Immunovant, Inc. (IMVT) 2022 Q4 法說會逐字稿

Good morning. My name is Melissa, and I will serve as your conference call operator. (Operator Instructions) As a reminder, this call is being recorded.

各位早安。我叫 Melissa，將擔任本次電話會議的接線員。（接線員指示）提醒各位，本通話將被錄音。

Joining me on the call today will be Dr. Pete Salzmann, Chief Executive Officer of Immunovant. Before we begin, I would like to remind everyone that today's conference call will include certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, among other things, statements regarding Immunovant's plan to initiate 2 Phase III clinical trials for batoclimab in TED in the second half of calendar year 2022, with an expected top line data readout in the first half of calendar year 2025, and its plan to initiate a Phase III clinical trial in MG by the end of June 2022, with an expected readout in the second half of calendar year 2024.

今天與我一同參與電話會議的有 Immunovant 的執行長 Pete Salzmann 博士。在開始之前，我想提醒各位，今天的電話會議將包含若干前瞻性陳述，其意義符合 1995 年《私人證券訴訟改革法》（Private Securities Litigation Reform Act of 1995）。這些前瞻性陳述包括但不限於：Immunovant 計畫於 2022 年下半年在 TED 適應症中啟動 2 項 batoclimab 的第三期臨床試驗，並預期於 2025 年上半年取得主要（top line）數據讀出；以及計畫於 2022 年 6 月底前在 MG 適應症中啟動一項第三期臨床試驗，並預期於 2024 年下半年取得讀出。

Immunovant's plans to develop batoclimab across a broad range of autoimmune indications, the potential efficacy and safety of Immunovant's product candidate, Immunovant's expectations regarding the timing, design and results of its clinical trials, including the timing of future data readouts and the announcement of additional indications and whether if approved, batoclimab will be successfully distributed, marketed and commercialized. All forward-looking statements are based on estimates and assumptions by Immunovant's management that, although Immunovant believes to be reasonable, are inherently uncertain.

Immunovant 計畫在廣泛的自體免疫適應症中開發 batoclimab、Immunovant 產品候選藥物的潛在療效與安全性、Immunovant 對其臨床試驗時程、設計與結果的預期（包括未來數據讀出時點、額外適應症的宣布時點），以及若獲核准，batoclimab 是否能成功進行配送、行銷與商業化。所有前瞻性陳述均基於 Immunovant 管理層的估計與假設；儘管 Immunovant 認為其合理，但本質上具有不確定性。

All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Immunovant expected. For more information, investors are encouraged to review Immunovant's annual report on Form 10-K for the year ended March 31, 2022, filed with the SEC on June 8, 2022, and Immunovant's subsequent filings with the SEC. Any forward-looking statement speaks only as of the date on which it was made and Immunovant undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

所有前瞻性陳述均受風險與不確定性影響，可能導致實際結果與 Immunovant 的預期存在重大差異。欲了解更多資訊，建議投資人查閱 Immunovant 截至 2022 年 3 月 31 日止年度的 Form 10-K 年報（已於 2022 年 6 月 8 日向美國證券交易委員會（SEC）提交），以及 Immunovant 其後向 SEC 提交的文件。任何前瞻性陳述僅截至其作出之日有效，Immunovant 不承擔公開更新或修訂任何前瞻性陳述之義務，不論係因新資訊、未來事件或其他原因。

Now I'd like to turn the call over to Dr. Pete Salzmann. Thank you. Dr. Salzmann, please go ahead.

現在我想把電話交給 Pete Salzmann 博士。謝謝。Salzmann 博士，請開始。

Thank you, Melissa, and thanks to everyone for joining the call today. I'm very excited to share that Immunovant recently achieved alignment with the FDA Division of Ophthalmology to move forward with a pivotal program in thyroid eye disease or TED. This is a big milestone for Immunovant, and we now plan to initiate 2 placebo-controlled Phase III trials for TED in the second half of 2022. We expect to have top line data for these trials in the first half of 2025.

謝謝你，Melissa，也感謝各位今天加入本次電話會議。我非常高興分享，Immunovant 近期已與 FDA 眼科部門（Division of Ophthalmology）就推進甲狀腺眼病（thyroid eye disease，TED）的關鍵性（pivotal）計畫達成一致。這對 Immunovant 而言是一個重要里程碑；我們目前計畫於 2022 年下半年在 TED 中啟動 2 項安慰劑對照的第三期試驗。我們預期在 2025 年上半年取得這些試驗的主要（top line）數據。

TED is the second pivotal program we have announced for batoclimab and represents a first-in-class program with an exciting market opportunity. As we heard from physicians and as we discussed at our R&D Day this past March, there has been a paradigm shift in the treatment of TED. As many of you know, the FDA approved teprotumumab in January of 2020, which is now the only FDA-approved treatment option for thyroid eye disease.

TED 是我們為 batoclimab 所宣布的第二個關鍵性計畫，並代表一個同類首創（first-in-class）的計畫，具有令人振奮的市場機會。正如我們從醫師端所聽到的，以及我們在今年 3 月的研發日（R&D Day）所討論的，TED 的治療已出現典範轉移。各位多半知道，FDA 已於 2020 年 1 月核准 teprotumumab，而它目前仍是唯一獲 FDA 核准用於甲狀腺眼病的治療選項。

When new medications are approved for a disease with high unmet need and a historical lack of innovation, then some patients who are already under the care of a physician can rapidly gain access to the new medication. In addition, these types of approvals raise awareness of the disease among other patients who may not yet be under the care of a physician or specialist. The growing patient awareness also impacts physician decision-making and the market expands.

當新的藥物在一個未被滿足需求高、且歷史上缺乏創新的疾病領域獲得核准時，一些原本已在醫師照護下的患者，可能會迅速取得新藥的使用機會。此外，這類核准也會提升其他患者對該疾病的認知；這些患者可能尚未接受醫師或專科醫師的照護。患者認知的提升也會影響醫師的決策，並使市場擴大。

We've seen this unfold in thyroid eye disease. The market opportunity continues to grow as the awareness of the disease continues to expand, and we believe this will be the case for quite a while, similar to the steady market growth experienced in other immunology markets after the first big innovation. At the same time, the TED market has some very unique features. The disease itself is heterogeneous and, therefore, lends itself to complementary mechanisms of action. Fixed duration of dosing specified in the FDA labels for TED also supports the development of new and complementary mechanisms of action.

我們已在甲狀腺眼病中看到這樣的發展。隨著疾病認知持續擴大，市場機會也持續成長；我們相信這種情況將維持相當一段時間，類似於其他免疫學市場在首次重大創新之後所經歷的穩健市場成長。同時，TED 市場也具有一些非常獨特的特徵。疾病本身具有異質性，因此適合採用互補的作用機轉。FDA 對 TED 的標籤中所規定的固定療程（fixed duration）給藥，也支持開發新的、互補的作用機轉。

The net result is what we believe to be an exciting opportunity for patients and for batoclimab. Today, I will introduce our TED Phase III clinical design and focus on the important points of differentiation for batoclimab in thyroid eye disease. I'll start by reviewing some of the fundamental biology for how batoclimab may work in TED and why we believe that TSH receptor autoantibodies are key drivers of Graves hyperthyroidism and TED.

最終結果是，我們認為這對患者以及 batoclimab 都是一個令人振奮的機會。今天我將介紹我們 TED 第三期臨床試驗的設計，並聚焦於 batoclimab 在甲狀腺眼病中的重要差異化重點。我將先回顧一些基礎生物學，說明 batoclimab 可能如何在 TED 中發揮作用，以及為何我們認為 TSH 受體自體抗體是葛瑞夫茲甲狀腺機能亢進（Graves hyperthyroidism）與 TED 的關鍵驅動因子。

In the top row of the figure, anti-TSH receptor autoantibody circulating the body and bind to the TSH receptor. In the rightmost figure, the auto antibody is binding to a TSH receptor in the thyroid gland. This activates the thyroid follicle, increasing cellular metabolism and the release of thyroid related hormone. Of course, this is not the end of the story since TSH receptor antibodies can circulate in the blood and bind to other target cells that also express the TSH receptor.

