All righty. Hi everybody. Thank you for joining us for this next session. My name is Nevin Varghese. I'm one of the biotech analysts here at RBC Capital Markets, joined on stage by Pharvaris and the head of IR there, Maggie Beller. Maggie, thank you so much for being here with us.
Thanks, Nevin Varghese. Thanks for having us.
Of course. Let's get into it. I think I'd love to start with the recent pivotal data that we saw from the RAPIDe-3 trial of deucrictibant IR, where we saw significant on-demand efficacy in acute HAE attacks. I'm curious, since the data and as you've been doing more market research, what specific endpoints that you've seen resonating most with clinicians and patients, whether that be the time to symptom relief or attack severity reductions, or the time to end of progression?
Yes. Before I start off, I just want to remind everybody that I'm going to be making forward-looking statements. For full disclosures, please take a look at our SEC website. We were really excited to put out our data in December of last year for RAPIDe-3. One of the things that is especially important about this deucrictibant data is that, in addition to hitting our primary endpoint, which was time to symptom relief of a little better in 1.28 hours, we also hit all 11 key secondary endpoints with statistical significance in a hierarchical fashion. As you mentioned, Nevan, there are a bunch of endpoints within that. The full attack trajectory is an important aspect of addressing HAE attacks. End of progression in 17.5 minutes is a very important psychological endpoint for patients.
This is the first time that they stop feeling worse in their attack. That means that they know that the medicine is working again. A really quick endpoint there is important. We of course have our primary endpoint of 1.28 hours. As you mentioned, another key important endpoint here is time to complete symptom resolution. deucrictibant showed that in a little less than 12 hours, we're able to have no symptoms anymore. This is incredibly important. That means that you can basically take deucrictibant at night when you start to feel an attack coming on. By the time you wake up in the morning, your symptoms are gone. The last really important endpoint here is our single-dose resolution. 83% of attacks treated were addressed with a single dose of deucrictibant.
This is important not only for the patient experience, but also when we start to communicate with payers about how many doses it takes to completely treat an attack.
How do you see perhaps some of these endpoints potentially changing in a real-world scenario as well? Were we seeing different data in the pivotal, how is that kind of related to what we've seen in the open-label extension data? How do some of these endpoints that we've seen compare to some of the other competitive entrants that we've seen too, one from KalVista's sebetralstat, which is already commercial, and also from the generic icatibant as well?
Absolutely. In our phase III study, we intentionally designed the study to evaluate the efficacy of deucrictibant in HAE attacks. We actually asked people to confirm that they were having an HAE attack with their investigator. With that, inherently, you have some delay to treatment. One of the things that we are seeing in our open-label extension is there's a lack of delay of treatment there. We would anticipate in real-world people treating as soon as they start to feel symptoms, not waiting to confirm an attack.
Okay.
Across the board, anytime you treat an attack earlier, you tend to have faster resolution. We may even see that in real world, those times to all of the endpoints end up being a little bit faster. You end up having milder attacks if you're able to treat them faster. That's one thing that we're looking forward to in our open-label data and also in the real world evidence that we have with use of deucrictibant. With respect to comparison to standard of care and also the recently approved oral, I will highlight that there are no head-to-head studies right now, so really we're just comparing numbers to numbers, so it's not exactly comparable.
One of the things that we were thrilled to see is that once again, across the board, across all the endpoints, deucrictibant numerically outperforms standard of care, which is icatibant in most cases, as well as numerically is faster to time to initial symptom relief and complete symptom resolution than EKTERLY, which is the recently approved oral in the on-demand space.
Got it. As you've been talking to patients and doctors, how has the oral formulation resonated, and what takeaways have you derived from KalVista's recent launch, and how that de-risks the commercial opportunity?
Absolutely. Across the board, both we, KalVista, and physicians agree that the oral entry in the acute market really is important because it decreases the treatment burden.
that you have. That means that of the 70% of attacks that currently are treated, there's still 30% that are not treated, whether that's because people leave their icatibant at home, they don't want to excuse themselves because they have to inject over a long period of time. By having an oral that works, there will be trust built in the fact that you can discreetly and quickly treat an attack. We would anticipate that the number of attacks that are now left untreated would decrease because that treatment burden decreases. We think that that's across the board. Actually, the number of attacks treated could increase over time.
