Arrowhead Pharmaceuticals Inc (ARWR) 2024 Q1 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call.

女士們、先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。

(Operator instructions) I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead.

（操作員指示）我現在將電話會議交給 Arrowhead 投資者關係副總裁 Vince Anzalone。

Please go ahead, Vince.

請繼續，文斯。

Thank you, Amy, and good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for fiscal 2024 first quarter ended December 31, 2023.

謝謝艾米，大家下午好，謝謝您今天加入我們討論 Arrowhead 截至 2023 年 12 月 31 日的 2024 財年第一季度的業績。

With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter.

今天與我們一起出席管理層的是總裁兼首席執行官 Chris Anzalone 博士，他將概述本季的情況。

We also welcome back Dr. Bruce Given who previously served as Arrowhead's Chief Operating Officer and Head of R&D and who has rejoined the company on an interim basis as chief medical scientist.

我們也歡迎布魯斯·吉文博士的回歸，他曾擔任 Arrowhead 的首席營運長和研發主管，現在以臨時首席醫學科學家的身份重新加入公司。

Bruce will provide an update on our cardiometabolic pipeline, Dr. James Hamilton, our Chief of discovery and translational medicine will provide an update on our earlier-stage programs, and Ken Myszkowski, our Chief Financial Officer, will give a review of the financials.

Bruce 將提供有關我們心臟代謝管道的最新信息，我們的發現和轉化醫學主管 James Hamilton 博士將提供有關我們早期項目的最新信息，我們的首席財務官 Ken Myszkowski 將對財務狀況進行審查。

In addition, Patrick O'Brien, our Chief Operating Officer and General Counsel will be available during the Q&A portion of the call.

此外，我們的營運長兼總法律顧問 Patrick O'Brien 將出席電話會議的問答部分。

Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27 A. of the Securities Act of 1933 and Section 21 E. of the Securities Exchange Act of 1934.

在我們開始之前，我想提醒您，今天電話會議中發表的評論包含 1933 年證券法第 27 A 條和 1934 年證券交易法第 21 E 條含義內的某些前瞻性陳述。

All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

除歷史事實陳述外的所有陳述均為前瞻性陳述，並受到眾多風險和不確定性的影響，可能導致實際結果與任何前瞻性陳述中表達的結果有重大差異。

For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10 K on Form 10 K and our quarterly reports on Form 10 Q.

有關這些風險和不確定性的更多詳細信息，請參閱我們向 SEC 提交的文件，包括我們最新的 10 K 表年度報告和 10 Q 表季度報告。

I'd now like to turn the call over to Chris Anzalone, President and CEO of the Company.

我現在想將電話轉給公司總裁兼執行長 Chris Anzalone。

Chris?

克里斯？

Thanks, Vince.

謝謝，文斯。

Good afternoon, everyone, and thank you for joining us today.

大家下午好，感謝您今天加入我們。

Everyone has made a name for itself as a company capable of rapid innovation and development that is building a broad-based, diverse business.

每個人都以一家能夠快速創新和發展、正在建立基礎廣泛、多元化業務的公司而聞名。

This is exemplified by our 2025 initiative where we expect to grow our pipeline of RNA therapeutics to at least 20 clinical stage or marketed products by the year 2025.

我們的 2025 年計畫就是例證，我們預計在 2025 年將我們的 RNA 療法產品線擴大到至少 20 個臨床階段或上市產品。

This commitment to creating a large number of new medicines as quickly as we can speak to our dual mandate to maximize number of patients we can help and to maximize our ability to create durable value for our shareholders.

這種盡快創造大量新藥的承諾體現了我們的雙重使命：最大限度地增加我們可以幫助的患者數量，並最大限度地提高我們為股東創造持久價值的能力。

These mandates can be entirely aligned during early development.

這些任務可以在早期開發過程中完全一致。

We decreased biology risk by focusing on well-validated targets in our proven delivery product and our proven delivery platforms.

我們透過專注於經過驗證的交付產品和經過驗證的交付平台中經過充分驗證的目標來降低生物學風險。

At this stage the cost of discovery and early development are relatively low, particularly when considering the potential value we can create with novel medicines.

在這個階段，發現和早期開發的成本相對較低，特別是考慮到我們可以用新藥創造的潛在價值。

In short, we can do many things at this stage without spending too much money and without building large teams with a deep therapeutic area expertise.

簡而言之，我們現階段可以做很多事情，無需花費太多資金，也無需建立具有深厚治療領域專業知識的大型團隊。

However, as our pipeline grows and we enter later-stage expensive and complex clinical studies requiring significant capital, deeper domain expertise and ultimately commercial infrastructure.

然而，隨著我們的管道不斷增長，我們進入後期昂貴且複雜的臨床研究，需要大量資金、更深入的領域專業知識和最終的商業基礎設施。

We need to prioritize what we do internally.

我們需要優先考慮我們內部所做的事情。

That is where we are now.

這就是我們現在的處境。

And we are currently building out late-stage development and commercial infrastructure to serve the cardio-metabolic vertical.

我們目前正在建造後期開發和商業基礎設施，以服務心臟代謝垂直領域。

This is the primary engine of our near-term value proposition.

這是我們近期價值主張的主要引擎。

We expect to follow that up and add a pulmonary vertical as our lung targeted platform candidates mature, and we have the data we need to make commitments to build out specialized commercial infrastructure.

隨著我們的肺部目標平台候選人的成熟，我們希望跟進並增加肺部垂直領域，並且我們擁有做出承諾建立專業商業基礎設施所需的數據。

So does this mean that we will slow down or stop early development outside our focus areas.

那麼這是否意味著我們將放慢或停止我們重點領域之外的早期開發。

It does not we will continue to develop new candidates outside these verticals because, A., we have confidence in our ability to find appropriate partners to continue development and commercialized programs that are non-core for us.

我們不會繼續在這些垂直領域之外開發新的候選者，因為，A.，我們有信心找到合適的合作夥伴來繼續開發和商業化對我們來說非核心的專案。

And B, we anticipate adding new verticals in the future.

B，我們預計未來會增加新的垂直領域。

Think of this part of our business of generating capital to support our internal programs and as a farm system to create additional focus areas that could create long-term value as platforms and candidates mature.

將我們的這部分業務視為產生資本以支持我們的內部計劃，並將其視為一個農場系統，以創建額外的重點領域，隨著平台和候選人的成熟，這些領域可以創造長期價值。

Let's start with our cardiometabolic vertical.

讓我們從心臟代謝垂直領域開始。

Our lead program is pedestrian which targets a liver protein C three or APOC. three.

我們的主導項目是針對肝臟蛋白 C 3 或 APOC 的 Walking 項目。三。

This is potentially a big year for pedestrian and for the cardiometabolic vertical, broadly PALISADE Phase three study of patisiran in patients with genetically or clinically confirmed familial chylomicronaemia syndrome or FCS is on schedule for the last patient to have their last study visit in the second quarter of this year.

對於行人和心臟代謝垂直、廣泛的 PALISADE 來說，今年可能是重要的一年。Patisiran 在遺傳或臨床確診的家族性乳糜微粒血症綜合徵或FCS 患者中進行的第三期研究已按計劃在第二季度進行最後一次研究訪視。今年的。

This will be the first complete Phase three dataset for Arrowhead that potentially would allow us to file our first NDA and launch our first commercial product.

這將是 Arrowhead 第一個完整的第三階段資料集，它可能使我們能夠提交第一份 NDA 並推出我們的第一個商業產品。

Fcs is a severe disease in which patients have extraordinarily high triglyceride levels, often in the thousands of milligrams per decilitre.

Fcs 是一種嚴重的疾病，患者的三酸甘油酯水平非常高，通常達到每分升數千毫克。

For many of these patients experienced painful and recurrent bouts of severe abdominal pain, pancreatitis and hospitalization.

其中許多患者經歷了劇烈腹痛、胰臟炎和住院治療的痛苦和反覆發作。

These patients at these patients have inadequate treatment options and we believe the pause after and could represent a significant leap forward.

這些患者的治療選擇不足，我們相信之後的暫停可能代表著重大的飛躍。

We see the data from the Phase two studies is compelling for Astra and has been generally well-tolerated and consistently did what it was designed to do.

我們看到第二階段研究的數據對 Astra 來說是令人信服的，並且普遍具有良好的耐受性，並且始終如一地達到了其設計目的。

We have a high degree of confidence that this will be a powerful drug for this patient population with very high unmet medical needs, we believe pedestrian could also help a broader population of patients.

我們非常有信心，這對於醫療需求未被滿足的患者群體來說將是一種強大的藥物，我們相信行人也可以幫助更廣泛的患者群體。

Therefore, we plan to initiate Phase three studies in patients with severe hypertriglyceridemia or SHTG.

因此，我們計劃針對嚴重高三酸甘油脂血症或 SHTG 患者啟動第三期研究。

These studies will likely begin next quarter and are aimed at addressing a larger patient population that we believe totals 3 million to 4 million in the US alone.

這些研究可能會在下個季度開始，旨在解決更大的患者群體問題，我們認為僅在美國就有 300 萬至 400 萬名患者。

As with the FCS population, our Shaft two study gives us confidence that those assets are in will do exactly what it is designed to do we believe it will be a powerful and welcome to leap forward for patients.

與 FCS 人群一樣，我們的第二軸研究讓我們相信，這些資產將完全按照其設計目的進行，我們相信這將是一個強大且值得患者歡迎的飛躍。

Bruce will discuss study designs for SHTG. in a moment.

Bruce 將討論 SHTG 的研究設計。一會兒。

We are still considering whether we also wanted to study with us or in the broader atherosclerotic cardiovascular disease or ASCVD population but have not yet made a final decision on that.

我們仍在考慮是否也想與我們一起研究或更廣泛的動脈粥狀硬化性心血管疾病或 ASCVD 族群，但尚未就此做出最終決定。

We will be completing our analysis this quarter and we'll communicate our plans after they are finalized.

我們將在本季度完成分析，並在計劃最終確定後傳達我們的計劃。

And we have had some regulatory interactions if our cardiometabolic vertical represents the foundation of our value proposition for vascular and is the bedrock of that foundation for the following reasons.

如果我們的心臟代謝垂直代表了我們血管價值主張的基礎，並且由於以下原因成為該基礎的基石，那麼我們就會有一些監管相互作用。

The target APOC3 is well validated across a variety of genetic studies.

目標 APOC3 在各種遺傳學研究中得到了充分驗證。

Our data across hundreds of human subjects indicates consistent target engagement with deep and durable APOC3 silencing triglyceride levels were deeply reduced in patients and healthy volunteers treated with progesterone.

我們對數百名人類受試者的數據表明，在接受黃體酮治療的患者和健康志願者中，透過深度和持久的 APOC3 沉默實現一致的目標參與，三酸甘油酯水平大幅降低。

We know that elevated triglyceride levels in certain patient populations can lead to severe abdominal pain, acute pancreatitis, hospitalizations and other difficult downstream effects.

我們知道，某些患者族群中三酸甘油酯水平升高會導致嚴重腹痛、急性胰臟炎、住院治療和其他困難的下游影響。

And even in rare cases death, there is currently no FDA approved therapy that lowers triglycerides by more than 20% or 30% and with Astra and has been generally well tolerated in prior studies together, these set up an attractive opportunity we just need to get to market.

即使在極少數死亡病例中，目前還沒有FDA 批准的治療方法可以將三酸甘油酯降低20% 或30% 以上，並且與Astra 一起使用，並且在先前的研究中普遍具有良好的耐受性，這些為我們提供了一個有吸引力的機會，我們只需要獲得市場。

We expect to launch with Astra and as early as next year in FCS., we would hope to follow that relatively quickly by launching into larger SHTG. markets and we will see if we follow that with even larger ASCBD. markets, this brings me next to Zone ASRN., which targets angiopoietin-like protein three or HPTL. three.

我們預計將與 Astra 一起推出，並最早於明年在 FCS 中推出。我們希望能夠相對快速地推出更大的 SHTG。市場，我們將看看我們是否會遵循更大的 ASCBD。市場，這讓我想到了 ASRN 區域，它的目標是血管生成素樣蛋白 3 或 HPTL。三。

As we've discussed, we are assessing both with Aster and amplify faster and to determine which may be better suited for investment in a cardiovascular outcome study.