在圖示的最上排，抗 TSH 受體自體抗體在體內循環並與 TSH 受體結合。在最右側的圖中，自體抗體與甲狀腺中的 TSH 受體結合。這會活化甲狀腺濾泡，增加細胞代謝並促進甲狀腺相關荷爾蒙的釋放。當然，故事並未到此為止，因為 TSH 受體抗體可以在血液中循環，並與其他同樣表現 TSH 受體的標的細胞結合。

In the middle figure, the autoantibodies are shown binding to the TSH receptor in the periorbital space where they activate orbital fibroblast. This leads to proliferation of the periorbital tissue and differentiation of these fibroblasts. In the absence of batoclimab, anti-TSHR antibodies are recycled back into the blood by the Fc receptor and endothelial cells. They remain present to recirculate and reengage receptors throughout the body.

在中間的圖中，自體抗體被顯示與眼眶周圍（periorbital）空間中的 TSH 受體結合，並在該處活化眼眶纖維母細胞（orbital fibroblast）。這會導致眼眶周圍組織增生，以及這些纖維母細胞的分化。在沒有 batoclimab 的情況下，抗 TSHR 抗體會透過 Fc 受體與內皮細胞被回收再循環回到血液中。它們會持續存在，以再次循環並在全身重新與受體結合。

Note that beside the TSH receptor, the insulin growth factor I receptor, shown on this slide in blue and adjacent to the TSH receptor also plays a role in the pathophysiology of the disease. Once an autoantibody binds to the TSH receptor, there is crosstalk between the TSH and the IGF-1 receptors, and the engagement of both receptors leads to activation of intracellular pathways linked to the clinical science and symptoms of TED.

請注意，除了 TSH 受體之外，胰島素樣生長因子 I 受體（insulin growth factor I receptor），在本投影片中以藍色顯示並位於 TSH 受體旁邊，也在疾病的病理生理中扮演角色。一旦自體抗體與 TSH 受體結合，TSH 與 IGF-1 受體之間會產生交互作用（crosstalk），而兩個受體的共同參與會導致細胞內路徑的活化，與 TED 的臨床表現與症狀相關。

So this crosstalk between the TSH receptor and the IGF-1 receptor appears to be crucial to the pathophysiology of the disease. As most of you likely know, batoclimab reduces circulating IgG by binding to the Fc receptor and inhibiting FcRn-mediated recycling of IgG that normally takes place in endothelial cells. I'll review some data later in the presentation regarding batoclimab's observed impact on anti-TSHR antibody in TED patients from a prior study.

因此，TSH 受體與 IGF-1 受體之間的這種交互作用似乎對疾病的病理生理至關重要。各位多半知道，batoclimab 透過與 Fc 受體結合並抑制在內皮細胞中通常發生的 FcRn 介導 IgG 回收再循環，從而降低循環中的 IgG。我稍後會在簡報中回顧一些數據，說明在先前研究中，batoclimab 對 TED 患者抗 TSHR 抗體所觀察到的影響。

Although proptosis is a prominent and important feature of thyroid eye disease, TED is actually a heterogeneous condition. Indeed, patients experience a variety of symptoms. This slide includes pictures of 2 different people with thyroid eye disease and together provide an example of how TED can vary from patient to patient. Both people in these photos have proptosis, but the degree of inflammatory changes differs between them. The patient in the top panel has much more eyelid edema and conjunctival redness than the patient in the bottom panel.

雖然眼球突出（proptosis）是甲狀腺眼病的一個顯著且重要的特徵，但 TED 實際上是一種具有異質性的疾病。確實，患者會經歷多種不同症狀。本投影片包含兩位不同 TED 患者的照片，合在一起示範 TED 如何因人而異。這兩張照片中的兩位患者都有眼球突出，但發炎變化的程度不同。上方照片的患者眼瞼水腫與結膜發紅明顯比下方照片的患者更嚴重。

The symptom heterogeneity is common in TED. We also found that even with treatment, patients with active TED report making substantial lifestyle modifications. Based on our market research, 80% of participants reported making moderate or major lifestyle modifications despite ongoing systemic therapy to which they were responding. The patients we surveyed were between 30 and 60 years old, reflecting a prime working age range consistent with the TED population. In fact, the impact on work-life was highlighted as particularly challenging as participants reported difficulty working on electronic devices, difficulty driving and challenges engaging in social situations.

症狀的異質性在 TED 中很常見。我們也發現，即使接受治療，活動期 TED 患者仍表示需要做出相當程度的生活型態調整。根據我們的市場研究，儘管受試者正在接受且對其有反應的全身性治療，仍有 80% 的參與者表示做出了中度或重大生活型態調整。我們調查的患者年齡介於 30 至 60 歲，反映出與 TED 人口相符的主要工作年齡層。事實上，對工作與生活的影響被特別指出具有挑戰性，因為參與者回報在使用電子裝置工作方面有困難、駕駛有困難，以及在社交情境中參與的挑戰。

When we ask participants to rank their most important treatment goal, there was not a single top treatment goal shared across the patient population; Rather, the most important goal varied patient to patient. While improving proptosis by 2 millimeters or more is clinically significant and very important, there are symptoms other than proptosis that can be an even higher priority for certain patients. We believe it's possible that mechanisms with different -- medications with different mechanisms of action will assess different symptoms in different ways and can therefore be complementary in the treatment paradigm.

當我們請參與者排列他們最重要的治療目標時，整體患者族群並沒有一個共同的單一首要治療目標；相反地，最重要的目標會因患者而異。雖然眼球突出改善 2 毫米或以上在臨床上具有顯著意義且非常重要，但對某些患者而言，除了眼球突出之外的其他症狀可能具有更高優先順序。我們認為，不同作用機轉的治療——具有不同作用機轉的藥物——可能會以不同方式評估不同症狀，因此在治療典範中可以彼此互補。

As I mentioned in my opening comments, teprotumumab has made a meaningful impact on the treatment of TED since its launch in early 2020. The (inaudible) launch has probably improved diagnosis rates in TED and has certainly reframed the urgency to treat compared to the historic watch-and-wait approach that was frequently applied. This sort of post-launch market development is common for a disease that hasn't had any innovation in a long time. In addition to this favorable market growth, which we expect to continue, the TED market also has some unique features centered around the fixed duration of dosing specified in the FDA label.

如我在開場評論中提到的，自 2020 年初上市以來，teprotumumab 已對 TED 的治療帶來具實質意義的影響。該（聽不清）上市可能提高了 TED 的診斷率，並且確實重新界定了治療的急迫性，相較於過去經常採用的「觀察等待」方式。對於長期缺乏創新的疾病而言，這類上市後的市場發展相當常見。除了我們預期將持續的有利市場成長之外，TED 市場也具有一些獨特特徵，核心在於 FDA 標籤中所規定的固定給藥療程長度。

Fixed duration of dosing is uncommon in immunology, but common in ophthalmology. In fact, we believe that FDA labels for TED will continue to specify a dosing duration defined by the length of the controlled period of the clinical trial. This is important because the dosing duration specified in the label may be insufficient for many patients. As noted here in the OPTIC 48-week off-treatment follow-up period, 44% of Tepezza patients who were proptosis responders at week 24 in OPTIC were not proptosis responders at week 72, highlighting an opportunity for additional treatment.

