Rhythm Pharmaceuticals Inc (RYTM) 2024 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Rhythm Pharmaceuticals third-quarter 2024 earnings conference call. (Operator Instructions)

美好的一天，感謝您的支持。歡迎參加 Rhythm Pharmaceuticals 2024 年第三季財報電話會議。（操作員說明）

Please be advised that today's conference is being recorded.

請注意，今天的會議正在錄製中。

I would now like to hand the conference over to your speaker today, David Connolly, Head of Investor Relations and Corporate Communications. Please go ahead.

現在我想將會議交給今天的演講者、投資者關係和企業傳播部主管 David Connolly。請繼續。

Thank you, Shannon. I'm Dave Connolly here at Rhythm Pharmaceuticals. For those of you participating on the conference call, our slides can be accessed and controlled by going to the Investors section of our website, ir.rhythmtx.com. This afternoon, we issued our press release that provides our third quarter 2024 financial results and business update, and that press release is available on our website.

謝謝你，香農。我是 Rhythm Pharmaceuticals 的 Dave Connolly。對於那些參加電話會議的人，可以透過造訪我們網站 ir.rhythmtx.com 的投資者部分來存取和控制我們的幻燈片。今天下午，我們發布了新聞稿，其中提供了 2024 年第三季的財務業績和業務更新，該新聞稿可在我們的網站上取得。

We are coming to you today from San Antonio, the site of ObesityWeek, the Annual Meeting of The Obesity Society. Listed on slide 2 is our agenda. On the call today are David Meeker, our Chairman, Chief Executive Officer and President; Jennifer Lee, Executive Vice President, Head of North America; Hunter Smith, Chief Financial Officer; and Yann Mazabraud, Executive President, Head of International is on the line joining us from Europe.

我們今天從聖安東尼奧來到這裡，這是肥胖協會年會「肥胖週」的舉辦地點。第 2 投影片中列出的是我們的議程。今天參加電話會議的是我們的董事長、執行長兼總裁 David Meeker； Jennifer Lee，執行副總裁，北美區負責人；亨特‧史密斯，財務長；執行總裁兼國際主管 Yann Mazabraud 正在從歐洲加入我們。

On slide 3, I'll remind you that this call contains remarks concerning future expectations, plans and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly reports on file with the SEC.

在投影片 3 上，我將提醒您，本次電話會議包含有關未來預期、計劃和前景的評論，這些評論構成前瞻性陳述。由於各種重要因素，包括我們向美國證券交易委員會提交的最新年度或季度報告中討論的因素，實際結果可能與這些前瞻性陳述所示的結果有重大差異。

In addition, any forward-looking statements represent our views as of only today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David Meeker, who will begin on slide 5.

此外，任何前瞻性陳述僅代表我們截至今天的觀點，不應被視為代表我們在任何後續日期的觀點。我們特別聲明不承擔更新此類聲明的義務。接下來，我會將電話轉給 David Meeker，他將從投影片 5 開始。

Thank you, Dave. So thank you all for joining today. We realize we're probably not the lead story today, November 5, Election Day. But we are really pleased with both the quarter and the progress we have made in 2024. We recognized at the start of 2024, this would be a year of execution with the highly anticipated readouts coming in 2025.

謝謝你，戴夫。謝謝大家今天的加入。我們意識到我們可能不是今天 11 月 5 日選舉日的頭條新聞。但我們對本季以及 2024 年的進展感到非常滿意。我們在 2024 年初就認識到，這將是執行的一年，備受期待的讀數將在 2025 年公佈。

We have executed and in addition to the expected readouts we have one unexpected readout, which was presented today at the TOS meeting, an early look at the real-world data in French hypothalamic obesity patients. I'll say a little more about that shortly.

除了預期的讀數外，我們還執行了一項意想不到的讀數，在今天的 TOS 會議上發布，這是對法國下丘腦肥胖患者真實世界數據的早期觀察。我稍後會詳細介紹這一點。

As shown on slide 5, we remain focused on our three main value drivers. First, the team continues to drive results through strong execution of our global commercial strategy.

如投影片 5 所示，我們仍然專注於三個主要價值驅動因素。首先，團隊繼續透過強而有力地執行我們的全球商業策略來推動業績。

Second, we are positioned to expand this patient opportunity to include hypothalamic obesity and we have increased confidence in the potential for this indication based on the new real-world data efficacy data from the early access program in France. We remain on track to report top line data from our Phase III trial and acquired hypothalamic obesity in the first half of 2025.

其次，我們的定位是擴大這一患者的機會，將下丘腦肥胖納入其中，並且根據法國早期訪問計劃的新的真實世界數據療效數據，我們對該適應症的潛力增強了信心。我們仍有望在 2025 年上半年報告 III 期試驗和下視丘肥胖的主要數據。

Third, we continue to make progress with our MC4R agonist pipeline with day rate data presented at The Obesity Society's ObesityWeek, demonstrating potential new expansion opportunities in genetic indications. And we continue to progress our next-generation MC4R agonist, the weekly RM-718 and the oral daily small molecule bivamelagon.

第三，我們繼續在 MC4R 激動劑管道方面取得進展，並在肥胖協會的 ObesityWeek 上提供日費率數據，展示了遺傳適應症方面潛在的新擴展機會。我們繼續開發下一代 MC4R 激動劑、每週一次的 RM-718 和每日口服的小分子 bivamelagon。

Steady growth continues with IMCIVREE revenues for the third quarter coming in at $33.3 million, driven primarily by BBS sales globally. We continue to identify patients, physicians continue to prescribe IMCIVREE and payers are supporting access. We have an experienced rare disease team executing in challenging environments. And of note, we are only two years post approval in the US and continuing to introduce new markets internationally. It is early in the commercial life span of this opportunity.

IMCIVREE 第三季營收持續穩定成長，達到 3,330 萬美元，這主要是由全球 BBS 銷售推動的。我們繼續識別患者，醫生繼續開立 IMCIVREE 處方，付款人也支持使用。我們擁有一支經驗豐富的罕見疾病團隊，在充滿挑戰的環境中執行任務。值得注意的是，我們在美國獲得批准僅兩年時間，並繼續在國際上引入新市場。該機會尚處於商業生命週期的早期階段。

Our clinical programs are progressing as we remain on track to report top line data from the Phase III HO trial in the first half 2025. The dropout rate remains less than 10%. We are targeting full enrollment of the Japanese cohort of patients by year-end. Our small molecule program has 50% of the targeted number of patients dosed or in screening.

我們的臨床計畫正在取得進展，我們仍有望在 2025 年上半年報告 III 期 HO 試驗的主要數據。輟學率仍低於10%。我們的目標是在年底前完成日本患者隊列的全部入組。我們的小分子計畫已對 50% 的目標患者進行了給藥或篩選。

For the RM-718 study, we are completing the rat and nonhuman primate toxicology studies and will submit those along with an amendment to allow dosing patients with hypothalamic obesity for more than four weeks to the FDA. We are targeting dosing the first type of hypothalamic obesity patients with 718 in the first quarter of 2025.

對於 RM-718 研究，我們正在完成大鼠和非人靈長類動物毒理學研究，並將向 FDA 提交這些研究以及允許下丘腦肥胖患者給藥超過 4 週的修正案。我們的目標是在 2025 年第一季對 718 名第一類下丘腦肥胖患者進行給藥。

We are doing this call, as Dave said, from ObesityWeek, and I want to highlight two of our poster presentations. First, are the full results from the DAYBREAK trial. This was an ambitious undertaking where we sought to enroll patients with genetic variants in any 1 of 30 genes, which the literature suggested may be linked to the MC4R pathway.

正如戴夫在 ObesityWeek 上所說，我們正在進行這次電話會議，我想強調我們的兩個海報演示。首先是 DAYBREAK 試驗的完整結果。這是一項雄心勃勃的任務，我們試圖招募 30 個基因中任意一個基因存在變異的患者，文獻顯示這些基因可能與 MC4R 路徑有關。

On slide 6, you can see the design of the two-part trial. In the open-label Part 1 we reported out last December, patients who lost 5% or more after 16 weeks were eligible to enter the double-blind randomized withdrawal Part 2, where patients were randomized 2:1 to either continued setmelanotide therapy or placebo for 24 weeks.

