DO NOT USE - Transcript: Treatments to streamline CSU

Declaration of sponsorship Novartis Pharma AG

Last updated:24th Oct 2024

Published:24th Oct 2024

Professor Ana Maria Giménez-Arnau

All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.

Thank you so much, Martin. We will wait the answer for this question because really we will address now from new drugs and old drugs then, okay. Currently everyone, almost everyone said potential to improve symptoms, control, and quality of life, 88.3%. All of us, we agree on this, Martin and Simon? Yeah, all of us, we agree. Then let's proceed with this talk, which will be focused on treatments mainly when the anti-H1 fails, no? And the first thing that we should consider is that obviously our goal on the treatment or challenge is to obtain, as fast as possible, no symptoms. That means no itch, no angioedema, no hives, but also we should consider that our patients suffering CSU or inducible urticaria also suffer other things that we can say are systemic or different from these three very basic things that you want to obtain. Such are, as it was mentioned, the sleeping problems, or the painful sensation that people suffer, or fatigue, or the reduce of concentration due to the proper disease or the treatments that we use sometimes. The flushing, which is not hives, flushing is a different sensation. Headaches, gastrointestinal symptoms, and I will add even arthritis or arthritis that sometimes even are misdiagnosed with rheumatoid diseases. Then such patients suffer a systemic disease that mainly is expressed in the skin.

And the skin, the main lesion is the hive. The angioedema is present around 40% of our patients, but mainly is the hive. And the hive has a complex pathophysiology and based on the knowledge that we have and after 2014 that we had omalizumab in the market, then this disease, the pathogenesis of the hive became in the middle of the translational medicine because as you know the mast cell is a pluripotential mast cell, autocrine and exocrine who express, Marcus said this morning, more than 80 receptors and some of them are functional and the high affinity IgE receptor is probably the most common functional but isn't the only one, no, the mast-relating G protein X2 is there, the siglec-8 is there, IL-4 is there, and also those receptors are expressed because they are in an intracellular activation of certain transcriptional factors with Syk, and especially Bruton's tyrosine kinase is involved. But Bruton's tyrosine kinase is not just involved in mast cell, it's also involved in vessels and is pluripotential and yeah, after the activation of the muscle and the degranulation of certain mediators, mainly histamine, both path and other ones, then there's a sudden chemoattraction of a lot of cells that mainly are lymphocytes, lots of eosinophils in certain patients, lots of neutrophils, and somehow we can detect basophils. And such cells induce the wheal to expand and disappear in hours, appearing in other parts of the site.

And we have many, many options nowadays to go to the different potential triggers or targets in this path complex, physio-pathogenic. But I will remind you what was OMA. 10 years after its registration for the first time at the EMA and the second time in the FDA, OMA was based in their development just in three trials. The ASTERIA I and the ASTERIA II, people were included when they were refractory to labelled anti-H1, labelled anti-H1. And in the GLACIAL when they were refractory to labelled anti-H1, up-dosing anti-H1, and leukotriene. And here you see how there is a modification on the urticaria activity score after three shots of omalizumab. That means after 12 weeks. And when I will introduce the new treatment, we will focus in the same parameters. How does it benefit in the urticaria activity score 7 after 12 weeks? But you as urticariologists or GPs or dermatologists or allergologists, you know that we will need to treat our patients with CSU or inducible, maybe three years with a safe treatment. And as you can see here, 300 milligrammes and 150 milligrammes were significantly better than placebo, extremely better than placebo reducing the urticaria activity score seven. For the GLACIAL we used the 300 milligrammes that was the unique dose that we use in Europe. Then the first question is for you. How, in your knowledge, okay? How many emerging treatments are currently in clinical development for CSU? Could you answer this, please? One to five, five to 10. This is very good because initially I had a slide with at least 10 and now I have a slide with at least five because there were in the intermediate period some potential good treatments that really stopped its development, for example a new anti-IgE that was ligelizumab or for example an anti-IL-5 as was benralizumab. And the fact that what we have now, we have mostly these four things.

