InflaRx NV (IFRX) 2023 Q4 法說會逐字稿

Good morning, everyone. Thank you for standing by and thank you for joining InflaRx's conference call to discuss the company's expected development plans for INF904, our orally available C5aR inhibitor with best-in-class potential. Presenting on today's call, we have Niels Riedemann, CEO and Founder; and Camilla Chong, Chief Medical Officer; with Renfeng Guo as CSO and founder; and Thomas Taapken, CFO available during the Q&A session.

大家，早安。感謝您的耐心等待，並感謝您參加 InflaRx 的電話會議，討論公司對 INF904 的預期開發計劃，INF904 是我們具有一流潛力的口服 C5aR 抑製劑。在今天的電話會議上，我們有執行長兼創辦人 Niels Riedemann；和首席醫療官 Camilla Chong；郭仁峰擔任 CSO 和創始人；財務長 Thomas Taapken 出席問答環節。

During today's presentation, all participants will be in a listen only mode. Please note that today's call is being recorded. The presentation will be followed by a Q&A session where you may ask written or audio questions and please note that you can ask questions only online. I would now like to turn the call over to Dr. Niels Riedemann, CEO and Founder of InflaRx. Niels, please go ahead.

在今天的演示中，所有參與者都將處於只聽模式。請注意，今天的通話正在錄音。演示結束後將進行問答環節，您可以提出書面或音訊問題，請注意，您只能在線上提問。我現在想將電話轉給 InflaRx 執行長兼創辦人 Niels Riedemann 博士。尼爾斯，請繼續。

Yes. Thank you so much, Jan. We're really excited to have everyone on the call today to share with you our development plans and I will dive right back in into our topic. But before I do that, I think next slide would be just the cautionary note on the forward-looking statements we're going to make today. So please take note of them. Next slide, please.

是的。非常感謝，Jan。 我們非常高興今天能與大家一起參加電話會議，與大家分享我們的開發計劃，我將立即回到我們的主題。但在此之前，我認為下一張投影片只是對我們今天將要發表的前瞻性聲明的警告。所以請注意它們。請下一張投影片。

So we are really about harnessing C5a and C5aR that part of the complement pathway for controlling inflammation in the I&I space. And we have, as highlights, really uniquely targeting mechanism and drug candidates. And these are validated mechanisms in the meantime, and there are a critical part of the inflammation cascade.

因此，我們真正致力於利用 C5a 和 C5aR 這部分補體途徑來控制 I&I 領域的發炎。作為亮點，我們擁有真正獨特的標靶機制和候選藥物。同時，這些都是經過驗證的機制，也是發炎級聯反應的關鍵部分。

We have a first-in-class, highly potent anti-C5a monoclonal antibody, known as Vilobelimab, plus a second-generation IFX-2 in the pipeline as a lifecycle molecule. And we have a best-in-class potential oral C5aR inhibitor, INF904. And that inhibitor is exciting the team a lot because first of all, we are trying to address certain limitations of the marketed comparator. And we are at least from our Phase 1 data, clearly differentiated, especially on the plasma PK and inhibitory potential.

我們擁有一流的高效抗 C5a 單株抗體（稱為 Vilobelimab），以及正在研發中的第二代 IFX-2 作為生命週期分子。我們擁有同類最佳的潛在口服 C5aR 抑制劑 INF904。這種抑制劑讓團隊非常興奮，因為首先，我們正在努力解決市售比較器的某些限制。至少從我們的 1 期數據來看，我們有明顯的差異，特別是在血漿 PK 和抑制潛力方面。

But we also are excited because this is a pipeline in a drug potential here in this candidate and that can address some larger markets likely and also markets in the immune derm space, which we'll be talking today, but also outside. So we have set an initial focus here on immunohematology, and we believe that we can drive pipeline value in these markets.

但我們也很興奮，因為這是該候選藥物潛力的管道，可以解決一些可能更大的市場以及免疫皮膚領域的市場，我們今天將討論這一點，但也包括外部市場。因此，我們最初將重點放在免疫血液學上，我們相信我們可以推動這些市場的管道價值。

In immunoderm are we have a strong IP coverage and medical use coverage. And we have both vilobelimab with a late-stage development Phase 3 ongoing in pyoderma gangrenosum, and I know for that, we'll enter Phase 2 in two initial indications, the chronic spontaneous urticaria and hidradenitis suppurativa. I just want to make sure to mention that we feel very lucky that we are supported by world-class scientists and researchers and clinicians, key opinion leaders in this space. We have a large upside potential in additional indications, and we are open and exploring potential collaborations to unlock additional value here.

在immunoderm 中，我們擁有強大的智慧財產權覆蓋範圍和醫療用途覆蓋範圍。我們的 vilobelimab 正在針對壞疽性膿皮症進行後期開發第 3 期，我知道，我們將在兩個初始適應症（慢性自發性蕁麻疹和化膿性汗腺炎）中進入第 2 期。我只是想確保提到，我們感到非常幸運，我們得到了世界一流的科學家、研究人員和臨床醫生以及該領域關鍵意見領袖的支持。我們在其他適應症方面擁有巨大的上升潛力，我們持開放態度並探索潛在的合作，以釋放額外的價值。

We have a strong balance sheet that we just reported today, and that takes us at least into 2026 to advance our programs towards the next milestones. And our team has a proven track record in delivering clinical trials and also regulatory success with the emergency use authorization we've received last year. Next slide, please.

今天剛報告的我們擁有強大的資產負債表，這至少需要我們到 2026 年才能推進我們的計劃，邁向下一個里程碑。我們的團隊在提供臨床試驗方面擁有良好的記錄，並且在監管方面取得了成功，我們去年獲得了緊急使用授權。請下一張投影片。

So why immunoderm? Well, first of all, there are several attractive multi-billion dollar commercial opportunity markets to be explored. And then also, we have identified crucial unmet medical needs that we believe INF904 may address strongly. There's a sound scientific rationale, and also in the meantime, some clinical data on the role of C5a, C5aR, and this new mechanism in this space, they're established endpoints that are established for approval. And there's no known safety concerns and a broad potential therapeutic index for INF904.

那為什麼選擇免疫皮膚呢？首先，有幾個有吸引力的數十億美元的商業機會市場有待探索。此外，我們也發現了未滿足的關鍵醫療需求，我們相信 INF904 可以有力地解決這些需求。有一個合理的科學原理，同時，還有一些關於 C5a、C5aR 的作用的臨床數據，以及這個領域的這種新機制，它們是已建立的終點，可供批准。INF904 沒有已知的安全性問題和廣泛的潛在治療指數。

So on this oral C5aR antagonist has a differentiated pathway. It addresses the mechanism of action that is currently not addressed by any competitor in the immunoderm space, and we're very excited about moving that in there. We have an established network of experts and also in-house trial expertise in this area and the -- I mentioned already, the strong IP coverage.

所以對這種口服C5aR拮抗劑有一個分化的途徑。它解決了目前免疫皮膚領域任何競爭對手都沒有解決的作用機制，我們非常高興能將其轉移到那裡。我們在該領域擁有成熟的專家網絡和內部試驗專業知識，以及我已經提到的強大的知識產權覆蓋範圍。

Next slide, please. So this just depicts our initial focus in immunoderm, and we will be talking about these two indications, chronic spontaneous urticaria and hidradenitis suppurativa today and there are others that we may explore in the future.

請下一張投影片。所以這只是描述了我們最初關注的免疫皮膚病，我們今天將討論這兩種適應症，慢性自發性蕁麻疹和化膿性汗腺炎，以及我們將來可能探索的其他適應症。

Now we also list here a few selected indications in neurology and in the nephrology/hematology space, and that is to demonstrate that we've done quite a bit of work in many other disease indications. These are some where we are very excited about the opportunity either from our research also from initial clinical data for example, the competitor drug avacopan that has shown initial efficacy in some of the nephrology indications here listed, and of course, here gotten approval in ANCA-associated vasculitis. Next slide, please.

現在我們在這裡還列出了神經病學和腎臟病學/血液病學領域的一些選定適應症，這是為了證明我們在許多其他疾病適應症方面已經做了相當多的工作。我們對這些機會感到非常興奮，無論是我們的研究還是初始臨床數據，例如，競爭對手藥物 avacopan 已在此處列出的一些腎病適應症中顯示出初步療效，當然，這裡已獲得 ANCA 的批准相關血管炎。請下一張投影片。

So this brings us on to the pipeline here. This is basically showing our focus that I've just explained. So I don't want to reiterate that. I just want to make sure to reflect the strong focus on immunoderm and the potential outside. I do want to mention that vilobelimab does have an Emergency Use Authorization for certain critically ill COVID-19 patients and a potential to go to broader areas. And we would cover that at the end of the talk briefly.

這讓我們進入了這裡的管道。這基本上表明了我剛才解釋的我們的重點。所以我不想重申這一點。我只是想確保反映出對immunoderm 的強烈關注以及外部的潛力。我確實想提一下，維洛貝利單抗確實擁有針對某些重症 COVID-19 患者的緊急使用授權，並且有可能進入更廣泛的地區。我們將在演講結束時簡要介紹這一點。

Next slide. Okay. So let's talk about the strategic positioning and let's talk about the target just for a minute before we dive into the indications. Next slide, please.

下一張投影片。好的。因此，在我們深入探討跡象之前，讓我們先談談策略定位和目標。請下一張投影片。

So we are uniquely positioned here. We have two validated drug targets covered by two very exciting molecule, C5a, the ligand, covered by vilobelimab and the receptor covered by INF904, our new small oral inhibitor. Now it's important to note that if you want to have control over this path, you need targeted inhibition. Why is that? Because upstream blockers, like at the level of C5 or higher in the complement system, they lack the ability to block the cleavage that occurs through multiple enzymes.

所以我們在這裡處於獨特的地位。我們有兩個經過驗證的藥物標靶，由兩個非常令人興奮的分子覆蓋，C5a（配體，由 vilobelimab 覆蓋）和受體由 INF904（我們的新型小型口服抑制劑）覆蓋。現在要注意的是，如果你想控制這條路徑，你需要有針對性的抑制。這是為什麼？因為上游阻斷劑，例如補體系統中 C5 或更高水平的阻斷劑，它們缺乏阻斷透過多種酵素發生的裂解的能力。

So in other words, while they're very sufficient in blocking the complement mediated cleavage, there's another mechanism that is not touched by them. So there's no evidence that these drugs can block C5a in humans in disease in a sufficient manner. So we need targeted drugs. We have two. We are very excited about them. Why? Because C5a is upstream of the cytokine network, it actually boosts a lot of unknown cytokine. Some of them are listed here. It's a strong activator of neutrophils, macrophages, and other immune cells.

換句話說，雖然它們足以阻止補體介導的切割，但還有另一種機制未被它們觸及。因此，沒有證據表明這些藥物可以在人類疾病中充分阻斷 C5a。所以我們需要標靶藥物。我們有兩個。我們對他們感到非常興奮。為什麼？因為C5a位於細胞激素網絡的上游，所以它實際上增強了許多未知的細胞激素。這裡列出了其中一些。它是中性粒細胞、巨噬細胞和其他免疫細胞的強激活劑。

And what does it mean? It means that it attracts neutrophils, chemotaxis, and it just makes them generate oxidative radicals and granular enzymes that is the tissue damaging effect you will see in many of the diseases and there's an increasing knowledge around the role of CFA inducing NETosis. And I'm going to be speaking about that a bit later because NETosis is increasingly of interest in the immunoderm space.

這意味著什麼？這意味著它會吸引中性粒細胞，產生趨化性，並且只會使它們產生氧化自由基和顆粒酶，這是您在許多疾病中會看到的組織損傷效應，並且人們對CFA 誘導NETosis的作用的了解越來越多。我稍後會討論這個問題，因為免疫皮膚領域對 NETosis 的興趣越來越濃厚。

Now, there's over 6,000 publications in many different disease settings. And we are very excited, but we've chosen initial immunoderm indications and we will be showcasing them a bit today.