在投影片 6 上，您可以看到由兩部分組成的試驗的設計。在我們去年12 月報告的開放標籤第1 部分中，16 週後體重下降5% 或更多的患者有資格進入雙盲隨機退出第2 部分，其中患者按2:1 隨機分配至繼續setmelanotide 治療或安慰劑24 週。

On slide 7, you can see the patient demographics, 49 responder patients entered Part 2 and 39 patients completed this part of the trial. We had equal numbers of adult and pediatric patients. On average, they live with severe obesity based on their BMI or BMIZ measurements.

在投影片 7 上，您可以看到患者人口統計數據，49 名有反應的患者進入了第 2 部分，39 名患者完成了試驗的這一部分。我們有相同數量的成人和兒童患者。平均而言，根據 BMI 或 BMIZ 測量結果，他們患有嚴重肥胖症。

Slide 8 shows the summary results with a mean decrease in BMI of 12.4% in the 32 patients on continuous setmelanotide therapy for a total of 40 weeks. And 84% of patients on setmelanotide maintained or further decreased their BMI beyond the initial 5%, as opposed to only 29% of patients randomized to placebo during the 24-week Stage 2 of the trial.

投影片 8 顯示了 32 名連續接受 Setmelanotide 治療總共 40 週的患者的 BMI 平均下降 12.4% 的總結結果。在為期 24 週的第 2 階段試驗中，84% 的 Setmelanotide 患者的 BMI 維持不變或進一步降低至超過最初的 5%，而只有 29% 的患者被隨機分配至安慰劑組。

Overall, we are quite pleased with the results. The trial design worked. The open-label trial period identified patients who seem to be true responders in that -- those randomized to continue treatment continued to respond, whereas those randomized to placebo mostly regressed towards baseline.

總的來說，我們對結果非常滿意。試驗設計奏效了。開放標籤試驗期確定了似乎是真正反應者的患者——那些隨機接受治療的患者繼續有反應，而那些隨機接受安慰劑的患者大多回歸到基線。

On slide 9, you can see the individual spaghetti plots for the four of these genes or gene groups. The blue lines represent setmelanotide, whereas the green lines represent the placebo patients.

在幻燈片 9 上，您可以看到其中四個基因或基因組的單獨義大利麵條圖。藍線代表setmelanotide，而綠線代表安慰劑患者。

Also note that scales on the graph for each gene group different and were adjusted to accommodate those patients with the greatest decrease in their BMI for that gene group. I won't go through each of the panels, but if you look at the PHIP gene in the upper left, you can see the adult patients on the left and the pediatric patients on the right.

另請注意，圖表中每個基因組的刻度不同，並進行了調整以適應該基因組 BMI 下降幅度最大的患者。我不會逐一介紹每個面板，但如果您查看左上角的 PHIP 基因，您可以看到左側為成人患者，右側為兒童患者。

In general, those continuing on setmelanotide had a good response, whereas the three patients randomized to placebo regained weight. The PHIP gene was the gene with the highest overall percentage of responders, particularly in those who completed Part 1. The key learnings from this trial is that there are patients who seem to have a clear response to setmelanotide, suggesting their variant is impairing signaling through the MC4R pathway.

一般來說，持續服用setmelanotide的患者有良好的反應，而隨機接受安慰劑的三名患者體重卻增加。PHIP 基因是應答者總百分比最高的基因，特別是在完成第 1 部分的應答者。該試驗的主要結論是，有些患者似乎對 setmelanotide 有明顯的反應，這表明他們的變異體正在損害通過 MC4R 通路的信號傳導。

The challenge for future development will be identifying those patients with true loss of function variants, recognizing for many of these genes, relatively little work has been done in the different variants, leaving most variants classified today as VUS or variants of unknown significance. Our expectation is that we will do additional research on one or more of these genes. That work will be done with one or both of our second-generation programs.

未來發展的挑戰將是識別那些真正喪失功能變異的患者，並認識到對於這些基因中的許多基因，在不同變異中所做的工作相對較少，使得大多數變異今天被分類為VUS 或未知意義的變異。我們的期望是我們將對這些基因中的一個或多個進行額外的研究。這項工作將透過我們的一個或兩個第二代項目來完成。

Now I want to finish my introductory comments talking about HO. We know there is a significant unmet medical need with no approved therapies. We believe the prevalence is in the range of 5,000 to 10,000 patients in each of the US and Europe, as we've described previously, and we believe there may be similar numbers of patients in Japan.

現在我想結束關於 HO 的介紹性評論。我們知道，目前尚無核准的治療方法，因此存在大量未滿足的醫療需求。正如我們之前所描述的，我們認為美國和歐洲的盛行率在 5,000 至 10,000 名患者之間，我們相信日本也可能有類似數量的患者。

Importantly, unlike BBS, most of these patients are diagnosed and under the care of endocrinologists. We reported out Phase II data in mid-2022 and moved directly to the randomized placebo-controlled 60-week Phase III trial.

重要的是，與 BBS 不同的是，這些患者中的大多數都是由內分泌科醫生診斷並接受治療的。我們在 2022 年中期報告了 II 期數據，並直接進入為期 60 週的隨機安慰劑對照 III 期試驗。

Both France and Italy in recognition of the significant unmet medical need, the absence of approved therapies and the strength of the Phase II data, in an unusual move have made setmelanotide available through paid early access programs.

法國和義大利認識到巨大的未滿足的醫療需求、缺乏批准的療法以及二期數據的強度，採取了不同尋常的舉措，透過付費早期訪問計劃提供了塞黑諾肽。

Patients from France began enrolling late last year and Italian patients are just beginning to receive treatment under the program. Real-world data from the initial French patients was presented today at [TOSH] is shown on slide 10.

來自法國的患者在去年年底開始入組，義大利患者剛開始接受該計畫的治療。今天在 [TOSH] 上發布的第一批​​法國患者的真實數據如幻燈片 10 所示。

Eight adult patients with a mean age of 31 who undergone brain surgery 12 years earlier at the mean age of 19 have been followed for three to six months on setmelanotide.

8 名平均年齡 31 歲的成年患者在 12 年前接受了腦部手術，平均年齡為 19 歲，接受了 Setmelanotide 治療後為期 3 至 6 個月的追蹤。

As you can see from the slide, they were severely affected with a mean BMI of 44. On average, these 8 adult patients had a mean BMI decrease of 5.6% and 12.8% at 1 in 3 months, respectively, after initiating treatment. Patients have continued to lose weight with 5 patients who have reached the 6-month time point, experiencing a 21.3% on average decrease in their BMI.

從幻燈片中可以看出，他們受到了嚴重影響，平均 BMI 為 44。平均而言，這 8 名成年患者在開始治療後 3 個月內 1 時的平均 BMI 分別下降了 5.6% 和 12.8%。患者體重持續減輕，其中 5 名患者已達到 6 個月的時間點，BMI 平均下降 21.3%。

We see this data as important for multiple reasons. It is the first new data we have presented since the original Phase II readout in 2022. We had relatively few adult patients in the Phase II trial and almost no adults in the long-term extension, leaving us with an important unanswered question: would adults be less responsive than children who are being treated in closer proximity to the onset of their HO? This data set goes a long way in answering that question.

我們認為這些數據很重要，原因有很多。這是自 2022 年最初的第二階段讀數以來我們提供的第一個新數據。我們在II 期試驗中的成年患者相對較少，並且在長期擴展中幾乎沒有成人，這給我們留下了一個重要的懸而未決的問題：成人的反應是否會比在HO 發作時接受治療的兒童更差？該資料集對回答這個問題大有幫助。

These patients were adults with a mean age of 31, as I said, who are on average 12 years out from the time of their injury. The response to date has been consistent, and that's one of the most remarkable things is the consistency of the response, and robust, further strengthening our conviction in the importance of the MC4R pathway in this disorder and the potential role setmelanotide may play in the management of hypothalamic obesity.

