Dr. Wim Souverijns, Pharvaris: Developing Novel Treatments for Hereditary Angioedema

Pharvaris is a clinical-stage company which develops novel therapies oral bradykinin B2-receptor antagonists to treat hereditary angioedema, a rare and debilitating disease which blocks normal blood flow, causing rapid and significant swelling.

DocWire News spoke with Wim Souverijns, PhD, Chief Community Engagement & Commercial Officer, Pharvaris, about the company and its therapies.

DocWire News: Can you tell us about yourself, and the company, Pharvaris?

Dr. Wim Souverijns: Absolutely. My name is Wim. I’m the Chief Community Engagement and Commercial Officer at Pharvaris. It’s a long title, but we felt it’s important to express that we really want to engage with the community. It’s something I’ll talk about later, as well. As Pharvaris, we tend to focus very much on partnership with the different stakeholders. So that’s my role here, to prepare for commercialization, but really doing that in partnership with the outside community. Background, I spent over 25 years in big biotech. I worked at Amgen and Celgene for a long time. And previously, I was Chief Commercial Officer at another small startup in women’s health called ObsEva. So, Pharvaris today is a clinical-stage company, and we are focused on the development of novel, oral, small molecules that are B2 receptor antagonists. They’re intended to be developed for the treatment and prevention of HAE or hereditary angioedema.

The company was founded in October 2015 by executives with a lot of experience in pharmaceutical development, as well as in rare disease, and particularly in HAE. So our scientific leadership, for instance, has been personally involved in both the discovery and development of icatibant, which is another B2 receptor antagonist many, many years ago, as well as the development of lanadelumab, which is probably the standard of care in prophylaxis in HAE. So a very strong basis in this therapeutic area. Now, what is unique about Pharvaris is that we’re targeting bradykinin. Bradykinin is a protein that’s really the cause for the attacks that are associated with HAE. And so that’s something unique that we’re doing that we try to put forward.

What is hereditary angioedema (HAE), and how is it characterized? 

So HAE, or hereditary angioedema, is a very rare disease. There are about one in 20,000 to one in 50,000 patients in any given country. It’s not limited to specific countries. It’s globally the same prevalence, but it’s very rare. It means that in U.S., there are between 6,000 and 10,000 patients. It’s a condition, which is associated with unpredictable, very debilitating swelling attacks. So what happens is that these patients in different parts of their body, can all of a sudden experience swellings. And that can be in the extremities, the feet, the hands. It can be in the abdomen. And women, actually, that are suffering from these attacks are telling you that it’s worse than delivering a baby from a pain perspective. So these are really, really serious attacks and they can be lethal if they’re happening in the facial area. So if the throat closes, you can suffocate from this.

So it’s a very serious disease, very few patients. Now what’s driving this disease is an enzyme. It’s called the C1 esterase inhibitor. And in the case of the absence of this enzyme or the deficiency in working of this enzyme, you get an overproduction of this protein that I mentioned before, bradykinin. And bradykinin will then connect to a very specific receptor in the cell, it’s called the B2 receptor, and by doing that, it sends a signal to the cell to vasodilate, to open up its pores. As a result of that, it takes in liquids. And so the tissue will take up the liquid, will swell, and you get these massive attacks with patients. So there are three types of HAE. The first one, type I, is where there’s an absence of the C1 esterase inhibitor and you get this downstream cascade of events, which leads to the overproduction of bradykinin. The bulk of the patients in HAE are in this category, about 80%.

About 15% of the patients have type II HAE, where there is still some C1 esterase inhibitor present, but it’s not functioning properly and so you get the same effects downstream. And the last category is very, very rare. It’s not really known how it works, it’s functions. It’s called normal C1 inhibitor. So these patients do have normal enzymes. They function properly, but still they are showing attacks. They get these attacks. That’s the makeup of the disease. Bottom line, I would say it’s extremely debilitating. It’s unpredictable. It’s putting a lot of stress in people’s lives because they never know when that is going to happen. It’s very often associated with stress, to give you an example of going to the dentist, typical example, when they have exams for kids in school. So it’s a really very serious condition.

Pharvaris is developing an oral therapy for HAE in clinical trials. Tell us about the drug and how it works.

