United Therapeutics Corp (UTHR) 2019 Q3 法說會逐字稿

Good morning, and welcome to the United Therapeutics Corporation Third Quarter 2019 Earnings Call. My name is Justin, and I will be your conference operator today. (Operator Instructions)

早安，歡迎參加聯合治療公司 2019 年第三季財報電話會議。我叫賈斯汀，今天我將擔任你們的會議操作員。（操作員說明）

I would now turn the call over to James Edgemond, Chief Financial Officer of United Therapeutics. Sir, you may begin.

我現在將電話轉給聯合治療公司財務長詹姆斯·埃奇蒙德。先生，您可以開始了。

Thank you, Justin. Good morning, everyone. It is my pleasure to welcome you to the United Therapeutics Corporation Third Quarter 2019 Earnings Call. Accompanying me on today's call are Dr. Martine Rothblatt, our Chairman and Chief Executive Officer; and Mr. Michael Benkowitz, our President and Chief Operating Officer.

謝謝你，賈斯汀。大家，早安。我很高興歡迎您參加聯合治療公司 2019 年第三季財報電話會議。陪同我參加今天的電話會議的是我們的董事長兼執行長 Martine Rothblatt 博士；以及我們的總裁兼營運長 Michael Benkowitz 先生。

Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Form 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update forward-looking statements.

今天的言論將包括代表我們對未來事件的期望或信念的前瞻性陳述。這些陳述涉及風險和不確定性，可能導致實際結果有重大差異。我們最新的 SEC 文件（包括表格 10-K 和 10-Q）包含有關這些風險和不確定性的更多資訊。我們不承擔更新前瞻性陳述的義務。

Today's remarks may also include financial measures that were not prepared in accordance with U.S. generally accepted accounting principles. Reconciliation of non-GAAP financial measures to the most directly comparable GAAP financial measures can be found in our earnings release available on our website at www.unither.com.

今天的言論可能還包括未按照美國公認會計原則制定的財務措施。非 GAAP 財務指標與最直接可比較的 GAAP 財務指標的調整可以在我們網站 www.unither.com 上發布的收益報告中找到。

Today's remarks may discuss the progress and results of clinical trials and other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for these products is available on our website.

今天的發言可能會討論臨床試驗的進展和結果以及我們產品的其他發展。這些言論僅旨在教育投資者，無意作為醫療決策的基礎，或表明任何產品對於任何未經批准或研究用途都是安全有效的。這些產品的完整處方資訊可在我們的網站上找到。

Now I will turn the call over to Dr. Rothblatt for an overview of our third quarter 2019 financial results and business activities of United Therapeutics.

現在我將把電話轉給 Rothblatt 博士，概述一下 United Therapeutics 2019 年第三季的財務表現和業務活動。

Thank you, James. Good morning, everybody. As James mentioned, I'm pleased to be joined today by our President and Chief Operating Officer, Mike Benkowitz, and he and James and I will answer questions after I give a brief business overview of United Therapeutics as well as the third quarter 2019.

謝謝你，詹姆斯。大家早安。正如 James 所提到的，我很高興今天能與我們的總裁兼營運長 Mike Benkowitz 一起參加會議，他、James 和我將在我簡要介紹 United Therapeutics 的業務概況以及 2019 年第三季後回答問題。

We're pleased with our financial results over the past quarter, and I -- they're available in the press release. But on every metric, we're very pleased with how everything came out.

我們對過去一個季度的財務業績感到滿意，我——它們可以在新聞稿中找到。但在每一個指標上，我們對一切的結果都非常滿意。

Let me give a bit of an overview now on some of the exciting business progress going on at United Therapeutics. Last month, my colleague, Dr. Peterson, reported the FDA approval of our new label for Orenitram. This was really a signal accomplishment for United Therapeutics. It's something that we worked on steadfastly for just about a decade. And for those of you who are kind of pulmonary hypertension geeks or are really into the deep history on the drugs used to treat pulmonary hypertension, it's interesting that even though the active pharmaceutical ingredient in Orenitram, treprostinil was discovered by the Nobel laureate, Sir John Vane. He himself did not believe that this API would be able to be successfully developed as an oral treatment that could reduce the rate of progression of pulmonary hypertension, much less reduce outright morbidity or mortality. And he was a great guy. Unfortunately, he passed, but it was, thanks to him, that we developed our parenteral form of treprostinil, which the brand name is Remodulin, and he was a spot on correct that, that would be a highly effective treatment for patients with pulmonary hypertension.

現在讓我概述一下聯合治療公司正在取得的一些令人興奮的業務進展。上個月，我的同事 Peterson 博士報告 FDA 批准了我們的 Orenitram 新標籤。對於 United Therapeutics 來說，這確實是一項重大成就。這是我們堅持不懈地努力了大約十年的事情。對於那些肺動脈高壓極客或真正了解用於治療肺動脈高壓的藥物的深厚歷史的人來說，有趣的是，儘管奧瑞尼曲中的活性藥物成分曲前列環素是由諾貝爾獎得主約翰爵士發現的葉片。他自己並不相信這種 API 能夠成功開發為口服治療藥物，從而降低肺動脈高壓的進展速度，更不用說降低直接發病率或死亡率了。他是一個很棒的人。不幸的是，他通過了，但多虧了他，我們開發了曲前列環素注射劑，其商品名為瑞莫杜林（Remodulin），他正確地指出了這一點，這將是治療肺動脈高壓患者的一種高效方法。

But it's kind of a little bit of like a pinch-me moment when you have a Nobel laureate thinking that this is just not going to be able to work as a PO. And you slug away for 10 years, and during the course of that 10 years, you're always thinking, "Geez, maybe Sir John was right, maybe Sir John was right," and then you end up with this absolutely beautifully executed FREEDOM-EV study with the excellent results that we shared with everybody last year, and then we're still crossing our fingers up until we get the final FDA stamp of approval on the results, which occurred just earlier this month. So that was really I think beyond the result -- beyond the doubt not only that signal result of -- since our last earnings call, but also of 2019.

