Gossamer Bio Inc (GOSS) 2021 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Gossamer Bio Q4 Earnings Call. (Operator Instructions) Without further ado, I would like to welcome your speaker for today, Mr. Bryan Giraudo. Sir, the floor is yours.

美好的一天，感謝您的支持。歡迎參加 Gossamer Bio 第四季度收益電話會議。 （操作員說明） 話不多說，我歡迎今天的發言者 Bryan Giraudo 先生。先生，地板是你的了。

Thank you, operator, and thank you all for joining us this afternoon. I am joined on today's call by Gossamer's Co-Founder, Chairman and Chief Executive Officer, Faheem Hasnain; Gossamer's Chief Medical Officer, Dr. Richard Aranda; and Gossamer's Chief Scientific Officer, Dr. Laura Carter.

謝謝接線員，也謝謝大家今天下午加入我們。 Gossamer 聯合創始人、董事長兼首席執行官 Faheem Hasnain 參加了今天的電話會議。 Gossamer 首席醫療官 Richard Aranda 博士；以及 Gossamer 的首席科學官 Laura Carter 博士。

Earlier today, Gossamer issued a press release announcing its year-end 2021 financial results and provide a corporate update. Please note that certain information discussed on the call is covered under the safe harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Gossamer management will be making forward-looking statements. Actual results may differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the statements contained in Gossamer's news releases, SEC filings, including in the annual report on Form 10-K and subsequent filings.

今天早些時候，Gossamer 發布新聞稿，宣布其 2021 年年底財務業績並提供公司最新情況。請注意，電話會議中討論的某些信息受《私人證券訴訟改革法案》的安全港條款管轄。我們提醒聽眾，在本次電話會議中，Gossamer 管理層將做出前瞻性聲明。由於與公司業務相關的風險和不確定性，實際結果可能與這些前瞻性陳述中明示或暗示的結果存在重大差異。這些前瞻性陳述受到 Gossamer 新聞稿、SEC 文件（包括 10-K 表格年度報告和後續文件）中包含的聲明的限制。

This conference call also contains time-sensitive information that may be accurate only for a limited period of time. Our ability to meet our guidance, especially that related to the timely initiation and completion of clinical studies, in addition to our ability to release results from our clinical trials in a timely manner, may be adversely affected by the ongoing COVID-19 pandemic. Gossamer Bio undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now I'd like to turn the call over to Faheem. Faheem?

此電話會議還包含時間敏感信息，這些信息可能僅在有限的時間內準確。我們滿足指導意見的能力，特別是與及時啟動和完成臨床研究相關的能力，以及我們及時發布臨床試驗結果的能力，可能會受到持續的 COVID-19 大流行的不利影響。 Gossamer Bio 不承擔修改或更新任何前瞻性陳述以反映本次電話會議之後發生的事件或情況的義務。現在我想把電話轉給 Faheem。法希姆？

Thank you, Bryan, and thanks to everyone for joining us on this afternoon's call. 2021 was the year of execution for the Gossamer team, despite the challenges that the preceding 2 years have provided. We at Gossamer are excited and energized to enter 2022 with 2 upcoming proof-of-concept Phase II readouts in ulcerative colitis and Pulmonary Arterial Hypertension.

謝謝布萊恩，也感謝大家參加今天下午的電話會議。 2021 年是 Gossamer 團隊的執行年，儘管前兩年面臨著挑戰​​。進入 2022 年，我們 Gossamer 感到興奮和充滿活力，即將推出兩項關於潰瘍性結腸炎和肺動脈高壓的概念驗證 II 期讀數。

Now while these product candidates, seralutinib and GB004 target different indications utilizing different approaches, we view them both alike in the sense that they're using novel mechanisms to target populations that continue to be underserved. And if approved, we believe both molecules hold treatment paradigm shifting potential. First, let's start with GB004.

現在，雖然這些候選產品塞拉魯替尼和 GB004 使用不同的方法針對不同的適應症，但我們認為它們都是相似的，因為它們都使用新穎的機制來針對仍然得不到充分服務的人群。如果獲得批准，我們相信這兩種分子都具有改變治療範式的潛力。首先，我們從GB004開始。

The Phase II SHIFT-UC study is on track to read out week 12 primary endpoint top line results early in the second quarter of this year. And as a quick reminder, the SHIFT-UC study is a randomized, double-blind, placebo-controlled global clinical trial studying GB004 in patients with active mild-to-moderate UC despite treatment with 5-ASA therapy. Patients were randomized in a 1:1:1 ratio between 2 doses of GB004 in tablet form and placebo. The 12-week primary end point of this trial is clinical remission, And secondary end points include clinical response, histological remission, endoscopic improvement and mucosal healing. Relevance safety and exploratory end points are also being assessed during the clinical trial.