正如我所說，這些患者都是平均年齡 31 歲的成年人，距離受傷時平均還有 12 歲。迄今為止的反應是一致的，最值得注意的事情之一是反應的一致性和穩健性，進一步增強了我們對MC4R 通路在這種疾病中的重要性以及setmelanotide 在治療中可能發揮的潛在作用的信念下視丘肥胖。

So finally, on slide 11 is a summary of our upcoming milestones. The PDUFA date for our U.S. and survey label expansion to include patients ages two to -- up to six years old as December 26, and Jennifer will touch on that.

最後，投影片 11 總結了我們即將到來的里程碑。我們美國的 PDUFA 日期和調查標籤擴展包括 2 歲至 6 歲的患者，即 12 月 26 日，Jennifer 將談到這一點。

Based on the progress of initial enrollment and sites opening, we expect to complete enrollment in the 12-patient Japanese cohort of our Phase III acquired hypothalamic obesity trial by the end of this year. We also expect to complete enrollment in two of the M&A substudies, POMC, PCSK1 and SH2B1 by the end of the year.

根據初始入組和站點開放的進展情況，我們預計在今年年底前完成 III 期獲得性下丘腦肥胖試驗的 12 名日本患者隊列的入組。我們也預計在今年年底前完成兩項併購子研究 POMC、PCSK1 和 SH2B1 的註冊。

We do not anticipate being able to achieve a full enrollment in the other two sub-studies, LEPR and SRC1. In the first quarter of 2025, we anticipate we will complete enrollment in the 28 patient Phase II trial evaluating bivamelagon and also in the first quarter begin dosing patients with acquired hypothalamic obesity in Part C of our Phase I trial with weekly MC4R agonist RM-718.

我們預計其他兩項子研究 LEPR 和 SRC1 無法實現全部註冊。在2025 年第一季度，我們預計將完成評估bivamelagon 的28 名患者II 期試驗的入組，並在第一季度開始在I 期試驗C 部分中開始給患有獲得性下丘腦肥胖的患者每週服用MC4R 激動劑RM-718 。

And as we have said many times, our top line data readout from the pivotal 120 patient cohort in our global Phase III trial setmelanotide and acquired hypothalamic obesity is on track for the first half of the year.

正如我們多次說過的那樣，我們從全球 III 期試驗中關鍵的 120 名患者隊列中讀出的頂線數據在今年上半年正在按計劃進行。

With that, I'll turn the call over to Jennifer.

這樣，我就把電話轉給詹妮弗。

Thank you, David. I will start today on slide 13. We are continuing to see growth in prescriptions, approvals for reimbursement as well as increased breadth and depth amongst prescribers. In the third quarter, we received approximately 100 new prescriptions and approximately 80 approvals for reimbursement, resulting in a steady increase of commercially reimbursed patients.

謝謝你，大衛。我今天將從幻燈片 13 開始。我們不斷看到處方數量、報銷批准數量以及處方者的廣度和深度不斷增加。第三季度，我們收到約100個新處方和約80個報銷批准，導致商業報銷患者穩定增加。

We are pleased with this sustained growth and the continued demand for a therapy that addresses the root cause of hyperphagia and severe obesity in BBS patients. This growth is driven by increases in both the number of first-time prescribers as well as repeat prescribers. With positive experience with patients on IMCIVREE, the number of physicians with two or more prescriptions continues to increase.

我們對這種持續增長以及對解決 BBS 患者食慾過盛和嚴重肥胖根本原因的治療的持續需求感到高興。這一增長是由首次處方者和重複處方者數量的增加所推動的。隨著 IMCIVREE 患者的積極體驗，持有兩種或更多處方的醫生數量持續增加。

At any point of time in the future, this quarter or prior quarters first-time prescribers may become a repeat prescriber as they are now more in tune to recognizing the symptoms of BBS, and diagnosing additional BBS patients in their practice. As you would expect to see in rare diseases, these patients are -- these physicians are becoming experts in their city and regions, which helps to create a network of BBS disease experts throughout the nation to support the optimal care of BBS patients.

在未來的任何時間點，本季或前幾季的首次處方者可能會成為重複處方者，因為他們現在更適合識別 BBS 症狀，並在實踐中診斷更多 BBS 患者。正如您在罕見疾病中所看到的那樣，這些患者正在成為所在城市和地區的專家，這有助於在全國範圍內建立 BBS 疾病專家網絡，以支持 BBS 患者的最佳護理。

The breakdown by specialty remains consistent with about half of prescribers falling into the endocrinologists bucket and about half in the primary care or pediatrician bucket, with a small number of prescribers and other specialties including medical geneticists, nephrologists and ophthalmologists. We remain pleased with the consistency of payer approvals as initial approvals for reimbursement continue at a steady pace, as have reauthorizations, which allow patients to maintain on therapy.

按專業劃分的情況仍然一致，大約一半的處方者屬於內分泌科醫生，大約一半屬於初級保健或兒科醫生，少數處方者和其他專業人士包括醫學遺傳學家、腎臟病學家和眼科醫生。我們對付款人批准的一致性感到滿意，因為報銷的初始批准繼續穩步進行，重新授權也是如此，這允許患者繼續接受治療。

Consistent with prior quarters, there will remain a small number of denials for reauthorization, though we continue to work with patients and providers through the appeals process to regain reimbursement.

與前幾季一樣，儘管我們繼續透過上訴程序與患者和提供者合作以重新獲得報銷，但仍將有少量拒絕重新授權的情況。

Next slide. The recognition of the differentiation of BBS patients from the population with general obesity as well as the differentiation of IMCIVREE as a targeted therapy for BBS patients, is appreciated by both ACPs and payers.

下一張投影片。ACP 和付款人都讚賞 BBS 患者與一般肥胖人群的區別以及 IMCIVREE 作為 BBS 患者標靶治療的區別。

To further support this differentiation, we are looking forward to potentially expanding the label from IMCIVREE to include patients as young as two years of age in the US in our current indications. Early onset obesity that goes untreated can lead to multiple comorbidities and negatively affect quality of life and life expectancy. We believe that treating patients at an early age will positively impact the lives of these children and their families.

為了進一步支持這種差異化，我們期待有可能擴大 IMCIVREE 的標籤範圍，將美國兩歲的患者納入我們目前的適應症中。未經治療的早發性肥胖可能會導致多種合併症，並對生活品質和預期壽命產生負面影響。我們相信，對患者進行早期治療將對這些兒童及其家人的生活產生積極影響。

Last quarter, Yann reported the European Commission expanded the marketing authorization for IMCIVREE to include children as young as two years of age. And the FDA has accepted with priority review our sNDA for the same expansion and assigned a PDUFA date of December 26, 2024.

上個季度，Yann 報告稱，歐盟委員會擴大了 IMCIVREE 的營銷授權，將年僅兩歲的兒童納入其中。FDA 已優先審查我們針對相同擴充的 sNDA，並指定 PDUFA 日期為 2024 年 12 月 26 日。

Our submission was based on our Phase III data in children that demonstrated a 3.04 mean reduction in BMI-Z score, a measure of body mass index deviation from what is considered normal. And an 18.4% mean reduction in BMI in 12 patients at 12 months on setmelanotide therapy.

我們的提交是基於兒童的 III 期數據，該數據表明 BMI-Z 評分平均降低了 3.04，BMI-Z 評分是衡量身體質量指數與正常值的偏差的指標。在接受 setmelanotide 治療 12 個月後，12 名患者的 BMI 平均降低了 18.4%。

Approval in the US on top of EMA authorization would reinforce IMCIVREE's unique position in the market and recognize and differentiate were MC4 pathway diseases and associated hyperphagia and severe early onset obesity from general obesity.