但這有點像一個捏我的時刻，當你有一位諾貝爾獎得主認為這無法作為 PO 工作時。你苦苦掙扎了10年，在這10年的過程中，你總是在想，「天哪，也許約翰爵士是對的，也許約翰爵士是對的，」然後你最終得到了這個絕對完美執行的自由-去年我們與大家分享了 EV 研究的出色結果，然後我們仍在祈禱，直到本月早些時候獲得 FDA 對結果的最終批准印章。所以，我認為這確實是自我們上次財報電話會議以來的結果，毫無疑問不僅是訊號結果，也是 2019 年的結果。

I really personally believe that due to the great label that the FDA approved on Orenitram, that over the next 2 to 3 years, we're going to able to double the number of patients that we have on Orenitram and then actually be able to double that, again, in the following 2 to 3 years after that.

我個人確實相信，由於 FDA 批准 Orenitram 的出色標籤，在未來 2 到 3 年內，我們將能夠將 Orenitram 的患者數量增加一倍，然後實際上能夠將其增加一倍在那之後的2 到3 年內，同樣如此。

So it's a really good outlook for Orenitram, thanks to this accomplishment of our new greatly expanded label for that product.

因此，Orenitram 的前景非常好，這要歸功於我們為該產品大幅擴展的新標籤所取得的成就。

Now there is some other really good things that are coming up in the approval category. During the next 12 months, and frankly, we've never had a greater perspective news flow for United Therapeutics than we do in the next 12 months.

現在，審批類別中還出現了其他一些非常好的事情。在接下來的 12 個月裡，坦白說，對於 United Therapeutics 來說，我們從未有過比未來 12 個月更有前景的新聞流。

In the next 12 months, we hope for and expect there to be no fewer than 3 new approvals for United Therapeutics out of the FDA. First, the one that we have also been working on for just about 10 years, the ISR, Implantable System for Remodulin. We hope to get the final approvals for that. As those of you who have been following us for a while know, actually it's -- United Therapeutics already got its approvals from the FDA, and we're waiting for the final Medtronic approvals before we could commercially launch that project.

在接下來的 12 個月裡，我們希望並預計 FDA 將有不少於 3 個針對 United Therapeutics 的新批准。首先，我們也已經研究了大約 10 年，即 ISR（Remodulin 植入式系統）。我們希望得到最終批准。正如那些一直關注我們一段時間的人所知，實際上，United Therapeutics 已經獲得了 FDA 的批准，我們正在等待美敦力的最終批准，然後才能商業啟動該專案。

Second up, we expect to get FDA approvals needed for the commercial launch of RemUnity. Also for those of you who've been following us, we actually did get an initial 510(k) approval on RemUnity, and we're just waiting for a final approval on a kind of special 510(k) or regulatory analog of that, that we would expect in the next 12 months, that would be truly transformative for the patients on subcutaneous Remodulin. And then third, we expect, within the next 12 months, to have an FDA approval for Trevyent. That's the project that we acquired along with the acquisition of SteadyMed.

其次，我們希望獲得 RemUnity 商業推出所需的 FDA 批准。另外，對於那些一直關注我們的人來說，我們實際上確實獲得了 RemUnity 的初步 510(k) 批准，我們只是在等待某種特殊 510(k) 或類似監管的最終批准，我們預計在接下來的12 個月內，這對皮下注射Remodulin 的患者來說將是真正的改變。第三，我們預計 Trevyent 在未來 12 個月內將獲得 FDA 批准。這是我們在收購 SteadyMed 的同時獲得的項目。

This one is going to be transformative for a very large segment of the pulmonary hypertension population, especially that segment that suffers from connective tissue disease. And there's a whole spectrum of connective tissue disease state such as scleroderma and Raynaud's disease. And all of these kind of conditions, they make it very difficult for patients to activate the tiny buttons that we have on all of our devices.

這對於很大一部分肺動脈高壓人群，尤其是患有結締組織疾病的人來說，將是一場變革。還有一系列結締組織疾病，例如硬皮症和雷諾氏症。所有這些情況，都使患者很難啟動我們所有裝置上的小按鈕。

So I think that, that one being so simple, no buttons involved for the patients to have to adjust the dosage or anything like that, truly just a plug-and-play system. I believe that Trevyent, together with RemUnity, is going to allow us to significantly expand the reach of subcutaneous Remodulin patients well beyond the number of patients that we have already been able to help and serve with that product.

所以我認為，這個系統非常簡單，不需要病人調整劑量或類似的按鈕，真正只是一個即插即用的系統。我相信 Trevyent 與 RemUnity 一起將使我們能夠顯著擴大皮下注射 Remodulin 患者的覆蓋範圍，遠遠超出我們已經能夠使用該產品幫助和服務的患者數量。

Speaking of number of patients that we're helping and serving, I hope my colleague, Mike, won't be angry with me for stealing his thunder a little bit, but we are now serving more patients with treprostinil than we have ever served in the history of the company. So it's really a great launching point for 2020 because, here, we are serving more patients than we've ever served before. And we are on the cusp of launching in the next 12 months, not to mention the true launch of Orenitram with a new label, so really 4 new products, each of which have an ability to significantly expand the number of patients that can be served by the treprostinil family of products here at UT.