II 期 SHIFT-UC 研究有望在今年第二季度初公佈第 12 週的主要終點頂線結果。快速提醒一下，SHIFT-UC 研究是一項隨機、雙盲、安慰劑對照的全球臨床試驗，研究 GB004 在接受 5-ASA 治療的活動性輕至中度 UC 患者中的作用。患者按 1:1:1 的比例隨機分配服用 2 劑 GB004 片劑和安慰劑。該試驗的12週主要終點是臨床緩解，次要終點包括臨床緩解、組織學緩解、內鏡改善和粘膜癒合。臨床試驗期間還將評估相關安全性和探索性終點。

The GB004 is distinct and may have a differentiated profile from the immunomodulatory or immunosuppressive mechanisms of approved IBD medications and those in late-stage development. GB004 is designed to be gut-targeted with higher intestinal exposure than systemic exposure, and clinical and preclinical data generated to date support this thesis. By reducing local inflammation and potentially restoring intestinal epithelial barrier function and restitution through GB004's gut-targeted nature and preferential stabilization of HIF-1 alpha. We believe GB004 could improve outcomes for IBD patients. We believe this mechanism has potential as a stand-alone therapeutic as well as a combination therapy with other therapeutic mechanisms in IBD.

GB004 是獨特的，並且可能與已批准的 IBD 藥物和處於後期開發的藥物的免疫調節或免疫抑制機制不同。 GB004 被設計為腸道靶向，腸道暴露量高於全身暴露量，迄今為止產生的臨床和臨床前數據支持了這一論點。通過 GB004 的腸道靶向性質和 HIF-1 α 的優先穩定作用，減少局部炎症並可能恢復腸上皮屏障功能和恢復。我們相信 GB004 可以改善 IBD 患者的預後。我們相信這種機制具有作為 IBD 的獨立治療以及與其他治療機制的聯合治療的潛力。

Now in addition to the week 12 primary end point coming early in the second quarter, in the fourth quarter of this year, the SHIFT-UC trial is also expected to read out week 36 treat-through endpoints in the fourth quarter. Now as some of you may know, we had a number of our sites and patients within the ongoing Phase II SHIFT-UC study in Ukraine and Russia. First, and most importantly, our hearts go up to our Ukrainian patients, caregivers, investigators, study coordinators and, of course, the Ukrainian people as a whole. Above all else, we hope for their health and safety in this horrific situation.

現在，除了在第二季度初公佈的第 12 週主要終點外，SHIFT-UC 試驗預計還將在今年第四季度公佈第 36 週的治療終點。現在，你們中的一些人可能知道，我們在烏克蘭和俄羅斯正在進行 II 期 SHIFT-UC 研究，其中有許多研究中心和患者。首先，也是最重要的，我們的心與烏克蘭的患者、護理人員、研究人員、研究協調員，當然還有整個烏克蘭人民同在。最重要的是，我們希望他們在這種可怕的情況下保持健康和安全。

In terms of impact to our ongoing trials, Gossamer Bio's clinical operations team has been vigilant and proactive throughout the escalation of tensions and the tragic breakout of hostilities. We anticipate no impact on data to our 12-week primary end point. Understandably, communication into Ukraine has been challenging, and we're continuing to monitor for impacts to our 36-week data set.

就對我們正在進行的試驗的影響而言，Gossamer Bio 的臨床操作團隊在緊張局勢升級和敵對行動悲劇爆發的整個過程中一直保持警惕和積極主動。我們預計不會對 12 週主要終點數據產生影響。可以理解的是，與烏克蘭的溝通一直充滿挑戰，我們正在繼續監測對 36 週數據集的影響。

Moving on to seralutinib, also known as GB002. Gossamer continues to enroll patients in its ongoing Phase II's TORREY study in patients with functional Class II and III PAH patients. As you may recall, the wave of COVID-19 related to the Delta variant in the late summer and fall of 2021 raised barriers to enrollment. But we're pleased to say that, at this point, the wave of COVID-19 related to Omicron variant has not significantly impacted patient enrollment. Today, we're able to reiterate our current guidance that we expect to read out top line data from the ongoing TORREY study in the second half of this year, of course, barring any further developments in the ongoing COVID-19 viral pandemic.

接下來是塞拉魯替尼，也稱為 GB002。 Gossamer 繼續招募患者參加其正在進行的針對功能性 II 類和 III 類 PAH 患者的 II 期 TORREY 研究。您可能還記得，2021 年夏末和秋季與 Delta 變種相關的 COVID-19 浪潮增加了入學障礙。但我們很高興地說，目前與 Omicron 變異相關的 COVID-19 浪潮尚未對患者入組產生重大影響。今天，我們可以重申當前的指導意見，即我們預計將在今年下半年讀出正在進行的 TORREY 研究的主要數據，當然，除非當前的 COVID-19 病毒大流行出現任何進一步發展。

Now once patients complete the blinded 24-week study period as part of the TORREY study, they are granted the option of enrolling into an open-label extension trial. This extension trial should allow us to generate valuable and elucidating long-term data in patients. To date, we continue to see a very high percentage of patients who have completed the 24-week study period elect to continue on to the open-label extension, similar to the IMPRESS study of imatinib and the PULSAR study of sotatercept.