固定療程長度在免疫學領域並不常見，但在眼科領域很常見。事實上，我們認為 TED 的 FDA 標籤將持續指定一個由臨床試驗受控期長度所界定的給藥療程。這點很重要，因為標籤所規定的給藥療程對許多患者而言可能不足。如同此處 OPTIC 試驗 48 週停藥追蹤期所示，在 OPTIC 試驗第 24 週為突眼（proptosis）反應者的 Tepezza 患者中，有 44% 在第 72 週不再是突眼反應者，凸顯了追加治療的機會。

We believe this opportunity is ideally suited for a new mechanism of action, not only because reimbursement is often strictly limited to the frequency and duration specified in the FDA label, but also because TED is a heterogeneous disease that is likely amenable to complementary mechanisms of action. Such complementary treatment in series will, of course, be longer, and so a simple subcutaneous route of information -- of administration becomes even more important, at least for one of the medications.

我們認為這個機會非常適合採用新的作用機轉，不僅因為給付通常嚴格受限於 FDA 標籤所規定的頻率與療程長度，也因為 TED 是一種異質性疾病，可能適合以互補的作用機轉來治療。當然，這種序列式的互補治療會更長，因此簡便的皮下注射給藥途徑——給藥方式——就變得更為重要，至少對其中一種藥物而言是如此。

So what is the bottom line? How many TED patients do we believe could benefit from a therapy with a new mechanism of action? We estimate this total addressable population in the U.S. to be between 8,000 and 18,000 patients annually. Assuming success in our pivotal program and product approval, we anticipate some patients will be treated first with batoclimab. When comparing potential product profiles, many patients and physicians in our market research selected a profile like the one batoclimab may have for patients on the moderate side of the moderate to severe active TED spectrum.

那麼結論是什麼？我們認為有多少 TED 患者可能受益於具有新作用機轉的療法？我們估計美國每年的總可及族群（TAM）約為 8,000 至 18,000 名患者。假設我們的關鍵性（pivotal）計畫成功並獲得產品核准，我們預期部分患者將先以 batoclimab 治療。在比較潛在產品特性時，我們的市場研究顯示，許多患者與醫師為處於中度至重度活動性 TED 光譜中較偏中度的患者，選擇了類似 batoclimab 可能具備的產品特性。

A chronic given by simple subcutaneous injection without hearing loss issues and with solid proptosis efficacy, even if a bit less than Tepezza on this dimension, is attractive as initial therapy for patients on the moderate end of the moderate to severe spectrum. This group makes up about half of the potential addressable market for a new mechanism of action. The second logical group is made up of patients who respond well to Tepezza, but have some residual symptoms at the end of their 24-week course of treatment or relapse at some point off treatment. This group also makes up about half of the potential addressable market for a new mechanism of action.

以簡單的皮下注射作為慢性治療、沒有聽力損失問題，且在突眼方面具有穩健療效——即使在此面向可能略低於 Tepezza——對於位於中度至重度光譜中較偏中度的患者而言，作為初始治療具有吸引力。這一族群約占新作用機轉可及市場的一半。第二個合乎邏輯的族群，是對 Tepezza 反應良好，但在 24 週療程結束時仍有部分殘餘症狀，或在停藥後某個時間點復發的患者。這一族群同樣約占新作用機轉可及市場的一半。

Collectively, we believe 8,000 to 18,000 patients in the United States could be candidates for treatment with batoclimab, and this may even be complementary to Tepezza's growth. So we see this as a very exciting market that is really just beginning to show its full potential.

綜合而言，我們認為美國有 8,000 至 18,000 名患者可能成為 batoclimab 的治療候選者，而這甚至可能與 Tepezza 的成長相互補強。因此我們認為這是一個非常令人振奮、且才剛開始展現其全部潛力的市場。

Now I'd like to briefly review our clinical development with TED to date. The data on this slide is from a cell-based assay that looks specifically at those auto antibodies, which stimulate the TSH receptor, not just those antibodies that bind to it. This is important because some antibodies bind the receptor, but they don't stimulate it. And it's really only the stimulatory antibodies that are important to the pathophysiology of TED.

接下來我想簡要回顧我們迄今在 TED 的臨床開發。此投影片上的數據來自一種細胞為基礎的檢測（cell-based assay），其專門檢視那些會刺激 TSH 受體的自體抗體，而不僅是會與其結合的抗體。這點很重要，因為有些抗體會結合受體，但不會刺激它。而真正與 TED 病理生理相關的，主要是這些具刺激性的抗體。

The primary graph shows the dose-dependent decreases in stimulatory auto antibodies that were observed with 12 weeks of dosing and the gradual recovery of auto antibodies after the dosing period. Data in the table on the right side of the slide shows the percentage of subjects in each group whose stimulatory auto antibodies came down into the normal range based on the cell-based functional assay. The upper limit of normal in this assay is 140, and getting below 140 indicates a seroconversion where the level of stimulatory auto antibodies is no longer considered different than what is observed in control serum.

主要圖表顯示在 12 週給藥期間觀察到的具刺激性自體抗體隨劑量增加而下降，以及在給藥期結束後自體抗體逐步回升。投影片右側表格的數據顯示，依據該細胞為基礎的功能性檢測，各組受試者中具刺激性自體抗體下降至正常範圍的比例。此檢測的正常上限為 140，低於 140 代表發生血清轉換（seroconversion），亦即具刺激性自體抗體的水準不再被認為與對照血清所觀察到的水準不同。

So over a 12-week period, the observed level of seroconversion was highest in the 680-milligram arm. This was one of several data points leading to our final study design that includes an initial 12 weeks of dosing with 680 milligrams delivered subcutaneously. This slide shows exploratory proptosis data from the same study. As a reminder, the data on this slide is from week 6 of our TED Phase IIb trial. Although the primary endpoint for this prematurely terminated trial was not significant at week 12, we selected week 6 for this post hoc analysis because it represents the latest time point with the largest amount of patient data available prior to dosing being stopped due to the voluntary pause.

因此在 12 週期間，觀察到的血清轉換比例以 680 毫克組最高。這是促成我們最終研究設計的多項數據之一；該設計包含先以 680 毫克皮下注射進行 12 週的初始給藥。本投影片顯示同一研究的探索性突眼數據。提醒一下，本投影片的數據來自我們 TED 第 IIb 期試驗的第 6 週。雖然這項提前終止的試驗在第 12 週的主要終點未達顯著，但我們選擇第 6 週進行此事後（post hoc）分析，因為在因自願性暫停而停止給藥之前，第 6 週是可取得最多患者數據的最晚時間點。

At this early time point at week 6, the observed proptosis response rate was numerically higher at the higher dosages. Again, all treatment was weekly by subcutaneous injection. This slide shows CT scan data that I find very intriguing. CT scans were done in a few centers and were interpreted by a specialized central reader. This graph shows data for all subjects who had a baseline CT, and who also had an end-of-treatment CT scan after completing 12 weeks of dosing. As you can see on the Y axis, the bars show percent change from baseline in total extraocular muscle volume.

在第 6 週這個較早的時間點，觀察到的突眼反應率在較高劑量下於數值上更高。同樣地，所有治療皆為每週皮下注射。本投影片顯示我認為非常耐人尋味的 CT 掃描數據。CT 掃描在少數中心進行，並由專門的中央判讀者解讀。此圖表顯示所有具有基線 CT，且在完成 12 週給藥後也有治療結束 CT 的受試者數據。如同您在 Y 軸所見，長條顯示外眼肌總體積相較基線的百分比變化。

Looking at week 12 CT scan data on this slide, we observe a suggestion of a dose-dependent effect on muscle volume with a 30% reduction of total muscle volume observed in the 680-milligram batoclimab group. We observed numerically smaller decreases in other batoclimab groups, while placebo subjects increased slightly on average. Of course, these are exploratory endpoints in a small number of patients. At the same time, the readings were done by a blinded central reader and this is the complete CT data set from the trial.