在 EMA 授權的基礎上在美國獲得批准將鞏固​​ IMCIVREE 在市場上的獨特地位，並識別和區分 MC4 途徑疾病以及相關的食慾過盛和嚴重早發性肥胖與一般性肥胖。

While the overall patient numbers may provide modest growth, we are excited about what this potential opportunity means for patients and their families. Early onset obesity and hyperphagia driven behaviors are more identifiable in children than in adults, and their caregivers are often more engaged in actively seeking answers. This will be an important and meaningful milestone for the BBS community.

雖然患者總數可能會出現適度增長，但我們對這一潛在機會對患者及其家人意味著什麼感到興奮。與成人相比，兒童的早發性肥胖和食慾過多驅動的行為更容易識別，而且他們的照顧者通常更積極地尋求答案。這對BBS社區來說將是一個重要且有意義的里程碑。

On to my final slide. We are preparing for a positive outcome in our Phase III trial in acquired hypothalamic obesity and are investing to prepare for the next potential launch. We are engaging in market research to gain insights from physicians, payers and patients and families and actively engaging with patient advocacy groups.

轉到我的最後一張投影片。我們正在為獲得性下丘腦肥胖的 III 期試驗取得積極成果做準備，並正在投資為下一次可能的推出做準備。我們正在進行市場研究，以獲取醫生、付款人、患者和家屬的見解，並積極與患者權益團體合作。

Also, we are planning to expand our different field and support teams in 2025 as we anticipate increasing physician engagement efforts to provide education on acquired hypothalamic obesity. The unmet need in hypothalamic obesity is significant, and there are no approved therapies. We look forward to sharing more details with you next year as we prepare for top line data and get closer to a potential FDA submission and launch.

此外，我們計劃在 2025 年擴大我們的不同領域和支持團隊，因為我們預計將增加醫生的參與力度，以提供有關獲得性下丘腦肥胖的教育。下視丘肥胖的未滿足需求是巨大的，並且沒有批准的治療方法。我們期待明年與您分享更多細節，因為我們正在準備頂線數據並接近潛在的 FDA 提交和上市。

I'll now turn it over to Yann to provide an update on the international region.

現在我將把它交給 Yann，以提供國際區域的最新情況。

Thank you, Jennifer. I will start on slide 17. The international region is an important contributor to our recent success. In this quarter, we delivered a strong revenue growth. IMCIVREE is now available for [Bardet-Biedl] or BBS or both in more than 15 countries outside the United States, with reimbursement through various government administered programs on inpatient sales.

謝謝你，詹妮弗。我將從幻燈片 17 開始。國際地區是我們近期成功的重要貢獻者。在本季度，我們實現了強勁的營收成長。IMCIVREE 現已在美國以外的超過 15 個國家/地區提供 [Bardet-Biedl] 或 BBS 或兩者，並透過各種政府管理的住院銷售計劃進行報銷。

The initial month for the BBS launches in Spain and Italy have started well, but the main drivers of revenues for the ex-US countries continue to be France and Germany.

在西班牙和義大利推出 BBS 的第一個月開局良好，但美國以外國家的主要收入驅動力仍然是法國和德國。

In Germany, our BBS launch is steady and mirrors the consistent growth pattern of the US, and we are benefiting from expanding the number of centers that are now treating BBS patients. As Jennifer mentioned, this summer, the EMA expanded the marketing authorization for IMCIVREE to the treatment of children as young as two years old in approved indications.

在德國，我們的 BBS 啟動穩定，反映了美國的持續成長模式，我們正受益於擴大目前治療 BBS 患者的中心數量。正如 Jennifer 所提到的，今年夏天，EMA 將 IMCIVREE 的營銷授權擴大到在批准的適應症中治療兩歲以下的兒童。

And last month, in Germany, the Federal Joint Committee, or [GBA] voted to exclude IMCIVREE for children two to six years old from the country's lifestyle exemption list, and thereby make it eligible for full reimbursement for both PPL and BBS.

上個月，在德國，聯邦聯合委員會 (GBA) 投票決定將針對 2 至 6 歲兒童的 IMCIVREE 從該國的生活方式豁免清單中排除，從而使其有資格獲得 PPL 和 BBS 的全額報銷。

While this was expected, we are pleased that the committee entertained very little debate on this topic, which illustrates that Germany recognizes the need to treat patients with MC4R pathway disease because this rare disease are distinct from general obesity. Talking about Germany, I would like to share an IMCIVREE success story from a German patient. One of several.

雖然這是預料之中的，但我們很高興委員會對此主題幾乎沒有進行辯論，這表明德國認識到治療 MC4R 通路疾病患者的必要性，因為這種罕見疾病與一般肥胖不同。說到德國，我想分享一個來自德國患者的IMCIVREE成功故事。幾個之一。

One 12 years old girl with BBS with pronounced hyperphagia, the BMA-Z score of plus 1.5% and the fear of needles, began therapy more than six months ago. At first, she refused injection. But our [resum] at home nursing team helped her overcome our fears and develop within a few weeks, a routine for injection.

一名患有 BBS 的 12 歲女孩，患有明顯的食慾過盛，BMA-Z 評分+1.5%，並且害怕針頭，她在 6 個多月前開始接受治療。起初，她拒絕注射。但我們的[簡歷]家庭護理團隊幫助她克服了恐懼，並在幾週內養成了注射常規。

After one month, she started to inject herself, and now we see a normalized hyperphagia, normalized to what is considered LC by our [trade] indication. She has lost 9.1 kilos and has now a normal body weight for her age.

一個月後，她開始給自己注射，現在我們看到正常化的食慾亢進，正常化為我們的[貿易]適應症所認為的 LC。她減重了 9.1 公斤，目前體重處於正常年齡。

And importantly, our family reports that she has a new sense of independence she did not have before. Anecdotes like this from Germany and elsewhere in the international region and of course the difference we can make in many lives with ancillary and also our patient support program.

重要的是，我們的家人報告說她有了以前沒有的新獨立感。來自德國和國際地區其他地方的此類軼事，當然還有我們透過輔助和患者支持計劃可以為許多人的生活帶來的改變。

In France, the reimbursed early access one for BBS has been ongoing for more than one year now, while we continue to negotiate reimbursement with the authorities. Once we complete negotiation, we will be able to promote IMCIVREE through physician engagement activities. We will be in a strong position to build on the success of the early access program as we are expanding the number of clinical centers with positive insurer experience.

在法國，BBS 的報銷搶先體驗已經持續了一年多，同時我們仍在與當局協商報銷事宜。一旦我們完成談判，我們將能夠透過醫生參與活動來推廣 IMCIVREE。隨著我們正在擴大具有積極保險公司經驗的臨床中心的數量，我們將處於有利地位，能夠在早期訪問計劃的成功基礎上再接再厲。

Next slide. We also have in place paid-early access programs in both France and Italy for patients with hypothalamic obesity. In France, we began treating patients earlier this year, and we're already seeing positive data reports, as David shared. We are quite pleased that patients with hypothalamic obesity have access to setmelanotide are responding well to the therapy, and that treating physicians are reporting positive outcome.

下一張投影片。我們也在法國和義大利為下丘腦肥胖患者制定了付費早期訪問計劃。在法國，我們今年早些時候開始治療患者，正如大衛分享的那樣，我們已經看到了積極的數據報告。我們非常高興的是，下丘腦肥胖患者能夠使用setmelanotide，並且對治療反應良好，並且治療醫生報告了積極的結果。

The uptake of setmelanotide through this program has been increasing with an approval decision process led by a joint federal multidisciplinary committee which means monthly, a process that is similar to how access is allowed for patients with BBS. In Italy, we are seeing the first patients with hypothalamic obesity begin therapy with setmelanotide under the low 648 early access program.