現在，一旦患者完成 TORREY 研究一部分的為期 24 週的盲法研究期，他們就可以選擇參加開放標籤擴展試驗。這項擴展試驗應該使我們能夠生成有價值的、闡明患者的長期數據。迄今為止，我們仍然看到完成 24 週研究期的患者中有很高比例選擇繼續進行開放標籤擴展，類似於伊馬替尼的 IMPRESS 研究和 sotatercept 的 PULSAR 研究。

If you recall, the IMPRESS study was hindered by a very high discontinuation rate due to adverse events with roughly 1/3 of patients in the imatinib arm, dropping out prior to the 24-week primary end point. The majority of these dropouts in the IMPRESS study occurred in the first 8 weeks. And we've been pleased to see that, to date, the blinded discontinuation rate in the TORREY study has been more comparable to the more manageable discontinuation rate observed in the PULSAR study of sotatercept.

如果您還記得的話，IMPRESS 研究因不良事件而導致極高的中止率，伊馬替尼組中約 1/3 的患者在 24 週主要終點之前退出。 IMPRESS 研究中的大多數退出發生在前 8 週。我們很高興地看到，迄今為止，TORREY 研究中的盲法停藥率與 sotatercept PULSAR 研究中觀察到的更易於管理的停藥率更具可比性。

Now moving on from seralutinib. Our CNS-penetrant BTK inhibitor, GB5121 and is expected to enter a global Phase Ib/II clinical study in PCNSL in CNS lymphoma patients the first half of this year. We previously announced on our prior earnings call that GB5121 had entered a clinical trial in healthy volunteers outside of the U.S. Since then, in the fourth quarter of 2021, we're happy to announce today that our IND application has been submitted with and accepted by the U.S. FDA.

現在繼續從塞拉魯替尼開始。我們的中樞神經系統滲透性 BTK 抑製劑 GB5121 預計將於今年上半年進入中樞神經系統淋巴瘤患者 PCNSL 的全球 Ib/II 期臨床研究。我們之前在之前的財報電話會議上宣布，GB5121 已在美國境外的健康志願者中進入臨床試驗。從那時起，在 2021 年第四季度，我們很高興今天宣布，我們的 IND 申請已提交並接受美國FDA。

Now with that, I'll hand it over to our CFO and COO, Bryan Giraudo, for a final update. Bryan?

現在，我將把它交給我們的首席財務官和首席運營官 Bryan Giraudo，以進行最終更新。布萊恩？

Thank you, Faheem. We will now review the year-end financial results for the full year 2021. We ended the year with $325 million of cash and cash equivalents. We continue to maintain a robust value and anticipate our cash and cash equivalents, plus the capital available to us in our debt facility will provide us sufficient capital resources in the second half of 2023.

謝謝你，法希姆。現在，我們將回顧 2021 年全年的年終財務業績。年底，我們擁有 3.25 億美元的現金和現金等價物。我們繼續保持穩健的價值，並預計我們的現金和現金等價物，加上債務融資中的可​​用資本將為我們在 2023 年下半年提供充足的資本資源。

For the quarter ended December 31, 2021, R&D expenses were $41 million compared to R&D expenses of $39 million for the same period in 2020. R&D expenses for the full year 2021 were $170 million compared to $161 million for 2020. The increase was primarily due to an increase of clinical trial and preclinical study costs associated with seralutinib GB004, GB5121 and preclinical programs. This increase was partially offset by decreases in clinical trial and preclinical study costs related to GB001 and 1275.

截至2021年12月31日的季度，研發費用為4100萬美元，而2020年同期的研發費用為3900萬美元。2021年全年的研發費用為1.7億美元，而2020年為1.61億美元。增加的主要原因是與塞拉替尼 GB004、GB5121 和臨床前項目相關的臨床試驗和臨床前研究成本增加。這一增長被 GB001 和 1275 相關臨床試驗和臨床前研究成本的下降部分抵消。

G&A expenses in the fourth quarter were $11 million compared to $16 million for the same period in 2020. G&A express full in the full year 2021 were $46 million compared to $50 million for the full year of 2020. The net loss for the 3 months ended December 31, 2021, was $56 million or $0.74 per share compared to a net loss of $65 million or $1.05 per share for the same period in 2020. The net loss for the full year ended December 31, 2021, was $234 million or $3.13 per share compared to a net loss of $243 million or $3.55 per share for the full year ended December 31, 2020.