說到我們正在幫助和服務的患者數量，我希望我的同事邁克不會因為我搶了他的風頭而生氣，但我們現在為更多的曲前列環素患者提供服務，比以往任何時候都多。公司的歷史。因此，這確實是 2020 年的一個很好的起點，因為在這裡，我們為比以往任何時候都多的患者提供服務。我們正處於未來 12 個月內推出的風口浪尖，更不用說真正推出帶有新標籤的 Orenitram，所以實際上有 4 個新產品，每一個都有能力顯著擴大可以服務的患者數量UT 的曲前列環素系列產品。

So on the FDA approval front, I think, things could not be going better. But let's take a look at what's going to come next after these approvals.

因此，我認為，在 FDA 批准方面，事情進展得再好不過了。但讓我們看看這些批准後接下來會發生什麼。

So we have also found ourselves in a very good position because of all the stage work and seed planting that we've done over the past few years to harvest 2 unblindings in the next -- coming quarter, by that mean -- by that, I mean the first quarter of 2020. We expect to unblind, first of all, our distinct study of Unituxin or dinutuximab for our small cell lung cancer. That's really exciting because right now, we've been able to serve, roughly speaking, about 1,000 patients with Unituxin. Those are the patients suffering from neuroblastoma. But the small cell lung cancer patient population is in the tens of thousands. It's really an order of magnitude more than we're able to serve with -- in neuroblastoma. So we're really, really hoping for a positive unblinding of Unituxin, dinutuximab in the first quarter. And then upwards set us on a course of FDA filings and then launch within a year after that to a tenfold larger population than we're able to serve with -- in neuroblastoma.

因此，我們也發現自己處於非常有利的位置，因為我們在過去幾年中所做的所有舞台工作和播種工作，都是為了在下一個季度（也就是下個季度）收穫2 次揭盲，也就是說，我指的是2020年第一季。首先，我們希望揭開我們對 Unituxin 或 dinutuximab 治療小細胞肺癌的獨特研究。這真的很令人興奮，因為現在，粗略地說，我們已經能夠為大約 1,000 名 Unituxin 患者提供服務。這些是患有神經母細胞瘤的患者。但小細胞肺癌患者人數卻有數以萬計。這實際上比我們在神經母細胞瘤中所能提供的服務要大一個數量級。因此，我們真的非常希望 Unituxin、dinutuximab 在第一季能積極揭盲。然後向上讓我們進行 FDA 備案，然後在一年內向比我們能夠服務的人群多十倍的人群推出——神經母細胞瘤。

And then another very similar story, but different disease state. We will we unblinding our INCREASE study, and this is of Tyvaso in Group 3 pulmonary hypertension.

然後是另一個非常相似的故事，但疾病狀態不同。我們將揭曉我們的 INCREASE 研究，這是 Tyvaso 在第 3 組肺動脈高壓的研究。

This is a group of patients characterized by interstitial lung disease and pulmonary fibrosis. A group of patients that payers will not approve the use of Tyvaso in this patient population today because they have very different characteristics. They are, for example, not cardiac catheterized, which is definitely a checkmark that payers require before reimbursement for the drugs in the Group 1 idiopathic or secondary pulmonary hypertension population.

這是一組以間質性肺部疾病和肺纖維化為特徵的患者。一群患者的付款人不會批准在今天的患者群體中使用 Tyvaso，因為他們具有非常不同的特徵。例如，它們沒有插入心導管，這絕對是付款人在為第 1 組特發性或繼發性肺動脈高壓人群報銷藥物之前要求的一個勾號。

So this population is also 10x larger than the number of patients that we're able to serve with Tyvaso today.

因此，這個人群也比我們今天能夠使用 Tyvaso 服務的患者數量多 10 倍。

So it's a very analogous parallel situation with the cancer situation, where we've got a great drug, Tyvaso, similar to a great dug, Unituxin, able to serve single-digit thousands of patients, doing very well with those. And now we'll be able to unblind, in the next quarter, basically the same drug, so very much reduced risk in terms of the regulatory process, but for a patient population that's 10x larger than the one that we're already serving.

因此，這與癌症情況非常相似，我們有一種很棒的藥物 Tyvaso，類似於一種偉大的藥物 Unituxin，能夠為數以千計的患者提供服務，並且效果很好。現在，我們將能夠在下個季度對基本上相同的藥物進行揭盲，因此在監管過程方面的風險大大降低，但對於比我們已經服務的患者群體多 10 倍的患者群體。

So again, very, very sweet situation with those 2 unblindings in the first quarter.

再說一次，第一季兩次揭盲的情況非常非常甜蜜。

Let me just wrap up with kind of a flyover of the deeper pipeline just because we've got so much exciting stuff going on in the current 12-month pipeline. But there is upcoming a IND filing to begin the formal clinical development of our once-daily formulation of Orenitram.

讓我以一種對更深層管道的飛越作為結束，因為我們在當前 12 個月的管道中發生了很多令人興奮的事情。但即將提交 IND 申請，開始我們每日一次的 Orenitram 製劑的正式臨床開發。

There will be a movement right through the IND or just thereabouts for RemoPro. That will be the much less painful or painless form of Remodulin, again, certainly a game changer in subcutaneous treprostinil because of its ability to greatly mitigate, and for some patients, eliminate the site pain. The very exciting TreT program, which we've done in combination with Mannkind, where we're able to reduce the burden associated with Tyvaso to something that is truly de minimis, fits right in like a clutch purse or just a little -- even a jean pocket and really liberate thousands and thousands of patients from one of the burdens of dealing with drug delivery systems for pulmonary hypertension.