從本投影片的第 12 週 CT 掃描數據來看，我們觀察到肌肉體積可能存在隨劑量增加而變化的效果；在 680 毫克 batoclimab 組中，外眼肌總體積下降 30%。在其他 batoclimab 組中，我們觀察到數值上較小的下降，而安慰劑受試者平均則略有上升。當然，這些是在少數患者中的探索性終點。同時，判讀由盲態的中央判讀者完成，且這是該試驗完整的 CT 數據集。

Overall, we believe that data from our prior TED trials are very encouraging for our pivotal development program in batoclimab in thyroid eye disease. We also believe that these data suggest that higher levels of IgG suppression may be required initially, and that leads to our trial side. Whereas our 340-milligram weekly dose provides IgG lowering typical of other anti-FcRns in development, our 680-milligram weekly dose has consistently shown IgG reduction around 80% with subcutaneous dosing, something unique to batoclimab within the anti-FcRn class. This initial 12-week dosing period with 680 milligrams adds differentiation beyond even first-in-class.

整體而言，我們認為先前 TED 試驗的數據，對於 batoclimab 在甲狀腺眼病的關鍵性開發計畫而言非常令人鼓舞。我們也認為這些數據顯示，初期可能需要更高程度的 IgG 抑制，這也引導了我們的試驗設計。相較之下，我們每週 340 毫克的劑量所帶來的 IgG 降幅，與其他正在開發中的抗 FcRn 藥物相當；而我們每週 680 毫克的劑量在皮下給藥下，已一再顯示 IgG 約 80% 的降低，這在抗 FcRn 類別中對 batoclimab 而言是獨特的。這段以 680 毫克進行的初始 12 週給藥期，帶來了甚至超越同類首創（first-in-class）的差異化。

As the ophthalmology division of the FDA has provided guidance that 2 pivotal trials are required for new medications in TED, we've designed 2 identical studies to run in parallel. We expect to enroll approximately 100 subjects for each trial with 2:1 randomization to either batoclimab or to placebo for a 24-week treatment period. Subjects randomized to the batoclimab arm will receive 680 milligrams of batoclimab delivered weekly for the first 12 weeks, followed by 340 milligrams of batoclimab delivered weekly for the next 12 weeks.

由於 FDA 眼科部門已提供指引，指出 TED 的新藥需要 2 項關鍵性試驗，我們設計了 2 項完全相同的研究並行進行。我們預期每項試驗收納約 100 名受試者，並以 2:1 隨機分派至 batoclimab 或安慰劑，治療期為 24 週。隨機分派至 batoclimab 組的受試者，前 12 週每週接受 680 毫克 batoclimab 皮下給藥，接著後 12 週每週接受 340 毫克 batoclimab 給藥。

The key inclusion criteria are similar to other pivotal programs in TED and the primary efficacy endpoint will be measured as proptosis responders at week 24 versus placebo, where responders are defined as a greater than or equal to 2-millimeter reduction from baseline in proptosis in the study eye without deterioration in the fellow eye. As I mentioned previously, this design takes advantage of batoclimab's specific attributes, namely the deep IgG reduction and simple subcutaneous route of administration. We plan to initiate these Phase III trials in TED in the second half of calendar year 2022 and expect to have top line data from both trials in the first half of 2025.

關鍵納入標準與 TED 其他關鍵性計畫相似；主要療效終點將以第 24 週相較安慰劑的突眼反應者比例衡量，其中反應者定義為研究眼突眼程度相較基線減少大於或等於 2 毫米，且對側眼未惡化。如我先前提到，這個設計運用了 batoclimab 的特定屬性，亦即深度的 IgG 降低以及簡便的皮下給藥途徑。我們計畫於 2022 年下半年啟動這些 TED 第 III 期試驗，並預期在 2025 年上半年取得兩項試驗的主要（top line）數據。

Finally, here's a review of our overall development program for batoclimab. We plan to initiate our Phase III myasthenia gravis trial later this month. And as a reminder, this Phase III MG trial represents our first pivotal program with batoclimab with top line data expected in the second half of calendar year 2024. Building on our progress in MG and TED, we plan to engage with the hematology division of the FDA to discuss development for warm autoimmune hemolytic anemia.

最後，以下是我們針對 batoclimab 的整體開發計畫回顧。我們計畫於本月稍晚啟動第三期重症肌無力（myasthenia gravis, MG）試驗。並提醒一下，這項第三期 MG 試驗代表我們以 batoclimab 進行的第一個關鍵性（pivotal）計畫，預計在 2024 年下半年公布主要（top line）數據。在我們於 MG 與 TED 的進展基礎上，我們計畫與 FDA 的血液學部門（hematology division）交流，討論溫抗體自體免疫性溶血性貧血（warm autoimmune hemolytic anemia）的開發。

We also expect to announce 2 new indications as previously committed by August of 2022. Beyond MG and TED, we're planning to initiate a pivotal trial in one more indication in 2022, bringing the total to 3 pivotal trials expected to be initiated in calendar year 2022. This development plan reflects the enthusiasm our team has for the anti-FcRn space in general and for batoclimab in particular.

我們也預期將如同先前於 2022 年 8 月承諾的那樣，宣布 2 個新的適應症。除了 MG 與 TED 之外，我們計畫在 2022 年再啟動另一個適應症的關鍵性試驗，使得預計於 2022 年曆年啟動的關鍵性試驗總數達到 3 項。這項開發計畫反映了我們團隊對整體 anti-FcRn 領域，以及對 batoclimab 尤其抱持的熱忱。

Thank you so much for your time. And with that, I'd like to open it up for questions.

非常感謝各位撥冗。接下來，我想開放提問。

(Operator Instructions) Our first question comes from the line of Robyn Karnauskas with Truist Securities.

（接線員指示）我們的第一個問題來自 Truist Securities 的 Robyn Karnauskas。

First, can you just talk a little bit about, in your market research, about -- I think you mentioned in the beginning that for some moderate patients, if it has a similar profile to Tepezza, which I think you're seeing around 88% -- are you assuming 83% for the primary endpoint that you could see a use as a first-line therapy? So what sort of market research was thought around -- thoughts around why you choose one product over the other and what would make a patient or a doctor to do that?

首先，能否請你稍微談一下你們的市場調查——我想你一開始提到，對於一些中度患者，如果它的特徵與 Tepezza 類似，我想你們看到大約是 88%——你們是否假設主要終點為 83%，因此可能作為第一線治療使用？那麼在市場調查中，你們對於——為什麼會選擇某一個產品而不是另一個產品，有哪些想法？以及什麼因素會讓患者或醫師做出那樣的選擇？

And the second question is for follow-up for -- do you expect that the FDA will give you a similar label? I assume that you say it will be around 6 months. Do you think there's any flexibility there? Have you guys anything like that?

第二個問題是延伸追問——你們預期 FDA 會給你們類似的標示（label）嗎？我猜你們說大概會是 6 個月。你覺得在這方面有任何彈性嗎？你們是否有做過任何類似的溝通？

Thanks, Robyn, for those questions. I appreciate it. So for the first question with regard to the market research, just to go into a little bit more detail there. The market research we conducted, it was relatively recently conducted. So it was in the U.S. It was after the launch of Tepezza. And patients in the market research had active thyroid eye disease across the spectrum for moderate to severe, and they were on systemic therapy with either steroids or Tepezza with about an even split in terms of medication between both of those groups.

謝謝你，Robyn，提出這些問題，我很感謝。先回答第一個關於市場調查的問題，我再多補充一些細節。我們進行的市場調查是相對近期完成的，地點在美國，且是在 Tepezza 上市之後。參與市場調查的患者涵蓋從中度到重度的活動性甲狀腺眼病（thyroid eye disease, TED）全光譜，並且正在接受全身性治療，使用類固醇或 Tepezza，兩組用藥比例大致各半。

They all actually reported -- 100% of them reported improvement in their symptoms. But 80% of them, as I mentioned, reported that they were still making moderate or even more than moderate lifestyle modifications in spite of improvements with therapy. There was -- then there was a section of the market research where we asked them to consider product profiles. So for Tepezza, the product profile was just equivalent to the FDA-approved label.

