Halting HAE Attacks Via Oral Delivery With Pharvaris' Wim Souverijns And Stefan Abele

Patients suffering from the rare disease hereditary angioedema, or HAE, experience sudden attacks of severe swelling, which can be life-threatening. In this episode of Sit and Deliver, host Tom von Gunden talks with Chief Commercial Officer Wim Souverijns and Chief Technical Operations Officer Stefan Abele from Pharvaris, a developer of orally administered treatments for HAE. Wim and Stefan share with Tom development work on rapidly absorbing capsules that address HAE attacks on-demand, as they occur. They also discuss an extended-release tablet that supports the prevention of HAE attacks as part of proactive maintenance of a chronic condition.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver, the series in which we hear about advancements and innovations in the delivery of therapies. My name is Tom von Gunden, Chief Editor and Community Director at Drug Delivery Leader, and your host for the series. Today I am joined by Wim Souverijns and Stefan Abele, the chief commercial officer and the chief technical operations officer at Pharvaris, a late-stage clinical company focusing on treatments for hereditary angioedema (HAE).

Welcome, Wim.

Wim Souverijns, Chief Commercial Officer, Pharvaris:

Thanks, Tom, for having us.

Welcome, Stefan.

Stefan Abele, Chief Technical Operations Officer, Pharvaris:

Thanks. I'm glad to be here.

It’s my pleasure to have you both; thanks for joining. For those folks in the audience who may not be familiar with hereditary angioedema as a patient condition, can you tell us a little bit about what that is and who suffers from it? Who is in the patient population, and what is that condition like for those folks?

Souverijns: Hereditary angioedema, or HAE like we say, is a rare condition. It can be life-threatening for some patients. Because it's rare, it's something that is not very noticeable for everyone. It’s not a very known condition. There are about 1 in 30,000 to 1 in 80,000 patients from a prevalence perspective, globally. 1 in 30,000 is more in developed markets like the U.S. and western Europe. If you go to the 1 in 80,000, that is more in those developing markets and due to the diagnosis rates being lower in those countries. That means that there are about 7,000 patients in the U.S., about 15,000 in Europe, and, globally, there are probably around 100,000 patients.

Now what is hereditary angioedema? What is causing it? The cause of it is a mutation in a gene that produces an enzyme called a C1 inhibitor. When a C1 inhibitor is either absent or deficient, it causes a cascade of effects, which ultimately, in the case of a trigger, leads to an overproduction of bradykinin. Bradykinin is a protein that will connect to a receptor, and by doing that, induces an angioedema swelling attack.

What are the triggers for these kinds of attacks? They can be very different. They can be hormonal changes. They can be emotional stress, simple trauma, or even medical procedures. They're highly unpredictable and can happen in many different locations in the body. It can happen in the extremities, in the hands or feet. It can happen in the abdomen. Women will tell you that an abdominal attack from a pain perspective is worse than delivering a baby. It can even happen in the facial area. If it happens around the larynx, there's a risk of asphyxiation. That’s why it can be life-threatening if it's not treated. If it goes untreated, it takes about five days to go through the whole episode. It’s something that really knocks somebody out of their normal life.

There are two ways of managing this condition. You can either treat symptoms of an attack on an ongoing basis whenever they happen, which is called an on-demand treatment, or you can decide to prevent attacks from happening, which is a more recent therapeutic strategy.

For the patients that you've described, historically or currently, what would they have done to either treat an attack in the moment or try to prevent them? What options have been available?

Souverijns: The first therapies that were on the market or approved were on-demand therapies. The most commonly used on-demand product is Icatibant, which is a B2 receptor antagonist. All the on-demand therapies on the market are injectables, which means that they require either an intravenous or subcutaneous injection. Icatibant, for instance, is subcutaneous. You inject it into your belly, and it takes about 60 seconds to be injected.

In the last eight years, preventative therapies have come to market. The preventative therapies come in a subcutaneous form, and there is also one oral product on the market. In talking with the HAE community, whether it is the doctors, the people living with HAE, or their caregivers, we learned that there is a high desire for effective oral therapies in this market.