第四季度的一般管理費用為 1100 萬美元，而 2020 年同期為 1600 萬美元。2021 年全年的一般管理費用為 4600 萬美元，而 2020 年全年為 5000 萬美元。截至 3 個月的淨虧損截至 2021 年 12 月 31 日，淨虧損為 5,600 萬美元，即每股 0.74 美元，而 2020 年同期淨虧損為 6,500 萬美元，即每股 1.05 美元。截至 2021 年 12 月 31 日的全年淨虧損為 2.34 億美元，即每股 3.13 美元。截至 2020 年 12 月 31 日的全年淨虧損為 2.43 億美元，即每股 3.55 美元。

With that, I'll turn the call back over to Faheem for some closing comments before we open up for Q&A.

這樣，在我們開始問答之前，我會將電話轉回給 Faheem，以徵求一些結束語。

Thanks, Bryan. Operator, please go ahead and open the line to questions.

謝謝，布萊恩。接線員，請繼續提問。

(Operator Instructions) Our first question comes from the line of Brian Cheng.

（操作員說明）我們的第一個問題來自Brian Cheng。

I have a couple on the UC side since that's going to be your next coming catalyst. Just on the efficacy perspective, we're pretty clear on what we should expect in terms of the placebo rate and also the efficacy rates, the clinical remission rates specifically. Can you just remind us how the histologic benefits associated with remission? It will be great if we can -- if you can help us to get a bit more color on how we can extrapolate early histologic benefits to remission later on? I have 1 more follow-up.

我在加州大學方面有幾個，因為這將是你的下一個催化劑。僅從療效角度來看，我們非常清楚我們對安慰劑率和有效率，特別是臨床緩解率的預期。您能否提醒我們組織學益處如何與緩解相關？如果我們可以的話，那就太好了——如果你能幫助我們更多地了解如何推斷早期的組織學益處到以後的緩解？我還有 1 個後續行動。

I'll turn that question over to Richard Aranda, our Chief Medical Officer.

我會將這個問題轉交給我們的首席醫療官理查德·阿蘭達。

Yes. Thank you, Faheem. Yes. It's a challenging endeavor to predict early histologic results to later clinical responses. There has been recently several reviews in the literature that have specifically looked at that. 3 reviews, for example, one was around stelara. The other one was around the VARSITY study. And the third review was one of the golimumab and JAK inhibitor programs. And fundamentally, what they showed is with -- at early time points, which were different throughout those studies when they looked at histologic improvement and mucosal healing improvements early, for example, at weeks 4 and 8. And those studies, they seem to be associated with more robust clinical end points later in those studies. For example, the stelara was week 44. And the golimumab, I think, was 6 months in the VARSITY trials at week 52.

是的。謝謝你，法希姆。是的。預測早期的組織學結果和後來的臨床反應是一項具有挑戰性的工作。最近文獻中有幾篇評論專門研究了這一點。例如，有 3 條評論，其中一條是關於 stelara 的。另一個是關於 VARSITY 研究的。第三次審查是戈利木單抗和 JAK 抑製劑項目之一。從根本上說，他們所展示的是在早期時間點，這些研究在早期（例如第 4 周和第 8 週）觀察組織學改善和粘膜癒合改善時的情況是不同的。與這些研究後期更穩健的臨床終點相關。例如，stelara 是第 44 週。我認為 golimumab 在 VARSITY 試驗中是第 52 週的 6 個月。

So it's not a perfect relationship, and it's not a perfect association, but it's probably the best that we have that early histologic and particularly mucosal healing changes can potentially reflect the more robust clinical end points later.

因此，這不是一個完美的關係，也不是一個完美的關聯，但它可能是我們所擁有的最好的，早期的組織學，特別是粘膜癒合的變化可以潛在地反映以後更穩健的臨床終點。

Okay. And then one quick follow-up. So in terms of the background therapies that patient is allowed to be on during the SHIFT-UC study, how should we think about the level of background uses of 5-ASA and also, I assume intermittent use of steroids in these mild-to-moderate patients? And what guidance do you give to physicians on the steroid use during the 12-week induction period?

好的。然後是快速跟進。因此，就 SHIFT-UC 研究期間允許患者接受的背景治療而言，我們應該如何考慮 5-ASA 的背景使用水平，而且，我假設在這些輕度至 -中度患者？您對醫生在 12 週誘導期使用類固醇方面有何指導？

So Brian, all patients will be on background 5-ASAs as they enter the trial. We anticipate anywhere from 20% to 40% could be on concomitant background corticosteroids. That seems to be the range if you look throughout the various studies. During the first 12 weeks of the trial, patients are instructed not to change any of the background medications, Once they go beyond the 12 weeks, we do have a provision that they're able to taper the background steroids at the discretion of the patient and the investigator.

