BioCryst Pharmaceuticals Inc (BCRX) 2022 Q3 法說會逐字稿

Hello, and welcome to the BioCryst Third Quarter 2022 Earnings Conference Call. My name is Michelle, and I will be your operator for today's conference. (Operator Instructions) As a reminder, the conference is being recorded.

您好，歡迎來到 BioCryst 2022 年第三季度收益電話會議。我叫米歇爾，我將擔任今天會議的接線員。 （操作員說明）提醒一下，會議正在錄製中。

I will now turn the call over to Mr. John Bluth with BioCryst. Sir, you may begin.

我現在將把電話轉給 BioCryst 的 John Bluth 先生。先生，您可以開始了。

Thanks, Michelle. Good morning, and welcome to BioCryst's Third Quarter 2022 Corporate Update and Financial Results Conference Call. Today's press release and accompanying slides are available on our website. Participating with me today are CEO, Jon Stonehouse; CFO, Anthony Doyle; Chief Commercial Officer, Charlie Gayer; and Chief R&D Officer, Dr. Helen Thackray. Following our remarks, we will answer your questions.

謝謝，米歇爾。早上好，歡迎來到 BioCryst 2022 年第三季度公司更新和財務業績電話會議。今天的新聞稿和隨附的幻燈片可在我們的網站上獲取。今天和我一起參加的有首席執行官 Jon Stonehouse；首席財務官安東尼道爾；首席商務官 Charlie Gayer；和首席研發官 Helen Thackray 博士。在我們的評論之後，我們將回答您的問題。

Before we begin, please note that today's conference call will contain forward-looking statements, including those statements regarding future results, unaudited and forward-looking financial information as well as the company's future performance and/or achievements. These statements are subject to known and unknown risks and uncertainties, which may cause our actual results, performance or achievements to be materially different from any future results or performance expressed or implied in this presentation. You should not place undue reliance on these forward-looking statements. For additional information, including a detailed discussion of our risk factors, please refer to the company's documents filed with the Securities and Exchange Commission, which can be accessed on our website.

在我們開始之前，請注意今天的電話會議將包含前瞻性陳述，包括關於未來結果、未經審計和前瞻性財務信息以及公司未來業績和/或成就的陳述。這些陳述受到已知和未知的風險和不確定性的影響，這些風險和不確定性可能導致我們的實際結果、業績或成就與本演示文稿中明示或暗示的任何未來結果或業績存在重大差異。您不應過分依賴這些前瞻性陳述。如需更多信息，包括對我們風險因素的詳細討論，請參閱公司向美國證券交易委員會備案的文件，這些文件可在我們的網站上訪問。

I'd now like to turn the call over to Jon Stonehouse.

我現在想把電話轉給 Jon Stonehouse。

Thanks, John. We continue to see steady progress with the ORLADEYO launch, and underlying growth trends remain strong. New patient starts are consistent with previous quarters, discontinuations appear to have stabilized, and we are investing more to keep this momentum going. Based on our expectations for continued growth in Q4, we plan to exit 2022 having more than doubled sales from the great start we had last year, and we'll be a 1/4 of the way to our expected peak of $1 billion globally in just the second year of launch. We've shown you long-term data from our trials, and we will continue to show you real world data that our drug works very well in many patients.

謝謝，約翰。我們繼續看到 ORLADEYO 推出的穩步進展，並且潛在的增長趨勢依然強勁。新患者的開始與前幾個季度一致，停藥似乎已經穩定下來，我們正在加大投資以保持這種勢頭。根據我們對第四季度持續增長的預期，我們計劃到 2022 年銷售額比去年的良好開端翻一番以上，我們將達到 10 億美元全球預期峰值的 1/4剛剛推出的第二年。我們已經向您展示了我們試驗的長期數據，我們將繼續向您展示真實世界的數據，表明我們的藥物對許多患者都非常有效。

The competitive landscape has changed, too, and is a reminder of how challenging it is to pursue a strategy of oral drugs in HAE. Right now, and perhaps for some time to come, ORLADEYO is the only direct-acting oral with once-daily dosing to prevent HAE attacks. With this unique offering and product profile, we believe this is a therapy every patient should have the opportunity to try to see if it works for them. Charlie will share more specifics on the ORLADEYO quarter performance in a minute.

競爭格局也發生了變化，這提醒人們在 HAE 中推行口服藥物戰略是多麼具有挑戰性。現在，也許在未來一段時間內，ORLADEYO 是唯一一種每天一次給藥的直接作用口服藥物，可預防 HAE 發作。憑藉這種獨特的產品和產品概況，我們相信這是一種療法，每個患者都應該有機會嘗試看看它是否對他們有效。查理將在一分鐘內分享更多關於 ORLADEYO 季度表現的細節。

Our strategy of going after challenging targets, specifically serine proteases for patients suffering from rare diseases, is rooted in our ability to discover potent, specific and bioavailable molecule. In the case of HAE, we were able to do that -- do what others haven't: develop an oral once-daily kallikrein inhibitor. We believe this allows us to offer something unique to these patients, and we believe HAE is just the start.

我們追求具有挑戰性的目標，特別是針對患有罕見疾病的患者的絲氨酸蛋白酶，其戰略植根於我們發現強效、特異性和生物可利用分子的能力。在 HAE 的案例中，我們能夠做到這一點——做其他人做不到的事情：開發一種每天口服一次的激肽釋放酶抑製劑。我們相信這使我們能夠為這些患者提供一些獨特的東西，我們相信 HAE 只是一個開始。

In addition, because these are difficult targets, we don't stop at the first molecule we discover. We work on improved next-generation compounds. We saw that with avoralstat and ORLADEYO. We believe we've done it again with Factor D. We are fortunate to have 2 molecules again, and that puts us in a position to potentially have the first oral Factor D monotherapy molecule to market and the next generation that perhaps will be the best. While the future of 9930 is still to be determined, our expectation is we will get an answer to our hypothesis on data from the first 15 or so patients treated for 2 to 3 months by the middle of next year.

此外，因為這些是困難的目標，我們不會停留在我們發現的第一個分子上。我們致力於改進下一代化合物。我們通過 avoralstat 和 ORLADEYO 看到了這一點。我們相信我們已經用 D 因子再次做到了。我們很幸運再次擁有 2 個分子，這使我們有可能將第一個口服 D 因子單一療法分子推向市場，而下一代可能是最好的.雖然 9930 的未來仍有待確定，但我們預計我們將在明年年中之前從前 15 名左右接受治療 2 至 3 個月的患者的數據中得到對我們假設的答案。

We have also been working on additional next-generation complement inhibitors, including BCX10013, a potential once-daily oral Factor D inhibitor that we have advanced into the clinic. In Q1 of next year, we plan to show you data in humans that supports the potential of once-daily dosing. Our plan is to go into rare disease patients in dose-ranging proof-of-concept studies with 10013 next year as well. But we won't stop there.

我們還一直在研究其他下一代補體抑製劑，包括 BCX10013，這是一種潛在的每日一次口服 D 因子抑製劑，我們已將其推進臨床。在明年第一季度，我們計劃向您展示支持每日一次給藥潛力的人體數據。我們的計劃是明年也對 10013 名患者進行劑量範圍概念驗證研究。但我們不會就此止步。

The complement system is complex, and blocking more than one pathway allows us to go after more rare diseases and may be necessary to successfully treat some patients. So we also have a discovery effort, and we're making great progress on other targets in the complement system. If successful, we'll be able to go after other rare diseases and possibly combine molecules to make the best therapy in one capsule or tablet. We plan to show you more in our R&D Day next year.

補體系統很複雜，阻斷不止一種途徑使我們能夠治療更多罕見疾病，並且可能是成功治療某些患者所必需的。所以我們也有發現的努力，我們在補體系統的其他目標上取得了很大進展。如果成功，我們將能夠研究其他罕見疾病，並可能將分子結合起來，在一個膠囊或藥片中製成最佳療法。我們計劃在明年的研發日向您展示更多。

So the goal, simply stated, is to be the global leader in complement, simple to state but very challenging to do. We believe this strategy and our discovery platform allows us to do things that others may not be able to do, and we look forward to showcasing it to you next year.

因此，簡單地說，目標是成為補品領域的全球領導者，說起來簡單，但做起來卻非常具有挑戰性。我們相信這一戰略和我們的發現平台可以讓我們做其他人可能做不到的事情，我們期待明年向您展示它。

So what does this mean for you as a shareholder? It starts with the evidence that we can successfully discover, develop and launch an oral drug directed at a challenging target that offers something unique to patients. The result we expect is ORLADEYO will fill an unmet need for thousands of HAE patients and will reach $1 billion in global peak sales. That is a major accomplishment that sets us apart to create meaningful value for patients and shareholders.