他們其實都回報——100% 都回報症狀有所改善。但如我提到的，其中 80% 表示即使治療後有所改善，仍然需要做出中度甚至高於中度的生活型態調整。接著，在市場調查中有一個部分，我們請他們考量產品特徵（product profiles）。對 Tepezza 而言，產品特徵就是等同於 FDA 核准的標示內容。

For batoclimab, the profile included the -- what I mentioned. So subcutaneous route of administration, a proptosis efficacy that was a little bit less than Tepezza and the lack of any hearing loss as an assumption in that product profile. And when comparing those 2 product profiles, different people chose different things. And across the spectrum, actually, some people chose the Tepezza profile, some people chose the batoclimab profile. But there was more -- there were more people in the -- on the moderate side of the spectrum who tended towards the batoclimab profile.

對 batoclimab 而言，產品特徵包含我剛才提到的內容：皮下注射給藥途徑、突眼（proptosis）療效略低於 Tepezza，以及在該產品特徵假設中不會出現任何聽力損失。當比較這兩種產品特徵時，不同的人會選擇不同的方案。整體而言，有些人選擇 Tepezza 的特徵，有些人選擇 batoclimab 的特徵。不過，在疾病光譜中偏中度的族群，較傾向選擇 batoclimab 的特徵。

And I think that's consistent with just treatment of a lot of conditions where when someone has a very -- they're very, very severely impacted, then the outstanding efficacy that Tepezza has demonstrated is probably going to lead to that being the first choice in spite of any adverse events. On the other hand, for someone who's impacted, for sure, but a little bit more moderate, they're more drawn to a profile that provides efficacy, but with potentially less safety issues and no irreversible safety issues. So that was how that split came out.

我認為這與許多疾病的治療情況一致：當患者受影響非常、非常嚴重時，Tepezza 已展現的卓越療效，很可能會使其成為第一選擇，即便存在某些不良事件。另一方面，對於確實受影響、但程度較中等的患者，他們更容易被一種能提供療效、但可能有較少安全性問題、且沒有不可逆安全性問題的特徵所吸引。因此，結果就呈現出這樣的分布。

And the subcutaneous route of administration also played a pretty big role, I have to say, in spite of the fact that these were people who were being treated with a systemic course of therapy and were aware that the total duration of therapy was only 6 months. To that point, with regard to the label, our interactions with the division of ophthalmology strongly suggest that they have a really standard approach to development programs in TED and are likely to have a very standard approach to labeling.

另外我必須說，皮下注射的給藥途徑也扮演了相當重要的角色，儘管這些受訪者正在接受一個全身性療程，且也知道整體治療期間只有 6 個月。就你提到的標示（label）而言，我們與眼科部門（division of ophthalmology）的互動強烈顯示，他們對 TED 的開發計畫有非常標準化的做法，且很可能也會以非常標準化的方式來處理標示。

So I think the key tenets of the Tepezza label will be reflected in any other product that's approved for thyroid eye disease that has a similar program, meaning a 24-week placebo-controlled program.

因此我認為，Tepezza 標示中的關鍵原則（key tenets）將會反映在任何其他獲准用於甲狀腺眼病、且採用相似開發計畫的產品上，也就是一個 24 週的安慰劑對照試驗計畫。

Got it. And just as a follow-up, do you think you'll be allowed to have patients that have previously been on Tepezza and would there be a washout period? And also I was going to ask you just around the guidance for 2025 data, given the shorter time frame for the trial. Like what is your assumption for enrollment seems slower, given that there's more awareness of the disease?

了解。再追問一下，你覺得你們會被允許納入先前使用過 Tepezza 的患者嗎？是否會需要一段洗脫期（washout period）？另外我也想問一下，關於 2025 年數據的指引（guidance），考量試驗時間框架較短：你們對收案（enrollment）的假設是什麼？因為疾病的認知度更高了，但看起來收案似乎更慢？

Right. So in terms of the timing for the trial, the -- our enrollment assumptions for these 2 trials, which will be run in parallel, is sort of halfway between the actual experience of the 2 Tepezza trials for their first trial and the second trial. The second trial was obviously faster. They had sites up and running, and the first trial was positive. So those 2 things, I think, were an accelerator for the second trial compared to the first one. So we took a position sort of down the middle. There's no question that the approval of Tepezza has generated additional awareness. And we do expect to enroll patients in the U.S. in spite of Tepezza being on the market.

好的。就試驗時程而言——我們對這兩項將平行進行的試驗之收案假設，大致介於 Tepezza 兩項試驗的實際經驗之間，也就是第一項試驗與第二項試驗的中間值。第二項試驗顯然更快，因為他們的試驗中心已經建置完成，而且第一項試驗結果為正向。我認為這兩點相較於第一項試驗，確實加速了第二項試驗。因此我們採取一個折衷、取中間的假設。毫無疑問，Tepezza 的核准提高了額外的疾病認知度。我們也確實預期即使 Tepezza 已在市場上，我們仍能在美國收案。

But there will be a little bit -- there's always more competition when you have an approved product, which is true, for now at least only in the U.S. And that leads a little bit to the first question, which was, will we include patients who were previously treated with Tepezza and we will not, for the pivotal program, the -- our goal with the pivotal program is to have as close to an apples-to-apples comparison with regard to the patient population as Tepezza had in there. So that's the rationale for having naive patients in our pivotal trial.

但當你有一個已核准產品時，競爭總是會多一些——至少目前這點只在美國成立。這也帶到你第一個問題：我們是否會納入先前接受過 Tepezza 治療的患者？在關鍵性計畫中我們不會納入——我們的目標是讓關鍵性計畫的患者族群，盡可能與 Tepezza 當時的患者族群做到「蘋果對蘋果」的可比性。因此，我們在關鍵性試驗中納入未曾治療（naive）的患者，就是基於這個理由。

That could be an opportunity for a future Phase IV trial or something like that. But for the Phase III trial, it will be patients who are naive to any biologic therapy.

這可能會是未來第四期（Phase IV）試驗或類似研究的機會。但在第三期試驗中，將會是對任何生物製劑治療皆為未曾使用（naive）的患者。

Our next question comes from the line of Derek Archila with Wells Fargo.

我們下一個問題來自 Wells Fargo 的 Derek Archila。

Just a couple from us, different track though. I mean, I just wanted to kind of get your thoughts, Pete, on the recent kind of failure in WAIHA for fostamatinib and how that might kind of enter your thinking about moving forward in WAIHA with batoclimab and thinking about the opportunity there? And then second question, just on the cash guidance out to 2025, does that assume that you have cash through the top line TED data?

我們這邊有幾個問題，但方向不同。我想請教你，Pete，對於最近 fostamatinib 在 WAIHA 的失敗，你的看法是什麼？這會如何影響你們以 batoclimab 推進 WAIHA 的後續思考，以及對該機會的評估？第二個問題是關於到 2025 年的現金指引（cash guidance）：這是否假設你們的現金可以支撐到 TED 的主要（top line）數據出爐？

Yes. Great questions, Derek. I'll ask the first one -- the second one first. Yes, that's an easy answer, easy and direct answer. The first question is very interesting, and that call is happening, I guess, in parallel to this one. I did have a chance to review the press release, which had a fair amount of information this morning. And as I'm sure you saw, there is a big variation in the placebo response rate by geography, whereas the response rate for fostamatinib by geography was relatively similar.

