福泰製藥 (VRTX) 2019 Q1 法說會逐字稿

Welcome. This is Michael Partridge, Senior Vice President of Investor Relations. Tonight, we will review with you Vertex's business progress and provide our first quarter financial results.

歡迎。這是投資者關係高級副總裁邁克爾·帕特里奇。今晚，我們將與大家一起回顧Vertex的業務進展，並提供我們第一季的財務表現。

Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer; and I would like to welcome to the call Charlie Wagner, Vertex's new Chief Financial Officer. Dr. Reshma Kewalramani, Chief Medical Officer; and Paul Silva, our Corporate Controller and Chief Accounting Officer, will join us for Q&A.

今晚在電話會議上發表準備好的演講的有：董事長兼首席執行官傑夫·萊頓博士；首席商務官斯圖爾特·阿巴克爾；我還要歡迎Vertex新任首席財務官查理·瓦格納參加電話會議。首席醫療官雷什瑪·凱瓦拉馬尼博士和公司財務總監兼首席會計官保羅·席爾瓦將參加問答環節。

We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded, and a replay will be on our website.

我們建議您在收聽本次電話會議的同時，請造訪我們網站上的網路直播投影片。本次電話會議正在錄音，稍後將在我們的網站上提供回放。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, the ongoing development and potential commercialization of our triple combination regimens for cystic fibrosis, Vertex's other programs and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受到今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於有關 Vertex 已上市的 CF 藥物、我們用於治療囊性纖維化的三聯療法的持續開發和潛在商業化、Vertex 的其他項目以及 Vertex 未來的財務業績的聲明，均基於管理層目前的假設。實際結果和事件可能與此有重大差異。

I will now turn the call over to Dr. Jeff Leiden.

現在我將把電話交給傑夫·萊頓博士。

Thanks, Michael. Good evening, everyone. During the last several years, Vertex has continued to pursue its strategy of investing in scientific innovation to create transformative medicines for serious diseases and then bringing these medicines to more patients around the world to drive significant revenue and operating income growth. In 2019, our success in executing against this strategy can be measured by the many important clinical, regulatory and commercial milestones that we expect to achieve this year in both CF and in our non-CF pipeline.

謝謝你，麥可。各位晚上好。在過去的幾年裡，Vertex 一直堅持其策略，即投資科學創新，為嚴重疾病創造變革性藥物，然後將這些藥物帶給世界各地更多的患者，從而推動收入和營業利潤的顯著增長。2019 年，我們執行這項策略的成功程度可以透過我們預計今年在 CF 和非 CF 產品線中實現的許多重要的臨床、監管和商業里程碑來衡量。

As we look forward to the next several years, we are more confident than ever that the continued execution of this strategy will allow us to create more new medicines that change patients' lives and in so doing deliver outstanding value to our shareholders.

展望未來幾年，我們比以往任何時候都更加確信，繼續執行這項策略將使我們能夠創造出更多改變患者生活的新藥，從而為我們的股東帶來卓越的價值。

In CF, we're bringing our approved medicines to more patients globally through recent label expansions for KALYDECO and ORKAMBI and the approval and successful launch of SYMDEKO.

在 CF 領域，我們透過 KALYDECO 和 ORKAMBI 近期擴大適應症範圍以及 SYMDEKO 的核准和成功上市，將我們已獲批准的藥物帶給全球更多患者。

Approximately half of all people with CF are today eligible for a Vertex CF medicine. Our goal in CF is to develop medicines for all people with this disease, and we've made significant progress toward that goal with our triple combination regimens that we believe could treat up to 90% of all people with CF in the future, providing many patients with the first medicine to treat the underlying cause of their disease and also providing enhanced benefit for the vast majority of patients currently eligible for our 3 approved medicines.

目前，大約一半的囊性纖維化患者符合使用 Vertex CF 藥物的條件。我們在囊性纖維化領域的目標是為所有患有這種疾病的人開發藥物，我們透過三聯療法朝著這個目標取得了重大進展，我們相信該療法未來可以治療高達 90% 的囊性纖維化患者，為許多患者提供治療其疾病根本原因的第一種藥物，並為目前符合我們 3 種已獲批准藥物條件的絕大多數患者帶來更大的益處。

With both of our triple combination regimens, we have now reported Phase III data that showed potentially transformative clinical benefit for CF patients with 2 F508del mutations as well as for those with 1 F508del mutation and 1 minimal function mutation.

我們目前已報告了我們兩種三聯療法的 III 期數據，這些數據表明，對於攜帶 2 個 F508del 突變的 CF 患者以及攜帶 1 個 F508del 突變和 1 個最小功能突變的 CF 患者，這些療法可能帶來變革性的臨床益處。

In the second quarter, we expect to obtain the final 24-week data from our Phase III triple combination programs, which will allow us to choose the best regimen to submit for regulatory approvals globally.

在第二季度，我們預計將獲得 III 期三聯療法計畫的最終 24 週數據，這將使我們能夠選擇最佳方案，並提交全球監管部門批准。

We remain on track to submit an NDA in the U.S. in the third quarter followed by an MAA in Europe later this year. We look forward to updating you on our plans and to sharing additional data for our chosen triple combination regimen later this quarter.

我們仍按計畫於第三季在美國提交新藥申請，隨後於今年稍晚在歐洲提交上市許可申請。我們期待在本季稍後向您匯報我們的計劃，並分享我們選擇的三聯療法的更多數據。

I want to also highlight our recent progress outside the CF, where we are advancing potentially transformative medicines for pain, alpha-1 antitrypsin deficiency, sickle cell disease, beta-thalassemia, focal segmental glomerulosclerosis and other serious diseases. Our discovery efforts are focused on validated targets in diseases in which we have a deep understanding of the underlying biology and genetics.

我還想重點介紹我們在囊性纖維化以外的最新進展，我們正在推進治療疼痛、α-1抗胰蛋白酶缺乏症、鐮狀細胞病、β-地中海貧血、局部節段性腎小球硬化症和其他嚴重疾病的潛在變革性藥物。我們的研發工作主要集中在已驗證的疾病標靶上，我們對這些疾病的潛在生物學和遺傳學機制有著深刻的理解。

By using early clinical markers to predict the potential for these medicines to have transformative benefit, we believe we will significantly increase our probability of success in early proof-of-concept trials, enabling rapid development time lines.

透過使用早期臨床標記來預測這些藥物具有變革性益處的潛力，我們相信我們將大大提高早期概念驗證試驗的成功機率，從而加快開發進程。

In our AAT program, we initiated clinical development of our first small molecule corrector, VX-814, in late 2018 and are now moving this molecule through Phase I development. Today, we announced that we have received Fast Track Designation from the FDA for this molecule.

在我們的 AAT 計畫中，我們於 2018 年底啟動了第一個小分子矯正劑 VX-814 的臨床開發，目前正在推進該分子進入 I 期開發階段。今天，我們宣布該分子已獲得美國食品藥物管理局 (FDA) 的快速通道資格認定。

We're also advancing other small molecule correctors of AAT through late preclinical development and expect to begin clinical development of a second small molecule AAT corrector in 2019.

我們也正在推動其他 AAT 小分子矯正劑的後期臨床前開發，並預計將於 2019 年開始第二個 AAT 小分子矯正劑的臨床開發。

In pain, we've established proof-of-concept for NaV1.8 inhibition across multiple Phase II studies of VX-150 in acute, neuropathic and musculoskeletal pain conditions. Data from these studies together with data from a Phase II dose-ranging study of VX-150 will inform our potential development paths in pain.

在疼痛治療方面，我們已經透過 VX-150 在急性疼痛、神經性疼痛和肌肉骨骼疼痛等多種 II 期研究中的 NaV1.8 抑製作用，建立了概念驗證。這些研究的數據以及 VX-150 II 期劑量範圍研究的數據將為我們在疼痛治療領域的潛在發展路徑提供資訊。

In addition to our lead molecule VX-150, we have the portfolio of multiple additional NaV1.8 inhibitors in late preclinical development and expect to advance the first of these molecules into the clinic in 2019.

除了我們的主導分子 VX-150 之外，我們還有多個處於臨床前開發後期階段的 NaV1.8 抑制劑產品組合，並預計在 2019 年將其中第一個分子推進到臨床階段。

In sickle cell disease and beta-thalassemia, we are making rapid progress with our partner, CRISPR Therapeutics, on the development of the gene editing therapy, CTX001. Earlier this year, the first patient with beta-thalassemia was infused with CTX001, marking a significant scientific milestone for the field of gene editing and also a remarkable milestone for our collaboration with CRISPR. We remain on track to dose the first patient with sickle cell disease with CTX001 in the middle of the year.

在鐮狀細胞疾病和β地中海貧血方面，我們與合作夥伴CRISPR Therapeutics在基因編輯療法CTX001的開發方面取得了快速進展。今年早些時候，首例β-地中海貧血患者接受了CTX001輸注，這標誌著基因編輯領域的重要科學里程碑，也是我們與CRISPR合作的顯著里程碑。我們仍按計畫在年中為第一位鐮狀細胞疾病患者使用 CTX001 進行治療。

In addition to our internal R&D efforts, we are focused on gaining access to new technologies, platforms and development assets through external partnerships that fit our strategy of developing transformative medicines for serious specialty diseases. Toward that end, we have entered into multiple collaborations over recent months, including those with Arbor Biotechnologies, Merck KGaA, Genomics plc and X-Chem, which together provide us with access to a broad range of new scientific capabilities. And with our growing free cash flow, we have increased flexibility to enter into additional collaborations to further bolster our pipeline and provide access to new technologies.

除了內部研發工作外，我們還致力於透過外部合作獲取新技術、平台和開發資產，以符合我們為嚴重專科疾病開發變革性藥物的策略。為此，近幾個月來，我們與多家公司開展了合作，包括 Arbor Biotechnologies、Merck KGaA、Genomics plc 和 X-Chem，這些合作使我們能夠獲得廣泛的新科學能力。隨著自由現金流的成長，我們擁有更大的靈活性，可以進行更多合作，進一步加強我們的產品線，並獲得新技術。

Before I close, I'd like to welcome Charlie Wagner to Vertex as our new Chief Financial Officer. Charlie joins us from Ortho-Clinical Diagnostics, where he served as CFO and Executive Vice President of Finance. Charlie has served as CFO for public and private companies for more than 10 years, including roles as CFO for Bruker, Progress Software and Millipore. Charlie brings to Vertex significant financial and operational expertise that will help guide us over the coming years as our business becomes more complex through continued global expansion, the treatment of many more patients and the future launches of new medicines.

在結束演講之前，我想歡迎查理·瓦格納加入 Vertex，擔任我們的新財務長。Charlie 先前在 Ortho-Clinical Diagnostics 擔任財務長兼財務執行副總裁。Charlie 曾擔任上市公司和私人公司的財務長超過 10 年，其中包括 Bruker、Progress Software 和 Millipore 的財務長。Charlie 為 Vertex 帶來了重要的財務和營運專業知識，這將有助於指導我們在未來幾年應對業務日益複雜的挑戰，包括持續的全球擴張、治療更多患者以及未來推出新藥。

In welcoming Charlie, I'd also like to thank Paul Silva for his leadership over the last 3 months as our Interim CFO. Paul will continue to play an integral role within the finance organization just as he has since joining the company in 2007.

