrictibant for the on-demand treatment of HAE attacks. Additionally, we just read out our pivotal CHAPTER-3 prophylactic data in September of this year, and we are on track to submit an NDA for that. As Peng mentioned, we are hoping to submit it for bradykinin-mediated angioedema because we are also going to be reading out top-line data from our CREATE study, which is the deucrictibant for the prevention of acquired angioedema attacks. That will be in the first quarter of next year. Lots of really exciting things happening for Pharvaris right now.
Let us unpack that a little bit, the CREATE data. If that reads out positively, you are going to wait for that data before you submit the NDA for deucrictibant XR, right?
The rate-limiting step for the NDA is actually our open-label extension data, the safety database from CHAPTER-4. It happens to be that the CREATE data will align with our timing for the submission of the HAE NDA. By combining the AAE dataset with our HAE dataset, we can actually apply for a broader label of bradykinin-mediated angioedema, and that may open us up to priority review.
So that's what I was going to get at. How important are the CREATE data for a priority review versus a standard review?
Yeah, maybe I can help address it. Currently, both our CHAPTER-4 study and CREATE study, as Maggie introduced, on track here, that we expect we will move forward at very simultaneous time. But as mentioned, there is no bundling together here, that no matter for HAE or CREATE, that acquired angioedema study, is we're discussing with the agency. But as Maggie mentioned, for the deucrictibant, especially for our prophylactic treatment, that acquired patients, they have no any treatment available. From the whole community, they have strong desire for the treatment available for them. That's exactly we try all the best to give these patients that available treatment as soon as possible. That's why we targeted to submit both HAE and acquired angioedema in parallel at the same time for bradykinin-mediated angioedema, the more broad umbrella term here.
Got it. There's not much of a clinical debate right now, given that the CHAPTER-3 had injectable-like efficacy for an oral product. How are you guys internally thinking about the commercial landscape, given that this is a complicated, or not complicated, but it's a crowded commercial landscape, right? How are you thinking about what could happen, say, 12 months from now?
Actually, maybe I can start here. That's definitely, that currently, as mentioned, the next year is incredible exciting for Pharvaris. And currently, that we have built up the commercial team, especially U.S. commercial team. As mentioned, that's a highly competitive field, but meanwhile, we have very strong team and have that no matter for our R&D team and the commercial team have deep root in the HAE field, have very good connection with the whole community and also with the patient advocacy group here. Therefore, so far, we are very proud, right? We have almost 80%, 90% commercial team on board, and we are quite ready to move towards that our, knock on wood, get the PDUFA, that get approval in U.S., that April next year, and get a strong launch there.
Maybe I can add a little bit just to the dynamics between some of the competitors in this space. In the on-demand side of the business, we really feel that orals will dominate, seeing as you need to treat an attack after it happens to be able to address the signs and symptoms. The decreased treatment burden that one has when treating with an oral as opposed to an injectable is highly prefers an oral, because it is just easier to take, it is more discreet. The current injections sting when you have to inject them. One of the things that deucrictibant brings to the table is that it utilizes the same mechanism of action as icatibant, which is the most widely used on-demand therapy right now. What we view it as is a B2 receptor antagonist, just like icatibant, but this time oral.
That is really where we see the on-demand shaking out is that orals will dominate, and we have the benefit of the same mechanism. With prophylaxis, we think that there are likely going to be a winner in the oral space and a winner in the injectable space. This is the benefit of having multiple therapies that are approved is that each patient and physician can select what is best for that person's life. As you mentioned before, we are showing injectable-like efficacy. For the first time, people are not needing to make a decision between their efficacy, their tolerability, and their convenience. Somebody can prefer an oral, or they may prefer an injectable, but now for the first time with our CHAPTER-3 data, they do not have to forego efficacy to have the convenience of an oral.
Got it. On the CHAPTER-3, when you think about the baseline, the attack rate at baseline was relatively high compared to some of the other studies. When you look through your data, does the efficacy hold up across patients with higher baseline attack rates versus those with lower?
Yeah. Actually, that is a very interesting question that here that I understand that people ask us, right? Why the baseline that attack rate is high, 3.6, something like that? Because for baseline, actually, there is a running period. It is a very short period compared to the general screening period in the past for phase II study. If we look at the other pivotal study, as you look at it here, no matter for the donidalorsen or the lonvo-z or even Takhzyro around that time, all the baseline attack rate is around a similar range. It is between 3.5- 3.6 there. As mentioned, if we look at for the placebo group, for the CHAPTER-3 study, it is also around the two attack per month. It is very comparable across that all the other pivotal trials.
Therefore, overall, the CHAPTER-3, the patient segmentation is, I think, is quite similar to other pivotal trial there. Also, as Maggie mentioned, it really reflect that the deucrictibant, that for prophylactic treatment effect is comparable to injectable.
