Altamira Therapeutics Ltd (CYTO) 2022 Q4 法說會逐字稿

Good morning, and welcome to the Altamira Therapeutics 2022 Results Conference Call. On today's call are Thomas Meyer, Altamira's Founder, Chairman and Chief Executive Officer; and Covadonga Pañeda, Altamira's Chief Operating Officer.

早上好，歡迎來到 Altamira Therapeutics 2022 年結果電話會議。參加今天電話會議的有 Altamira 的創始人、董事長兼首席執行官 Thomas Meyer；和 Altamira 的首席運營官 Covadonga Pañeda。

Earlier today, Altamira issued a news release with the full year 2022 financial results as well as a comprehensive business update. The release is available on the company's website at www.altamiratherapeutics.com and has been filed with the SEC. During today's call, the company will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These include statements that address future operating, financial or business performance or its strategies or expectations. Forward-looking statements are based on management's current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include, but are not limited to, the timing and conduct of our clinical trials, the clinical utility of our product candidates, the timing or likelihood of regulatory filings and approvals, our intellectual property position and our financial position as well as those described in the Risk Factors section on our annual report on Form 20-F and future filings with the Securities and Exchange Commission.

今天早些時候，Altamira 發布了一份新聞稿，其中包含 2022 年全年的財務業績以及全面的業務更新。該新聞稿可在公司網站 www.altamiratherapeutics.com 上查閱，並已提交給美國證券交易委員會。在今天的電話會議上，公司將根據 1995 年《私人證券訴訟改革法案》作出前瞻性陳述。這些陳述包括涉及未來運營、財務或業務績效或其戰略或預期的陳述。前瞻性陳述基於管理層當前的預期和信念，涉及重大風險和不確定性，可能導致實際結果、發展和業務決策與這些陳述預期的結果、發展和業務決策存在重大差異。這些風險和不確定性包括但不限於我們臨床試驗的時間和進行、我們產品候選人的臨床效用、監管備案和批准的時間或可能性、我們的知識產權狀況和我們的財務狀況以及我們在 20-F 表格年度報告和未來向美國證券交易委員會提交的文件中的風險因素部分中描述的那些。

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing its views as of any subsequent date. While it may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so even if its views change. With that, I will hand the call over to Thomas Meyer.

此外，任何前瞻性陳述僅代表公司截至今日的觀點，不應被視為代表其在任何後續日期的觀點。雖然它可能會選擇在未來的某個時候更新這些前瞻性陳述，但它明確表示不承擔任何義務，即使其觀點發生變化也是如此。有了這個，我將把電話交給托馬斯邁耶。

Thank you, operator. Hello, everyone, and thank you for joining our 2022 earnings and business update call. I will provide an update on our various development projects, an overview of recent corporate developments as well as an update on our strategy. Our Chief Operating Officer, Covadonga Paneda will discuss our RNA delivery technology, market position and strategy.

謝謝你，運營商。大家好，感謝您加入我們的 2022 年收益和業務更新電話會議。我將提供我們各種開發項目的最新情況、最近公司發展的概述以及我們戰略的最新情況。我們的首席運營官 Covadonga Paneda 將討論我們的 RNA 遞送技術、市場地位和戰略。

Finally, I will discuss our financials and outlook for the rest of 2023. We will then open the call for any questions. All in all, 2022 reflects continued progress on our strategic repositioning to become a leading pure play in RNA delivery technology for targets beyond the liver and with the effective and rapid release of RNA payloads within target cells. It is an incredibly exciting and dynamic emerging field of medicine.

最後，我將討論我們 2023 年剩餘時間的財務狀況和展望。然後我們將公開徵求任何問題。總而言之，2022 年反映了我們在戰略重新定位方面的持續進展，成為 RNA 遞送技術領域的領先者，針對肝臟以外的目標，並在目標細胞內有效快速地釋放 RNA 有效載荷。這是一個令人難以置信的令人興奮和充滿活力的新興醫學領域。

Many of you are already familiar with the nascent therapeutic RNA sector, which we and much of Wall Street believe has massively disruptive potential to transform the medical landscape. This is validated in part by the increasing sell-side coverage, strong investment capital flows and M&A in the sector over the past couple of years from big pharma. As to our legacy assets, we are fast approaching important clinical and regulatory milestones with our programs in OTC Consumer Health and in our Ear Therapeutics, which are key components in our strategy to divest or partner these legacy programs as the second and final step in our transformation to a pure-play RNA delivery technology company. In addition, through this process, we expect to unlock the intrinsic value of our legacy businesses.

你們中的許多人已經熟悉新興的治療性 RNA 領域，我們和華爾街的許多人都認為該領域具有巨大的顛覆性潛力，可以改變醫學領域。過去幾年大型製藥公司在該行業的賣方覆蓋範圍擴大、投資資本流動強勁以及併購活動在一定程度上證實了這一點。至於我們的遺留資產，我們正在快速接近重要的臨床和監管里程碑，我們在 OTC 消費者健康和耳部治療方面的項目是我們剝離或合作這些遺留項目戰略的關鍵組成部分，作為我們的第二步也是最後一步轉型為一家純粹的 RNA 遞送技術公司。此外，通過這一過程，我們希望釋放我們傳統業務的內在價值。

While the transformation has taken longer than initially expected, as these are valuable assets, we look forward to its conclusion this year, unpacking our strategic repositioning further, we have now essentially completed the clinical development program for Bentrio. Our FDA cleared drug free nasal spray for protection against harmful airborne particles such as allergens.

雖然轉型花費的時間比最初預期的要長，但由於這些都是寶貴的資產，我們期待著今年的結束，進一步展開我們的戰略重新定位，我們現在已經基本完成了 Bentrio 的臨床開發計劃。我們的 FDA 批准了不含藥物的鼻腔噴霧劑，以防止空氣中的有害顆粒（例如過敏原）。

We await top line data from our NASAR clinical trial later this month. We have also completed all planned development steps for our main inner Ear Therapeutic asset, AM-125, our betahistine nasal spray for the treatment of vertigo. Based on the positive outcomes from the Phase II TRAVERS clinical study in Europe, I'm delighted to announce today that we have just submitted an investigational new drug or IND application to the FDA for AM-125. We are actively engaged in divesting or out-licensing both Bentrio and AM-125. I will circle back with more detail on both our legacy assets Bentrio and AM-125 in a few minutes. At this time, I'm pleased to introduce Covadonga Paneda to discuss our flagship RNA programs. Cova?