在歡迎查理加入的同時，我也要感謝保羅·席爾瓦在過去三個月裡擔任我們的臨時財務長期間的領導。保羅將繼續在財務部門發揮不可或缺的作用，就像他自 2007 年加入公司以來一直發揮的作用一樣。

I'll now turn the call over to Stuart to review our commercial progress.

現在我將把電話交給斯圖爾特，讓他回顧一下我們的商業進展。

Thanks, Jeff. Tonight, I'll review our commercial performance for the first quarter driven by the strong underlying demand for our medicines in the U.S. and internationally.

謝謝你，傑夫。今晚，我將回顧我們第一季的商業業績，這主要得益於美國和國際市場對我們藥品的強勁潛在需求。

In the first quarter, we continued to increase the number of patients being treated with our CF medicines globally, resulting in product revenues of $857 million. Compared to the fourth quarter of 2018, our first quarter 2019 revenues were negatively impacted by channel inventory build that occurred at the end of 2018 and by higher gross to net adjustments that we typically experienced early in the year as we highlighted on our call in January.

第一季度，我們持續增加全球使用 CF 藥物治療的患者人數，產品收入達到 8.57 億美元。與 2018 年第四季相比，我們 2019 年第一季的營收受到了 2018 年底通路庫存增加以及年初通常出現的毛利淨利調整增加的負面影響，正如我們在 1 月的電話會議上強調的那樣。

The first quarter included $320 million of SYMDEKO revenues, including $32 million of SYMKEVI revenues from outside the U.S., primarily from Germany.

第一季 SYMDEKO 的收入為 3.2 億美元，其中 SYMKEVI 在美國以外的收入為 3,200 萬美元，主要來自德國。

SYMKEVI launch in Germany is off to a strong start, with demand coming from patients who never initiated treatment with ORKAMBI as well as patients who discontinued or have switched from ORKAMBI. Throughout 2019, we anticipate additional patients will initiate treatment with SYMDEKO in the U.S. and EU, including younger patients, ages 6 to 11 in the U.S., following potential FDA approval later this year.

SYMKEVI 在德國的上市取得了強勁的開局，需求來自從未接受過 ORKAMBI 治療的患者，以及停止使用 ORKAMBI 或已從 ORKAMBI 轉用 SYMKEVI 的患者。預計在 2019 年全年，隨著 FDA 可能在今年稍後批准 SYMDEKO，美國和歐盟將有更多患者開始接受 SYMDEKO 治療，其中包括美國 6 至 11 歲的年輕患者。

With KALYDECO and ORKAMBI, we continue to see new patients initiating treatment as we've secured new reimbursement agreements and received new regulatory approvals for young children around the globe.

隨著 KALYDECO 和 ORKAMBI 獲得新的報銷協議和新的監管批准，我們不斷看到新的患者開始接受治療，這些藥物適用於全球各地的幼兒。

Based on our performance in the first quarter, we remain on track to deliver total CF product revenues of $3.45 billion to $3.55 billion for the full year.

根據我們第一季的業績，我們仍有望實現全年CF產品總收入34.5億美元至35.5億美元的目標。

Outside the U.S., we continue to make progress achieving reimbursement for our CF medicines. We are focused on obtaining long-term agreements that provide access to all eligible patients. We are seeking agreements that appropriately value our scientific innovation and enable us to continue to invest in the discovery of future CF medicines and medicines for other serious diseases.

在美國以外，我們繼續努力爭取囊性纖維化藥物的報銷。我們致力於達成長期協議，以確保所有符合資格的患者都能獲得醫療服務。我們正在尋求能夠恰當評估我們的科學創新成果並使我們能夠繼續投資於未來囊性纖維化藥物和其他嚴重疾病藥物的研發的協議。

I'm pleased in the first quarter of this year, we've achieved multiple pricing agreements and reimbursement milestones. In Germany, we successfully expanded our pricing agreement for ORKAMBI prompted by the EMA approval of the product in children ages 6 to 11 years. We've seen strong demand for ORKAMBI in Germany since the medicine was approved for these younger patients in January of last year. And this recent pricing agreement is further validation of the value that ORKAMBI provides.

我很高興今年第一季我們達成了多項定價協議和報銷里程碑。在德國，由於 EMA 批准 ORKAMBI 用於 6 至 11 歲兒童，我們成功擴大了 ORKAMBI 的定價協議。自去年 1 月該藥物獲準用於年輕患者以來，我們在德國看到了對 ORKAMBI 的強勁需求。而最近達成的這項定價協議進一步驗證了 ORKAMBI 所提供的價值。

In Ireland, as part of our previously reached portfolio agreement, our medicines have now become available to children as young as 1 year old for KALYDECO, children as young as 2 years old for ORKAMBI and patients ages 12 and older for SYMKEVI, including those with a residual function mutation.

在愛爾蘭，作為我們先前達成的投資組合協議的一部分，我們的藥物現在已經可以用於 1 歲及以上的兒童（KALYDECO）、2 歲及以上的兒童（ORKAMBI）以及 12 歲及以上的患者（SYMKEVI），包括那些有殘餘功能突變的患者。

We've also reached multiple new reimbursement agreements in smaller countries like Israel and Sweden, reflecting our commitment to bringing our CF medicines to all eligible patients around the world. And in Australia, we recently received a positive recommendation for SYMDEKO from the Pharmaceutical Benefits Advisory Committee, an important first step toward formal reimbursement in patients ages 12 and older.

我們也與以色列和瑞典等較小國家達成了多項新的報銷協議，這體現了我們致力於將我們的囊性纖維化藥物帶給世界各地所有符合條件的患者的承諾。在澳大利亞，我們最近收到了藥品福利諮詢委員會對 SYMDEKO 的積極推薦，這是 12 歲及以上患者獲得正式報銷的重要第一步。

The positive recommendation of SYMDEKO comes as a result of our prior agreement in Australia for ORKAMBI, where we also defined a pathway for rapid access to SYMDEKO.

SYMDEKO 的積極建議源於我們先前在澳洲就 ORKAMBI 達成的協議，當時我們也為快速獲得 SYMDEKO 制定了途徑。

In summary, I'm pleased that we are bringing our medicines to more patients around the globe and with the resulting strong revenue performance in the first quarter of the year.

總而言之，我很高興我們的藥品能夠惠及全球更多患者，並且在今年第一季取得了強勁的營收業績。

With that, I will now turn the call over to Charlie to further review our financial results.

接下來，我將把電話交給查理，讓他進一步分析我們的財務表現。

Thanks, Stuart, and good evening, everyone. I'm excited to join Vertex at such an important time in the company's growth, and I look forward to meeting many of you in the coming months.

謝謝你，斯圖爾特，大家晚上好。我很高興能在Vertex公司發展如此重要的時期加入，並期待在接下來的幾個月與大家見面。

In addition to Stuart's comments on the performance of our CF products, tonight, I'll review our first quarter financial results and our 2019 financial guidance. All of the results and guidance I will discuss are non-GAAP.

除了 Stuart 對我們 CF 產品表現的評論之外，今晚我還會回顧我們第一季的財務表現和 2019 年的財務預期。我將要討論的所有結果和指導意見均不符合公認會計準則。

2019 is off to a strong start. Product revenues of $857 million represent an increase of 34% compared to the first quarter of 2018. This increase was driven primarily by the launch of SYMDEKO in the U.S. in 2018 and the recent launch of SYMKEVI in Germany.

2019年開局強勁。產品收入為 8.57 億美元，比 2018 年第一季成長了 34%。這一增長主要得益於 2018 年 SYMDEKO 在美國的推出以及最近 SYMKEVI 在德國的推出。

Our first quarter 2019 combined R&D and SG&A expenses were $388 million compared to $360 million in the first quarter of 2018. This increase was primarily due to the incremental investment to support the global use of Vertex's medicines and the expansion of Vertex's pipeline in CF and other new disease areas.

2019 年第一季度，我們的研發與銷售、管理及行政費用合計為 3.88 億美元，而 2018 年第一季為 3.6 億美元。這一增長主要是由於為支持 Vertex 的藥物在全球範圍內的使用而進行的增量投資，以及 Vertex 在囊性纖維化和其他新疾病領域的研發管線的擴展。

A significant growth in revenues and disciplined spending in the first quarter resulted in operating income of $377 million, an 81% increase compared to the first quarter of 2018.

第一季營收大幅成長，加上支出控制得當，營業收入達到 3.77 億美元，比 2018 年第一季成長了 81%。

Net income for the first quarter of 2019 was $296 million compared to $196 million in the first quarter of 2018.

2019 年第一季淨收入為 2.96 億美元，而 2018 年第一季淨收入為 1.96 億美元。

We also continue to strengthen our balance sheet, ending the first quarter with approximately $3.48 billion in cash and marketable securities compared to $3.17 billion at the end of 2018. We expect to continue to generate significant cash flow throughout 2019 and beyond as more patients are treated with our medicines, which will enable us to continue our significant investment in internal R&D and in external innovation through business development activities.

我們也持續加強資產負債表，截至第一季末，我們的現金和有價證券約為 34.8 億美元，而 2018 年底為 31.7 億美元。我們預計，隨著越來越多的患者接受我們的藥物治療，我們將在 2019 年及以後繼續產生可觀的現金流，這將使我們能夠繼續對內部研發和透過業務發展活動進行外部創新進行大量投資。

Now on to our 2019 guidance. Today, we are reiterating our financial guidance for total product revenues, combined R&D and SG&A expenses and our non-GAAP anticipated effective tax rate. As Stuart mentioned, we continue to expect total CF product revenues in the range of $3.45 billion to $3.55 billion. Our revenue guidance reflects anticipated revenues from countries where our medicines are currently reimbursed. Achieving additional significant reimbursement agreements in 2019 may provide upside to our revenues, and we would update our guidance as appropriate at that time.

接下來是我們的2019年指導方針。今天，我們重申我們對產品總收入、研發和銷售、管理及行政費用以及非GAAP預期有效稅率的財務預期。正如史都華所提到的，我們仍然預計 CF 產品總收入將在 34.5 億美元至 35.5 億美元之間。我們的收入預期反映了我們藥品目前已納入醫保報銷範圍的國家的預期收入。2019 年達成更多重要的報銷協議可能會增加我們的收入，屆時我們將視情況更新我們的業績預期。

We also continue to expect combined R&D and SG&A expenses of $1.65 billion to $1.7 billion. The key investment drivers are ongoing CF development efforts supporting the potential launch of a triple combination regimen and expanding our pipeline into additional diseases.

我們也繼續預期研發和銷售、管理及行政費用合計為 16.5 億美元至 17 億美元。主要投資驅動因素是持續的囊性纖維化研發工作，旨在支持三聯療法的潛在推出，並將我們的產品線擴展到其他疾病領域。

Our full year 2019 non-GAAP tax rate guidance of 21% to 22% is also unchanged. The vast majority of our tax provision will be a noncash expense until we fully use our net operating losses.