Brian，所有患者在進入試驗時都將接受 5-ASA 背景治療。我們預計 20% 到 40% 的患者可能會同時使用皮質類固醇激素。如果你仔細查看各種研究，這似乎就是這個範圍。在試驗的前 12 週內，患者被指示不要改變任何背景藥物。一旦超過 12 週，我們確實有一項規定，他們可以根據患者的判斷逐漸減少背景類固醇的用量和調查員。

Our next question comes from the line of Yasmeen Rahimi.

我們的下一個問題來自亞斯明·拉希米 (Yasmeen Rahimi)。

Faheem, I really appreciate your commentary on that, in the current TORREY study, there's a high interest of patients rolling over into the open-label. Is there an opportunity to maybe comment a little bit beyond that, like quantify it, like what percentage of patients are rolling over? And then in regards to lower discontinuation rate, what discontinuation rates did you guys assume into the study? What type of discontinuation do you see at this junction? And then the third component is how many safety data monitoring committees has TORREY gone through? And that's basically it.

Faheem，我真的很感謝您對此的評論，在當前的 TORREY 研究中，患者對轉向開放標籤非常感興趣。是否有機會對此進行一些評論，例如量化它，例如患者翻身的百分比是多少？那麼關於較低的停藥率，你們在研究中假設的停藥率是多少？您在這個路口看到什麼類型的中斷？第三個組成部分是TORREY經歷了多少次安全數據監測委員會？基本上就是這樣。

Yes. Thanks for your questions. As it relates to the first question, we're not going to be disclosing anything around enrollment or any of the specifics on that. That's kind of been our approach thus far. So we'll kind of just reiterate the fact that we're really pleased with the level of continued engagement that patients have into the OLE, and it's at a rate that we think is consistent, as we said, with basically what we saw in the PULSAR study, and I think that kind of set a really good framework of reference for us. Richard, do you want to add anything else to that?

是的。感謝您的提問。由於它涉及第一個問題，我們不會透露有關註冊的任何信息或任何具體細節。到目前為止，這就是我們的方法。因此，我們只是重申這樣一個事實，即我們對患者對 OLE 的持續參與水平感到非常滿意，正如我們所說，我們認為這種參與率基本上與我們在 OLE 中看到的情況一致。 PULSAR 研究，我認為這為我們建立了一個非常好的參考框架。理查德，你還想補充什麼嗎？

Yes. No, I think, Yasmeen, we're seeing good retention. And it's -- as Faheem was mentioning, the brackets around the IMPRESS trial, which had a high rate, and our PULSAR study, which had a very low rate, and we're much closer to the PULSAR. So it's very encouraging for us.

是的。不，我認為，亞斯明，我們看到了良好的保留率。正如 Faheem 提到的，IMPRESS 試驗的括號內的比率很高，而我們的 PULSAR 研究的比率非常低，而且我們更接近 PULSAR。所以這對我們來說非常鼓舞人心。

And then the DSMB, I think we've had a couple.

然後是 DSMB，我想我們已經有幾個了。

2 meetings.

2次會議。

Yasmeen, does that cover it?

亞斯明，這涵蓋了嗎？

Yes, that's it.

對，就是那樣。

Our next question comes from the line of Joseph Schwartz.

我們的下一個問題來自約瑟夫·施瓦茨（Joseph Schwartz）。

Congrats on all the progress. I was wondering on GB004, if you'd be able to disclose the 2 doses that you're studying in the SHIFT-UC study. I know you've said that both are higher than the 120 milligrams once a day. I was just wondering what they are and what the rationale was for using higher doses versus the Phase Ib?

祝賀所有的進展。我想知道 GB004，您是否能夠透露您在 SHIFT-UC 研究中研究的 2 個劑量。我知道你說過，兩者都高於每天一次120毫克。我只是想知道它們是什麼以及使用比 Ib 期更高劑量的理由是什麼？

Joe, we'll let Rich speak to the rationale, but we have not disclosed it. We won't disclose it. But we are in the middle of enhancing our intellectual property position. And so I would like to get that done before we come forth with those dose levels, which will be around the time of our data disclosure. But Rich, rationale?

喬，我們會讓里奇談談理由，但我們還沒有透露。我們不會透露它。但我們正在加強我們的知識產權地位。因此，我希望在我們公佈這些劑量水平之前完成這項工作，這將在我們的數據披露前後完成。但是里奇，理由是什麼？

Yes. I think the way I would frame it is we were very encouraged with the 120-milligram 28-day study in our Phase Ib that I'd like to call it provided us the floor of exposure, if you will. And within that floor of exposure within the gut mucosa as well as our plasma PK, we saw good signs of, obviously, biomarkers, histologic activity and hints of clinical activity. So if you consider that as a foundation, our idea is perhaps we would amplify the signal that we saw there by dosing higher to increase the exposure within the gut and also treating longer and, hence, our Phase II trial was designed with those 2 aspirations.