我們等待本月晚些時候來自 NASAR 臨床試驗的頂級數據。我們還完成了我們的主要內耳治療資產 AM-125 的所有計劃開發步驟，AM-125 是我們用於治療眩暈的倍他司汀鼻腔噴霧劑。基於歐洲 II 期 TRAVERS 臨床研究的積極成果，我今天很高興地宣布，我們剛剛向 FDA 提交了 AM-125 的研究性新藥或 IND 申請。我們正積極參與剝離或授權 Bentrio 和 AM-125。幾分鐘後，我將詳細介紹我們的遺留資產 Bentrio 和 AM-125。此時，我很高興介紹 Covadonga Paneda 來討論我們的旗艦 RNA 項目。科瓦？

Thanks, Thomas, and good morning, everyone. Our RNA delivery technology center on our OligoPhore and SemaPhore platforms. The technology is based on a patented [platform] for delivery of RNA in nanoparticles to extrahepatic tissues with efficient endosomal release inside target cells. Both the delivery of RNA to tissues and organs beyond the liver and the speed and quantity of RNA payloads getting released into the cells [cytoplast] have remained major challenges for the application of RNA Therapeutics to date.

謝謝，托馬斯，大家早上好。我們的 RNA 遞送技術以我們的 OligoPhore 和 SemaPhore 平台為中心。該技術基於專利[平台]，用於將納米顆粒中的 RNA 遞送至肝外組織，並在靶細胞內有效釋放內體。迄今為止，RNA 向肝臟以外的組織和器官的遞送以及 RNA 有效載荷釋放到細胞 [細胞質] 中的速度和數量仍然是 RNA 治療應用的主要挑戰。

Those features coupled with good stability, a great tolerability profile as well as a strong versatility for (inaudible) technology extraordinarily powerful cutting edge, and we believe is quite valuable. The versatility is shown by the large and still growing number of disease models in which delivery technology has already been successfully tested. To date, OligoPhore and SemaPhore have been tested in 17 different studies in vivo with both short interfering RNA and messenger RNA.

這些特性加上良好的穩定性、良好的耐受性以及強大的通用性（聽不清）技術非常強大的前沿，我們相信這是非常有價值的。已經成功測試遞送技術的大量且仍在增長的疾病模型顯示了多功能性。迄今為止，OligoPhore 和 SemaPhore 已在 17 項不同的體內研究中用短干擾 RNA 和信使 RNA 進行了測試。

The 2 most recent additions evaluated SemaPhore with mRNA into interesting models. At the 2023 Osteoarthritis Research Society International World Congress held in March in Denver, a Washington University Research Group presented data from a mouse model of meniscal injury, referring to the meniscus, which is a cartilage tissue patch that cushions the new joint. Systemic delivery of DNA methyltransferase 3 beta mRNA with SemaPhore nanoparticles, significantly reduced bone sclerosis, cartilage degeneration and synovitis compared to controls. In addition, functional studies showed significantly decreased pain sensitivity and improved weight bearing. In a March 2023 Article Preprint, another Washington University Research Group presented data from the mouse model of sarcoma, metastatic breast cancer; systemic delivery of zinc finger and BTB domain containing 46 mRNA a transcription factor with SemaPhore nanoparticles promoted antitumor components in the tumor [marker] environment and resulted in restriction of tumor growth.

最近添加的 2 個將帶有 mRNA 的 SemaPhore 評估為有趣的模型。在 3 月於丹佛舉行的 2023 年骨關節炎研究協會國際世界大會上，華盛頓大學的一個研究小組展示了來自小鼠半月板損傷模型的數據，指的是半月板，它是一種緩衝新關節的軟骨組織貼片。與對照組相比，使用 SemaPhore 納米粒子全身遞送 DNA 甲基轉移酶 3 beta mRNA，可顯著減少骨硬化、軟骨退化和滑膜炎。此外，功能研究表明顯著降低了疼痛敏感性並改善了負重。在 2023 年 3 月的文章預印本中，另一個華盛頓大學研究小組展示了來自肉瘤、轉移性乳腺癌小鼠模型的數據；鋅指和含有 46 個 mRNA 轉錄因子的 BTB 結構域與 SemaPhore 納米顆粒的全身遞送促進了腫瘤 [標記] 環境中的抗腫瘤成分，並導致腫瘤生長受限。

When the nanoparticle treatment was combined with an anti-PD-1 checkpoint inhibitor, significantly to synergistic effects in the control of tumor growth were observed, generating long-term complete remission of tumor mass in many of the treated animals. Our business model is to make our delivery technology available for use by biopharmaceutical companies with their own RNA sequences under license. That is we are providing the modern version of picks and shovels rather than (inaudible). This business model is capital efficient, scalable and therefore offers great potential.

當納米顆粒治療與抗 PD-1 檢查點抑製劑聯合使用時，觀察到在控制腫瘤生長方面的顯著協同效應，在許多接受治療的動物中產生了腫瘤質量的長期完全緩解。我們的商業模式是讓我們的交付技術可供擁有自己的 RNA 序列並獲得許可的生物製藥公司使用。也就是說，我們提供的是現代版的鎬和鏟，而不是（聽不清）。這種商業模式具有資本效率、可擴展性，因此具有巨大的潛力。

Since 2022, we have stepped up our efforts to present and promote our OligoPhore and SemaPhore platforms by presenting at international conferences, submitting our research, studies to medical journals and increasing our business development activities targeted at potential partners in the biopharmaceutical industry. As I often attend or speak at this conferences, I can report we have increasingly succeeded with injecting OligoPhore and SemaPhore into the biotech industry.