RemoPro 將會在 IND 期間或之後發生變更。這將是瑞莫杜林的一種疼痛更少或無痛的形式，同樣，它肯定會改變皮下注射曲前列環素的遊戲規則，因為它能夠極大地減輕疼痛，對於某些患者來說，甚至可以消除部位疼痛。我們與 Mannkind 合作完成了非常令人興奮的 TreT 計劃，我們能夠將與 Tyvaso 相關的負擔減輕到真正最小的程度，就像手拿包一樣適合，甚至只是一點點——甚至一個牛仔褲口袋，真正將成千上萬的患者從處理肺動脈高壓藥物輸送系統的負擔中解放出來。

That program is going very well, also being managed by Dr. Peterson and patients already being dosed. The PERFECT trial of Tyvaso in COPD, this is a trial that we're very grateful to Dr. Waxman leading the way with his early proof of concept of the excellent results of Tyvaso in the very large and oftentimes difficult to treat COPD population. So that program is being run by our one biotechnology unit, and also proceeding straightforward with patients already being enrolled. Again, just to be clear, that's also a Phase III trial.

該計劃進展順利，也由彼得森博士管理，患者已經接受了給藥。Tyvaso 治療 COPD 的完美試驗，我們非常感謝 Waxman 博士引領了這項試驗，他早期證明了 Tyvaso 在非常大且通常難以治療的 COPD 人群中取得了優異的效果。因此，該計劃由我們的一個生物技術部門負責運行，並且對已經入組的患者也直接進行。再次強調一下，這也是第三階段試驗。

Our humanized form of dinutuximab, we're not resting on any laurels with the good results of Unituxin. And thanks to a great partnership we entered into with St. Jude Medical, we've been able to in-license the rights and now begin manufacturing a humanized form of dinutuximab. This might be delving a little bit into the uber geekiness, but I am personally very proud as I'm kind of a manufacturing geek myself, there were like multiple-fold improvements in the efficiency of our production of that humanized monoclonal. So hats off to our totally awesome biologics and manufacturing group.

我們的人源化形式的 dinutuximab，我們不會滿足於 Unituxin 良好結果的任何成就。感謝我們與聖路易斯建立的良好合作關係。Jude Medical，我們已經獲得了權利許可，現在開始生產人源化的 dinutuximab。這可能是對超級極客的深入研究，但我個人非常自豪，因為我自己就是一個製造極客，我們生產人源化單株抗體的效率提高了數倍。向我們出色的生物製劑和製造團隊致敬。

And last, but not least, very, very exciting progress on the Xeno-Kidney front. We will open up, in the next quarter, the company's first designated pathogen-free facility for Xeno-Kidney. The acronym for that is called a D, delta; P, pafa; F, foxtrot; DPF. And what that means is that the kidney is being produced in a pig in that facility in a way that the FDA agrees the organs from that pig can be put into a person.

最後但並非最不重要的一點是，在異種腎臟方面取得了非常非常令人興奮的進展。我們將在下個季度開設公司第一個指定的異種腎臟無病原體設施。其縮寫稱為 D，delta； P，帕法； F、狐步舞；柴油顆粒過濾器。這意味著該設施中的豬正在生產腎臟，FDA 同意將豬的器官移植到人體。

The FDA does not allow you, and thank goodness for that, just taking any former job pig's organs and put them into a person. They are very, very strict that you have to have a completely still environment just as you would have for any other drug or biologic that you're putting inside a person.

謝天謝地，FDA 不允許你將任何前工作豬的器官移植到人體。他們非常非常嚴格，你必須有一個完全靜止的環境，就像你放入人體內的任何其他藥物或生物製劑一樣。

So a Xeno-Kidney is just a giant biologic, and there are very strict rules in terms of every aspect of infection testing and C-sectioning in of the genetically modified pigs for those organs to end up being tested in man.

因此，異種腎臟只是一個巨大的生物製品，在感染測試和基因改造豬的剖腹產各個方面都有非常嚴格的規定，以便這些器官最終在人體上進行測試。

So that facility will come online in 2020 and then pave the way for us to be able to actually, with FDA approval, accomplish the first-in-man of our xenograft in the 2021, 2022 time frame. So I've probably gone a little bit over my allotted time period, I guess, a bit by 5 minutes. But in any event, I'm so excited about all the stuff going on in UT.

因此，該設施將於 2020 年上線，然後為我們能夠在 FDA 批准的情況下，在 2021 年和 2022 年的時間範圍內完成首次人體異種移植鋪平道路。所以我可能比規定的時間多了一點，我猜，多了 5 分鐘。但無論如何，我對 UT 發生的所有事情感到非常興奮。

So operator, if you can please open up the phone lines, and I will sort the questions to Mike and James.

接線員，如果可以的話，請打開電話線路，我會將問題整理給麥克和詹姆斯。

(Operator Instructions) Our first question is going to come from Jessica Fye from JPMorgan.

（操作員說明）我們的第一個問題將來自摩根大通的 Jessica Fye。

I was hoping you could elaborate on the earlier pump comments. I guess, specifically, can you help me understand the timing and order in which you expect those 3 different pumps to launch?

我希望您能詳細說明先前的泵評論。我想，具體來說，您能幫我了解您期望這 3 個不同泵浦啟動的時間和順序嗎？

Yes. Thanks, Jessica. Everything's up to the FDA. So it's really difficult to be precise about that. You can be -- the Trevyent is one that I think you can follow from the PDUFA time line of the FDA. RemUnity, the FDA filing is actually not done by United Therapeutics, it's done by DEKA, who is our pump partner; and the ISR, as I mentioned in my opening remarks, it's also -- it's a Medtronic product.