那麼這對您作為股東意味著什麼？首先是有證據表明，我們可以成功發現、開發和推出針對具有挑戰性目標的口服藥物，為患者提供獨特的東西。我們預期的結果是 ORLADEYO 將填補數千名 HAE 患者未滿足的需求，並將達到 10 億美元的全球峰值銷售額。這是一項重大成就，使我們與眾不同，能夠為患者和股東創造有意義的價值。

And we plan to do it again in complement, but not with one molecule or one pathway. Imagine many molecules for multiple pathways making the best and unique therapies others may not. That value is many, many more patients and potentially multiples of ORLADEYO peak sales.

我們計劃在補體中再做一次，但不是用一種分子或一種途徑。想像一下，許多用於多種途徑的分子可以做出其他人可能無法做到的最好和獨特的療法。這個價值是很多很多的患者，並且可能是 ORLADEYO 峰值銷售額的倍數。

Now I'll turn the call over to Charlie to go over the ORLADEYO performance.

現在我將電話轉給查理，讓他回顧一下 ORLADEYO 的表演。

Thanks, Jon. The core metrics for ORLADEYO were strong once again in the third quarter. New patient starts were right in line with our 6 quarter running average. The absolute number of discontinuations was flat to slightly improved for the second quarter in a row, and we saw a 9% growth in patients on paid therapy. All these metrics point to what we have described previously, a pattern of consistent linear growth for ORLADEYO. I'll share more detail on what we saw in the quarter, and later Anthony will provide context for how patient growth translated to revenue.

謝謝，喬恩。 ORLADEYO 的核心指標在第三季度再次表現強勁。新患者的開始與我們的第 6 個季度運行平均值一致。停藥的絕對數量連續第二個季度持平或略有改善，我們看到付費治療的患者增長了 9%。所有這些指標都指向我們之前描述的內容，即 ORLADEYO 的持續線性增長模式。我將分享我們在本季度看到的更多細節，稍後安東尼將提供患者增長如何轉化為收入的背景。

We continue to add breadth and depth to the ORLADEYO prescriber base and several facts point to our ability to expand ORLADEYO use. The overall prescriber base grew by another 11% in Q3, and we had the largest number of repeat prescribers in the quarter as more physicians offer ORLADEYO to additional patients in their practices. Top 500 HAE treaters accounted for 54% of new ORLADEYO prescriptions, and about 25% of top 500 prescribers in Q3 were newly activated. We also had the largest number of Tier 2 prescribers in any quarter to date.

我們繼續增加 ORLADEYO 處方者基礎的廣度和深度，有幾個事實表明我們有能力擴大 ORLADEYO 的使用。第三季度整體開處方者人數又增長了 11%，隨著越來越多的醫生在他們的實踐中向更多患者提供 ORLADEYO，我們在本季度擁有最多的重複開處方者。前 500 名 HAE 治療師佔 ORLADEYO 新處方的 54%，Q3 前 500 名處方者中約有 25% 是新激活的。迄今為止，我們在任何季度都擁有數量最多的 2 級處方醫生。

These trends are consistent with another survey that we conducted with 60 allergists in September. As we have seen in prior surveys, physicians anticipated the percentage of their patients treated with ORLADEYO would grow more than any other HAE therapy over the next 12 months. They anticipate expanding use because they have seen our long-term clinical data, many also have firsthand experience with ORLADEYO. And our physician survey shows that ORLADEYO is the most requested HAE prophylaxis medication amongst patients.

這些趨勢與我們在 9 月份對 60 名過敏症專家進行的另一項調查一致。正如我們在之前的調查中看到的那樣，醫生預計在未來 12 個月內，接受 ORLADEYO 治療的患者比例將增長超過任何其他 HAE 治療。他們預計會擴大使用，因為他們已經看到了我們的長期臨床數據，許多人還擁有 ORLADEYO 的第一手經驗。我們的醫生調查顯示，ORLADEYO 是患者最需要的 HAE 預防藥物。

Next week, at the American College of Asthma, Allergy and Immunology Congress, we will have an oral presentation and a poster from large cohorts of patients who started on ORLADEYO after the launch. This real-world evidence confirms what physicians are seeing. Regardless of baseline attack rate or prior therapy, patients experience excellent long-term control.

下週，在美國哮喘、過敏和免疫學學會大會上，我們將有一個口頭報告和一張來自在 ORLADEYO 上市後開始使用 ORLADEYO 的大量患者的海報。這一真實世界的證據證實了醫生所看到的。無論基線發病率或既往治療如何，患者都能獲得出色的長期控制。

Even with the success we've seen since launch, we constantly evaluate opportunities to invest to do more. In Q3, we identified 2 such opportunities. The first is to add incrementally to our sales team to further accelerate impact in top 500 physicians. The second is to add to our field market access team so that as we broaden our prescriber base, we can help practices that have less experience seeking payer authorization for HAE therapies.

即使我們自推出以來取得了成功，我們也會不斷評估投資機會以做更多事情。在第三季度，我們確定了 2 個這樣的機會。首先是逐步增加我們的銷售團隊，以進一步加快對 500 強醫生的影響。第二個是增加我們的現場市場准入團隊，這樣當我們擴大我們的處方者基礎時，我們可以幫助那些在尋求 HAE 療法的付款人授權方面經驗較少的實踐。

As we round out the second year on the market for ORLADEYO, we are excited about the future potential. One month into this quarter, our underlying metrics remain strong. We expect to see a double-digit revenue growth percentage in the fourth quarter with total ORLADEYO sales for the year ending at $255 million, more than doubling 2021 sales.

隨著 ORLADEYO 進入市場的第二年，我們對未來的潛力感到興奮。本季度一個月後，我們的基本指標仍然強勁。我們預計第四季度的收入增長率將達到兩位數，ORLADEYO 全年的總銷售額將達到 2.55 億美元，是 2021 年銷售額的兩倍多。

Helen, I'll turn the call over to you.

海倫，我會把電話轉給你。

Thanks, Charlie. Today, I'll discuss a few significant updates on our pipeline programs, including progress with our current molecules and our future goals for advancing multiple new drug candidates to treat complement-mediated diseases. As we continue to advance our pipeline, an important goal which we believe is achievable, is to bring novel orally-delivered products forward to treat many complement-mediated diseases. Our vision is to be the global leader in delivering medications targeting dysfunction across the complement system.

謝謝，查理。今天，我將討論我們管道計劃的一些重要更新，包括我們當前分子的進展以及我們推進多種新候選藥物治療補體介導疾病的未來目標。隨著我們繼續推進我們的管道，我們認為可以實現的一個重要目標是推出新型口服產品來治療許多補體介導的疾病。我們的願景是成為提供針對整個補體系統功能障礙的藥物的全球領導者。

What's new at BioCryst today is some important progress we've made towards that vision. We have expanded our Factor D inhibitor program targeting the alternative pathway with a second potentially best-in-class molecule in the clinic. And we've identified several additional targets where there is potential for oral drugs to address the other major pathways of the complement system. Our discovery team has already made progress towards generating molecules for each of these targets, giving us confidence that our unique discovery platform has the capability to produce oral drugs for these challenging targets. If successful, this would multiply our opportunities to treat diseases mediated by dysregulation of the complement cascade.

今天 BioCryst 的新內容是我們在實現這一願景方面取得的一些重要進展。我們已經擴展了我們的因子 D 抑製劑計劃，目標是在臨床上使用第二個可能同類最佳的分子來替代途徑。我們已經確定了幾個額外的目標，口服藥物有可能解決補體系統的其他主要途徑。我們的發現團隊已經在為每個目標生成分子方面取得了進展，這讓我們相信我們獨特的發現平台有能力為這些具有挑戰性的目標生產口服藥物。如果成功，這將增加我們治療由補體級聯失調介導的疾病的機會。

So in total, we are not only adding a second oral Factor D inhibitor to our portfolio for the alternative pathway, but also building the potential for multiple additional oral drugs to address diseases across the complement system, including those with the classical pathway, lectin pathway and terminal pathway.

因此，總的來說，我們不僅在我們的替代途徑產品組合中添加了第二種口服 D 因子抑製劑，而且還建立了多種額外口服藥物的潛力，以解決整個補體系統的疾病，包括那些具有經典途徑、凝集素途徑的疾病和終端路徑。

We intend to invest in the development of a number of oral medicines for these targets. If we are successful in delivering oral treatments for more than 1 pathway in the complement system, imagine also the possibility of addressing several pathways at once with combined oral drugs. This could expand treatment opportunities even further with monotherapy, single pathway approaches and with combination multiple pathway approaches for treatment of the most complex or serious diseases.

我們打算針對這些目標投資開發多種口服藥物。如果我們成功地為補體系統中的一種以上途徑提供口服治療，那麼還可以想像使用聯合口服藥物同時解決多種途徑的可能性。這可以通過單一療法、單一途徑方法和組合多途徑方法進一步擴大治療機會，以治療最複雜或嚴重的疾病。

Now I'll go into some of the specifics, illustrating why we believe we can deliver both the first and then a best-in-class oral monotherapy Factor D inhibitor for our program targeting the alternative pathway. Overall, the goals of this program are twofold: one, to quickly bring a first molecule to market, putting BioCryst in a position to deliver the first safe and effective oral monotherapy Factor D inhibitor to patients across multiple complement-mediated diseases. BCX9930 has the potential to achieve this, and our near-term focus is on assessing swiftly and efficiently whether we have successfully identified a safe and effective dose regimen that will keep our REDEEM pivotal trial in PNH on a path to registration.