是的。很好的問題，Derek。我先回答第二個——是的，這個答案很簡單、也很直接。第一個問題非常有意思，而那通電話我想應該正好與這通同時進行。我今天早上有機會看過新聞稿，裡面提供了相當多資訊。正如你所看到的，安慰劑反應率（placebo response rate）在不同地理區域之間有很大的差異；相對地，fostamatinib 的反應率在不同地理區域之間則相對一致。

Why might that be? I think in any trial in immunology where there's a potential to use nonsteroid immunosuppressant therapy, which was allowed, I think at least one of them were with cloud in the Phase II trial, the protocol for which has been published. I'm not totally sure about the Phase III trial, but I would guess there might be a similarity there. Nonsteroid immunosuppressants, as you know, one of their big limitations is they take a long time to work. That's a big limitation clinically. It's also something that can cause issues in clinical trials if you have someone in the placebo arm, whose nonsteroid immunosuppressant therapy is just kicking in midway through the trial.

為什麼會這樣？我認為在任何免疫學試驗中，只要允許使用非類固醇免疫抑制治療（nonsteroid immunosuppressant therapy）——而這是被允許的——我記得在第二期試驗中至少有一種（用藥）被允許；該第二期試驗的方案已經發表。我不完全確定第三期試驗是否相同，但我猜可能有類似之處。你也知道，非類固醇免疫抑制劑的一大限制是起效需要很長時間；這在臨床上是很大的限制。在臨床試驗中也可能造成問題：如果安慰劑組受試者所使用的非類固醇免疫抑制治療，剛好在試驗進行到一半時才開始起效。

This is an area where you've got a lot of nuanced feedback from investigators across our clinical trials, particularly the ones that have a longer duration, but it actually applies everywhere where these medications are used. So it's possible that, that might explain it. The placebo response rate that they saw in Eastern Europe or in some of those geographies seem much higher than, again, what hematologists are telling us, one would expect in a true placebo arm, so then you wonder if the concomitant medications are kicking in and causing a compounding there.

這是一個我們在臨床試驗中從研究者那裡收到許多細緻回饋的領域，特別是那些試驗期間較長的研究，但其實也適用於這些藥物被使用的所有情境。因此有可能，這或許可以解釋這個現象。他們在東歐或某些地區看到的安慰劑反應率似乎高得多；同樣地，這遠高於血液科醫師告訴我們在真正的安慰劑組中所預期的水準，所以你就會想，是否合併用藥正在發揮作用並造成疊加效應。

I guess and how does that kind of like factor into your thoughts about going into WAIHA now that maybe that competitor is not there versus the undisclosed indications?

我想問的是，這樣的情況會如何影響你們現在進入 WAIHA 的想法——尤其是在那個競品可能不在了的情況下——相較於那些未揭露的適應症？

Yes, yes, yes. Well, I mean, I think the first thing is to make sure the trial design is really carefully done, to the points I was just making. In terms of WAIHA, with or without fostamatinib, we're really excited about this opportunity because there's just been a lack of innovation in WAIHA. The therapies that are mostly used are steroids actually, even more so than non-steroids, at least within the major markets, moderate doses of prednisone with occasional blood transfusions, which is really just not a very satisfactory long-term solution to come up with a targeted therapy.

是的，是的，是的。嗯，我的意思是，我認為第一件事是要確保試驗設計真的非常謹慎，呼應我剛才提到的重點。就 WAIHA 而言，不論是否有 fostamatinib，我們都對這個機會感到非常興奮，因為 WAIHA 長期缺乏創新。現在主要使用的治療其實多半是類固醇，甚至比非類固醇還常見，至少在主要市場是如此；中等劑量的 prednisone，偶爾搭配輸血，但這並不是一個令人滿意的長期解決方案，因此需要一個標靶治療。

And even if fostamatinib had reported positive results this morning, I mean, it is an oral therapy, but the GI side effects, I think, may be limiting for chronic use. So this is -- I'm not sure it changes the law. Our thinking is centered around what batoclimab can do, which we believe could be pretty exciting in WAIHA.

而且即使 fostamatinib 今天早上公布了正向結果，我的意思是，它是口服療法，但我認為腸胃道（GI）副作用可能會限制其慢性使用。所以這——我不確定這是否改變了遊戲規則。我們的思考核心在於 batoclimab 能做到什麼；我們相信它在 WAIHA 可能會相當令人振奮。

Our next question comes from the line of Thomas Smith with SVB Securities.

我們的下一個問題來自 SVB Securities 的 Thomas Smith。

Just a couple on the plans in TED. Can you give us a little bit more visibility into some of the regulatory dialogue and achieving alignment here with FDA? Like were there any discussions around the need for a lipid management program in TED? And I guess, where did you guys settle on that?

關於 TED 的計畫我有幾個問題。你們能否讓我們更清楚了解一些與 FDA 的法規溝通，以及如何在這裡達成一致？例如，在 TED 是否需要脂質管理計畫方面，有沒有任何討論？以及我想問，你們最後是怎麼定案的？

Great question, Tom. Thanks for asking. We will apply the same identical safety and monitoring program to the TED clinical trial as we have previously discussed for MG, the same narrow exclusion criteria for people who have a baseline LDL greater than 190 or who have existing cardiovascular disease and have an LDL greater than 160. As with the myasthenia trial, should a patient come into the trial on a statin, that's fine. And we would expect that there'll be some patients who have controlled hyperlipidemia statin, just based on the broad prevalence of that in the population, and that's not a problem. However, there won't be any statin use initiated during the clinical trial, and there won't be any unblinding due to LDL excursions. So the discussion was straightforward and similar to the one with the neuro division for our MG program.

好問題，Tom，謝謝你提出。我們會在 TED 臨床試驗中採用與先前針對 MG 所討論的完全相同的安全性與監測方案：同樣嚴格的排除條件——基線 LDL 大於 190 的人，或是已有心血管疾病且 LDL 大於 160 的人。和重症肌無力試驗一樣，如果受試者進入試驗時已在使用 statin（他汀類），那沒問題。我們也預期會有一些受試者有在 statin 控制下的高血脂，因為這在一般族群中的盛行率很高，這不是問題。不過，在臨床試驗期間不會新啟用 statin，也不會因為 LDL 波動而進行揭盲。因此這次的討論很直接，且與我們在 MG 計畫中和神經科審查部門的討論相似。

Okay. Got it. That makes sense. And then maybe following up on Robyn's question on the targeted patient enrollment. You've highlighted the potential role in patients with maybe less severe disease, more on the moderate end of the moderate-to-severe spectrum. Is there anything specific in the inclusion/exclusion criteria for these Phase III studies that could drive maybe greater enrollment of a more moderate patient population on the disease severity spectrum?

好的，了解。這很合理。接著可能延續 Robyn 關於目標病人收案的問題。你們提到在疾病嚴重度光譜中，可能在較不嚴重、偏中度（moderate-to-severe 中較 moderate 端）的病人身上扮演角色。那在這些第三期研究的納入/排除標準中，有沒有任何特定設計，可能會讓收案更偏向較中度的病人族群？

No. In fact, it's probably a little bit the opposite in the sense that there's a 4 -- clinical activity score of 4, which is common, versus dropping it to a 3 or something like that. And so the population is really the same. It's the moderate to severe population. And often, people who are enrolled in clinical trials just generally are a little bit more severe. I mean that's totally fine. I mean we expect to have good efficacy in the more severe group on that moderate to severe spectrum.

沒有。事實上，某種程度上可能還有點相反，因為臨床活動分數（clinical activity score）設定為 4——這是常見的——而不是降到 3 之類的。所以收案族群其實是一樣的：中度到重度。通常，參加臨床試驗的病人整體而言會稍微更嚴重一些。我的意思是這完全沒問題。我們預期在中度到重度光譜中較重度的族群也會有良好療效。

What I was discussing really related more just kind of to clinical decision-making, if you have 2 different products that have a different profile, and you have a spectrum of patients. Physician will generally pick sort of a sub profile that they prefer for one product, sub profile of patients that they prefer for one product and sub profile of the other, that's just kind of natural. And the moderate-to-severe TED patients, that's a large and heterogeneous pool. So I think it's actually going to be relatively straightforward for physicians to make a decision that works for each of them clinically to decide where they would use batoclimab first or they would use Tepezza first assuming batoclimab's approved.