正如我們所討論的，我們正在對 Aster 和 amplify 進行更快的評估，以確定哪一個更適合投資心血管結果研究。

In patients with ASCVD, the data we presented at AHA in November on the data and the ability to reduce remnant cholesterol, which is believed to be a major contributor to the residual risk of ASCBD. after LDL-cholesterol is well-controlled was very encouraging.

在 ASCVD 患者中，我們在 11 月的 AHA 上展示了關於降低殘餘膽固醇的數據和能力，這被認為是 ASCBD 殘餘風險的主要貢獻者。低密度脂蛋白膽固醇在良好控制後非常令人鼓舞。

In fact, we have not seen any other therapy capable of the type of reductions seen after that after end treatment in the Phase two study, just as available drugs have shown only modest lowering of triglycerides available therapies have similarly produced only modest reductions in remnant cholesterol.

事實上，我們還沒有看到任何其他療法能夠在第二階段研究結束治療後出現這種類型的降低，正如現有藥物僅顯示出適度降低三酸甘油酯一樣，可用療法同樣僅產生適度降低殘餘膽固醇。

So Darren has also shown promising results in a Phase two study in patients with homozygous familial hypercholesterolemia or HOFH.

因此，Darren 在針對純合子家族性高膽固醇血症或 HOFH 患者的第二期研究中也顯示出了有希望的結果。

We are currently preparing materials for an end-of-Phase two meeting with the FDA and intend to begin a Phase three study in HOFH.

我們目前正在為與 FDA 舉行的第二階段結束會議準備材料，並打算在 HOFH 開始第三階段研究。

After we have regulatory feedback on our plans, we could also expand into the much larger heterozygous or HGFH. population.

在我們收到有關我們計劃的監管回饋後，我們還可以擴展到更大的雜合子或 HGFH。人口。

If we decide to conduct a Phase three study of that Astra and in a C CBD, the commercial plan will likely follow a similar path as pedestrian.

如果我們決定對 Astra 和 C CBD 進行第三階段研究，商業計劃可能會遵循與步行類似的路徑。

That plan is to launch in a rare population and continued to build our commercial infrastructure and capabilities support larger patient populations.

該計劃是在稀有人群中推出，並繼續建立我們的商業基礎設施和能力，以支持更多的患者群體。

While the additional Phase three studies are being conducted pursuant to out there.

同時，額外的第三階段研究正在進行中。

And that could mean addressing the small HOFH. population relatively quickly than expanding into a TFH.

這可能意味著解決小型 HOFH 問題。人口成長速度比擴張為 TFH 的速度還要快。

And ultimately, the very large ASCBD. market as we get each approval.

最後是非常大的 ASCBD。當我們獲得每項批准時，我們就會進入市場。

This path makes a lot of sense for us as an emerging commercial company and would allow us to grow in a measured stepwise fashion.

作為一家新興的商業公司，這條道路對我們來說很有意義，並使我們能夠以有節制的逐步發展方式成長。

We believe that pimavanserin and ends at Asurion clearly Ward's investment into cardiometabolic infrastructure I'm sorry, Cardiome of all commercial infrastructure.

我們相信 pimavanserin 和 Asurion 顯然是 Ward 對心臟代謝基礎設施的投資，對不起，Cardiome 是所有商業基礎設施的投資。

Those outlays become increasingly cost efficient as we increase the number of drugs that infrastructure managers.

隨著我們增加基礎設施管理的藥品數量，這些支出變得越來越具有成本效益。

Therefore, it makes sense to expand the cardiometabolic vertical to include additional complementary medicines in the portfolio.

因此，擴大心臟代謝垂直領域以在產品組合中納入其他補充藥物是有意義的。

And we have several in mind.

我們有幾個想法。

One is based on our adipose targeting TRiM platform, which has shown impressive preclinical data, we have seen target gene silencing with this platform in excess of 90% after a single dose in animal models with the activity that lasted over six months.

一個是基於我們的脂肪靶向TRiM 平台，該平台已顯示出令人印象深刻的臨床前數據，我們發現在動物模型中單劑量給藥後，該平台的靶基因沉默率超過90%，且活性持續超過六個月。

Adipose tissue is the largest endocrine organ in the body, and there are multiple attractive metabolic targets that may be amenable to an R&I based knockdown strategy.

脂肪組織是體內最大的內分泌器官，有多個有吸引力的代謝標靶可能適合基於 R&I 的敲低策略。

We are not prepared to disclose the first gene target we are addressing, but it is in the metabolic space.

我們不准備透露我們正在解決的第一個基因目標，但它是在代謝領域。

Another program we are adding to the cardiometabolic vertical is aero INHBE.

我們添加到心臟代謝垂直領域的另一個項目是 aero INHBE。

This utilizes deliver targeted TRiM platform and targets.

這利用了交付有針對性的 TRiM 平台和目標。

The INHB. gene, which encodes inhibitor subunit beta E James will talk about the target in a moment.

該INHB。基因，編碼抑制劑亞基β E 詹姆斯稍後將討論該標靶。

But the intention is to study this in an obesity and metabolic disease population, both programs but well in our cardiometabolic vertical and are on schedule for CTA filings as early as the end of this year.

但我們的目的是在肥胖和代謝疾病人群中進行研究，這兩個項目都在我們的心臟代謝垂直領域開展得很好，並且最早將於今年年底按計劃進行 CTA 備案。

It is difficult to overstate the importance of our cardiometabolic vertical in driving our value proposition.

心臟代謝垂直領域在推動我們的價值主張的重要性怎麼強調都不為過。

We have near term commercial opportunities in pedestrian ends at Asurion, a high expectation of success surrounding the programs and longer term opportunities with future drug candidates.

我們在 Asurion 的步行街有近期的商業機會，對這些項目的成功抱有很高的期望，並有未來候選藥物的長期機會。

The next vertical we expect to invest in late-stage clinical studies and commercialization is pulmonary there only about 16,000 pulmonologists United States, and we believe it's an attractive prospect to build a specialized commercial sales organization to support a growing pipeline of medicines that addresses various respiratory diseases.

我們預計投資後期臨床研究和商業化的下一個垂直領域是肺部疾病，美國祇有約16,000 名肺科醫生，我們相信建立一個專門的商業銷售組織來支持不斷增長的治療各種呼吸系統疾病的藥物管道是一個有吸引力的前景。疾病。

We currently have three programs in clinical studies that collectively address three major components of chronic lung disease, inflammation, NewCo obstruction and interstitial lung disease.

我們目前有三個臨床研究項目，共同解決慢性肺病的三個主要組成部分：發炎、NewCo阻塞和間質性肺病。

We also see the pulmonary space as a target-rich environment where we believe we can advance and ultimately bring to market a number of different drugs for various diseases treated by a relatively small number of physicians.

我們也認為肺部空間是一個目標豐富的環境，我們相信我們可以在其中推進並最終將多種不同的藥物推向市場，這些藥物用於由相對少數的醫生治療的各種疾病。

We like the leverage.

我們喜歡槓桿。

This creates the current program.

這將創建當前程式。

The current programs in clinical studies are aero rage, Mach five, AC and aero, and then P. seven we expect to have multiple clinical readouts for these programs this year and intend to start at least one Phase two study in two or in 2024.

目前的臨床研究項目包括Aero rage、Mach 5、AC 和aero，然後是P.7。我們預計今年將獲得這些計畫的多項臨床結果，並打算在兩年內或2024 年啟動至少一項二期研究。

We also expect additional targets potentially this year.

我們也預計今年可能會實現更多目標。

Cardiometabolic and pulmonary are where we are focusing a lot of our attention and will represent quite a bit of our spend moving forward.

心臟代謝和肺臟是我們重點關注的領域，並將占我們未來支出的相當大一部分。

So what does that mean for the rest of our existing and future pipeline.

那麼這對我們現有和未來管道的其餘部分意味著什麼呢？

As I mentioned, we are not slowing down our discovery organization and will not limit growth in our early-stage pipeline for example, in 2023, we nominated nine new clinical candidates and filed four new CTAs.

正如我所提到的，我們不會放慢我們的發現組織速度，也不會限制我們早期管道的增長，例如，在2023 年，我們提名了9 名新的臨床候選藥物，並提交了4 份新的CTA。

These are promising programs.

這些都是有前途的計劃。

So the question is where do they fit strategically and what role does each play in our business, I think of three primary categories that the new programs can slot into one new candidates, the fit into existing verticals, Aero INHBE. is a good example of this.

因此，問題是它們在策略上適合哪裡，以及它們在我們的業務中扮演什麼角色，我認為新計劃可以將三個主要類別歸入一個新候選者中，即適合現有垂直行業的航空 INHBE。就是一個很好的例子。

It fits neatly into the cardio-metabolic vertical two new candidates that pending clinical proof of concept could warrant an expansion into a new vertical.

它完全適合心臟代謝垂直領域的兩個新候選者，等待臨床概念驗證可能需要擴展到新的垂直領域。

Our work in CNS is very early.

我們在中樞神經系統的工作還很早。

But given the vast unmet medical needs in the broad target-rich environment, this could be an area we build out should clinical data supported and three new candidates that are interesting for our medical and commercial standpoint but may not fit into one of our verticals.

但考慮到在廣泛的目標豐富的環境中存在巨大的未滿足的醫療需求，如果臨床數據得到支持，這可能是我們構建的一個領域，並且三個新的候選藥物對我們的醫療和商業立場很有趣，但可能不適合我們的垂直領域之一。

This is an important category for us and can serve as a substantial source of capital to fund the other two categories.

這對我們來說是一個重要的類別，可以作為資助其他兩個類別的重要資金來源。

We brought in close to $1 billion in partnering capital over the past seven years, and we anticipate this will be increasingly important piece of our financing plan going forward as existing partnerships mature and we continue to do new deals, our partnerships with and our partnership with Amgen on old Pastor and formerly of AROLTA. is a good example of what we can do after even a modest investment in discovery in late 2016 when we partnered with Amgen aero LPA was still an early preclinical program.

在過去七年裡，我們引入了近10 億美元的合作資本，我們預計，隨著現有合作夥伴關係的成熟，以及我們繼續開展新交易、我們的合作夥伴關係以及我們的合作夥伴關係，這將成為我們未來融資計劃中越來越重要的一部分安進（Amgen）對老牧師和前阿羅塔（AROLTA）。這是一個很好的例子，說明我們在 2016 年底與 Amgen aero LPA 合作時進行了適度的發現投資，但仍然是一個早期的臨床前計畫。

Since then, we have received around $362 million in cash and are still eligible to receive another $535 million in potential payments as certain clinical and commercial milestones are achieved.

自那時以來，我們已收到約 3.62 億美元現金，並且在實現某些臨床和商業里程碑時仍有資格獲得另外 5.35 億美元的潛在付款。

In fact, we are eligible to receive $50 million when they'll pass or in Phase three study is fully enrolled, which Amgen recently publicly guided could be in the first half of this year.

事實上，當他們通過或第三階段研究完全註冊時，我們就有資格獲得 5000 萬美元，安進最近公開指導可能會在今年上半年進行。

Business development is an important source of capital, but of course, not the only source we will rely on last month, we announced a $450 million equity financing the first such deal we have done in approximately four years.

業務發展是重要的資金來源，但當然，這並不是我們依賴的唯一來源，上個月我們宣布了 4.5 億美元的股權融資，這是我們大約四年來完成的第一筆此類交易。

That transaction was confidentially marketed to just a handful of funds, and we were pleased with the results were substantially oversubscribed and saw terrific participation from high-quality investors.

該交易僅向少數基金秘密推銷，我們對結果大幅超額認購感到滿意，並看到高品質投資者的大力參與。

We viewed that as the first step in substantially increasing our balance sheet.

我們認為這是大幅增加資產負債表的第一步。

We expect the second step to be a structured finance transaction that could be based around taking capital in return for royalties on one of our future products that is capped at some return.

我們預計第二步將是結構性融資交易，其基礎是獲取資本以換取我們未來產品之一的特許權使用費，該特許權使用費的上限為一定回報。

This could also have a debt component to it.

這也可能有債務成分。

We anticipate executing such a transaction in the coming months.

我們預計在未來幾個月內執行此類交易。

We expect the third step to be one or more partnership transactions.

我們預計第三步將是一項或多項合作交易。

And while we cannot control the exact timing of these, our goal is to do one or more economically meaningful deals this year together, we expect these multiple steps to provide a strong financial base on which we may continue to invest in our core programs and new innovations.

雖然我們無法控制這些交易的確切時間，但我們的目標是今年共同完成一項或多項具有經濟意義的交易，我們預計這些多個步驟將為我們提供堅實的財務基礎，在此基礎上我們可以繼續投資我們的核心項目和新項目。創新。

There's also cost management side to creating a strong financial base.