現在，已有 6,000 多篇針對多種不同疾病的出版品。我們非常興奮，但我們已經選擇了最初的免疫皮膚適應症，今天我們將對其進行一些展示。

Next slide. So I want to start with our running Phase 3 in ulcerative pyoderma gangrenosum with vilobelimab, our first-in-class monoclonal antibody covering the ligand. Next slide. Principally, just as a very brief recapitalization here, it's a highly selective, C5a blocker. It blocks it very effectively up to 100% in human blood. It doesn't touch the MAC formation, so it leaves the defense mechanism that is known and important in the complement space intact. So fast binder is commercially available under the EUA that I mentioned, so it's uniquely positioned to be a fast and strong binder of the ligand.

下一張投影片。因此，我想從我們使用 vilobelimab 治療潰瘍性壞疽性膿皮病的第三階段開始，這是我們一流的覆蓋配體的單株抗體。下一張投影片。原則上，正如這裡非常簡短的資本重組一樣，它是一種高度選擇性的 C5a 阻斷劑。它在人體血液中可以非常有效地阻斷它，高達 100%。它不觸及 MAC 形態，因此它完整地保留了補體空間中已知且重要的防禦機制。因此，快速結合劑可以根據我提到的 EUA 進行商業化購買，因此它具有獨特的定位，可以成為快速且強大的配體結合劑。

Next slide. So pyoderma gangrenosum is a terrible disease. There is no drug approved in the US or in Europe. It's a neutrophilic skin disease that manifests with large, sometimes very large debilitating ulcers. Patients suffer from these ulcers dramatically as they are very painful. They can occur on all body parts, but typically start on the lower legs.

下一張投影片。所以壞疽性膿皮症是一種可怕的疾病。目前還沒有藥物在美國或歐洲獲得批准。這是一種中性粒細胞性皮膚病，表現為大的、有時非常大的虛弱性潰瘍。由於這些潰瘍非常痛苦，患者會遭受嚴重的痛苦。它們可以發生在身體的所有部位，但通常始於小腿。

And it's a rare disease. We're estimating about 50,000 patients in the US and in Europe altogether. But there's a significant market potential because premium pricing is possible. We have orphan drug status in the US and in Europe, and there's nothing else approved and there's not even a consensus guideline yet in most countries, how to even address this disease. So typically, these patients are treated with all sorts of anti-inflammatory agents, sometimes even cocktails until either something works, or they are deferred to another physician.

而且這是一種罕見的疾病。我們估計美國和歐洲總共約有 5 萬名患者。但由於溢價是可能的，所以市場潛力巨大。我們在美國和歐洲擁有孤兒藥地位，沒有其他藥物獲得批准，大多數國家甚至還沒有關於如何解決這種疾病的共識指引。因此，通常情況下，這些患者會接受各種抗發炎藥物的治療，有時甚至是雞尾酒療法，直到某種藥物有效為止，或將他們轉交給另一位醫生。

Next slide, please. So I just want to share with you some of the new research that has an increasing body of evidence why neutrophils and also NETosis, which I mentioned before, plays a role. And I want to draw your attention first to the picture on the lower right side. So this was C5a measurements here from a research group in a wound fluid, and you see that the PG wound fluid showed a higher C5a load clearly. And also, you see that these wounds were containing elastase, a marker for NETosis.

請下一張投影片。所以我只想與大家分享一些新的研究，這些研究有越來越多的證據證明中性粒細胞和我之前提到的 NETosis 發揮了作用。我想先請您注意右下角的圖片。這是一個研究小組對傷口液中 C5a 的測量結果，您可以看到 PG 傷口液明顯顯示出更高的 C5a 負荷。而且，你會看到這些傷口含有彈性蛋白酶，這是 NETosis 的標記物。

And finally, these parameters correlated so the higher the C5a, the higher the elastase levels. That's not necessarily surprising knowing that there's a lot of research showing that C5a uses NETosis and the same paper concluded that in the slide above that controlled neutrophils do not undergo a significant NETosis, but if they are stimulated with C5a here in nanomolars that are found in humans, you see that this is a staining marker here for extracellular staining and C5a by far is the strongest inducer of this NETosis marker. One can even say they couldn't really find another one, maybe IL-8 after a long period of stimulation. You see that on the right side, gave a bit of a signal. So there's an increasing body of evidence on that mechanism.

最後，這些參數相互關聯，因此 C5a 越高，彈性蛋白酶水平就越高。這不一定令人驚訝，因為有許多研究表明C5a 使用NETosis，同一篇論文得出的結論是，在上面的幻燈片中，受控的中性粒細胞不會經歷顯著的NETosis，但如果它們受到C5a 的納摩爾刺激，對於人類，您會發現這是細胞外染色的染色標記，而 C5a 迄今為止是該 NETosis 標記的最強誘導劑。甚至可以說，經過長時間的刺激，他們真的找不到另一種，也許是IL-8。你看，在右側，給了一些訊號。因此，關於該機制的證據越來越多。

Next slide, please. So we had a very interesting Phase 2 with a strong result on the benefits for the patient. So in our high-dose group, we had 86% of the patients going into clinical remission. So these patients all ultimately close their target also. And you'll see the overall results showed also in over 50% that is across all three dose groups.

請下一張投影片。因此，我們進行了非常有趣的第二階段，在為患者帶來的益處方面取得了很好的結果。因此，在我們的高劑量組中，86% 的患者進入臨床緩解。所以這些患者最終也都接近了他們的目標。您會看到所有三個劑量組的整體結果也超過 50%。

And then the remarkable other thing is that all of the patients that were evaluable, 17 altogether, had an improvement. Not everyone at clinical remission, but over 50%. One additional patient response, and then others seven, other eight, slight improvement. So we didn't have any safety signals of larger concern. We had two reported SAEs; you find them here below. One is a typical problem that these patients have, wound infections and the other one was a rash likely due to the drug as a hypersensitivity reaction on.

另一件值得注意的事情是，所有可評估的患者（總共 17 名）都有改善。並非每個人都達到臨床緩解，但超過 50%。又有一名患者有反應，然後其他七名患者有反應，另外八名患者也有輕微改善。所以我們沒有任何更值得關注的安全訊號。我們報告了兩起嚴重不良事件；你可以在下面找到它們。一個是這些患者的典型問題，傷口感染，另一個是皮疹，可能是由於藥物過敏反應。

So we -- I mentioned the orphan drug status in the EU and the US and we also have Fast Track. We did discuss our Phase 3 trial with the FDA, and that brings me to some of the results on the next slide, please. Why did we get so excited? Now, when you see these patients and when you work with these patients, you get excited when you can help them because they're really suffering a lot. And these are just two examples.

所以我們——我提到了歐盟和美國的孤兒藥地位，我們也有快速通道。我們確實與 FDA 討論了我們的 3 期試驗，這讓我看到了下一張投影片上的一些結果。為什麼我們如此興奮？現在，當你看到這些患者並與這些患者一起工作時，當你能夠幫助他們時，你會感到很興奮，因為他們真的承受了很多痛苦。這只是兩個例子。

The left side is one of my favorite examples because this is a patient that developed a PG ulcer under adalimumab treatment, under TNF-α inhibition. And that was the patient's medication for an underlying other disease, in this case, psoriasis. And this wound was difficult to treat. He was actually the fastest responder in the trial and healed that ulcer very rapidly.

左側是我最喜歡的例子之一，因為這是一位在阿達木單抗治療和 TNF-α 抑制下出現 PG 潰瘍的患者。這是患者治療其他潛在疾病（在本例中為牛皮癬）的藥物。而且這個傷口很難治療。他其實是試驗中反應最快的人，潰瘍很快就痊癒了。

And on the right side, you see a patient that had multiple treatment attempts with the bad ulcer on the right, lower leg or above the ankle. And this patient was up dose from the medium dose to the high-dose group, which then ultimately close the wound relatively rapidly when being up dose. And this is actually remarkable result because these wounds above the ankle are very difficult to heal.

在右側，您會看到一名患者因右側、小腿或腳踝上方的嚴重潰瘍而嘗試過多次治療。而該患者從中劑量組到高劑量組的劑量增加，最終在增加劑量時傷口相對較快閉合。這實際上是一個了不起的結果，因為腳踝以上的傷口很難癒合。

Next slide, please. So this brings me to the running Phase 3 trial in PG. This trial is currently recruiting. This trial is a placebo controlled trial with two arms, very simple. The arm, vilobelimab and the other one placebo, both on a low dose of prednisone, which is tapered off during an eight-week process. And then the patients have preset dates where we are checking for patient level stopping criteria. And when a patient hits the stopping criteria, meaning the patient doesn't show wound improvement, then the patient is transitioned out of the trial and considered a non-responder for the primary endpoint.

請下一張投影片。這讓我想到了 PG 中正在進行的第三階段試驗。該試驗目前正在招募中。這個試驗是雙臂安慰劑對照試驗，非常簡單。手臂、維洛貝利單抗和另一種安慰劑都服用低劑量的潑尼松，並在八週的過程中逐漸減量。然後患者有預設的日期，我們將在其中檢查患者層級的停止標準。當患者達到停止標準時，意味著患者沒有表現出傷口改善，則患者將退出試驗並被視為主要終點的無反應者。

This is the way we discussed the trial with the FDA. You see that we have an interim analysis after about 30 patients, 15 in each arm. And I wanted to be talking about that just a second here because I think it's important to understand that this is an important interim for us. It is unblinded for the IDMC, but blinded for the team and for the trial and it can lead to stopping of futility or to an adjustment of between a final total number of patients enrolled between 50 and 100.

這就是我們與 FDA 討論試驗的方式。您會看到，我們對大約 30 名患者（每組 15 名）進行了中期分析。我想在這裡談談這個，因為我認為重要的是要了解這對我們來說是一個重要的過渡時期。它對於 IDMC 來說是非盲的，但對於團隊和試驗來說是盲的，它可能會導致無效的停止或導致最終入組患者總數在 50 到 100 之間進行調整。

Now this is a meaningful size in PG arena. And obviously to have a p-value positive readout with the patients in the range of 50 to 100 patients, you need to have substantial difference between placebo and your drug. And so for us that interim analysis, if it does not stop for futility, it's certainly a positive sign. And of course, if it were to adjust only to the minimum enrollment, this installed further confidence in us.

現在這個尺寸在 PG 舞台上是一個有意義的尺寸。顯然，要在 50 至 100 名患者範圍內獲得 p 值正讀數，安慰劑和藥物之間需要有顯著差異。因此，對我們來說，中期分析如果不是徒勞而停止，那肯定是一個正面的訊號。當然，如果只調整到最低入學人數，這會進一步增強我們的信心。

However, it's important to note that we don't stop enrollment during this interim read, so at this stage where we know if and how the trial adapts, we are really -- may have reached the final enrollment, at least on the low end here. And so for us, this is an interesting read, and it's an important read, and this will occur as we just today, guided next year in 2025. Just to mention, the primary endpoint will be complete target ulcer closure, which we've seen with the drug in Phase 2.

然而，值得注意的是，我們在中期閱讀期間不會停止註冊，因此在我們知道試驗是否以及如何適應的這個階段，我們確實 - 可能已經達到了最終註冊，至少在低端這裡。因此，對我們來說，這是一本有趣的讀物，也是一本重要的讀物，這將在我們今天指導的明年 2025 年發生。順便提一下，主要終點將是完全目標潰瘍閉合，我們在第二階段的藥物中已經看到了這一點。

Next slide, please. So this brings me to our exciting C5aR inhibitor, our oral drug INF904, and I'll be introducing the drug briefly before we go into the indications.

請下一張投影片。因此，這讓我想到了我們令人興奮的 C5aR 抑制劑，即我們的口服藥物 INF904，在我們討論適應症之前，我將簡要介紹該藥物。

Next slide. So the key feature's really, I'm not going to read all of this, but we are really excited because we were able to reach a very differentiated PK/PD profile when compared to the reported data from avacopan. We had a 3-fold higher C-max, 10-fold higher plasma exposure and which is probably most significant, significantly increased blocking activity, which showed or above 90% blocking activity for comparable doses starting at 30 mgs.