是的。謝謝，傑西卡。一切都取決於FDA。所以很難準確地說出這一點。我認為您可以從 FDA 的 PDUFA 時間表中了解 Trevyent 的情況。RemUnity，FDA備案其實不是United Therapeutics做的，是我們幫浦合作夥伴DEKA做的；正如我在開場白中提到的，ISR 也是美敦力 (Medtronic) 的產品。

So I wouldn't want to really fine tune it so much as to like line them up as 1, 2, 3 or 2, 3, 1, but we do feel quite confident that all 3 will launch in the next 12 months.

因此，我不想對其進行太多微調，而是將它們排列為 1、2、3 或 2、3、1，但我們確實非常有信心所有 3 個都將在未來 12 個月內推出。

Our next question is from Martin Auster from Crédit Suisse.

我們的下一個問題來自瑞士信貸銀行的馬丁·奧斯特。

On Remodulin, Martine, I'm curious, in the early days of generics, if you're seeing any sources of pressure at all, specific to kind of either Medicaid or Medicare or in commercial, if there is relatively any one area that you're seeing more pressure, more vulnerably for the franchise? And then also the ex-U. S. Remodulin sales, I noticed those were up pretty sharply from 2018 to 2019 year-to-date. Just curious if there was any color you guys can provide around that?

關於 Remodulin，Martine，我很好奇，在仿製藥的早期，您是否看到任何壓力來源，具體到醫療補助或醫療保險或商業方面，是否有相對任何一個領域您球隊是否面臨更大的壓力、更脆弱的局面？然後還有前美國。S. Remodulin 的銷售額，我注意到從 2018 年到 2019 年迄今為止，銷售額大幅成長。只是好奇你們是否可以提供任何顏色？

Sure, Marty. Nice to hear your voice this morning. I'm going to sort those questions, the first one to Mike as he has overall authority -- both questions to Mike, sorry, I'm going to sort both questions to Mike, as he's got overall authority on all commercialization matters at UT.

當然，馬蒂。很高興今天早上聽到你的聲音。我將對這些問題進行排序，第一個問題交給麥克，因為他擁有全面的權力——這兩個問題都交給麥克，抱歉，我將把這兩個問題交給麥克，因為他對UT的所有商業化事務擁有全面的權力。

Yes. Thanks, Martine. So, Marty, we're now with -- I guess 2 full quarters in and facing competition and really have not seen a material impact to Remodulin business. For the second quarter in a row, we've achieved a record number of Remodulin patients on therapy. I think I mentioned in Q2 that we saw the highest number of new patients starts in almost 10 years. And Q3, we didn't quite hit that number, we came just by -- came a few prescriptions short.

是的。謝謝，馬丁娜。所以，馬蒂，我們現在——我想已經有兩個完整季度了，面臨著競爭，而且確實沒有看到對 Remodulin 業務的實質影響。連續第二個季度，我們接受 Remodulin 治療的患者數量創下了紀錄。我想我在第二季度提到過，我們看到新患者數量達到了近 10 年來的最高水平。第三季度，我們並沒有完全達到這個數字，我們只是勉強達到了——缺少一些處方。

So we're really pleased with how things have evolved in the face of generic competition.

因此，我們對面對仿製藥競爭時的發展感到非常滿意。

We really have not seen any clear pressure of note. I mean there is -- there are one-off payers, I think, that these -- what they call dual-eligible Medicare-Medicaid patients, where we're seeing a little of pressure, but it's such a small part of the business that it's really not material in the grand scheme of things. And beyond that, there's really just, at this point no pressure -- no payer pressure of note. So that's actually, I think, where things sit with respect to the first question.

我們確實沒有看到任何明顯的壓力。我的意思是，我認為，有一些一次性付款人，他們稱之為具有雙重資格的醫療保險-醫療補助患者，我們在這些患者中看到了一點壓力，但這只是業務的一小部分從宏偉的計劃來看，這其實並不重要。除此之外，目前確實沒有任何壓力——沒有值得注意的付款人壓力。我認為這實際上就是第一個問題的情況。

Second question, on the international business, we have -- similar to the U.S., we actually have seen nice uptick in demand, patient demand, prescriber demand for Remodulin outside the U.S. The other thing that's happened I think is the change in our relationship with Ferrer that happened over the last 12 to 18 months or so. So they've taken on more responsibility for labeling and packaging of our product. As a result of that, their orders are up because it takes them more time to go through that process. In the past, we were doing the labeling and the packaging and sending it to them. And so their orders were up relative to what they've been in the past because they need more time to get through our labeling and packaging process.

第二個問題，關於國際業務，與美國類似，我們實際上看到了美國以外地區對瑞莫杜林的需求、患者需求、處方者需求的大幅增長。我認為發生的另一件事是我們與美國的關係發生了變化。費雷爾的經歷是在過去 12 到 18 個月左右的時間裡發生的。因此，他們對我們產品的標籤和包裝承擔了更多責任。結果，他們的訂單增加了，因為他們需要更多的時間來完成這個過程。過去，我們負責貼標籤和包裝並將其發送給他們。因此，他們的訂單相對於過去有所增加，因為他們需要更多時間來完成我們的標籤和包裝流程。

Great. Thanks, Mike. Thank you so much.

偉大的。謝謝，麥克。太感謝了。

Our next question comes from Liana Moussatos from Wedbush Securities.