建立強大的財務基礎也涉及成本管理。

As I discussed, we have reached the point where we need to be more strategic about the particular drug candidates we take into late-stage studies and ultimately to commercialization.

正如我所討論的，我們已經到了需要對進入後期研究並最終商業化的特定候選藥物採取更具策略性的階段。

It is simply not economically feasible to do everything on our own past a certain stage of development.

發展到某個階段之後，一切都靠自己做，在經濟上根本不可行。

That means looking more vigorously for partners and potentially pausing or even calling some programs that are outside our chosen verticals.

這意味著更加積極地尋找合作夥伴，並可能暫停甚至調用一些超出我們選擇的垂直領域的項目。

To that end, we've recently conducted a portfolio review.

為此，我們最近進行了投資組合審查。

We are moving forward with clinical studies for our complement programs, AROC. three and aero CFP and our muscle targeted programs, Aero ducks for an arrow DM1.

我們正在推進我們的補體計畫 AROC 的臨床研究。三、aero CFP 和我們的肌肉目標計劃，Aero 鴨子用於箭頭 DM1。

We're continuing to assess clinical the clinical path and designing Phase Ib IIa studies for our NASH candidate, Aero P. and PLA. three, the GalXC candidate, HZN. four five seven, which was returned to us by Amgen after its Horizon acquisition is being terminated and will not move forward.

我們正在繼續評估臨床路徑，並為我們的 NASH 候選藥物 Aero P. 和 PLA 設計 Ib IIa 期研究。三、GalXC候選者，HZN。四五七，這是安進在終止對 Horizo​​​​n 的收購後退還給我們的，並且不會繼續進行。

In addition, Aero SOD1, our CNS candidate against SOD1 ALS, will not move forward.

此外，Aero SOD1（我們針對 SOD1 ALS 的 CNS 候選藥物）將不會繼續推進。

We are continuing to work on additional CNS programs and expect a new candidate against a different target to begin clinical studies later this year.

我們正在繼續進行其他中樞神經系統項目，並預計針對不同目標的新候選藥物將在今年稍後開始臨床研究。

It is more commercially attractive and Arrow side one, while still serving as a good proof of concept for the CNS platform.

它更具商業吸引力，也是 Arrow 的一方面，同時仍然可以作為 CNS 平台的良好概念證明。

Our portfolio review also affected some undisclosed preclinical programs.

我們的投資組合審查也影響了一些未公開的臨床前項目。

We have revised our budget to reflect an anticipated reduction in growth of our spend over this fiscal year and beyond.

我們修改了預算，以反映本財年及以後支出成長的預期減少。

Ken will talk about specifics in a moment, but we are reducing our guidance on fiscal year operating burn by approximately $100 million.

Ken 稍後將討論具體細節，但我們將把財政年度營運消耗的指導減少約 1 億美元。

We are achieving these estimates while importantly, continuing to fully fund our core pulmonary and cardiometabolic verticals and innovative new technologies and programs continuously assessing our anticipated uses and sources of capital and ensuring they lie that they align with the overall goals of the business is, of course, a critical exercise.

我們正在實現這些估計，同時重要的是，繼續為我們的核心肺和心臟代謝垂直領域以及創新的新技術和計劃提供充分資金，不斷評估我們的預期用途和資本來源，並確保它們符合業務的總體目標，當然，這是一個關鍵的練習。

I think our revised budget puts us in a stronger position strategically as well as financially.

我認為修訂後的預算使我們在策略和財務上處於更有利的地位。

With that overview, I'd now like to turn the call over to Dr. Bruce Given.

有了上述概述，我現在想將電話轉給布魯斯·吉文博士。

Bruce.

布魯斯.

Thank you, Chris, and good afternoon, everyone.

謝謝克里斯，大家下午好。

It's great to be back, helping Arrowhead move forward in the most effective and efficient way possible.

很高興能回來，幫助 Arrowhead 以最有效和最有效率的方式前進。

I've been doing a good amount of work, getting up to speed with the cardiometabolic clinical development teams, which are operating at a very high level.

我一直在做大量的工作，跟上心臟代謝臨床開發團隊的步伐，這些團隊的運作水平非常高。

We are doing important design and analysis work to assure our studies a world-class shortly.

我們正在進行重要的設計和分析工作，以確保我們的研究很快就會達到世界一流水準。

We will beginning centers initiated two additional Phase three studies can get up and running rapidly.

我們將開始中心發起兩項額外的第三階段研究，以便能夠快速啟動並運行。

Chris mentioned that we are in the middle of a process to assess which program was asked around or so DAS Rand, we want to take forward into an ASCBD. population, and we have nothing new to update on that front today.

Chris 提到，我們正在評估 DAS Rand 詢問了哪個計劃，我們希望將其納入 ASCBD。人口，今天我們在這方面沒有什麼新的更新。

So I will focus my time today on where we are with please ask around and the progress we've made to review put plus after and is designed to reduce production of APOC3, a component of triglyceride rich lipoproteins or TRL.s and a key regulator of triglyceride metabolism.

因此，今天我將重點討論我們的進展情況以及我們在審查put plus 之後取得的進展，該計劃旨在減少APOC3 的產生，APOC3 是富含甘油三酯的脂蛋白或TRL.s 的一個組成部分，也是一個關鍵的調節劑甘油三酯代謝。

APOC. three increases plasma triglyceride levels by inhibiting breakdown of TRL.s by lipoprotein light base and uptake of TRL remnants by hepatic receptors in the liver.

APOC。第三是透過抑制脂蛋白輕鹼對 TRL.s 的分解以及肝臟中肝受體對 TRL 殘餘物的攝取來增加血漿三酸甘油酯水平。

We have study possess ran in multiple clinical studies in different patient populations.

我們已經在不同患者群體中進行了多項臨床研究。

With several hundred patients having been dosed, we have been consistently encouraged by safety and tolerability results with treatment emergent adverse treatment emergent adverse events reported to date that generally reflect the co-morbidities and underlying conditions of each study population.

隨著數百名患者接受了給藥，我們一直對安全性和耐受性結果感到鼓舞，迄今為止報告的治療緊急不良事件通常反映了每個研究族群的共病和基礎狀況。

This is encouraging and consistent with our expectations of a properly designed R&I therapeutic that leverages our proprietary TRiM platform in addition, plus Astra and has demonstrated a high level of pharmacodynamic activity with a mean maximal reduction in APOC3 of around 90%, give or take regardless of the patient population studied.

這是令人鼓舞的，符合我們對正確設計的R&I 療法的期望，該療法還利用我們專有的TRiM 平台以及Astra，並表現出高水平的藥效活性，無論給予或接受，APOC3 的平均最大減少量約90%研究的患者族群。

This is also consistent with our expectations and speaks to the consistency of the RNA mechanism.

這也符合我們的預期，並且說明了RNA機制的一致性。

This was a hallmark of Arrowhead candidates in our earlier days in the HPB. and AT. space and continues to be the case as we have developed new candidates targeting diverse genes.

這是我們早期在 HPB 的 Arrowhead 候選人的一個特點。和AT。空間，隨著我們開發出針對不同基因的新候選藥物，情況仍然如此。

So where is pedestrian going and what has changed over the last couple of months first and most critically in the short term, we are making some changes to the proposed design of the suite of Phase three shaft studies for patients with SHTG.

因此，行人將走向何方以及過去幾個月發生了什麼變化，首先，最重要的是，在短期內，我們正在對針對 SHTG 患者的三期豎井研究套件的建議設計進行一些更改。

Our goal with these changes, which I will discuss in a moment is twofold.

我們的這些改變的目標是雙重的，我稍後將討論這些改變。

First, we want to accelerate enrolment and enable regulatory filings in the US and other key markets as quickly as possible.

首先，我們希望加快註冊速度，並儘快在美國和其他主要市場進行監管備案。

And second, we want to maximize the probability to show an effect on severe abdominal pain and acute pancreatitis, which could be a significant differentiator from other triglyceride lowering therapies and could aid in value and access discussions with payers.

其次，我們希望最大限度地提高對嚴重腹痛和急性胰臟炎的療效的可能性，這可能是與其他降低三酸甘油酯療法的顯著區別，並且可以有助於價值和與付款人進行討論。

So what are we doing towards events?

那我們對事件做了什麼？

Our plan was to conduct two similar Phase three studies Shafts three and Chester four and approximately 700 patients with triglycerides greater than 500 milligrams per decilitre across the two studies, combined with a primary endpoint of lowering triglycerides after one year of treatment.

我們的計劃是在三號井和切斯特四號井進行兩項類似的三期研究，這兩項研究涉及大約700 名甘油三酯大於500 毫克/分升的患者，並結合治療一年後降低三酸甘油酯的主要終點。

This general design remains largely unchanged, but we have streamlined several features of the study to potentially speed up time to NDA submission in Europe in the US.

這一整體設計基本上保持不變，但我們簡化了研究的幾個特徵，以可能加快在歐洲和美國提交 NDA 的時間。

We also intended to include a predefined number of patients.

我們也打算納入預定數量的患者。

It's higher risk of severe abdominal pain and acute pancreatitis events with the goal potentially characterizing an expected reduction in risk of these events in HSHTG. patients treated with patisiran.

嚴重腹痛和急性胰臟炎事件的風險較高，目標可能是降低 HSHTG 中這些事件的風險。接受 patisiran 治療的患者。

This remains an important goal, but we believe the best way to assure ourselves have adequate power to show this effect is to run a separate study designed specifically for that purpose.

這仍然是一個重要的目標，但我們相信，確保自己有足夠的能力來證明這種效果的最佳方法是進行一項專門為此目的而設計的單獨研究。

This separate study will be called chest of five, and we'll provide more details in the design sizing and inclusion criteria when we initiate the study, this separate study strategy could potentially do two things.

這項單獨的研究將被稱為五項之箱，當我們啟動研究時，我們將提供有關設計規模和納入標準的更多詳細信息，這項單獨的研究策略可能會做兩件事。

It gives us the best chance of showing a reduction in events versus placebo in second removing the predefined number of high-risk patients and shafts to three adjusted for is expected to further speed enrolment for these studies.

與安慰劑相比，它為我們提供了最好的機會來顯示事件的減少，第二次將高風險患者的預定數量和軸調整為三個，預計將進一步加快這些研究的入組速度。

Between these changes and a handful of others, we estimate that we can get to full enrolment for shifts to three shifts to four more rapidly and potentially get to an NDA six to 10 months faster than the original plan.

在這些變化和其他一些變化之間，我們估計我們可以更快地實現三班製到四班制的全面註冊，並且有可能比原始計劃更快 6 到 10 個月達成 NDA。

This is a significant advance.

這是一個重大進步。

If our predictions are correct, we were actively working on getting these studies ready to go.

如果我們的預測是正確的，我們正在積極努力讓這些研究做好準備。

We asked we estimate adjusted three-inch after four and will begin next quarter at Shafter five shortly thereafter, plus Astra and has demonstrated best-in-class data at each prior step of the clinical development process.

我們要求我們估計四英寸後調整後的三英寸，並將在下個季度的沙夫特五英寸之後不久開始，加上阿斯特拉，並在臨床開發過程的每個先前步驟中展示了一流的數據。

So we're eager to move more rapidly through these Phase three studies.

因此，我們渴望更快完成這些第三階段的研究。

The next important event for us around is the completion and readout of the Phase three PALISADE study.

對我們來說下一個重要事件是第三階段 PALISADE 研究的完成與宣讀。

This is in patients with genetically confirmed or clinically diagnosed familial chylomicronaemia syndrome or FCS.

這是針對經基因證實或臨床診斷的家族性乳糜微粒血症綜合症或 FCS 的患者。

This is a severe disease of extremely high triglyceride levels that puts patients at high risk of episodes of severe abdominal pain, acute pancreatitis, hospitalization, and it can be fatal.

這是一種三酸甘油酯水平極高的嚴重疾病，使患者面臨嚴重腹痛、急性胰臟炎、住院治療的高風險，並且可能致命。

There are no adequate treatment operating options for these patients.

這些患者沒有足夠的治療操作選擇。

Palisade is a one-year study with a primary endpoint of triglyceride lowering versus placebo.

Palisade 是一項為期一年的研究，其主要終點是與安慰劑相比降低三酸甘油酯。

We have enrolled 75 patients globally.