我們對 2019 年全年非 GAAP 稅率的預期仍為 21% 至 22%，維持不變。在我們完全利用淨營業虧損之前，我們的大部分稅收準備金將以非現金支出的形式存在。

The financial profile of our business is strong and getting stronger. We continue to execute across all aspects of our business, enabling significant revenue and operating income growth, advancement of our pipeline and investment in external innovation. I look forward to updating you on our progress going forward.

我們公司的財務狀況穩健，而且還在持續增強中。我們繼續在業務的各個方面穩步推進，從而實現了收入和營業利潤的顯著增長，推進了產品線的研發，並加大了對外部創新的投資。我期待著向您報告我們接下來的進展。

With that, I'll turn the call back to Jeff.

這樣，我就把電話轉回給傑夫了。

Thanks, Charlie. I'm pleased that Vertex is on track to achieve the key goals we established at the start of this year and that we remain well positioned to bring our medicines to more patients, thereby driving significant continued growth in revenue and operating income in 2019 and beyond. Our strategy of creating transformative medicines through serial innovation is working and continues to drive all parts of our business. And I look forward to updating you on our progress over the coming year.

謝謝你，查理。我很高興Vertex正朝著我們今年年初制定的關鍵目標穩步前進，並且我們仍然處於有利地位，能夠將我們的藥物帶給更多的患者，從而在2019年及以後推動收入和營業利潤的持續顯著增長。我們透過連續創新創造變革性藥物的策略正在奏效，並將繼續推動我們業務的各個方面。我期待在未來一年向您報告我們的進展。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) Our first question comes from Geoff Meacham of Barclays.

（操作員說明）我們的第一個問題來自巴克萊銀行的傑夫·米查姆。

I have a commercial and a clinical one. From the commercial side, when I compare the time needed to gain full reimbursement broadly across the EU for you guys versus others in this space, it seems substantially longer for Vertex. I guess it's, obviously, pretty important, given the upcoming filing of the triple. So the question is, what do you think is the tipping point from here to change the conversation with payers across the EU? And what is the plan B? And then I'll follow up on the clinical question.

我有一個商用的和一個醫用的。從商業角度來看，當我比較你們公司在整個歐盟範圍內獲得全額報銷所需的時間與該領域其他公司所需的時間時，Vertex 的時間似乎要長得多。鑑於即將提交的三重申報文件，這顯然非常重要。所以問題是，你認為從現在開始，改變歐盟各地支付方對話的轉捩點是什麼？那麼備用方案是什麼呢？然後我會跟進這個臨床問題。

Yes. Thanks for the question, Geoff. It's Stuart here. Yes, it's certainly taken longer than we would have liked to gain reimbursement, but I would like to remind you we've got reimbursement in many, many countries around the world, including in Europe. There are certainly some countries where we don't yet have access and certainly we're not going to give up for the patients who are waiting there until we do have access. As you know, every market is different and so it's hard to generalize about the time. It's -- the time that it's taken. Certainly, I think the individual tipping point is really very hard to say market-by-market because all of those markets are very different. Certainly, I think we've seen a significant increase in patient advocacy since triple results were released because, clearly, with a medicine which has that kind of level of benefit-risk profile, clearly, there are patients who are going to want those medicines, and I find it very hard to believe that there's going to be government sitting around to deny patients access to such an important medicine that can treat the underlying cause of their disease.

是的。謝謝你的提問，傑夫。我是史都華。是的，獲得報銷確實比我們預期的要花費更長的時間，但我想提醒您，我們在世界各地許多國家，包括歐洲，都獲得了報銷。當然，目前我們還沒有能力進入某些國家，但我們絕不會放棄那些在那裡等待的患者，直到我們能夠進入這些國家。如您所知，每個市場的情況都不同，因此很難對時間進行概括。是——所花費的時間。當然，我認為很難逐個市場說出具體的臨界點，因為所有市場的情況都大不相同。當然，我認為自從三重試驗結果公佈以來，患者權益倡導活動顯著增加，因為很明顯，對於一種具有如此高獲益風險比的藥物，顯然會有患者想要獲得這些藥物，我很難相信會有政府袖手旁觀，拒絕患者獲得這種可以治療其疾病根本原因的重要藥物。

Okay. And then on the clinical side, in CF, you guys have been able to very quickly develop a whole series of compounds, next-gen correctors and pretty rapidly, and they look very effective. But I'm just curious if -- and I know you have a pipeline that's non-CF, but in other pulmonology diseases, COPD and IPF or something like that, is there a way to leverage what you have had success with in San Diego to look at the same assays and the like to come to the same kind of concept in other diseases where you have multiple shots [on goal in] a whole series of compounds?

好的。而在臨床方面，在囊性纖維化領域，你們已經能夠非常迅速地開發出一系列化合物，即下一代矯正劑，而且速度非常快，看起來非常有效。但我很好奇——我知道你們有一條非囊性纖維化的研發管線，但在其他肺部疾病，比如慢性阻塞性肺病和特發性肺纖維化之類的疾病中，是否有辦法利用你們在聖地亞哥取得的成功，研究同樣的檢測方法等等，從而在其他疾病中得出同樣的概念，從而在一系列化合物中嘗試多種方法？

Yes, Geoff, thanks for the question. This is Jeff Leiden. I'll take it in a couple of different pieces. First of all, we are really pleased with the speed at which we've been able to develop a whole portfolio of molecules in CF. Just to remind you, molecules like VX-659 and 445 were first synthesized in the laboratory less than 3 years ago. So we are not only through preclinical development, but through Phase III development 3 years in synthesis, which at least in my 30 or 40 years in the industry I haven't seen before. And we've taken a lot of learnings from that. And when I say we, I mean both David Altshuler in research and Reshma in development. The first thing is that we work on validated targets. With cell markers and biomarkers in preclinical development, they can predict clinical success, and that both increases the probability of success when we get into the clinic, but also speeds the work forward. Don't spend a lot of time in animal models. We move more rapidly into humans. And in all cases, and we'll talk about our pipeline, we have biomarkers in the clinic that predict early success with small clinical trials in CF. As you'll remember, 18- or 20-patient phase II trials pretty much tells us the answer. And as you'll see, that's true also of diseases like AAT and sickle cell and pain. And so we're certainly taking that lesson forward as well.

是的，傑夫，謝謝你的提問。這是傑夫·萊頓。我會分幾部分接收。首先，我們對在 CF 領域開發出一整套分子產品組合的速度感到非常滿意。提醒一下，像 VX-659 和 445 這樣的分子是不到 3 年前才在實驗室裡首次合成的。因此，我們不僅完成了臨床前開發，而且完成了 III 期開發，合成時間長達 3 年，這至少在我從事該行業的 30 或 40 年裡，我從未見過。我們從中吸取了很多經驗教訓。我說的「我們」指的是負責研究的 David Altshuler 和負責開發的 Reshma。首先，我們只針對經過驗證的目標進行工作。借助臨床前開發中的細胞標記物和生物標記物，他們可以預測臨床成功，這不僅提高了我們進入臨床階段時成功的機率，而且還加快了工作的進展。不要在動物模型上花費太多時間。我們向人類的轉變速度更快。在所有情況下，我們都會談到我們的研發管線，我們在臨床上都有生物標記物，可以預測囊性纖維化小型臨床試驗的早期成功。你應該還記得，18 或 20 名患者的 II 期試驗基本上就能告訴我們答案。你會發現，AAT 和鐮狀細胞貧血症以及疼痛等疾病也是如此。因此，我們當然也會將這教訓銘記於心。

You also asked about leveraging knowledge, and I do want to comment on one distinction. The way that we believe in leveraging knowledge is by leveraging scientific knowledge and not therapeutic area knowledge. In other words, you asked about COPD as an example. We don't have COPD programs even given what we've done in CF because we don't see the same scientific opportunity in COPD that we see in CF. And so we really pick by disease, not by therapeutic area. Disease is where we see large unmet need and scientific opportunity. And then we do leverage that experience and knowledge into those. AAT is probably the best example because it looks and smells so much like CF. But obviously, it's a genetic disease like CF. It's protein folding disorder like CF. We have a cell system and an animal system that we believe will predict clinical efficacy, and we have a simple biomarker and small trials that will tell us whether we're going to succeed or not. And so I think you can expect to see very rapid progress in the disease like AAT for the same reasons as in CF. And then maybe the final thing I would say is we do believe very strongly in this portfolio approach, and so you won't see us take rifle shots in these diseases. You'll see us create multiple molecules, and we have that in pain, we have it in AAT, we have it in FSGS, and we'll take multiple molecules into the clinic, which I think is a very important way to reduce risk.

您也問到如何運用知識，我想就其中一點差異發表一下看法。我們認為利用知識的方式是利用科學知識，而不是治療領域的知識。換句話說，你問的是慢性阻塞性肺病（COPD）的例子。鑑於我們在囊性纖維化領域的成就，我們還沒有針對慢性阻塞性肺病 (COPD) 開展項目，因為我們沒有看到 COPD 領域像囊性纖維化領域那樣具有同樣的科學研究機會。因此，我們實際上是按疾病類型而不是治療領域進行選擇。疾病領域存在著巨大的未滿足需求和科研機會。然後，我們會將這些經驗和知識運用在這些工作上。AAT 可能是最好的例子，因為它看起來和聞起來都和 CF 非常相似。但很顯然，它是一種像囊性纖維化一樣的遺傳性疾病。它是一種類似囊性纖維化的蛋白質折疊紊亂症。我們擁有細胞系統和動物系統，我們相信它們可以預測臨床療效；我們還有一個簡單的生物標記和小規模試驗，可以告訴我們是否會成功。因此，我認為可以預見，像 AAT 這樣的疾病也會像 CF 一樣取得非常迅速的進展。最後我想說的是，我們非常相信這種投資組合策略，所以你不會看到我們盲目地投資這些疾病。你會看到我們研發出多種分子，我們在疼痛治療中應用了這些分子，在 AAT 治療中應用了這些分子，在 FSGS 治療中應用了這些分子，我們將把多種分子帶入臨床，我認為這是降低風險的一種非常重要的方法。

And our next question comes from Phil Nadeau of Cowen & Company.

下一個問題來自 Cowen & Company 的 Phil Nadeau。

A commercial one and a clinical one for me, too. First, on the commercial side, could you give us an update on where the negotiations with England and France over reimbursement stand and whether there's any milestones that we externally could look for through the remainder of 2019 for progress in those negotiations? Then secondly, on the clinical side, I'm curious about VX-121 and VX-561. You mentioned that has moved into Phase II. When could we see that Phase II data? And is that combo now the most likely route to registration for VX-561?

對我來說，既有商業方面的，也有臨床方面的。首先，在商業方面，您能否向我們介紹一下與英格蘭和法國就補償問題進行的談判進展情況，以及在 2019 年剩餘時間裡，我們是否可以從外部觀察這些談判的進展里程碑？其次，在臨床方面，我對 VX-121 和 VX-561 很感興趣。您提到已經進入第二階段了。我們什麼時候可以看到二期臨床試驗數據？那麼，這種組合是否是目前VX-561註冊的最可能途徑？

Phil, it's Stuart here. I'll take your commercial question and then Reshma will take the clinical question. So as I said previously, we've reached multiple reimbursement agreements around the world over the last couple of years, and I'm pleased to say, as I mentioned in my prepared remarks, we've continued to make a good progress in the first quarter. But we are certainly fully committed to securing access where we don't, so that all eligible patients can have access to our approved medicines. Every country is different, so I'll talk about England, and then I'll talk about France. As you know, we participated in the Health Select Committee inquiry in England in March that allowed us to explain our position on our company, the value of our medicines and the approach that we were taking to those negotiations. And I think one of the most positive things out of that inquiry was that we are now back at the table with the NHS and NICE, and I see that as a very positive impact from the Health Select Committee inquiry.