現在我將詳細介紹一些細節，說明為什麼我們相信我們可以為我們針對替代途徑的項目提供第一個和隨後最好的口服單一療法 D 因子抑製劑。總體而言，該計劃的目標有兩個：第一，快速將第一個分子推向市場，使 BioCryst 能夠為多種補體介導疾病的患者提供第一個安全有效的口服單一治療因子 D 抑製劑。 BCX9930 有可能實現這一目標，我們近期的重點是快速有效地評估我們是否已成功確定一種安全有效的劑量方案，使我們在 PNH 的 REDEEM 關鍵試驗走上註冊之路。

And two, to continue to produce and advance unique new molecules to achieve best-in-class outcomes for patients. By this, we mean molecules that bring some combination of improved potency, improved safety, or with longer exposure at therapeutic levels with oral delivery. And even more specifically, we mean a therapy that is differentiated in the field by delivering a safe and effective therapy in a once-daily dose. We did this with ORLADEYO, and we believe we can do it again.

第二，繼續生產和推進獨特的新分子，為患者實現一流的結果。通過這種方式，我們指的是分子能夠帶來更高的效力、更高的安全性，或者在口服給藥的治療水平下具有更長的暴露時間。更具體地說，我們指的是通過以每日一次的劑量提供安全有效的療法而在該領域脫穎而出的療法。我們用 ORLADEYO 做到了這一點，我們相信我們可以再次做到。

With BCX9930, we've made steady progress towards reinitiating enrollment with the pivotal program. We've begun screening new patients for enrollment in the REDEEM trials and are gaining some initial experience at the lower dose in patients already on our studies. You will remember that we amended the REDEEM and RENEW protocols with a new dosing regimen of 400 milligrams twice daily with a brief step up at the start of dosing in our effort to confirm a safe and effective dose for BCX9930. Our hypothesis is that this new dosing regimen, together with attention to simple hydration, may prevent the rise in serum creatinine observed in some patients previously at 500 milligrams twice daily.

借助 BCX9930，我們在重新啟動關鍵計劃的註冊方面取得了穩步進展。我們已經開始篩選新患者以加入 REDEEM 試驗，並在已經參與我們研究的患者中獲得一些較低劑量的初步經驗。您會記得，我們修改了 REDEEM 和 RENEW 方案，採用每天兩次 400 毫克的新給藥方案，並在開始給藥時短暫增加，以確認 BCX9930 的安全有效劑量。我們的假設是，這種新的給藥方案，加上註意簡單的水合作用，可能會阻止以前在每天兩次 500 毫克時觀察到的一些患者的血清肌酐升高。

All patients who continue on BCX9930 have been switched from 500 milligrams to a lower dose. At this point, and with initial and limited experience, it is too early to draw any conclusions about the success of these steps. Of course, if we observe something that warrants holding or discontinuing the program, we will update you earlier as that occurs. Otherwise, our plan is to bring an update mid-2023 with more robust data from approximately 15 newly enrolled patients. If the new dosing regimen resolves the observations of renal injury, our plan would be to invest fully in the pivotal program and bring BCX9930 to market as quickly as possible. And if this is not demonstrated, we will discontinue the program.

所有繼續服用 BCX9930 的患者都已從 500 毫克劑量改為較低劑量。在這一點上，根據初步和有限的經驗，現在就這些步驟的成功得出任何結論還為時過早。當然，如果我們觀察到需要暫停或終止該計劃的情況，我們會在發生這種情況時提前通知您。否則，我們的計劃是在 2023 年年中更新，其中包含來自大約 15 名新入組患者的更可靠數據。如果新的給藥方案解決了腎損傷的觀察結果，我們的計劃將是對關鍵項目進行全面投資，並儘快將 BCX9930 推向市場。如果沒有證明這一點，我們將終止該計劃。

In addition, as I mentioned earlier, we are also advancing BCX10013 as the second unique molecule with the potential to be a differentiated product for the proximal alternative pathway of complement with once-daily dosing. BCX10013 has been moving at full speed for some time and as a result is already in the clinic. We are reporting today that BCX10013 is being assessed in healthy volunteers at multiple dose levels, including at potentially therapeutic dose levels with single ascending doses and multiple ascending doses.

此外，正如我之前提到的，我們還在推進 BCX10013 作為第二個獨特的分子，有可能成為補體近端替代途徑的差異化產品，每日一次給藥。 BCX10013 已經全速發展了一段時間，因此已經進入臨床。我們今天報告說，BCX10013正在健康志願者中進行多劑量水平評估，包括單次遞增劑量和多次遞增劑量的潛在治療劑量水平。

Approximately 90 healthy volunteers have been dosed with BCX10013 at this point, and so far, we have observed an initial safety, tolerability and PK profile that's not only supportive of advancing into evaluation in patients, but also looks promising for once-daily dosing. Our plan is to initiate patient studies to confirm the best dose level for advancement into a registration program. We'll have more to share with you about the data and the plan for this program in first quarter 2023.

此時大約有 90 名健康志願者接受了 BCX10013 給藥，到目前為止，我們已經觀察到初步的安全性、耐受性和 PK 概況，這不僅支持推進對患者的評估，而且看起來有希望每天給藥一次。我們的計劃是啟動患者研究，以確認進入註冊計劃的最佳劑量水平。我們將在 2023 年第一季度與您分享更多有關該計劃的數據和計劃。

Finally, another pipeline update, I'll turn to BCX9250 and FOP. Here, the competitive landscape for the ultra-rare disease -- this ultra-rare disease is increasingly crowded, including with several late-stage programs assessing the same mechanism of action for the treatment of this disease as BCX9250, that of ALK-2 inhibition. We have concluded that it's increasingly likely the needs of patients here may be served by other products before BCX9250 can achieve registration. We are, therefore, discontinuing development of BCX9250 and redirecting the investment of this program towards our many opportunities in complements.

最後，另一個管道更新，我將轉向 BCX9250 和 FOP。在這裡，超罕見疾病的競爭格局——這種超罕見疾病越來越擁擠，包括幾個後期項目評估與 BCX9250 相同的治療這種疾病的作用機制，即 ALK-2 抑制.我們得出的結論是，在 BCX9250 獲得註冊之前，其他產品可能會越來越有可能滿足這裡患者的需求。因此，我們將停止 BCX9250 的開發，並將對該計劃的投資重新轉向我們在補充方面的許多機會。

To conclude today's update on our pipeline, I'll repeat a theme you've heard from us before. We have succeeded with delivering orally administrated -- orally administered small molecules for challenging targets. This capability gives us very high confidence that we can achieve our goal discussed today to deliver oral drugs across multiple very difficult targets in the complement system.

為了結束今天關於我們管道的更新，我將重複你之前從我們這裡聽到的一個主題。我們已經成功地提供口服給藥——針對具有挑戰性的目標的口服給藥小分子。這種能力使我們非常有信心能夠實現我們今天討論的目標，即在補體系統中為多個非常困難的目標提供口服藥物。

Now I'll pass it to Anthony.

現在我將它傳遞給安東尼。

Thanks, Helen. With ORLADEYO net revenue for the quarter coming in at $66 million, that puts trailing 12-month revenue at around $227 million. That's already over $100 million more than our 2021 full year revenue. When comparing Q2 ORLADEYO revenue, which came in at $65.2 million to Q3 revenue at $66 million, there are a couple of things that we need to review to align to our comments on steady growth.

謝謝，海倫。 ORLADEYO 本季度的淨收入為 6600 萬美元，這使得過去 12 個月的收入約為 2.27 億美元。這已經比我們 2021 年的全年收入多出 1 億多美元。在比較第二季度 ORLADEYO 的收入（6520 萬美元）和第三季度的收入 6600 萬美元時，我們需要審查幾件事以與我們對穩定增長的評論保持一致。

For Q2, we had a $2.2 million positive out-of-period reimbursement adjustment. We also had over $1 million of what would ordinarily have been July shipment that patients requested to ship in June due to the 4th of July holiday. For Q3, we also had a $500,000 negative out-of-period reimbursement adjustment. Factoring in these elements, Q2 revenue would have come in at closer to $62 million, while Q3 revenue would have come in at $67.5 million. That's around 9% growth quarter-over-quarter.