下一張投影片。所以關鍵的特點是，我不會閱讀所有這些，但我們真的很興奮，因為與 avacopan 報告的數據相比，我們能夠獲得非常差異化的 PK/PD 配置文件。我們的C-max 高出3 倍，血漿暴露高出10 倍，這可能是最顯著的，顯著增加的阻斷活性，從30 mg 開始的相當劑量顯示出90% 或以上的阻斷活性。

And that was our goal, and this Phase 1 trial to really reached all of our goals. We didn't have any safety signals of concern. We were able to show there's over broad dose range. We also know that the drug has less inhibitory potential on the import liver enzyme, CYP3A4/5 when compared to the avacopan data. And we have strong IP position. So we'll be taking this to immunoderm because this is an oral drug, very differentiated mechanism of action and we believe that this can really bring a lot of benefit to patients that have a high unmet need.

這就是我們的目標，而這階段的試驗真正實現了我們的所有目標。我們沒有任何值得關注的安全訊號。我們能夠證明劑量範圍很廣。我們也知道，與 avacopan 數據相比，該藥物對輸入肝酵素 CYP3A4/5 的抑制潛力較小。我們擁有強大的知識產權地位。因此，我們將把它帶到immunoderm，因為這是一種口服藥物，作用機制非常獨特，我們相信這確實可以為需求未滿足的患者帶來許多好處。

Next slide. So this is important. I'm not going to go into the details of the experiment, but this is a head-to-head experiment preclinical in a life in vivo experiments in rodents see in hamsters. And what that shows is on the left side that, you know, at the exact same formulation, at the exact same dose in this model in the hamster, we doubled the inhibitory effect with INF904 compared to avacopan. So this doubling of the effect was really very encouraging, and we've seen pretty much almost a doubling of the inhibitory potential in the Phase 1 already. So we expect that this will translate to a potential of higher efficacy in human disease as well.

下一張投影片。所以這很重要。我不打算詳細介紹實驗的細節，但這是在倉鼠身上進行的囓齒動物體內實驗中的臨床前頭對頭實驗。左邊顯示的是，在倉鼠模型中，在完全相同的配方、完全相同的劑量下，與 avacopan 相比，我們使用 INF904 的抑制效果增加了一倍。因此，效果加倍確實非常令人鼓舞，我們已經看到第一階段的抑制潛力幾乎翻倍。因此，我們預計這也將轉化為對人類疾病具有更高功效的潛力。

Okay. So again, I'm not going to go into the details, but just want to flag one thing. You see the plasma concentration is quite different, and we believe that this is really an important differentiator that we reach very different plasma levels very rapidly with the drug. So we are just able to come into the range where the drug can do the full trick, which may be much more tricky task for our comparator.

好的。再說一遍，我不會詳細說明，只是想指出一件事。您會看到血漿濃度非常不同，我們相信這確實是一個重要的區別因素，我們使用該藥物非常快速地達到非常不同的血漿水平。因此，我們只能進入藥物可以發揮全部作用的範圍，這對我們的比較器來說可能是一項更棘手的任務。

Next slide. And this gives you a visual. This is just the single dosing and from our just reported Phase 1 study. And you can see in the red dotted line, this is superimposed, so this is not a head-to-head study, but the data reported from avacopan that's superimposed into this graph and you see the comparable doses, the blue line of INF904, 30 mgs one shot. And you see that there is a very differentiated PK profile. You see that the time to max occurs, the peak occurs later. There's a much broader area under the curve. And again, this confirms the 3-fold higher C-max, but also the 10-fold higher plasma exposure. And that was true for all comparative doses. And then you can see above the dose, we tested up to 240 milligrams without any safety signal.

下一張投影片。這給了你一個視覺效果。這只是我們剛報告的第一階段研究的單次給藥。你可以在紅色虛線中看到，這是疊加的，所以這不是頭對頭研究，而是 avacopan 報告的數據疊加到這張圖中，你可以看到可比較的劑量，INF904 的藍線，一劑30 毫克。而且你會看到，PK 的情況非常不同。您會看到達到最大值的時間出現，高峰出現較晚。曲線下有一個更廣闊的區域。這再次證實了 C-max 高出 3 倍，而且血漿暴露也高出 10 倍。所有比較劑量都是如此。然後你可以看到上面的劑量，我們測試了高達 240 毫克，沒有任何安全信號。

Next slide. And this is the size that we are most excited about is that shows, in this case, in a 14-day dosing, multiple ascending dose with three different doses, that we have a very tight control over the C5a induce signaling. So when the drug is taken out of the blood patients at trough, and we challenge that with new C5a, it blocks it over a very broad dose range, up to 90% and higher, and that really is for us, something that we wanted to see and really confirmed all the preclinical work.

下一張投影片。這是我們最興奮的大小，在這種情況下，在 14 天的給藥、三種不同劑量的多次遞增劑量中，我們對 C5a 誘導訊號傳導有非常嚴格的控制。因此，當藥物在低谷時從血液患者體內取出時，我們用新的C5a 挑戰這一點，它在非常寬的劑量範圍內阻斷它，高達90% 甚至更高，這確實適合我們，我們想要的東西看到並真正確認了所有的臨床前工作。

So next slide, please. So we will begin our Phase 2 development this year. Still, we want to start with an initial Phase 2a, demonstrating the pipeline and a drug potential ready for this drug. This will be an exploratory study, but a PK/PD and safety basket study, that means a four-week initial treatment and into immunoderm indication, CSU and HS And we will also look into three different doses here to assess PK and safety. So the catalyst was, we want to start this trial end of year 2024, and we want to have data in 2025 that we can share while preparing for meaningful substantial larger Phase 2b studies in this indication and they are expected to begin also in 2025.

請下一張投影片。因此，我們將在今年開始第二階段的開發。儘管如此，我們還是想從最初的 2a 階段開始，展示該藥物的管道和藥物潛力。這將是一項探索性研究，而是一項PK/PD 和安全籃研究，這意味著為期4 週的初始治療，並針對免疫皮膚適應症、CSU 和HS。不同的劑量，以評估PK 和安全性。因此，催化劑是，我們希望在2024 年底開始這項試驗，我們希望在2025 年獲得可以分享的數據，同時為該適應症進行有意義的大規模2b 期研究做準備，預計這些研究也將於2025年開始。

Next slide, please. So with that, we're going down the road now to go into the initial indications chosen and I'm very happy to hand this over here to our Chief Medical Officer Camila Chong. And Camilla, please help us and speak about chronic spontaneous urticaria Thank you.

請下一張投影片。因此，我們現在正在著手研究所選的初步適應症，我很高興將其交給我們的首席醫療官 Camila Chong。卡米拉，請幫我們談談慢性自發性蕁麻疹，謝謝。

Thanks, Niels. And so next slide, please. I just wanted to start by saying that, we are really thrilled to be able to first of all, collaborate with Professor Marcus Maurer whom from Charité Berlin, who many of you who have worked in this space will know is a world-leading expert in CSU, and it really his conviction and persuasion that with the increasing scientific evidence that have been generated recently to suggest that C5aR signaling is involved in histamine release from both mast cells and basophils in CSU patients in an IgE independent manner.

謝謝，尼爾斯。請下一張投影片。我首先想說的是，我們真的很高興能夠首先與柏林慈善學院的 Marcus Maurer 教授合作，在這個領域工作過的許多人都知道他是一位世界領先的專家他堅信並堅信，最近產生的越來越多的科學證據表明，C5aR 訊號傳導以獨立於IgE 的方式參與CSU 患者肥大細胞和嗜鹼性粒細胞的組織胺釋放。

So this mechanism may play a role, which is important for both described endotypes, which I will go into a little bit more later on, so called Type I and Type IIb. So there is also belief from his group and others that despite availability of current treatment options such as antihistamines and an anti-IgE therapy, there is and not an insubstantial number or percentage of patients of either who have not responded to antihistamines or omalizumab therapy who remain non-responsive and is therefore symptomatic.

因此，這種機制可能會發揮作用，這對於所描述的兩種內型都很重要，稍後我將詳細介紹這兩種內型，即所謂的 I 型和 IIb 型。因此，他的團隊和其他人也相信，儘管目前有抗組織胺和抗 IgE 療法等治療選擇，但對抗組織胺或奧馬珠單抗療法沒有反應的患者數量或百分比並不低。反應，因此有症狀。

We believe that therefore, INF904 can be a convenient oral therapeutic option, particularly for those who do not want a continuous subcut injection every month and those who may not tolerate quadrupling therapies with antihistamines or IgE. We believe that the CSU market potential is estimated to exceed over $3 billion by 2032.

因此，我們相信，INF904 可以成為一種方便的口服治療選擇，特別是對於不想每月連續分段注射的人以及那些可能無法耐受抗組織胺或 IgE 四倍療法的人。我們相信，到 2032 年，科羅拉多州立大學的市場潛力預計將超過 30 億美元。

Next, please. For some of you who are familiar with CSU, you will recognize that, you know, as described in literature and by many experts that this is an immune-mediated chronic inflammatory skin disease, which you know, have dysregulated inflammatory processes involved, leaving patients very predisposed to symptoms, which are both debilitating and are chronic in nature, predominantly the development of itchy hives and wheals that do not go away for a period of over six weeks and some are often associated with angioedema.

下一個。對於一些熟悉 CSU 的人來說，您會認識到，正如文獻和許多專家所描述的那樣，這是一種免疫介導的慢性發炎性皮膚病，您知道，它涉及發炎過程失調，使患者非常容易出現使人虛弱且慢性的症狀，主要是發癢的蕁麻疹和風團，這些症狀在六週以上的時間內不會消失，有些通常與血管性水腫有關。

I think the important thing to highlight about this condition, as many of you will know, is that it has high physical and economic burden, not just for patients and families, but also for health care system. The estimated prevalence is has been described to be around 1% of the general population in most countries and that up to 20%, if not more of this so-called population experienced symptoms for more than five years.

我認為，正如你們許多人都知道的那樣，關於這種情況需要強調的重要一點是，它不僅對患者和家庭，而且對醫療保健系統都有很高的身體和經濟負擔。根據描述，在大多數國家，估計盛行率約為總人口的 1%，而在這些所謂的人口中，高達 20%（如果不是更多）出現症狀的時間超過五年。

20- to 40-year-olds are particularly affected, some have described 30- to 60-year-old and with women being impacted, you know, twice as often compared to men. Current treatments, as I've already mentioned, the only approved treatments are antihistamines and anti-IgE therapy.

20 至 40 歲的人尤其受到影響，有些人描述了 30 至 60 歲的人，女性受到影響的幾率是男性的兩倍。正如我已經提到的，目前的治療方法唯一被批准的治療方法是抗組織胺和抗 IgE 治療。

Next, please. So as described earlier, Professor Maurer and group have done a lot of work to based on their observations of treatment in CSU patients and they have described these two main endotypes for CSU. These are basically broken into Type I, which is characterized by IgE autoantibodies directed to self-antigens and therefore, the term Type I autoallergens.

下一個。因此，如前所述，Maurer 教授和團隊根據他們對 CSU 患者治療的觀察做了很多工作，他們描述了 CSU 的這兩種主要內型。這些基本上分為 I 型，其特徵是針對自身抗原的 IgE 自身抗體，因此稱為 I 型自體過敏原。

But they also believe that there is a Type IIb autoimmunity of which this makes up something like 30% of these so-called CSU patients. And this is more IgE, IgG mediated antibody directed specifically to the anti-IgG or to the FC epsilon receptor on both mast cells and basophils. So both these pathways is believed to involve C5a and therefore, the C5a signaling is important in these two cascades as shown on the diagram on the left-hand side.

但他們也認為，在這些所謂的 CSU 患者中，約有 30% 存在 IIb 型自體免疫疾病。這是更多 IgE、IgG 介導的抗體，特異性針對肥大細胞和嗜鹼性粒細胞上的抗 IgG 或 FC epsilon 受體。因此，這兩個途徑被認為都涉及 C5a，因此，C5a 訊號傳導在這兩個級聯中很重要，如左圖所示。

Next slide, please. Now I know that this is a slightly busy slide. So if you'll indulge me to spend a little bit of time to walk you through it starting from the left-hand side. So the left-hand side is basically an experiment in CSU patients where they measured C5a levels. And as you can see here, C5a levels are significantly increased compared to the controlled group. So C5a levels are elevated, we know in CSU patients. And then at the bottom on the left-hand side, what you would see is essentially staining of skin biopsy in CSU patients of C4d, suggesting that basically there is activation of the complement system.