菲爾，我是史都華。我來回答你的商業問題，然後 Reshma 會回答你的臨床問題。正如我之前所說，在過去的幾年裡，我們在世界各地達成了多項報銷協議，我很高興地說，正如我在準備好的發言稿中提到的，我們在第一季繼續取得了良好的進展。但我們絕對致力於確保在無法獲得藥物的情況下，所有符合條件的患者都能獲得我們批准的藥物。每個國家都不一樣，所以我先談英國，然後再談法國。如您所知，我們於 3 月參加了英國衛生專責委員會的調查，這使我們能夠解釋我們公司的立場、我們藥品的價值以及我們在談判中採取的方法。我認為那次調查最積極的結果之一是，我們現在又與英國國家醫療服務體系 (NHS) 和國家衛生與臨床優化研究所 (NICE) 重新坐到了一起，我認為這是衛生專責委員會調查帶來的非常積極的影響。

In France, we continue to be in productive discussions with the French authorities and, likewise, we're fully committed there to securing access for any patients that don't have access. I would remind you in France, approximately 1,100 or so of the 1,700 ORKAMBI-eligible patients above 12 were initiated on ORKAMBI and continue to be on ORKAMBI through our early-access programs. And we are being kind of paid for those patients, but we won't recognize revenue for those patients till a final reimbursement agreement is secured. So what I can tell you is we are fully committed to getting access for those patients who've been waiting too long in England and those patients who are still waiting in France as well. I wish I could tell you exactly when we're going to reach a successful conclusion. Unfortunately, that's just not within our ability to predict that. So unfortunately, I can't point you to any specific milestones because there really aren't any along the way that would be externally visible.

在法國，我們繼續與法國當局進行富有成效的討論，同樣，我們也全力致力於確保任何無法獲得醫療服務的患者都能獲得醫療服務。我想提醒各位，在法國，1700 名 12 歲以上符合 ORKAMBI 治療條件的患者中，大約有 1100 人透過我們的早期准入計劃開始接受 ORKAMBI 治療，並繼續接受 ORKAMBI 治療。我們已經收到了一些患者的報酬，但在最終的報銷協議達成之前，我們不會確認這些患者的收入。我可以告訴大家的是，我們全力以赴，確保那些在英國等待時間過長的患者以及那些仍在法國等待的患者都能獲得治療。我真希望我能準確地告訴你我們何時才能成功。很遺憾，這超出了我們的預測能力。所以很遺憾，我無法指出任何具體的里程碑，因為在過程中真的沒有任何可以從外部看到的里程碑。

Phil, it's Reshma. With regard to VX-121, this is our next next-generation corrector, and we have initiated these trials, and this is now in its Phase II proof-of-concept stage. It's a little too early to tell you when we're going to have the results, but I think from the speed that you can see us moving, I expect that we're going to continue to move with that kind of pace as VX-121 makes it through Phase II.

菲爾，我是雷什瑪。關於 VX-121，這是我們的下一代矯正器，我們已經啟動了這些試驗，目前正處於第二階段概念驗證階段。現在說什麼時候能得出結果還為時過早，但我認為從我們目前的進展速度來看，隨著 VX-121 進入第二階段，我們預計會繼續保持這樣的速度。

With regard to VX-561, that's the deuterated ivacaftor molecule, and you'll remember the FDA asked us to take that through full-dose ranging in monotherapy, and that's the study that we're initiating now. You are right that VX-561 is in combination with VX-121 in the proof-of-concept study. But I will say that because we're doing the monotherapy full-dose ranging, actually, we compare VX-561 with any next-generation corrector pair that we think is most appropriate. 121 is certainly one of those opportunities.

關於 VX-561，它是氘代伊伐卡托分子，您應該記得 FDA 要求我們進行單藥治療的全劑量範圍研究，而這正是我們現在正在進行的研究。您說得對，VX-561 是與 VX-121 結合用於概念驗證研究的。但我要說的是，因為我們實際上進行的是以單藥治療為主的全劑量範圍試驗，所以我們會將 VX-561 與我們認為最合適的任何下一代矯正器組合進行比較。121號公路無疑是這樣的機會之一。

And our next question comes from Michael Yee of Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

Question on the CF triple program. I know that you -- or it appears that you're filing in the het/min and homozygous population together, if I have that correct. Can you just maybe walk through what you're comparing and what you're looking at to figure out at what point you're going to pick one of those for both het/min and homozygous? And then my second question was on the AAT program. You've made some comments about that. Could you just confirm what you might see in Phase I, if anything, from a PK/PD standpoint that could be helpful. Or you really need to see Phase II data? I think you need to get to like 11 micromolar of AAT. Maybe just talk about Phase I and Phase II a bit.

關於CF三聯體計畫的問題。我知道你——或者看起來你是把雜合子/最小雜合子和純合子群體一起歸檔了，如果我理解正確的話。您能否詳細說明您正在比較的內容以及您正在觀察的內容，以便確定在什麼情況下您會選擇其中一個來表示雜合子/最小雜合子和純合子？我的第二個問題是關於AAT專案的。你對此發表了一些評論。能否請您確認一下，從藥物動力學/藥效學的角度來看，您在 I 期臨床試驗中可能會觀察到什麼（如果有的話），這將很有幫助。還是您真的需要查看二期臨床試驗數據？我認為你需要將AAT的濃度提高到11微摩爾左右。或許可以稍微談談第一階段和第二階段。

Sure. This is Reshma. Let me take the first question first and then we'll get to AAT. So as we've discussed on our calls in the past, we are marching down the strategy that we laid out with regard to asset selection. And really, if I break that down, what that means is that we are going to be looking at 24-week data for both FS and FMS for both assets, VX-659 and VX-445. The 445 study went even faster than the 659 study, and that's really what set us up to have this opportunity to look at both sets of 24-week data. And you've actually gleaned exactly the right point. Because we can look at both 24-week data sets, we're going to be filing for both, FS and FMS, regardless of which asset we choose.

當然。這是雷什瑪。讓我先回答第一個問題，然後再討論AAT。正如我們過去在電話會議中討論的那樣，我們正在推進我們制定的資產選擇策略。實際上，如果我仔細分析一下，這意味著我們將查看 VX-659 和 VX-445 這兩個資產的 FS 和 FMS 的 24 週資料。445 研究的進展速度甚至比 659 研究還要快，這才讓我們有機會查看這兩組 24 週的數據。而你恰恰抓住了重點。因為我們可以查看這兩個 24 週的資料集，所以無論我們選擇哪個資產，我們都會同時申請 FS 和 FMS。

With regard to how we're going to make the asset decision, you know who would have ever guessed that the efficacy would be at this level and literally superimposable. And that means we're going to be looking at the full totality of evidence. And of course, it means ppFEV1, but it also means things like pulmonary exacerbation, all the other secondary endpoints and, importantly, the full package of safety information. We're on track to make this decision in Q2 of this year and, importantly, file in Q3 of this year, regardless of whether the asset selection is 445 or 659.

至於我們如何做出資產決策，你知道，誰會想到其效果會達到如此高的水平，而且完全可以重疊呢？這意味著我們將審視所有證據。當然，這意味著 ppFEV1，但也意味著肺部急性惡化、所有其他次要終點以及非常重要的，完整的安全性資訊包。我們預計在今年第二季做出決定，更重要的是，無論資產選擇是 445 還是 659，我們都將在今年第三季提交申請。

An important thing to share with you is with regard to VX-445. That study has achieved its last patient last visit as of very recently, and so we're really in very good shape and a lot of progress since the last call.

有一件關於 VX-445 的重要事情需要和大家分享。該研究最近完成了最後一位患者的最後一次訪視，因此我們目前情況非常好，自上次訪視以來取得了很大進展。

With regard to the AAT program, I'm going to step back a little bit just to make sure everyone has all the information. So that molecule is VX-814, and we just announced today, and I'm delighted to reiterate that, that molecule has received fast track status from the FDA. That's important because I think it gives you an indication of the high unmet need as well as the recognition that therapies are needed to improve the condition of these patients who have a very serious illness. That study started the SAD, single ascending dose, multiple ascending dose in December of last year. We're going to have the PK results from that study. And then well, I don't know the exact size. It's going to be efficient, as Jeff described in his prepared remarks. This is very much like CF, and we anticipate that 30, 40, 50 patients, something like that, is what we're going to need to examine, and the readout is very straightforward. It's AAT levels, and we know how to do that. So I anticipate that, that's kind of what you're going to expect to see as this program comes to fruition.

關於AAT項目，我打算先退後一步，確保每個人都了解所有資訊。所以，這種分子是 VX-814，我們今天剛剛宣布，而且我很高興地重申，這種分子已經獲得了 FDA 的快速通道資格。這一點很重要，因為我認為這表明了未滿足的巨大需求，以及人們認識到需要採取治療措施來改善這些患有嚴重疾病的患者的病情。該研究於去年 12 月開始進行 SAD（單次遞增劑量）和多次遞增劑量試驗。我們將獲得該研究的藥物動力學結果。至於具體尺寸，我就不太清楚了。正如傑夫在事先準備好的演講稿中所描述的那樣，這將非常有效率。這與囊性纖維化非常相似，我們預計需要檢查 30、40、50 名患者，差不多就是這個數量，而且結果非常直接。這是AAT水平測試，我們知道該怎麼做。所以我預計，隨著這個專案的逐步實現，你會看到類似這樣的結果。

And our next question comes from Alethia Young of Cantor Fitzgerald.

下一個問題來自 Cantor Fitzgerald 公司的 Alethia Young。

I was just curious as to a little bit more about the alpha-1 antitrypsin program, your second molecule. Are you guys thinking that over time it will kind of be a combination game? Or are you just kind of developing this molecule as a backup molecule? And if I may, on pain, can you just discuss some of the rate-limiting steps around making a strategic decision there?

我只是對你們的第二個分子——α-1抗胰蛋白酶計畫——有點好奇，想了解更多。你們覺得隨著時間的推移，這會不會變成一種組合遊戲？還是你只是把這個分子當備用分子來開發？如果可以的話，關於疼痛問題，您能否談談在製定策略決策過程中一些限速步驟？

Sure. With regard to alpha-1 antitrypsin, we have a approach here that is very, very similar to CF, and that is to say to have a portfolio of molecules, as we like to say internally once you crack the biology, it's all about pouring on the chemistry. And so portfolio of molecules, including the one that's in the preclinical development, is there to allow us to choose the very best molecules to bring forward. Unlike CF, just to comment very specifically on your question about is it going to be a combination of monotherapy approach, that's where it's not like CF. A single molecule, we believe, will be sufficient to treat the underlying cause of disease here. So that's AAT.