Got it. On the safety side, there were obviously those two patients with grade 3 liver enzyme elevations. It is pretty well explained, one with fatty liver disease, the other with prior anabolic treatment. How do you think FDA is going to handle those?
Go ahead.
Yeah. I can take it here that as Maggie mentioned here, that for the currently, the prophy market here, right, that the patient really prefers the oral treatment with injectable-like efficacy, but there is no sacrifice for safety part. As we always discussed here, that for the deucrictibant, no matter for the CHAPTER-1 that we just published our long-term safety data, and also the CHAPTER-3 we just released here, that deucrictibant was very well tolerated. There are indeed that two, that level two, that liver enzyme elevation we shared during the public top-line readout there. Actually, that for the HAE patients, that due to the C1s, that SERPING1 gene mutation, C1 deficiency, that the patients have fragile liver. Therefore, liver enzyme elevation as a background to the disease there is not rare.
Meanwhile, all these patients have that long-term, especially for international ex-U.S. patients, they have long-term androgen use and also have the concomitant some, for example, fatty liver and all the disease there. Therefore, we can tell almost for every prophylactic treatment trial there is a liver enzyme elevation reported.
Do you have a sense of what percentage of patients in the United States are on danazol, if any, at this point, given all the options? Also, on a fatty liver side, do we have a sense of what these numbers could be from an exclusion perspective?
Yeah. Currently, the danazol use in U.S., because all the modern therapy available is very low now. Pretty much, I think less than 5% U.S. patients still on danazol use. There is some patients still stick on danazol, but less and less here. But compared to international or ex-U.S., this number is much higher, especially, for example, for the CHAPTER-3 trial, we include patients from Latin American countries, from Asian Pacific countries. These countries, danazol use is maybe still 20%-30%.
Got it. Beyond the two patients, the rest of the safety profile was clean, right? There were no other, call it, grade one, two, liver enzyme elevations?
Actually, I have to say that the overall, that the liver enzymes, the lab abnormality part for the CHAPTER-3 trial is very comparable or within the range to other prophylactic treatment trial there.
I'd also add that one of the things we were really proud to see was very clean safety from a cardiovascular perspective and also from a GI side effect perspective. Those were two things that we were focused on because of just other discussions that have been going on in the KOL space and the other approved orals. We really wanted to make sure to demonstrate deucrictibant's generally well-tolerated profile, and we were happy to see that with the data across the board.
What do you need to see from the CHAPTER-4 safety database? Do you have insights into how that's playing out right now?
Yeah, that's typically very standard for all the HAE treatment development. Typically, the agency will expect one year safety data. That's exactly as Maggie at the beginning mentioned. Currently, critical path for our NDA filing for prophylaxis actually is the long-term safety package there. We expect we collect all the data the first half of 2027 there, then we can submit that the NDA filing for the prophy. Meanwhile, for the acquired angioedema, as we mentioned, they only need the efficacy data because the safety data we will leverage that as a safety package for HAE. That's the whole, that our development strategy and the filing strategy, how we can use that as a parallel, that development here, that is a totality of package and the target for broader indication.
Got it. Let's fast-forward, call it 24 months from now, when both of these are in the market. What's the low-hanging fruit commercially? Is it the patients who are on ORLADEYO, given that's about a 47% response rate at best? Do you try to switch those, or are you going after Takhzyro because of the injection site issues and all that, all the painful infusions?
Yeah, actually, Maggie has already mentioned here that currently, I think no matter from the ORLADEYO or the EKTERLY early launch, they've already confirmed that the whole community desire for oral treatment. Therefore, I just say that I don't know whether it's a low-hanging fruit or not, but around that time when we consider deucrictibant, we really, the development of this treatment for all the HAE patients who prefer oral, that options oral treatment with injectable like efficacy. Therefore, as mentioned, typically we have designed that strategy for different segment of the patients. But meanwhile, we can tell, right, that for the new patient, it's definitely the patients that they will, for oral treatment, it's easy for them to take, and to see that, how about their treatment effect? Of course, the patients in the past use oral prophylaxis, but not satisfied for efficacy or safety.
It's also our target patient population, or even current, that oral treatment patient, they maybe prefer that a better efficacy and/or the injectable like the patients, that they are tired of it and also consider oral treatment. All these, I have to say that deucrictibant, hopefully, that it can help them.
Got it. With the IR approval coming up next year, are there any outstanding questions with respect to the FDA, and how do you think the label discussions are going to shape up there?