我們已在全球招募了 75 名患者。

And the last patient is in is scheduled to have their last visit in May.

最後一位患者預計五月進行最後一次就診。

After that visit, we will work quickly to complete sample analysis and data collection preparation and analyse the data.

訪問結束後，我們將迅速完成樣品分析和數據採集準備工作，並對數據進行分析。

We intend to report top line results from this study in the third quarter and begin work towards.

我們打算在第三季報告這項研究的主要結果，並開始努力。

Finally, there are its first NDA that will likely be at the end of the year or into the first quarter of 2025.

最後，第一份 NDA 可能會在今年年底或 2025 年第一季發布。

This is an exciting time.

這是一個令人興奮的時刻。

I'm thrilled to be back and to be part of this next big milestone for Arrowhead.

我很高興能回來並成為 Arrowhead 下一個重大里程碑的一部分。

I'll now turn the call over to Dr. James Hamilton.

我現在將電話轉給詹姆斯·漢密爾頓博士。

Jacques?

雅克？

Thank you, Bruce.

謝謝你，布魯斯。

As you know, we have a very robust pipeline of early clinical stage programs and even more even more robust pipeline of discovery stage programs, most of which we haven't disclosed yet.

如您所知，我們擁有非常強大的早期臨床階段項目管道，甚至更強大的發現階段項目管道，其中大部分我們尚未披露。

I want to talk about a few of the newer programs and give an update on where we are with some of the clinical programs that are approaching readouts.

我想談談一些較新的項目，並介紹一些即將公佈的臨床項目的最新進展。

First, Chris mentioned two programs that we are.

首先，克里斯提到了我們的兩個項目。

We've added to our Cardio-Metabolic pipeline.

我們已經添加到我們的心臟代謝管道中。

One utilizes our new adipose delivery platform and the other utilizes our liver-targeted platform.

一種利用我們新的脂肪輸送平台，另一種利用我們的肝臟靶向平台。

We intend to talk more about the adipose platform program later in the year.

我們打算在今年稍後更多地討論脂肪平台計劃。

So I will focus on the liver targeted program.

所以我會重點關注肝臟標靶方案。

This new liver-targeted program is called aero inhibitor.

這種新的肝臟標靶方案稱為空氣抑制劑。

E. inhibitor E. is a gene that codes for a serum measurable protein activity, which is primarily synthesized by the hepatocytes, increased circulating activity levels signal adipose tissue to store excess nutrients as fat inhibit the expression is increased in obesity and inhibit any loss of function variants identified in human genetic databases are protective of type two diabetes and are associated with reduced visceral fat and are reduced waste to hit ratio.

E.抑制劑E.是編碼血清可測量蛋白質活性的基因，其主要由肝細胞合成，增加的循環活性水平向脂肪組織發出信號，以儲存過量的營養物質，因為脂肪抑制在肥胖症中表達增加，並抑制任何損失人類基因資料庫中發現的功能變異可以預防二型糖尿病，並且與減少內臟脂肪有關，並降低廢物命中率。

We have conducted studies in mouse obesity models where inhibiting silencing with SIRNA. reduced weight gain by over 20% compared to controls.

我們在小鼠肥胖模型中進行了研究，其中使用 SIRNA 抑制沉默。與對照組相比，體重增加減少了 20% 以上。

Importantly, the difference in weight gain was primarily due to changes in fat mass with no difference seen in lean mass.

重要的是，體重增加的差異主要是由於脂肪量的變化，而瘦體重沒有差異。

We hope that inhibiting therapeutic silencing could be an interesting adjunct to GLP-1 agonists.

我們希望抑制治療沉默可以成為 GLP-1 激動劑的一個有趣的輔助手段。

We think the potential benefits of combination therapy could include the ability to use a lower dose of the GLP-1 agonist, which might result in reduced lean mass loss, reduce gastrointestinal side effects and prevention or slowing of weight regain post cessation of GLP-1 agonist therapy.

我們認為合併治療的潛在好處可能包括能夠使用較低劑量的 GLP-1 激動劑，這可能會減少瘦體重損失，減少胃腸道副作用，並預防或減緩停止 GLP-1 後體重反彈激動劑療法。

We have selected a clinical lead and are on schedule to file a CTA by the end of 2024.

我們已經選擇了一位臨床負責人，並計劃在 2024 年底之前提交 CTA。

Moving on to our two muscle targeted programs, Aero ducks for patients with fascias, Capula humeral muscular dystrophy or FSHD and Arrow DM one for patients with Type one myotonic dystrophy or DM one.

接下來是我們的兩個肌肉目標項目：針對筋膜、肩胛肱骨肌肉營養不良症或 FSHD 患者的 Aero ducks，以及針對 1 型強直性肌肉營養不良症或 DM 1 患者的 Arrow DM 1。

Both of these programs are in Phase one to a dose escalating studies to evaluate the safety, tolerability and PK and PD profiles of single and multiple ascending doses.

這兩個項目均處於劑量遞增研究的第一階段，以評估單次和多次遞增劑量的安全性、耐受性以及 PK 和 PD 概況。

Both studies have ethics and regulatory clearance to initiate, and we expect first patient in for both in Q1 or Q2 of this year to review Arrow ducks for is designed to target the gene that encodes human double holmium box for docs for protein as a potential treatment for patients with FSHD at this HD. is an autosomal dominant disease associated with the failure to maintain complete epigenetic suppression of docs for expression in differentiated skeletal muscle over expression of ducks for is my a toxic and can lead to muscle degeneration.

這兩項研究都已獲得倫理和監管許可，我們預計今年第一季或第二季的第一名患者將審查 Arrow ducks 的設計目標是編碼人類雙钬盒蛋白質的基因作為潛在的治療方法對於處於此HD 的FSHD 患者。是一種體染色體顯性遺傳疾病，與鴨的分化骨骼肌中表達過度表達的文檔未能保持完全表觀遺傳抑制相關，這是一種有毒物質，可能導致肌肉退化。

Arrow DM one is designed to reduce expression of the dystrophy and myotonic of protein kinase or DMPKG.

Arrow DM 1 旨在減少蛋白激酶或 DMPKG 的營養不良和肌強直的表達。

DM1 is the most common adult-onset muscular dystrophy, and there is currently no approved disease-modifying therapy.

DM1 是最常見的成人肌肉營養不良症，目前尚無核准的疾病緩解療法。

I also want to give a status update on our two complement programs.

我還想提供我們兩個補充計劃的最新狀態。

At the end of last year, we filed a CTA to begin a Phase one two study of AROCFP. for the treatment of various complement mediated diseases and possibly geographic atrophy or GA.

去年年底，我們提交了 CTA，開始 AROCFP 的一、二期研究。用於治療各種補體介導的疾病以及可能的地圖狀萎縮或GA。

ROCFP. is designed to reduce hepatic expression of complement Factor B, which has been identified as a promising therapeutic target.

ROCFP。旨在減少補體因子 B 的肝臟表達，補體因子 B 已被確定為有前途的治療標靶。

Our preclinical studies have demonstrated that AROCFB. can achieve deep and durable reductions in liver protein.

我們的臨床前研究顯示 AROCFB。可以實現肝臟蛋白質的深度和持久性減少。

Liver production of complement Factor B, which plays a key role in the activation of the alternative complement pathway involved in the pathogenesis of renal diseases such as IGA nephropathy as well as other conditions like at GA, we anticipate that first patient in for the Phase one two study will occur in Q2 of this year.

肝臟產生補體因子 B，它在激活替代補體途徑中發揮關鍵作用，該途徑涉及 IGA 腎病等腎臟疾病以及 GA 等其他疾病的發病機制，我們預計第一階段的第一名患者兩項研究將於今年第二季進行。

Our more advanced complement program is AROC. three.

我們更高級的補充計劃是 AROC。三。

As you may recall, AROC. three is designed to reduce production of complement component three or C. three as a potential therapy for various complement mediated diseases.

您可能還記得，AROC。三旨在減少補體成分三或C的產生。三作為各種補體介導的疾病的潛在療法。

We previously presented data from our Part one from part one of the study in healthy volunteers, an ongoing Phase one two study that demonstrated the following promising results, a dose-dependent reduction in serum C3 with 88% mean reduction at the highest dose, tested a dose-dependent reduction in age 50, a marker of alternative complement pathway hemolytic activity with 91% mean reduction at the highest dose tested and duration of pharmacologic effect supportive of quarterly or less frequent subcutaneous dose administration.

我們先前提供了健康志願者研究第一部分的數據，這是一項正在進行的第二階段研究，證明了以下有希望的結果，血清C3 呈劑量依賴性降低，在最高劑量下平均降低88%，經測試50 歲時劑量依賴性降低，這是替代補體途徑溶血活性的標誌，在最高測試劑量下平均降低 91%，藥理作用持續時間支持每季或較低頻率的皮下劑量給藥。

These results make us confident to move on to part two in patients with IgA nephropathy and C3 glomerulopathy.

這些結果使我們有信心繼續研究 IgA 腎病和 C3 腎小球病患者的第二部分。

We are currently enrolling that part of the study and intend to present patient data around year end 2024.

我們目前正在招募這部分研究，並打算在 2024 年底左右提供病患資料。

Lastly, the three clinical stage pulmonary programs continue to progress efficiently and are all on schedule for clinical readouts this year.

最後，三個臨床階段的肺部項目持續高效進展，今年均按計畫進行臨床讀數。

These pulmonary programs are as follows a rage which is designed to reduce expression of the receptor for advanced application and products or rage as a potential treatment for inflammatory pulmonary diseases.

這些肺部計劃如下：旨在減少受體表達的高級應用和產品或作為炎症性肺部疾病的潛在治療方法的產品。

For the Phase one two study, we have fully enrolled and dosed all healthy volunteer cohorts and the mild to moderate asthma patient cohorts as well.

對於第一階段和第二階段的研究，我們已經完全招募了所有健康志願者隊列以及輕度至中度哮喘患者隊列並對其進行了給藥。

We should have additional PD. data by the end of the first quarter.

我們應該有額外的PD。截至第一季末的數據。

For both of these, we are also in the process of enrolling three cohorts of asthma patients with high baseline levels of fractional exhaled nitric oxide or FeNO, which is a biomarker for IL-13 driven type two, inflammation and alone.

對於這兩種疾病，我們也正在招募三組呼出一氧化氮或 FeNO 基線水平較高的氣喘患者，FeNO 是 IL-13 驅動的二型發炎和單獨發炎的生物標記。

We believe we will have initial results from these high FeNO cohorts in the third quarter of this year, the biology of rage and where it sits in the inflammatory cascade as well as our own preclinical studies have suggested that rage inhibition may provide potent anti-inflammatory effects that impacts with impacts on an array of cytokines, including IL-13, IL-5 TSLPIL.

我們相信，我們將在今年第三季度從這些高FeNO 隊列中得到初步結果，憤怒的生物學及其在炎症級聯中的位置以及我們自己的臨床前研究表明，憤怒抑制可能提供有效的抗炎作用對一系列細胞激素的影響，包括 IL-13、IL-5 TSLPIL。

18 IL.

18伊爾。

33 IL. one B. and IL-6.

33伊利諾州。 B.和IL-6。

In addition to FeNO, we are assessing other potential biomarkers of anti-inflammatory effect, including sputum and blood cytokine in the asthma patient cohorts.

除了 FeNO 之外，我們還在評估其他潛在的抗發炎作用生物標記，包括氣喘患者群體中的痰液和血液細胞因子。

Next two programs, our April month five AC, which is designed to reduce production of nuisance five AC. or month five AC as a potential treatment for NewCo obstructive pulmonary diseases and Arrow MMP. seven, which is designed to reduce expression of Matrix metallic protein is seven or MMP. seven as a potential treatment for idiopathic pulmonary fibrosis or IPF in both programs.

接下來的兩個計劃，我們四月五交流，其目的是減少滋擾五交流的生產。或第五個月的 AC 作為 NewCo 阻塞性肺病和 Arrow MMP 的潛在治療方法。七，其旨在減少基質金屬蛋白七或MMP的表達。七個作為兩個項目中特發性肺纖維化或 IPF 的潛在治療方法。

We are conducting Phase one two studies in healthy volunteers.

我們正在健康志願者中進行第一階段和第二階段的研究。

And then in patients, both programs require patient data to assess PD. unlike Arrow rage, which has the benefit of a readily available and measurable PD biomarker in healthy volunteers.