請下一張投影片。現在我知道這是一張有點繁忙的幻燈片。因此，請允許我花一點時間從左側開始引導您完成它。因此，左側基本上是在 CSU 患者中進行的一項實驗，他們測量了 C5a 水平。正如您在這裡所看到的，與對照組相比，C5a 水平顯著增加。因此我們知道 CSU 患者的 C5a 水平升高。然後在左側底部，您將看到的基本上是 CSU 患者 C4d 皮膚活檢的染色，表明基本上存在補體系統的活化。

And then now if you focus your attention to the middle graph, what's interesting here is that this was an experiment done over 20 years ago, where essentially, they've been able to show from healthy donors' blood C5a in itself can actually induce histamine release from basophils in a very nice dose dependent manner.

現在，如果您將注意力集中在中間的圖表上，這裡有趣的是，這是20 多年前進行的一項實驗，從本質上講，他們已經能夠從健康捐贈者的血液中證明C5a 本身實際上可以誘導組織胺以非常好的劑量依賴性方式從嗜鹼性粒細胞中釋放。

And then last but not least, the last part of this graph shows that actually the C5a mediated histamine release is independent of the IgE pathway. This is an ex-vivo human skin experiment where they incubated it with a SYK inhibitor, which was a GSK compound that basically were predominantly via the IgE pathway, and they then added increasing levels of concentration of C5a. And as you can see, the C5a stimulation of histamine release is not affected at all via this IgE pathway with the SYK inhibitor GSK2646264.

最後但並非最不重要的一點是，該圖的最後部分錶明實際上 C5a 介導的組胺釋放獨立於 IgE 途徑。這是一項離體人體皮膚實驗，他們將其與 SYK 抑制劑（一種 GSK 化合物，基本上主要透過 IgE 途徑）一起孵育，然後添加濃度不斷增加的 C5a。正如您所看到的，透過 SYK 抑制劑 GSK2646264 的 IgE 途徑，C5a 對組織胺釋放的刺激完全不受影響。

Next slide, please. So here, what I wanted to demonstrate to you is a piece of work done by a Japanese group recently published in 2022. And what they have tried to do is they took blood from CSU patients and measured the different levels of basophils after stimulating it with an anti-IgE stimulus. And on the left-hand side, what you can see is that basophils from these patients with an anti-IgE stimulus, and hence they call it IgE stimulus positive patients. With histamine release, they show really good response and I think interestingly, these basophils also showed histamine release in a dose-dependent manner in -- with C5a stimulation. If you then focus on the graph on the right-hand side, CSU patients who do not respond to the anti-IgE stimulus continues to be responsive to C5a stimulation.

請下一張投影片。那麼在這裡，我想給大家展示的是日本一個團體在2022年最近發表的一個作品。他們試圖做的是，從 CSU 患者身上採集血液，並在用抗 IgE 刺激物刺激後測量嗜鹼性粒細胞的不同水平。在左側，您可以看到這些患者的嗜鹼性粒細胞具有抗 IgE 刺激，因此他們稱之為 IgE 刺激陽性患者。隨著組織胺的釋放，它們表現出非常好的反應，我認為有趣的是，這些嗜鹼性粒細胞在 C5a 刺激下也以劑量依賴的方式釋放組織胺。如果您隨後關注右側的圖表，則會發現對抗 IgE 刺激沒有反應的 CSU 患者仍然對 C5a 刺激有反應。

Next, please. So what they propose is that actually, C5a induced histamine release is important for both pathways. IgE dependent as well as IgE independent, whereby if you look at the IgE dependent pathway C5a still plays a role in addition to the other pathway where it is non-IgE dependent. And I think in addition to that, what they have managed to also showed is that the C5a generation in CSU may be further amplified because of the activation of the coagulation pathways via tissue factor release. In addition so this acts as almost like a continuous amplification loop which further drives disease.

下一個。因此他們提出實際上 C5a 誘導的組織胺釋放對於這兩種途徑都很重要。IgE 依賴性以及 IgE 獨立性，如果您觀察 IgE 依賴性途徑，除了其他非 IgE 依賴性途徑外，C5a 仍然發揮作用。我認為除此之外，他們還成功地表明，由於透過組織因子釋放激活凝血途徑，CSU 中的 C5a 生成可能會進一步放大。此外，這幾乎就像一個連續的放大循環，進一步驅動疾病。

Next slide, please. So in conclusion, I hope you would have seen that C5aR signaling is involved in histamine release from both mast cells and basophils. And that certainly this has been the conviction from Professor Maurer and group that the C5a mediated histamine release is suggested to play a really important role in both subtypes of CSU, even though it can be shown to be released independent of the IgE pathway. And we really believe that this C5a inhibition represents a novel mechanism to address an unmet need in CSU and that INF904 has the oral -- the potential to offer an oral drug, which is potent for the development in CSU.

請下一張投影片。總之，我希望您已經看到 C5aR 訊號傳導參與肥大細胞和嗜鹼性粒細胞的組織胺釋放。當然，Maurer 教授和團隊堅信 C5a 介導的組胺釋放在 CSU 的兩種亞型中發揮著非常重要的作用，儘管它可以被證明是獨立於 IgE 途徑釋放的。我們確實相信，這種 C5a 抑制代表了一種解決 CSU 未滿足需求的新機制，而 INF904 具有口服藥物的潛力，這對 CSU 的開發非常有效。

Thank you. I'm now going to hand back to Niels, who will take you through to our next indication.

謝謝。我現在將交回尼爾斯，他將帶您了解我們的下一個指示。

Yes. Thank you so much, Camilla. I really appreciate it. I'm excited now to speak a bit about hidradenitis suppurativa. Next slide, please.

是的。非常感謝你，卡米拉。對此，我真的非常感激。我現在很高興能談談化膿性汗腺炎。請下一張投影片。

So this is another indication that we want to show the potential of the drug and show that the drug is active initially. So when you look at this disease, it's probably well known to some of the people here on the call. There's still -- new mechanisms are needed and that's what we hear from KOLs, and we are very attached to that scene, generally speaking. So moderate to severe patient have active draining disease are oftentimes left with non-ideal or non-working options even though recent progress has certainly produced drugs that are approved, like the anti-TNF-alpha class, like HIMURA actually and some anti-IL-17 agents. At least one proof the other one on the path and the third one coming.

因此，這是我們想要展示該藥物的潛力並表明該藥物最初具有活性的另一個跡象。因此，當您了解這種疾病時，參加電話會議的一些人可能對此非常了解。仍然需要新的機制，這就是我們從 KOL 那裡聽到的，一般來說，我們非常喜歡這個場景。因此，患有活動性引流疾病的中度至重度患者常常會面臨不理想或無效的選擇，儘管最近的進展確實產生了獲得批准的藥物，例如抗TNF-α 類藥物，實際上像HIMURA 和一些抗IL 藥物。至少有一個證明另一個在路上，第三個即將到來。

So but these patients that respond to these drugs, they're known that this -- for them it's known that a significant number will have the efficacy or the effect wane over time. And so there is a high unmet need for additional mechanisms, and again, there may be also a need that is not ideally addressed by these drugs. So we know that HS patients have a preference for oral medications over injections, that has been suggested in research.

所以，但是這些對這些藥物有反應的患者，他們知道這一點——對他們來說，他們知道相當多的人會產生療效，或者隨著時間的推移，效果會減弱。因此，對額外機制的需求高度未被滿足，並且這些藥物也可能無法理想地解決這些需求。因此我們知道，研究表明，熱射病患者更喜歡口服藥物而不是注射藥物。

And we have an oral C5aR inhibitor with a mechanism that really is addressing something, and I come back to the word NETosis here, but also just the effect on neutrophils, again HS is a neutrophilic dermatoses that is not necessarily addressed by any of the other drugs. And there's a clinical evidence, I'll be speaking about in a second, about the pathway, that this pathway when addressed can reduce lesion counts in HS. And this drug has a favorable PK/PD profile with a broad dose range for systemic exposure.

我們有一種口服C5aR 抑制劑，其機制確實可以解決某些問題，我在這裡回到NETosis 這個詞，但也只是對中性粒細胞的影響，同樣，HS 是一種中性粒細胞性皮膚病，不一定能透過任何其他藥物來解決藥物。我稍後會談到有關該途徑的臨床證據，表明該途徑得到解決後可以減少 HS 中的病變數量。該藥物具有良好的 PK/PD 特性，全身暴露劑量範圍廣。

Well, that's set aside, the HS market has been described to be a very attractive commercial market. There are estimates that this market has a multi-billion peak potential for drugs by 2032. And that is an exciting side note, of course.

好吧，拋開這一點，HS 市場被描述為一個非常有吸引力的商業市場。據估計，到 2032 年，這個市場的藥品高峰潛力將達到數十億美元。當然，這是一個令人興奮的附註。

Next slide, please. So I'm not going to be speaking too much about HS as I believe it's been much discussed by also recent research. And I just want to mention that this -- for the patients affected this is really a truly living nightmare especially those that are progressed in the disease to moderate severe stage and those that have active draining tunnel because they can -- a single tunnel, and if you go to the Internet and research that there are -- I think there's even a video that show that a tunnel produces up to a liter of puss.

請下一張投影片。因此，我不會過多談論 HS，因為我相信最近的研究也對此進行了很多討論。我只想提一下，對於受影響的患者來說，這確實是一場活生生的噩夢，尤其是那些疾病進展到中度嚴重階段的患者，以及那些擁有主動引流隧道的患者，因為他們可以——一條隧道，並且如果你去互聯網上研究一下——我想甚至有一個視頻顯示隧道會產生多達一公升的糞便。

Just one single tunnel because the tunnel is the outside that you see, but underneath the tunnel has a deep seeded lesion and these lesions in the skin. They are hurtful, the puss is really carrying a huge social burden, and you have to imagine that this disease occurs under the armpits and oftentimes in the groin area. So it really has a social life destroying character.

只有一條隧道，因為隧道是您看到的外部，但隧道下方有一個深層的種子病變，這些病變在皮膚中。它們是有害的，貓確實承擔著巨大的社會負擔，你必須想像這種疾病發生在腋下，並且經常發生在腹股溝區域。所以它確實具有破壞社會生活的性質。

Okay. So next slide, please. Or maybe the last thing I wanted to add is that this is clearly a market with a lot of patients affected. There are varying reports about how large it is, but it's clearly more than 200,000 patients even in the more severe stage in the US.

好的。請下一張投影片。或者也許我想補充的最後一件事是，這顯然是一個有許多患者受到影響的市場。關於其規模有不同的報導，但即使在美國，即使處於更嚴重的階段，也顯然有超過 20 萬名患者。

So on this slide, I want to just basically convey one message. I don't want to walk you through the whole slide, but there's recent progress on the understanding of the pathogenesis of the disease. And this just shows that research, which is not coming out of our Group, but out of people we know suggests a central role for C5a and C5aR in the pathogenesis, in the mechanism that is set into place when these follicles rupture and when in the initiation phase an immune reaction to this rupture to this clotted follicular rupture, this is the current hypothesis, is set in motion. And so it's really recognized in the field that this is a central role.

所以在這張投影片上，我只想基本上傳達一個訊息。我不想向您介紹整張投影片，但最近在了解疾病的發病機制方面取得了進展。這只是表明，研究不是來自我們的小組，而是來自我們認識的人，表明 C5a 和 C5aR 在發病機制中、在這些卵泡破裂時以及在起始階段，針對這種破裂和凝結的卵泡破裂的免疫反應開始啟動，這是目前的假設。因此，該領域確實認識到這是一個核心角色。

Next slide, please. So we've produced data a while ago that these patients have elevated C5a levels. This is with a validated ELISA, and this is not surprising. And actually, in the Phase 3 study that -- in the Phase 2b study that we ran, we showed quite substantial C5a levels in these patients.