透過該計劃，Setmelanotide 的使用量一直在增加，其審批決策流程由聯邦多學科聯合委員會領導，即每月一次，該流程類似於允許 BBS 患者使用的流程。在義大利，我們看到第一批下丘腦肥胖患者在低 648 早期訪問計劃下開始接受塞美諾肽治療。

The process is a little different than France as the physician directly asks the Ministry of Health to enable his or her patients to participate in the program. Also this program is limited to patients between 6-years old and 24-years old where hypothalamic obesity was caused by craniopharyngioma.

這個過程與法國略有不同，因為醫生直接要求衛生部允許他或她的患者參與該計劃。此外，該計劃僅限於6歲至24歲因顱咽管瘤引起下丘腦肥胖的患者。

Next slide. Our BBS launch is beginning this quarter in England and Wales following the positive recommendation from NICE. We expect to start deferred BBS patients on IMCIVREE therapy during the fourth quarter. We anticipate the uptake for IMCIVREE in the UK to be more measured than Germany as the NICE recommendation limits reimbursement to patients who are younger than 18-years old, when they begin therapy.

下一張投影片。在 NICE 的積極推薦下，我們的 BBS 將於本季在英格蘭和威爾斯啟動。我們預計在第四季度開始推遲 BBS 患者接受 IMCIVREE 治療。我們預計英國對 IMCIVREE 的接受程度將比德國更為嚴格，因為 NICE 建議將報銷限制在開始治療時年齡小於 18 歲的患者。

In the UK, there are four national health service BBS specialized clinics that provide care for patients with BBS, two centers that treat adults and two centers that treat children. Each center sees a handful of patients with BBS each month, and we know that the treating physicians will discuss IMCIVREE therapy as a new option with these patients and families.

在英國，有四個國家衛生服務 BBS 專門診所為 BBS 患者提供護理，兩個治療成人的中心和兩個治療兒童的中心。每個中心每個月都會接待少數 BBS 患者，我們知道治療醫生將與這些患者和家屬討論 IMCIVREE 療法作為新的選擇。

If they decide to proceed, they will be educated on IMCIVREE and train on the daily administration. Following on the positive experience from our launch in Germany, we have commissioned a very comprehensive patient support program with nurses visiting homes, assisting in the administration and addressing any questions or concerns.

如果他們決定繼續，他們將接受 IMCIVREE 教育並接受日常管理培訓。繼我們在德國推出的積極經驗之後，我們委託開展了一項非常全面的患者支持計劃，護士上門服務，協助管理並解決任何問題或疑慮。

The BBS community of patients, families, physicians and other members of the clinical care team have been very supportive of one another and supportive of Rhythm in our approval and launch efforts. In England, we are very excited to bringing then IMCIVREE.

由患者、家屬、醫生和臨床護理團隊其他成員組成的 BBS 社區一直相互支持，並支持 Rhythm 我們的批准和推出工作。在英格蘭，我們非常高興能推出 IMCIVREE。

Next slide and my last slide. One of our strategic priorities is to continue engagement with and support for the growing network of physicians who are becoming experts in [the real] MC4R pathway diseases.

下一張投影片和我的最後一張投影片。我們的策略重點之一是繼續與不斷壯大的醫生網絡合作並提供支持，這些醫生正在成為[真正的] MC4R 通路疾病的專家。

With that, I want to offer details on two events where we are focused on supporting and building up this network. On October 30 and 31, we sponsored TRANSFORM, a scientific meeting designed to engage with and educate the experts of tomorrow or physician in the early part of their career on rare MC4R pathway diseases.

在此，我想提供有關我們重點支援和建立該網路的兩項活動的詳細資訊。10 月 30 日至 31 日，我們贊助了 TRANSFORM，這是一次科學會議，旨在與未來的專家或處於職業生涯早期的醫生就罕見的 MC4R 通路疾病進行交流和教育。

It was attended by 44 physicians from 14 countries. This event was endorsed by the European Association for the Study on Obesity, the European Society for Pediatric Endocrinology and the European Society of Endocrinology and co-chaired by Professor Volkan Yumuk, the President of the European Association for the Study on Obesity himself. And next week, we will have a strong presence at the 62nd Annual Meeting of the European Society for Pediatric Endocrinology, which is from November 16 to 18 in Liverpool.

來自 14 個國家的 44 名醫生參加了這次會議。本次活動得到了歐洲肥胖研究協會、歐洲兒科內分泌學會和歐洲內分泌學會的認可，並由歐洲肥胖研究協會主席 Volkan Yumuk 教授擔任聯合主席。下週，我們將強勢出席 11 月 16 日至 18 日在利物浦舉行的歐洲兒科內分泌學會第 62 屆年會。

We are expecting strong attendance at our satellite symposium entitled Early Treatment of Hyperphagia and Early Onset Severe Obesity in children with rare MC4R pathway diseases, with a focus on BBS and other rare MC4R pathway diseases. Professor Sadaf Farooqi of the University of Cambridge is the event Chair, and she will be joined by Professor Philip Beales of the University College of London among others.

我們期待大量參加我們題為「患有罕見 MC4R 通路疾病的兒童的食慾過盛和早發嚴重肥胖的早期治療」的衛星研討會，重點關注 BBS 和其他罕見的 MC4R 通路疾病。劍橋大學的 Sadaf Farooqi 教授擔任活動主席，倫敦大學學院的 Philip Beales 教授等人也將參與活動。

We also have three abstracts accepted for oral presentation, all on our sequencing data and analysis from URO, our genetic -- European genetic sequencing program as well as real-world data from the French early access program for hypothalamic obesity.

我們還有三份摘要被接受進行口頭報告，全部是關於我們的測序數據和 URO 分析、我們的歐洲基因測序計劃以及來自法國下丘腦肥胖早期獲取計劃的真實數據。

These new pediatric data are from pediatric patients with hypothalamic obesity following three to six months on setmelanotide therapy. And now I turn the call over to Hunter.

這些新的兒科數據來自接受 Setmelanotide 治療三到六個月後患有下丘腦肥胖的兒科患者。現在我把電話轉給亨特。

Thank you, Yann. Turning to slide 22. Net revenue from global sales in IMCIVREE continued to grow steadily and came in at $33.3 million in Q3 as compared to $22.5 million during the third quarter of last year.

謝謝你，揚。轉到投影片 22。IMCIVREE 全球銷售淨收入持續穩定成長，第三季達到 3,330 萬美元，而去年第三季為 2,250 萬美元。

On a sequential basis, Q3 revenue represents 14% growth over the second quarter of this year. US revenue in the third quarter was $23.3 million, accounting for 70% of product revenue during the quarter and an increase of 8% in US sales on a sequential basis over the second quarter.

以環比計算，第三季營收較今年第二季成長 14%。第三季美國營收為2,330萬美元，佔該季產品營收的70%，美國銷售額較第二季較上季成長8%。

Driving this growth was an increase in the number of reimbursed patients on therapy and corresponding increase in volume of [bio] dispensed to patients. Gross to net for US sales in the third quarter decreased slightly quarter over quarter to 85% from 86% in the second quarter of the year.

推動這一增長的是接受治療的報銷患者數量的增加以及向患者分配的[生物]數量的相應增加。第三季美國銷售額的毛淨額較上季略有下降，從今年第二季的 86% 降至 85%。

International revenue was $10 million which accounted for 30% of product revenue and represented an increase of 35% over Q2. More than half of [access] US sales continue to come from the commercial launch in Germany and the early access programs for both BBS and HO in France.

國際營收為 1,000 萬美元，佔產品收入的 30%，較第二季成長 35%。美國銷售的一半以上仍來自德國的商業發布以及法國 BBS 和 HO 的搶先體驗計劃。

We are also seeing solid revenue contributions from named patient sales in several countries and the launches in Italy and Spain, which are still in their early phases but progressing well. We are now generating revenue in more than 15 countries outside the United States.

我們也看到多個國家的指定患者銷售以及義大利和西班牙的推出帶來了穩定的收入貢獻，這些產品仍處於早期階段，但進展順利。我們現在在美國以外的超過 15 個國家創造收入。

Some of these countries receive shipments on a more intermittent basis or once or twice a quarter, and hence, we believe some of our Q3 revenue represented a pull forward of demand from Q4. Nonetheless, we are excited that we hit the $10 million mark on international quarterly revenue in Q3.