So maybe before I start to talk about our drug, let me give you a bit of background on how this condition is being treated today. There are actually two treatment modalities that are being applied for HAE. One is you treat the attacks when they happen, on-demand, as it’s called. The second one is you try to prevent the attacks and that’s called prophylaxis. And so within each treatment approach, there are multiple therapies already existing today. In the on-demand setting, you can either go after the enzyme I talked about, the C1 esterase inhibitor. You can replace that, but plasma version of it that requires an injection intravenous. You can either go after the enzyme that causes the overproduction of bradykinin, it’s called kallikrein. Again, you need an injection for that. And the most common used product in on-demand treatment is icatibant.

It’s also a B2 receptor antagonist like we are developing. But the interesting thing is this molecule, which was developed many years ago, and actually, our CSO was part of that process, is a peptide. And because it’s a peptide, it can only be administered through an injection. It’s a subcutaneous injection, and the problem with it is that it’s pretty painful. There are quite a lot of patients that have site injection reactions, to the extent that patients sometimes decide not to treat their attack because they don’t want to have the pain of the injection. It’s not very convenient. On top of that, a lot of patients with that treatment need multiple doses. One dose doesn’t suffice to mitigate the symptoms of the attack. That’s the on-demand setting.

If you now look at the prevention side, the standard of care is a monoclonal antibody called lanadelumab. That molecule, because it’s a monoclonal antibody, also needs to be administered with an injection. That’s done every two weeks. So it’s less frequent, but still every two weeks, those patients have to inject themselves with this product. And it was very interesting to see that since the first oral molecule got launched in prevention, berotralstat, about a year and a half ago, that molecule really has shown based on the uptake it had, how eager patients are to get away from injections and to go for oral treatments. And so in that context, that’s the background, the treatment landscape. What we are doing is we’re uniquely targeting directly bradykinin. Bradykinin is the protein, which is responsible for the attack. So the moment you have too much bradykinin, it connects to the receptor, it creates a signal, and the cell will be starting to swell.

So what we are doing is we actually have a molecule that selectively and successfully competes with bradykinin for the receptor. So when you administer that drug, it’s a small molecule, and there’s overproduction of bradykinin, it will displace bradykinin from the receptor, or it’ll prevent bradykinin to attach to the receptor. And by doing that, it basically mitigates the symptom and also can be used as prevention. Now, the beauty that we have is because we have a small molecule, contrary to the icatibant, the icatibant is also B2 receptor antagonist that’s a peptide. It’s a big molecule. Because it’s a small molecule here, we’re able to administer that as an oral therapy. We can give it as a liquid. We can give it as a soft gel capsule. We can give it as a tablet. And that really was crucial for us, because that provides us a unique opportunity to develop two distinct products.

We know that the basis of the condition, the real drive for this condition, is bradykinin. Whether it’s in an on-demand setting where you treat the attack, or when you try to prevent the attack, the same molecule will drive the two conditions. But what we did here is we developed a dedicated formulation for on-demand and a very different one, distinct one, for prevention. The first one is called PHVS416, complex name, and it’s a soft gel capsule. And it’s basically constructed in such a way, designed in a way, that the active ingredient in the soft gel capsule, very quickly absorbs into the stomach. In 15 minutes, you basically have this drug exerting its effect and displacing bradykinin from the receptor.

On the contrary, PHVS719, which is the extended-release tablet, is a tablet, and like the word says, which allows for a long-term exposure, a release of the drug in the body, instead of giving it, the patient swallows it, and it gets absorbed immediately, it actually is intended to stay in the body for a long time. It goes into the colon even and is absorbed over time. So that allows you to give patients one pill in the morning or the evening and have coverage exposure of the drug over the course of the whole day. And so that’s really the attractiveness because for patients, the patients sometimes swap between on-demand and prophylaxis. Taking a drug all the time is not always what they are preferring, but then they also don’t want to be too reactive with on-demand. And so with our drug, you have the same active ingredient, the same molecule that exerts the action on the receptor, but you can use it in both therapeutic approaches. So we’re very excited about that, obviously.

Why is it important to have an oral treatment therapy for HAE?