I see. Yeah, just given that a lot of these attacks are mediated by stress responses, having the confidence of having an oral that you can take with you wherever you go could also potentially moderate the severity of these attacks as well if they do occur. Okay. I know you guys have been hard at work on the NDA filing. Just wondering if we could get a status update on that. If there's any consideration for looking at accelerated pathways to get this to market sooner.
We're on track to file our NDA in the first half of this year, so no update there, but no news is good news on our side.
Still in the first half.
Exactly
Getting close.
We would expect to have a normal review period for that. We would be pleasantly surprised if we received priority review, but we haven't seen a priority review for other acute therapies.
Got it. Let's talk about what the commercial launch could potentially look like. I guess before we get into the commercial dynamics, if you can talk a little bit about what the pre-commercial work that the company has been doing in order to prep for the launch of IR and any learnings, again, that you've taken away from KalVista's recent launch that you might be able to apply here to perhaps accelerate uptake of IR and how you see the dynamics of that playing out as well with EKTERLY on the market.
Absolutely. Yeah. I think that the EKTERLY launch confirms that there is an unmet need for an oral. I think frankly they've done a great job with their launch, and we're hoping to see the same sort of adoption of deucrictibant that EKTERLY has seen. Some of the things that we've already been doing on our end, we've been building out our commercial infrastructure, so that includes making key hires. For us, we would anticipate our U.S. commercial infrastructure to be about 70 people for the IR launch. We'll probably add another 10 people to that when we hopefully launch in prophylaxis as well. Of that, about 30-40 people should be salespeople. We can expect to have similar to other HAE companies, that commercial infrastructure in the United States.
Some of the things that we're thinking about right now, not only in terms of segmentation of patients and also profiling of physicians for appropriate communication, is also just raising the treatment expectations. Right now, people are needing to forego, whether it's efficacy, tolerability or convenience between their injectables if they're, for example, taking icatibant, it works really well, but of course, you sting yourself, and you have to inject. It's not very convenient. There are some other trade-offs with respect to efficacy if you end up having the convenience of an oral therapy. What we're trying to do right now is communicate to the market about raising those expectations and not allowing good to be good enough. We're hoping that deucrictibant's label also reflects the fact that we believe that we have a highly effective, tolerable, and convenient therapy for on-demand.
Those are some of the things that we're doing right now with respect to disease state education and communication with the market. When we think about switching behavior, we really think about 3 main areas, right? You have the people who are on icatibant right now, where they've either decided to remain on icatibant or they have switched to EKTERLY and then come back to icatibant. One of the things that we're really excited about is the ability to utilize the same mechanism of action for icatibant, which is the widest used on-demand therapy right now, with, like I said, though not head-to-head, potentially faster time to onset of symptom relief, complete symptom resolution, and single-dose durability.
Same mechanism, potentially improved efficacy, and single dose there. People who trust that B2 receptor antagonism is the appropriate way to manage their HAE can now have the same mechanism, but with a potentially better option for them.
Got it.
Next is people who are on C1 replacement right now. Most of those patients tend to be normal C1 patients. Now, as you may know, HAE types one and two are due to C1 inhibitor deficiency or dysfunction. However, normal C1 results in excess bradykinin from other mutations, whether that's plasminogen mutation, kininogen mutation, angiotensin, factor XII, right? There are a bunch of other ways.
that you can have excess bradykinin. deucrictibant acts at the bottom of the cascade, we're able to address all of these patients regardless of where their excess bradykinin comes from. We believe that those normal C1 patients would be ideal for a deucrictibant treatment, and we have data from RAPIDe-3 that show that normal C1 patients in both factor XII and plasminogen mutation, the efficacy matched across HAEs type 1 and 2 and normal C1. That's sort of the second area. Last, we think about people who are on the oral EKTERLY right now, right? Is there an opportunity for them to have single-dose durability, potentially faster time to onset of symptom relief, complete symptom resolution, like I said, in 12 hours as opposed to over 24 hours for EKTERLY. We think about that improved efficacy as a key switch opportunity for us.
What we've heard anecdotally is that people who have treated their attack with deucrictibant and treated their attack with sebetralstat is that there's a marked difference between these two. Our opportunity is to be able to just decrease the burden that's associated with just trying deucrictibant. Try, treat your attack, see if you like it better.
