Silence Therapeutics PLC (SLN) 2021 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Silence Therapeutics Full Year 2021 Earnings Conference Call and Webcast. (Operator Instructions) I will now hand over to Gem Hopkins, Head of IR and Corporate Communications, to open the webcast. Go ahead, madam.

女士們、先生們，美好的一天，歡迎參加 Silence Therapeutics 2021 年全年收益電話會議和網路廣播。 （操作員指示）我現在將由 IR 和企業傳播主管 Gem Hopkins 主持網路廣播。繼續吧，女士。

Good morning and good afternoon, everyone. Thank you for joining us today. My name is Gem Hopkins, Head of Investor Relations and Corporate Communications at Silence. Joining me today on the call are Craig Tooman, our President and Chief Executive Officer, who will provide an update on the business; Rhonda Hellums, our Chief Financial Officer, who will review our financials; and Dr. Giles Campion, our Head of R&D, who will provide an update on our clinical programs before opening the call to your questions. For those of you participating via conference call, the accompanying slides can be accessed by going to the Investors section of our corporate website at www.silent-therapeutics.com.

大家早安，下午好。感謝您今天加入我們。我叫 Gem Hopkins，Silence 投資人關係與企業傳播主管。今天與我一起參加電話會議的是我們的總裁兼執行長 Craig Tooman，他將提供有關業務的最新資訊； Rhonda Hellums，我們的財務官，她將審查我們的財務狀況；以及我們的研發主管 Giles Campion 博士，他將在開始回答您的問題之前提供我們臨床計畫的最新資訊。對於那些透過電話會議參加的人，可以透過造訪我們公司網站 www.silent-therapeutics.com 的投資者部分來存取隨附的幻燈片。

Turning to Slide 2, I'd like to remind you that during today's call management will make projections or other forward-looking statements regarding anticipated future events or the future financial performance of the company, including clinical development timing and objectives, the therapeutic potential of our product candidates, our operational plans and strategies, anticipated milestone payments, anticipated operating and capital expenditures, business prospects and projected cash runway. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

轉向投影片 2，我想提醒您，在今天的電話會議中，管理層將就預期的未來事件或公司未來的財務業績做出預測或其他前瞻性陳述，包括臨床開發時間和目標、治療潛力我們的候選產品、我們的營運計劃和策略、預期里程碑付款、預期營運和資本支出、業務前景和預計現金跑道。由於各種重要因素，包括我們向美國證券交易委員會提交的最新年度報告中討論的因素，實際結果可能與這些前瞻性陳述所示的結果有重大差異。此外，任何前瞻性陳述僅代表我們截至本紀錄之日的觀點，不應被視為代表我們在任何後續日期的觀點。我們特別聲明不承擔更新此類聲明的義務。

With that, I'd like to turn the call over to Craig. Craig?

有了這個，我想把電話轉給克雷格。克雷格？

Thank you, Gem, and welcome, everyone. Thank you for making the time to join us today. Turning to Slide 3. 2021 was a remarkable year for Silence, highlighted by the first successful clinical data from our proprietary mRNAi GOLD platform and the emergence of the company as a globally recognized peer trading on NASDAQ with top-tier investors. Silence is well positioned for long-term growth in the very dynamic siRNA space and we are very excited about our future prospects.

謝謝你，Gem，歡迎大家。感謝您今天抽空加入我們。轉向幻燈片3。2021 年對Silence 來說是非凡的一年，我們專有的mRNAi GOLD 平台首次獲得成功的臨床數據，以及該公司成為納斯達克全球公認的同行交易公司，並與頂級投資者合作，凸顯了這一點。 Silence 在充滿活力的 siRNA 領域處於長期成長的有利位置，我們對未來的前景感到非常興奮。

Regarding our pipeline, the results from the SLN124 healthy volunteer study last May demonstrated proof of mechanism and showed our ability to effectively translate preclinical results into the clinic. With this backdrop, we made excellent progress during the year, advancing both our wholly owned and partnered programs targeting genetic diseases in the liver. We completed enrollment in the SLN360 Phase I study in healthy adults with high LP(a), setting us up for the positive data readout we just reported this quarter. We also started dosing patients in the SLN124 Phase I program. Giles will provide an update on both programs later in the call.

關於我們的產品線，去年 5 月 SLN124 健康志願者研究的結果證明了機制，並表明我們有能力有效地將臨床前結果轉化為臨床。在此背景下，我們在這一年中取得了巨大進展，並推進了針對肝臟遺傳疾病的全資和合作計畫。我們完成了 SLN360 一期研究的入組，對像是具有高 LP(a) 的健康成人，為我們本季度剛剛報告的積極數據做好了準備。我們也開始對 SLN124 I 期計畫的患者進行給藥。賈爾斯稍後將在電話會議中提供這兩個項目的最新資訊。

On the partnering side, we secured a new collaboration with Hansoh Pharma that added 3 new targets to our pipeline. We also continued to advance our collaborations with AstraZeneca and Mallinckrodt. Collectively, these collaborations brought in a total of $58 million in nondilutive cash in 2021. This really demonstrates the value of our hybrid business model to expand our pipeline and provide a steady stream of nondilutive capital to support our internal R&D efforts.