請下一張投影片。因此，我們不久前得出的數據顯示，這些患者的 C5a 水平升高。這是經過驗證的 ELISA，這並不奇怪。事實上，在第 3 期研究中——在我們進行的 2b 期研究中，我們發現這些患者的 C5a 水平相當高。

Now we also have shown some interesting data that HS patient plasma strongly provokes neutrophil activation. So when you take plasma from HS patients and you subject fresh neutrophils from fresh donors to that plasma, they get activated immediately. And both drugs, vilobelimab and also new data with INF904 with our oral C5aR inhibitor have shown that they can pretty much completely abrogate that activation. So meaning that obviously, it is C5a and that plasma from HS patients that excites fresh neutrophils and stimulates them strong.

現在我們也顯示了一些有趣的數據，即熱射病患者血漿強烈激發嗜中性球活化。因此，當您從熱射病患者身上獲取血漿，並將來自新鮮捐贈者的新鮮中性粒細胞加入該血漿中時，它們會立即被激活。這兩種藥物 vilobelimab 以及 INF904 與我們的口服 C5aR 抑制劑的新數據表明，它們幾乎可以完全消除這種活化。因此，很明顯，C5a 和來自 HS 患者的血漿可以激發新鮮的中性粒細胞並強烈刺激它們。

Next slide, please. So is the receptor present? So a recent study has shown that beautifully for all three stages of the disease. So you always have the common tissue hematoxylin and eosin staining in red above and you see that the lesions are marked. And then below, there is sustaining for C5aR and neutrophils, but it's also found in other cells, like histiocytes and giant cells. And you'll see that C5aR staining is found strongly around these lesions, particularly in the middle -- in this stage, early Stage 2, also around when patients develop draining tunnels, they tend to rupture, and they tend to create that large intradermal lesion. You see that when that happens, there's a lot of C5aR around. And then also on the right-hand side, in the most progressed depictions.

請下一張投影片。那麼受體存在嗎？因此，最近的一項研究表明，對於該疾病的所有三個階段來說，這一點都非常出色。因此，常見的組織蘇木精和伊紅染色總是呈現紅色，您會看到病灶被標記。以下是 C5aR 和嗜中性球的維持，但它也存在於其他細胞中，如組織細胞和鉅細胞。你會發現 C5aR 染色在這些病變周圍強烈存在，特別是在中間 - 在這個階段，第 2 階段早期，也在患者出現引流隧道時，它們傾向於破裂，並且它們傾向於產生大的皮內病變。你會看到，當這種情況發生時，周圍就會有很多 C5aR。然後也在右側，在最先進的描述中。

So C5aR is present. Not surprising because neutrophils are present certainly in all three disease stages. And something that I won't show you with this slide, but we will go into more detail in another day is that NETosis occurs quite substantially in these patients. And that's also new research, again, C5a being one of the key inducers of NETosis in neutrophils.

所以C5aR 存在。這並不奇怪，因為中性粒細胞肯定存在於所有三個疾病階段。我不會在這張投影片中向您展示，但我們將在另一天更詳細地討論的是，NETosis 在這些患者中發生得相當頻繁。這也是新的研究，C5a 是中性粒細胞中 NETosis 的關鍵誘導物之一。

Next slide, please. So that's clinical evidence I mentioned, and I just wanted to go into that very briefly. So with vilobelimab, we did a Phase 2b study and that clearly created are on the high dose level evidence that that C5a inhibition can reduce the inflammatory lesions at all of them. There was a particularly noteworthy effect on the draining tunnels that we spoke about. And this was actually the higher -- the tighter the C5a levels were controlled, the higher the drainage tunnel reduction was.

請下一張投影片。這就是我提到的臨床證據，我只想簡單地討論一下。因此，對於 vilobelimab，我們進行了一項 2b 期研究，並且在高劑量水平上清楚地創建了證據，表明 C5a 抑制可以減少所有發炎病變。我們談到的排水隧道受到了特別值得注意的影響。這實際上是越高——C5a水平控制得越嚴格，排水隧道的減少量就越大。

And the key learnings from our like substantial work in the field was really that we -- that vilobelimab was needed to adequately control C5a, C5aR signaling only when it's given in a higher dose. So in other words, you need a very high dose. The dose we've chosen is probably -- was according to our PK/PD and popPK modeling, not enough to adequately cover the signal. So that's the key learning. But the other learning is, it is an interesting path that is promising for the future to decrease these lesion counts.

我們從該領域的類似實質工作中得到的主要經驗是，只有當給予較高劑量時，才需要 vilobelimab 來充分控制 C5a、C5aR 訊號傳導。換句話說，您需要非常高的劑量。根據我們的 PK/PD 和 popPK 模型，我們選擇的劑量可能不足以充分覆蓋訊號。所以這就是關鍵的學習。但另一個教訓是，這是一條有趣的途徑，預計在未來減少這些病變數量。

On the oral C5aR inhibitor side, on avacopan there has also been studies done. And I want to share with you that at a standard dose, which is the approved dose in another disease indication at ANCA vasculitis, which is 30 mgs twice per day, there was a p-value positive efficacy signal when they look at the subgroup of severe HS patients, Hurley Stage 3, on high score with a clear separation from placebo group emerging late only mostly on at week 12.

在口服 C5aR 抑制劑方面，也對 avacopan 進行了研究。我想與您分享的是，在標準劑量下，即 ANCA 血管炎的另一種疾病適應症的批准劑量，即每天兩次 30 毫克，當他們觀察亞組時，出現了 p 值正療效信號嚴重HS 患者，Hurley 3 期，得分較高，與安慰劑組有明顯區別，僅在第12 週較晚才出現。

Now, we do want to mention that this study was also negative on the overall study population when it comes to high score. There was also a very high placebo response in the Hurley Stage 2 patients, which probably is able to see an effect. But the interesting part is really that in the Stage 3 patients, these groups and the lesion count separated really at week 12. And so when we looked into the switching to ANCA vasculitis, which is the area where avacopan has approved, the filing data showed that the drug has a very strong accumulation pattern [4x] and it takes approximately three months until it reaches the plateau of the accumulation phase.

現在，我們確實想提一下，就高分而言，這項研究對整體研究人群的影響也是負面的。Hurley 2 期患者的安慰劑反應也非常高，這可能能夠看到效果。但有趣的是，在第 3 階段的患者中，這些組別和病變計數在第 12 週時確實分開了。因此，當我們研究轉向 ANCA 血管炎（avacopan 已批准的領域）時，備案數據顯示該藥物具有非常強的積累模式 [4x]，大約需要三個月的時間才能達到治療的平台期。

So that's fitted quite well with this observation. I'm going to show you a picture here just a second. So how we interpret that is that the 30 mgs twice per day dosing regimen of that drug, because of its PK features, was probably not adequate, not high enough to show an efficacy early on to separation early. And of course, we conclude from that, that is a problem that could be handled with the right PK and the right drug.

所以這與這個觀察結果非常吻合。我馬上給你看一張照片。因此，我們的解釋是，該藥物每天兩次 30 毫克的給藥方案，由於其 PK 特徵，可能不夠充分，不夠高，不足以在早期和早期分離之間顯示出療效。當然，我們從中得出的結論是，這個問題可以透過正確的 PK 和正確的藥物來解決。

Next slide, please. So these are the data from the ChemoCentryx reports back then from the AURORA study. And again, I mentioned that the overall trial results were p-value positive, but the Hurley Stage 3 patients showed the separation. You see the gray curves are placebo, the orange curves were avacopan at the dose that I explained. And you see the end count on the left side, you see the nodule count in the middle, and you see the draining tunnel count and you see that really the separation starts only to be -- like strongly visible at week 12.

請下一張投影片。這些是來自 AURORA 研究當時 ChemoCentryx 報告的數據。我再次提到，整體試驗結果的 p 值為正，但 Hurley 3 期患者顯示分離。你看，灰色曲線是安慰劑，橘色曲線是我解釋的劑量下的阿瓦科潘。您可以看到左側的最終計數，您可以看到中間的結節計數，您可以看到引流隧道計數，並且可以看到真正的分離僅在第 12 週時才開始明顯可見。

So somewhere between the last visit at week 8 and the second last visit at week 8 and week 12, there was a separation occurring and you see the high scores pleading also relatively late here on the right side. Now, again, I explained already that from another disease, from the ANCA disease, we learned about the late accumulation, and again, our conclusion is that this may not be the right dosing and the right PK profile, but there is efficacy.

因此，在第 8 週的最後一次訪問和第 8 週和第 12 週的倒數第二次訪問之間，發生了分離，您會看到右側的高分請求也相對較晚。現在，我再次解釋說，從另一種疾病，即 ANCA 疾病中，我們了解了晚期積累，我們的結論是，這可能不是正確的劑量和正確的 PK 曲線，但有療效。

Next slide. And this is the -- that we graphically worked this up. This is the publicly filed NDA filing for the ANCA-associate vasculitis PK accumulation. Again, it's a different disease, but it's interesting because it shows this roughly 4-fold accumulation, and you see the steep curve has kind of started flattening out around week 12. In fact, it was week 13 where the steady state was reached there's plasma exposures given here on the right side.

下一張投影片。這就是我們用圖形方式解決的問題。這是針對 ANCA 相關血管炎 PK 累積公開提交的 NDA 申請。同樣，這是一種不同的疾病，但很有趣，因為它顯示了大約 4 倍的積累，並且您會看到陡峭的曲線在第 12 週左右開始變平。事實上，在第 13 週達到了穩定狀態，右側給出了血漿暴露情況。

So Next slide. I have come to a conclusion here and the conclusion is overall, speaking with the available evidence and knowledge is that there's a strong scientific rationale for the role of C5aR in HS. Now both C5a and C5aR signaling or a blockade of that signaling has resulted in signals of efficacy in HS patients. We believe that a tight control over the signaling of C5aR signaling is required to achieve an optimal efficacy.

那麼下一張投影片。我在這裡得出了一個結論，這個結論是總體性的，根據現有的證據和知識，C5aR 在 HS 中的作用有強有力的科學依據。現在，C5a 和 C5aR 訊號傳導或該訊號傳導的阻斷已在 HS 患者中產生了療效訊號。我們認為，需要嚴格控制 C5aR 訊號傳導以達到最佳功效。

So we all know dosing is important in HS, which is basically true for all drugs tested if you consider that some of the approved drugs were only showing efficacy when they're approved dose from other indications was doubled, take, for example, HUMIRA. So that brings us to our conclusion that INF904 is ideally positioned as an oral C5aR inhibitor with optimized PK/PD profile, which we addressed an existing high unmet medical need in these patients, and we are really excited to move this drug into this new direction.

因此，我們都知道劑量對於HS 很重要，這對於所有測試的藥物來說基本上都是如此，如果您認為某些已批准的藥物只有在其他適應症的批准劑量加倍時才顯示出療效，例如修美樂(HUMIRA)。因此，我們得出的結論是，INF904 是一種理想的口服C5aR 抑制劑，具有優化的PK/PD 特性，我們解決了這些患者現有的高度未滿足的醫療需求，我們非常高興將該藥物推向這個新方向。

Next slide, please. So at the end of our presentation, I want to speak about Gohibic briefly. Now this is for the vilobelimab where we got the Emergency Use Authorization. And I want to first mention that our team feels privileged, honored, and is very excited about the fact that we were able to get an Emergency Use Authorization. This was the only Emergency Use Authorization granted in 2023. It's the only one for a small biotech company. And it's also the only one with a first-in-class mechanism that addresses an unmet need in the immunomodulatory space.

請下一張投影片。因此，在我們演講的最後，我想簡單談談 Gohibic。現在這是我們獲得緊急使用授權的 vilobelimab。我想首先提到的是，我們的團隊對能夠獲得緊急使用授權感到非常榮幸和興奮。這是 2023 年授予的唯一緊急使用授權。這是一家小型生技公司唯一的一家。它也是唯一一個擁有一流機制的藥物，可以解決免疫調節領域未被滿足的需求。

So we're excited. We are definitely committed to continue making the drug available to patients at need. We have recently press released our commitment program that helps addressing some of the issues that the acute care/hospital health care system has. And we're in active discussions. And we get a lot of good feedback about this commitment program.

