Advancing an Oral Alternative to Infused and Injected Therapies for HAE
September 16, 2022
Hereditary angioedema is a rare and potentially life-threatening genetic disease that causes sudden and prolonged swelling to various parts of the body. While there are therapies available today, they require either injection or infusions, carry inconvenient dosing regimens, and can cause undesirable side effects. Pharvaris is developing an oral therapy to treat HAE that it says could provide an effective and more convenient alternative to existing therapies. We spoke to Wim Souverijns, chief community engagement and commercial officer for Pharvaris, about hereditary angioedema, Pharvaris’ efforts to develop a convenient oral alternative to existing therapies, and why it believes it will be able to provide an effective alternative that is safe, tolerable, and convenient.
Daniel Levine: Wim, thanks for joining us.
Wim Souverijns: Thanks for having me, Danny.
Daniel Levine: We’re going to talk about the rare and life threatening condition, hereditary angioedema, Pharvaris, and its efforts to bring a new treatment to the market for HAE. Perhaps we can start there. What is hereditary angioedema?
Wim Souverijns: Well, Danny, hereditary angioedema, like the word says, is a disease that is passed on from parents to their children, which is hereditary. It’s a very rare disease. There are about one in 21, 50,000 in the U.S. So, about 60,000 patients, depending on the number you use and what it leads to, or manifests itself as, are unpredictable swelling attacks in different parts of the body. They can be very painful and sometimes even lethal. They are caused essentially by the absence or deficiency of a particular enzyme called C1 inhibitor esterase. I mean, you don’t have that enzyme. It causes a downstream cascade which ultimately leads to an overproduction of a protein called bradykinin. And when in tissue cells you have too much bradykinin, it will connect to a receptor called the B2 receptor, and by doing that, it will send a signal to the cell that it should uptake fluids. As a result, you get those swellings. They’re very localized. They’re very painful. And there are different types of HAE. They have type 1, type 2 HAE. The first type is when you don’t have, or not enough, C1 inhibitor esterase. Type 2 is you do have some C1 inhibitor esterase, but it’s not working effectively and is very rare, which is pretty hard to describe. And people don’t know exactly what it is called normal C1 esterase inhibitor HAE where patients do have the enzyme, but still have the same type of attacks.
Daniel Levine: How well understood is what would trigger an episode for a particular patient?
Wim Souverijns: Well, it’s very hard to say. There’s not really an answer to that. What we do know is that patients typically under stressful conditions have more, a higher chance of having attacks. So when you go to the dentist, when people graduate or have their wedding, that’s the moments that patients typically tell us that attacks occur. But in nature, they’re unpredictable. So, it’s very hard for patients because it’s kind of a sword of Damocles hanging over their head. It can happen anytime and in different parts of the body. It’s not always in the same place. So, it’s a pretty hard condition to live with.
Daniel Levine: And how disruptive and dangerous can these episodes be?
Wim Souverijns: Well, first of all, they can be extremely painful. Women tell you that if they have severe abdominal attacks, they can be more painful than delivering a baby. So that gives you a sense of how painful it can be. Attacks in the extremities, the hands and the feet, they’re typically less painful, less disturbing, but they obviously debilitate you. You can’t walk or you can’t handle tools, et cetera. And then there’s actually been very rare cases, situations where the disease can be lethal. And that’s when the attacks happen in the laryngeal area. It’s very rare; probably one in a hundred attacks is a laryngeal attack, but still every year there are people passing away from suffocation because of laryngeal attacks. Now on top of these kinds of physical phenomena, there is a very significant social aspect to disease. The embarrassment: I’m walking around on the fair, I got to be hit by somebody in the streets, and I get an attack. How do I manage that? I’m with people, there’s a lot of social burden, social embarrassment that goes with it. And that then leads, in a lot of cases, to anxiety and depression because of the unpredictability and impact it has. So, one woman told us that for her, every single important moment in her life she can associate with an attack where it was her graduation, her wedding, her first baby, every important moment that was there, led to an attack because of stress, because of the emotion, but we don’t really know exactly scientifically why these attacks are happening.
Daniel Levine: I imagine that’s compounded by the fact that someone with this condition would appear otherwise normal to anyone else. So, does a lack of appreciation for what a person with this condition might face compound that?