在合作方面，我們與豪森製藥達成了新的合作，為我們的產品線增加了 3 個新標靶。我們也繼續推進與阿斯特捷利康和 Mallinckrodt 的合作。總的來說，這些合作在2021 年帶來了總計5,800 萬美元的非稀釋性現金。內部研發工作的價值。

Earlier in the year, we completed a $45 million private placement that laid the groundwork for expanding our global shareholder base. We built on this in the second half of the year with our successful AIM delisting in November, a move we made to support increasing interest from new investors. Along with our exclusive NASDAQ listing, we welcomed several new U.S. health care funds as key shareholders to Silence.

今年早些時候，我們完成了 4500 萬美元的私募，為擴大我們的全球股東基礎奠定了基礎。在此基礎上，我們在下半年成功實現了 AIM 退市，並於 11 月成功退市，此舉是為了支持新投資者日益增長的興趣。隨著我們在納斯達克的獨家上市，我們迎來了幾個新的美國醫療保健基金作為 Silence 的主要股東。

Turning to Slide 4. We've entered 2022 with incredible momentum. As you probably know, we just reported very encouraging clinical data for SLN360 last month. That's the second positive clinical data set from our GOLD platform. This is a real tribute to Giles and the R&D team who have strategized and led this effort, and I know he's looking forward to telling you more about this. SLN360 is a priority asset for us where we see substantial opportunity to build value. We're looking forward to the full study results being presented in a late-breaker at ACC on April 3. Beyond the ACC presentation, we expect more durability data in the third quarter and remain on track to start the Phase II ASCVD study later this year, pending regulatory feedback. We expect to capitalize on the growing appreciation for SLN360 and are engaged in global partnership discussions to ensure we maximize this high-value program going forward.

轉向幻燈片 4。您可能知道，我們上個月剛報告了 SLN360 非常令人鼓舞的臨床數據。這是我們 GOLD 平台的第二個積極的臨床數據集。這是對賈爾斯和研發團隊的真正致敬，他們制定了策略並領導了這項工作，我知道他期待著向您介紹更多相關資訊。 SLN360 是我們的優先資產，我們看到了創造價值的巨大機會。我們期待 4 月 3 日在 ACC 的晚會上公佈完整的研究結果。年，等待監管回饋。我們期望利用 SLN360 日益增長的價值，並參與全球合作夥伴討論，以確保我們在未來最大限度地發揮這一高價值計劃的作用。

Moving to SLN124, we have now fully enrolled the thalassemia study and remain on track for top line data in the third quarter. Given enrollment challenges in the MDS study and our commitment to prioritize investment in areas where we believe we can create the most value, we've decided to discontinue the MDS cohorts and focus on thalassemia and polycythemia vera, or PV. We are very pleased that the FDA recently granted SLN124 orphan drug designation for PV last month, adding to the other designations we already have, and we expect to start a Phase I study later this year.

轉向 SLN124，我們現已全面納入地中海貧血研究，並預計在第三季度獲得頂線數據。鑑於 MDS 研究中的入組挑戰以及我們承諾優先投資於我們認為能夠創造最大價值的領域，我們決定停止 MDS 隊列，並將重點放在地中海貧血和真性紅血球增多症（PV）上。我們非常高興 FDA 上個月最近授予了 SLN124 用於治療 PV 的孤兒藥資格，這增加了我們已經擁有的其他資格，我們預計將在今年晚些時候開始 I 期研究。

On the partnering side, we're on track to move the SLN501 program with Mallinckrodt for complement-mediated diseases into the clinic in the first half of this year. We are very pleased that the pipeline continues to progress very well both internally and with our partners.

在合作方面，我們預計在今年上半年將與 Mallinckrodt 合作的用於補體介導疾病的 SLN501 計畫轉移到臨床。我們非常高興該管道在內部以及與我們的合作夥伴之間繼續取得良好進展。

Before I turn the call over to Rhonda for an update on our financials, I just want to highlight an important point. What is particularly attractive about our GOLD platform and the GalNAc siRNA approach is its well-established modality, with a track record of clinical success. In fact, historically, GalNAc siRNA programs have had a much higher success rate in moving from Phase I to Phase III compared to the pharma industry average. That's why we're so excited about our advancing clinical pipeline. Going forward, we will prioritize investment in our clinical pipeline in the areas where we believe we can generate the most value while always being careful stewards of our shareholders' capital.

在我打電話給朗達詢問我們的財務狀況最新情況之前，我想強調一個重要的觀點。我們的 GOLD 平台和 GalNAc siRNA 方法特別有吸引力的地方在於其完善的模式，以及臨床成功的記錄。事實上，從歷史上看，與製藥業的平均水平相比，GalNAc siRNA 計畫從 I 期轉向 III 期的成功率要高得多。這就是為什麼我們對不斷推進的臨床管道感到如此興奮。展望未來，我們將優先投資於我們認為能夠產生最大價值的領域，同時始終謹慎管理股東資本的領域。

With that, I'd like to turn the call over to Rhonda for an update on our financial performance. Rhonda?