對於第二季度，我們進行了 220 萬美元的正期外報銷調整。由於 7 月 4 日假期，我們還有超過 100 萬美元的運費，通常是 7 月運費，患者要求在 6 月運費。對於第三季度，我們還進行了 500,000 美元的負期外報銷調整。考慮到這些因素，第二季度的收入將接近 6200 萬美元，而第三季度的收入將達到 6750 萬美元。環比增長約 9%。

Even without taking into consideration these adjustments, the compounded quarterly growth rate from the end of last year where Q4 came in at around $46 million to Q3 of 2022 is over 9% growth quarter-over-quarter. This steady growth, driven by the consistency of new starts and stabilizing DC rates, coupled with continued global expansion, gives us confidence that Q4 will deliver double-digit percentage growth over Q3, and as Charlie said, we are forecasting revenue for full year 2022 at $255 million. That's more than double our net revenue from last year and positions us well on our path to $1 billion of global peak sales.

即使不考慮這些調整，從去年年底第四季度的複合季度增長率約為 4600 萬美元到 2022 年第三季度的環比增長率也超過 9%。在新開工的一致性和穩定的 DC 費率以及持續的全球擴張的推動下，這種穩定的增長使我們相信第四季度將比第三季度實現兩位數的百分比增長，正如查理所說，我們預測 2022 年全年的收入2.55億美元。這是我們去年淨收入的兩倍多，使我們在實現 10 億美元全球銷售額峰值的道路上處於有利地位。

You can find our detailed third quarter financials in today's earnings press release, and I'd like to call your attention to a few items. Total revenue for the quarter was $75.8 million. Outside of the $66 million for ORLADEYO, the remaining revenue came from a $6.9 million RAPIVAB stockpile order and $2.9 million from RAPIVAB API sales to our partners.

您可以在今天的收益新聞稿中找到我們詳細的第三季度財務數據，我想提請您注意一些事項。本季度的總收入為 7580 萬美元。除了 ORLADEYO 的 6600 萬美元外，其餘收入來自 690 萬美元的 RAPIVAB 庫存訂單和 290 萬美元的 RAPIVAB API 銷售給我們的合作夥伴。

Operating expenses not including non-stock cash compensation for the quarter was $83.3 million, and cash at the end of the quarter was at $463 million. That includes the $75 million that we drew from the Athyrium facility in July. Capital allocation is critical to growing biotechs like ours. And when 9930 enrollment was paused, our team did a great job of controlling both internal and external spend, at the same time, as identifying a hypothesis to potentially remediate the issue, getting agreement from the FDA to list the partial clinical hold and ultimately getting the trial back up and running as quickly as they did.

本季度不包括非股票現金補償的運營費用為 8330 萬美元，本季度末現金為 4.63 億美元。這包括我們在 7 月份從 Athyrium 設施中提取的 7500 萬美元。資本配置對於像我們這樣的生物技術公司的成長至關重要。當 9930 註冊暫停時，我們的團隊在控制內部和外部支出方面做得很好，同時，確定了一個可能解決問題的假設，獲得 FDA 的同意列出部分臨床暫停並最終獲得試驗像他們一樣快速地恢復和運行。

When we started the year, we guided to ORLADEYO net revenue of no less than $250 million and OpEx of between $440 million and $480 million. Before the enrollment hold for 9930, we were definitely looking at being at the higher end of that OpEx guidance. We're now guiding to $255 million in revenue and between $365 million and $370 million of OpEx for full year 2022, which is more than $100 million less in OpEx than the higher end of that initial guidance. Net cash utilization is therefore significantly lower than we had anticipated coming into the year, which in the current macroeconomic environment is tremendously valuable.

今年年初，我們指導 ORLADEYO 的淨收入不少於 2.5 億美元，運營支出在 4.4 億美元至 4.8 億美元之間。在 9930 註冊暫停之前，我們肯定希望處於該 OpEx 指南的高端。我們現在指導 2022 年全年的收入為 2.55 億美元，運營支出在 3.65 億美元至 3.7 億美元之間，這比最初指導的上限低 1 億多美元。因此，淨現金利用率大大低於我們今年的預期，這在當前的宏觀經濟環境下非常有價值。

As Helen mentioned, we're also discontinuing BCX9250, which would have required more than $100 million of investment over the coming years. This disciplined approach to capital allocation and our healthy balance sheet puts us in a strong position to invest in our future growth opportunities.

正如 Helen 提到的，我們還將停止 BCX9250，這在未來幾年需要超過 1 億美元的投資。這種嚴格的資本配置方法和我們健康的資產負債表使我們在投資未來增長機會方面處於有利地位。

Now operator, we'll be happy to open up to Q&A.

現在是接線員，我們很樂意開放問答環節。

(Operator Instructions) And the first question in the queue comes from Ken Cacciatore with Cowen and Company.

（操作員說明）隊列中的第一個問題來自 Cowen and Company 的 Ken Cacciatore。

Great explanation on Q3. I appreciate that on ORLADEYO. I was just wondering with the investments that you're making to continue to press the advantage you have with the commercial spend, do you want to give us a little bit of thoughts as we look into 2023? It seems like Q4 is on a nice trend already. Maybe any context you can provide for ORLADEYO and maybe discuss when we should start seeing a little bit more ex-U.S. contribution.

關於 Q3 的很好的解釋。我很欣賞 ORLADEYO。我只是想知道您為繼續發揮商業支出優勢而進行的投資，在我們展望 2023 年時，您是否想給我們一些想法？看起來第四季度的趨勢已經不錯了。也許你可以為 ORLADEYO 提供任何背景，也許可以討論我們什麼時候應該開始看到更多的美國以外的人。貢獻。

And I wanted to give a follow-up now because I know you want to limit to one question. Jon, just in general, as you think about the company, wonderful success commercially with ORLADEYO and on the pathway to $1 billion, but an earlier stage pipeline. We saw Biohaven take the opportunity to really maximize the value of their lead commercial asset with a pipeline that was trailing. As you kind of look at the company and how the value you've created in ORLADEYO plus kind of the little bit of an earlier stage pipeline, albeit we hope 9930 continues to progress, can you just talk about how the company is looking at maybe maximizing the value of these 2? Would something like Biohaven's approach makes sense to your organization?

我現在想跟進，因為我知道你想限制一個問題。喬恩，總的來說，當你想到這家公司時，ORLADEYO 在商業上取得了巨大的成功，並在通往 10 億美元的道路上，但處於早期階段。我們看到 Biohaven 藉此機會通過落後的管道真正最大化其主要商業資產的價值。當你看待公司以及你在 ORLADEYO 中創造的價值以及早期管道的一點點時，儘管我們希望 9930 繼續取得進展，你能談談公司的看法嗎？最大化這兩個的價值？ Biohaven 的方法對您的組織有意義嗎？

Yes. Charlie, you want to -- I'll take the first one.

是的。查理，你想——我要第一個。

You want to start with the last one, and I'll come back to...

你想從最後一個開始，我會回來...

Yes. So Ken, the strategy, I guess I look at it slightly differently. We have a pivotal program going on with 9930. And our expectation is if we find a safe and effective dose, we're off to the races with that molecule and competing with an oral drug in an injectable space. So I don't see a big gap there. And at the end of the day, it's steady revenue growth. So if we're not burning a lot of capital on the R&D side, the revenue catches up. And you saw that this year with Anthony's guidance, I mean, we're a little more than what, $100 million apart for the year in terms of revenue and expense.

是的。所以 Ken，這個策略，我想我對它的看法略有不同。我們有一個關於 9930 的關鍵計劃。我們的期望是，如果我們找到安全有效的劑量，我們將開始與該分子競賽，並在可注射空間與口服藥物競爭。所以我看不出那裡有很大的差距。歸根結底，這是穩定的收入增長。因此，如果我們不在研發方面消耗大量資金，收入就會迎頭趕上。你看到今年在安東尼的指導下，我的意思是，我們今年的收入和支出相差 1 億美元。

So if you look at all the other biotech companies around our size, that is a unique position to be in. We'll always be open to other options and other creative solutions like Biohaven has done. But right now, we're building a pipeline and we're launching a drug that we believe is going to be $1 billion. Charlie?

因此，如果你看看我們規模附近的所有其他生物技術公司，這是一個獨特的位置。我們將始終對其他選擇和其他創造性解決方案持開放態度，就像 Biohaven 所做的那樣。但現在，我們正在建設一條管道，我們正在推出一種我們認為價值 10 億美元的藥物。查理？

Ken, so on your other questions around the commercial investments. Yes, I think the first thing to say is, and Jon mentioned this upfront, we still have all confidence in the world that this is a $1 billion peak sales drug. And so as we look to make other investments, it's really about being as efficient and accelerated in that process as possible. You're asking around 2023. I think we'll give guidance for 2023 in early next year. But we feel good -- very good about our trajectory based on the underlying trends. And then as far as ex U.S., eventually, at some point, we'll probably start to break that out. It's still for 2022 a small percentage of sales. But everything that we see in the underlying trends in Europe and beyond gives us confidence that, that will contribute $200 million plus at peak sales. So we're feeling really good about where we are.