所以我們很興奮。我們絕對致力於繼續向有需要的患者提供該藥物。我們最近發布了我們的承諾計劃，該計劃有助於解決急診/醫院醫療保健系統存在的一些問題。我們正在積極討論。我們得到了很多關於這個承諾計劃的良好回饋。

And so next slide, please. So this just summarizes the Gohibic Emergency Use Authorization and our commitment to keep the drug available for patients. And also we did talk about the fact that we may get a full BLA with one additional study in the ARDS trial. Now we are very frugal with our spend in this area because we had never anticipated and clearly anticipate how this market may look like, which comes along with the situation switching from a pandemic into maybe an endemic state. So we're very frugal. And we also mentioned that we would only look into such development if we get public funding or the help or other non-dilutive funding in the company.

請下一張投影片。因此，這只是總結了 Gohibic 緊急使用授權以及我們為患者提供該藥物的承諾。我們也確實談到了這樣一個事實，即我們可能會透過 ARDS 試驗中的一項額外研究獲得完整的 BLA。現在我們在這個領域的支出非常節儉，因為我們從未預料到也清楚地預見到隨著形勢從大流行轉變為流行狀態，這個市場會是什麼樣子。所以我們非常節儉。我們也提到，只有在獲得公共資金或公司的幫助或其他非稀釋性資金的情況下，我們才會考慮這種發展。

So with that statement, I want to close our today's presentation and open for Q&A. Again, I want to summarize the excitement of the entire team to focus now on immunoderm with our upfront running Phase 3 program, but also with the new additions with our oral INF904. So with that, I hand back to you, Jan, and thank you for your attention and we are the team is happy to answer any questions you might have. Thank you.

因此，我想結束今天的演講並開始問答。我想再次總結整個團隊現在的興奮之情，他們現在專注於免疫皮膚，透過我們的前期運行第 3 期計劃，以及我們的口服 INF904 的新補充。因此，Jan，我再次感謝您的關注，我們團隊很樂意回答您可能提出的任何問題。謝謝。

Thanks, Niels. So audience this concludes the formal presentation. So we'll open the call to questions now. And there are two ways you can do so first or you can submit a question in writing via the Q&A button below the presentation window. I will then read that question aloud during the Q&A session, or you can ask a question live by raising your hand icon under the presentation window, and then we'll announce call for each person at that point.

謝謝，尼爾斯。觀眾的正式演講到此結束。我們現在開始提問。您可以透過兩種方式先這樣做，或者您可以透過示範視窗下方的「問答」按鈕提交書面問題。然後，我將在問答環節大聲朗讀該問題，或者您也可以通過在演示窗口下舉起手形圖標來現場提問，然後我們將在此時宣布對每個人進行呼叫。

So we do have a question from Steve Seedhouse.

我們確實收到了 Steve Seedhouse 提出的問題。

Hi, everyone. Can you hear me okay, Jan?

大家好。你聽得到我說話嗎，簡？

Yes.

是的。

Okay, great. Thanks so much for hosting this call and for the overview and all of the detail and context. A couple of questions here. Just starting with HS, maybe obviously, interesting opportunity you have experienced here to maybe offer an orthogonal mechanism to IL-17s or TNFs and also the oral presentation is a differentiator. But widening the lens also just seems like an opportunity to establish really in patients the PK/PD advantages that INF904 if that translates from what you've seen so far versus avacopan or IFX-1, of course.

好的，太好了。非常感謝您主持這次電話會議並提供概述以及所有細節和背景。這裡有幾個問題。剛從 HS 開始，也許很明顯，您在這裡經歷過有趣的機會，也許可以為 IL-17 或 TNF 提供正交機制，而且口頭陳述也是一個差異化因素。但擴大視野似乎也是一個機會，可以在患者中真正確立 INF904 的 PK/PD 優勢，當然，如果這是從您迄今為止所看到的與 avacopan 或 IFX-1 相比的結果來看的話。

So just curious in that regard if you -- will you be sort of closely analyzing PK/PD data in these patients? Will you be able to compare to maybe some of the avacopan data that's publicly available. You shared some on ANCA vasculitis or your own IFX-1 data and really determine if you're getting a better coverage of C5aR inhibition essentially in patients in this Phase 2a?

因此，在這方面我很好奇，您是否會仔細分析這些患者的 PK/PD 數據？您能否與一些公開的 avacopan 數據進行比較。您分享了一些關於 ANCA 血管炎或您自己的 IFX-1 數據，並真正確定您是否在 2a 期患者中獲得了更好的 C5aR 抑制覆蓋？

Yes. Thank you, Steve. I'm happy to take that on that question, if I may. So first of all, it's great question. Thanks for asking that. And the answer is yes, we will closely monitor PK. This is a PK focused study. And on the PD angle, we're looking, of course, at various efficacy signals. Now you may see it's a four-week initial exposure on, and we, of course, have done a lot of work into thinking what can we show at four weeks and we're quite convinced that with the high doses that we can administer on our drug, INF904, and we will end being a small molecule and anticipated high tissue penetration levels that we can see a differentiation or that we can see also the efficacy signals at week four.

是的。謝謝你，史蒂夫。如果可以的話，我很樂意回答這個問題。首先，這是一個很好的問題。謝謝你這麼問。答案是肯定的，我們會密切關注PK。這是一項以 PK 為重點的研究。在 PD 角度，我們當然會關注各種功效訊號。現在你可能會看到這是一個為期四個星期的初始暴露，當然，我們已經做了很多工作來思考我們可以在四個星期內展示什麼，並且我們非常確信，通過我們可以施用的高劑量我們的藥物INF904，我們將最終成為一種小分子，並預期高組織滲透水平，我們可以看到差異，或者我們也可以在第四週看到功效信號。

Now there are comparatives. We have the week four data with our slightly under dosed vilobelimab while we had the week four data, at least in the early stage. We reported by avacopan, and we have a lot of inhouse data. So I think the goal is really to say on the PD level that may translate into, I would say, a signal that when you compare it especially to known placebo responses at week four that will at least give us a good confidence that we're seeing efficacy of the drug here.

現在有對比了。我們有第四週的數據，我們的維洛貝利單抗劑量略低，而我們有第四週的數據，至少在早期階段是如此。我們是avacopan報導的，我們有許多內部數據。所以我認為我們的目標實際上是在PD 層面上說，我想說，當你將其與第四週已知的安慰劑反應進行比較時，這至少會給我們一個很好的信心，即我們在這裡看到藥物的功效。

So we've done a lot of -- and we will go into this into more detail. The press release today has also announced that we are planning an R&D Day in due course, so one of our goals for that R&D Day is to have some of the experts we're working with speaking about what we're doing and about and what they get -- what excites them but also bit more into exactly such details that you just mentioned about the trial.

我們已經做了很多工作，我們將對此進行更詳細的探討。今天的新聞稿還宣布，我們計劃在適當的時候舉辦研發日，因此我們研發日的目標之一是讓一些與我們合作的專家談論我們正在做什麼、關於什麼以及什麼他們得到了讓他們興奮的東西，但也更多地了解了你剛才提到的有關試驗的細節。

Now what is difficult to do is the PD, as we've done in the Phase 1 where you have this flow cytometry data on the neutrophil ex-vivo excitation, which requires really a very full on-site training of a team that on-site does the measurement with a fresh, strong blood. So that can be done in trained Phase 1 units, but you have to almost train the entire team and we're looking into whether we can get some of the data, maybe at few sites, but that is something we cannot fully promise at this point in time. That will be, of course, nice because you can directly compare that to the Phase 1 data there.

現在很難做的是PD，正如我們在第一階段所做的那樣，您擁有有關中性粒細胞離體興奮的流式細胞術數據，這實際上需要對團隊進行非常全面的現場培訓，以便在-現場用新鮮、強烈的血液進行測量。因此，這可以在訓練有素的第一階段單位中完成，但你幾乎必須培訓整個團隊，我們正在研究是否可以獲得一些數據，也許是在幾個站點，但這是我們目前無法完全承諾的事情時間點。當然，這很好，因為您可以直接將其與第一階段的數據進行比較。

Okay. Thanks, Niels. And just you I mean, you guys have much more experience than maybe anyone with regulators discussing HS and the endpoints and the evolving landscape. I guess, where are we at today from your perspective with draining tunnels and endpoints and how to develop something to the finish line in HS.

好的。謝謝，尼爾斯。我的意思是，你們比任何與監管機構討論 HS、端點和不斷變化的格局的人都更有經驗。我想，從您的角度來看，我們今天在排水隧道和端點方面處於什麼位置，以及如何在 HS 的終點線開發一些東西。

Yeah, great question. So first of all, I want to make sure that it's clear that we're not like basing the entire development on draining tunnels or on whether or not we can add maybe develop better tools to show something. We believe that we -- that this drug can also be successful on the high score. It's an oral drug that has an improved endpoint, which is the high score. The orals have in the past shown consistently lower placebo response rates when you compare that to on IV infusions, for example, and that has to do with placebo response (inaudible) But that set aside, we know that there is a very special additional mechanism of action, as you pointed out on the most severe lesions. And of course, that can be worked out nicely either on secondary endpoints.

是的，很好的問題。首先，我想確保我們不會把整個開發項目建立在排水隧道的基礎上，或者我們是否可以開發更好的工具來展示一些東西。我們相信，這種藥物也能取得高分成功。它是一種口服藥物，具有改善的終點，即高分。例如，當您將其與靜脈輸注進行比較時，過去口服的安慰劑反應率始終較低，這與安慰劑反應有關（聽不清楚）但拋開這一點，我們知道有一個非常特殊的附加機制正如您在最嚴重的病變上指出的那樣。當然，這可以在次要端點上很好地解決。

Yeah, we've come back then very close. I think we have -- with a minimum ambiguity, had had an agreement on running into Phase 3 trial with a new endpoint. We are consulted by former office directors of the FDA on that and there's certainly something we can work out. But I do want to flag that we're not like basically basing our whole development on whether or not we can come to terms for exciting research, we think that we can win the game and win the market approval also on the high school.

是的，我們已經非常接近了。我認為我們已經就進入具有新終點的第三階段試驗達成了最小限度的協議。FDA 前辦公室主任就此向我們進行了諮詢，我們當然可以解決一些問題。但我確實想指出，我們的整個發展基本上不是基於我們是否能夠就令人興奮的研究達成協議，我們認為我們也可以贏得比賽並贏得市場認可。

Great. And just to wrap the parallel track here in CSU is interesting. So a two-part question on that. First, I mean, do you view this as really just the sort of lowest hanging fruit proof of concept for mast cell biology in general that would open up myriad development opportunities across the spectrum of mast cell biology? Or is there something specific about CSU that drew your attention?

偉大的。僅僅將平行軌道包裹在科羅拉多州立大學這裡就很有趣。這是一個由兩部分組成的問題。首先，我的意思是，您是否認為這真的只是肥大細胞生物學概念上最容易實現的成果，它將為肥大細胞生物學的整個領域開闢無數的發展機會？或者 CSU 有什麼特別之處引起了您的注意嗎？

And then also do you think -- you mentioned the two endotypes and the contribution of C5aR to both. Is that something that you think you can parse out the relative activity in this Phase 2a? Or would that be too challenging to do?

然後您是否也認為 - 您提到了兩種內型以及 C5aR 對這兩種內型的貢獻。您認為您可以解析出第 2a 階段的相關活動嗎？或者說這樣做會不會太具挑戰性？

Yeah. I'm happy to pass over to Camilla and maybe I'll chime in with an additional thought but Camilla, please.

是的。我很高興把電話轉給卡米拉，也許我會補充一些額外的想法，但卡米拉，請。

Sure. I'd be happy to perhaps answer the last part of your question. So we believe that in our Phase 2a study that we're looking at, that we should be able to address both endotypes, right? We're not just restricting it to the very refractory type of CSU patients, so there is no reason why it should not work in either endotypes, firstly. And I think CSU is one of those conditions where you can show relatively quick clinical effect within two weeks, if not up to four weeks.