說到這裡，我想將電話轉給朗達，以了解我們財務表現的最新情況。朗達？

Thank you, Craig. Turning to Slide 7. For the period ending December 31, 2021, the company recorded GBP 12.4 million in revenues versus GBP 5.5 million in 2020. The increase of GBP 6.9 million was primarily driven by the advancement of targets in our Mallinckrodt and AstraZeneca collaborations, which together delivered GBP 11.4 million in 2021. We also recorded approximately GBP 392,000 in royalty revenue during 2021. As a reminder, we record revenue from our collaborations based on a percentage of contract completion. Therefore, as our current collaboration programs progress, such as SLN501 did in 2021, and additional programs are initiated, such as those programs associated with our Hansoh agreement, which was executed in October of 2021, our revenues are also estimated to increase. The expenses related to our partner program, including the portion of our employees' time dedicated to these programs, are recorded as cost of sales as they are attributed to the revenues.

謝謝你，克雷格。轉向幻燈片 7。年總共交付了1,140 萬英鎊。因此，隨著我們目前合作項目的進展（例如 2021 年的 SLN501）以及其他項目的啟動（例如與 2021 年 10 月執行的豪森協議相關的項目），我們的收入預計也會增加。與我們的合作夥伴計劃相關的費用，包括我們員工專門用於這些計劃的時間部分，被記錄為銷售成本，因為它們歸因於收入。

As expected, R&D costs rose in 2021 to GBP 30.8 million versus GBP 20.2 million in 2020. This increase was primarily due to advancing our proprietary SLN360 and SLN124 programs and the increase in head count costs due to the addition of R&D expertise to support our innovative pipeline.

正如預期，研發成本在2021 年上升至3080 萬英鎊，而2020 年為2020 萬英鎊。導致的人員成本增加。

General and administrative costs were GBP 20 million in 2021 versus GBP 14 million in 2020. The increase was primarily driven by requirements of being a public company dual listed on both the NASDAQ and AIM for most of 2021 and support [for] the growth of our R&D program. These costs include an increase in noncash share-based expenses related to the granting of employee share options and further enhancement of our support functions, including personnel. As Craig mentioned earlier, in late November, we delisted from the AIM and are now solely listed on the NASDAQ.

2021 年的一般和管理成本為2000 萬英鎊，而2020 年為1400 萬英鎊。我們的成長而推動的。這些成本包括與授予員工股票選擇權相關的非現金股票費用的增加以及我們的支援職能（包括人員）的進一步增強。正如克雷格之前提到的，11 月底，我們從 AIM 退市，現在只在納斯達克上市。

The company's net loss for the full year of 2021 was GBP 39.4 million versus GBP 32.5 million in 2020. The increase of GBP 13.2 million is related primarily from the R&D and G&A expenses, but those are partially offset by the increase in gross profit from our collaborations.

該公司 2021 年全年的淨虧損為 3,940 萬英鎊，而 2020 年為 3,250 萬英鎊。 合作 增加的 1,320 萬英鎊主要與研發和一般行政費用有關，但這部分被我們的毛利潤的增加所抵消。 。

Turning to Slide 8, the company's cash and cash equivalents were GBP 73.5 million or approximately $99 million at the end of December 2021. As Craig mentioned, during 2021 we received GBP 44.4 million or $58.4 million from our collaboration partners. This includes proceeds of $40 million or GBP 30.8 million from AstraZeneca in May and a $16 million upfront payment from Hansoh in December which, net of taxes, was approximately GBP 10.7 million. We also received proceeds of $45 million or approximately GBP 33 million from our oversubscribed private placement of our ADSs in February of 2021.

轉向幻燈片8，截至2021 年12 月底，該公司的現金和現金等價物為7350 萬英鎊或約9900 萬美元。 5840 萬美元。其中包括阿斯特捷利康 5 月的 4,000 萬美元（即 3,080 萬英鎊）收益以及豪森 12 月的 1,600 萬美元預付款，扣除稅項後，約為 1,070 萬英鎊。我們也從 2021 年 2 月超額認購的美國存託股私募中獲得了 4,500 萬美元（約 3,300 萬英鎊）的收益。

We are not providing any specific guidance on spending today, but we are committed to responsibly investing in initiatives that will advance our pipeline and in the valuable programs that offer the potential to address important diseases that impact many individuals worldwide. We estimate that our current cash balance of GBP 73.5 million will last until early 2023. We will continue to leverage our hybrid business model and evaluate new additional nondilutive collaboration agreements.

我們今天沒有提供任何具體的支出指導，但我們致力於負責任地投資於將推進我們的管道的舉措和有價值的計劃，這些計劃有可能解決影響全世界許多人的重要疾病。我們估計目前 7,350 萬英鎊的現金餘額將持續到 2023 年初。

With that, I will turn the call over to Giles for clinical updates. Giles?