自 2022 年以來，我們加大了展示和推廣我們的 OligoPhore 和 SemaPhore 平台的力度，包括在國際會議上展示、向醫學期刊提交我們的研究、研究報告以及增加我們針對生物製藥行業潛在合作夥伴的業務發展活動。由於我經常參加這些會議或在這些會議上發言，我可以報告我們在將 OligoPhore 和 SemaPhore 注入生物技術行業方面取得了越來越大的成功。

We continue to step up our business development efforts. As a result of these outreach efforts, we are confident to enter into the first collaboration agreements with biopharmaceutical companies this year. Concurrent with our development of OligoPhore and SemaPhore platforms, we have continued the development work in our 2 showcase program with OligoPhore platform for sRNA delivery. AM-401 for the treatment of KRAS-driven tumors, and AM-411 for the treatment of Rheumatoid Arthritis. As a reminder, AM-401 is our program for the treatment of KRAS-driven cancers. KRAS is the most frequently mutated oncogene in human cancer. Currently, only one specific mutation name G12C is addressable through pharmacological treatment, but there are many more oncogenic mutations that occur within this gene and the (inaudible) disease. Our approach seeks to tackle several mutations with one single product, which we call polyKRASmut. That is all one word spell lower case poly, upper case KRAS, with a superscript MUT tagged on.

我們繼續加大業務發展力度。由於這些外展工作，我們有信心在今年與生物製藥公司簽訂首批合作協議。在我們開發 OligoPhore 和 SemaPhore 平台的同時，我們繼續在我們的 2 展示計劃中使用 OligoPhore 平台進行 sRNA 遞送的開發工作。 AM-401 用於治療 KRAS 驅動的腫瘤，AM-411 用於治療類風濕性關節炎。提醒一下，AM-401 是我們治療 KRAS 驅動的癌症的項目。 KRAS 是人類癌症中最常發生突變的致癌基因。目前，只有一個特定的突變名稱 G12C 可以通過藥物治療解決，但在該基因和（聽不清）疾病中發生了更多的致癌突變。我們的方法試圖用一種產品解決多個突變，我們稱之為 polyKRASmut。這是所有一個單詞拼寫小寫字母 poly，大寫字母 KRAS，並帶有上標 MUT 標記。

We are testing AM-401 in different in vitro and in vivo models with the aim of moving into IND-enabling toxicology studies by Q4 2023. In February of this year, we expanded our intellectual property estate by filing a provisional patent application relating to polyKRASmut. If granted, the patent would extend IP coverage for the AM-401 program out to year 2043. AM-411 targets a component of the NF-kB inflammatory pathway and is under development for the treatment of rheumatoid arthritis. NF-kB is the main inflammation checkpoint in this disease and has for a long time been considered undruggable. The reasons behind these are 2 fold. On the one side, it is an intracellular protein, and as such, difficult to target using traditional small molecules. On the other hand, NF-kB has important physiological function in nondisease cells. With the combination of an RNA-based therapy and OligoPhore platform, we can address an intracellular target specifically in sites of inflammation, which in the case of rheumatoid arthritis are typically the joints.

我們正在不同的體外和體內模型中測試 AM-401，目標是到 2023 年第四季度進入支持 IND 的毒理學研究。今年 2 月，我們通過提交與 polyKRASmut 相關的臨時專利申請擴大了我們的知識產權資產.如果獲得批准，該專利將把 AM-401 計劃的知識產權覆蓋範圍擴大到 2043 年。AM-411 靶向 NF-kB 炎症通路的一個組成部分，目前正在開髮用於治療類風濕性關節炎。 NF-kB 是這種疾病的主要炎症檢查點，長期以來一直被認為是不可治癒的。這些背後的原因有兩個。一方面，它是一種細胞內蛋白，因此難以使用傳統的小分子進行靶向。另一方面，NF-kB 在非疾病細胞中具有重要的生理功能。通過結合基於 RNA 的療法和 OligoPhore 平台，我們可以專門針對炎症部位的細胞內靶標，在類風濕性關節炎的情況下，炎症部位通常是關節。

For AM-411 we're aiming to start IND-enabling toxicology studies in the first half of 2024. The use of RNA therapeutics is start to offer significant advantages for the treatment of diseases who were resistant to develops over time, as is the case for KRAS-driven cancer are Rheumatoid arthritis. RNA silencing, down regulates the target protein rather than inhibiting it. Consequently, reducing the likelihood of resistance because the target protein is simply not present in the tissue or it would induce resistance. Looking further forward, we aim to advance both AM-401 and AM-411 to an IND-filing with the FDA next year. Until then out-license them either following the IND or after our Phase I clinical trial at the latest. Thomas, that's my report. Back to you.

對於 AM-411，我們的目標是在 2024 年上半年開始支持 IND 的毒理學研究。RNA 療法的使用開始為治療隨著時間的推移產生耐藥性的疾病提供顯著優勢，情況就是如此KRAS 驅動的癌症是類風濕性關節炎。 RNA沉默，下調靶蛋白而不是抑制它。因此，降低了耐藥性的可能性，因為目標蛋白根本不存在於組織中，否則會誘發耐藥性。展望未來，我們的目標是明年將 AM-401 和 AM-411 推進到 FDA 的 IND 備案。在那之前，要么在 IND 之後，要么最遲在我們的 I 期臨床試驗之後，向他們授予許可。托馬斯，這是我的報告。回到你身邊。

Thanks, Cova. I will now unpack in greater detail our strategy for Bentrio and AM-125. On Bentrio, we are looking forward to the full top line data readout from the NASAR trial in seasonal allergic rhinitis in Australia, which we expect to announce later this month. That will complete the Bentrio development program in allergic rhinitis and will close out the last remaining clinical study. With this, we have accumulated clinical data from 2 challenged studies under controlled allergen exposure, one in seasonal and the other in perennial allergic rhinitis as well as data from one outdoor study, NASAR, which has been performed under real-life conditions. The NASAR study enrolled 100 patients suffering from seasonal allergic rhinitis, more commonly known as hay fever, who were treated for 2 weeks either with Bentrio or a classic saline nasal spray, which is the current standard of care and drug-free treatments.