Right.
Whether that's a quick start program, free sampling, keeping people on our open label extension until we have hopeful approval, whether that's post-trial access. We have an expanded access program that we're running for people who don't have access to either icatibant or sebetralstat or any HAE therapy. Really just making sure that we can get in front of people and make that try it as simple as possible.
Got it. Okay. I guess moving to the XR opportunity. We had seen with the CHAPTER-1 trial, there was impressive efficacy, though in this case you were utilizing 2 IR BID doses. The team had done some work to create an XR formulation in order to have a QD version, which is currently being tested in the CHAPTER-3 trial. Wondering how this change in the difference from the BID IR formulation to the XR formulation, how de-risked that is, and if you think that the XR formulation, the PK advantages that we see there would be able to recapitulate the prior data that we saw.
Great question. As you said, in our CHAPTER-1 data, we saw 85% reduction in attacks. That puts us squarely within the competition for injectables right now. We're really happy with that phase II data. Our goal for phase III is to be able to confirm those findings. We're hoping to see 80%-85% attack reduction in our phase III. As you mentioned, in the phase II, we were using BID dosing of a PK that is rapidly absorbed, so there's a very quick peak, and then it comes to a trough at about hour 12. Around hour 12 and hour 24, there is an opportunity for vulnerability for a breakthrough attack. This is when the therapeutic threshold drops below, or the plasma exposure drops below the therapeutic threshold, which could open somebody up to a breakthrough attack.
Because the tablet form is acid stable, so it passes through the stomach into the gut, once the pH starts to raise in your gut, the tablet will release deucrictibant. That slow absorption through the gut and in the colon enables a much stabler PK curve.
PK. Right
that we have seen from phase I modeling enables you to have coverage for over 24 hours.
Yep.
Which is ideal for once-daily dosing. We've only seen this in phase I. Of course, our phase III data will show what it shows, but we have seen in an investigator-initiated trial in acquired angioedema in four patients, so still very small, that those four patients, save one attack on day two of one patient, were attack-free for almost two years. We're hoping that this XR formulation protects from any phase II to phase III efficacy degradation that some people see when they expand out their-
Yeah
clinical trial.
Yeah. I guess, is there any color that you might be able to provide on what the fidelity of the ongoing phase III is, at least even in terms of study conduct, in terms of all other things different? We know the formulation is different, but how has the study conduct been versus what we saw before? Is there anything you might be able to speak to on the baseline characteristics of the patients that were enrolled?
We have not seen baseline characteristics in terms of attack rates yet.
Okay.
We stay very clean and blinded to that data. We want to be as pristine as possible when we're looking at that data. Haven't seen that information. Of course, we have a DSMB that monitors the data for any safety concerns. As we've moved from phase II to phase III, we have included adolescent patients in our study. We have a more global footprint, so in addition to North America and Europe, we're also enrolling in Latin America and Asia Pacific. We included about 90% of the same sites in RAPIDe-3, which was our phase III on-demand study, as we did in the CHAPTER-3, the phase III prophylactic study. With that, we have confidence in just the quality of data that these sites are giving us.
We saw from RAPIDe-1 to RAPIDe-3 that actually there was an improvement in efficacy, and that the data quality was really clean. Although we're going to new sites compared to other HAE studies, they're not new to us and not new to Pharvaris. We're really pleased with the quality of data that we've seen there. Like I said before, we're also including normal C1 patients in that study. All of these kinds of opportunities for more heterogeneity, we have done the same things in the RAPIDe-3 study, and like I said, saw an improved efficacy. That gives us some confidence in our ability to run a good study.
Got it. We tend to be bullish on our end too based on the analysis that we've done that CHAPTER-3 has a very good chance of working out and showing good efficacy. Assuming everything goes well and this is approved, how do you see the commercial dynamics playing out, especially the switching of patients from those who are otherwise maybe well-controlled on oral prophylactics already? Some of the survey work that we've done as well seems to indicate that some doctors might actually think about switching a portion of their patients off. How do you see patient behavior changing with the potential oral that might have injectable-like efficacy with a very tolerable safety profile?