這樣，我會將電話轉給賈爾斯以獲取臨床最新資訊。賈爾斯？

Thank you, Rhonda. Turning to Slide 10. As Craig mentioned, we've now generated clinical data in 2 separate wholly owned programs that demonstrate the consistency of the siRNA modality and breadth of our GOLD platform: SLN360, targeting high Lp(a), a genetic risk factor for cardiovascular disease affecting up to 20% of the world's population, and SLN124, targeting TMPRSS6, a gene that prevents the liver from producing hepcidin, which is a key natural regulator of iron. We're using this approach to potentially address a range of rare hematological diseases. In both Phase I studies, we saw robust knockdown of the target gene, strong durability of effect after a single dose and a good safety/tolerability profile. These findings are consistent with what we observed preclinically and why we believe the siRNA approach is so attractive.

謝謝你，朗達。轉向幻燈片10。 （一種遺傳風險因子）用於治療影響多達20% 世界人口的心血管疾病，以及針對TMPRSS6 的SLN124，TMPRSS6 是一種阻止肝臟產生鐵調素的基因，而鐵調素是鐵的關鍵天然調節劑。我們正在使用這種方法來潛在地解決一系列罕見的血液疾病。在兩項 I 期研究中，我們看到了目標基因的穩健敲除、單劑量後效果的持久性以及良好的安全性/耐受性。這些發現與我們在臨床前觀察到的結果一致，也是我們相信 siRNA 方法如此有吸引力的原因。

Turning to Slide 11 and our SLN360 Lp(a) lowering program, Lp(a) is an independent risk factor for cardiovascular disease affecting 1 in 5 people worldwide. Lp(a) levels are genetically determined and not modifiable through diet or lifestyle changes. There is currently no specific treatment option approved for high Lp(a) and existing cholesterol-lowering drugs are not effective.

轉向幻燈片 11 和我們的 SLN360 Lp(a) 降低計劃，Lp(a) 是心血管疾病的獨立危險因素，影響全球五分之一的人。 Lp(a) 水平由基因決定，不能透過飲食或生活方式的改變來改變。目前尚無批准用於高 Lp(a) 的特定治療方案，且現有的降膽固醇藥物無效。

On Slide 12, you can see that high Lp(a) significantly increases risk of serious cardiovascular events like heart attack, aortic stenosis and heart failure. Clearly, this is a major public health issue with a huge unmet need.

在投影片 12 上，您可以看到高 Lp(a) 會顯著增加心臟病、主動脈瓣狹窄和心臟衰竭等嚴重心血管事件的風險。顯然，這是一個重大的公共衛生問題，存在著巨大的未滿足需求。

Turning to Slide 13 and our SLN360 Phase I program. This program includes a single ascending dose and multiple dose part. Both are randomized, double-blind, placebo-controlled studies. In February, we reported positive top line data in the single [ascending] dose cohorts that evaluated 32 healthy adults with high Lp(a) at or above 60 milligrams per deciliter. The multiple ascending dose study is ongoing, and that's looking at adults with stable atherosclerotic cardiovascular disease and high Lp(a).

轉向幻燈片 13 和我們的 SLN360 第一階段計劃。此方案包括單次遞增劑量和多次劑量部分。兩者都是隨機、雙盲、安慰劑對照研究。 2 月份，我們報告了單劑量[遞增]劑量組的陽性頂線數據，該組評估了 32 名 Lp(a) 等於或高於 60 毫克/分升的健康成年人。多劑量遞增研究正在進行中，研究對象為患有穩定的動脈粥狀硬化性心血管疾病和高 Lp(a) 的成年人。

Turning now to Slide 14, here's a look at the SLN360 top line data we reported. As I mentioned, SLN360 was well tolerated, and there were no clinically important safety concerns identified. SLN360 reduced Lp(a) in a dose-dependent manner from 46% up to a maximum of 98%, with an 81% reduction persisting at 150 days. Longer-term follow-up to 365 days is ongoing to further assess the duration of action.

現在轉到投影片 14，看看我們報告的 SLN360 頂線數據。正如我所提到的，SLN360 的耐受性良好，並且沒有發現任何臨床上重要的安全性問題。 SLN360 以劑量依賴的方式降低 Lp(a)，從 46% 降低到最高 98%，150 天時持續降低 81%。長達 365 天的長期追蹤正在進行中，以進一步評估作用的持續時間。

While we're limited in what we can disclose right now due to ACC embargo policy, detailed results will be presented in a late breaker at ACC on April 3 by our lead study investigator, Dr. Steve Nissen from the Cleveland Clinic.

雖然由於 ACC 禁運政策，我們目前可以披露的資訊有限，但詳細結果將由我們的首席研究研究員、來自克利夫蘭診所的 Steve Nissen 博士在 4 月 3 日的 ACC 晚會上公佈。

Moving now to our SLN124 hepcidin regulation program. This is a program where we see broad therapeutic potential based on SLN124's ability to regulate hepcidin, known as the master regulator of iron in the body. We've generated strong preclinical data in a number of disease models including thalassemia, polycythemia vera and hereditary hemochromatosis. We've also established proof of mechanism in healthy volunteers. SLN124 has rare pediatric disease designation for beta-thalassemia and orphan drug designations for thalassemia, MDS, and now PV.