謝謝，科瓦。我現在將更詳細地闡述我們對 Bentrio 和 AM-125 的戰略。在 Bentrio 上，我們期待著澳大利亞季節性過敏性鼻炎 NASAR 試驗的完整頂線數據讀出，我們預計將在本月晚些時候公佈。這將完成 Bentrio 在過敏性鼻炎方面的開發計劃，並將結束剩下的最後一項臨床研究。有了這個，我們從 2 項受控過敏原暴露下的挑戰研究中積累了臨床數據，一項是季節性的，另一項是常年性過敏性鼻炎，以及一項戶外研究 NASAR 的數據，該研究是在現實生活條件下進行的。 NASAR 研究招募了 100 名患有季節性過敏性鼻炎（通常稱為花粉症）的患者，他們接受了 Bentrio 或經典鹽水噴鼻劑治療 2 週，這是目前的標準護理和無藥物治療。

Back in January, we announced the results from an interim analysis of 53 patients, which showed a statistically significant improvement for Bentrio treated patients versus controls as well as good safety and tolerability. That improvement was well above the minimal clinically important difference and even approach the magnitude achieved with certain medicated nasal sprays. (inaudible) and saline nasal spray aims to rinse out allergen particles. Bentrio forms a thin protective layer, which prevents contact of those particles with the nasal mucosa and helps to remove them through natural mucociliary clearance.

早在 1 月份，我們就公佈了對 53 名患者進行的中期分析的結果，該結果顯示接受 Bentrio 治療的患者與對照組相比在統計學上有顯著改善，並且具有良好的安全性和耐受性。這種改善遠高於最小的臨床重要差異，甚至接近某些藥物鼻腔噴霧劑所達到的程度。 （聽不清）和鹽水鼻腔噴霧劑旨在沖洗掉過敏原顆粒。 Bentrio 形成一層薄薄的保護層，可防止這些顆粒與鼻粘膜接觸，並有助於通過自然粘膜纖毛清除將其清除。

As demonstrated in yet another study, which was published recently in a peer-reviewed scientific journal, Bentrio stays for about 3.5 hours within the nasal cavity where it can exert its protective effects. In contrast, saline spray was present for only about 1 hour and showed narrow distribution and less coverage within the nasal cavity. Overall, we have a strong set of data for Bentrio in the management of allergic rhinitis, which we have considered as the principal application for this product right from the start.

最近發表在同行評議的科學期刊上的另一項研究表明，Bentrio 在鼻腔內停留約 3.5 小時，可以發揮其保護作用。相比之下，鹽水噴霧僅存在約 1 小時，並且在鼻腔內顯示出狹窄的分佈和較少的覆蓋範圍。總的來說，我們在治療過敏性鼻炎方面擁有一組強大的 Bentrio 數據，我們從一開始就將其視為該產品的主要應用。

We are addressing here a very sizable market. It is estimated to reach close to $4 billion in U.S. sales in 2023 alone. In our view, there are particularly great market opportunities in the segment of non-medicated preservative-free treatments. As for the development of Bentrio for use in viral infections, we very much remain convinced of the product's utility based on how it works and based on the wealth of supportive data. The thin protective film formed by Bentrio on top of the nasal mucosa helps to defend not only against airborne allergen particles, but also against airborne virus particles.

我們在這裡針對的是一個非常龐大的市場。據估計，僅在 2023 年，美國的銷售額就將達到近 40 億美元。我們認為，非藥物無防腐劑治療領域的市場機會尤其巨大。至於 Bentrio 用於病毒感染的開發，我們非常相信該產品的實用性，基於它的工作原理和大量的支持數據。 Bentrio 在鼻粘膜頂部形成的薄保護膜不僅有助於抵禦空氣中的過敏原顆粒，還有助於抵禦空氣中的病毒顆粒。

Unfortunately, the design and setup of clinical studies in viral infection are much more challenging than for allergic rhinitis, which was very much evident during the COVID-19 pandemic as case numbers were waxing and waning. In addition, the time course of an infection is also challenging, and that symptoms typically start to appear only once the viral load in the nasal cavity has already started to decline, which means that one may only start treatment late. And then one has to beat the natural recovery. That is the fact that typically infections tend to recover on their own over time.

不幸的是，病毒感染臨床研究的設計和設置比過敏性鼻炎更具挑戰性，這在 COVID-19 大流行期間非常明顯，因為病例數時好時壞。此外，感染的時間進程也具有挑戰性，通常只有在鼻腔中的病毒載量已經開始下降時才會出現症狀，這意味著人們可能只能晚開始治療。然後必須擊敗自然恢復。這就是感染通常會隨著時間的推移自行恢復的事實。

With our COVAMID trial with Bentrio in 160 patients suffering from acute COVID-19, we face these types of challenges. As reported back in January, the results from the study were inconclusive under the specific test conditions. Also a trend for faster, more pronounced reduction in nasal viral load and symptoms was observed as Bentrio compared to untreated controls. The differences were not deemed statistically significant. Altamira considers that the more benign outcomes from the Omicron variant resulted in more pronounced spontaneous recovery and treatment may have started too late in the trial, about 4.5 days after infection. As previous studies with Bentrio on cultured human nasal epithelial cells exposed to various types of viruses, have shown best results from prophylactic treatment application.