我們的下一個問題來自 Wedbush Securities 的 Liana Moussatos。

What would be clinically meaningful for overall survival in DISTINCT and for the 6-minute walk distance in INCREASE? And in INCREASE, why did you use 6-minute walk distance for a primary endpoint instead of morbidity, mortality?

對於 DISTINCT 中的總存活率和 INCREASE 的 6 分鐘步行距離有什麼臨床意義？在 INCREASE 中，為什麼使用 6 分鐘步行距離而不是發病率、死亡率作為主要終點？

Yes. Thank you, Liana. Nice to hear your voice this morning. With regard to DISTINCT, I'm actually not really qualified to answer that question. It's the -- our oncology programs run by the Dr. Golden, who's not on the conference call this morning. So I'm going to punt on the detailed answer to that question other than to say, it is a survival endpoint study.

是的。謝謝你，莉安娜。很高興今天早上聽到你的聲音。關於DISTINCT，我其實不太有資格回答這個問題。這是我們的腫瘤學項目，由戈爾登博士負責，他今天早上沒有參加電話會議。因此，我將押注於該問題的詳細答案，而不是說這是一項生存終點研究。

So we are currently, within a handful of patients from having the survival endpoint and then we needed to unblind and see the difference between the non-dinutuximab-treated and the dinutuximab-treated group. All of those patients have, of course, had their conventional therapy treatment for their cancers.

因此，目前我們只有少數患者能夠達到存活終點，然後我們需要揭盲並觀察非 dinutuximab 治療組和 dinutuximab 治療組之間的差異。當然，所有這些患者都接受了針對癌症的常規治療。

But beyond just mere survival, I'm just not up to speed on maybe next level of details below that.

但除了生存之外，我還不太了解下面的下一個細節。

With regard to the 6-minute-walk endpoint for INCREASE, the reason for that is, I would say twofold. First of all, 6-minute-walk has long been the gold standard for measurement of whether or not somebody has obtained an improvement in their clinical status with pulmonary hypertension.

關於 INCREASE 的 6 分鐘步行終點，我認為有雙重原因。首先，步行6分鐘長期以來一直是衡量肺動脈高壓臨床狀況是否有改善的黃金標準。

For those of us who are around pulmonary hypertension patients a lot, you hear all the time that their inability to do simple matters of exercise is the bellwether sign of a decline in their health status, whether it's like not being able to walk around Walmart or not being able to walk even to the mailbox and then not being able to walk up their stairs. So 6-minute-walk is definitely a good FDA multiple-time-left endpoint for pulmonary hypertension.

對於我們這些經常接觸肺動脈高壓患者的人來說，您總是會聽到他們無法進行簡單的運動是他們健康狀況下降的先兆，無論是像無法在沃爾瑪周圍散步還是無法在超市裡散步一樣。甚至無法走到信箱，然後無法走上樓梯。所以6分鐘步行絕對是FDA多次左肺動脈高壓的一個很好的終點。

Secondly, because there are no other treatments available for the patients with interstitial lung disease and pulmonary fibrosis, there was no need to have a mortality or morbidity or combined mortality-morbidity endpoint as there is in Group 1 pulmonary hypertension, where there's upwards of a dozen different approved therapies and one wants to have the high mark in terms of -- the highest possible mark in terms of your data, which is what we were able to achieve with FREEDOM-EV.

其次，由於間質性肺病和肺纖維化患者沒有其他治療方法，因此不需要像第1 組肺動脈高壓那樣有死亡率或發病率或死亡-發病率聯合終點，其中第1 組肺動脈高壓的發生率高於第1 組。十幾種不同的已獲批准的療法，人們希望在數據方面獲得高分——盡可能高的分數，這就是我們透過 FREEDOM-EV 能夠實現的目標。

So it's kind of a -- it's really 2 completely different markets. There is -- we've done a lot of research on this. There's very, very few patients with -- in the Group 3 who are treated with any of the drugs approved for Group 1 for the reasons that I said before. It's just not something that has been proven to work. In fact, it's something, if you're treating the patients in Group 3 with a systemic drug, like a parenteral drug or a oral drug, it's actually contraindicated in most people's points of view due to the occurrence of perfusion-ventilation mismatch. So it's something that can only be treated with an inhaled drug. And now you come down to just 2 inhaled drugs, iloprost and Tyvaso. And as good as United Therapeutics is at helping patients get reimbursement for their drugs, the payers say, this drug has not been approved for Group 3. And we're not going to pay for it.

所以這其實是兩個完全不同的市場。我們對此做了很多研究。由於我之前說過的原因，第 3 組中很少有患者接受任何核准用於第 1 組的藥物治療。這只是尚未被證明有效的東西。事實上，如果你用全身性藥物治療第3組的患者，例如注射藥物或口服藥物，在大多數人看來實際上是禁忌的，因為會發生灌注-通氣不匹配。因此，這種情況只能透過吸入藥物來治療。現在只剩下兩種吸入藥物：伊洛前列腺素和泰瓦索。付款人表示，儘管 United Therapeutics 在幫助患者獲得藥物報銷方面表現出色，但該藥物尚未獲得第 3 類藥物的批准。而且我們不會為此付費。

So unfortunately, many, many patients in this category, today, have a foreshortened lives and foreshortened qualities of life due to the absence of any drug, at all, approved for the treatment of their condition. So as the first one, it's no real sense to like leap further than you have to go, and jump higher than you have to go. Getting Tyvaso approved for this population will be huge. And as I mentioned, there will be a tenfold increase in our addressable market population for Tyvaso.