現在轉向我們的 SLN124 鐵調素調節程序。在這個計畫中，我們看到了基於 SLN124 調節鐵調素（被稱為體內鐵的主要調節劑）的能力的廣泛治療潛力。我們在多種疾病模型中產生了強有力的臨床前數據，包括地中海貧血、真性紅血球增多症和遺傳性血色素沉著症。我們也在健康志工中建立了機制證明。 SLN124 被指定為治療 β 地中海貧血的罕見兒科疾病，以及治療地中海貧血、MDS 和現在的真性紅斑狼瘡的孤兒藥。

As I mentioned, SLN124 targets the TMPRSS6 gene in the liver. By reducing TMPRSS6 expression, we can raise endogenous hepcidin. This, in turn, lowers systemic iron levels and normalizes distribution, improving red cell production. In this preclinical thalassemia model, you can see that SLN124 increased hemoglobin by a robust 2.5 grams per deciliter. An increase of 1.5 grams per deciliter is considered clinically significant.

正如我所提到的，SLN124 靶向肝臟中的 TMPRSS6 基因。透過減少 TMPRSS6 表達，我們可以提高內源性鐵調素。反過來，這會降低全身鐵水平並使分佈正常化，從而改善紅血球的生成。在這個臨床前地中海貧血模型中，您可以看到 SLN124 使血紅蛋白增加了 2.5 克/分升。每分升 1.5 克的增加被認為具有臨床意義。

Turning now to Slide 18 and our healthy volunteer study that we reported out last May. This was a randomized double-blind placebo-controlled single dose study in 24 healthy adults. We presented full results at the American Society of Hematology Annual Meeting last December. Slide 19 shows you that SLN124 increased average hepcidin in a dose-dependent manner of up to approximately fourfold after a single dose, with effects persisting throughout the study period.

現在轉向幻燈片 18 以及我們去年 5 月報告的健康志願者研究。這是一項針對 24 名健康成年人的隨機雙盲安慰劑對照單劑量研究。去年 12 月，我們在美國血液學會年會上發表了完整的結果。投影片 19 向您展示了 SLN124 在單次給藥後以劑量依賴性方式使平均鐵調素增加了約四倍，並且在整個研究期間效果持續存在。

Slide 20, you can see that SLN124 induced durable reductions in serum iron. Percentage change from baseline was around 50% at day 29 with 3 and 4.5 milligram per kilogram doses.

在投影片 20 中，您可以看到 SLN124 誘導血清鐵持續降低。在第 29 天，劑量為每公斤 3 毫克和 4.5 毫克時，與基線相比的百分比變化約為 50%。

Turning to Slide 21, and in summary, this was an important study because it was the first clinical study from our GOLD platform and established proof of mechanism for SLN124. SLN124 showed durable reductions in serum iron and transferrin saturation, a strong safety profile and long duration of action. We remain encouraged by these results and expect to build on this with the ongoing study in thalassemia patients.

轉向幻燈片 21，總而言之，這是一項重要的研究，因為它是我們 GOLD 平台的第一個臨床研究，並為 SLN124 建立了機制證明。 SLN124 顯示出血清鐵和轉鐵蛋白飽和度的持久降低、強大的安全性和長的作用持續時間。我們仍然對這些結果感到鼓舞，並期望在此基礎上繼續對地中海貧血患者進行研究。

Turning to Slide 22, here you can see the design of our ongoing Phase I program in thalassemia. We have now fully enrolled the single ascending dose cohorts, which includes 24 patients, and expect top line data in the third quarter of this year. As Craig mentioned, we have decided to discontinue the MDS cohort. This study is particularly challenging to enroll due to the highly specific patient entry criteria required for Phase I. MDS is a rare disease and very low -- low-risk MDS is a small subgroup of MDS patients. While we see opportunity for SLN124 in MDS, we are prioritizing thalassemia and PV indications where we believe we can derive the most value near term.

轉向投影片 22，在這裡您可以看到我們正在進行的地中海貧血一期計畫的設計。我們現已完全入組單劑量遞增隊列，其中包括 24 名患者，預計今年第三季將獲得頂線數據。正如 Craig 提到的，我們決定停止 MDS 隊列。由於第一階段所需的高度特定的患者進入標準，這項研究的招募特別具有挑戰性。雖然我們看到 SLN124 在 MDS 中的機會，但我們優先考慮地中海貧血和真性紅斑狼瘡適應症，我們相信我們可以在短期內獲得最大價值。

PV is an area of high unmet need and one that we believe SLN124 is particularly well suited to address. We plan to start the Phase I study later this year.

光伏是一個需求未被滿足的領域，我們認為 SLN124 特別適合解決這個問題。我們計劃在今年稍後開始第一階段研究。

With that, I'll hand the call back over to Craig.

這樣，我會將電話轉回給克雷格。

Thanks, Giles. Our accomplishments in 2021, both clinically and as a business, give us a lot of optimism for our future. We kicked off 2022 with impressive clinical data from our SLN360 program and look forward to the late-breaker at ACC on April 3. We expect data from the longer-term follow-up in the SLN360 single ascending dose cohorts later this year and are well positioned to start our Phase II ASCVD study pending regulatory feedback.