當然。關於α-1抗胰蛋白酶，我們在這裡的方法與CF非常非常相似，也就是說，要有一個分子組合，正如我們內部常說的，一旦你破解了生物學，剩下的就是運用化學方法了。因此，我們擁有包括處於臨床前開發階段的分子在內的多種分子組合，以便選擇最好的分子進行推進。與 CF 不同，我特別要回答你關於是否會採用單藥療法的問題，這就是它與 CF 不同的地方。我們相信，只需一種分子就能治療這種疾病的根本原因。這就是AAT。

With regard to pain, what we're really looking at here is positive studies with VX-150 in a model of acute pain, that was bunionectomy; musculoskeletal pain, that was the osteoarthritis study; and small fiber neuropathy, that's the model of neuropathic pain. And then we went on to do a dose-ranging study in bunionectomy because that was a good model for us to use. We're going to look at all of that data and look at our portfolio of molecules, again, same strategy, once we crack the biology, and I really do believe we've cracked the biology of 1.8, which is no easy task. You know many, many people have worked on this over a long period of time, including ourselves. We're going to have that all together, and in the second half of this year, I anticipate we'll have all the information we need to decide on which molecule or molecules and exactly what the next step is.

關於疼痛，我們真正看到的是 VX-150 在急性疼痛模型（拇外翻切除術）、肌肉骨骼疼痛（骨關節炎研究）和小纖維神經病變（神經性疼痛模型）中的積極研究。然後，我們繼續對拇外翻切除術進行了劑量範圍研究，因為這是一個很好的模型供我們使用。我們將研究所有這些數據，並再次審視我們的分子組合，採取同樣的策略，一旦我們破解了生物學，我真的相信我們已經破解了 1.8 的生物學，這絕非易事。你知道，包括我們自己在內，很多人為此付出了很長時間的努力。我們將把所有這些整合起來，我預計在今年下半年，我們將掌握所有必要的信息，以決定選擇哪種或哪些分子，以及下一步的具體步驟是什麼。

And our next question comes from Ying Huang of BoA Merrill Lynch.

下一個問題來自美國銀行美林證券的黃穎。

First one is on U.K. reimbursement. I believe Jeff mentioned previously that even with the clinical benefit of the triple combination you observed, still the NICE methodology may not come out with the pricing that's close to what you think is the value of this medication. So do you think, based on your interaction with NICE recently, is there any change in the NICE thought process of how to evaluate this? And then secondly, I think you previously also disclosed that the average blended revenue per patient was about $150,000 in 2018. Can you comment on the trend for that number going forward?

第一個例子是關於英國的報銷。我相信 Jeff 之前提到過，即使你觀察到了三重療法的臨床益處，NICE 的方法仍然可能無法得出接近你認為這種藥物價值的定價。那麼，根據你最近與 NICE 的互動，你認為 NICE 在評估這個問題上的想法是否有改變？其次，我認為您之前也透露過，2018 年每位患者的平均綜合收入約為 15 萬美元。您能否對該數位未來的發展趨勢發表一下看法？

Yes. This is Jeff, Ying. Thanks for the 2 questions and, obviously, they're a bit related. So just to be clear on the triple, the NICE methodology has, as you know, a number of different components to it, major one is the value of medicine to patients as described by the clinical results and, clearly, there the triple is significantly better than the other 2 existing medicines that they've already evaluated. They haven't yet evaluated the triple in their system, so it's a little early to tell, but we certainly know from the clinical data that there is that major benefit.

是的。這是傑夫，英。感謝您提出的兩個問題，顯然，它們之間有些關聯。為了明確三重療法，如您所知，NICE 方法論包含許多不同的組成部分，其中一個主要組成部分是藥物對患者的價值，如臨床結果所述，顯然，三重療法在這方面明顯優於他們已經評估過的其他兩種現有藥物。他們還沒有在自己的系統中評估三重療法，所以現在下結論還為時過早，但我們從臨床數據中可以肯定地知道，它具有重大益處。

With respect to the more general question of the NICE methodology and how well it applies to these kinds of precision medicines, I think you know that there's been quite a bit of discussion in the U.K. and in Parliament about the fact that it's probably time to take another look at that NICE methodology, not for community medicines and not for the ultra-orphans, where it seems to work well, but for exactly this kind of precision medicine for the patient populations that fall in between. And we do anticipate and hope over the next couple of years that, that methodology may be revised as per the current discussions to better evaluate the value of these medicines. Obviously, that's going to help, too.

關於 NICE 方法論及其對這類精準醫療的適用性這一更普遍的問題，我認為您也知道，英國和議會已經就此進行了相當多的討論，認為現在或許應該重新審視一下 NICE 方法論，不是針對社區藥物，也不是針對那些似乎效果不錯的罕見病，而是針對介於兩者之間的患者群體的精準醫療。我們預計並希望在未來幾年內，該方法能夠根據目前的討論進行修訂，以便更好地評估這些藥物的價值。顯然，那也會有所幫助。

With respect to the average blended price, I think you can -- we, obviously, don't give long-term guidance on price. Certainly, it's too early for triple price. We don't give long-term guidance on revenue either, but I think one way to think about this is we're currently treating about 18,000 patients, generating about $3 billion in revenue. As we go to a triple world, where the benefit to patients is greater, we certainly don't anticipate major decrease as in the price of our triple versus our other medicines, given its value. And so you can begin to sort of do some rough math around as we move from 18,000 to potentially [65,000] or 68,000 eligible patients what that might look like across the world.

至於平均混合價格，我認為你可以——顯然，我們不提供長期價格指引。當然，現在就漲到三倍價格還為時過早。我們也不提供長期收入指引，但我認為可以這樣理解：我們目前正在治療約 18,000 名患者，創造了約 30 億美元的收入。隨著我們邁向三聯療法時代，患者獲益更大，考慮到其價值，我們當然不指望三聯療法的價格會像其他藥物一樣大幅下降。因此，隨著符合條件的患者人數從 18,000 增加到可能達到 65,000 或 68,000，你可以開始粗略地計算一下，這在全世界範圍內可能會是什麼樣子。

And our next question comes from Geoffrey Porges of SVB Leerink.

下一個問題來自 SVB Leerink 的 Geoffrey Porges。

Jeff, just a follow-up on a prior question. Wondering if you could just confirm the year-over-year and sequential treated patient number trend so that we can see what the underlying dynamics are across all the different products? And could you give us a sense of what the sequential trend in the gross to net in the U.S. was? And then lastly, just wondering if you could give us an update on alpha-1? Is it your belief that a serum alpha-1 antitrypsin level will be sufficient for approval? Or is that just for the next study that you plan? Is there any obligation to show a pulmonary outcome benefit the way you do in CF?

傑夫，我只是想跟進一下之前的問題。能否請您確認一下同比和連續的治療患者人數趨勢，以便我們了解所有不同產品的潛在動態？能否簡單介紹一下美國毛利與淨利的連續變動趨勢？最後，能否請您提供一下 alpha-1 的最新進展？您認為血清α1-抗胰蛋白酶濃度足以作為核准的依據嗎？或者這只是您計劃的下一項研究？是否必須像在囊性纖維化治療中一樣，證明肺部治療結果有益？

Yes. Thanks for the questions, Geoff. Maybe we'll do them in a reverse order. Reshma will do the AAT question with respect to endpoints. Paul will do a bit on gross to net and how we're seeing that going forward for the year. And I'll give you some color on how we think patient penetration will go over the next several years.

是的。謝謝你的提問，傑夫。或許我們會反過來做。Reshma 將解答有關端點的 AAT 問題。Paul 將談論毛利與淨利的關係，以及我們今年將如何看待這段關係的發展。接下來，我將詳細介紹我們對未來幾年患者滲透率的看法。

So Geoff, this is Reshma. With regard to exactly what the regulatory enabling endpoint will be for our program, it's a bit too early to call that because we haven't engaged in all of those regulatory discussions. But what I can tell you is a little bit about the context of the currently available medicines, and then you could start to think about how this might all work. So there are about 4 companies out there that make augmentation therapies. This is a therapy that you go into center once a week and you get an infusion of the protein. And this, as you know, has its own limitations in that it only really has the opportunities to treat the lung disease part of it. It really doesn't do anything for the liver disease, which is different than our approach, which is going to be able to target both liver and lung. So with that approach, all the companies have been able to secure U.S. FDA approval based on AAT level. So that's a data point, and we have to go through our process to determine exactly how it's going to work for us. Stuart -- sorry, that's Paul. Over to you.

傑夫，這位是雷什瑪。至於我們計畫的監管審批終點究竟是什麼，現在下結論還為時過早，因為我們還沒有參與到所有相關的監管討論中。但我可以先告訴你一些關於目前可用藥物的背景信息，然後你就可以開始思考這一切是如何運作的了。目前市面上約有 4 家公司生產增強療法產品。這種療法需要你每週去中心一次，接受蛋白質輸液。如您所知，這種方法也有其局限性，因為它實際上只能治療肺部疾病部分。它對肝臟疾病實際上沒有任何作用，這與我們的方法不同，我們的方法能夠同時針對肝臟和肺部。因此，透過這種方法，所有公司都能夠根據 AAT 水平獲得美國 FDA 的批准。所以這是一個數據點，我們需要走完我們的流程來確定它究竟對我們有什麼作用。史都華——抱歉，那是保羅。接下來該你了。

Yes. Geoff, thanks for the question. So when we exited 2018, the gross to net in the U.S. was approximately 10%. And I think we said in Q1 call and [it's been] now that we expect 2019 to be between 10% and 12%. And that's driven by 2 things: one is increased purchases by 340B entities, which have a statutory rate discount similar to Medicaid; and then the second one would be the anticipated spend on our cost-sharing program. So those 2 things are kind of bringing that number up a little bit over the course of 2019.

是的。傑夫，謝謝你的提問。因此，到 2018 年底，美國毛利與淨利比約為 10%。我認為我們在第一季電話會議上說過，現在我們預計 2019 年的成長率將在 10% 到 12% 之間。這主要受兩方面因素驅動：一是 340B 實體採購量的增加，這些實體享有類似於 Medicaid 的法定價格折扣；二是預計在成本分攤計劃上的支出。所以，這兩件事在 2019 年都在某種程度上拉高了這個數字。

And then Geoff, maybe for your final question, which is really how do we see the penetration going with our medicines as we go forward, I think there's going to be 2 phases. You can think about 2019 as being a continuation of some of the things that you've heard about plus the new label expansion. So SYMKEVI, I think, as Stuart mentioned, is off to a very nice start in Germany, and we expect to see continued growth there. There's still a bit of growth with SYMDEKO here in the U.S., although we've probably seen most of that. And then these new label indications for younger ages for KALYDECO, for SYMDEKO in the U.S. for the younger age, et cetera, will provide more growth this year. And all of that is accounted for in our guidance for the year. What is not accounted for in our guidance for the year is, if we were able to obtain reimbursement in one of the major countries, for instance, in England or France, the 2 big companies, obviously, that would have a positive effect on this year's growth rate. Obviously, any early approvals for some of these label indications also might have a positive effect. And then we're really into the world of triple. As we get approval in triple, which as we've said we believe can ultimately treat 90% of all patients, we do see significant penetration into that, that group going from 30,000 eligible patients to 65,000 or 68,000 and penetration of that age group that looks a lot like KALYDECO because of the efficacy of the drug. So I think that's the way to think about the growth ramp going forward.