當然。我很樂意回答你問題的最後一部分。所以我們相信，在我們正在研究的 2a 期研究中，我們應該能夠解決這兩種內型，對吧？我們不僅將其限制在非常難治的 CSU 患者類型，因此首先沒有理由認為它不適用於任何一種內型。我認為 CSU 是可以在兩週（甚至長達四週）內顯示出相對快速臨床效果的疾病之一。

Now obviously, that's different from showing maintenance, but I think this could be a very quick indication for us to be able to really dwell into -- to really be able to explore the biology of this drug. And the endpoints are fairly straightforward, they're fairly well accepted by regulators. So we feel that this this would be a relatively not easy, but it would be a less complicated one to be able to do plus the fact that, you know it is not a rare indication, so we will get the patients that we would need to be able to study this in a relatively efficient manner.

顯然，這與顯示維護不同，但我認為這可能是一個非常快速的跡象，讓我們能夠真正深入研究這種藥物的生物學特性。而且終點相當簡單，監管機構也很容易接受。所以我們覺得這將是一個相對不容易的事情，但它會是一個不太複雜的事情，而且事實上，你知道這不是一種罕見的適應症，所以我們會得到我們需要的患者能夠以相對有效的方式進行研究。

Yeah. Maybe -- and just to add to that, Camilla, I think we are very close here with a team of Dr. Maurer at the Charité in Berlin. They have worked out the concept. They had been initially suggested to us that we should do this development some while ago with vilobelimab. And when they heard we have the oral, we came back into really strong discussions. So yes, the idea would be -- and there's a strong support, so they are willing to support us also by recruiting patients and by recruiting both subtypes as Camilla just said.

是的。也許——補充一點，卡米拉，我認為我們與柏林慈善醫院毛雷爾博士的團隊非常接近。他們已經提出了這個概念。他們最初向我們建議，我們應該在不久前使用 vilobelimab 進行這項開發。當他們聽到我們進行口頭發言時，我們又進行了非常激烈的討論。所以是的，這個想法是——並且有強有力的支持，所以他們也願意透過招募患者和招募兩種亞型來支持我們，正如卡米拉剛才所說的那樣。

Now you asked for the more broad general like mast cell biology. I would say at this point in time, we are focusing on this attractive market and we know -- and that was part of the central discussions with Maurer team is we know that there is like really a decent number of patients that are underserved even with the treatments one of the thoughts is they may be underserved because that second angle which is independent of IgE is not addressed.

現在你要求更廣泛的一般知識，例如肥大細胞生物學。我想說，在這個時候，我們正在專注於這個有吸引力的市場，我們知道——這是與 Maurer 團隊的核心討論的一部分，我們知道，即使有相當數量的患者得不到充分的服務，治療方法之一的想法是它們可能得不到充分服務，因為獨立於IgE 的第二個角度沒有得到解決。

And that's exactly -- if that's true, we may address a very broad patient population. We may address all of the population and that's something we need to work out. So that's too early to make that statement but we are excited about this indication and all the work that the Maurer group and others have done so far. Whether we take it to more broader mast cell, I think we will definitely not make these conclusions before we don't have the data to speak about it.

確實如此——如果這是真的，我們可能會針對非常廣泛的患者群體。我們可能會向全體人民提供協助，這是我們需要解決的問題。因此，現在發表這一聲明還為時過早，但我們對這一跡像以及 Maurer 小組和其他人迄今為止所做的所有工作感到興奮。無論我們是否把它帶到更廣泛的肥大細胞，我想在沒有數據說話之前我們肯定不會做出這些結論。

Thanks for the questions.

感謝您的提問。

Great. So we have a few here from -- they've been submitted in writing, so I'll go to the first by Joe Schwartz at Leerink Partners. So the first part is to asking us about the goals of the Phase 2a study in terms of what kind of early efficacy endpoints will be, including how informative we think the endpoints will be at four weeks, and anything we'll be looking for as we consider a go, no-go in either of the indications.

偉大的。我們這裡有一些——它們已經以書面形式提交，所以我將看第一位由 Leerink Partners 的 Joe Schwartz 撰寫的。因此，第一部分是詢問我們 2a 期研究的目標，即早期療效終點是什麼樣的，包括我們認為終點在 4 週時將提供多少信息，以及我們將尋找的任何內容我們考慮對任一適應症進行或不進行。

Yeah. I'm happy to tackle that. So that's very straightforward. On the efficacy side, this is exploratory, but Camilla already mentioned, in CSU there is this seven-day score from established that is the primary endpoint in trials and very broadly used and accepted. And that gives you a very good look and should give you a read whether the patients respond to the drug in four weeks or not. So that is something you can definitely scout at four weeks and that endpoint is clear. So the [EUA-7] is something that is broadly used.

是的。我很樂意解決這個問題。這非常簡單。在功效方面，這是探索性的，但卡米拉已經提到，在科羅拉多州立大學，有一個7天的評分，這是試驗的主要終點，並且被廣泛使用和接受。這可以讓您很好地了解患者在四個星期內是否對藥物有反應。所以這是你絕對可以在四個星期內發現的東西，而且終點是明確的。所以[EUA-7]是被廣泛使用的東西。

Then in the hidradenitis suppurativa population, we will look at reductions of all three lesions and compare that to the four-week reductions either reported from other drugs or seen with our own drug to discard. And you know, we've just shown you some of the data that were public from the avacopan trial. And we've shown you that there was a very late onset of efficacy, for example, if you noted, the draining tunnels did not even move before week 12.

然後，在化膿性汗腺炎人群中，我們將觀察所有三種病變的減少情況，並將其與其他藥物報告的或我們自己丟棄的藥物所觀察到的四周減少情況進行比較。您知道，我們剛剛向您展示了 avacopan 試驗的一些公開數據。我們已經向您展示了療效的出現非常晚，例如，如果您注意到，排水隧道在第 12 週之前甚至沒有移動。

And we will definitely see and compare that and hope that we see already the signals moving at week four quite a bit. And of course, we will -- with the three lesion counts established, we can then, of course, derive all the typical endpoints that you look at, obviously with a lower number and with a PK focused study, things like high score are not extremely informative. For us, the key is at that stage of the development to show you how much the three lesions moved at week four. I hope that helps for -- and again, we will probably provide them more color in our R&D event following.

我們肯定會看到並比較這一點，並希望我們已經看到第四週的訊號有很大變化。當然，我們會 - 建立三個病變計數後，我們當然可以得出您所看到的所有典型終點，顯然數字較低並且以 PK 為重點的研究，像高分之類的東西不是信息非常豐富。對我們來說，關鍵是在發展的這個階段向您展示三個病變在第四周移動了多少。我希望這能有所幫助——我們可能會在接下來的研發活動中為他們提供更多的色彩。

Great. And then you have a follow-up there in terms of the preclinical tox work. Could you remind us where we are in the progress? And if this will be a gating factor for the Phase 2 or will the timing line up where you can start -- go seamlessly into the Phase 2b next year?

偉大的。然後就臨床前毒理學工作進行後續工作。您能提醒我們進展到什麼程度了嗎？如果這將成為第 2 階段的限制因素，或者時間安排是否與您可以開始的時間一致——明年無縫進入第 2b 階段？

Yeah. Maybe I can take that. So yeah, for tox, we already start with a chronic tox, as we mentioned earlier, that you plan to do six months rather than the nine-months monkey. It does already start early this month. So yeah, we are planning seamlessly with all the clinical development, including Phase 2a, Phase 2b. So data expected for six months RAB will be end of this year and early next year for the nine months monkey. So to answer your question, we are -- the answer is that together with all the clinical developments.

是的。也許我可以接受。所以，是的，對於毒素，我們已經從慢性毒素開始，正如我們之前提到的，你計劃進行六個月而不是九個月的猴子。它確實已經在本月初開始了。所以，是的，我們正在無縫規劃所有臨床開發，包括 2a 期、2b 期。因此，預計六個月 RAB 的數據將在今年年底公佈，九個月猴子的數據將在明年年初公佈。因此，為了回答你的問題，我們的答案是連同所有的臨床進展。

Yeah. And so we have a couple of questions from [Edwin] today, at Guggenheim again on the preclinical. What kind of preclinical work have we done with INF904 in CSU? Can INF904 decrease the number of mast cells? And given its unique MOA, how are you thinking about positioning in CSU?

是的。今天，我們在古根漢再次就臨床前問題提出了 [Edwin] 的幾個問題。我們在CSU用INF904做了哪些臨床前工作？INF904 可以減少肥大細胞的數量嗎？鑑於其獨特的 MOA，您如何考慮在 CSU 的定位？

Yeah. Maybe for the second one, we don't know if INF904 kind of decrease the number of mast cells. In theory, they shouldn't. There's no reason to believe that INF904 to decrease mast cells based on the mode of actions. And for the first one in the in the literature, there's tons of study that's already been in workout for the role of C5aR in the CSU, where the CSU patient samples, especially the serum and plasma samples with a blockade of C5aR and with antibody or peptide, it shows like pretty good of blockades to the [histamine] needs for either mast cells or on the basophils.

是的。也許對於第二個，我們不知道 INF904 是否會減少肥大細胞的數量。從理論上講，他們不應該這樣做。沒有理由相信 INF904 根據作用方式可以減少肥大細胞。對於文獻中的第一個，已經有大量研究探討 C5aR 在 CSU 中的作用，其中 CSU 患者樣本，特別是具有 C5aR 阻斷和抗體或抗體的血清和血漿樣本。肥大細胞或嗜鹼性球的[組織胺]需求。

So we are currently working with a pretty well-known laboratory plus the [isometric] work out more details with the INF904. So yeah, I think the second question, Niels and Camilla have already addressed, [the pathation within CSU] you are now thinking that there's going to be just to treat the failures but, you know, basically we are able to -- should be able to treat both types of CSU.

因此，我們目前正在與一家相當知名的實驗室合作，並使用 INF904 [等距] 研究出更多細節。所以，是的，我認為第二個問題，尼爾斯和卡米拉已經解決了，[科羅拉多州立大學內部的路徑]你現在認為只會處理失敗，但是，你知道，基本上我們能夠——應該是能夠治療兩種類型的 CSU。

And then a follow-up. What would you expect the C5aR coverage required for clinical benefit at CSU and HS? Would they be different in one versus the other and in the other indications?

然後是後續行動。您期望 CSU 和 HS 臨床受益所需的 C5aR 承保範圍是多少？它們在一種與另一種以及其他適應症方面是否會有所不同？

Yeah. For CSU and HS, they are both skin disease and we generate the data, we do need a higher dose (inaudible) are good coverage on the scale for the drug. So yeah, so maybe -- but I don't -- there is no reason to believe that it's going to be a different dose for two disease at this point but we have to remain to see the data because our Phase 2a, we do plan how to bring out those coverage that was great and to able to work out a dose rate. With regarding to the other disease, I think it is too early to say for that. So in theory for ANCA, probably you don't need a lot of coverage because the focus on the vasculature. And that's pretty general answer for this one.

是的。對於 CSU 和 HS，它們都是皮膚病，我們產生數據，我們確實需要更高的劑量（聽不清楚）以便在藥物規模上得到良好的覆蓋。所以，是的，所以也許——但我不認為——目前沒有理由相信兩種疾病的劑量會有所不同，但我們必須繼續觀察數據，因為我們的 2a 階段，我們確實計劃如何實現良好的覆蓋範圍並且能夠計算出劑量率。至於另一種疾病，我認為現在說還太早。因此，從理論上講，對於 ANCA，您可能不需要大量覆蓋，因為重點是脈管系統。這是這個問題的一個非常籠統的答案。

Great. And then I've got a couple questions regarding the partnering strategy that we mentioned. So I'm wondering if you can provide us some high-level thinking of strategy on how we would approach or could approach partnering.

偉大的。然後我有幾個關於我們提到的合作策略的問題。因此，我想知道您是否能為我們提供一些關於我們將如何或可能開展合作的高級策略思考。

Yeah. Tom, do you want to take that?

是的。湯姆，你想要那個嗎？

Yeah. Happy to do that. Well, I mean, obviously, our focus in immunodermatology will lead us to put our efforts in this area, but we see the broader potential both of INF904 and of Vilobelimab in other indications. So we have initiated discussions with a variety of pharmaceutical companies that might have an interest in also helping us develop it in other indications.