謝謝，賈爾斯。我們在 2021 年在臨床和業務方面的成就讓我們對未來充滿樂觀。我們以SLN360 計畫令人印象深刻的臨床數據拉開了2022 年的序幕，並期待4 月3 日在ACC 上的最新進展。並且進展順利準備開始我們的 II 期 ASCVD 研究，等待監管回饋。

In the SLN124 program, we expect top line data in thalassemia in Q3 and plan to start the PV study in the second half of this year. On the partnering side, we expect to start the Phase I SLN501 study for complement-mediated diseases with Mallinckrodt in the first half of this year.

在 SLN124 計畫中，我們預計在第三季度獲得地中海貧血的第一線數據，並計劃在今年下半年開始 PV 研究。在合作方面，我們預計在今年上半年與 Mallinckrodt 啟動針對補體介導疾病的 SLN501 I 期研究。

Along with our progress in the clinic, partnering interest also remains very strong. This is a very exciting time for Silence by all accounts.

隨著我們在臨床上的進展，合作夥伴的興趣仍然非常強烈。對所有人來說，這對沉默來說是一個非常令人興奮的時刻。

I'd like to thank everyone for listening today, and I'll pass over to the operator for your questions.

我要感謝大家今天的收聽，我將把你們的問題轉交給接線員。

(Operator Instructions) Your first question today is from the line of Tom Shrader from BTIG.

（操作員說明）您今天的第一個問題來自 BTIG 的 Tom Shrader。

I have an ACC question. Is that set in stone that we're only going to see single dose data? Or is it are we really going to see up to some cutoff where you're sure of the data? Just can you say anything about what we might see?

我有一個 ACC 問題。我們只會看到單劑量數據，這是否是一成不變的？或者我們真的會看到你確定數據的某個截止點嗎？您能談談我們可能會看到什麼嗎？

Giles?

賈爾斯？

Yes, well, yes, I think we're pretty sure about the single ascending dose data. I mean that's what we're going to be disclosing there. As we had indicated, we have started the multiple dose session, but that won't be ready for discussion. But just to emphasize, I mean a single dose has produced up to 98% knockdown. This persists up to 82% [some] day 150. So (technical difficulty), you're just seeing a hint of efficacy and in short-duration action. I mean this is just showing (technical difficulty). So I think it's a good indication of what

是的，是的，我認為我們對單次劑量遞增數據非常確定。我的意思是這就是我們將要在那裡披露的內容。正如我們所指出的，我們已經開始了多劑量會議，但還沒有準備好進行討論。但我要強調的是，我的意思是單次劑量即可產生高達 98% 的擊倒率。 [某些]第 150 天這種情況持續高達 82%。我的意思是這只是展示（技術難度）。所以我認為這很好地表明了

(technical difficulty)

（技術難度）

Okay. Sorry if I said only the single -- single dose data. And I had a little clarification on the Asian partnership. Are these new targets where you're going to get data in Asia first and then maybe go global, or are these liable to be Asian applications of targets that we've seen anywhere -- see where you're working elsewhere? Could you just give us a little bit of -- what you can say about that?

好的。抱歉，如果我只說單次劑量數據。我對亞洲夥伴關係做了一些澄清。這些新目標是您首先在亞洲獲取數據，然後可能走向全球，還是這些可能是我們在任何地方看到的目標的亞洲應用 - 看看您在其他地方工作的地方？您能為我們介紹一下您對此有何看法嗎？

Giles?

賈爾斯？

Yes. I mean, the nature of this relationship means that these will be targets sort of applicable globally. Two of the targets, we have worldwide rights and the second target is primarily in China, but we'll also have an option there as well. So these have broadly applicable targets.

是的。我的意思是，這種關係的性質意味著這些目標將在全球範圍內適用。其中兩個目標，我們擁有全球權利，第二個目標主要在中國，但我們也有一個選擇。所以這些都有廣泛適用的目標。

And they are new targets, not things we've heard about before.

它們是新目標，而不是我們以前聽說過的目標。

Tom, this is Gem. Just that we actually haven't disclosed specifics around whether or not they are new targets. We've just said undisclosed targets at this point.

湯姆，這是傑姆。只是我們實際上還沒有透露它們是否是新目標的具體細節。我們剛才已經提到了未公開的目標。

As part of the partnership agreement.

作為合夥協議的一部分。

Exactly.

確切地。

The next question is from the line of Patrick Trucchio from H.C. Wainwright.

下一個問題來自 H.C. 的 Patrick Trucchio。溫賴特。

I have a few follow-up questions on both SLN360 and SLN124. So just first, in the SLN360 Phase I program, can you discuss the dose response you've seen so far? Do you know which dose or doses you expect to bring forward to the Phase II program, or would you need some additional data from either multiple dose cohort or from the long-term follow-up to determine the dose you plan to bring forward?

我還有一些關於 SLN360 和 SLN124 的後續問題。首先，在 SLN360 一期專案中，您能討論一下您迄今為止看到的劑量反應嗎？您是否知道您希望將哪些劑量提前到 II 期項目，或者您是否需要來自多劑量隊列或長期隨訪的一些額外數據來確定您計劃提前的劑量？

Giles.

賈爾斯.