肯，關於商業投資的其他問題。是的，我想首先要說的是，喬恩提前提到了這一點，我們仍然對世界充滿信心，認為這是一種 10 億美元的峰值銷售藥物。因此，當我們尋求進行其他投資時，它實際上是關於在該過程中盡可能高效和加速。你問的是 2023 年左右。我想我們會在明年初給出 2023 年的指導。但我們感覺很好——基於潛在趨勢的軌跡非常好。然後就前美國而言，最終，在某個時候，我們可能會開始打破它。到 2022 年，它仍然只佔銷售額的一小部分。但我們在歐洲及其他地區的潛在趨勢中看到的一切都讓我們相信，這將在銷售高峰期貢獻 2 億美元以上。所以我們對我們所處的位置感覺非常好。

Next question in the queue comes from Chris Raymond with Piper Sandler.

隊列中的下一個問題來自 Chris Raymond 和 Piper Sandler。

So a question and also a follow-up. Just on the ORLADEYO quarter-to-quarter dynamics. I appreciate the color on the puts and takes from Q2 and also Q3. But can you maybe provide some color on the timing for understanding this dynamic and recognizing that pull forward? I'm just curious because it wasn't mentioned last quarter, and I'm just getting hit by some investors wondering why.

所以一個問題也是一個後續行動。就 ORLADEYO 的季度動態而言。我很欣賞 Q2 和 Q3 的看跌期權和賣出價的顏色。但是，您能否提供一些關於理解這種動態並認識到這種推動力的時機的顏色？我很好奇，因為上個季度沒有提到它，我只是被一些想知道為什麼的投資者打擊了。

And then maybe as a follow-up, on the next-generation molecule 10013, can you walk us through what you know preclinically that gives you confidence that you won't run into the same sort of renal signal as 9930?

然後也許作為後續行動，關於下一代分子 10013，您能否向我們介紹一下您在臨床前了解的內容，讓您有信心不會遇到與 9930 相同類型的腎臟信號？

Yes. So maybe I'll take the first one. Anthony, if I go the wrong direction, you can correct me. But we did point out that there was $2.2 million of non-period accrual adjustment in the second quarter that made that higher than normal. And then you don't know the differences between the two until you finish a quarter, right? And so we had some -- or finish a month like July. And what happened in retrospect is July 4 landed on a Monday, I believe this year, and a bunch of shipments came in prior to that because I'm sure people weren't home. And as a result, it got shipped in June instead of July. So I don't know if there's anything else to add to that.

是的。所以也許我會拿第一個。安東尼，如果我走錯了方向，你可以糾正我。但我們確實指出，第二季度有 220 萬美元的非期間應計調整使這一數字高於正常水平。然後直到你完成一個季度你才知道兩者之間的區別，對吧？所以我們有一些 - 或者像 7 月那樣完成一個月。回想起來發生的事情是 7 月 4 日在星期一降落，我相信今年，並且在此之前收到了一堆貨物，因為我確定人們不在家。結果，它在 6 月而不是 7 月發貨。所以我不知道是否還有什麼要補充的。

No, just, I mean, will things like this happen? They will, right? I think what we're not going to do is solely focus on that quarter-to-quarter. But that's why we lean into the idea of the underlying strength, right? We feel really good around where we are, where we're going from a growth perspective and that we're on that path to $1 billion. So in the future, will there be some kind of quarter-over-quarter as it relates to holidays or seasonality? Maybe. But I think hitting on that underlying growth factors and how confident it makes us in terms of getting to the $255 million for this year and $1 billion thereafter is our focus.

不，只是，我的意思是，這樣的事情會發生嗎？他們會的，對吧？我認為我們不會做的只是專注於那個季度到季度。但這就是為什麼我們傾向於潛在力量的想法，對吧？從增長的角度來看，我們對我們所處的位置、我們的發展方向以及我們正在通往 10 億美元的道路上感到非常滿意。那麼在未來，是否會出現與假期或季節性相關的某種季度環比？也許。但我認為，擊中潛在的增長因素以及它使我們有多大信心在今年達到 2.55 億美元，此後達到 10 億美元是我們的重點。

Yes. Last thing I'd say on that front is, we're the only ones with the data at the end of the day. No offense to those of you trying to guess. And so we think we're the most accurate guider. And we believe we're telling you right now that we believe we'll finish the year at $255 million. And that's a spectacular outcome given that we blew away the first year with $122 million, so more than doubling. Helen, do you want to take the second part of Chris' question?

是的。在這方面我要說的最後一件事是，我們是唯一在一天結束時擁有數據的人。對那些試圖猜測的人沒有冒犯。所以我們認為我們是最準確的嚮導。我們相信我們現在告訴你，我們相信我們將在今年結束時達到 2.55 億美元。這是一個了不起的結果，因為我們第一年就以 1.22 億美元的價格大賺一筆，翻了一番還多。海倫，你想回答克里斯問題的第二部分嗎？

Yes. So with BCX10013, we don't know yet that we will not see what we're seeing with 9930. However, we do know a number of things that give us confidence. One is it's a unique molecule, which means it has its own unique characteristics, and so we expect it to behave differently in the clinic. And we're seeing that. Two, as we know what we saw with 9930 -- with BCX9930, we've learned from that. We've applied that in our process with both preclinical and clinical data. And again, what we're seeing in the clinic with BCX10013 is supportive of proceeding into patient trials and supportive of a potential for once-daily dosing.

是的。因此，對於 BCX10013，我們還不知道我們將不會看到我們在 9930 上看到的情況。但是，我們確實知道一些可以給我們信心的事情。一是它是一種獨特的分子，這意味著它有自己獨特的特性，因此我們希望它在臨床上表現不同。我們正在看到這一點。第二，正如我們所知道的，我們在 9930 上看到了什麼——對於 BCX9930，我們從中吸取了教訓。我們已經在我們的過程中應用了臨床前和臨床數據。再一次，我們在臨床上看到的 BCX10013 支持繼續進行患者試驗，並支持每日一次給藥的潛力。

Yes, so some of it, we've gathered data that gives us confidence that it could be different. And then there's some that's just not mature enough that we can't declare that it's that different. We won't see it. But we wouldn't be moving it forward if we thought there was a high risk here.

是的，所以其中一些，我們收集的數據讓我們相信它可能會有所不同。還有一些還不夠成熟，我們不能說它有什麼不同。我們不會看到它。但如果我們認為這裡存在高風險，我們就不會推進它。

And the next question in the queue comes from Jessica Fye with JPMorgan.

隊列中的下一個問題來自摩根大通的 Jessica Fye。

This is Daniel for Jess. A couple of questions. First, I guess you've elaborated a little bit on this, but what were the inputs you considered when narrowing down the full sales for year's guidance to the lower end of the prior numbers? And two, understanding that we'll see detailed data in early 2023 for 10013, but can you maybe elaborate on some of the early clinical details that have generated with that product, for example, in terms of AP Hemolysis, that was just once-a-day oral therapy.

這是傑西的丹尼爾。幾個問題。首先，我想您已經對此進行了詳細說明，但是在將年度指導的全部銷售額縮小到先前數字的下限時，您考慮了哪些輸入？第二，了解到我們將在 2023 年初看到 10013 的詳細數據，但您能否詳細說明該產品產生的一些早期臨床細節，例如，就 AP 溶血而言，這只是一次-一天口服治療。

If I can sneak one more is assuming that -- maybe assuming you're still in a position -- assuming you still positioned 10013 similarly to which you have been developing for 9930 before by targeting multiple oral indications, how are you thinking about the potential impact of an IRA and how that might not encourage drug developers to develop more than one orphan indication for the asset?

如果我可以再偷偷假設一下 - 也許假設你仍然處於一個位置 - 假設你仍然定位 10013 類似於你之前通過針對多種口服適應症開發的 9930，你如何考慮潛力IRA 的影響以及這如何不鼓勵藥物開發商為該資產開發多個孤兒適應症？

You're referring to the Inflation Reduction Act and multiple indications on one molecule?

你指的是通貨膨脹減少法案和一個分子的多種適應症？

Yes.

是的。

I'll come back to that. Helen, you can take the 10013, I'll take the lower end, and Anthony, again, help me here. So I mean, it's real simple, Daniel. We have another quarter's worth of data and we're into November now. And so we've said we would be the accurate guider, and we believe we're going to be at $255 million. And this is -- I think, one big difference in rare diseases versus mass markets is, it doesn't take a lot of patients to have a movement in one direction or another. So we're real confident in the $255 million and that's a doubling or more than a doubling of the first year great start. Helen, you want to take 10013?

我會回到那個。海倫，你可以選擇 10013，我選擇低端，安東尼，再次幫我。所以我的意思是，這真的很簡單，丹尼爾。我們有另一個季度的數據，現在已經進入 11 月了。所以我們已經說過我們將成為準確的指導者，我們相信我們將達到 2.55 億美元。這是——我認為，罕見疾病與大眾市場的一大區別是，不需要很多患者就可以朝一個或另一個方向移動。因此，我們對 2.55 億美元非常有信心，這是第一年良好開端的兩倍或更多倍。海倫，你想去 10013 嗎？

Yes, sure. So in terms of the early clinical data with 10013, this is -- just to be clear, this is in healthy volunteers. So we have about 90 healthy volunteers who have been dosed with the drug. And so we have safety data and pharmacokinetics data for those individuals. We have that, including dose levels that may be therapeutic in range. And we do not have data on patients at this point. So our plan is to move into patients next to assess the potential for the complement activity.