其中一些國家的出貨情況較為間歇性或每季一次或兩次，因此，我們認為我們第三季的部分收入代表了第四季度需求的拉動。儘管如此，我們很高興第三季的國際季度營收達到 1,000 萬美元大關。

Cost of sales during the quarter was $3.8 million or approximately 11.5% of net product revenue versus 10.1% of net product revenue in the second quarter of this year and 10.7% during the same quarter last year.

本季的銷售成本為 380 萬美元，約佔產品淨收入的 11.5%，而今年第二季為 10.1%，去年同期為 10.7%。

The primary driver of COGS continues to be the 5% royalty to Ipsen under our licensing agreement with setmelanotide as well as higher labor and overhead costs capitalized to inventory, based on high production in Q2 which was expensed to COGS in Q3 based on shipments.

銷貨成本的主要驅動因素仍然是根據我們與setmelanotide 的許可協議向Ipsen 收取5% 的特許權使用費，以及資本化到庫存的更高的勞動力和間接費用，這是基於第二季度的高產量，而第三季則根據出貨量計入銷貨成本。

R&D expenses were $37.9 million for the third quarter compared to $33.6 million during the third quarter of last year. Sequentially, we experienced a 25% increase from R&D expenses of $30.2 million in the second quarter due to a $3 million benefit recorded for changes in scopes to the DAYBREAK and M&A trials during Q2.

第三季研發費用為 3,790 萬美元，去年第三季研發費用為 3,360 萬美元。隨後，由於第二季 DAYBREAK 和併購試驗範圍變化記錄了 300 萬美元的收益，我們的研發費用比第二季的 3,020 萬美元增加了 25%。

Plus, there were additional cost increases in both of those trials this quarter and increased manufacturing development work related to bivamelagon, formerly known as LB54640.

此外，本季這兩項試驗的成本都增加了，與 bivamelagon（以前稱為 LB54640）相關的製造開發工作也有所增加。

SG&A expenses were $35.4 million for the third quarter compared to $30.5 million for the same quarter last year. Q3 SG&A expenses represent a $1 million decrease sequentially versus $36.4 million for the second quarter of 2024.

第三季銷售、管理及行政費用為 3,540 萬美元，去年同期為 3,050 萬美元。第三季的 SG&A 費用比 2024 年第二季的 3,640 萬美元減少了 100 萬美元。

The quarter-over-quarter decrease was largely driven by a reduction in payroll tax expense based on changes in French equity tax loss for nonqualified options this quarter. For the third quarter, weighted average common shares outstanding were $61.2 million.

環比下降主要是由於本季不合格選擇權法國股權稅損失的變化導致工資稅費用減少。第三季度，加權平均已發行普通股為 6,120 萬美元。

Now let's move to slide 23. As of September 30, 2024, we reported $298.4 million in cash and cash equivalents. Cash used in operations was approximately $22.6 million in Q3. This was the first quarter as a public company in which Rhythm used less than $25 million in cash for operations, another significant milestone.

現在讓我們轉到投影片 23。截至 2024 年 9 月 30 日，我們報告的現金和現金等價物為 2.984 億美元。第三季營運中使用的現金約為 2,260 萬美元。這是 Rhythm 作為上市公司首次使用不到 2500 萬美元現金用於營運的季度，這是另一個重要的里程碑。

The trailing 12 months quarterly average cash burn was approximately $28.7 million. So we continue to generate improvements in operating leverage as revenues grow.

過去 12 個月的季度平均現金消耗約為 2,870 萬美元。因此，隨著收入的成長，我們將繼續改善營運槓桿。

On a year-to-date basis, cash used for operations was $89.3 million, a reduction of 11% versus the comparable period of 2023. Third quarter operating expenses included total stock-based compensation of $11 million for the quarter compared to $10.4 million in the previous quarter.

年初至今，用於營運的現金為 8,930 萬美元，與 2023 年同期相比減少了 11%。第三季營運支出包括本季以股票為基礎的薪酬總額 1,100 萬美元，而上一季為 1,040 萬美元。

Reported GAAP EPS for the third quarter was a net loss per basic and diluted share of $0.73, which includes accrued dividends on convertible preferred stock of $1.3 million. As a reminder, this ongoing [prevented] accrual will be $1.3 million per quarter or $0.02 per share at the current share count. No cash dividends are payable prior to the end of the second quarter of 2026.

報告的第三季 GAAP 每股基本每股收益和攤薄每股淨虧損為 0.73 美元，其中包括 130 萬美元的可轉換優先股應計股息。提醒一下，這種持續[阻止]的應計費用將為每季 130 萬美元，或以當前股數計算每股 0.02 美元。2026年第二季末前不支付現金股利。

Turning to slide 24. Today, with only one quarter remaining in the year, we have reduced our 2024 OpEx guidance to a range of $245 million to $255 million from the prior guidance range of $250 million to $270 million. This updated guidance is comprised of R&D, non-GAAP operating expenses of approximately $137 million and SG&A, non-GAAP operating expenses of approximately $113 million, both of which represent midpoint numbers of these components in our updated estimated guidance range.

轉到投影片 24。如今，距離今年僅剩四分之一，我們已將 2024 年營運支出指引範圍從先前的 2.5 億美元至 2.7 億美元降至 2.45 億美元至 2.55 億美元。此更新後的指引包括約 1.37 億美元的研發、非 GAAP 營運支出和約 1.13 億美元的 SG&A、非 GAAP 營運支出，這兩者均代表我們更新的估計指引範圍中這些組成部分的中點數字。

Lastly, we continue to expect cash on hand to be sufficient to fund planned operations well into 2026, potentially beyond multiple value-creating milestones, including the top line data readout from our Phase III trial in hypothalamic obesity currently planned for the first half of 2025.

最後，我們仍然預計手頭現金足以為 2026 年的計劃運營提供資金，可能會超越多個創造價值的里程碑，包括目前計劃於 2025 年上半年進行的下丘腦肥胖 III 期試驗的頂線數據讀出。

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

這樣，我會將電話轉回大衛。

Thanks, Hunter. So in summary, I think you've heard a very good quarter. And we're entering -- finishing the year and entering 2025 with a lot of momentum. So we look forward to future updates. With that, we'll open the call for Q&A.

謝謝，獵人。總而言之，我認為您聽到了一個非常好的季度報告。我們正以強勁的勢頭結束這一年並進入 2025 年。所以我們期待未來的更新。至此，我們將開始問答環節。

(Operator Instructions) Phil Nadeau, TD Cowen.

（操作員說明）Phil Nadeau，TD Cowen。

Congrats on a strong quarter. Hunter, first question for you. In the prepared remarks, you mentioned there was some pull forward of demand from Q4 into Q3. Would you be able to quantify what the impact was on Q3 from that pull forward? And any other lumpy items included in the IMCIVREE revenue number?

恭喜季度表現強勁。亨特，你的第一個問題。在準備好的發言中，您提到需求從第四季提前到了第三季。您能否量化這提前對第三季產生的影響？IMCIVREE 收入數字中還包括任何其他塊狀物品嗎？

It's a little imprecise and it depends, obviously, on the timing and the nature of these orders. But sometimes, if they come late in the quarter, we think it's more attributable to the future quarter. So that's -- we estimate that could be around $0.5 million in Q3.

這有點不精確，顯然取決於這些訂單的時間和性質。但有時，如果它們在本季晚些時候出現，我們認為這更多地歸因於未來的季度。我們估計第三季的收入可能約為 50 萬美元。

Okay. That is very helpful. And then second question on the DAYBREAK trial, congrats on the data. They continue to look strong. Can you talk about what you need to see to advance one of those populations to a pivotal study? And when do you think you might be in a position to make a go, no-go decision on those populations?