是的。我認為我的框架方式是，我們對 Ib 期 120 毫克、為期 28 天的研究感到非常鼓舞，如果你願意的話，我想稱其為我們提供了暴露的底線。在腸道粘膜暴露的底層以及我們的血漿 PK 中，我們顯然看到了生物標誌物、組織學活性和臨床活性暗示的良好跡象。因此，如果您認為這是一個基礎，我們的想法也許是我們會通過更高劑量來增加腸道內的暴露並治療更長時間來放大我們在那裡看到的信號，因此，我們的 II 期試驗是根據這兩個願望設計的。

Okay. And then kind of a similar question on GB5121. I was wondering if you could talk about the range of doses that you're studying in the Phase I healthy volunteer study and how they relate to the dose range that you're anticipating, could be efficacious? And are you looking for a strong safety profile with every dose you're assessing? Or are you doing, as is often done in some oncology studies, where you push the higher end of the dose range in order to find the maximum tolerated dose?

好的。然後是關於 GB5121 的類似問題。我想知道您是否可以談談您在第一階段健康志願者研究中研究的劑量範圍，以及它們與您預期的劑量範圍有何關係，是否有效？您是否正在為您正在評估的每個劑量尋找強大的安全性？或者，您是否像某些腫瘤學研究中經常進行的那樣，將劑量範圍推高以找到最大耐受劑量？

Joe, you're talking about our normal healthy volunteer study?

喬，你是在談論我們正常的健康志願者研究嗎？

Yes.

是的。

Yes. I think the good thing about BTKs is we have an opportunity to use a great target of receptor occupancy assay to guide us, and that's historically been done. And our -- just to remind you, our profile is such that we believe we have superior CNS penetrants relative to what our systemic exposure is going to be. And so utilizing a BTK receptor occupancy, we're able to model pretty good in a way that helps guide us our lower dose. And we're going to push the dose to achieve maximal receptor occupancy and then go above -- typically, you go above 99%, at least in the systemic circulation and go above that and look for the safety within that context. So that's our plan. We're going to use -- start at a dose that gives us an assumed mid-range receptor occupancy then to escalate fairly rapidly with guidance there.

是的。我認為 BTK 的好處是我們有機會使用受體佔據分析的大目標來指導我們，而且歷史上已經這樣做了。我們只是提醒您，我們的概況是這樣的，我們相信相對於我們的全身暴露而言，我們擁有更優越的中樞神經系統滲透劑。因此，利用 BTK 受體佔用，我們能夠以有助於指導我們降低劑量的方式建立相當好的模型。我們將提高劑量以實現最大受體佔有率，然後超過——通常情況下，你會超過 99%，至少在體循環中，並在該範圍內尋找安全性。這就是我們的計劃。我們將使用——從給我們假定的中等受體佔據率的劑量開始，然後在指導下相當迅速地升級。

You are next, Carter Gould.

下一個就是你，卡特·古爾德。

Maybe to start, in terms of the SHIFT-UC top line, can you just comment about what you expect to disclose in the press release? Are you committing to sharing any quantitative disclosures around clinical remission? And then, separately, as I understand, the open-label extension shift you see is only 24 weeks. So my understanding is 36 weeks and then an additional 24 weeks. Has there been any consideration around maybe expanding that or lengthening it just to get some longer-term follow-up? Any thoughts there would be helpful.

首先，就 SHIFT-UC 的頂線而言，您能否評論一下您希望在新聞稿中披露的內容？您是否承諾分享有關臨床緩解的任何定量披露？然後，據我了解，您看到的開放標籤延伸班次僅為 24 週。所以我的理解是36週，然後再加24週。有沒有考慮過擴大或延長它以獲得一些長期的後續行動？任何想法都會有幫助。

Yes. Thanks, Carter. We'll be fairly robust in our disclosure, certainly around the primary and secondary end points and key biomarker data that we have at the time. So as in the past and certainly as Faheem and Richard did, going back to Receptos, you should expect a fairly transparent conversation. As far as the -- I'll turn it over to Rich.

是的。謝謝，卡特。我們的披露將相當穩健，尤其是圍繞我們當時擁有的主要和次要終點以及關鍵生物標誌物數據。因此，就像過去一樣，當然也像 Faheem 和 Richard 所做的那樣，回到 Receptos，您應該期待一場相當透明的對話。至於——我會把它交給里奇。

Yes, I just want to clarify, our the 36 weeks -- from week 12 to week 36 is still double blinded, if you will. So I just want to clarify that, the patients after week 12 stay on their allocation of their original randomization, assuming they don't worsen and need to roll over into the open label. And then the open label extends out [to move] at least 28 weeks in. Once again, we'll look at our top line results and decide on next steps if the open label should be extended.