是的，當然。因此，就 10013 的早期臨床數據而言，這是 - 需要明確的是，這是在健康志願者中進行的。所以我們有大約 90 名健康志願者服用過這種藥物。所以我們有這些人的安全數據和藥代動力學數據。我們有，包括可能在治療範圍內的劑量水平。目前我們還沒有關於患者的數據。因此，我們的計劃是下一步進入患者體內以評估補體活性的潛力。

And then on the Inflation Reduction Act, I think there's a lot of implementation, a lot of unknowns yet that have to occur before we can draw any conclusions and maybe we are different than others, but we're not going to say we're not going to bring a molecule forward in a bunch of other indications when patients are in need, and we think that we can create real value for shareholders. So it's certainly on our radar, but one of the beauties, I think, in the complement system is single molecules can go after multiple diseases. And so that's our plan.

然後關於通貨膨脹減少法案，我認為有很多實施，在我們得出任何結論之前必鬚髮生很多未知數，也許我們與其他人不同，但我們不會說我們是當患者有需要時，我們不會在一系列其他適應症中推出分子，我們認為我們可以為股東創造真正的價值。所以它肯定在我們的雷達上，但我認為，補體系統的優點之一是單個分子可以治療多種疾病。這就是我們的計劃。

The next question comes from Brian Abrahams with RBC Capital.

下一個問題來自 RBC Capital 的 Brian Abrahams。

This is Joe on for Brian. I just wanted to ask one question on ORLADEYO once again. If you can tell us anything about, like any improvement you're seeing in patient retention rate? And if there are any specific types of patients that tend to stay longer on ORLADEYO? And how is your education or awareness initiatives been impacting this retention rates as of late?

這是 Joe 代替 Brian。我只是想再問一次關於 ORLADEYO 的問題。如果你能告訴我們任何關於你在患者保留率方面看到的任何改進？是否有任何特定類型的患者傾向於在 ORLADEYO 上停留更長時間？您的教育或意識舉措最近如何影響這種保留率？

Charlie?

查理？

Sure. Yes. So as I mentioned on the call, first of all, we've seen 2 quarters in a row now of flat patient retention -- or patient discontinuations even as our overall patient base has grown. So I think we're making a difference. What we see is the patient types that do absolutely the best are patients who -- who are controlled on other prophylactic therapies and then switch over and, in particular, patients who had been on paid therapy, where as I've said previously, about 70% of those patients stay on ORLADEYO for at least 12 months. And so that's what we're really focused on, is getting the right patient type to switch to ORLADEYO. And then as any patient starts off, we really focus on setting expectations for both efficacy and any side effects that some patients may experience and we see that, that makes a difference. So we're pleased with where we are with patient retention, and we think that this is going to be pretty stable going forward.

當然。是的。因此，正如我在電話會議上提到的那樣，首先，我們已經連續兩個季度看到患者保留率持平——或者即使我們的整體患者群有所增長，患者也會停藥。所以我認為我們正在發揮作用。我們看到的是，做得絕對最好的患者類型是接受其他預防性治療控制然後轉換的患者，特別是那些接受過付費治療的患者，正如我之前所說的那樣，大約這些患者中有 70% 在 ORLADEYO 上停留至少 12 個月。所以這就是我們真正關注的是讓合適的患者類型切換到 ORLADEYO。然後，當任何患者開始時，我們真正專注於設定對一些患者可能經歷的療效和任何副作用的期望，我們看到，這會產生影響。因此，我們對保留患者的情況感到滿意，並且我們認為這將非常穩定地向前發展。

And Charlie mentioned this point around the college meeting. And I would just encourage people to watch the presentation and look at the poster because there's some real-world data in there that's incredibly encouraging around, as Charlie described, the best switches are the ones that are on -- controlled on prophy -- injectable prophy. So our view remains that if you could be controlled on our drug on a once-daily capsule, why on earth would you not try it and see if it works for you, right? And so that's our goal. We're continuing to chip away at this, and we believe we're making really good progress on our way to many thousands of patients and peak sales of $1 billion.

查理在大學會議上提到了這一點。而且我只是鼓勵人們觀看演示文稿並查看海報，因為那裡有一些真實世界的數據令人難以置信地鼓舞人心，正如查理所描述的那樣，最好的開關是那些打開的 - 受預防控制 - 可注射預言。所以我們的觀點仍然是，如果你可以通過每天一次的膠囊控制我們的藥物，你到底為什麼不嘗試一下看看它是否對你有用，對吧？這就是我們的目標。我們正在繼續努力，我們相信我們在為成千上萬的患者和 10 億美元的峰值銷售額的道路上取得了非常好的進展。

And the next question in the queue comes from Jon Wolleben with JMP Securities.

隊列中的下一個問題來自 JMP 證券公司的 Jon Wolleben。

Two for me. I was hoping you could comment a bit on what you're seeing on gross net adjustment. As we're moving forward, you gave some comments on paid patient growth, which is helpful. And then also, when you talk about the 15 patients from 9930 from which you want to see data to make this go/no-go decision, just wanted to check, is this strictly PNH patients? Or is it the renal patients as well or some combination? How are you thinking about what makes up that go/no-go population?

兩個給我。我希望你能對你所看到的淨調整總額發表一些評論。在我們前進的過程中，您對付費患者的增長發表了一些評論，這很有幫助。然後，當你談到 9930 中的 15 名患者時，你想從中查看數據來做出這個繼續/不繼續的決定，只是想檢查一下，這是否是嚴格的 PNH 患者？或者是腎病患者還是某種組合？您如何看待構成該去/不去人口的因素？

Yes. I'll take first one here. There's been no major movements in gross net. We talked about in Q1 the impact that we had there, but for Q2, 3 and 4 our expectation has been that it would be stable. On reimbursed patients, again, we said around 15% to 20%. Charlie talked previously around what we did from a PBM coverage and insurance or payer coverage perspective at north of 80%. So Jon, I don't think there's any kind of big drivers. We will continue to see from a percentage numerator versus denominator perspective, including free product that get towards that 15% to 20%, we still feel good about that. But no major movements from Q2.

是的。我會在這裡拿第一個。總淨額沒有重大變動。我們在第一季度談到了我們在那裡產生的影響，但對於第二、第三和第四季度，我們的預期是它會保持穩定。對於獲得報銷的患者，我們再次表示約為 15% 至 20%。 Charlie 之前談到了我們從 PBM 覆蓋範圍和保險或付款人覆蓋範圍的角度來看在 80% 以上所做的工作。所以喬恩，我認為沒有任何大的驅動因素。我們將繼續從分子與分母的百分比角度來看，包括達到 15% 到 20% 的免費產品，我們對此仍然感覺良好。但第二季度沒有重大變動。

And then the 15 patients, Helen, what's the source?

然後是 15 名患者，海倫，來源是什麼？

Yes. So the 15 patients -- we're looking for, first of all, approximately 15 patients. We think that's the right number for us to be able to have confidence in the data to continue to advance the program. Secondly, it's likely to be patients mostly from the REDEEM studies with PNH. That's a program where we have more site, there's two global pivotal trials, and we should likely to see enrollments faster there. In the RENEW program, we will continue to enroll in that program. There's also a run-in period built in, and so it may take longer for patients to be dosed and proceed to an outcome. So we assume it's going to be mostly PNH.

是的。所以這 15 名患者——我們首先要尋找大約 15 名患者。我們認為這是我們能夠對數據有信心繼續推進該計劃的正確數字。其次，它可能主要是來自 PNH REDEEM 研究的患者。這是一個我們有更多站點的項目，有兩個全球關鍵試驗，我們應該可以看到那裡的註冊速度更快。在 RENEW 計劃中，我們將繼續註冊該計劃。還有一個內置的磨合期，因此患者可能需要更長的時間才能給藥並取得結果。所以我們假設它主要是 PNH。

Yes. Remember, Jon, that they've got to have a biopsy to make sure that they truly have disease and the likes of that just takes longer.

是的。記住，喬恩，他們必須進行活組織檢查以確保他們確實患有疾病，而類似的事情只需要更長的時間。

The next question in the queue comes from Gena Wang with Barclays.

隊列中的下一個問題來自巴克萊銀行的 Gena Wang。

I have a question regarding ORLADEYO launch. So given your prior comment, just wondering, is retention rate now maintained at the mid-60? And then my next question is regarding 2022 annual guidance of $255 million. I just did a quick math that would translate to $74.5 million for 4Q. And if we use like $67.5 million for 3Q, then we have a $7 million growth. And we are only 1 month into 4Q and also, we have holidays in 4Q. Just wondering what makes you confident you could achieve 4Q numbers?