Wim Souverijns: You’re absolutely right. It’s those people who go from a total normal state to, if you see the pictures, completely deformed faces or hands or feet. So, it’s very difficult for them to really live their life in a normal fashion, because this can happen at any time. And particularly given that it starts at a very young age, three to five year old toddlers are when the disease starts to occur. Can you imagine when kids are playing and these attacks are happening, that’s has a huge impact on them socially.
Daniel Levine: Are there things patients can do to manage the anxiety of just the fear of having an attack?
Wim Souverijns: That’s a very good question. There are not really good remedies or not good guidance for people like that. I think at the moment, there are basically two options for people living with HAE: either they opt for an acute or an on-demand treatment of their attack. So, they basically say, “I’m going to live my life and whenever an attack happens, I’m going to take a therapy, a treatment that treats the symptoms of the attack.” Or alternatively, they say, “You know what? I don’t want to have attacks at all costs. So, what I’m going to do is I’m going to opt for a preventative or prophylactic treatment.” So, these are the two treatment modalities that are available and I can mitigate the symptoms in either fashion.
Daniel Levine: And how effective are these treatments?
Wim Souverijns: Well, current therapies are effective, but they’re not perfect and not perfect because in the first instance in the acute setting, all the therapies that are out there are either IV intravenous or subcutaneous injections. The standard of care for these patients is Icatibant. It’s a B2 receptor antagonist. Basically, what it does is it tries to displace, avoid that bradykinin can connect to the receptor. And by doing that, it mitigates the symptoms of an attack. The downside of icatibant is that because it’s an injection, it’s painful, and there are injection site reactions. So patients are actually suffering each time. They inject themselves with this drug. And as a result of that, you’ll see that a lot of attacks go untreated because people living with HAE say, “You know what? I think this is going to be a mild attack,” which they have a very hard time predicting, but they think it so that they don’t have to inject themselves. So, there’s a clear need in that segment of the marketing, the acute market for therapies that don’t have this inconvenience of injections on the prophylactic side. On the prevention side, there we are forced to make a trade off. On the one hand, probably the most used product at this moment in most countries is called lanadelumab. It’s a monoclonal antibody, but again, it’s a subcutaneous twice weekly injection. The drug is pretty effective, but you have to inject yourself. On the flip side, you can opt for the first oral therapy in HAE, berotralstat. The downside of berotralstat, though, is that if you look at the clinical trials, it’s significantly less effective than Takhzyro (lanadelumab), the subcutaneous injection. And it comes with some side effects. So patients do have to make a choice. They have to make a trade off.
Daniel Levine: And in terms of long term consequences with the disease—obviously there could be an attack that can be life threatening—but can people live a normal life expectancy with this condition?
Wim Souverijns: Yeah, the silver lining here is that indeed it’s not a degenerative disease. So patients are not worsening over their lifetime. But it’s something they have to live with from when it starts till the end of their days. What you typically see is that it starts to occur toddlers three to five years old at a relatively low attack frequency. And then when puberty kicks in, you see the attack frequency go up quite significantly. And then for a long period of time, patients can have a lot of attacks. There are patients that have two, three attacks per week, to give you an idea. And then when you get older at the end of life, you see there is typically a slowing down of the frequency of the attacks. But you still have attacks over the whole course of your life.
Daniel Levine: Pharvaris is developing PHA121. This is an experimental small molecule therapy. How does it work?
Wim Souverijns: PHA121 goes directly after the culprit that causes the swellings in a person’s body, which is really kind. It has the same mechanism of action as the standard of care in the acute setting, which I mentioned before Icatibant. So what it does is it will compete with bradykinin for the B2 receptor. And by doing that, it either prevents the attack or it mitigates the symptom of attack. The beauty of 121 is that we are actually developing two distinct products with it. On the one hand, we have a protocol PHVS416, which is intended for the acute market. It’s a soft gel capsule, which is prepared for rapid absorption in the stomach after you swallow the pill. And so that’s really used for treating an attack, but at the same time, we’re also developing an extended release tablet, PHVS719, a tablet taken once a day and the active drug in the tablet is released over the course of 24 hours, which means that over the whole day, you are protected against attacks. At least that’s what we aspire to. That’s what we want to demonstrate, obviously, in our clinical trials going forward.
Daniel Levine: And is binding with the bradykinin receptor an issue in terms of interfering with any normal immune system process?
Wim Souverijns: As far as we know, not. At the moment, there is no evidence that this has any negative effect on other physiological processes in the human’s body.