然後在患者中，這兩個程序都需要患者數據來評估 PD。與 Arrow rage 不同，Arrow rage 的優點是在健康志願者中具有易於獲得且可測量的 PD 生物標記。

Both Aramark five AC. and OMMP. seven have already enrolled and dosed healthy volunteers, and we anticipate that patient cohorts will be enrolled and dosed in time to enable initial clinical readouts in the second half of the year.

均為愛瑪客五AC。和 OMMP。七名健康志願者已經入組並接受了給藥，我們預計患者群體將及時入組並接受給藥，以便在今年下半年實現初步臨床讀數。

I will now turn the call over to Ken Myszkowski can.

我現在將把電話轉給 Ken Myszkowski 可以。

Thank you, James, and good afternoon, everyone.

謝謝詹姆斯，大家下午好。

As we reported today, our net loss for the quarter ended December 31, 2023, was $132.9 million or $1.24 per share based on 107.4 million fully diluted weighted average shares outstanding.

正如我們今天報道的，截至 2023 年 12 月 31 日的季度淨虧損為 1.329 億美元，即每股 1.24 美元，基於 1.074 億股完全稀釋加權平均流通股計算。

This compares with a net loss of $41.3 million or $0.39 per share based on 106 million fully diluted weighted average shares outstanding for the quarter ended December 31, 2022.

相比之下，根據截至 2022 年 12 月 31 日的季度的 1.06 億股完全稀釋加權平均流通股計算，淨虧損為 4,130 萬美元，即每股 0.39 美元。

Revenue for the quarter ended December 31, 2023, was $3.6 million compared to $62.5 million for the quarter ended December 31, 2022 to revenue in the current period primarily relates to our collaboration agreements with GSK on revenue in the prior period, primarily related to recognition of revenue from our license and collaboration agreements with Takeda and Amgen.

截至2023年12月31日的季度收入為360萬美元，而截至2022年12月31日的季度收入為6250萬美元，本期收入主要與我們與葛蘭素史克就上期收入達成的合作協議有關，主要與確認相關來自我們與武田和安進的許可和合作協議的收入。

All upfront payments from existing agreements have now been fully recognized.

現有協議的所有預付款現已全部確認。

Total operating expenses for the quarter ended December 31, 2023, were $140.1 million compared to $104.7 million for the quarter ended December 31, 2022.

截至2023年12月31日的季度的總營運費用為1.401億美元，而截至2022年12月31日的季度的總營運費用為1.047億美元。

The key drivers of this change were increased candidate costs and salaries as the Company's pipeline of clinical candidates has both increased and advanced into later stages of development.

這項變化的主要驅動因素是候選人成本和薪資的增加，因為公司的臨床候選人管道既增加又進入了後期開發階段。

Net cash used by operating activities during the quarter ended December 31, 2023, was $117.8 million compared with $75.5 million for the quarter ended December 31, 2022.

截至 2023 年 12 月 31 日的季度營運活動使用的現金淨額為 1.178 億美元，而截至 2022 年 12 月 31 日的季度為 7,550 萬美元。

The increase in cash used by operating activities is driven primarily by higher research and development expenses and lower cash revenue in the period.

經營活動所使用的現金增加主要是因為期內研發費用增加及現金收入減少所致。

We have reviewed our cash forecast, and we'd like to provide additional guidance on our expected cash burn for the next several quarters.

我們已經審查了現金預測，並希望就未來幾季的預期現金消耗提供額外指引。

We expect operating burn to be $80 million to $100 million per quarter.

我們預計每季營運消耗為 8,000 萬至 1 億美元。

Our footprint expansion is mostly complete with the final payments to be made over the next several months, totalling about $70 million, after which we expect capital expenditures to be nominal breaking the operating burn a bit further, our cash burn related to G&A has been about 10% of costs.

我們的足跡擴張已基本完成，最終付款將在未來幾個月內支付，總計約 7000 萬美元，之後我們預計資本支出將在名義上進一步打破營運消耗，我們與 G&A 相關的現金消耗約為成本的10%。

So think of that as about $10 million of G&A each quarter, which is expected to grow slowly going forward as we continue to advance commercial commercialization efforts, we expect quarterly R&D expenditures to be about $80 million this year, increasing modestly next year as our registrational studies advance.

因此，考慮到每季約1000 萬美元的一般管理費用，隨著我們繼續推進商業化努力，預計未來將緩慢增長，我們預計今年季度研發支出約為8000 萬美元，明年將適度增長，因為我們的註冊學業進步。

Turning to our balance sheet, our cash and investments totalled $220.3 million at December 31, 2023 pro forma cash and investments accounting for the recent capital raise would be approximately $649 million.

轉向我們的資產負債表，截至 2023 年 12 月 31 日，我們的現金和投資總額為 2.203 億美元，預計近期融資的現金和投資約為 6.49 億美元。

Our common shares outstanding at December 31, 2023 were $107.5 million and pro forma shares outstanding account accounting for the capital raise would be $123.8 million for that overview.

截至 2023 年 12 月 31 日，我們已發行的普通股為 1.075 億美元，預計本次融資的已發行股票帳戶為 1.238 億美元。

I will now turn the call back to Chris.

我現在將把電話轉回給克里斯。

Thanks, Ken.

謝謝，肯。

This is an important year for Arrowhead in five primary areas.

今年對於 Arrowhead 的五個主要領域來說是重要的一年。

First, we expect a lot of activity within our cardiometabolic vertical, we will have our first Phase three readout for pimavanserin in and plan to file our first NDA.

首先，我們預計心臟代謝垂直領域將出現大量活動，我們將獲得 pimavanserin 的第一個三期讀數，並計劃提交第一份新藥申請 (NDA)。

We plan to initiate several additional Phase three studies in patient populations, including HOFHAGFHSHTG. and potentially ASCBD. across two different drug candidates for Vascular and Endovascular.

我們計劃在患者群體中啟動幾項額外的第三期研究，包括 HOFHAGFHSHTG。以及潛在的 ASCBD。涵蓋血管和血管內兩種不同的候選藥物。

And we also intend to expand the cardiometabolic vertical to include two additional candidates, Aero INHBE., and then in an undisclosed adipose targeted candidate.

我們還打算擴展心臟代謝垂直領域，以包括另外兩種候選藥物：Aero INHBE.，然後是一種未公開的脂肪目標候選藥物。

Second, we plan to have multiple clinical readouts in our pulmonary vertical across three different drug candidates and initiate at least one Phase two study.

其次，我們計劃在肺部垂直領域對三種不同候選藥物進行多項臨床讀數，並啟動至少一項二期研究。

Third, we intend to continue to strengthen our balance sheet with a structured finance transaction and one or more business development transactions.

第三，我們打算透過結構性融資交易和一項或多項業務發展交易繼續加強我們的資產負債表。

Fourth, our other clinical programs continue to move forward.

第四，我們的其他臨床項目繼續推進。

These include continuing enrollment of the disease or end Phase three study with Takeda Amgen potentially completing enrollment of its Phase three study of all pasts ran progress in Phase two studies in HBV with GSK progress in Phase two studies of GSK. four five three two nine and zero in NASH planning for Phase two studies in PNPLA. and aero PMP only three progress in Phase one studies for our neuromuscular candidates, Aero ducks for an arrow DM. one and progress in Phase one studies of our complement-based candidates, AROC. three and Arrow CFP.

其中包括繼續進行該疾病的招募或結束第三階段研究，武田安進可能完成其過去所有乙肝病毒第二階段研究的進展以及葛蘭素史克在葛蘭素史克第二階段研究中的進展。 PNPLA 第二階段研究 NASH 規劃中的四五三二九和零。和 aero PMP 在我們的神經肌肉候選者的第一階段研究中僅取得了三個進展，Aero 鴨子用於箭頭 DM。一以及我們基於補體的候選藥物 AROC 的第一階段研究進展。三、Arrow CFP。

And fifth, we are not done innovating.

第五，我們的創新還沒結束。

As I mentioned, we expect to bring our first adipose targeted candidate to the clinic and initiate clinical studies for an undisclosed CNS candidate this year. thanks for joining us today, and I would now like to open the call to your questions.

正如我所提到的，我們預計今年將我們的第一個脂肪標靶候選藥物引入臨床，並針對未公開的中樞神經系統候選藥物啟動臨床研究。感謝您今天加入我們，現在我想開始回答您的問題。

Operator?

操作員？

(Operator instructions)

（操作員說明）

Luca Issi, RBC Capital.

盧卡·伊西，加拿大皇家銀行資本。

Your line is open.

您的線路已開通。

All right.

好的。

Thanks so much for taking my question.

非常感謝您提出我的問題。

A quick one here, maybe James, first on FeNO.

在這裡，也許是詹姆斯，首先是 FeNO。

I know the data for the high FeNO cohort is in U.S. The third quarter on, however, I was under the impression that you were planning to show us the FeNO data from the mild to moderate patients potentially ahead of that.

我知道美國第三季有高 FeNO 隊列的數據，但是，我的印像是您計劃在此之前向我們展示輕度至中度患者的 FeNO 數據。

Is that no longer to plan?

難道不再計劃了嗎？

And if so, what drove that decision?

如果是這樣，是什麼推動了這個決定？

And then maybe second, either Chris or Ken, on the I think it's the first time I'm hearing you directly talk to you about potentially using debt and given the broader macroeconomic environment and where the rates are.

然後也許是第二，克里斯或肯，我想這是我第一次聽到你直接與你談論可能使用債務的問題，並考慮到更廣泛的宏觀經濟環境和利率。

Why do you think that adding debt is the right strategic decision at this point?

為什麼您認為目前增加債務是正確的策略決策？

Thanks so much.

非常感謝。

Sure, Luca.

當然，盧卡。

Thanks for the question.

謝謝你的提問。

I'll take the first one at in the mild to moderate asthma patient cohorts.

我將在輕度至中度氣喘患者群體中選擇第一個。

We didn't have a FeNO cutoff.

我們沒有 FeNO 截止值。

So it was sort of an all-comers asthma, a series of cohorts.

所以這有點像是一種全民氣喘，一系列族群。

And we just don't have the numbers.

我們只是沒有數字。

I think in the top dose cohort, we have one patient with high FeNO.

我認為在最高劑量隊列中，我們有一名 FeNO 高的患者。

So it's just not enough to make a call based on or present data based on that's why we're waiting for the high FeNO cohorts.

因此，僅僅根據呼叫或提供數據是不夠的，這就是我們等待高 FeNO 群體的原因。

Yes.

是的。

So even though while interest rates are higher than they have been historically, the cost of debt is certainly lower than our cost of equity capital.

因此，儘管利率高於歷史水平，但債務成本肯定低於我們的股本成本。

And it's a, we think, an important part of nondilutive financing.

我們認為，這是非稀釋性融資的重要組成部分。

So that's why we're looking at that possibility.

這就是我們正在研究這種可能性的原因。

And I think that we're at stage the stage of this company where we can consider that we are close to commercialization that it makes sense, I think, to start exploring those options.

我認為我們正處於這家公司的階段，我們可以認為我們已經接近商業化，我認為開始探索這些選擇是有意義的。

Got it.

知道了。

Thanks so much.

非常感謝。

One moment for our next question.

請稍等一下我們的下一個問題。

Ted Tenthoff , Piper Sandler.

特德·滕索夫，派珀·桑德勒。

Your line is open.

您的線路已開通。

Great.

偉大的。

Thank you very much and thanks for the thorough uptake and really exciting year, you know, as you're getting ready for PALISADE data and again, fingers crossed, assuming success based on the mechanism and the integration in the past, how do you start to think about the commercial build out for that indication, you know, especially in the U.S. Obviously I know it's not a huge indication, but it would be the company's first commercial build-out and then you discuss partnerships.

非常感謝你們的全面採用和真正令人興奮的一年，您知道，當您正在為 PALISADE 數據做好準備時，再次祈禱，假設基於過去的機制和集成取得了成功，您如何開始考慮一下該適應症的商業建設，你知道，尤其是在美國。顯然我知道這不是一個巨大的適應症，但這將是該公司的第一個商業建設，然後你討論合作關係。

Is it something where you would envision us seeking distribution partners overseas?

您是否希望我們在海外尋找分銷合作夥伴？

Are what's sort of the thinking on OUS?

OUS 有什麼想法嗎？

Thanks a ton.

萬分感謝。

I think Ken?

我認為肯?

Yes, we're really excited to make this transition.

是的，我們真的很高興能夠實現這一轉變。

We're excited about seeing those data, the Phase two data we're compelling.