通過我們在 160 名急性 COVID-19 患者中使用 Bentrio 進行的 COVAMID 試驗，我們面臨著這些類型的挑戰。正如 1 月份報導的那樣，該研究的結果在特定測試條件下尚無定論。與未治療的對照組相比，Bentrio 還觀察到鼻病毒載量和症狀更快、更明顯減少的趨勢。這些差異不被認為具有統計學意義。 Altamira 認為 Omicron 變體的更良性結果導致更明顯的自發恢復，並且在試驗中治療可能開始得太晚，大約在感染後 4.5 天。正如之前使用 Bentrio 對暴露於各種病毒的培養的人鼻上皮細胞進行的研究一樣，預防性治療應用顯示出最佳結果。

We concluded that Bentrio is best used right before or while being exposed to virus particles. No further studies in viral infection are ongoing or planned at this point. As part of our strategic pivot to become a pure play RNA delivery technology company, we initiated last year discussions with several well-established OTC Consumer Health companies for the partnering of Bentrio for North America, Europe and other key international markets. These discussions and related due diligence have extended into 2023 and are still ongoing at this point. In the context of these partnering discussions, the company suspended preparations for launching the product in the U.S. on its own and minimize marketing and sales activities in Europe. Meanwhile, the company's existing distribution partners launched Bentrio in several Asian geographies, including Singapore, Malaysia, Indonesia, the Philippines and Hong Kong. Through partnering with well-established players in OTC Consumer Health, we expect to unlock and realize the significant value of Bentrio and look forward to moving these discussions to the finish line.

我們的結論是，Bentrio 最好在接觸病毒顆粒之前或接觸病毒顆粒時使用。目前沒有正在進行或計劃對病毒感染進行進一步的研究。作為我們成為一家純粹的 RNA 遞送技術公司的戰略支點的一部分，我們去年開始與幾家成熟的 OTC 消費者健康公司討論 Bentrio 在北美、歐洲和其他主要國際市場的合作。這些討論和相關的盡職調查已經延續到 2023 年，目前仍在進行中。在這些合作討論的背景下，該公司暫停了在美國自行推出該產品的準備工作，並最大限度地減少了在歐洲的營銷和銷售活動。與此同時，該公司現有的分銷合作夥伴在多個亞洲地區推出了 Bentrio，包括新加坡、馬來西亞、印度尼西亞、菲律賓和香港。通過與 OTC 消費者健康領域的知名企業合作，我們期望釋放並實現 Bentrio 的重要價值，並期待將這些討論推進到終點。

After Bentrio, let me turn now to AM-125. In June of 2022, we announced positive top line data from our Phase II TRAVERS trial with AM-125. This is a patented nasal spray formulation of betahistine for the treatment of surgery-induced acute vestibular syndrome abbreviated as AVS. Detailed results were published last month in a peer-reviewed article. AVS is characterized by the sudden onset of continuous vertigo lasting days to weeks and may be associated with nausea, head motion intolerance and unstable balance. The randomized double-blind placebo-controlled TRAVERS trial enrolled a total of 124 patients at more than 10 study sites across Europe who suffered from AVS following surgery for the removal of the tumor growing behind the inner ear.

在 Bentrio 之後，讓我現在轉向 AM-125。 2022 年 6 月，我們公佈了 AM-125 II 期 TRAVERS 試驗的正面頂線數據。這是獲得專利的倍他司汀鼻腔噴霧劑，用於治療手術引起的急性前庭綜合徵，縮寫為 AVS。詳細結果於上個月發表在一篇同行評議的文章中。 AVS 的特徵是持續數天至數週的持續性眩暈突然發作，可能與噁心、頭部運動不耐受和平衡不穩定有關。隨機雙盲安慰劑對照 TRAVERS 試驗在歐洲 10 多個研究地點共招募了 124 名患者，這些患者在手術切除內耳後生長的腫瘤後患有 AVS。

The trial demonstrated good tolerability of 125. Further, administration of 125 resulted in a dose and time-dependent improvement in balance and signs and symptoms of vestibular dysfunction. Based on the positive outcomes from our TRAVERS study, we have just submitted the IND to the FDA, which, if cleared, will allow conducting clinical trials also in the U.S. The submission includes the protocol for a Phase II trial or the treatment of Posterior Canal Benign Paroxysmal Positional Vertigo, or BPPV which is the most common type of AVS and is characterized by repeated episodes of vertigo produce by changes in the head position relative to gravity.

該試驗證明了 125 的良好耐受性。此外，125 的給藥導致前庭功能障礙的平衡和體徵和症狀的劑量和時間依賴性改善。基於我們 TRAVERS 研究的積極成果，我們剛剛向 FDA 提交了 IND，如果獲得批准，將允許在美國進行臨床試驗。提交的文件包括 II 期試驗或後管治療的方案良性陣發性位置性眩暈，或 BPPV，是最常見的 AVS 類型，其特徵是頭部位置相對於重力的變化會反復發作眩暈。

We are confident that the IND will increase both AM-125's attractiveness and value. At a minimum, the FDA review will take 30 days in case of questions that we will need to answer, clearance could take longer. In the context of our strategic pivot to RNA delivery technology, we intend to divest or partner the AM-125 program for further development and commercialization. To this end, we have entered discussions with a number of potential partners, and we expect to broaden and intensify those activities now that the IND has been filed. On one hand, we see an attractive market potential for 125 in all those markets where all betahistine is currently being marketed, and that is more than 115 countries worldwide with the U.S. being a notable exception.

我們相信 IND 將增加 AM-125 的吸引力和價值。如果我們需要回答問題，FDA 審查至少需要 30 天，批准可能需要更長時間。在我們以 RNA 遞送技術為戰略重點的背景下，我們打算剝離或合作 AM-125 計劃，以進一步開發和商業化。為此，我們已經與一些潛在的合作夥伴進行了討論，我們希望在提交 IND 後擴大和加強這些活動。一方面，我們在所有目前正在銷售所有倍他司汀的市場中看到了 125 個有吸引力的市場潛力，全球超過 115 個國家/地區，美國是一個明顯的例外。

In most of these countries, all betahistine is the standard-of-care treatment for vertigo and is actually the only vestibular stimulant available. The global market for oral betahistine is about $450 million per year in revenues to the manufacturers. Importantly, AM-125 has a 5 to 29 fold higher bioavailability than oral betahistine. On the other hand, we see in the U.S. what could be the largest potential market for AM-125 as there is no approved vestibular stimulant drug product at all. AM-125 benefits from patent protection until 2038. Apart from AVS, AM-125 could have utility also in other CNS therapeutic areas. Clinical studies with betahistine, which were conducted independently from us suggests potential therapeutics benefits also in attention deficit hyperactivity disorder, ADHD, atypical depression, Prader-Willi syndrome or dementia.