那麼，Geoff，關於你最後一個問題，也就是我們未來如何看待藥物的滲透率，我認為將會經歷兩個階段。你可以把 2019 年看成是之前一些事情的延續，再加上新的廠牌擴張。所以，正如史都華所提到的那樣，我認為SYMKEVI在德國的開局非常好，我們預計它在那裡將繼續增長。SYMDEKO 在美國仍然有一些成長空間，儘管我們可能已經看到了大部分成長潛力。此外，KALYDECO、SYMDEKO 等產品在美國針對較年輕年齡層推出的新標籤說明，將在今年帶來更大的成長。所有這些都已納入我們今年的業績預期中。我們今年的業績指引中沒有考慮到的是，如果我們能夠從英國或法國等主要國家獲得報銷，那麼這兩家大公司顯然會對今年的成長率產生正面影響。顯然，如果這些適應症中的某些方面能夠儘早獲得批准，也可能會產生正面的影響。然後我們就真正進入三重奏的世界了。隨著我們獲得三重療法的批准（正如我們所說，我們相信該療法最終可以治療 90% 的患者），我們確實看到了顯著的滲透率，符合條件的患者人數從 30,000 人增加到 65,000 或 68,000 人，並且由於該藥物的療效，該年齡組的滲透率看起來很像 KALYDECO。所以我認為這就是未來發展加速的正確想法。

And our next question comes from Brian Abrahams of RBC Capital Markets.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Congrats on all the progress. Two questions for me. On the AAT program, what gives you the most confidence that the AAT produced will be functional and that the liver outflow will reverse damage from the prior accumulation of toxic polymers to the same degree in humans who may have the disease long term as you saw in the transgenic mouse model? And then just a second question, commercially, I was wondering if you could help quantify the quarter-over-quarter impact of inventory draw-downs across the CF portfolio?

祝賀你們取得的所有進展。我有兩個問題。在 AAT 計畫中，是什麼讓您最有信心所生產的 AAT 將具有功能性，並且肝臟排出能夠逆轉先前積累的有毒聚合物造成的損害，從而在可能長期患有這種疾病的人類身上達到您在轉基因小鼠模型中看到的程度？第二個問題，從商業角度來說，我想知道您是否可以幫忙量化CF投資組合中庫存下降的季度環比影響？

Yes. Maybe I'll take the AAT question and Stuart will like the inventory question, I think. So on AAT, those -- you're asking the most important questions. And one of the things we really like about the program is that we're able to test our correctors in both cells and in a transgenic animal that are actually expressing the mutant human protein, not a mutant mouse protein. So they're engineered with the human protein. And we can measure not only the levels, but we can actually measure functional levels. So we're not simply measuring by immunoassay the levels of this protein, we're actually measuring the functional levels. And that's how we have great confidence that we're actually producing functional protein and, in fact, we're clearing both the cells, and as you've seen -- if you saw my JPMorgan presentation, we're clearing the liver in these animals of the misfolded human mutant protein. And that gives us a high level of confidence that we are actually able to produce -- not only to correct the folding, but produce functional protein once we do it, and that's a very, very important piece of the data package, which has encouraged us to move rapidly with humans.

是的。也許我會選擇 AAT 問題，而 Stuart 會喜歡庫存問題，我想。所以在AAT考試中，你問的都是最重要的問題。我們非常喜歡這個項目的一點是，我們能夠在細胞和基因改造動物中測試我們的校正劑，這些動物實際上表達的是突變的人類蛋白質，而不是突變的小鼠蛋白質。所以它們是用人類蛋白質改造的。我們不僅可以測量水平，而且還可以實際測量功能水平。因此，我們不僅僅是透過免疫測定法測量這種蛋白質的水平，我們實際上是在測量其功能水平。正因如此，我們才有十足的信心，相信我們確實在生產功能性蛋白質，而且事實上，我們正​​在清除細胞中的蛋白質，正如你所看到的——如果你看過我在摩根大通的演講，我們正在清除這些動物肝臟中錯誤折疊的人類突變蛋白。這讓我們有很高的信心，我們不僅能夠糾正折疊，而且一旦糾正就能生產出功能性蛋白質，這是數據包中非常非常重要的一部分，這鼓勵我們在人類身上快速發展。

Now humans, as Reshma said, we're going to be able to measure the same thing. We'll not only measure the serum levels of protein, which we can obviously do, but we'll actually measure the functional levels of protein in the serum. And we know from essentially an experimentative nature from the heterozygous parents of these patients, who are normal, by the way, and they express anywhere from 11 micromolar on up, probably 17 micromolar is really -- a functional protein is really fully protective. And so we can simply measure the levels of functional protein in these treated patients and, again, with rather small trials, like the CF trials, know exactly where we are. But the cell data and the mouse data used in the human protein gives us the high level of confidence. Did that answer your question?

正如雷什瑪所說，現在人類也將能夠測量同樣的東西。我們不僅要測量血清中的蛋白質水平（這顯然可以做到），還要實際測量血清中蛋白質的功能水平。我們從這些患者的雜合子父母身上，透過實驗得知，順便說一句，他們是正常的，他們的表達量從 11 微摩爾到 17 微摩爾不等——功能性蛋白質確實具有完全的保護作用。因此，我們可以簡單地測量這些接受治療的患者體內功能性蛋白質的水平，並且，透過像 CF 試驗這樣規模較小的試驗，就能準確地知道我們處於什麼位置。但是，用於研究人類蛋白質的細胞數據和鼠類數據給了我們高度的信心。這樣回答了你的問題嗎？

That's really helpful.

這真的很有幫助。

And in the liver, as I said, we're looking directly at the livers of the mice, and we're seeing clearing. And at some point in this clinical program, we will also look at the livers of patients to confirm if that's true. Stuart...

正如我剛才所說，我們在肝臟中直接觀察老鼠的肝臟，我們看到肝臟組織正在變得清澈。在這個臨床計畫的某個階段，我們也會檢查患者的肝臟，以確認這是否屬實。史都華…

Yes. And Brian, on inventory. So at the end of 2018, we had about $10 million worth of inventory build here in the U.S. This is typical towards the end of the calendar year. That excess inventory was more than burnt off during the course of the first quarter.

是的。還有布萊恩，負責盤點庫存。因此，在 2018 年底，我們在美國累積了價值約 1,000 萬美元的庫存。這在年底是正常的。第一季期間，過剩庫存已被全部消化掉。

And the next question comes from Cory Kasimov of JPMorgan.

下一個問題來自摩根大通的科里·卡西莫夫。

A couple of quick CF ones for you. First of all, with SYMDEKO, at this stage of launch, roughly what percent of patients are still switching to SYMDEKO from other regimens versus those that are new to therapy altogether? And secondly, thinking about VX-561, how important do you believe a once-a-day regimen is for CF patients? Do you hear much pushback on the twice-a-day administration you have out there now?

這裡有幾個關於CF的簡短問題。首先，在 SYMDEKO 上市的現階段，大約有多少比例的患者是從其他治療方案轉而使用 SYMDEKO，又有多少比例的患者是完全第一次接受治療？其次，關於 VX-561，您認為對於 CF 患者來說，每天一次的給藥方案有多重要？你有沒有聽到很多人對目前一天兩次的行政管理方式提出反對意見？

Yes. So Cory, I'll take those. So in terms of the switching and where are we versus uptake in [naïve], we've really only got data around that for a substantial period of time here in the U.S., obviously, because we launched SYMDEKO here in February of 2018. What I'll tell you is we've actually seen really high levels of uptake in whole of the populations you might expect, those patients who are naïve to ORKAMBI, those who've never been exposed to a CFTR modulator before, those who were on ORKAMBI and those who had tried ORKAMBI and discontinued. So all of those groups we saw very substantial uptake. We're on the flatter path of the launch curve, I would say, here in the U.S., but we're certainly not flat. There are still patients being added in all of those categories just about every day. And the other one, I think, I would say that we are able to be much more confident about now in the real world is we had always thought that given the profile of SYMDEKO that we would expect to see high levels of persistence and compliance, higher than we had seen with ORKAMBI. And I'm pleased to say that's exactly what's playing out in the real world.

是的。那科里，我收下這些吧。所以就轉換情況以及我們與[naïve]的接受度相比所處的位置而言，顯然，我們只有在美國有相當長一段時間的相關數據，因為我們是在 2018 年 2 月在這裡推出了 SYMDEKO。我可以告訴你們的是，我們實際上在你們可能預期的所有人群中都看到了非常高的接受度，包括那些從未接觸過 ORKAMBI 的患者、那些以前從未接觸過 CFTR 調節劑的患者、那些正在服用 ORKAMBI 的患者以及那些嘗試過 ORKAMBI 但後來停止服用的患者。所以我們看到所有這些群體都獲得了非常顯著的參與。我認為，在美國，我們的發展曲線相對平緩，但肯定還不是平坦的。幾乎每天都有新的患者被納入這些類別。而另一點，我認為，我們現在在現實世界中更有信心的是，我們一直認為，鑑於 SYMDEKO 的特性，我們預計會看到更高的持久性和合規性，高於我們在 ORKAMBI 上看到的水平。我很高興地說，現實世界也正是如此。

In terms of deuterated ivacaftor 561, certainly, given the uptake rates we see with our medicines, clearly, a twice-a-day regimen for medicines, which are as important as this, treating the underlying cause of the disease is not something which is inhibiting people from taking our medicines. And then indeed, as you know, these patients are taking many, many different types and forms of medicines every day. And so twice-a-day medicine is not difficult for them. However, our goal is to get to the carrier levels of status and provide as much convenience as we possibly can for the patients. And so we do see once-a-day being something that would be an advantage for our medicines, and that's why we want to bring 561 to patients as soon as we possibly can.

就氘代伊伐卡托 561 而言，當然，鑑於我們所見的藥物的接受率，很明顯，每天兩次的用藥方案（對於像這樣治療疾病的根本原因如此重要的藥物來說，這並不會阻止人們服用我們的藥物。而且，如您所知，這些患者每天都要服用許多不同種類和形式的藥物。所以對他們來說，一天兩次服藥並不難。但是，我們的目標是達到承運商級別，並盡可能為患者提供便利。因此，我們認為一天一次的用藥方式對我們的藥物來說是一個優勢，這也是為什麼我們希望盡快將 561 帶給患者的原因。

And our next question comes from Paul Matteis with Stifel.

下一個問題來自 Stifel 公司的 Paul Matteis。

Just continuing the trend on alpha-1 antitrypsin. I was wondering if there are any biomarkers you can look at in early studies that can detect whether or not your compound is having the benefit in the liver that you hope, anything related to inflammation or liver enzyme elevations? And then secondarily, I was wondering if you can just clarify when or the current thinking on specific study design for NaV1.8 in Phase III and whether or not the next compound might go after any other pain indications outside of the ones you pursued thus far.