我們很高興看到這些數據，我們引人注目的第二階段數據。

And so we are optimistic that those data are going to continue to look to look good look, but we like the way the way this this transition into a commercial company is panning out.

因此，我們樂觀地認為這些數據將繼續看起來不錯，但我們喜歡這種轉型為商業公司的方式。

It's we are not a commercial company right now.

我們現在不是一家商業公司。

And so it can be jarring.

所以這可能會讓人感到不舒服。

One could imagine going from zero to into a very large market that could be a bit diffused.

人們可以想像從零到進入一個非常大、可能有點分散的市場。

And so we get to take a baby step, if you will, in FCS either way, I the way I sort of segregate the triglyceride market is, is there those genetically defined FCS patients, those patients are known and physicians who treat them know where they are.

因此，如果你願意的話，我們可以邁出一小步，在FCS 中，無論哪種方式，我隔離三酸甘油酯市場的方式是，是否有那些基因定義的FCS 患者，這些患者是已知的，治療他們的醫生知道在哪裡他們是。

They are relatively easy to address.

它們相對容易解決。

You take one step down, if you will.

如果你願意的話，你可以退一步。

I'd say patients who are not genetically FCS but have triglycerides over eight, 80 and history of pancreatitis.

我想說的是那些不是遺傳性 FCS 但三酸甘油酯超過 8、80 且有胰臟炎病史的患者。

Again, those patients are relatively well known and relatively easy to address it as it is or it is those populations that we will be addressing initially, I mean, so it's a nice entry, if you will, into commercial as we as we grow and as we continue the other phase study of the other Phase three studies, and it will be increasing our ability to go after those harder to find patients, those that tracked and untracked with right side, those patients who have triglycerides above 500 and who may not have history of pancreatitis.

再說一遍，這些患者是相對知名的，​​也相對容易解決，或者說我們最初要解決的就是這些人群，我的意思是，所以如果你願意的話，隨著我們的成長和發展，這是一個很好的進入商業領域的入口。隨著我們繼續其他三期研究的另一階段研究，這將提高我們追蹤那些更難找到的患者、那些用右側追蹤和未追蹤的患者、那些三酸甘油酯高於500 的患者以及可能無法找到的患者的能力。有胰臟炎病史。

And that's a very large number, we believe.

我們相信，這是一個非常大的數字。

But we'll take some education of the market and we'll take some digging, of course.

但我們會對市場進行一些教育，當然也會進行一些挖掘。

And so we've got extra time to work to develop our ability to do that.

因此，我們有額外的時間來培養我們的能力。

So that's domestically internationally.

所以國內國際都是如此。

And we feel like we can handle the FCS market in certain ex U.S. markets.

我們覺得我們可以處理某些美國以外市場的 FCS 市場。

And so we intend to do that longer term, I would expect for us to find good local partners for SHTG., we'll see where we are with ASCVD. with AGFH. and the like, but at least for SHTG., it would probably make some sense for us to find the right local partners in other countries.

因此，我們打算從長遠來看，我希望我們能夠為 SHTG 找到良好的當地合作夥伴。我們將看看 ASCVD 的進展。與 AGFH。等等，但至少對於 SHTG 來說，我們在其他國家找到合適的當地合作夥伴可能是有意義的。

Great.

偉大的。

Thanks for the update.

感謝更新。

You're welcome.

不客氣。

One moment for our next question.

請稍等一下我們的下一個問題。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley 證券。

Your line is open.

您的線路已開通。

Hey, Tim, thanks for taking my questions and good to have Bruce back on the call.

嘿，提姆，感謝您回答我的問題，很高興布魯斯再次接聽電話。

So on the an outcome trial consideration and deliberation.

所以對一個結果進行審判考慮和商議。

So that ran Bruce, could you point to any on meta-analysis informing correlation of TRL some percent reduction or cumulative lowering that informs the event rate with outcomes, I believe you and possibly another peer might be doing a similar exercise in coming months.

Bruce 說，您能否指出任何元分析，告知TRL 一定百分比減少或累積降低的相關性，從而告知事件發生率與結果，我相信您和可能的其他同行可能會在未來幾個月內進行類似的練習。

And like you said, there might be additional external partners.

正如您所說，可能還有其他外部合作夥伴。

And Rod, as you look to I do a structured financing process, and I would love to hear your thoughts.

羅德，正如你所期望的那樣，我做了一個結構性融資流程，我很想聽聽你的想法。

And I have a quick follow-up after that.

之後我會進行快速跟進。

Well, you there's a lot of interest in the remnant cholesterol field concept, a lot of Mendelian randomization, data and other data pointing to these remnant cholesterol as being highly atherogenic in some of these analyses are even more atherogenic than April B and your LDL on a milligram per milligram basis.

嗯，你對殘餘膽固醇場的概念很感興趣，許多孟德爾隨機化、數據和其他數據都表明這些殘餘膽固醇具有高度動脈粥樣硬化性，在某些分析中甚至比April B 和你的LDL 更容易導致動脈粥狀硬化。以毫克每毫克為基礎。

It's as yet, you know, some improvement in clinical trials because frankly, there just haven't been good enough drugs for treating these.

你知道，臨床試驗到目前為止還取得了一些進展，因為坦白說，還沒有足夠好的藥物來治療這些疾病。

And so it has been on testable, they were waiting for the good drug to come along that you could you could test this remnant cholesterol hypothesis and both So DAS are in place after and are really incredibly good drugs in yield from a pharmacologic perspective.

所以它一直是可測試的，他們正在等待好的藥物出現，你可以測試這個殘餘膽固醇假說，所以 DAS 都已經到位，從藥理學的角度來看，它們確實是產率非常好的藥物。

So they offer that opportunity.

所以他們提供了這個機會。

And it's not actually an easy choice between the two because they're both equivalent in a lot of ways with respect to their ability to address that particular question.

實際上，這兩者之間的選擇並不是一個容易的選擇，因為它們在解決特定問題的能力方面在許多方面都是相同的。

So I think it's, you know, it's there's plenty of room plenty of paper out there, plenty of no genetic studies that point us this way that give us reason to be hopeful as a field but alone as a company.

所以我認為，你知道，有足夠的空間、足夠的論文、大量的非基因研究為我們指出了這一點，這讓我們有理由對這個領域充滿希望，但作為一家公司卻只能如此。

But ultimately we have to we have to prove it.

但最終我們必須證明這一點。

We have to do the old-fashioned thing.

我們必須做老式的事。

We have to actually do the clinical trials, improve it.

我們必須實際進行臨床試驗，改進它。

Got it.

知道了。

And then on the Pheno HyCO, James, I hope scrutiny of that biomarker data will also be part of the 3Q analysis.

然後，關於 Pheno HyCO，James，我希望對該生物標記數據的審查也將成為第三季分析的一部分。

Could you just maybe talk to the significance of that and broadly in your preliminary pipeline for Mach five and other patient cohorts on IU. also assessing that?

您能否談談這一點的重要性以及在 IU 上馬赫 5 和其他患者隊列的初步管道中的廣泛意義。還評估那個？

And what's the relevance of that as we look to make some go, no-go decisions this year.

當我們希望今年做出一些可行或不可行的決定時，這有何意義？

Thanks for taking the questions.

感謝您提出問題。

Sure.

當然。

Rates of the had the additional biomarker data, specifically the cytokine, as I mentioned, I mean, I think that those are an important piece of the readouts, but that will have this year.

正如我所提到的，我的意思是，我認為這些是讀數的重要組成部分，但今年將會有。

And in addition to FeNO, we are not assessing those in the level of detail and that we're doing in the rage cohorts with the other pulmonary programs like Block five AC. or MMP. seven just yet and not as relevant.

除了 FeNO 之外，我們還沒有詳細評估這些項目，我們正在與其他肺部項目（如 Block 5 AC）的憤怒隊列中進行評估。或 MMP。七個還沒有那麼相關。

We do measure cell counts on Bell for all the pulmonary programs, just to give indication of if we're seeing any kind of pro-inflammatory effect.

我們確實測量了貝爾所有肺部項目的細胞計數，只是為了表明我們是否看到任何促炎作用。

And we've not seen such an effect to date in the belt for any of those three programs.

到目前為止，我們還沒有在這三個項目的腰帶上看到這樣的效果。

Got it.Thanks for taking the question.

明白了。感謝您提出問題。

One moment for our next question.

請稍等一下我們的下一個問題。

Jason Gerberry, Bank of America.

傑森‧格伯里，美國銀行。

Your line is open.

您的線路已開通。

You guys thanks for take my question on a one for me on RAGE.

感謝你們在 RAGE 上為我提出問題。

Can you just remind us on what your cutoff is for high FeNO And will there be placebo patients that you're actually comparing against with that data update in 3Q?

您能否提醒我們高 FeNO 的截止值是多少？您是否會實際與第三季度的數據更新進行比較的安慰劑患者？

And what I'm trying to get at is thinking about your confidence you can derive from about 25 patients of data here and with respect to like FeNO variability as a measure?

我想了解的是，您是否有信心從這裡大約 25 名患者的數據中得出有關 FeNO 變異性作為衡量標準的信心？

And just lastly, do you think there's a chance that aero rage could achieve even higher than this 30% to 40% bogey set by biologics on the Pheno measure, just given it targets multiple interleukins involved in the type two inflammatory pathway?

最後，您認為空氣怒氣是否有可能實現比生物製劑在 Pheno 測量中設定的 30% 至 40% 的目標更高的目標，只要它針對參與二型發炎途徑的多種白細胞介素？

Thanks.

謝謝。

Sure.

當然。

Yes, I can't really comment on the magnitude question of that and what we expect or if we think we can have a higher FeNO reduction compared to the biologics, the FeNO cutoff is 35.

是的，我無法真正評論這個問題的嚴重性以及我們的期望，或者如果我們認為與生物製劑相比我們可以實現更高的 FeNO 減少，FeNO 截止值為 35。

And there are, I think 38 total patients across the high FeNO cohort.

我認為高 FeNO 隊列中共有 38 名患者。

So we should have a pretty good number and that includes placebo patients.

所以我們應該有一個相當不錯的數字，其中包括安慰劑患者。

So as you know, we'll be able to compare the active treatment arm two to a placebo group.

如您所知，我們將能夠將兩個積極治療組與安慰劑組進行比較。

Got it.

知道了。

Okay.

好的。

Thank you.

謝謝。

One moment for our next question.

請稍等一下我們的下一個問題。

Patrick R. Trucchio, H.C. Wainwright.

特魯基奧 (Patrick R. Trucchio)，H.C.溫賴特。

Your line is open.

您的線路已開通。

I think some have a couple of follow-up questions.

我認為有些人還有幾個後續問題。

The first is just on the CMO role.

第一個是 CMO 角色。

If you can maybe discuss the reasoning behind the de-central sizing the Chief Medical Officer function and what impact this is expected to have as well as potential advantages of this decentralized approach?

您是否可以討論一下首席醫療官職能去中心化規模背後的原因以及這預計會產生什麼影響以及這種去中心化方法的潛在優勢？

And then secondly, just on the CNS platform, can you talk a bit more about what went wrong with Arrow SOD one more specifically, was it a decision based on market potential or with the SRA. or something else?

其次，就 CNS 平台而言，您能否更具體地談談 Arrow SOD 出了什麼問題，是基於市場潛力還是基於 SRA 的決定。還是其他東西？

And maybe just give us an idea of how you expect this that's planning on the build-out going forward?

也許只是讓我們了解一下您對未來擴建計劃的期望如何？

Sure.

當然。

So it's so with the with the slight restructuring of R&D, but we just thought that we would need it good, good.

研發的輕微重組也是如此，但我們只是認為我們需要它，很好。

It leaders with deep expertise in our chosen verticals.

它是在我們選擇的垂直領域擁有深厚專業知識的領導者。

So far that's can be cardiometabolic.

到目前為止，這可能是心臟代謝的。

We expect pulmonary to be to be the next vertical.

我們預計肺部將成為下一個垂直領域。

We just need a deep expertise there.

我們只需要那裡深厚的專業知識。

We expect those not to be the last verticals that we're going to create.

我們希望這些不會是我們要創建的最後一個垂直領域。

We're probably going to have several others going forward.

未來我們可能還會有其他幾個項目。

And they just needed their own leaders and so made.

他們只需要自己的領導人，因此就產生了。

So for us, it made sense to restructure on towards that guarding side one, look, there's nothing there's nothing within Aerostat one that pushed us off it, to be honest, and we liked it.