是的，我只是想澄清一下，如果你願意的話，我們的 36 週——從第 12 周到第 36 週仍然是雙盲的。所以我只是想澄清一下，第 12 週後的患者仍保留原來的隨機分配，假設他們沒有惡化並且需要轉入開放標籤。然後開放標籤將延長[移動]至少 28 週。我們將再次查看我們的頂線結果，並決定是否應延長開放標籤的後續步驟。

Our next question comes from the line of Patrick Trucchio.

我們的下一個問題來自 Patrick Trucchio。

The first question is just regarding seralutinib. So on the primary end point of change in PVR from baseline at week 24, I think in the past, you've discussed an expectation of an approximate 20% improvement relative to placebo. I'm wondering if that remains the expectation. And secondly, in addition to safety and tolerability, can you discuss what additional data points you'll be looking to hit to give confidence to move the program forward to Phase III?

第一個問題是關於塞拉魯替尼。因此，關於第 24 週 PVR 相對於基線的變化的主要終點，我認為過去您已經討論過相對於安慰劑而言大約改善 20% 的預期。我想知道這是否仍然是期望。其次，除了安全性和耐受性之外，您能否討論一下您希望獲得哪些額外的數據點，以增強該項目進入第三階段的信心？

Yes. Just to clarify, the guidance we're giving is between 18% to 32% improvement from baseline in PVR not necessarily a treatment effect from placebo. What we're -- and that's based on looking at the totality of the data from the IMPRESS trial as the recent sotatercept, where the PVR changes bracketed those end points and seem to be clinically meaningful.

是的。需要澄清的是，我們給出的指導是 PVR 較基線提高 18% 至 32%，並不一定是安慰劑的治療效果。我們所做的——這是基於對最近 sotatercept 的 IMPRESS 試驗的全部數據的觀察，其中 PVR 的變化將這些終點括起來，似乎具有臨床意義。

Obviously, in addition to PVR, the other premise we have for the inhaled route administration is a good safety profile. And that's the other key component that we will be evaluating. We are -- we'll be looking at 6-minute walk, but we're not powered for that. Yet, hopefully, we will see good trends and we will do the other standard biomarker NT-proBNP as a measure of right heart function.

顯然，除了 PVR 之外，我們吸入途徑管理的另一個前提是良好的安全性。這是我們將評估的另一個關鍵組成部分。我們將考慮步行 6 分鐘，但我們沒有足夠的動力。然而，希望我們能看到良好的趨勢，我們將使用其他標準生物標誌物 NT-proBNP 作為右心功能的衡量標準。

Yes. That's helpful. And then can you describe for us what the clinical development path for seralutinib could look like if you see the promising data as just described? Or is there an opportunity for an accelerated approval pathway?

是的。這很有幫助。那麼，如果您看到剛才描述的有希望的數據，您能否為我們描述一下塞拉魯替尼的臨床開發路徑會是什麼樣子？或者是否有機會加快審批途徑？

I would say that, Pat, first and foremost, we want to get through the TORREY study and, with that data, have the right conversations with regulators. And obviously, we will push as hard as we can for the most efficient Phase III clinical plan. We know that patients are desperate for new options, and we want to be able to push as hard as we can. But really to have any comments before we spend time with regulators would just be premature.

我想說的是，帕特，首先也是最重要的是，我們希望完成托里研究，並利用這些數據與監管機構進行正確的對話。顯然，我們將盡最大努力推動最有效的 III 期臨床計劃。我們知道患者迫切需要新的選擇，我們希望能夠盡力推動。但在我們與監管機構接觸之前真正發表任何評論還為時過早。

Your next question comes from the line of David Hoang.

你的下一個問題來自 David Hoang。

I just had -- I had 2 on each on UC and PAH. So maybe first for UC. Are we -- can we make any inferences on the expectations for the week 36 responses based on what we see at week 12 and maybe considering some of the other molecules and other trials, which have used the treat-through design?

我剛剛在 UC 和 PAH 上各做了 2 個。所以也許首先是加州大學。我們是否可以根據我們在第 12 週看到的情況，並可能考慮使用治療貫穿設計的一些其他分子和其他試驗，對第 36 週反應的預期做出任何推斷？

Yes. There's clearly -- potentially one expectation is that we could see incremental sort of more -- better treatment effect as we treat longer. That's something that we experienced, for example, on ozanimod when we worked on that program. So -- and then we also have the opportunity to look at some degree of maintenance as well as patients at week 12 that they have a certain response, do they maintain that response as they continue into week 36, looking at 2 time points, for example. So at the end of the day, it will give us a hint of the ability of 004 to maintain a response.