只是延續了α-1抗胰蛋白酶的趨勢。我想知道在早期研究中是否有任何生物標記可以檢測出你的化合物是否對肝臟產生了你所期望的益處，例如與發炎或肝臟酵素升高相關的任何標記？其次，我想請您澄清一下，關於 NaV1.8 在 III 期臨床試驗中的具體研究設計，目前的想法是什麼，以及下一個化合物是否會針對您迄今為止研究的疼痛適應症之外的其他疼痛適應症。

Sure. Let me take the NaV1.8 first and then I'll go backwards to AAT. So with regard to Phase III designs, I think the 3 models that we've talked about are a good way to think about it, the musculoskeletal pain and osteoarthritis, but there are, obviously, a number of other pain conditions in musculoskeletal that we could pursue. And in the small fiber neuropathy, which is what we did in the VX-150 example, there is, of course, trigeminal neuralgia and other pain conditions that one would pursue to get the full breadth of neuropathic pain. And bunionectomy as a model of acute pain, I think the kind of studies you could imagine are bunionectomy, which would be the hard tissue, something like an abdominoplasty or a hernia repair as some of the soft tissue examples. And the guidance is actually fairly straightforward with regard to what kind of studies you need to do and the approximate sample size for any one of these conditions. So I think what you'll see us do is bring the best molecule forward and then use the fairly typical Phase III development path to get these approved.

當然。我先學習 NaV1.8，然後再回頭學習 AAT。所以關於 III 期設計，我認為我們討論過的 3 個模型是一個很好的思考方式，即肌肉骨骼疼痛和骨關節炎，但顯然，肌肉骨骼疼痛領域還有許多其他疼痛疾病值得我們研究。在小纖維神經病變中（就像我們在 VX-150 的例子中所做的那樣），當然還有三叉神經痛和其他疼痛疾病，人們會研究這些疾病以獲得神經性疼痛的全部範圍。以拇外翻切除術為例來研究急性疼痛，我認為你可以想像的研究類型是拇趾外翻切除術（屬於硬組織），以及腹部整形術或疝氣修補術（屬於軟組織）。對於需要進行哪些類型的研究以及每種疾病的大致樣本量，指導意見實際上相當明確。所以我認為你們將會看到我們推出最好的分子，然後採用相當典型的 III 期開發路徑來獲得批准。

With regard to AAT, I think the question was around how we're going to figure out whether or not there is liver impact. So this is kind of interesting. There is a paper from the Brantly Lab down in Florida, and it was out maybe 2 years ago, November or something like that, and what you can tell is that perhaps AAT is best known clinically as a disease that looks like COPD, just COPD in younger people. There's actually a substantial burden of liver disease, and that liver disease is manifest when you do something like a liver biopsy, which is what that Brantly series did. It actually looked at about 100-or-so patients over time.

關於 AAT，我認為問題在於我們如何確定它是否會對肝臟造成影響。這挺有意思的。佛羅裡達州布蘭特利實驗室有一篇論文，大概是兩年前，11 月左右發表的。論文指出，AAT 在臨床上最廣為人知的症狀是類似 COPD 的疾病，只不過是年輕人的 COPD。實際上，肝臟疾病負擔相當重，而肝臟疾病會在進行肝臟活檢等檢查時顯現出來，布蘭特利系列節目就是這麼做的。實際上，該研究對大約 100 名患者進行了一段時間的觀察。

Now with regard to inflammatory markers, or markers of liver disease, AST, ALT, that actually doesn't give you a very good idea. GGT is said to be very best, but it's not very sensitive nor is it particularly specific. But I think it was something that Jeff said is really the important point. In our animal models, what we're doing is actually looking at liver tissue. So there's no guesswork here, and it's not a question of whether we see enzymes moving. We're actually looking at the liver cells with the misfolded protein and then the clearance of that with VX-814. And I anticipate that as we go to clinical studies, biopsies are going to be an important part of that. I hope that answers the question.

至於發炎標記或肝病標記物，如 AST、ALT，其實並不能給你一個很好的概念。GGT 據說是最好的，但它的敏感性不高，特異性也不強。但我認為傑夫說的那句話才是真正重要的。在我們的動物模型中，我們實際上是在觀察肝臟組織。所以這裡不存在猜測，也不是我們是否能看到酵素運動的問題。我們實際上是在觀察含有錯誤折疊蛋白質的肝細胞，然後用 VX-814 清除這些蛋白質。我預計，隨著我們進入臨床研究階段，活檢將成為其中的重要組成部分。希望這能解答你的疑問。

Yes, it does.

是的，確實如此。

And our next question comes from Ravi Mehrotra of Evercore ISI.

下一個問題來自 Evercore ISI 的 Ravi Mehrotra。

Thank you for taking my question, which is around possible pharmacoeconomic arguments for broader utilization of your CF franchise. You've got over a decade now of real-world clinical experience with your agents. So understanding that [PE] is an art form rather than science per se, can you give us some color on some of the [key] data points you can or have taken to resistant payers.

感謝您回答我的問題，我的問題是關於擴大貴公司囊性纖維化產品線的藥物經濟學論點。您與您的代理人之間已經累積了十多年的實際臨床經驗。既然我們理解[PE]是一種藝術形式而不是科學本身，您能否為我們詳細介紹一下您可以或已經向頑固的支付方提供的一些[關鍵]數據點？

Yes. Ravi, this is Stuart. Thanks very much for the question. Yes, as you say, pulmonary exacerbation themselves are very, very important endpoints certainly for patients and physicians, but also they are of interest too to payers as well. The kinds of things that we've looked at on pulmonary exacerbations, both actually in our clinical trials, but also in our longer-term follow-up studies include dissecting the pulmonary exacerbations into those that lead to things like IV antibiotics, those that lead to hospitalizations, what the length of those hospitalization stays are and things like that because, obviously, those are of interest to payers. As you say, we have the benefit of being on the market for a while now. And with KALYDECO, we have the longest experience, but we've got increasingly large volumes of data on ORKAMBI as well. And so we're able to take not only data on pulmonary exacerbations, but increasingly being able to take data on perhaps even the most important outcomes, which are things like survival rates, things like avoidance of lung transplants and things like that. And so that database continues to increase. We certainly utilize that with payers around the world, are building that into our pharmacoeconomic arguments. Obviously, it requires a bit of a leap of faith for some of our newer medicines because it's asking them to extrapolate from KALYDECO and ORKAMBI to right now SYMKEVI and eventually to the triple combinations, but I don't think it's too much of a leap of faith for them to translate the benefits of 1 CFTR modulator to other CFTR modulator.

是的。拉維，這位是史都華。非常感謝您的提問。是的，正如你所說，肺部急性惡化本身是非常非常重要的終點，對於患者和醫生來說當然如此，但對於支付者來說，它們也同樣重要。我們在臨床試驗以及長期追蹤研究中研究的肺部急性惡化包括：將肺部急性惡化細分為需要靜脈注射抗生素等治療的情況、需要住院治療的情況，以及住院時間的長短等等，因為很明顯，這些都是支付方感興趣的問題。正如你所說，我們的優勢在於我們已經在市場上待了一段時間了。我們擁有 KALYDECO 最豐富的經驗，但我們也累積了越來越多的 ORKAMBI 數據。因此，我們不僅能夠收集肺部疾病加重的數據，而且越來越能夠收集一些最重要的結果數據，例如存活率、避免肺臟移植等等。因此，該資料庫持續增長。我們當然會與世界各地的支付方合作，並將此納入我們的藥物經濟學論點中。顯然，對於我們的一些新藥來說，這需要一些信心，因為這要求他們從 KALYDECO 和 ORKAMBI 推斷到現在的 SYMKEVI，最終到三聯療法，但我認為，將一種 CFTR 調節劑的益處轉化為另一種 CFTR 調節劑，對他們來說並不算太大的信心。

And, Ravi, this is Jeff. Just to give you some of the data around that if you're not familiar with it. The results that we're seeing with KALYDECO and some of these long-term registry studies are things like 50%-plus decreases in mortality, 50% decrease in the slope of decline of lung function, 70% decrease in transplantation. So these are not subtle kinds of results, these are true disease-modifying kinds of results. And when those are plugged into these pharmacoeconomic models, they have real impact.

拉維，這位是傑夫。如果你還不熟悉這方面的情況，我提供你一些相關數據。我們從 KALYDECO 和一些長期註冊研究中看到的結果是，死亡率下降了 50% 以上，肺功能下降速度降低了 50%，移植率降低了 70%。所以這些不是細微的結果，而是真正能改變疾病的結果。當這些數據被納入藥物經濟學模型時，它們會產生實際影響。

And our next question comes from Hartaj Singh of Oppenheimer & Company.

下一個問題來自奧本海默公司的哈塔吉·辛格。

I just had a question on the SYMDEKO launch, it's been going very well. And I think you've got a (inaudible) with ORKAMBI with payer uptake both in the United States and ex U.S. And my sense is that the pace of uptake for SYMDEKO, which had better data than ORKAMBI, has been broader and quicker in the United States than in Europe and the rest of the world. Maybe you can just talk to that a little bit. Or maybe I'm mistaken. I would really appreciate it.

我有個關於 SYMDEKO 發布的問題，目前進展非常順利。我認為你們在 ORKAMBI 的支付方接受度方面，無論是在美國還是美國以外，都存在（聽不清楚）問題。我的感覺是，SYMDEKO 的數據比 ORKAMBI 更好，在美國的接受度比在歐洲和世界其他地區更高、更廣泛。或許你可以跟它聊一會兒。或許是我弄錯了。我將不勝感激。

Yes. So I would say, in the U.S., we have always managed to get very broad access to our CFTR modulators, starting with KALYDECO and through ORKAMBI and now to SYMDEKO and even for each of the individual label expansions that we've had over time. So I don't think there's really a very substantial time difference. Certainly, I think payers are getting more accustomed to these agents and to the disease, and I think that's helping. So I think we are seeing some acceleration here in the U.S., but it's not huge. What I think you're seeing play out outside the U.S. actually is the -- is a couple of things. Firstly, you're seeing the benefit of our portfolio agreements, and this was exactly what they were designed to do. They were designed to reduce the time lag between regulatory approval and reimbursement approval so the patients and physicians could access to our newest and best medicines as soon as they possibly can. And so that I think is what's leading to the acceleration in patients being able to access SYMDEKO or SYMKEVI outside the U.S. versus what we saw with ORKAMBI. And then separately, in Germany, what you're seeing is actually the launch of SYMKEVI is going substantially better than the launch of ORKAMBI. I think the team has done a terrific job there. Certainly, the benefit-risk profile of the agent helps, but certainly, the team has done an excellent job executing there in Germany, and the SYMKEVI launch is tracking substantially above the ORKAMBI launch at the same time point. We're seeing initiations in naïve patients. We're seeing initiations in patients who had discontinuations. And we're also seeing some switching as well. And so I think that's really an example of the team executing really well.