因此，對我們來說，朝著防守一側進行重組是有意義的，看，浮空器一號內沒有任何東西將我們推離它，說實話，我們喜歡它。

We liked aero side one, we'd like that would be the opportunity because it gave us a good chance to interrogate on the platform.

我們喜歡航空方面一，我們希望這將是一個機會，因為它給了我們一個很好的機會在平台上詢問。

It was it was going to give us a good.

它會為我們帶來好處。

I think we thought proof of concept of the platform is working or not working the problem was solved with unwanted.

我認為我們認為平台的概念證明是否有效，問題已經解決了不必要的問題。

That is that it was becoming it was appearing to be increasingly commercially unviable.

也就是說，它在商業上似乎越來越不可行。

So the good news is we could seem to work in the bad news is it didn't make economic sense to develop that drug.

因此，好消息是我們似乎可以在壞消息中開展工作，因為開發這種藥物沒有經濟意義。

We thought and we and we had a fast follower at least one on that that we think, you know, at once gives us the ability to interrogate the platform.

我們認為，我們和我們至少有一個快速追隨者，我們認為，您知道，這立即使我們有能力詢問該平台。

It gives us good proof-of-concept platform, but also will be a more commercially viable drug.

它為我們提供了一個良好的概念驗證平台，也將成為更具商業可行性的藥物。

So it just made sense to allocate resources to get into others.

因此，分配資源進入其他領域是有意義的。

So it was less of a SOD one failing then and then a lack of confidence in the SOD1 ALS market.

因此，當時的情況並不是 SOD 失敗，而是對 SOD1 ALS 市場缺乏信心。

Got it.

知道了。

That's helpful.

這很有幫助。

Thank you very much to welcome one on their phone question.

非常感謝您歡迎一位透過電話提問的人。

Mani Foroohar, Leerink Partners

Mani Foroohar，Leerink Partners

Your line is open associated with questions of a couple of quick ones.

您的線路處於開放狀態，涉及幾個快速問題。

You talk about $100 million step down in operating expenses, which obviously buys a lot of wiggle room for the Company and it allows you to maximize your HR investments.

您談到減少 1 億美元的營運費用，這顯然為公司帶來了很大的迴旋空間，並且可以讓您最大限度地提高人力資源投資。

Could you give us any sort of color on the tempo at which we'll see that flow into OpEx over the course of this year, just for our modelling and then I've got a couple of quick pipeline questions to follow.

您能否為我們提供有關今年期間流入運營支出的節奏的任何信息，僅用於我們的建模，然後我有幾個快速的管道問題需要遵循。

So I think you should expect those results immediately.

所以我認為你應該立即期待這些結果。

If you look at what our burn was in the current quarter, it was it was high compared to previous quarters, but we think it will go back to a on normalized spend, like I had mentioned before, of about $80 million to $100 million and you could expect that beginning with the second fiscal quarter.

如果你看看我們本季的燒錢情況，你會發現與前幾季相比很高，但我們認為它將回到正常化支出，就像我之前提到的那樣，約為8000 萬至1 億美元，您可以預期從第二財季開始就會出現這種情況。

Okay.

好的。

And hopping over to the pipeline for Aero IHPE. or in heavy, how we're going to pronounce it.

並跳到 Aero IHPE 的管道。或重音，我們要如何發音。

That's a that's a target for which we've seen some of it, some evidence in broad margin and population studies, et cetera, for a change in adipose phenotype into the distribution to the hip to waste ratio even after what accounts for BMI.

這是一個目標，我們已經看到了其中的一些目標，在廣泛的邊緣和人口研究等中發現了一些證據，表明即使在考慮了 BMI 之後，脂肪表型也會改變為臀部與廢物比率的分佈。

So should we be thinking of that as a place where we're going to eventually see data that thing that targets, weight loss, adipose distribution, what are the endpoints we should be thinking of in humans?

那麼，我們是否應該將其視為最終看到目標數據的地方，減肥、脂肪分佈，我們應該考慮人類的終點是什麼？

And then what are the endpoints we should be thinking about from earlier stage studies as we sort of as this Asic, it's progressively derisked.

然後，我們應該從早期研究中考慮哪些終點，因為我們有點像 Asic，它逐漸降低了風險。

Yes, sure.

是的，當然。

I think about all of the above for at least in terms of our initial clinical study, we'll look at all of that and investigate not just changes in body weight loss, but will evaluate body composition, loss of lean mass distribution of adipose tissue is the visceral fat stores shrinking.

我至少在我們最初的臨床研究方面考慮了上述所有內容，我們將研究所有這些，不僅研究體重減輕的變化，還將評估身體組成、脂肪組織瘦質量分佈的損失是內臟脂肪儲存減少。

What happens to lean mass.

瘦體重會發生什麼事。

And we're also interested in what happens to measures of climate control like A1c or oral glucose tolerance testing.

我們也對 A1c 或口服葡萄糖耐受性測試等氣候控制措施的變化感興趣。

So I think and there are quite a few endpoints that we can study in even a Phase one study and learn a lot about our drug is about that particular target.

所以我認為，即使在第一階段研究中，我們也可以研究很多終點，並了解我們的藥物與特定目標有關的許多資訊。

And then as a follow-up, is there is there an opportunity in the initial human data set to see this to see this asset tested in both in patients who are on and off grip on GLP-1, given how broadly they're taken amongst the population of the US and other places where you guys have done clinical trials?

然後作為後續行動，考慮到 GLP-1 的使用範圍，在最初的人類數據集中是否有機會看到這一資產在服用和未服用 GLP-1 的患者中進行測試在美國和你們進行過臨床試驗的其他地方的人口中？

Yes, I think so.

是的，我想是這樣。

I think that would be we're still a little ways away from the clinic.

我認為那是我們距離診所還有一段距離。

But I would anticipate a study design that first starts in obese patients that are not on those drugs and then also investigates the combination of the GLP-1 agonist with inhibiting knockdown and see how the combination plays out.

但我預期研究設計首先從未服用這些藥物的肥胖患者開始，然後研究 GLP-1 激動劑與抑制基因敲除的組合，看看該組合的效果如何。

Great.

偉大的。

I'm going to I'm going to hop off.

我要去 我要下車了。

I know Elliot, a couple of others are still waiting on the queue.

我認識艾利歐特，還有其他幾個人還在排隊等候。

Thanks.

謝謝。

Guys One moment for our next question.

夥計們，請稍等一下我們的下一個問題。

Brendan Smith, TD Cowen.

布倫丹·史密斯，TD·考恩。

Hi, this is Gina on for Brendan.

大家好，我是布倫丹的吉娜。

Thanks for taking our question.

感謝您提出我們的問題。

I just want to ask which, again, on pork, ischemic muscle adipose tissue cancer in development, commercialization partnership would be the highest priority.

我只是想再問一下，關於豬肉、缺血性肌肉脂肪組織癌的發展、商業化合作關係將是最優先的。

Yes, sorry, sorry, you're breaking up.

是的，對不起，對不起，你們要分手了。

Can you repeat that your non-core pipeline programs.

您能重複一下您的非核心管道程序嗎？

would you consider for a development commercialization partnership and which of these would be the highest priority for you?

您會考慮建立開發商業化合作夥伴關係嗎？其中哪一個對您來說是最優先考慮的？

Yes.

是的。

So unfortunately, we don't do that entirely, we need a counterparty that's going to be interested as well.

不幸的是，我們並沒有完全做到這一點，我們需要一個也會感興趣的交易對手。

But look, there are we would we would certainly I'd be happy to talk about C. three, for instance, and we'd be happy to talk about the muscle assets.

但看，我們當然會很樂意談論 C.3，例如，我們很樂意談論肌肉資產。

We think those are We think those are all good assets, but at least right now, don't fit neatly into a plan vertical one would think that the muscle now gives will be a natural vertical for us and it could morph into that.

我們認為這些都是很好的資產，但至少現在，並不能完全符合垂直計劃，人們會認為現在提供的肌肉對我們來說將是一個自然的垂直方向，它可能會演變成那樣。

But right now, we are happy to talk and to the right partner about it's about one or both of those assets on PMP three potentially could be something that would that we are interested in NASH is it is a bit in flux right now.

但現在，我們很高興與合適的合作夥伴討論 PMP 3 上的一項或兩項資產可能是我們對 NASH 感興趣的東西，因為它現在有點變化。

And but that's something that we will consider discussing as we as a partner in HSD. to GSK.

但作為 HSD 的合作夥伴，我們會考慮討論這個問題。到葛蘭素史克。

We could talk about that as well.

我們也可以討論這個。

And that's sort of that's sort of what feels like right now in our existing clinical pipeline.

這就是我們現有的臨床管道中現在的感覺。

I welcome One moment for our next question.

歡迎大家花一點時間來回答我們的下一個問題。

Mike Olson, Morgan Stanley.

麥克‧奧爾森，摩根士丹利。

Your line is open for, Joe. Thanks for taking the question.

您的電話已接通，喬。感謝您提出問題。

And maybe just a quick follow-up here.

也許只是在這裡進行快速跟進。

In terms of Beauty Club, you mentioned maybe one or two potential deals this year.

就美容俱樂部而言，您提到今年可能會有一兩筆潛在交易。

Could they potentially include the core areas like cardio, metabolic and pulmonary or those are going to be excluded from potential royalty deals?

它們是否可能包括有氧運動、代謝和肺臟等核心領域，或者那些將被排除在潛在特許權使用費交易之外的領域？

Thanks.

謝謝。

Let's deal with those separately.

讓我們分別處理這些。

So cardiometabolic and we are we are full speed ahead with that answer and input after end of right now.

因此，心臟代謝和我們在現在結束後全速前進，給出答案和輸入。

And so we are not actively looking to partner those on the on the pulmonary side, we are not actively seeking partners for our three clinical assets.

因此，我們並沒有積極尋找肺部方面的合作夥伴，我們也沒有積極為我們的三個臨床資產尋找合作夥伴。

We could be we would be happy to discuss with a potential partner a platform partnership whereby somebody would bring in a target that we would we may not be working on for us to together build a drug candidates, but at least right now, we are not looking at partnering those existing clinical assets.

我們可能會很樂意與潛在合作夥伴討論平台合作夥伴關係，透過這種合作夥伴關係，有人會引入我們可能不會致力於共同構建候選藥物的目標，但至少現在，我們還沒有考慮與現有的臨床資產進行合作。

That's helpful.

這很有幫助。

Thank you.

謝謝。

So welcome.

非常歡迎。

One moment for our next question.

請稍等一下我們的下一個問題。

Ellie Merle, UBS.

艾莉·梅爾，瑞銀。

Your line is open.

您的線路已開通。

Yes, thanks for squeezing me in.

是的，謝謝你拉我進去。

And does in the past on rate, you had mentioned your program, I guess just what's the latest on the status and timelines there and just the focus of that program.

在過去的費率問題上，您曾提到您的計劃，我猜想那裡的最新狀態和時間表以及該計劃的重點是什麼。

And then just on a related note, as you think about planning on a larger Phase two study in asthma and what are the considerations and the design and what you're looking to see in the high dose cohort later this year?

然後，關於相關的說明，當您考慮計劃進行一項更大規模的哮喘二期研究時，考慮因素和設計是什麼，以及您希望在今年晚些時候的高劑量隊列中看到什麼？

And just what everything from the subdue program perhaps plan to some of the considerations in the design phase, certainly the onset of the subdue program, we said we are seeing not within reach knockout, and that's the good news.

從制服計劃的一切可能計劃到設計階段的一些考慮因素，當然是製服計劃的開始，我們說我們看到的淘汰賽還不是遙不可及的，這是好消息。

And we just weren't seen as deeper knockdown as we've seen with the inhaled time.

我們只是沒有看到像吸入時間那樣更深的擊倒。

And so we are really focusing our future development on the inhaled.

因此，我們真正將未來的發展重點放在吸入型產品上。

But again, but he did work it just it just was not U.S. as strong as the as the inhaled version.

但同樣，他確實做到了，但它不像美國的吸入式那麼強大。

I James, you want to.

我是詹姆斯，你願意。

I don't have anything to add to that.

我沒有什麼要補充的。

I don't think it will play into our Phase two plans, though, and we'll answer was the second question about again, what can you repeat the oh nine theatrical comments relative to our Amazon consideration, unlike what you're looking to see from a high FeNO cohort and how that might inform some of the design competition?