在大多數這些國家中，所有倍他司汀都是治療眩暈的標準療法，實際上是唯一可用的前庭興奮劑。口服倍他司汀的全球市場每年為製造商帶來的收入約為 4.5 億美元。重要的是，AM-125 的生物利用度比口服倍他司汀高 5 到 29 倍。另一方面，我們在美國看到什麼可能是 AM-125 最大的潛在市場，因為根本沒有批准的前庭興奮藥物產品。 AM-125 在 2038 年之前享有專利保護。除了 AVS 之外，AM-125 還可以在其他 CNS 治療領域發揮作用。獨立於我們進行的倍他司汀臨床研究表明，在註意力缺陷多動障礙、多動症、非典型抑鬱症、普瑞德-威利綜合徵或癡呆症方面也有潛在的治療益處。

Turning next to our financial highlights for the full financial year ending on December 31, 2022. Unless indicated otherwise, all numbers will be in Swiss francs. As of today, CHF 1 approximately buys USD 1.1. In 2022, revenue from Bentrio sales was CHF 0.3 million compared to CHF 0.1 million for 2021. As mentioned before, we decided not to push marketing and sales activities to build the Bentrio brand and grow sales as we intend to partner the product. Further, the waning of the COVID-19 pandemic reduced the demand for protection against viral infection. Please note that the 2022 revenues exclude a nonrefundable upfront cash license fee of USD 1 million from Nuance Pharma related to the marketing and distribution of Bentrio in Mainland China, Hong Kong, Macau and South Korea, which was deferred for revenue recognition.

接下來是我們截至 2022 年 12 月 31 日的整個財政年度的財務亮點。除非另有說明，否則所有數字均以瑞士法郎為單位。截至今日，1 瑞士法郎約可兌換 1.1 美元。 2022 年，Bentrio 的銷售收入為 30 萬瑞士法郎，而 2021 年為 10 萬瑞士法郎。如前所述，我們決定不推動營銷和銷售活動來打造 Bentrio 品牌並增加銷售額，因為我們打算與產品合作。此外，COVID-19 大流行的減弱減少了對病毒感染防護的需求。請注意，2022年的收入不包括 Nuance Pharma 與 Bentrio 在中國大陸、香港、澳門和韓國的營銷和分銷相關的 100 萬美元不可退還的預付現金許可費，該費用被推遲確認收入。

Total operating expenses in 2022 were CHF 25.1 million (sic) [CHF 26.1 million] or CHF 13.7 million before a onetime noncash write-off all capitalized development expenditures for the AM-125 project based on the impairment testing performed under IFRS, International Financial Reporting Standards. This compares with CHF 16.8 million for 2021. R&D expenses were CHF 19.7 million or CHF 7.3 million before the aforementioned impairment compared with CHF 8.4 million for 2021. General and admin expenses were CHF 3.6 million compared with CHF 4.9 million for 2021. The net loss was CHF 26.5 million or CHF 14.1 million before the aforementioned onetime impairment compared with a net loss of CHF 17.1 million for 2021. Cash and cash equivalents on December 31, 2022, totaled CHF 15,000 compared with CHF 1 million on December 31, 2021.

2022 年的總運營費用為 2510 萬瑞士法郎（原文如此）[2610 萬瑞士法郎] 或 1370 萬瑞士法郎，根據 IFRS、國際財務報告進行的減值測試，一次性註銷 AM-125 項目的所有資本化開發支出之前標準。相比之下，2021 年為 1680 萬瑞士法郎。研發費用在上述減值之前為 1970 萬瑞士法郎或 730 萬瑞士法郎，而 2021 年為 840 萬瑞士法郎。一般和管理費用為 360 萬瑞士法郎，而 2021 年為 490 萬瑞士法郎。淨虧損在上述一次性減值之前為 2650 萬瑞士法郎或 1410 萬瑞士法郎，而 2021 年的淨虧損為 1710 萬瑞士法郎。2022 年 12 月 31 日的現金和現金等價物總計 15,000 瑞士法郎，而 2021 年 12 月 31 日為 100 萬瑞士法郎。

Over the last quarters, we have decreased our cash burn significantly as studies for our legacy assets have been completed or winding down. We have been adjusting our staffing levels accordingly. Cash burn is expected to increase again later in the year as we will ramp up several projects in RNA delivery. Overall, we expect for 2023 operating expenses of CHF 12 million to CHF 13 million and our cash requirement to be in the range of CHF 15 million to CHF 17 million, which we intend to fund through proceeds from the planned divestiture of partnering of our legacy assets, issuances of equity, debt financings as well as grants. During the first 4 months of 2023, we already raised USD 5.1 million from share issuances under the at-the-market program with A.G.P and the equity line with Lincoln Capital Partners.

在過去幾個季度中，隨著對遺留資產的研究已經完成或逐漸結束，我們大幅減少了現金消耗。我們一直在相應地調整我們的人員配置水平。現金消耗預計將在今年晚些時候再次增加，因為我們將增加 RNA 交付的幾個項目。總體而言，我們預計 2023 年的運營費用為 1200 萬至 1300 萬瑞士法郎，我們的現金需求將在 1500 萬至 1700 萬瑞士法郎之間，我們打算通過計劃剝離我們的遺產合作夥伴關係的收益來提供資金資產、股權發行、債務融資以及贈款。在 2023 年前 4 個月，我們已經通過與 A.G.P 的上市計劃和與 Lincoln Capital Partners 的股權發行籌集了 510 萬美元。

Further, in early May 2023, we raised CHF 2.5 million through a convertible loan provided by FiveT investment management. That loan bears interest at the rate of 10% per annum and matures 22 months from May 4, 2023. Last but not least, in April, the CHF 5 million convertible loan issued to Altamira 14 months earlier by FiveT was converted, including accrued interest by the lender into common shares, reducing financial liabilities by CHF 5.6 million.