是的。顯然，一種潛在的期望是，隨著治療時間的延長，我們可以看到更多更好的治療效果。例如，當我們在 ozanimod 上開發該程序時，我們就經歷過這種情況。因此，我們還有機會觀察某種程度的維持以及患者在第 12 週時是否有一定的反應，他們是否在持續到第 36 週時保持這種反應，觀察 2 個時間點，例子。所以歸根結底，它會給我們暗示004維持反應的能力。

Okay. That's helpful. And then on PAH, just in terms of how you think about the total addressable market for seralutinib? I know that, for example, Merck, when they had their acquisition of Acceleron, they discussed in their presentation some numbers around market sizing and opportunity for sotatercept. I'm just wondering if you think that's comparable or if there are any patients that you would or would not include in the seralutinib opportunity that might not overlap with sotatercept.

好的。這很有幫助。然後就 PAH 而言，您如何看待塞拉魯替尼的總體潛在市場？我知道，例如默克公司，當他們收購 Acceleron 時，他們在演示中討論了有關 sotatercept 的市場規模和機會的一些數字。我只是想知道您是否認為這具有可比性，或者是否有任何患者會或不會納入塞拉魯替尼機會，而這些患者可能與 sotatercept 不重疊。

Yes. I think it's appropriate to look at it as kind of -- our view is pretty consistent with the way sotatercept has been described in the addressable market. So I don't think that we've got any significant deviation from that.

是的。我認為將其視為適當的——我們的觀點與 sotatercept 在目標市場中的描述方式非常一致。所以我認為我們沒有任何重大偏差。

(Operator Instructions) Our next question comes from the line of Gavin Clark-Gartner.

（操作員說明）我們的下一個問題來自 Gavin Clark-Gartner。

So I just had one on seralutinib. Could you explain how exactly the dose titration protocol works for TORREY. And thus far, like roughly what proportion of patients are making it on to the 90 mg dose?

所以我只服用了一粒塞拉魯替尼。您能否解釋一下 TORREY 的劑量滴定方案到底是如何運作的？到目前為止，大約有多少比例的患者接受了 90 毫克劑量？

Yes. We're -- we start patients out at 60 milligrams twice a day, and they -- during the first 2 weeks -- first 2 to 3 weeks of the trial, they rapidly dose escalate up to 90 milligrams twice a day. They're able to dose de-escalate in the opinion of the investigator and, obviously, the tolerability profile of the patient that they're able to dose de-escalate once they reach the 90. What the second part of your question, please? Could you repeat that?

是的。我們開始給患者服用 60 毫克，每天兩次，他們在試驗的前 2 週，前 2 到 3 週，劑量迅速增加到每天兩次 90 毫克。他們能夠根據研究者的意見逐步降低劑量，顯然，根據患者的耐受性情況，一旦達到 90，他們就能夠逐漸降低劑量。請問您問題的第二部分是什麼？ ？你能再說一遍嗎？

Just roughly what proportion of patients have made it on to your [study] on the 90 mg dose?

大約有多少比例的患者參加了您接受 90 毫克劑量的[研究]？

It's as we were alluding to very, very high as patients are rolling over into the open label. So I think that's reassuring since we see high rollover. And the dose there is also 90 milligrams twice a day that it's being very well tolerated.

正如我們所提到的，隨著患者轉向開放標籤，這種情況非常非常高。所以我認為這讓人放心，因為我們看到了高額的換手率。而且劑量也是 90 毫克，每天兩次，耐受性很好。

(Operator Instructions) We have no further questions at this time. I will now turn the call over back to Mr. Bryan Giraudo.

（操作員說明）目前我們沒有其他問題。我現在將把電話轉回給 Bryan Giraudo 先生。

Actually, this is Faheem Hasnain. I just want to thank everyone who joined us today. I also want to give heartfelt thanks to the team here at Gossamer. We have a group of incredibly dedicated and passionate professionals, and the team has made really fantastic progress. So I just would like to thank everybody that's involved with these programs. We're honored to share our progress with you as we move our gaze forward towards an exciting 2022. So thank you again, everybody, for joining us.

事實上，這是法希姆·哈斯奈恩。我只想感謝今天加入我們的所有人。我還要向 Gossamer 的團隊表示衷心的感謝。我們擁有一群非常敬業和熱情的專業人士，並且團隊取得了巨大的進步。所以我想感謝所有參與這些​​計劃的人。我們很榮幸能與您分享我們的進展，展望激動人心的 2022 年。再次感謝大家加入我們。

Thank you again for your participation. This concludes today's conference call. You may now disconnect.

再次感謝您的參與。今天的電話會議到此結束。您現在可以斷開連接。