不過，我認為這不會進入我們的第二階段計劃，我們將再次回答第二個問題，您可以重複相對於我們的亞馬遜考慮的哦九戲劇評論，這與您想要的不同從高FeNO 隊列中看到的情況以及這對某些設計競賽有何影響？

Thanks.

謝謝。

Yes.

是的。

So we're talking around and thinking about a lot of different designs right now, I think the design win would certainly want to be able to study both a high Type two in the non Type two patients in a single design.

因此，我們現在正在討論並考慮許多不同的設計，我認為設計獲勝肯定希望能夠在單一設計中研究非二型患者的高二型患者。

And I think that the FeNO readout Q. three may inform on the which patient population we want to favor one more than the other, but I think we'll want to plan to study both.

我認為 FeNO 讀數 Q.3 可能會告訴我們哪些患者群體更適合其中一種患者，但我認為我們會計劃對這兩種患者進行研究。

Yes.

是的。

And keep in mind with the FeNO data, you look, we're looking forward to seeing that, of course.

請記住 FeNO 數據，您看，我們當然期待看到這一點。

But it really only reflects moving a single pathway, as James mentioned, in his prepared remarks, rage, we expect rates to move a number of different, a different cytokine.

但這實際上只反映了單一途徑的變化，正如詹姆斯在他準備好的演講中提到的那樣，憤怒，我們預計利率會移動許多不同的、不同的細胞因子。

And FeNO is only really detecting movement of one of those.

FeNO 只真正偵測到其中一個的運動。

And so while it's helpful.

雖然它很有幫助。

It's certainly not the only important data point.

這當然不是唯一重要的數據點。

Yes.

是的。

Okay, thanks.

好的謝謝。

That's helpful.

這很有幫助。

One moment for our next question.

請稍等一下我們的下一個問題。

Maury Raycroft , Jefferies Your line is open.

Maury Raycroft，Jefferies 您的線路已接通。

Hi.

你好。

Thanks for taking my questions.

感謝您回答我的問題。

I was going to ask one about RAGE to so for the higher dose PD asthma patient data that you're collecting, can you clarify if you'll do a public update on that at the end of this quarter on those data?

我本來想問一個關於 RAGE 的問題，所以對於您正在收集的高劑量 PD 哮喘患者數據，您能否澄清一下您是否會在本季度末對這些數據進行公開更新？

And will that only include knockdown or will that include cytokine and other PD. biomarkers as well.

是只包括敲除還是包括細胞激素和其他PD。生物標誌物也是如此。

And so it will include knock-down of for sure in and I'm not sure if there's if there's going to be a have a good venue in the near term to report those.

因此，這肯定會包括淘汰，我不確定近期是否會有一個好的場所來報告這些情況。

I can tell you that what we've seen so far and it's still an incomplete dataset.

我可以告訴你，到目前為止我們所看到的仍然是一個不完整的資料集。

What we've seen so far is consistent with what we said in the past, which is what we're seeing and knockdown in patients is really mapping on top of what we what we have seen the knockdown profile in healthy volunteers.

到目前為止，我們所看到的情況與我們過去所說的一致，這就是我們所看到的，患者的擊倒實際上是在我們所看到的健康志願者的擊倒概況之上繪製的。

And so that that continues on once we have a full dataset.

一旦我們擁有完整的資料集，這種情況就會繼續下去。

And given that again, I expect that to continue.

再次考慮到這一點，我希望這種情況能繼續下去。

I don't know that we'll rush out and have a press release based on that.

我不知道我們是否會匆忙發布基於此的新聞稿。

I think we'll probably have that as part of a some presentation at a conference or what have you.

我想我們可能會將其作為會議或其他會議上演示的一部分。

But to be honest, we really haven't put much thought into how we're going to disseminate those data because again, we expect those to be we expect that the knockdown in patients to be quite similar just to healthy volunteers that we've seen so far, Jim did anything else know that.

但說實話，我們確實沒有過多考慮如何傳播這些數據，因為我們再次期望這些數據是我們期望患者的擊倒效果與我們已經測試過的健康志願者非常相似。到目前為止，吉姆還知道除此之外還做了什麼。

Got it.

知道了。

Okay.

好的。

That's helpful.

這很有幫助。

And then maybe one follow up just for docs for ARM or DM. one, could you potentially have data updates from either of those programs this year?

然後可能會跟進 ARM 或 DM 的文檔。第一，今年您可能會從這些計劃中的任何一個獲得數據更新嗎？

Yes.

是的。

I think that depending on how enrollment goes, we could have some early data by end of the year.

我認為，根據招生情況，我們可能會在今年年底之前獲得一些早期數據。

But very enrollment contingent.

但招生隊伍非常龐大。

Got it.

知道了。

Okay.

好的。

Thanks for taking my questions.

感謝您回答我的問題。

Bright One moment for our next question.

明亮 一會兒我們的下一個問題。

Prakhar Agrawal, Cantor Fitzgerald

普拉卡·阿格拉瓦爾，坎托·菲茨杰拉德

Your line is open.

您的線路已開通。

Hi.

你好。

Thanks for taking my questions.

感謝您回答我的問題。

Are number one on 11 E preclinically, how out of your candidate profile differs versus some of our competitors or myeloma and wave in terms of the level of knockdown you're seeing, you mentioned 20% weight loss in the IO model.

在11 E 臨床前排名第一，您的候選者資料與我們的一些競爭對手或骨髓瘤和波在您所看到的擊倒水平方面有何不同，您提到IO 模型中體重減輕了20% 。

So maybe if you can compare and contrast that and then I had a follow-up.

所以也許如果你可以比較和對比的話，然後我有一個後續行動。

Sure.

當然。

Yes.

是的。

I think that that that level of differential in weight gain between the control animals and the animals receiving drug is similar to what others have reported in that study we were seeing and 90 plus, I think 96% knockdown in that, that obesity mouse model, which is, I believe, more than what others have reported.

我認為對照動物和接受藥物的動物之間體重增加的差異水平與我們在該研究中看到的其他人報告的相似，90+，我認為肥胖小鼠模型中的體重增加有96% 被擊倒，我相信，這比其他人報道的要多。

And I think that's probably the best I can tell you.

我想這可能是我能告訴你的最好的了。

Got it.

知道了。

And on the CV side of one of the key questions, do you need answers from the FDA to make a decision on which CV asset to move forward into the outcomes trial for the broader population?

在關鍵問題之一的 CV 方面，您是否需要 FDA 的答案來決定將哪種 CV 資產推進到更廣泛人群的結果試驗中？

Or is it just mostly an internal decision at this point?

或者目前這主要是一個內部決定？

Yes.

是的。

I mean, we haven't gone to the spruce given to get we haven't gone to the FDA at this point on that.

我的意思是，我們還沒有去找 FDA 來解決這個問題。

At some point, we will of course, go to the FDA would start a trial like that without their input.

在某個時候，我們當然會去FDA，在沒有他們意見的情況下開始類似的試驗。

But we're not at the point yet that we've engaged them in the discussion.

但我們還沒到讓他們參與討論的程度。

Again, thank you for taking the questions.

再次感謝您提出問題。

Short One moment for our next question.

請稍等一下我們的下一個問題。

And our next question comes from David Lebovitz, Citi

我們的下一個問題來自花旗銀行的 David Lebovitz

.

。

Your line is open.

您的線路已開通。

David Liebowitz, your line is open.

大衛·利博維茨，您的線路已接通。

Hello?

你好？

Hi, Jim.

嗨，吉姆。

I guess we can't.

我想我們不能。

Yes.

是的。

Hi.

你好。

How does the bank on for David.

大衛的銀行狀況如何？

Thanks for taking our question.

感謝您提出我們的問題。

We so maybe regarding the FTS. readout of that transaction, you mentioned that the last patient is scheduled for the visit in second quarter.

我們可能會考慮 FTS。在讀出該交易時，您提到最後一位患者計劃在第二季就診。

We were wondering if you could give us a little more color in terms of the data readout timing and maybe what data points can we expect to see the readout?

我們想知道您是否可以在數據讀出時間方面給我們更多的信息，也許我們可以期望看到讀數哪些數據點？

Well, I think you know, we would again be looking to present, I would think in a meeting I actually haven't spoken with Chris on this or maybe we would top line in some way once we did that, but we'd want to do that in such a way.

好吧，我想你知道，我們會再次尋求展示，我想在一次會議上我實際上還沒有與克里斯討論過這個問題，或者一旦我們這樣做了，我們可能會以某種方式頂線，但我們希望以這種方式做到這一點。

It's to not presented a fulsome presentation at a at an academic meeting at some point, and I think it's kind of the same sort of question the same answer we had before at this point, it's hard to predict what meeting that would be and when that would occur.

這是為了不在某個時候在學術會議上進行一次完整的演講，我認為這是同樣的問題，我們之前在這一點上得到了同樣的答案，很難預測那將是什麼會議以及何時舉行會發生。

But yes, I suspect we would, in some way, give some top line information, but most of the fulsome data would come out later.

但是，是的，我懷疑我們會以某種方式提供一些重要信息，但大多數豐富的數據將在稍後公佈。

I would expect.

我會期待。

Okay, thank you.

好的謝謝。

And just one follow-up.

只有一個後續行動。

Assuming that Lowe's asset and an Olive Garden are both approved, how do you think clinicians would choose between the two therapies?

假設 Lowe's 資產和 Olive Garden 都獲得批准，您認為臨床醫生會如何在這兩種療法之間進行選擇？

It's hard to answer that question in a setting where actually we don't have the comparative results of the of the two agents at this point on either efficacy or safety in the FCS population.

實際上，我們目前還沒有兩種藥物在 FCS 族群中的有效性或安全性的比較結果，因此很難回答這個問題。

So it's would it be wildly spec speculative at this point?

那麼此時此刻是否會引發瘋狂的猜測呢？

Just trying to make a call on that?

只是想打電話詢問一下嗎？

Yes, I don't I don't think we I don't think that we've seen triglyceride levels and from that Phase three, yet when we when we look at it of the available data from the pit from their Phase twos versus our Phase twos we are we are comfortable that our dosing interval will be longer, and it appears at least according to the Phase two data appears that our APOC3 knockdown is greater in our triglyceride lowering is greater.

是的，我不認為我們沒有看到第三階段的三酸甘油酯水平，但是當我們查看第二階段和第二階段的可用數據時我們對第二階段的給藥間隔會更長感到滿意，至少根據第二階段的數據看來，我們的APOC3 敲低幅度更大，三酸甘油酯的降低幅度更大。

But again, as Bruce says, we don't know what the Phase three looks like, I'm on their side or on our side, frankly.

但正如布魯斯所說，我們不知道第三階段是什麼樣子，坦白說，我站在他們這邊或我們這邊。

Thank you.

謝謝。

That's helpful.

這很有幫助。

Your question comes from the line of William Green with Bernstein.

你的問題來自威廉·格林和伯恩斯坦的對話。

Your line is open for.

您的線路已開通。

Good evening.

晚安.

Thank you for taking my question.

感謝您回答我的問題。

You've estimated the addressable FCS population at 70 to 100,000, which sounds like you have pretty large population to get approved based on a single 75 person study.

您估計可尋址 FCS 人群為 70 到 100,000 人，這聽起來似乎根據一項 75 人研究，您有相當大的人群需要獲得批准。

So can you just remind us of your agreement with the FDA on the exact definition of that FCS population for which they agreed to accept just a single trial.

那麼，您能否提醒我們，您與 FDA 就 FCS 人群的確切定義達成了一致，他們同意僅接受一項試驗。

Thank you.

謝謝。

In that in that Phase three study, we are studying people with genetically confirmed FCS and those patients with the with clinical FCS, if you will, which is patients with triglycerides above 80 and history of pancreatitis, that population in our study Thank you, Rocco.

在第三階段研究中，我們正在研究經基因證實的FCS 患者和臨床FCS 患者（如果您願意的話），即甘油三酯高於80 且有胰臟炎病史的患者，我們研究中的人群謝謝您， Rocco 。

And I would now like to turn the conference back to Chris Anzalone for closing remarks.

現在我想請克里斯安札龍 (Chris Anzalone) 致閉幕詞。

Thanks very much for tuning in today, and we look forward to speaking with you over the next quarter and those of you who are in Southern California, I hope you stay dry.

非常感謝您今天的收聽，我們期待在下個季度與您交談，而南加州的人們，我希望您保持乾燥。

This concludes today's conference call.

今天的電話會議到此結束。

Thank you for participating.

感謝您的參與。

You may now.

你現在可以了。