Daniel Levine: Well, what is known about the safety and efficacy of the therapy from studies that have been done to date?
Wim Souverijns: Well, as a matter of fact, we don’t really yet have clinical data. At the moment we are in two ongoing phase 2 studies, we have a phase 2 study for the acute setting called REPEAT1. And we have a phase 2 study for the preventative setting called CHAPTER1. But at the moment we don’t have data from these studies. We expect by the end of the year in the acute setting to have our first data and in Q1 of 2023 data for our preventative therapy as well.
Daniel Levine: You’re going after a target that’s currently used by an injectable therapy. How does having an oral alternative impact the patient?
Wim Souverijns: Well, the impacts on patients can really not be underestimated. I mean, it’s swapping bulky syringes and vials with these tiny capsules that we have or tablets, which are easy to carry and that avoid those painful injection site reactions. Patients love it. Whenever you talk to patients about this, they want an oral drug to treat their attacks. So this is a massive benefit for patient. And I think if you look at the very recent uptake of berotralstat in the preventative setting, that is testimony to how willing patients are to go after an oral product in this setting. As I mentioned due to before, because of the painful site injection reactions, only 60 to 70 percent of attacks in the U.S. are treated. So, it is a huge opportunity for having an earlier treatment for this patient. The sooner you treat, the less severe attacks will be, the easier it is to mitigate the symptoms. So I think an oral product in this setting can have a massive impact.
Daniel Levine: Why are so few patients with the condition treated? Is it difficult to diagnose?
Wim Souverijns: Well, as a matter of fact, I wouldn’t say too few patients are treated. We have made a ton of progress in the last 10 years in diagnosing these patients. But it’s still true that it takes sometimes a long time. As I mentioned, the disease typically starts in toddlers three to five years old. And what is the first type of attacks that they get? Abdominal attacks. They have a belly ache. Well, a toddler with a belly ache—who is going to think this is HAE? So that’s kind of a burden, that’s a hurdle for diagnosing these patients early. On top of that, what is interesting is that parents living with HAE, they’re sometimes embarrassed. They feel guilty that their children might have disease as well. And there’s kind of a bit of closing their eyes for those symptoms. And you would expect that if one of the parents has HAE that you automatically would test your children for the defect and they often don’t. So, that’s why, in reality, it still takes sometimes between three and five years before there’s an effective diagnosis made for people living with HAE.
Daniel Levine: And what’s the development path forward for you?
Wim Souverijns: Well, as I mentioned, we are currently in phase 2, both in the acute and in the preventative setting. If these trials react positively, then we will be initiating a phase 3 program, a development program. And the launch of our drug then will depend, obviously, on when we will complete the phase 3 program.
Daniel Levine: And would you expect to convert patients who are on an injectable therapy today, or would you be focused on bringing in new patients? Do you find there’s any resistance to a doctor switching a patient to an oral therapy if they feel their patients are well controlled with an existing treatment?
Wim Souverijns: Yeah, this is very interesting question. I don’t know yet. You followed the recent development in HAE with the launch of berotralstat. And I think what berotralstat really showed is that there’s a huge, huge need for oral therapies in this space. Berotralstat, based on the pure clinical data, is less efficacious as the standard of care Icatibant. It comes with GI side effects. So why would you try this drug if you are well controlled on lanadelumab? And what we do see in the market is that there’s a lot of needle fatigue. A lot of people that treat themselves for a long time with injections, now see an option there to have an oral therapy. And that’s really speaking to this attractiveness of oral drugs. And so we hope that we can bring not only that oral aspect to the drug, but what we are aspiring to is to really bring something that covers the full spectrum of needs of people living with HAE, meaning efficacy. They want a therapy that works. They want a therapy, which is tolerable and safe, and they want a therapy that’s convenient. And today, whenever they take a therapy, they have to choose, they have to drop one of these elements. And our aspiration is really to bring something to the market that can cover those three bases.
Daniel Levine: The company’s pipeline is completely focused on HAE. Is there expectation that you’re going to be looking at broader indications beyond that?
Wim Souverijns: Well, we do look internally at some other indications driven by the B2 receptor antagonism mechanism, but we haven’t disclosed yet what these are. So, I can’t share that with you yet.
Daniel Levine: Wim Souverijns, chief community engagement and commercial officer for Pharvaris. Wim, thanks so much for your time today.
Wim Souverijns: Thanks for having me, Danny.
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