此外，在 2023 年 5 月上旬，我們通過 FiveT 投資管理提供的可轉換貸款籌集了 250 萬瑞士法郎。該貸款按年利率 10% 計息，從 2023 年 5 月 4 日起 22 個月到期。最後但同樣重要的是，在 4 月，FiveT 14 個月前向 Altamira 發放的 500 萬瑞士法郎可轉換貸款被轉換，包括應計利息由貸方轉換為普通股，減少 560 萬瑞士法郎的金融負債。

Before we open for questions, I'd like to quickly summarize our report and outlook. With Bentrio, we expect to announce top line data from the complete NASAR trial for hay fever in Australia in the current month. In January, we had already reported positive interim data from that trial, and we are therefore confident about the further outcomes. It will be the last open remaining Bentrio study data readout. We are in advanced discussions with well-established OTC Consumer Healthcare companies to whom we seek to divest or out-license Bentrio. With AM-125, our clinical data has been positive. Accordingly, we submitted an IND with the FDA for a Phase II clinical study for BPPV, the most common type of vertigo. If granted, the opening of the IND will be another key milestone in the program.

在我們開始提問之前，我想快速總結一下我們的報告和展望。對於 Bentrio，我們預計將在本月公佈澳大利亞花粉熱的完整 NASAR 試驗的頂級數據。一月份，我們已經報告了該試驗的積極中期數據，因此我們對進一步的結果充滿信心。這將是最後一個開放的剩餘 Bentrio 研究數據讀數。我們正在與成熟的 OTC 消費者保健公司進行深入討論，我們尋求將 Bentrio 剝離或授權給這些公司。對於 AM-125，我們的臨床數據是積極的。因此，我們向 FDA 提交了一份 IND，用於 BPPV（最常見的眩暈類型）的 II 期臨床研究。如果獲得批准，IND 的啟用將成為該計劃的另一個重要里程碑。

Clinical data confirmed that AM-125 increases betahistine levels in the blood circulation, 5 to 29 fold compared to a standard oral dose of betahistine. We are actively engaged in discussions to divest or out-license AM-125. Now that we have filed the IND, we will step up our efforts here as in the case of Bentrio with outside specialist support. With our patented RNA delivery platforms, OligoPhore and SemaPhore, and our AM-401 and AM-411 showcase programs, we are continuing preclinical research and stepping up business development activities further. We are seeing growing interest in our RNA delivery technology and expect to enter into our first research collaborations with biopharmaceutical companies as we progress through 2023. Financially, we have essentially cleaned up our balance sheet, reduced financial liabilities and raise cash. The key focus will be on generating non-dilutive funding from the planned divestiture or partnering of our legacy assets. We expect this to support us in making further great progress advancing the exciting research and preclinical studies for our RNA platform and early stage product candidates. As always, we aim to be proactive in keeping our shareholders informed as we continue to advance our mission. I would now like to turn the call back to the operator to open the lines for questions.

臨床數據證實，與標準口服劑量的倍他司汀相比，AM-125 可使血液循環中的倍他司汀水平提高 5 至 29 倍。我們正在積極參與討論剝離或授權 AM-125。現在我們已經提交了 IND，我們將在外部專家支持下像 Bentrio 一樣在這方面加緊努力。憑藉我們獲得專利的 RNA 遞送平台 OligoPhore 和 SemaPhore，以及我們的 AM-401 和 AM-411 展示計劃，我們正在繼續臨床前研究並進一步加強業務開發活動。我們看到人們對我們的 RNA 遞送技術越來越感興趣，並期望在我們到 2023 年的過程中與生物製藥公司進行首次研究合作。在財務上，我們基本上清理了資產負債表，減少了金融負債並籌集了現金。重點將放在從計劃中的遺留資產剝離或合作中產生非稀釋性資金。我們希望這能支持我們取得進一步的重大進展，推進我們的 RNA 平台和早期候選產品的激動人心的研究和臨床前研究。一如既往，我們的目標是在繼續推進我們的使命時積極主動地讓我們的股東了解情況。我現在想將電話轉回給接線員以打開問題熱線。

Management will now answer questions. Thomas, your line is unmuted.

管理層現在將回答問題。 Thomas，您的線路未靜音。

Yes. Okay. So thank you, operator. We are going to answer a couple of questions that we received. Some of them were overlapping. So we tried here to consolidate those questions. So the first question that we want to address here is why was the AM-401 IND postponed from the end of 2023 to 2024. And for this question, I would like to ask Cova to step in.

是的。好的。所以謝謝你，運營商。我們將回答我們收到的幾個問題。其中一些是重疊的。所以我們在這裡嘗試整合這些問題。所以我們要在這裡解決的第一個問題是為什麼 AM-401 IND 從 2023 年底推遲到 2024 年。對於這個問題，我想請 Cova 介入。

Yes, Thomas. So the plan was to submit by the end of 2023, but this has now shifted towards 2024. And the reason behind it is we have to coordinate your capacities with CROs.

是的，托馬斯。所以計劃是在 2023 年底之前提交，但現在已經轉向 2024 年。其背後的原因是我們必須與 CRO 協調您的能力。

Okay. Thank you. The next question will be also related to RNA. So when do you expect joint sponsor development and FDA approval of mRNA products? Cova, if you could take that one as well, please?

好的。謝謝。下一個問題也將與RNA有關。那麼，您預計什麼時候聯合贊助商開發 mRNA 產品並獲得 FDA 批准？ Cova，你能不能也拿那個，好嗎？

Sure. As mentioned, we expect to enter into the first collaboration agreement this year, but our plans are not to take AM-401 or AM-411 beyond IND or Phase I, the latest.

當然。如前所述，我們預計今年將簽訂第一份合作協議，但我們的計劃不會讓 AM-401 或 AM-411 超過 IND 或最新的 I 期。

Right. And as Cova mentioned during the call, well, we expect to have here some active pipeline for collaborations. So we definitely expect here some news flow as we progress further through 2023.