我有一個關於 ORLADEYO 發布的問題。因此，鑑於您之前的評論，我只是想知道，現在的保留率是否保持在 60 左右？然後我的下一個問題是關於 2022 年 2.55 億美元的年度指導。我只是做了一個快速的數學計算，第四季度將轉化為 7450 萬美元。如果我們在第三季度使用 6750 萬美元，那麼我們就有 700 萬美元的增長。而且我們進入第四季度只有 1 個月，而且我們在第四季度有假期。只是想知道是什麼讓您有信心實現第四季度的數字？

Charlie, do you want to take the retention?

查理，你想保留嗎？

Sure. Yes. So Gena, the 1-year retention overall, yes, in the mid-60 percentage, and then what we're really seeing is, and we've talked about this before, is where we lose the majority of patients is in the first few months and up to 6 months. Once patients get out to a year, they're doing well and they're only going to stay on if they're doing well. And so those patients are much more likely to stay on for the long term.

當然。是的。所以 Gena，總體 1 年保留率，是的，在 60% 左右，然後我們真正看到的是，我們之前已經討論過，我們失去大多數患者的地方是第一個幾個月，最多 6 個月。一旦患者出院一年，他們就會表現良好，而且只有表現良好，他們才會繼續堅持下去。因此，這些患者更有可能長期堅持下去。

Do you want to take fourth quarter?

你想參加第四節嗎？

Sure. No, I think for Q4, Charlie talked about steady growth. That is, Gena, from an underlying perspective what we're seeing. And so I think getting to those numbers that you're talking about, right, to get to the $255 million, given where we are coming into November out of October, I think we feel really good and we feel really confident about hitting that $255 million.

當然。不，我認為對於第四季度，查理談到了穩定增長。也就是說，Gena，從我們所看到的潛在角度來看。所以我認為達到你正在談論的那些數字，對，達到 2.55 億美元，考慮到我們從 10 月到 11 月的情況，我認為我們感覺非常好，我們對達到 255 美元真的很有信心百萬。

Yes. And we don't guide quarterly, but by the fact that we say $255 million, and I've given you 3 quarters worth of revenue, we are basically guiding you in the fourth quarter. Yes.

是的。我們不是每季度指導，但事實上我們說 2.55 億美元，我已經給了你 3 個季度的收入，我們基本上是在第四季度指導你。是的。

And the next question comes from Justin Kim with Oppenheimer & Co.

下一個問題來自 Oppenheimer & Co. 的 Justin Kim。

As you think about sort of full speed ahead for the REDEEM studies later next year, could you describe how much separation you see between 9930 and the 10013 program just from a timing perspective? And any sort of progress with 100013 that might just incentivize prioritization of the next-generation inhibitor?

當您考慮明年晚些時候 REDEEM 研究的全速前進時，您能否描述一下您從時間角度來看 9930 和 10013 計劃之間的差距有多大？ 100013 的任何進展可能只會激勵下一代抑製劑的優先排序？

Yes. Sure, I can take that. We -- so the REDEEM studies, just to be clear, we are going quickly with REDEEM studies. And the question is whether we continue that. So they are advancing. This is a pivotal program. We expect it to be the first program to read out. We expect it to be the first program to market should we have successfully addressed the dose for a safe and effective drug. So that -- it is the -- in position to be the first to market. And we have a second-generation molecule that is also in a position to get to market. It's early. It's in Phase I. We have healthy volunteer data, but we think it has the potential to be best-in-class, and so we're bringing it through behind.

是的。當然，我可以接受。我們 - 所以 REDEEM 研究，為了清楚起見，我們正在快速進行 REDEEM 研究。問題是我們是否繼續這樣做。所以他們在進步。這是一個關鍵的程序。我們希望它是第一個被讀出的程序。如果我們已經成功解決了安全有效藥物的劑量問題，我們希望它成為第一個上市的項目。所以 - 它是 - 能夠成為第一個上市的人。我們還有第二代分子，也可以推向市場。現在還早。它處於第一階段。我們擁有健康的志願者數據，但我們認為它有可能成為一流的，因此我們將其落後。

Yes. I mean, it's about 2 years at the end of the day between the two. One of them is in a pivotal study and one of them is in a Phase I. And so if we find a safe and effective dose, we've got something that creates real value for patients in this market. And so of course, we would invest in it if we have a safe and effective dose. I think the more important question is, how do we allocate what we go after with each molecule. And our view is probably a skinnier set of indications for 9930, that's how we see it today. And then because we believe 10013 has the potential to be best, maybe a broader set of indications for that one. But that -- we'll see how the programs unfold over time and give you more clarity on that later.

是的。我的意思是，這兩者之間的一天結束時大約是 2 年。其中一項正在進行關鍵研究，其中一項處於 I 期。因此，如果我們找到安全有效的劑量，我們就會為這個市場上的患者創造真正的價值。因此，當然，如果我們有安全有效的劑量，我們會對其進行投資。我認為更重要的問題是，我們如何分配我們對每個分子的追求。我們的觀點可能是 9930 的一組更瘦的跡象，這就是我們今天的看法。然後因為我們相信 10013 有可能成為最好的，所以可能會有更廣泛的適應症。但是那——我們將看到這些項目是如何隨著時間的推移展開的，稍後會讓你更清楚。

The next question in the queue comes from Tazeen Ahmad from Bank of America.

隊列中的下一個問題來自美國銀行的 Tazeen Ahmad。

I think most of my questions have been answered. For 4Q, now that you have some experience calendar-wise with the launch, do you expect in general any kind of seasonality? And then secondly, on the subject of pricing, historically, rare drugs have been able to take at least annual price increases, but as you talk to insurers, payers, has there been any change in tone on that? Obviously, I'm not asking you to guide, but just in terms of any kind of sentiment shift that you may or may not be seeing from payers? And then lastly, as you think about 2023 sales for ORLADEYO, where do you think your biggest area of untapped demand lies going forward?

我想我的大部分問題都得到了回答。對於第 4 季度，既然您對發布有一些日曆方面的經驗，您是否預計會有任何季節性？其次，在定價問題上，從歷史上看，稀有藥物至少每年都可以漲價，但當你與保險公司、付款人交談時，在這方面的基調是否有任何變化？顯然，我不是要你指導，而是就你可能會或可能不會從付款人那裡看到的任何一種情緒轉變而言？最後，當您考慮 ORLADEYO 2023 年的銷售額時，您認為未來最大的未開發需求領域在哪裡？

So who wants to take the seasonality piece?

那麼谁愿意接受季節性因素呢？

I can. So Tazeen, I think looking forward into the new year, I think we'll see the same kind of seasonality that we saw last year kind of going into Q1. As we've talked about, that's always a time when the majority or a good portion of the patients have to go through prior authorization. So I think we'll comment more on that next quarter, but you can anticipate that. As far as pricing, we don't -- obviously, we don't comment on general pricing, but payer sensitivity, no, I think payers are always sensitive to high-priced therapies for rare diseases like HAE, but we're not seeing anything notable about that. And there was one other...

我可以。所以 Tazeen，我認為展望新的一年，我認為我們會看到與去年一樣的季節性進入第一季度。正如我們所談到的，那總是大多數或很大一部分患者必須經過事先授權的時候。所以我認為我們會在下個季度對此發表更多評論，但你可以預料到這一點。至於定價，我們不——顯然，我們不評論一般定價，但付款人的敏感性，不，我認為付款人總是對像 HAE 這樣的罕見疾病的高價療法敏感，但我們不是看到任何值得注意的事情。還有一個...

Yes, 2023 untapped potential. Let me start and you can add. I think this further investment that Charlie talked about, we'll see the bulk of the value of that coming in 2023 for sure. But the message has been consistent quarter after quarter after quarter. The best patients that we get are ones that are controlled on injectable prophy that switch over to ORLADEYO. And again, I'd encourage you to pay attention to what we're presenting at the college meeting. So continuing to pick away and chip away at that, I think, is the key.

是的，2023 年未開發的潛力。讓我開始，你可以添加。我認為查理談到的這項進一步投資，我們肯定會在 2023 年看到大部分價值。但這個信息一季度又一季度地保持一致。我們得到的最好的患者是那些在轉向 ORLADEYO 的可注射預防藥物上受到控制的患者。再一次，我鼓勵你關注我們在大學會議上展示的內容。因此，我認為，繼續挑选和削減是關鍵。

And Tazeen, you've heard me comment today and many times over the quarters around our top 500 versus Tier 2. And recall for everyone, the top 500 is about half the HAE market, and then there's Tier 2. And we had 54% of our new prescriptions come from the top 500, so really great balance. And we see opportunities in both ends, kind of at the top of the market and then expanding the market. And so as we've expanded our team a little bit, it's to take advantage of both of those segments.