我剛才談的其實更多是臨床決策層面：如果你有兩個不同產品、各自有不同的特性，而病人又是一個光譜，醫師通常會自然地為某個產品挑選他們偏好的某一類病人子族群，另一個產品則對應另一類子族群，這很自然。而中度到重度的 TED 病人是一個龐大且異質性很高的族群。所以我認為，對醫師而言，做出符合各自臨床需求的決策其實會相對直接——在 batoclimab 若獲核准的前提下，決定他們會先用 batoclimab 還是先用 Tepezza。

I think in the end of the day, many patients will end up getting both, which is what I meant by a complementary therapy giving in series. And the question then is, which one do you get first and that outlined our thinking in terms of how those decisions will be made, but individual clinicians will probably vary in their decisions there.

我想最後，很多病人最終會兩個都用到，這就是我所說的互補療法、以序列方式使用。那麼問題就變成：先用哪一個？這也勾勒了我們對這些決策如何形成的想法，但不同臨床醫師在這方面的選擇可能會有所差異。

Okay. Got it. That makes sense. And then just maybe lastly on enrollment. There are a few other programs out there that could also be enrolling later stage studies in TED. Just as you think about kind of the geographical and regional enrollment, I know you mentioned, Pete, that you're going to -- you expect to get some patients from the U.S., but do you have a sense for kind of regional breakdown between the U.S. and Canada versus Western Europe versus Eastern Europe at this point.

好的，了解。這很合理。最後再問一下收案。外面還有幾個其他計畫也可能在 TED 進行後期研究收案。當你們思考地理與區域收案時，我知道你提到，Pete，你們會——預期會有一些病人來自美國，但你們目前對美國與加拿大、相較於西歐、相較於東歐之間的區域占比，有沒有一個概念？

I don't have detailed projections by country yet, but we do expect all regions to be important, and that was true in our previous IIb trial, and we're looking to be as expansive as possible in all of our pivotal trials to ensure that anywhere there's a good clinical trial site that we have an opportunity to tap into that pool of potential patients, given the competing trials across a lot of rare diseases. So that's definitely something we're looking at just generally.

我目前還沒有按國家別的詳細預測，但我們確實預期所有區域都會很重要；這在我們先前的 IIb 試驗中也是如此。我們希望在所有關鍵性試驗中盡可能擴大佈局，以確保只要有優質的臨床試驗中心，我們就有機會觸及那一群潛在病人，尤其在許多罕見疾病領域都有競爭性試驗在同步進行。因此這確實是我們整體正在關注的事情。

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

我們的下一個問題來自 H.C. Wainwright 的 Douglas Tsao。

Just maybe, Pete, in terms of that work that you did that sort of suggests that sort of that moderate patients might be -- get to more traction as first-line therapy. I'm just curious from -- I think you mentioned tolerability as a key attribute for batoclimab in terms of attracting. So I'm just curious what the relative tolerability. Is there anything in particular that came out in terms of the market research? Any particular tolerability issues that (inaudible) physicians?

也許，Pete，關於你們做的那項工作——似乎顯示中度病人可能更容易作為第一線治療取得更大採用——我有點好奇：我記得你提到耐受性是 batoclimab 在吸引採用方面的一個關鍵屬性。所以我想問相對的耐受性如何？在市場調研中，有沒有特別浮現的內容？有沒有任何特定的耐受性議題是（聽不清）醫師在意的？

Right. So both -- that's great question, Doug. I appreciate you asking it. So both with (technical difficulty) patients, we did highlight in the potential product profiles that we are testing that in the batoclimab profile, there could be changes in LDL and that some physicians may choose to monitor, even though there's not monitoring in the trial that leads to unblinding in the clinical setting, that could be the case. And that didn't seem to be something which led to a negative perception with regard to decision-making on the part of physicians or preference on the part of patients outside of the blood monitoring, which for these types of patients with thyroid eye disease, is done regularly anyway because many of them have -- they are euthyroid in the trial, but many of them are being treated to maintain their euthyroid state.

對。所以兩方面——這是個好問題，Doug，謝謝你問。針對（technical difficulty）病人，我們在測試的潛在產品特性描述中確實有強調：在 batoclimab 的特性中，可能會出現 LDL 的變化，而部分醫師可能會選擇監測；即使在試驗中並沒有會導致揭盲的監測機制，但在真實臨床情境下可能會這樣做。而這似乎並沒有在醫師的決策或病人的偏好上造成負面觀感——除了抽血監測之外；但對於這類甲狀腺眼病（thyroid eye disease）的病人而言，本來就會定期抽血，因為他們很多人在試驗中是甲狀腺功能正常（euthyroid），但其中許多人仍在接受治療以維持其 euthyroid 狀態。

So they're used to getting blood draws for thyroid function levels. Outside of the blood draws that may be required, the anti-FcRn class as a whole and batoclimab specifically has been generally well tolerated. So some of the adverse events that have been reported consistently for Tepezza, for some people are a trade-off, particularly when they have another option. So that was kind of how the decision-making went in that market research.

所以他們本來就習慣為了甲狀腺功能指標抽血。除了可能需要的抽血之外，整體而言 anti-FcRn 類別、以及 batoclimab 本身，一般都具有良好的耐受性。相對地，Tepezza 一些一貫被回報的不良事件，對某些人來說是一種取捨，特別是當他們有其他選項時。因此在那項市場調研中，決策大致就是這樣形成的。

Okay. Great. And then just do you anticipate -- you'll have the MG Phase II completed, do you anticipate needing additional sort of safety extension data to potentially file in TED?

好的，很好。那最後，你們是否預期——在 MG 第二期完成之後，為了可能在 TED 送件申請，你們會需要額外的安全性延伸（extension）資料嗎？

Yes. So all these -- every division has slightly unique but generally similar requirements for safety exposures. And so we work with each division to understand them. And the good news is that consistently across the FDA, safety exposures can be pooled. So having patients in different -- being studied in different indications, those safety exposures that we'll have, for example, in TED outside of -- for a TED BLA patients in the MG program can be submitted and vice versa. So that's helpful in terms of meeting the safety database requirements.

是的。因此所有這些——每個審查部門對安全性暴露的要求略有不同，但整體上相當類似。我們會與各部門合作以了解其要求。好消息是，在 FDA 內部，安全性暴露可以彙總（pool）。因此，讓不同——在不同適應症中受試的病人，其安全性暴露資料可以互相併用。舉例來說，我們在 TED 的安全性暴露資料，除了——用於 TED 的 BLA 之外，MG 計畫中的病人資料也可以提交，反之亦然。這對於滿足安全性資料庫要求很有幫助。

Okay. And then just one final one. I think you indicated that of -- when you expect to initiate an additional pivotal trial by year-end, potentially one from the two indications that haven't been disclosed. I mean how are you thinking about sort of that risk reward in terms of going into indications in pivotal study where you haven't necessarily done as much clinical work previously?

好的。然後最後一個問題。我想你提到——你們預期在年底前啟動一項額外的關鍵性試驗（pivotal trial），可能會來自兩個尚未披露的適應症之一。我的意思是，在你們先前未必做過那麼多臨床工作的適應症上，直接進入關鍵性研究時，你們如何看待風險報酬的權衡？

Right. That's a great question, Doug. The decision on whether to go directly into a pivotal trial or a pre-pivotal trial, in some ways, the second order -- the second question is important question. The first and most important question we ask ourselves is, what are the indications we want to develop because maybe it's obvious. And there, we're looking at the (technical difficulty) unmet needs, the size of the patient population, I think is addressable for a new therapy. And then the probability of technical success that you highlighted in your question.