正確的。正如 Cova 在電話會議中提到的那樣，我們希望這裡有一些積極的合作渠道。因此，隨著我們在 2023 年的進一步發展，我們肯定會在這裡看到一些消息。

The next question relates to Bentrio. There has been no Bentrio distribution deal for an extended period of time. Are you still actively looking for distribution deals or waiting on divestiture?

下一個問題與本特里奧有關。很長一段時間內沒有 Bentrio 分銷協議。您是否仍在積極尋找分銷交易或等待資產剝離？

So clearly, the ongoing discussions with potential partners here for North America, Europe and other key markets are shaping here our strategy. Apart from these discussions, we do have, indeed, several programs ongoing for market access with our partners, and we expect to have further news here also for certain markets that are not covered currently.

很明顯，與北美、歐洲和其他主要市場的潛在合作夥伴正在進行的討論正在塑造我們的戰略。除了這些討論之外，我們確實有幾個與我們的合作夥伴正在進行的市場准入計劃，我們希望在這裡也有關於目前未涵蓋的某些市場的更多消息。

Let me just highlight the activities of our strategic partner, Nuance Pharma, which launched a Bentrio in late 2022 in Hong Kong. And Nuance is currently preparing for a submission of a request for marketing approval in Mainland China and South Korea. So just as a reminder, here in early 2022, we could enter into that strategic partnering relationship with Nuance Pharma. We have been very pleased with how it has been going so far. And as you can imagine here the potential in Asian countries, in particular, in larger Asian countries like China or Korea, they are quite significant here for Bentrio.

我只想強調我們的戰略合作夥伴 Nuance Pharma 的活動，該公司於 2022 年底在香港推出了 Bentrio。而Nuance目前正在準備提交在中國大陸和韓國上市許可的申請。因此，提醒一下，我們可以在 2022 年初與 Nuance Pharma 建立戰略合作關係。我們對到目前為止的進展感到非常滿意。正如您在這裡可以想像的那樣，亞洲國家的潛力，特別是中國或韓國等較大的亞洲國家的潛力，對於 Bentrio 而言非常重要。

Moving on to the next question. So what range of proceeds from transactions does the company reasonably hope to achieve in 2023?

繼續下一個問題。那麼公司合理希望在 2023 年實現的交易收益範圍是多少？

Well, of course, we do have an idea. But for obvious reasons, we are not disclosing our expectations for proceeds. I hope you will understand that. However, we do know and have already disclosed what we invested into the development of our legacy assets. Obviously, these were quite substantial amounts. We are seeking to unlock this intrinsic value through this divestiture or partnering process with partners.

嗯，當然，我們確實有一個想法。但出於顯而易見的原因，我們沒有透露我們對收益的預期。我希望你會明白這一點。但是，我們確實知道並且已經披露了我們對遺留資產開發的投資。顯然，這些都是相當可觀的數額。我們正在尋求通過這種資產剝離或與合作夥伴的合作過程來釋放這種內在價值。

So this has taken a bit longer than expected of the 2023 will be the year where we will have execution on these programs. Another question, Mr. Lachance left the company, what has happened to the OTC Consumer Health business unit? So that's referring to Bentrio again. Well, Jean Lachance, as the Head of the Business Unit, he indeed left the company last year as its family moved abroad. What we understood is a decision, but obviously, also regretted very much his departure. Now since then, I have assumed myself, management responsibilities for this business.

因此，這比 2023 年我們將執行這些計劃的預期時間要長一些。另外一個問題，Lachance 先生離開了公司，OTC Consumer Health 事業部怎麼了？所以這又是指本特里奧。好吧，Jean Lachance，作為業務部門的負責人，去年他確實離開了公司，因為它的家人搬到了國外。我們理解的是一個決定，但顯然，也很遺憾他的離開。從那時起，我就承擔了這項業務的管理責任。

And then another question that came in. So what news flow can investors expect this year? So just to summarize a few things that we already mentioned, but also to expand a little bit on that. So there will be indeed quite a few things that we expect to report this year. So in the near term, we expect news flow from the AM-125 IND submission. So we hope that things will run smoothly. We invested over the years quite a lot here into all the preclinical data, generating them and clinical data and well, on the production of the product and so on and also from the NASAR study with Bentrio. So as mentioned, NASAR is a very important study under realized conditions for 2 weeks against nasal spray saline spray, which is the key competitor here for drug-free allergic rhinitis management.

然後出現了另一個問題。那麼今年投資者可以期待什麼樣的新聞流？所以只是總結我們已經提到的一些事情，但也要對此進行一些擴展。因此，我們預計今年確實會報告很多事情。因此，在短期內，我們預計來自 AM-125 IND 提交的新聞流。所以我們希望事情會順利進行。多年來，我們在這裡對所有臨床前數據進行了大量投資，生成它們和臨床數據，以及產品的生產等等，還有來自 Bentrio 的 NASAR 研究。因此，如前所述，NASAR 是一項非常重要的研究，在已實現的條件下進行為期 2 週的鼻腔生理鹽水噴霧，這是這裡無藥物過敏性鼻炎管理的主要競爭對手。

Now apart from this, we expect news flow from our divestiture partnering process, probably first about Bentrio. Now within the RNA delivery technology area, while stay tuned for further updates on science, on development progress and partnering, as Cova already mentioned. There is really a lot going on currently. We are very busy, but this is all very exciting.

現在除此之外，我們預計我們的資產剝離合作流程會帶來新聞，可能首先是關於 Bentrio 的。正如 Cova 已經提到的，現在在 RNA 遞送技術領域，請繼續關注科學、發展進展和合作方面的進一步更新。目前確實發生了很多事情。我們很忙，但這一切都非常令人興奮。

So with this, I'm concluding the Q&A. Thank you very much for your interest. I will simply thank everyone for attending this morning's call and also for the good questions, and I will wish you a terrific day ahead. Thank you very much, and take care. With this, back to the operator.

因此，我要結束問答環節。非常感謝您的關注。我將簡單地感謝大家參加今天上午的電話會議並提出很好的問題，祝你們有美好的一天。非常感謝，保重。有了這個，回到運營商。

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.

今天的會議到此結束，此時您可以斷開您的線路。感謝您的參與。