是的。很高興這樣做。嗯，我的意思是，顯然，我們對免疫皮膚病學的關注將引導我們在這一領域投入努力，但我們看到 INF904 和 Vilobelimab 在其他適應症中更廣泛的潛力。因此，我們已經開始與多家製藥公司進行討論，這些公司可能有興趣幫助我們開發其他適應症。

So at this point, maybe too early to really say what it would look like and how these relationships could ultimately shape up being but I think that to explore the full potential of both drugs, it would be very advantageous to have somebody who would have an interest to focus on some of the areas that for resource reasons we have to live on the side for the time being.

因此，在這一點上，也許還為時過早，真正說出它會是什麼樣子以及這些關係最終會如何形成，但我認為，為了探索這兩種藥物的全部潛力，如果有人能夠擁有有興趣專注於一些由於資源原因我們暫時不得不暫時擱置的領域。

Yeah. So it's really like our wish to find pathways to faster unlock more value for the drug, right? As Tom just said, we are really convinced that there's a broad applicability to this pathway, wo our idea is like what can we do to speed up and unlock as much value as possible.

是的。所以這真的就像我們希望找到更快釋放藥物更多價值的途徑，對吧？正如湯姆剛才所說，我們確實相信這條途徑具有廣泛的適用性，我們的想法就是我們可以做些什麼來加速並釋放盡可能多的價值。

Great. So we've kind of covered this already, but I'll just bring it up since it was put in through the written dashboard. Again, from Joe at Leerink Partners saying the prior oral C5aR inhibitor showed better efficacy in HS patients who were more severe or Hurley Stage 3. Will you be targeting any particular kinds of HS patients in the studies?

偉大的。我們已經對此進行了介紹，但我只是將其提出來，因為它是透過書面儀表板放入的。Leerink Partners 的 Joe 再次表示，先前的口服 C5aR 抑制劑對更嚴重或 Hurley 3 期的 HS 患者顯示出更好的療效。您在研究中會針對任何特定類型的熱射病患者嗎？

And can you give us your thoughts on how trial endpoints and studies may have evolved since your initial and vilobelimab studies? And what learnings can you apply to the development of INF904 with that? So covered a fair bit of that. Maybe just kind of covering again?

您能否告訴我們您對自最初的維洛貝利單抗研究以來試驗終點和研究如何演變的看法？您可以將哪些經驗應用在 INF904 的開發中？所以涵蓋了其中的相當大一部分。也許只是再次掩蓋？

Yeah. I think it's -- I think from the general understanding of the disease, we all have learned that there are three lesions, and they need to be reduced if patients wanted to describe experienced an improvement. We know that the most difficult to treat are the draining tunnels, they are not captured by the currently use score, the high score. This score is established, it's been used now many times, it's been used in Phase 3 studies.

是的。我認為，從對這種疾病的一般理解來看，我們都知道有三種病變，如果患者想要描述經歷了改善，則需要減少它們。我們知道，最難處理的是排水隧道，它們不是由目前使用的分數（高分）捕獲的。這個分數已經建立，現在已經使用了很多次，已經用於第三階段的研究。

People have used the old high score, 50. Now there's even high score of 75 being explored. But we've also learned that high score is not used by physicians. I don't know any physician that would say I'm assessing my patients with a high score. It's a score that's only applied in clinical studies. And we've also learned that oftentimes, when you think about the IL-17 studies in Phase 3, they came in a bit underwhelming. So the score may not necessarily reflect the good path to differentiate from existing mechanisms, right?

人們已經使用了舊的高分，50。現在甚至還有75分的高分正在探索中。但我們也了解到，醫生並不使用高分。我不知道有哪個醫生會說我正在以高分評估我的病人。這是一個僅應用於臨床研究的分數。我們也了解到，當您想到第三階段的 IL-17 研究時，常常會發現它們的結果有點平淡。所以這個分數不一定能反映出有別於現有機制的好路徑，對嗎？

I think IL-17s are thought to be probably better drugs than anti-TNF in this disease, but yet on the high score, this could not be shown. So in other words, the field has -- the understanding about the limitations have involved, but it's been used and so it's the path to win the game. But I think thus far, as we know from our discussions, there's still a pretty high unmet need in patients with active draining tunnels.

我認為 IL-17 被認為在這種疾病中可能是比抗 TNF 更好的藥物，但從高分來看，這一點無法證明。換句話說，該領域已經了解了局限性，但它已經被使用，因此這是贏得比賽的途徑。但我認為到目前為止，正如我們從討論中了解到的那樣，對於具有主動引流通道的患者來說，仍然存在相當高的未滿足需求。

There's a belief that draining disease is still not adequately addressed even though there is a signal in IL-17 inhibitors that may not be strong enough to cover a lot of the patients. And so there are areas of unmet needs that relate to active draining disease, which is, you know, one area that we're definitely interested in looking in, whether we can bring more benefit to these patients. But it is at the same time, as I've shown you with the C5aR staining, there's no reason to believe why the drug shouldn't work in the overall patient population.

人們相信，儘管 IL-17 抑制劑發出的信號可能不足以覆蓋許多患者，但引流疾病仍未得到充分解決。因此，存在與主動引流疾病相關的未滿足的需求領域，您知道，這是我們肯定有興趣研究的一個領域，我們是否可以為這些患者帶來更多好處。但同時，正如我透過 C5aR 染色向您展示的那樣，沒有理由相信為什麼該藥物不適用於整個患者群體。

Second thing is also on maybe the -- you asked for the other endpoints, I think you know that the established endpoint is the high score, I mentioned that already, and then there's the lesions itself, and then there's lesion derived scores that don't vary as much. Most of them emphasize the draining tunnels at the most severe. So I would say there's another need I want to flag, which is -- I mentioned in the talk that a lot of the patients on these active drugs that are approved may have an efficacy loss over time where the efficacy wanes.

第二件事也可能是 - 你問了其他終點，我想你知道既定的終點是高分，我已經提到過，然後是病變本身，然後是病變衍生的分數差異如此之大。他們中的大多數都強調最嚴重的排水隧道。所以我想說，我還有另一個需要指出，那就是——我在演講中提到，許多使用這些已批准的活性藥物的患者可能會隨著時間的推移而出現療效損失，療效會減弱。

And I think one need is also to demonstrate at least in the Phase 3 studies that can certainly not be demonstrated early that a long-term exposure leads to significant improvement, long-term improvement in more patients. That is a big need. So if the average patient doesn't think that, with the 50% my efficacy wanes in the next six or nine months but I have a good chance, if I'm a responder, to stay responder, that would be a big win.

我認為還需要至少在第三階段研究中證明長期暴露會導致更多患者的顯著改善、長期改善，而這些研究肯定無法早期證明。這是一個很大的需求。因此，如果普通患者不認為我的療效在接下來的六到九個月內會減弱 50%，但如果我是響應者，我很有可能保持響應狀態，那將是一個巨大的勝利。

So I would say we understand the need that has evolved. There is need for new mechanisms, especially sustained improvement and our work on the active draining disease. It's too early for us to tell you exactly which one we will focus finally, but I would say, generally speaking, is our belief that the drug works in all disease stages, and that's our starting point. Okay.

所以我想說我們理解不斷變化的需求。需要新的機制，特別是持續的改善和我們在主動引流疾病方面的工作。現在告訴你我們最終會關注哪一個還為時過早，但我想說的是，一般來說，我們相信該藥物在所有疾病階段都有效，這就是我們的起點。好的。

Great. And so we have one more before we wrap up. It is again a written question asking us in terms of efficacy and safety, how does INF904 compare to avacopan? And are there any significant advantages or improvements for INF904, as a better choice for patients and for treating physicians? So I think just to summarize what we've discussed on that.

偉大的。在結束之前我們還有一個。這又是一個書面問題，從有效性和安全性方面詢問我們，INF904與avacopan相比如何？作為患者和治療醫生的更好選擇，INF904 是否有任何顯著的優勢或改善？所以我想總結一下我們就此討論的內容。

Yeah. I want to handle this very briefly and Renfeng please chime in if I forget anything. So I will start with the safety first. The one thing that is known about avacopan, I think in all standards, it's been a very safe drug. I don't -- there was one liver tox in the ANCA approval that was heavily discussed and that may have to do with the drug being like many oral chemical inhibitors, a CYP3A4 liver enzyme blocker, meaning it can lead to plasma accumulation of other drugs like corticosteroids or other drugs. And that can lead to other drugs getting higher and causing liver tox.

是的。我想簡單地處理一下這件事，如果我忘了什麼，請仁風插話。所以我會從安全第一開始。關於阿瓦科潘，我認為在所有標準中，已知的一件事是，它是一種非常安全的藥物。我不知道——ANCA 批准中有一種肝毒性引起了廣泛討論，這可能與該藥物像許多口服化學抑製劑一樣，即CYP3A4 肝酶阻斷劑有關，這意味著它可能導致其他物質在血漿中積聚。這可能會導致其他藥物的濃度升高並引起肝臟毒性。

Now we have in preclinical studies have shown that we have an over 30-fold less inhibitory potential to CYP3A4. So we have really very low if minimal engagement with CYP3A4, which is of course, comforting as we move forward. But again, flagging that, generally speaking, avacopan was a relatively safe drug as far as we know from the filings. So I hope that covers the safety question.

現在，我們的臨床前研究表明，我們對 CYP3A4 的抑制潛力降低了 30 倍以上。因此，我們與 CYP3A4 的接觸非常低，甚至是最小，這當然在我們前進的過程中令人感到欣慰。但再次強調，一般來說，據我們從文件中得知，avacopan 是一種相對安全的藥物。所以我希望這涵蓋了安全問題。

Now the other questions, the efficacy question, yes, we actually do believe that we can show a different efficacy and that is based on the fact that I showed you how long the drug takes, avacopan, takes to accumulate and what they are finally reaching, which was a bit over around 3,300, the area under the curve. And we can reach that with a higher dose on the first day of exposure and on the equivalent dose, certainly within the first 14 days.

現在是其他問題，功效問題，是的，我們確實相信我們可以表現出不同的功效，這是基於我向您展示了藥物需要多長時間，avacopan，需要多長時間才能積累以及它們最終達到的效果，略高於3,300，即曲線下面積。我們可以在接觸的第一天使用更高的劑量並使用相當的劑量（當然在前 14 天內）來達到這一目標。

So we have a very different bandwidth of reaching such an exposure level that they had have at their maximum extent accumulation, and we can exceed this by multiples, at least that's what our Phase 1 data indicate. Now, of course, we have to prove that that translates into better efficacy in humans. And there may be diseases where you can show that well and diseases where you cannot show it so well. We believe HS is a disease where you may be able to show that, especially with a more early onset and a more sustained reduction of these lesions. I hope that covers that.

因此，我們有一個非常不同的頻寬來達到他們在最大程度累積下的暴露水平，並且我們可以超過這個水平的倍數，至少這是我們第一階段數據所表明的。當然，現在我們必須證明這可以轉化為對人類更好的功效。可能有些疾病你可以很好地表現出來，有些疾病你則不能很好地表現出來。我們相信 HS 是一種您可以證明這一點的疾病，尤其是這些病變發病更早且持續減少。我希望這涵蓋了這一點。

Great. So we are finished with the Q&A session. If anyone in the audience, if we didn't get to your questions or didn't address it suitably, please feel free to reach out to IR at inflarx.de, and we can address at that point. So right now, I'll turn the call back over to Niels for closing remarks. Niels?

偉大的。那麼我們的問答環節就結束了。如果觀眾中的任何人，如果我們沒有回答您的問題或沒有適當地解決您的問題，請隨時聯繫 IR inflarx.de，我們可以在那時解決。現在，我將把電話轉回給尼爾斯，讓其結束語。尼爾斯？

Yeah, I'll make it short. Thanks so much for joining. We are very excited to have you and to share more with you to come in an R&D Day that we're planning on and happy to take calls and happy to take questions through the IR route as usual, in due course. So thank you, everyone. Have a great day, bye.

是的，我會簡短地說。非常感謝您的加入。我們非常高興您能來參加我們計劃舉辦的研發日活動，並與您分享更多信息，我們很高興在適當的時候像往常一樣接聽電話並通過 IR 途徑回答問題。謝謝大家。祝你有美好的一天，再見。