對。這是個很好的問題，Doug。是否直接進入關鍵性試驗或先做關鍵性前試驗（pre-pivotal trial）的決策，在某些方面，第二層——第二個問題確實重要。第一個、也是最重要的問題是：我們想要開發哪些適應症，因為有時候答案可能很明顯。在這方面，我們會看（技術困難）未被滿足的需求、病人族群的規模，以及我認為新療法可觸及的程度。然後也會看你在問題中提到的技術成功機率。

And when we're thinking about the probability of technical success, we consider not only our own data, but also other anti-FcRn since there's such a good biomarker, obviously, for anti-FcRn development programs. So then having selected a pool of indications, then we have a leading list that that's long and reasonably prioritized beyond the 3 that we've disclosed.

而在思考技術成功機率時，我們不僅考量我們自己的數據，也會參考其他抗 FcRn 的資料，因為抗 FcRn 的開發計畫顯然有非常好的生物標記可用。因此，在選定一個適應症池之後，我們會有一份領先清單，這份清單很長，且在我們已披露的 3 個適應症之外也做了相當合理的優先排序。

Then the next question is whether to go straight to pivotal, which is great for long-term value creation because you get faster to BLA or whether to do a pre-pivotal trial, and that advantage of generating some additional catalyst data, but also for certain indications has a chance of advancing our scientific understanding and making our pivotal program stronger. I think, ultimately, having a really, really strong result in your pivotal trial, that's the most important thing. If you can avoid an issue like what Rigel's announcing this morning by having your inclusion/exclusion criteria a little bit more optimized, then that's going to be desirable.

接下來的問題是是否直接進入關鍵性試驗——這對長期價值創造很有利，因為能更快走到 BLA；或是先做關鍵性前試驗，其優勢在於能產生一些額外的催化劑數據（catalyst data），而且對某些適應症而言，也有機會增進我們的科學理解，讓關鍵性計畫更強。我認為，最終在關鍵性試驗中取得非常、非常強的結果，才是最重要的事。如果你能透過把納入/排除標準再優化一些，來避免像 Rigel 今天早上宣布的那種問題，那會是更理想的。

And for some of the (technical difficulty) there is a little less scientific information, we continue to do (technical difficulty) approach and that'd be the most value creating. So that will be -- the most important thing is (technical difficulty) and the second most important thing, whether it's pivotal or (technical difficulty).

而對於某些（技術困難），科學資訊相對較少，我們會持續採取（技術困難）的方法，而那將是最能創造價值的。因此——最重要的是（技術困難），第二重要的是，究竟是做關鍵性試驗還是（技術困難）。

Our next question comes from the line of Yatin Suneja with Guggenheim Securities.

下一個問題來自 Guggenheim Securities 的 Yatin Suneja。

This is Evan on for Yatin. Two quick ones for me. First, can you remind us what the bar is for TED? And second, what gives you confidence to move forward in TED given some of the prior mixed results that you've seen?

我是代替 Yatin 的 Evan。我有兩個簡短問題。第一，能否提醒我們 TED 的門檻（bar）是什麼？第二，鑑於你們先前看到的一些結果好壞參半，你們為何仍有信心在 TED 上繼續推進？

Yes. Great questions, Evan. So I think the bar is -- for efficacy is equal to or greater than what you see with steroids. And the steroid data is not as robustly characterized as Tepezza data, obviously, which had 2 very well-controlled pivotal trials. But generally, steroids have an efficacy on proptosis response of around 50%. So I think anything between the steroid and the Tepezza result is where the efficacy bar lies for a new medication with a strong tolerability profile like we believe batoclimab will have.

是的。很好的問題，Evan。我認為療效的門檻是——要達到或超過類固醇的效果。而類固醇的數據不像 Tepezza 的數據那樣被充分且嚴謹地刻畫，因為 Tepezza 顯然有兩項控制良好的關鍵性試驗。不過一般而言，類固醇在眼球突出（proptosis）反應上的療效大約在 50% 左右。因此，我認為對於一款具有良好耐受性特徵、如我們相信 batoclimab 會具備的新藥而言，療效門檻大致落在類固醇與 Tepezza 結果之間的區間。

Our confidence really comes from triangulating a lot of information. So our IIb trial, we had deposit midstream, which made the data difficult to interpret. We had a lot of patients who had a varying degree of exposure throughout the trial. So rather than looking at it as you would evaluate a pivotal trial for you, first look at the primary endpoint, is it statistically significant and then which gated secondaries hit, we looked at it more as you would look at a proof-of-concept trial where you triangulate a lot of the information to see if there's consistency across various clinical scores and biomarkers and whether there's a dose response. That's one of the -- I think one of the most important things when making a decision for a proof of concept.

我們的信心主要來自於對大量資訊的三角驗證（triangulating）。在我們的 IIb 期試驗中，我們在試驗進行中途有存款（deposit），使得數據難以解讀；而且有許多病人在整個試驗期間的暴露程度不一。因此，我們不是像評估關鍵性試驗那樣，先看主要終點是否具統計顯著性、再看哪些分層（gated）的次要終點達標；我們更像是在看概念驗證（proof-of-concept）試驗，透過三角驗證大量資訊，去看各種臨床評分與生物標記之間是否一致，以及是否存在劑量反應。這是——我認為在做概念驗證決策時最重要的事情之一。

And because if you see inverse dose response or something like that, then you wonder if the results that you're seeing in the smaller trial are spurious. Across a lot of biomarkers and radiologic markers and clinical parameters, we saw that, that we observed in dose response, as I highlighted a little bit in the slides today and even in more detail at our R&D Day. So that gives us strong conviction that we have an effect here and that we're likely to hit the bar that I outlined in terms of efficacy.

因為如果你看到反向的劑量反應或類似情況，你就會懷疑在較小試驗中看到的結果是否只是偶然（spurious）。在許多生物標記、影像學標記以及臨床參數上，我們看到我們觀察到的劑量反應；我今天在投影片中也稍微強調了，並且在我們的 R&D Day 上更詳細地說明。因此，這讓我們非常確信我們在這裡確實有作用，且很可能能達到我所概述的療效門檻。

Got it. And maybe if I could, just one quick follow-up. For that post hoc proptosis data, what proportion of the total patient number in each arm is included in that analysis?

了解。也許我可以再追問一個簡短問題：對於那個事後分析（post hoc）的眼球突出數據，各組別納入該分析的人數占各組總病人數的比例是多少？

Yes, that's -- so that's a tricky question to answer because what do you put in the denominator? You put everybody who has ever randomized, everybody who finished the week 12, there were some people that got to 11 weeks and not 12 weeks. So I think just generally, there's about half as many people that got 2 weeks as to the later, say, week 11 or week 12. So it's a smaller number of people, sort of 1/2 to 2/3 depending on how you -- what you put in the denominator.

是的——這個問題其實很難回答，因為分母要放什麼？你是放所有曾被隨機分派的人、還是放完成第 12 週的人？也有一些人到第 11 週但沒有到第 12 週。所以我想大致而言，到第 2 週的人數大約是到後期（例如第 11 週或第 12 週）人數的一半。因此，納入的人數比較少，大概是 1/2 到 2/3，取決於你——分母怎麼定義。

Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Dr. Salzmann for any final comments.

各位女士、先生，我們的問答環節到此結束。我將把時間交回 Salzmann 醫師，請他做最後的結語。

Thanks, Melissa, and thanks again, everyone, for joining us this morning. We're really excited by this unique first-in-class opportunity in TED, and I appreciate very much the opportunity to discuss it with you all this morning. Goodbye.

謝謝你，Melissa，也再次感謝各位今天早上參與。我們對於在 TED 上這個獨特的同類首創（first-in-class）機會感到非常興奮，也非常感謝今天早上有機會與各位討論。再見。

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

謝謝。今天的會議到此結束。您現在可以中斷連線。感謝您的參與。