Yes. As you -- in the initial stages of development are all about establishing the dose regime that you really want to take into the pivotal study. So both Phase I and Phase II contribute to that. As -- we can tell a lot from our single ascending dose. We have a multiple dose study going on. The patient populations are slightly different. So in the single ascending dose, normal volunteers would have elevated Lp(a), with the multiple dose these individuals with established cardiovascular disease, so it will give us some information about that population. As far as the -- what we can disclose right now, as I said in the briefing, we're limited because of the embargo you see placed on this. But you will have a full disclosure in the presentation on April 3.

是的。對於您而言，在開發的初始階段，您需要建立您真正想要納入關鍵研究的劑量方案。因此，第一階段和第二階段都對此做出了貢獻。正如—我們可以從單次遞增劑量中看出許多資訊。我們正在進行一項多劑量研究。患者族群略有不同。因此，在單次遞增劑量中，正常志願者的Lp(a) 會升高，而在多次劑量中，這些患有心血管疾病的個體會升高，因此它將為我們提供有關該人群的一些資訊.至於我們現在可以透露的內容，正如我在簡報中所說，我們的資訊有限，因為你們看到對此實施了禁運。但您將在 4 月 3 日的演示中得到完整披露。

Yes. That's helpful. And then just regarding the SLN124 GEMINI II program, can you tell us what data that you expect to report in the third quarter? And specifically, what you would be looking for expecting on safety and PK and PD response that would give you confidence to move this program forward to Phase II?

是的。這很有幫助。那麼關於SLN124 GEMINI II項目，您能告訴我們您預計在第三季報告哪些數據嗎？具體來說，您對安全性以及 PK 和 PD 反應的期望是什麼，這將使您有信心將該專案推進到第二階段？

Well, as you know, we reported data in healthy volunteers last year in May. Essentially, we're looking at similar endpoints in terms of response, not only in terms of hepcidin, but also in iron parameters. And of course, this will be important because we'll actually see these individuals, rather than having normal line distribution, will have iron overload. So we'll be able to look at the impact of this situation on the effectiveness of 124. And this is -- again, it's just a single dose study. And there is a multiple dose component which will again give us more information about the longer-term effects of this. I mean, ultimately, what we've shown in the preclinical, and the nice thing is that the rodent models translate pretty well into the human situation, is we saw a really strong effect on hemoglobin. And obviously, that's what we need to see in terms of dealing with the anemia and reducing transfusion rate. In the single dose, it is primarily around the iron parameters. But at the moment, everything lines up pretty well with what we've seen preclinically.

嗯，如您所知，我們去年五月報告了健康志工的數據。本質上，我們正​​在研究類似的反應終點，不僅是鐵調素，還包括鐵參數。當然，這很重要，因為我們實際上會看到這些人鐵超載，而不是具有正常的線路分佈。因此，我們將能夠研究這種情況對 124 有效性的影響。還有一種多劑量成分，將再次為我們提供有關其長期影響的更多資訊。我的意思是，最終，我們在臨床前所展示的，好的一點是，囓齒動物模型可以很好地轉化為人類的情況，我們看到了對血紅蛋白的非常強烈的影響。顯然，這就是我們在處理貧血和降低輸血率方面需要看到的。在單劑量中，主要圍繞鐵參數。但目前，一切都與我們在臨床前所看到的情況非常吻合。

That's helpful. And then just kind of more of a broader strategic question on SLN124, I'm just wondering, with the decision to kind of pursue thalassemia and PV going forward, how are you thinking about this asset in terms of longer-term potential and how many indications and where ultimately you see the potential for SLN124 in the long term?

這很有幫助。然後是關於 SLN124 的更廣泛的戰略問題，我只是想知道，隨著決定繼續發展地中海貧血症和 PV，您如何看待這項資產的長期潛力以及有多少您最終認為 SLN124 的長期潛力在哪裡？

Well, clearly, we have a lot of shots on goal and want to prioritize for the best return on capital, but it's mechanistic. And as Giles alluded to, we see a lot of avenues for 124. Given the SLN360 recent data, clearly that's a high priority for us right now. We're going to draw a circle around that. So we really are very pleased with both of those options in the pipeline today. So we'll continue to look for the best opportunities, larger opportunities within the 124 franchise.

嗯，顯然，我們有很多射門機會，並且希望優先考慮最佳資本回報率，但這是機械性的。正如 Giles 所提到的，我們看到了 124 的多種途徑。我們將圍繞它畫一個圓圈。因此，我們對今天正在醞釀的這兩個選項感到非常滿意。因此，我們將繼續在 124 專營權中尋找最好的機會、更大的機會。

The next question is from the line of Myles Minter from William Blair.

下一個問題來自威廉·布萊爾的邁爾斯·明特。

Congrats on the progress. Just in terms of the regulatory feedback that you planned to procure from the FDA, have you scheduled that meeting or a series of correspondence yet? Are you having those currently? And I'm also wondering whether there's been any feedback from the regulators as to if they want to see the longer 365-day follow-up from APOLLO before you go ahead and start that Phase II study in the second half.