I can’t tell you how important it is for a patient. You really can’t underestimate that. Whenever you talk to patient or patient group, they will tell you, “HAE is a terrible disease.” As I said, in the beginning, painful attacks you want to avoid them at all costs. But today, patients always have to make a choice. And I think we are becoming a stage where patients want it all. They not only want to have a drug that is efficacious, that deals with the symptoms and prevents the attack, but they don’t want to do that with an injection, or they don’t want to have side effects that come from the drug. So what they’re looking for is this ideal sweet spot, is a therapy that’s convenient, that’s effective, and that’s safe and tolerable. And so our aspiration really is to hope that we can deliver that, all these three in one platform. And we’ll see with the data, obviously, whether that holds true, but that’s really our ambition.

And you shouldn’t underestimate. Every single patient with HAE has to carry with them, according to the guidelines, two dosages of rescue therapy. Rescue therapy is on-demand therapy, which means that today, all these patients, every single patient at all times, needs to have two injections of icatibant or two vials of one of the other products with them at all times. Now we have this tiny little pill, quite easy to take with you, to carry with you, easy obviously, to swallow, but also from a practical perspective. And for patients to not have to walk around with these bulky syringes is going to really be a benefit. But the main objective is to bring these three together, efficacy, tolerability, and convenience.

Tell me about the ongoing clinical studies at Pharvaris

So we are currently in Phase 2. That means that we are testing the drug in patients. Before that, there were healthy volunteers. And we have two studies running at the moment, one in on-demand and one in prophylaxis. The on-demand study is called RAPIDe-1. It’s executed in patients that are diagnosed with HAE. And what we try to achieve there is to test the safety and efficacy of PHVS416 in an on-demand setting. So basically patients enter the study, whenever they have an attack, they treat that attack, and we try to test that against placebo to see whether our drug is better from a safety as well from an efficacy perspective.

On the prophylaxis side, the study is called CHAPTER-1, and there again, we’re testing it in a patient diagnosed with HAE, but they’re looking at different dosages to test effectiveness of prevention of attacks in those patients.

What pipeline milestones are expected in 2022?

So these two studies I just mentioned are really critical for us, and they will be reading out by the end of the year, so that’s going to be very important milestones. For the first time, we’re going to see the effect of these drugs in real patients. We have crossed fingers. We hope that they obviously will be effective. We’re very confident about that, but that’s going to be very important end of the year.

The other thing, which is happening as we speak, is I mentioned to you that we’re developing this extended-release formulation, and we’re actually, for the first time, we’ll be showing soon, pharmacokinetic data from that formulation. And it sounds very simple to take an active ingredient and putting it in a soft gel capsule or put it in an extended-release tablet, but technologically, that’s not so easy. So we’re looking really forward to those data because those will help us to understand whether we have the support to develop a once-daily pill for prophylaxis, which would be crucial, as you can imagine.

Any closing thoughts?

Well, I think one of the reasons why I joined Pharvaris, is that there are two things where we try to be slightly different and distinguish ourselves beyond the pure science and the value we bring to the patient from a global perspective. And that’s, first of all, as I mentioned before, this partnership approach. We want to look at HAE in a holistic manner. We want to collaborate with the different partners there, and that’s something we do very actively. We engage on a very regular basis with both physicians, with patient groups, with payers as well, because we don’t believe we can live in a vacuum. We can’t do just what we do. It has to be together with the community. That’s the first thing.

And the second thing is more internally focused, that’s the reason why I joined, is that we have a very fresh approach attracting and retaining talent. The company, and that’s driven really, thanks to our CEO, is built on a foundation of freedom and independence. It’s a value, which is very important for Berndt, our CEO. Which means, that we create a flexibility in our culture for hiring. So we have actually a clause in our contract, which says that you can work from anywhere you live for the company. So we have three sites. We have a site in Boston, we have a site in the Netherlands, and we have a site in Switzerland. If you’re in one of those countries, it doesn’t matter where you live, you could work from home. And we work in a hybrid fashion with the team, and that’s important in these days. We did this before COVID, as a matter of fact. But it allows us to attract the top talent at a global level, and it really created a special atmosphere in the organization.