Yeah. Right. There are 4 main segments that we're thinking about when we approach the prophylactic space. Number 1 is new patients to prophylaxis. Assuming all things are the same, right? Same efficacy, same tolerability. We know that 80% of physicians would start a patient on an oral therapy, the least invasive route of administration.
You still have the same efficacy. Each year in the United States, there are about 200-250 new patients that start on prophy. We get 80% of that, let's say 200 of them. We're able to really stack those year-over-year, right? We're not going to keep 100% of patients on every year, but maybe the switch rate is 7%-10%, right? We're able to really stack that year-over-year.
Makes sense.
That's the first segment. Second segment is people who have tried the other prophylactic oral and come off of it for whatever reason, whether it's efficacy or tolerability. We know that that's about 1,900 people right now.
Those people are people who have already indicated that they are open to switch, and that they want an oral therapy, but they don't want to forego efficacy and tolerability. That, I don't want to say they're easy to switch, but they're certainly low-hanging fruit there that we would definitely target very early on in our launch. The third set of people are people who are on ORLADEYO right now, right? These are people who may be seeing improved efficacy, right? They may have gone from 8 attacks a month to 2 attacks a month. However, 2 attacks a month is just the baseline.
Right
where we start to provide efficacy. Although they may say, "Oh, this is so much better than what it used to be," there's still an opportunity for improvement there. If we were able to go to those people and say, "You still get to keep your daily oral, but instead of 2 attacks a month, why don't you have maybe 1 breakthrough attack a year?" That could be an interesting conversation with those patients. Lastly, there are the people who are still on injectables right now because they don't want to forego the efficacy. They may say, "I'll stick with my Takhzyro because I really am well protected. I would love to try an oral if the efficacy were equivalent to what I get with my ORLADEYO, Takhzyro.
Got it. We've seen some development of longer-acting injectables as well. How are you thinking about what the dynamics of the market may look like with those potentially approved as well?
Great question. As we've done our market research, we have asked people, when do you prefer a daily oral versus a long-acting injectable? We took daily oral versus once every 2 weeks, every month, 2 months, 3 months, 6 months. It's only when you get to a daily oral versus once every 6 months that you start to see about a 50/50 split in that market, right?
Okay.
Half the people prefer a daily oral, half the people prefer a long-acting injectable at 6 months. Let's assume that garadacimab, which is right now the only drug that can potentially get to 6 months, also has the same efficacy that we're seeing for deucrictibant, but also other injectables. They're in this 80%-85% attack reduction. 50% of the market goes to orals, 50% of the market goes to injectables. We also know that none of these therapies are going away completely, right? People are still on Cinryze and Haegarda.
Yep.
Let's assume that 5% of each drug is retained, right? 50% of the market on oral, 5% keeps with ORLADEYO, deucrictibant, as we're hoping to put up really strong efficacy, gets 45% of that market. Within the injectables, you've got Cinryze, you've got Haegarda, you've got Takhzyro, you've got ORLADEYO, you've got donidalorsen, you've got all of these other therapies. If each of those get 5%, then even the winner in the injectables is only getting a portion of that.
Right.
It's a crowded market in the injectable space.
Yeah. I guess if you could talk a little bit more about your unique role as a company, because I think Pharvaris is the only one that will potentially have an on-demand therapy and also prophylaxis available as well. How are you thinking about what commercial synergies you might be able to derive, and how you could potentially leverage that to gain more of a dominant market share within this market?
Yeah, absolutely. One really important strategic piece for us is the data that supports the use of deucrictibant extended-release plus deucrictibant immediate-release. We have some mechanism on mechanism data right now that says you can use a B2 receptor antagonist on top of a B2 receptor antagonist. We also have safety modeling supporting that use together. We hope to have in the future some deucrictibant plus deucrictibant data. Of course, we can't do that until one of them is approved.
With that, we can have some very interesting conversations with prescribers and with payers around the portfolio of deucrictibant, right? If you're able to have the broader label of bradykinin-mediated angioedema, plus the ability to be able to use one brand for prophy and one brand for on-demand, you could become sort of the broadest first-line therapy for all HAE and bradykinin-mediated angioedema.
Makes sense.
Yeah.
Maggie, I think we're just about at time, but I very much thank you for this opportunity to talk about the progress and looking forward to the data in a couple of months.
Yeah, absolutely.
Thanks.
Thanks, Nevan.