不幸的是，如今，由於根本沒有任何藥物被批准用於治療他們的病情，許多許多此類患者的生命和生活品質都被縮短了。因此，作為第一個，喜歡跳得比你必須走的更遠、跳得比你必須走的更高是沒有意義的。讓泰瓦索獲批用於這一人群將是一件巨大的事情。正如我所提到的，Tyvaso 的目標市場人口將增加十倍。

So we want to do that as quickly as possible, with as lowest risk as possible and the 6-minute-walk distance was kind of the most logical way to achieve that.

因此，我們希望以盡可能低的風險盡快做到這一點，而 6 分鐘步行距離是實現這一目標的最合理的方式。

Thanks, Liana.

謝謝，莉安娜。

Our next question comes from Hartaj Singh from Oppenheimer & Co.

我們的下一個問題來自 Oppenheimer & Co. 的 Hartaj Singh。

Martine, I just wanted to ask you a little bit about Orenitram. I know that's on the commercial side. So maybe, Mike, you had indicated that now would be a -- the label expansion, you'll be able to get 2, 3x more patients. Can you just talk a little bit about what kind of patients would these be? More of the new patients, would be able to get some of the prevalent patients? Are there may be some patients that might not have qualified before Orenitram that can get on that? Or on Orenitram now? I would really appreciate it. And by the way, congratulations on not having that generics apocalypse that supposedly is going happen.

馬丁，我只是想問你一些關於 Orenitram 的事情。我知道這是商業方面的。麥克，您可能已經表示，現在將進行標籤擴展，您將能夠獲得 2、3 倍以上的患者。能簡單談談這些患者是什麼樣的嗎？更多的新患者，是否能夠得到一些流行患者？是否有些病人可能不符合奧瑞尼曲治療的資格，可以繼續使用奧瑞尼曲？或現在服用奧瑞尼曲（Orenitram）？我真的很感激。順便說一句，恭喜你沒有發生所謂的仿製藥災難。

Thank you so much, Hartaj. Great hearing your voice this morning. Yes, we really -- we feel the love on that one so thank you so much. I'm going to bounce the Orenitram growth trajectory question over to Mike.

非常感謝你，哈塔傑。今天早上聽到你的聲音真好。是的，我們真的 - 我們感受到了對那個人的愛，所以非常感謝你。我將把 Orenitram 成長軌跡問題轉給 Mike。

Yes. Thanks, Hartaj. So I think, Martine mentioned, I think, in his opening comments that this is really sort of the first true launch. This is really a true launch of Orenitram. And I think that's accurate and that's certainly how we're thinking about it. And if I think about the challenges that we've had in the marketplace with Orenitram prior to the EV label, it's -- I would say, the #1 challenge is doctors who are really trying to figure out where -- what's the right patient to use Orenitram.

是的。謝謝，哈塔傑。所以我認為，馬丁在他的開場白中提到，這確實是第一次真正的發布。這確實是 Orenitram 的真正推出。我認為這是準確的，這也是我們的想法。如果我考慮一下在 EV 標籤之前我們在 Orenitram 市場上遇到的挑戰，我會說，第一大挑戰是醫生真正試圖弄清楚什麼是合適的患者使用奧瑞尼曲姆。

And I think the nice thing about the EV study is it answered that question definitively. It's those early-stage patients, it's your functional Class 2 patients that are starting to be symptomatic and where you're going to have time to start them on a low dose, titrate them up slowly, help them manage their side effects and get to a therapeutic dose in a sort of a 4- to 6-month timeframe.

我認為電動車研究的好處在於它明確地回答了這個問題。正是那些早期患者，即開始出現症狀的功能性 2 級患者，您將有時間開始給他們低劑量，慢慢滴定，幫助他們控制副作用並達到治療目的。在4 至6 個月的時間內服用治療劑量。

And then at that point, they sort of cross the -- they've crossed the side effects hurdle, so to speak. They're starting to see the benefit of the drug and then the doctors can titrate up accordingly, based on how their disease is progressing. And so I think in terms of the patient type, that's really, I think, the sort of the #1 thing that we've been able to answer with respect to the EV study.

然後到那時，他們就跨過了——可以這麼說，他們已經跨過了副作用的障礙。他們開始看到藥物的好處，然後醫生可以根據他們的疾病進展相應地調整劑量。因此，我認為就患者類型而言，我認為這確實是我們在 EV 研究中能夠回答的第一件事。

And then part and parcel of that, as I mentioned is, we're -- the other issue has always been sort of the tolerability and upside effect. And so I think by starting the right patient, giving them time to titrate up, we're really solving 2 problems with the drug. And so I think because of that, we now have doctors understanding that "okay, now I understand where to use the drug, now I understand how to use the drug." It will take a little bit of time because doctors that have historically believed in the drug, and this really confirmed their belief in the drug and how they're using it, and hopefully, we'll see them put more patients on therapy.

正如我所提到的，其中的一部分是，我們 - 另一個問題始終是耐受性和上行效應。因此，我認為透過開始選擇合適的患者，給他們時間進行滴定，我們確實解決了該藥物的兩個問題。所以我認為正因為如此，我們現在讓醫生明白“好吧，現在我知道在哪裡使用該藥物，現在我知道如何使用該藥物。”這需要一點時間，因為歷史上一直相信這種藥物的醫生，這確實證實了他們對這種藥物的信念以及他們如何使用它，希望我們會看到他們讓更多的患者接受治療。

Doctors that had maybe a poor experience with Orenitram in past, we know, are taking a look. I mean, I was at CHEST last week and talking to several doctors that have said either they have already taken another look at Orenitram based on the EV data or certainly are planning to. So I think, generally, they're impressed with the data, and it's bringing those doctors back to take a second look at the drug. I think the other place that we're going to use -- we're going to see this use, and we have seen this use, are patients that have been on Remodulin for some period of time, have started to stabilize and actually improve in functional class and the patients want to get off the pump. And so we have data from several years ago that talks about how patients can successfully transition from Remodulin to Orenitram. And they have done well over the long term, and we're looking at some other ways -- other studies that would further reinforce that. And so for patients that maybe aren't in that Functional Class -- Functional Class II category or maybe more Functional Class III, and they are sort of tweeners between, I'd say, do you start them on Orenitram, do you start them on Remodulin and maybe Tyvaso is not the right answer for them. You could potentially start them on Orenitram for, say, 30 to -- sorry, start them on Remodulin for 30 to 60 days, get them up to a dose and then quickly switch them over to Orenitram.