We can target these Bruton's tyrosine kinase in a way which is selective, covalent, or reversible or irreversible depending on the drug. We can target mostly mainly the Th2 pattern through dupilumab, or we can target even more than this, until the Th2 and the Th17 pattern going to the thymocitic stromal lymphopoietin, inhibiting it or we can remove the mast cells from the wheal. Then what do we have now? Then we will have lots of information from these drugs during the next years. But just focus in one image for each one and focusing in the urticaria activity score seven, no itch, no hives, no other things, and after just 12 or 24 weeks because it's what we have from this data now. And here you have the data from the phase 3 on remibrutinib. You know there are two parallel studies, REMIX-1 and REMIX-2. They are studied by separate. Those studies include around 600 patients and 400 controls and they show, both in parallel, how effective and fast is this oral drug which is selective and irreversible and covalent, showing a decrease in urticaria activity score 7 compared to placebo. But also you know that there is another anti-BTK that really is showing during this congress the result from the phase 2b. This is covalent, it's reversible, and it's selective, rilzabrutinib, and you can see that there is a benefit after 12 weeks also using this oral drug in the ITT population, that means include patients with even non-responders to omalizumab and the unique doses in this phase 2b which is helpful is 1,200 milligrammes per day in this oral form.

Then two anti-BTKs and one anti-IL-4 and IL-13, dupilumab. You know very well what's dupilumab, how many indications that are already approved, and we are looking for the indication which is already accepted in Japan for CSU. The only thing that has been done, the trials, the CUPID-1 and CUPID B and CUPID C include a few number of patients that means. But it seems that patients that are naive to omalizumab after in this case also they show a good benefit at 24 weeks, reducing the urticaria activity score seven which is significant. Remind, the urticaria activity score seven is the score that is accepted by the EMA, that itch score is what is accepted by the FDA. Then the itch score in the patients, in the patients who were previously refractory to omalizumab, who obtain a potential significant difference compared to placebo, using the urticaria activity score seven but not with the itch. And this is the different thing and the approach to the different national agencies in Europe has been submitted recently after in a position when omalizumab fails and we'll see what happened. For me, which is also very interesting is this graph, and maybe Martin we can comment after because we were involved also in the tezepelumab studies, but this slide was presented, I discovered it in San Diego during the American Academy of Dermatology because Marcus presented it and it was presented in the American Society of Allergy.

Then you can see the comparison of 220, 420 milligrammes of tezepelumab with omalizumab, which is the yellow line. And you can see at 16 weeks, omalizumab is much better than tezepelumab obviously and there is no significant difference between the two doses of tezepelumab compared to placebo. But when they stopped the drug, the patient stopped the drug at the 16 weeks, look the line of omalizumab, people relapse. But the people that were treated with tezepelumab, they maintained the disease control even they stopped the drug. Let's see how we will manage with this in the future, it will be very interesting to me to follow this. And finally this congress seems to be the new targeting way for CSU, removing by apoptosis mainly, the mast cell which is increased in number in the patients who suffer inducible urticaria and CSU in the skin. Then obviously the anti-KIT which is much more developed, in the development is barzolvolimab. As it was explained before, it doesn't help the stem cell factor to bind to the KIT. And in this case initially was safe, it was studied in intravenous form, afterwards developed how this subcutaneous form showed a good pharmacokinetic in the patients and now the phase 2 was addressed in a subcutaneous way. And is in CSU and inducible urticaria, they are developing and they will go for sure to the phase 3. And in this case here you have how the doses of 300 milligrammes, 150 milligrammes, and even 75 milligrammes. All of them are really superior than the placebo. Significantly superior in the placebo reducing the UAS7. And in this case, which is very, very interesting is to see in the things that are presented, how many patients obtained urticaria activity score 7, very fast zero after 12 weeks.

Compared to placebo, it reminds me a lot of omalizumab. Then we have now the different ways to approach to our patients with CSU and hopefully, Martin and Simon, to inducible urticaria. Probably they are not the only ones because the BTK inhibitors, they will one, go very fast we hope it, there are the different interleukin inhibitors, IL-5, forget it, let's go to the Th2 pattern. The TSLP, let's see what will happen, what they will decide, and the KIT inhibitors will go ahead for sure. Then we are here. We need to obtain a fast diagnosis, correct diagnosis, and we can address the public how many times they failed and they were treated CSU and afterwards on urticaria vasculitis or how many times you ask yourself in your own clinic if you even you see 30 patients per day with urticaria or urticaria rashes, you should identify always, which is the elemental agents and it's not an eczema. Also understanding the condition and the initiation of the treatment. We need to go fast, okay? Avoid the delay, go to the correct diagnosis, avoid in-useful complementary tests, and put your patient as fast as possible in the correct treatment. That will be long, not 12 weeks, maybe one year and a half or two years should be effective immediately because the people should live and after all should be safe.

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