是的。所以我想說，在美國，我們設法廣泛地獲得 CFTR 調製器，從 KALYDECO 開始，到 ORKAMBI，再到現在的 SYMDEKO，甚至隨著時間推移，我們每個單獨的標籤擴展都是如此。所以我覺得時間上並沒有太大的差異。當然，我認為支付方越來越習慣這些藥物和這種疾病，我認為這會有所幫助。所以我認為我們在美國看到了一些加速成長的趨勢，但幅度並不大。我認為你在美國以外地區看到的現像其實是──有兩件事。首先，您已經看到了我們投資組合協議的好處，而這正是這些協議的設計初衷。這些措施旨在縮短監管部門批准和報銷批准之間的時間差，以便患者和醫生能夠盡快獲得我們最新、最好的藥物。所以我認為，這正是導緻美國以外的患者能夠更快地獲得 SYMDEKO 或 SYMKEVI 的原因，而我們之前看到的 ORKAMBI 的情況則有所不同。另外，在德國，SYMKEVI 的上市情況實際上比 ORKAMBI 的上市情況好得多。我認為團隊在那裡做得非常出色。當然，該藥物的收益風險比肯定有所幫助，但毫無疑問，該團隊在德國的執行工作做得非常出色，而且 SYMKEVI 的上市進度遠超同期 ORKAMBI 的上市進度。我們看到一些初治患者也開始接受治療。我們發現一些曾經中斷治療的患者又重新開始接受治療。我們也看到一些轉變的跡象。所以我認為這確實是團隊執行力很強的一個例子。

Operator, we'll take 2 more questions.

接線員，我們再回答兩個問題。

And our next question comes from Brian Skorney of Baird.

下一個問題來自 Baird 公司的 Brian Skorney。

Jeff, I know we've kind of talked around this a little before, but I just wanted to kind of push you again on the consideration of 659 and 445 and which one you'll ultimately move forward with. I mean in chronic therapy, whether it's NRTIs in HIV or TNF-alphas, we really don't get kind of the full picture of efficacy and safety until you have tens of thousands of patient years behind you. So I guess my question is why not just submit both for approval and start to build that database and let patients and physicians ultimately decide which is the better triple combination when we have -- there's enough information out there to decide if there are subtle differences?

傑夫，我知道我們之前已經稍微討論過這個問題了，但我只是想再次敦促你考慮一下 659 和 445，以及你最終會選擇哪一個。我的意思是，在慢性治療中，無論是 HIV 的 NRTI 或 TNF-α，只有累積了數萬名患者年的臨床經驗，我們才能真正全面了解其療效和安全性。所以我想問的是，為什麼不把兩者都提交審批，開始建立資料庫，讓病人和醫生最終決定哪種三聯療法更好呢？畢竟我們已經有足夠的資訊來判斷是否存在細微差別。

Yes. It's a good question, Brian. We have talked about it a little bit before. And what we're balancing is our level of confidence in the information versus the potential confusion of patients and physicians when we're trying to launch 2 drugs simultaneously into the same population. And I think the good news here, and this is what Reshma said before, is just how good the efficacy data that we're seeing is. And so, so far what we're seeing is it's a hard choice because they're so similar. And if that turns out to be true when we look at the 24-week data, and we're seeing this kind of superior efficacy not only across the primary endpoint, but across all the secondary endpoints, I think we're going to have a very high level of confidence that whichever asset we choose as the best one is going to be very, very good for these patients. And then on the other side of the equation, as you know, as I know from being around for a while, trying to launch 2 drugs simultaneously into 1 patient population and explain that to doctors and patients can be very, very confusing. And once you do that, the ability to ultimately make your decision and withdraw 1 drug is virtually impossible. And so you're committed to, long term, having 2 drugs on the market that look identical and in different patient populations. And I think that's probably not the best thing to do for patients. So at the end of the day, the decision is it's best for patients to make the decision on the best asset and bring it to them. And we feel like we have enough data now in hundreds of patients so that we're going to be confident of what we're going to see.

是的。布萊恩，問得好。我們之前稍微討論過這個問題。我們正在權衡的是，我們對資訊的信心程度與同時向同一人群推出兩種藥物時可能給患者和醫生帶來的困惑。我認為這裡的好消息，也是雷什瑪之前說過的，就是我們看到的療效數據非常好。所以，目前我們看到的情況是，這是一個艱難的選擇，因為它們太相似了。如果查看 24 週的數據後證實了這一點，並且我們發現這種卓越的療效不僅體現在主要終點，也體現在所有次要終點，那麼我認為我們將非常有信心，無論我們選擇哪種最佳資產，對這些患者來說都將是非常非常好的。另一方面，正如你所知，也正如我多年經驗所表明的那樣，同時向同一患者群體推出兩種藥物，並向醫生和患者解釋這一點，可能會非常非常令人困惑。一旦你這樣做，最終做出決定並停止服用1種藥物的能力就幾乎不可能了。因此，從長遠來看，你們的目標是讓兩種外觀相同但針對不同患者群體的藥物上市。我認為這對病人來說可能不是最好的做法。所以歸根究底，最好的決定還是讓患者自己決定選擇最好的醫療資源，並帶給他們。我們感覺現在我們已經掌握了數百名患者的足夠數據，因此我們對即將看到的結果充滿信心。

And our last question comes from Alan Carr of Needham and Company.

最後一個問題來自 Needham and Company 的 Alan Carr。

I was wondering if you can elaborate a bit more about what's different with VX-121, what you're hoping to see there. And then with the pain program, maybe a little more detail around this too in terms of what you're looking for, for these next-generation compounds that you have in relation to VX-150. Why are you waiting to move forward with that? And what's involved in the decision process here?

我想請您詳細說明 VX-121 的不同之處，以及您希望在那裡看到什麼。然後，關於疼痛治療方案，或許也可以更詳細地說明一下，對於您與 VX-150 相關的這些下一代化合物，您正在尋找什麼。為什麼還在猶豫要不要推進這件事？那麼，這個決策過程涉及哪些面向呢？

Sure thing. This is Reshma. I'm going to tackle the first question, and I'm going to toss it over to Jeff to talk about pain. So as you know, our long-stated goal, and it remains today, is to bring therapies for all patients with CF. And in there, what we're trying to do is bring patients to carrier level. That's really, really important. And that also ties back to a point that Stuart made, we want to bring the most convenient regimen that brings all patients to carrier level. And so what we're doing is in our labs in San Diego is we have assays and many of you have seen them, our HBE cells that we now have a plethora of data of how these assays translate to the Phase II and Phase III results. And so we pick the best of the best molecules that come out of our labs. And when they meet these thresholds -- and I admit it, we have set an extremely high bar. But when there are molecules like VX-121 that meet this high bar, we advance them to the clinic to meet this ultimate goal. Jeff?

當然可以。這是雷什瑪。我先來回答第一個問題，然後把話題交給傑夫，讓他談談疼痛。如您所知，我們長期以來的目標，也是今天仍然不變的目標，是為所有囊性纖維化患者提供治療。在那裡，我們努力的目標是將患者提升到載體水平。這真的非常非常重要。這也與史都華提出的觀點相呼應，我們希望提供最方便的治療方案，讓所有患者都能達到攜帶者水準。因此，我們在聖地牙哥的實驗室裡進行了一些檢測，你們中的許多人都已經看到了，我們的 HBE 細胞，我們現在擁有大量數據，說明這些檢測如何轉化為 II 期和 III 期試驗結果。因此，我們從實驗室中挑選出最好的分子。當他們達到這些標準時——我承認，我們設定的標準非常高。但是，當出現像 VX-121 這樣符合這一高標準的分子時，我們會將其推進臨床試驗，以實現這一最終目標。傑夫？

Yes. With respect to the pain question, it's a bit similar to what Reshma was talking about before in terms of the portfolio modules. First thing I would say is we have, I think, convinced ourselves and others that we have very high efficacy molecules here with 150 and the approach we've taken. I think we've convinced ourselves [with a] reasonable number of patients that VX-150 is highly tolerable, and we're also very convinced that there's not addictive potential of these drugs. Those were the high things -- high bar we were trying to match for a new pain compound. Now we're in the process of picking the best drug, and that involves a lot of other things. So for example, is it formulatable to both IV and [PO], whether any manufacturing issues, cost of goods issues, dosing, dose scheduling. So in pain, what we'd like to have is the best molecule that combines efficacy, tolerability, lack of addictive potential, but also the right dose, the right dosing regimen, the IV to p.o. transition in the hospital. It's a pretty high bar, but because we have a whole portfolio of molecules, we believe we will find that molecule, and that's the one that we really want to take through Phase III and to commercialize.

是的。關於痛點問題，這和 Reshma 先前在投資組合模組方面談到的內容有點類似。首先我想說的是，我認為我們已經說服了自己和其他人，我們這裡有 150 種非常高效的分子，而且我們採取的方法也很有效。我認為我們已經透過相當數量的患者證實了 VX-150 具有很高的耐受性，我們也非常確信這些藥物沒有成癮性。這些都是很高的標準——我們試著為一種新的止痛化合物達到很高的標準。現在我們正在挑選最佳藥物，這涉及到許多其他因素。例如，它是否可以配製成靜脈注射和口服兩種劑型？是否有任何生產問題、商品成本問題、劑量問題、給藥方案問題？所以，在治療疼痛方面，我們希望找到一種最佳分子，它既具有療效，又具有耐受性，沒有成癮性，而且劑量合適，給藥方案合適，可以從靜脈注射到口服。醫院過渡期。這的確是一個很高的標準，但因為我們擁有一整套分子組合，我們相信我們會找到那個分子，而那個分子正是我們真正想要推進到 III 期臨床試驗並實現商業化的分子。

You're not running any efficacy studies with the earlier stage NaV1.8 compounds. It's just Phase I or...

你們沒有對早期 NaV1.8 化合物進行任何功效研究。這只是第一階段，或者…

Well, they're earlier, right? So they will enter -- we hope to enter the clinic this year with them. We again have learned a lot from our VX-150 experience and so we hope that as we get through to Phase I, we'll be able to pretty quickly go through Phase II programs and compare them to VX-150 and make decisions about which are the best molecules to take forward. And that doesn't mean, by the way, that it's not VX-150, but I just want to make it clear that we're taking a portfolio approach.

他們來得更早，對吧？所以他們將進入——我們希望今年能和他們一起進入診所。我們從 VX-150 的經驗中又學到了很多，所以我們希望，當我們進入 I 期臨床試驗後，能夠很快地開展 II 期臨床試驗，並將它們與 VX-150 進行比較，從而決定哪些分子最適合繼續推進。順便說一句，這並不意味著它不是 VX-150，但我只是想明確指出，我們正在採取組合策略。

And ladies and gentlemen, this does conclude our question-and-answer session. I would now like to turn the call back over to Michael Partridge for any closing remarks.

女士們、先生們，我們的問答環節到此結束。現在我想把電話轉回給麥可‧帕特里奇，請他作總結發言。

Thank you all for joining the call tonight. The Investor Relations team is here in the office if you have additional questions. Have a good evening.

感謝各位今晚參加電話會議。如果您還有其他問題，投資者關係團隊就在辦公室。祝你晚上愉快。

Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program. You may all disconnect. Everyone, have a great day.

女士們、先生們，感謝各位參加今天的會議。今天的節目到此結束。你們可以斷開連結了。祝大家今天過得愉快。