好的。這非常有幫助。然後是有關 DAYBREAK 試驗的第二個問題，恭喜取得數據。他們看起來仍然很強大。您能談談您需要看到什麼才能將其中一個人群推進關鍵研究嗎？您認為什麼時候您可以對這些人群做出走或不走的決定？

Yes. Thanks, Phil. So I think the general answer to that is, for each of these genes, the better we can understand the variance, as I said in my remarks, in terms of defining which of the variants are true loss of function.

是的。謝謝，菲爾。因此，我認為對此的一般答案是，對於這些基因中的每一個，我們可以更好地理解方差，正如我在評論中所說，在定義哪些變異是真正的功能喪失方面。

Because to the extent that we can do that post hoc, you do improve the results. In other words, and right now, many of those [loose] patients, I'm sure have benign variants in which case the -- we wouldn't expect that to be driving their underlying disease.

因為只要我們事後能做到這一點，您確實可以改善結果。換句話說，現在，我確信許多[鬆散的]患者都有良性變異，在這種情況下，我們不會期望這會導致他們的潛在疾病。

So that's the general comment is we've got to understand that better. A gene like PHIP, we have not a bad sense today. I think there's more work that can be done. That's a gene that has on the order -- prevalence numbers, which again are soft, but sort of BBS-like in the order of 4,000. That's a gene we might look to go earlier on, but I would -- earlier would mean we would do it with a next-generation program.

因此，總的意見是我們必須更好地理解這一點。像 PHIP 這樣的基因，我們今天已經有了不錯的感覺。我認為還有更多工作要做。這個基因的盛行率數字同樣是軟的，但有點像 BBS，大約是 4,000。這是一個我們可能希望更早使用的基因，但我會——更早意味著我們將透過下一代程式來做到這一點。

So one or both of those would need to have cleared Phase I NHL.

因此，其中一個或兩個都需要 NHL 第一階段的許可。

That is very helpful. Congrats again on the progress.

這非常有幫助。再次恭喜取得的進展。

That moves that out. That's a 2026 kind of activity, not a 2025, if we were to do that.

這樣就可以解決這個問題了。如果我們要這樣做的話，那是 2026 年的活動，而不是 2025 年。

Derek Archila, Wells Fargo.

德里克·阿奇拉，富國銀行。

This is Adam on for Derek. Congratulations on the quarter. Maybe just a couple on HO from us. Do you think the real-world data from France HO patients will be predictive of what we can see in the Phase III study in terms of BMI reduction? And then also, of the five patients who experienced weight loss at six months, can you let us know which patients had previously been on [GLP-1s]?

這是亞當替德瑞克發言。恭喜本季。也許只有我們幾個在 HO 上。您認為來自法國 HO 患者的真實世界數據能否預測我們在 III 期研究中看到的 BMI 降低？另外，在六個月內體重減輕的五名患者中，您能否讓我們知道哪些患者之前接受過治療？[GLP-1]？

Yes. So do I think this will be predictive? I think what we would say, the reason this data, I think, is so incredibly helpful. One, the original Phase II is only 18 patients, 1 patient who didn't take the drug. So 17 patients who took the drug.

是的。那麼我認為這會是預測性的嗎？我想我們會說，我認為這些數據是如此有用的原因。一、原來的二期只有18名患者，1名患者沒有吃藥。因此，有 17 名患者服用了該藥。

Now we have another eight patients. And what's most reassuring is literally every patient who has taken the drug with this diagnosis has had a good response.

現在我們還有另外八名患者。最令人放心的是，實際上每位在診斷後服用該藥物的患者都得到了良好的反應。

So in terms of reading through to Phase III, consistency in any clinical trial is incredibly reassuring. The magnitude of the decrease now, I think, remarkably, we're seeing very good percent decreases in the BMI. But we've discouraged trying to stay out of the arms race around percent decrease.

因此，就閱讀第三階段而言，任何臨床試驗的一致性都令人難以置信地放心。我認為，現在下降的幅度非常顯著，我們看到體重指數下降的百分比非常好。但我們不鼓勵試圖參與圍繞百分比下降的軍備競賽。

For these patients that have nothing, simply not gaining way it would be victory for them. So again, we're seeing good percentage decrease. But the more important part of this is the consistency, and I think that predicts well for a positive outcome in the Phase III trial.

對這些一無所有的病人來說，只要不退路，對他們來說就是勝利。因此，我們再次看到百分比下降。但更重要的部分是一致性，我認為這很好地預示了 III 期試驗的正面結果。

And then for the five patients, they don't have the breakout, which of the patients were on the GLP-1 specifically, so I can't answer your question whether they were on it. But the doses they are on, of the four patients, one of the patients stopped the GLP-1 before they started the trial.

然後，對於 5 名患者，他們沒有出現突破，其中哪些患者專門服用了 GLP-1，所以我無法回答你的問題，他們是否服用了 GLP-1。但就他們所服用的劑量而言，在四名患者中，其中一名患者在開始試驗之前就停止了 GLP-1。

So only three of them of the eight were actually on a GLP-1 during. And they were on, as I understood, for the treatment of their diabetes more than a specific attempt to get an obesity weight reduction. But beyond the drug, if they were losing -- actively losing weight, they would not have been enrolled in this early access program.

因此，八人中只有三人實際上在服用 GLP-1。據我了解，他們的目的不僅是為了減輕肥胖體重，而是為了治療糖尿病。但除了藥物之外，如果他們正在減肥——積極減肥，他們就不會參加這個早期訪問計劃。

Got it. And then maybe just one more from us. At our dinner at Obesity Week, we had (inaudible) that noted that they believe that the HO population may be close to 5,000 to 10,000 or even above in the US and they contribute to that somewhat to -- many patients who have brain tumors who receive radiation may also end up with HO over time. Is this a patient population you've been aware of? And if so, do you have any estimates on how many of these patients make up this.

知道了。然後也許我們還會再發一份。在肥胖週的晚餐上，我們（聽不清楚）指出，他們認為美國的HO 人口可能接近5,000 到10,000 甚至更多，他們在某種程度上對此做出了貢獻——許多患有腦腫瘤的患者隨著時間的推移，接受輻射也可能最終產生 H2O。這是您所了解的患者群嗎？如果是這樣，您對這些患者中有多少人有任何估計嗎？

Yes. I think -- so this whole area of HO injury and how do you get it as part of the evolution. We focused on those who have the benign tumors, which are a very well-defined group. And they have this very specific moment of injury, if you will, when they go to surgery. There are other ways you can injure the hypothalamus.

是的。我認為，HO 損傷的整個區域以及如何將其作為進化的一部分。我們專注於那些患有良性腫瘤的人，這是一個非常明確的群體。如果你願意的話，當他們接受手術時，他們有一個非常特定的受傷時刻。還有其他方法可以損傷下視丘。

We hear anecdotally from physicians that they see a similar picture in some of those patients, including radiation patients. So I think there's more to be learned there. We're very interested, obviously, in learning more about that.

我們從醫生那裡聽說，他們在其中一些患者（包括放射患者）身上看到了類似的情況。所以我認為那裡還有更多東西要學習。顯然，我們非常有興趣了解更多相關資訊。

I have no estimate as to what number of patients there might be, and I think there's more to be learned about their response. But the anecdote you're describing, we've heard that.

我無法估計可能有多少患者，而且我認為關於他們的反應還有更多需要了解。但你所描述的軼事，我們都聽過。

Corinne Johnson, Goldman Sachs.

科琳·約翰遜，高盛。

Maybe a couple of questions from us. First, how should we think about sort of the contribution from Europe as we look into 2025? And do you anticipate that it will become sort of a larger share of overall revenue as we get further into that launch? And then could you also provide us some updates on what you're seeing with respect to adherence and compliance in the BBS patient population?