我們知道，過去可能對奧瑞尼曲有不良經驗的醫生正在研究。我的意思是，我上週在 CHEST 與幾位醫生交談，他們說他們已經根據 EV 數據再次審視了 Orenitram，或者肯定正在計劃這樣做。所以我認為，總的來說，他們對這些數據印象深刻，這讓那些醫生重新審視該藥物。我認為我們將要使用的另一個地方 - 我們將看到這種用途，並且我們已經看到了這種用途，是那些已經服用瑞莫杜林一段時間、已經開始穩定並實際改善的患者在功能類別中，患者想要停止使用幫浦。因此，我們有幾年前的數據，講述了患者如何成功地從瑞莫杜林過渡到奧瑞尼曲。從長遠來看，他們做得很好，我們正在尋找其他一些方法——其他可以進一步強化這一點的研究。因此，對於可能不屬於功能類別的患者——功能類別 II 類別或可能更多的功能類別 III，他們是介於兩者之間的患者，我會說，你開始使用 Orenitram 嗎？瑞莫杜林（Remodulin）和泰瓦索（Tyvaso）對他們來說可能不是正確的答案。您可以開始使用 Orenitram，比如說 30 到 - 抱歉，開始使用 Remodulin 30 到 60 天，讓他們達到一定劑量，然後快速切換到 O​​renitram。

So again, I think what the EV label does, it really just kinds of open up -- really opens up the range of possibilities for where to use the drug. But I think to your original question, the main -- I think the main question to answer is, what's that early-stage patient look like that's the ideal candidate for Remodulin.

所以，我再次認為 EV 標籤的作用，它真的只是一種開放——真正開闢了在哪裡使用該藥物的可能性範圍。但我認為對於你最初的問題，主要的 - 我認為要回答的主要問題是，早期患者是什麼樣子，是瑞莫杜林的理想候選人。

Mike, thanks. That is such a great explanation. Thank you for laying all of that out.

麥克，謝謝。這是一個很好的解釋。感謝您列出所有這些。

So to wrap up here, we're very excited to have now crossed 7,500 patients on treprostinil. This has been a goal for our company for quite a while. And I really want to salute Mike and the entire commercialization, compliance, medical affairs teams that have been absolutely essential to accomplishing that goal.

總而言之，我們非常高興現在已經對 7,500 名使用曲前列環素的患者進行了檢查。這一直是我們公司長期以來的目標。我真的想向麥克和整個商業化、合規、醫療事務團隊致敬，他們對於實現這一目標至關重要。

And I think it's now -- as I hope everybody can see from the explanations given during the call very much reasonable within our sites to next lock onto the goal of 10,000 patients on treprostinil. And this could be done; one, as Mike explained, with the growth sector for Orenitram, thanks to the EV label; secondly, as I mentioned in the introductory remarks, with the 3 new transformative treprostinil parenteral delivery systems, the ISR, RemUnity and Trevyent; and then finally, with the current BREEZE trial that we have going on with TreT and the MannKind product, you combine that with, hopefully, a successful unblinding increase and opening up a very small, easy-to-act, easy to -- drug-delivery device with a tenfold larger population of Group 3. And it seems to me that 10,000 patients on treprostinil is a very readily achievable, reasonable goal for our company to set out for ourselves, and we have done that.

我認為現在 - 正如我希望每個人都能從電話會議期間給出的解釋中看到的那樣，我們網站內的下一步鎖定 10,000 名患者服用曲前列環素的目標非常合理。這是可以做到的；一是，正如麥克所解釋的，Orenitram 的成長部門得益於電動車標籤；其次，如我在介紹性發言中所提到的，3種新的變革性曲前列環素腸外給藥系統：ISR、RemUnity和Trevyent；最後，透過目前我們正在進行的 TreT 和 MannKind 產品的 BREEZE 試驗，您可以將其與成功的非盲性增加結合起來，並開發一種非常小、易於操作、易於使用的藥物-第3 組人口數量增加十倍的輸送裝置。在我看來，10,000 名接受曲前列環素治療的患者是我們公司為自己設定的一個非常容易實現、合理的目標，而且我們已經做到了。

So thanks so much for joining us this morning. And we look forward to seeing many of you certainly at J.P. Morgan in just a couple of months to come. Operator, you can wrap up the call.

非常感謝您今天早上加入我們。我們期待在接下來的幾個月內在摩根大通見到你們中的許多人。接線員，您可以結束通話了。

Thank you. Thank you for participating in today's United Therapeutics Corporation Conference Call. A rebroadcast will be available for replay for one week by dialing 1 (855) 859-2056, with international callers dialing in at 1 (404) 537-3406, using the access code 7462119. Thank you.

謝謝。感謝您參加今天的聯合治療公司電話會議。撥打 1 (855) 859-2056 即可重播一周，國際來電者可使用接入碼 7462119 撥打 1 (404) 537-3406。謝謝。