祝賀取得的進展。就您計劃從 FDA 獲得的監管回饋而言，您已經安排了這次會議或一系列信件嗎？你現在有那些嗎？我還想知道監管機構是否有任何回饋，表明他們是否希望在下半年開始 II 期研究之前看到 APOLLO 進行更長的 365 天追蹤。

I don't think it's anything specifically that we can comment on regulatory, but feel free, Giles.

我不認為我們可以對監管發表任何具體評論，但請隨意，賈爾斯。

Yes, I mean, what we've said is that our plan to start the Phase III is subject to regulatory approval. So clearly, the interactions that we are planning with the FDA and other authorities are sort of a key point in terms of being able to go forward. But we've not heard anything in terms of -- at the moment, we feel that the single ascending dose will be adequate to go into Phase II. And the reason why we feel that is that there's already precedent being set by Amgen, who did just that. They went from their single ascending dose data straight into a Phase II program.

是的，我的意思是，我們已經說過，我們啟動第三階段的計畫需要得到監管部門的批准。很明顯，我們計劃與 FDA 和其他當局的互動是能夠向前推進的關鍵點。但目前我們還沒有聽到任何消息，我們認為單次遞增劑量足以進入第二階段。我們之所以這麼認為，是因為安進已經開創了先例，他就是這樣做的。他們從單一劑量遞增數據直接進入第二階段計劃。

And then a clarification question just on the Lp(a) knockdown that you have described out of APOLLO, can you just put it on the record that -- is that the median number that you're giving there? Or is that the absolute range of values of the knockdown that you're seeing?

然後是關於您在 APOLLO 中描述的 Lp(a) 擊倒的澄清問題，您能否將其記錄在案 - 這是您給出的中位數嗎？或者這是您看到的擊倒值的絕對範圍？

Well, what we've said is that we saw a range in terms of dose response, so ranging from 46% up to 98%. And I think we can clarify that that's median levels.

嗯，我們說過的是，我們看到了一個劑量反應範圍，從 46% 到 98%。我認為我們可以澄清這是中位數水平。

And then on 124, just with the discontinue of MDS, did you enroll any low-risk MDS patients in GEMINI II? And if you did, I guess, what's happening with that data? I'm just curious as to -- like you obviously discontinued enrollment, but you also haven't boosted the number of patients with thalassemia, you've just cut the total enrollment by half. So I'm just wondering if we're going to see any data outside of thalassemia for 124.

然後在124，隨著MDS的停止，你們是否在GEMINI II中招募了任何低風險MDS患者？如果你這樣做了，我想，這些數據會發生什麼事？我只是很好奇——就像你們顯然停止了招募一樣，但你們也沒有增加地中海貧血患者的數量，你們只是將總招募人數減少了一半。所以我只是想知道我們是否會看到 124 地中海貧血以外的任何數據。

Yes, we partially enrolled the first cohort and obviously we'll be monitoring them in terms of the -- as described by the protocol. So the follow-up there will be for 104 days. I mean I think why we think that there are further options to pursue, one, as Craig said, this is a mechanistic approach that we're dealing with. Both indications are characterized by having iron-loading anemia. They both -- they have different genetic causes, of course, but the fundamental pathophysiology is the same. So we think there is some -- there will be lead-through from what we see in the beta-thalassemia and the MDS.

是的，我們部分招募了第一批患者，顯然我們將按照協議所述的方式監測他們。所以後續會有104天。我的意思是，我認為為什麼我們認為還有進一步的選擇可以追求，其中之一，正如克雷格所說，這是我們正在處理的機械方法。這兩種適應症的特徵都是鐵負荷性貧血。當然，它們都有不同的遺傳原因，但基本的病理生理學是相同的。因此，我們認為，從我們在 β 地中海貧血和骨髓增生異常綜合徵中看到的情況來看，將會有一些線索。

And I think, as Craig said, this is a prioritization in terms of making sure we put our resources where we think we're going to drive most value in the short term, but this doesn't stop us coming back at some stage once we've seen all the data and carrying on.

我認為，正如克雷格所說，這是一個優先事項，以確保我們將資源投入到我們認為能夠在短期內實現最大價值的地方，但這並不能阻止我們在某個階段回來一次我們已經看到了所有數據並繼續進行。

And we have no further questions at this time. So I'll hand back to the speakers for closing remarks.

目前我們沒有進一步的問題。我將請發言者做結束語。

Thank you again for joining us on this call today. Extremely proud of our 2021 performance and overall results. We're looking forward to the SLN360 late-breaking oral presentation at ACC on April 3 and what we can deliver from our platform, both internally and through ongoing partnership initiatives. And we look forward to keeping you updated on our progress this year.

再次感謝您今天參加我們的電話會議。我們對 2021 年的業績和整體業績感到非常自豪。我們期待 4 月 3 日在 ACC 上進行 SLN360 最新的口頭演示，以及我們可以透過我們的平台在內部和透過持續的合作夥伴計劃提供什麼。我們期待向您通報我們今年的最新進展。

Thank you, and have a great day, and hope to see some of you at ACC.

謝謝，祝您有美好的一天，並希望在 ACC 見到你們中的一些人。

Thank you. That does conclude the conference for today. Thank you for participating, and you may now disconnect.

謝謝。今天的會議到此結束。感謝您的參與，您現在可以斷開連接。