Tell us about that choice of route of administration. It might seem obvious that anybody who is currently being hooked up to an IV or injecting something would prefer something orally, but there must have been formulation challenges and thoughts around that decision to attempt to move in that direction. Tell us about the company's decision to try oral routes to deal with HAE.

Abele: I'm happy to do this. As we mentioned, there are two ways to address the therapeutic needs of people living with HAE, with the prophylaxis or the on-demand treatment. At Pharvaris, we are evaluating one drug substance to address both of these treatment strategies. Our investigational drug substance, Deucrictibant, has been formulated in two distinct ways to either treat an attack, which we call the on-demand, or to prevent attacks from occurring, which we call the prophylactic treatment.

For the on-demand treatment, a liquid formulation of Deucrictibant is embedded in a capsule which dissolves rapidly in the stomach, enabling a rapid absorption of the drug substance. Upon administration of the immediate release capsule, Deucrictibant rapidly reaches therapeutic threshold within about 15 to 30 minutes, supporting its development for on-demand oral treatment. In our Phase 2 clinical studies, Deucrictibant showed an early onset of action for HAE attack symptom relief as well as resolution of symptoms with a single dose for the vast majority of attacks. We do hope to confirm these findings in our Phase 3 studies.

For the prophylactic treatment, Deucrictibant is formulated as an extended-release tablet. The drug substance is embedded in an acid-stable polymer matrix; it passes the stomach and disintegrates in the gut resulting in a colonic absorption of the drug substance. Thus, Deucrictibant maintains a sustained therapeutic exposure over 24 hours, allowing for once-daily oral administration to prevent HAE attacks. In our ongoing Phase 3 study, we will be evaluating this once-daily Deucrictibant extended-release tablet for the prophylaxis of HAE attacks. We hope to confirm our proof-of-concept data from our Phase 2 study, which showed that Deucrictibant significantly reduced the monthly HAE attack rate.

If the advancements and offerings that you're bringing to market have the effect that we hope and believe they will, how do you envision that the lives and the health of patients currently suffering from HAE would change?

Abele: We have designed both our extended-release tablet and the immediate-release capsule to be easy to swallow and discreet. The goal of this is to help minimize the burden of integrating the treatment of Deucrictibant into a person's life.

Souverijns: To our knowledge, Pharvaris is the only company that is developing two distinct oral products that can be used for prevention and treatment using the same active ingredients. Why is that important? People living with HAE are not all the same. People have different desires, different needs, and different lifestyles. One patient might decide to just treat attack symptoms when they happen. They might have few attacks, or they might not care about it too much, and opt to treat it with on-demand. Other patients, though, really want to get those attacks out of their life. They want to have a normal life. What they will do is treatment for prevention. A third person might decide over the course of their life to switch back and forth between the two treatment strategies. Our opportunity here with Deucrictibant is to have a therapy that has the potential to offer both options to that patient community.

That all sounds very promising in terms of the options and the lifestyle changes that those can potentially provide. Beyond the HAE patient population, are there other therapeutic areas to which the formulations and delivery mechanisms that you're working on could apply?

Souverijns: Absolutely. Because Deucrictibant works on the spot where the swelling attack is initiated, the moment that bradykinin connects to the receptor, it has the potential to address any type of bradykinin-mediated angioedema, which is an angioedema swelling attack driven by an overproduction of bradykinin. When we talk about type 1 or type 2 HAE, that's driven by a mutation in the C1 inhibitor gene that creates a cascade of effects and, ultimately, an overproduction of bradykinin.

However, there are speculation and hypotheses that bradykinin is not just produced through that pathway, known as the kallikrein pathway. There might be other sources of bradykinin production. Now, if you have therapies that will work on that upper part of the pathway, replacing the C1 inhibitor or working on some of the intermediate enzymes, you might not be able to deal with bradykinin attacks when bradykinin is produced from different locations. That's why we are very excited about this opportunity to look into other bradykinin-mediated angioedema that we could treat with Deucrictibant. It will require further investigational research to confirm that, but it's a very exciting avenue for us.

Wim and Stefan, I'd like to thank you both for joining me to provide some detail into what you're working on to address HAE with oral delivery. I want to thank our audience for joining us for another episode of Sit and Deliver, and we'll see you next time.