Tazeen，你今天已經聽到我的評論，並且在我們的前 500 強與第 2 級的對比中多次聽到我的評論。每個人都記得，前 500 強大約佔 HAE 市場的一半，然後是第 2 級。我們有 54%我們的新處方中有 500 名來自前 500 名，所以非常平衡。我們在兩端都看到了機會，有點是在市場的頂端，然後是擴大市場。因此，當我們稍微擴大我們的團隊時，就是要利用這兩個部分。

And the next question in the queue comes from [Rohit] with Needham & Company.

隊列中的下一個問題來自 Needham & Company 的 [Rohit]。

This is [Rohit] on for Serge. Can you just talk about how the recent setbacks with other oral HAE prophylactic products and development changes to your long-term outlook for ORLADEYO? And how do you see the competitive landscape playing out?

這是 Serge 的 [Rohit]。您能否談談最近其他口服 HAE 預防產品的挫折和發展如何改變您對 ORLADEYO 的長期前景？您如何看待競爭格局的發展？

Yes. I think I said it in my comments. It's just a reminder of how challenging it is to make a potent specific orally bioavailable drug. I think there are now 5 companies, including us with avoralstat, that had programs that had to be stopped. So these are really hard. The flip side of that is it means we may be the only one at the end of the day. And so that puts us in a spectacular position because we know that patients really want an oral. They want a decreased burden of disease and a decreased burden of therapy, and you can offer that with 1 capsule once-a-day with ORLADEYO. So I don't think it dramatically changes.

是的。我想我在評論中說過了。這只是提醒人們製造一種有效的特定口服生物利用藥物是多麼具有挑戰性。我想現在有 5 家公司，包括我們的 avoralstat，都有必須停止的項目。所以這些真的很難。不利的一面是，這意味著我們可能是一天結束時唯一的人。因此，這使我們處於一個引人注目的位置，因為我們知道患者真的想要口服。他們希望減輕疾病負擔和減輕治療負擔，您可以使用 ORLADEYO 每天服用 1 粒膠囊來提供這一點。所以我認為它不會發生顯著變化。

The other piece I would say to Tazeen's question too is we're -- I mean, we're absolutely, and our competitors that are in the market that have prophy drugs are seeing this as well is, the market is definitely moving more and more and more to prophy and away from on-demand. And I think on-demand is going to be a tiny, tiny piece of the market ultimately and then we'll be battling out with injectables for the prophy.

對於 Tazeen 的問題，我還要說的另一件事是我們——我的意思是，我們絕對是，我們在市場上擁有預防藥物的競爭對手也看到了這一點，市場肯定在不斷變化，越來越多的預言和遠離點播。而且我認為按需最終將成為市場的一小部分，然後我們將與註射劑爭奪 prophy。

And our last question comes from Maury Raycroft with Jefferies.

我們的最後一個問題來自 Jefferies 的 Maury Raycroft。

I'm just wondering if you can elaborate more on the comment about investing more to keep the ORLADEYO momentum going. You mentioned the increase in sales team in addition to field market teams, is that the further investment you're referring to? And will you continue to add to these teams? Or are you at a status quo at this point heading into 2023?

我只是想知道您是否可以詳細說明關於投資更多以保持 ORLADEYO 勢頭的評論。您提到除了現場市場團隊之外還增加了銷售團隊，這是您指的進一步投資嗎？你會繼續增加這些團隊嗎？還是在進入 2023 年的這一點上您處於現狀？

Charlie, it might be good to just talk about, one of the keys to the success of the launch so far has been your agility, right, looking at data, understanding what the data is telling you and then making adjustments.

查理，談論一下可能會很好，到目前為止，發布成功的關鍵之一是你的敏捷性，對，查看數據，了解數據告訴你什麼，然後做出調整。

Yes. So Maury, to Jon's point, we have always looked where we can do more. And we -- when we built the launch when we built the team, we felt and we did have a great team that was ready to compete in this space, and I think we've seen that. And what we're always doing is looking where we can do just a little bit more at the margins. And so previously, I've talked about how we added some additional field-based patient-facing members of the team because that's a need that we saw. And now we saw an opportunity just to add a little more to our sales team and to market access team. So we'll continue to look for these opportunities. We feel good about where we're at right now. But at some point in the future, I may come back and say we've invested a little bit more because we've had other opportunities. That's the approach we take.

是的。所以莫里，就喬恩而言，我們一直在尋找我們可以做更多的事情。而我們——當我們在建立團隊時建立發射時，我們感到並且我們確實擁有一支準備好在這個領域競爭的偉大團隊，我認為我們已經看到了這一點。我們一直在做的是尋找我們可以在邊緣做更多的事情。所以之前，我已經談到了我們如何在團隊中增加一些基於現場的面向患者的成員，因為這是我們看到的需求。現在我們看到了一個機會，可以為我們的銷售團隊和市場准入團隊增加一點。所以我們會繼續尋找這些機會。我們對我們現在所處的位置感覺良好。但在未來的某個時候，我可能會回來說我們投資多了一點，因為我們還有其他機會。這就是我們採取的方法。

We have no further questions in the queue at this time. So I will now turn the call over to Mr. Stonehouse for closing remarks.

目前隊列中沒有其他問題。所以我現在將把電話轉給斯通豪斯先生作結束語。

Thank you, and thanks for your interest in BioCryst. I was recently shown some data from one of the banks around the number of publicly traded biotech companies. It's a really, really crowded space. And what was eye-popping was the number of companies that are trading below cash. It's a really tough time, and you guys know that better than anybody. But what I think what's interesting is how do you differentiate yourself when there are so many companies with gene editing, gene therapy, you name it. And I think at BioCryst, the way we see it is we've shown you that we have a discovery engine that can do things perhaps that others can't, right, in making an oral potent-specific once-a-day kallikrein inhibitor.

謝謝，也感謝您對 BioCryst 的興趣。最近，有人向我展示了其中一家銀行提供的有關上市生物技術公司數量的一些數據。這是一個非常非常擁擠的空間。令人大跌眼鏡的是低於現金交易的公司數量。這是一段非常艱難的時期，你們比任何人都清楚這一點。但我認為有趣的是，當有這麼多公司提供基因編輯、基因治療等服務時，你如何讓自己與眾不同。我認為在 BioCryst，我們看到它的方式是我們已經向你展示了我們有一個發現引擎，它可以做一些其他人做不到的事情，對吧，在製造一種口服強效特異性每天一次的激肽釋放酶抑製劑方面.

We've shown you that we can file in the U.S., Europe and Japan and get approvals all within 4 months of each other. That's even hard for a big company to do. And we've shown you that we can successfully launch a drug, right? I think the initial consensus was $30 million this year. I think it was $218 million. And we've consistently beat that, right? And why? Because we look at the data objectively, we develop a plan and then we figure out how to get the business. And so that puts us in a different category, I think, than a lot of other companies.

我們已經向您展示了我們可以在美國、歐洲和日本提交申請並在 4 個月內獲得批准。這對於一個大公司來說甚至很難做到。我們已經向您展示了我們可以成功推出一種藥物，對嗎？我認為今年最初的共識是 3000 萬美元。我認為是 2.18 億美元。我們一直在擊敗它，對吧？為什麼？因為我們客觀地看待數據，所以我們制定了一個計劃，然後我們弄清楚如何獲得業務。因此，我認為，與許多其他公司相比，我們屬於不同的類別。

And then the last point is we have access to capital, whether it's revenue or other sources of capital, we're not solely dependent on our shares to bring in additional capital into the market. So you add all those things together and then you have a team that -- I think your job is really hard and do you believe what you hear. And I hope we're convincing you that we're trying to be objective in what we see and what we do, that we're disciplined around how we allocate capital and what decisions we make.

最後一點是我們可以獲得資本，無論是收入還是其他資本來源，我們不僅僅依靠我們的股票來為市場帶來額外的資本。所以你把所有這些東西加在一起，然後你就有了一個團隊——我認為你的工作真的很難，你相信你聽到的嗎？我希望我們能讓你相信，我們正在努力客觀地看待我們所看到的和所做的事情，我們在如何分配資本和做出什麼決定方面受到紀律處分。

It's hard to make decisions to stop programs. It's hard to make decisions in this business in general, but we're not afraid of that. And hopefully, we're showing you that we're trustworthy and that we're disciplined in how we do it. So we think we stand out, and we look forward to talking to you more and sharing more with you about how that is and, hopefully, get you more interest in our company.

很難做出停止程序的決定。一般而言，在這項業務中很難做出決策，但我們並不害怕。希望我們能向您展示我們是值得信賴的，並且我們在做事方面遵守紀律。所以我們認為我們脫穎而出，我們期待與您更多地交談並與您分享更多關於我們公司的情況，並希望讓您對我們公司產生更多興趣。

So have a great day, and thanks for your interest in BioCryst.

祝您今天愉快，感謝您對 BioCryst 的關注。

Thank you, ladies and gentlemen. This concludes today's teleconference. Thank you for participating. You may now disconnect.

謝謝你們，女士們，先生們。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。