We haven't gotten into the details of how our regulatory interactions are proceeding. We've passed through our mid-cycle review, and all of the activities that should and are happening are continuing to progress as planned. We're really pleased with the engagements that we've had with regulators. For us, when we think about the label overall, we are really interested in having three key points included in the label. How this exactly works out, we obviously need to wait and have discussions with regulators. But for us, we believe that deucrictibant's differentiators include its rapid onset of action. If that's demonstrated either through our primary endpoint of 1.28 hours or a new endpoint of End of Progression that we included in our pivotal Phase 3, that is going to be an important aspect of our label. We also are really proud of our complete symptom resolution.
As a reminder, we were able to show that endpoint in less than 12 hours. The fact that 12 hours after taking deucrictibant, people had no more signs of their HAE attack. Then the third really important aspect here is the single-dose resolution. In our study, 83% of people were able to achieve their endpoint with a single dose of deucrictibant. Those three key aspects, rapid onset of action, complete symptom resolution, and single-dose durability, are really important for us in the label. However that ends up being built in, we have 11 key secondary endpoints that we achieved. We're excited to have conversations with regulators about how we're able to demonstrate the differentiation of deucrictibant.
Let's talk about that 83% of the patients having attack resolution with a single dose. Compare that with EKTERLY. How's that conversation going with payers? Because that's an interesting item from a differentiation perspective commercially.
Yeah, actually, our strength of the data, as Maggie just illustrated, and our initial interaction with the U.S. payers are very positive, I have to say. That from the payer side, from the patient side, you can tell that the fast onset is definitely a key attribute. But meanwhile, from the payer's perspective, that a high percentage of attack can treat it with a single dose is very attractive, especially compared to EKTERLY, right? It's around, I believe, that 38% or 39% of attack, they need the second dose, and even higher percentage of icatibant use a second dose here. If we integrate all together here, that from the payer perspective, you can see it not only help the patients, but it can help economic side.
Got it. Along those lines then, do you think you would price it in line with where everybody else is, or is there a premium to be had given the 83%, or given the 17% versus 39% delta?
I think when we- It's premature to get into the nitty-gritty details of our pricing strategy, but we're pleased to see that the pricing corridors within both on-demand and prophylaxis remain very compelling. For example, EKTERLY right now is about EUR 17,800 per dose. We, however, have the benefit of having an on-demand option and a prophylactic option. Instead of just looking at this and maximizing the cost of one singular asset, we are looking at the portfolio holistically and understanding the levers that need to be pushed or pulled to be able to maximize the value of the portfolio. So, we have the benefit of having really strong clinical data and very proactive payer engagements to be able to have those conversations to be creative with our pricing strategy.
Absolutely. As Maggie mentioned, we have pipeline within the molecule that we have both an on-demand and a prophy discussion with the payers ongoing that definitely give us the multiple options regarding the pricing part. But meanwhile, fundamentally, I have to say, our market access strategy is to help patients can access deucrictibant as rapid as possible, not only from pricing part, but also from, for example, the quick start sampling and also the contracting, all the different strategy. That's the whole goal for our market access group.
Got it. Currently, what is that, like 80% of the market is U.S.? From a global sales—
By value, even.
—Yeah, from the global sales perspective.
Absolutely. Yes.
What is the strategy for ex-U.S. for you guys?
Yeah. Ex-U.S. is definitely a very interesting topic and a lot of discussion with currently all the geographic, right? That's the policy and the different factors. Currently, I think that our priority is the U.S. launch, and for both on-demand and prophy. We do have a lot of discussion for international and for ex-U.S., that we also prioritize maybe in Japan and also the European countries. Currently, we don't have the details to share yet. But with the deucrictibant launch next year, we will gradually share more about our launch plan that are for international or ex-U.S.
Do you want to build an organization for ex-U.S., or would this be a good non-dilutive funding opportunity for the company?
Go ahead.
Yeah. Well, these are options that are on the table right now. We haven't committed to an ex-U.S. strategy. But I think importantly, we are also not hindering our ability to be able to move forward with an ex-U.S. launch, whether it's by us, by partner, or somebody else. Our MAA is validated and under review right now. We have a plan for other regulatory bodies throughout the globe. So, we haven't committed to a strategy yet.
Got it. Just walk me through your final headcount on the commercial side as you prepare for the launch next year and then the year after.
Yeah. Currently, as I mentioned at the beginning, we are almost there to wrap up the commercial team build-up. Currently, we target maybe very in line with the competitive benchmark here. I believe we shared in the past that we target maybe 80%-90% key members for U.S. commercial teams. That is including also the medical there. We have pretty much 90% team ready on board.
30- 40 of those people will likely be sales reps.
The number that you are, or the allergists and physicians you are targeting is about 2,500, is from what I remember from my other companies.
Yep, that's exactly right.
Got it. Awesome. Well, looking forward to a very compelling 2027 for you guys, and thank you for making time for us.
Thanks so much, Debjit.
Thank you.
We really appreciate it.
Really lovely chatting.
Appreciate it. Thank you.
Thanks.
Thanks, everyone.