Exploring EVO756 in Chronic Inflammatory Disease Treatment: Q&A with Evommune's Mark Jackson, MD

Evommune, Inc. recently unveiled compelling results from its first-in-human proof-of-concept study for EVO756, shared during the 7th GA²LEN Global Urticaria Forum in Berlin.¹

This investigational oral MRGPRX2 antagonist demonstrated a strong safety profile, notable efficacy, and pharmacokinetics conducive to once-daily dosing in a trial involving 132 participants. These findings highlight EVO756’s potential as a groundbreaking treatment for a variety of chronic inflammatory diseases, including multiple forms of urticaria. Building on these promising results, Evommune is advancing to phase 2 trials.

Dermatology Times recently connected with Evommune’s scientific team to discuss the study outcomes, the implications for patients with mast cell-mediated diseases, and the potential for EVO756 to reshape treatment approaches in this space. Mark Jackson, MD, vice president of clinical development at Evommune, shares more.

Mark Jackson, MD | Image Credit: © Evommune

Q&A

Q: Can you provide an overview of the mechanism of action of EVO756 and describe its role as an MRGPRX2 antagonist?

A: MRGPRX2 is a novel target loaded on mast cells. It's a receptor mast cell, and our therapeutic option targets that to act on both the mast cell and the sensory neuron, where there is also receptor activity. We feel like if we can work to block that, then we can block what is induced by mast cells as the symptoms that occur. Sensory neuron activation problems are really highly problematic in patients with chronic, spontaneous urticaria and other autoimmune inflammatory diseases.

Chronic inflammation destroys lives, and we really are trying to create solutions of that at Evommune. The World Health Organization ranks this as the greatest threat to human health, with people dying due to chronic inflammatory diseases, and we want to be able to create solutions for those.

Q: In the proof-of-concept trial for EVO756, what were some of the key safety and tolerability findings, and what are their significance?

A: We're trying to create solutions for people with chronic inflammatory diseases, and we also want to make sure that they're safe and well-tolerated. One of the first things you do when doing clinical research is you study it in healthy volunteers to make sure it is okay. We studied MRGPRX2 in a number of health volunteers who had no other underlying conditions to make sure it was safe and well-tolerated, and in our 2-week study in these patients, we demonstrated it was safe and well-tolerated. There were no adverse events that led to discontinuation, no lab abnormalities that gave us any worries or issues, and no intolerability that gave us worries. This is what we predicted based on our pre-clinical modeling, but it bore out in our studies in healthy volunteers, and we were very encouraged by the results we saw.

Q: How might those results suggest benefits for patients with conditions like chronic spontaneous urticaria or chronic inducible urticaria?

A: One of the things we added in this study was a novel opportunity to evaluate if we hit the target that we were trying to hit, and we utilized an agent called icatibant, and icatibant is known to induce mast cell degranulation, and we've proven that that works through the X2 receptor. If we can block icatibant's activity on the X2 receptor, we can prevent mast cell degradation. Icatibant is commercially available to treat patients with other inflammatory diseases, and we could utilize it in our patients to create wheals on their on their forearms. We administered this test in advance of any dosing, and then after 2 weeks of dosing, what we saw was that we reduced wheal size in these patients. It showed we were able to inhibit icatibant's activity on the X2 receptor to prevent mast cell degranulation. We felt like this was very encouraging, and it demonstrated meaningful target engagement on what we were actually going for. We feel like this translates nicely as a model to treat patients with chronic, spontaneous urticaria.

Q: Could you provide more details on the phase 2 trials that are currently underway or planned for this drug target?

A: As a dermatologist who treats patients with chronic spontaneous urticaria all the time, and only having one FDA-approved option, and it has to be administered as a subcutaneous, in-office agent, what we really want to be able to do is bring this safe, once- or twice- daily small molecule into the clinic where we can utilize it as a first-line option for chronic spontaneous urticaria and other inflammatory diseases. Our first studies will be in spontaneous urticaria and what we call chronic inducible urticaria. What we'll do is we'll study a patient population who has these who has not been adequately treated by standard of care, which is over-the-counter antihistamines. We'll study a patient population with varying doses of our MRGPRX2 inhibitor to see how those different doses impact patients with this very bothersome disease.

Q: What is Evommune's vision for EVO756 and its role beyond urticaria?

A: We're working on novel therapies to halt and treat the progression of chronic inflammatory diseases, and chronic spontaneous urticaria, also called chronic idiopathic urticaria, is just one of those. We feel like it has translatability to other inflammatory diseases such as asthma, chronic cough, and irritable bowel. One of the beauties of the skin is it serves as a map to really see what's going on in the rest of the body. My forte as a dermatologist is to really be able to read the skin and see what else is going on. That being said, the skin also serves as a great way to evaluate how a medicine is going to work on other inflammatory diseases, and that's one of the ways chronic spontaneous urticaria is a good first-line option in evaluating this, but we feel like it translates to other diseases and many others, as well.

Mast cell biology is evolving. We've really never been able to study the mast cell, and we feel like we're at the forefront of mast cell biology. We're excited to be able to bring these new options.

Q: What excites you most about the potential impact of this drug on patients' lives?

A: If you've ever had itch or severe itch or urticaria, you know how bad this disease can be. As someone who treats patients with chronic spontaneous urticaria, they describe their itch on a scale of 0 to 10 as 15. We know that it's a very bothersome condition, and if you can go every day not having an option to treat it, you can imagine the misery that some of these patients are in, and this creates a great option for those patients, being a safe option that for them to take orally and being a first-line option for for patients with this bothers condition. We're bringing solutions to these patients who currently don't have any solutions.

Q: What else would you like dermatology clinicians to know or consider?

A: The skin is the largest organ in the body, and just because we can't see something on it doesn't mean it's not significant: inflammation, chronic inflammation. We at Evommune really want to create solutions for all of those inflammatory-mediated diseases where patients are currently underserved, and it's a fun time to be involved in inflammation and immunology because there's there are a lot of exciting targets. We want to bring solutions to our patients. I need them in my clinic, and so do many other people.

We're entering our phase 2 programs, and our program is currently underway with chronic inducible urticaria, where patients who have urticaria that can be induced by pressure or cold develop welts that are extremely itchy and bothersome. We should have that information the first half of 2025. We're also initiating our phase 2b trial. It's a dose-ranging trial in chronic spontaneous urticaria, in the first half of 2025, and we look forward to bringing that opportunity to patients who have spontaneous urticaria in the future.

Reference

1. Evommune presents positive clinical results of its MRGPRX2 antagonist (EVO756) at the 7th GA²LEN Global Urticaria Forum. News release. PR Newswire. December 4, 2024. Accessed December 16, 2024. https://www.prnewswire.com/news-releases/evommune-presents-positive-clinical-results-of-its-mrgprx2-antagonist-evo756-at-the-7th-galen-global-urticaria-forum-302322332.html