也許我們會問幾個問題。首先，展望 2025 年，我們該如何看待歐洲的貢獻？您是否預計，隨著我們進一步推出該產品，它將在總收入中佔據更大的份額？那麼您能否提供我們一些關於 BBS 患者群體的依從性和依從性方面的最新情況？

So I'll take the first question, Corinne. I think we've built a solid base in international, and we continue to -- we continue to foresee growth there. But the degree to which it keeps pace with the U.S., which is starting from a larger base, I think, is going to be variable quarter-to-quarter.

那我將回答第一個問題，科琳。我認為我們已經在國際上建立了堅實的基礎，並且我們將繼續——我們繼續預見那裡的成長。但我認為，它與美國同步的程度（美國是從更大的基礎開始的），每個季度都會有所不同。

Okay. And the second question was on adherence. So are you talking about the discount rate? Is that what you're focusing on?

好的。第二個問題是關於堅持。那你說的是折扣率嗎？這就是你關注的重點嗎？

Yes, exactly.

是的，完全正確。

Yes. So that's remained -- as we said last time, we've ticked up closer to 30% in general, and that hasn't changed. Maybe Jennifer can provide a little more color on what we're doing to continue to work that problem because I think we have some good insight and we can do some things. Jen?

是的。所以這一點仍然存在——正如我們上次所說，我們總體上已經接近 30%，而且這一點沒有改變。也許珍妮佛可以為我們正在做的事情提供更多的信息，以繼續解決這個問題，因為我認為我們有一些很好的洞察力，我們可以做一些事情。珍？

To answer your question, I think like when we take a look at the discounts, there's different things that we have learned, many of these are coming early and with this insight, we have continued to really focus a lot of our efforts just in terms of educating and really setting clear expectations.

為了回答你的問題，我認為，當我們查看折扣時，我們學到了不同的東西，其中許多都是提前到來的，有了這種洞察力，我們繼續將我們的大量努力集中在以下方面：教育並真正設定明確的期望。

Initially, it was more on the AE profile of the drug, but we also recognized that we needed to provide more expectation around the timing of efficacy impact in patients as well. So we learn as we go, just in terms of being able to maintain those patients on therapy.

最初，更多的是關於藥物的 AE 情況，但我們也認識到，我們還需要圍繞對患者療效影響的時間提供更多期望。因此，我們邊走邊學，只是為了能夠讓這些患者繼續接受治療。

And I think one other piece that is also important is that there are a lot of different reasons that our patients [discount]. There may be different reasons from a life perspective that may make them potentially interested in it coming back.

我認為另一件同樣重要的事情是，我們的患者有許多不同的原因[折扣]。從生活的角度來看，可能有不同的原因使他們對回歸感興趣。

The vast majority of these patients are consented. So our patient support teams are able to maintain engagement with them. And we have seen patients who have been interested in getting back on therapy as well.

這些患者中的絕大多數都得到了同意。因此，我們的患者支援團隊能夠與他們保持接觸。我們也看到有興趣重新接受治療的患者。

Seamus Fernandez, Guggenheim Securities.

謝默斯·費爾南德斯，古根漢證券公司。

So just wanted to talk a little bit about -- a little bit more about HO and the pipeline assets. Just to start with the data coming out of the eight patients in France, obviously, an impressive result in the adult population.

所以我只是想多談談 HO 和管道資產。首先從來自法國八名患者的數據開始，顯然，這在成年人口中取得了令人印象深刻的結果。

I wanted to just get a little bit more color on the opportunity to continue expanding the early access opportunity in Europe with that data. Is that something that you're able to mobilize and then bring more patients onto therapy sooner with that result?

我只是想透過這些數據來進一步了解繼續擴大歐洲搶先體驗機會的機會。您是否能夠動員起來，然後讓更多的患者更快地接受治療並取得這樣的結果？

And then the second question is really on the pipeline. Obviously, I know there's a strong view that in IMCIVREE or setmelanotide will continue to be very durable. But I think the opportunity to void the MC1 receptor is certainly quite compelling from our conversations with physicians.

第二個問題確實正在醞釀。顯然，我知道有一種強烈的觀點認為 IMCIVREE 或 setmelanotide 將繼續非常耐用。但我認為，從我們與醫生的對話來看，消除 MC1 受體的機會無疑是相當引人注目的。

So just wanted to get a better sense of how those trials are progressing and when you would hope to really share those data? I believe you said midyear in the past, but I didn't know if there are any updates from a recruitment perspective and execution.

所以只是想更了解這些試驗的進展以及您何時希望真正分享這些數據？我相信你過去說過年中，但我不知道從招募角度和執行方面是否有任何更新。

Yes. So Yann, do you want to provide a little color on how the HO process is working and your expectations? Is that going to ramp or stay steady? What would you say?

是的。Yann，您想提供一些有關 HO 流程如何運作以及您的期望的資訊嗎？是會增加還是保持穩定？你會說什麼？

So thank you, yes. So for sure, in France, it will help, I think. A local physician always likes to have local data on top of global data, so it will help. For sure, it will also help the takeoff in Italy as well, French and Italian experts talk a lot and look at own data, respectively.

所以謝謝你，是的。所以我認為，在法國，這肯定會有所幫助。當地醫生總是喜歡在全球數據之上擁有本地數據，因此這會有所幫助。當然，這也將有助於義大利的起飛，法國和義大利專家分別討論了很多並查看了自己的數據。

And on top of that, I can say that there are not so many countries with large early access programs like France and Italy, but there are other smaller countries where we have named patient sales, which will look at this data and likely decide to start some patients, which are currently already identified in need.

最重要的是，我可以說，像法國和義大利這樣擁有大型早期訪問計劃的國家並不多，但還有其他較小的國家，我們已將其命名為患者銷售，這些國家將查看這些數據並可能決定開始目前已確定有需要的一些患者。

Great. And with regard to your second question, Seamus, on the next-generation programs, which we agree with you are incredibly important. So for the weekly, the 718, as we've said previously, there's no new update there in the sense that need to submit the rodent, the 6-month rodent and the nine-month nonhuman primate.

偉大的。關於你的第二個問題，Seamus，關於下一代計劃，我們同意你的觀點，這非常重要。因此，對於每週的 718，正如我們之前所說，沒有新的更新，需要提交囓齒動物、6 個月大的囓齒動物和 9 個月大的非人靈長類動物。

Those studies are ramping up. We need to submit those reports to the FDA and also, at the same time, an amendment which will allow us to treat patients for more than 4 weeks, which is how the original protocol was written.

這些研究正在加速進行中。我們需要向 FDA 提交這些報告，同時還需要一項修正案，使我們能夠治療患者超過 4 週，這就是最初方案的編寫方式。

And as we said, we had trouble. The physicians didn't think they could recruit if patients could only get the drug for four weeks because it's -- the first four weeks are quite intense. So the bottom line is, obviously, we want to be able to provide longer-term treatment for those patients.

正如我們所說，我們遇到了麻煩。醫生認為，如果患者只能服用四個星期的藥物，他們就無法招募患者，因為前四週非常緊張。因此，最重要的是，顯然，我們希望能夠為這些患者提供長期治療。

So that's the 718 program. Our goal, we've moved it out a bit is -- based on the timing of that amendment submission, is to dose the first patients in that program in 718. The bivamelagon, we had a very slow start. We got an early -- back midyear, I think the first patient in, and then we had a tough summer and just getting sites open on [Cothrabo].

這就是718計劃。我們的目標，我們已經把它移了一點——根據提交修正案的時間，是在 718 年對該計劃中的第一批患者進行給藥。bivamelagon，我們的起步非常緩慢。我們早在年中就迎來了第一個病人，然後我們度過了一個艱難的夏天，只是讓網站在[科斯拉博]。

A laundry list of reasons, but we have the sites open now and we're up and rolling. And so the update today is that we've got more than 50 -- just about a little more than 50% of the patients either dosed or in screening.

原因一長串，但我們現在已經開放了這些網站，我們正在全力以赴。今天的更新是，我們已經有超過 50 名患者——略多於 50% 的患者要么接受了給藥，要么正在接受篩檢。

So there it's always hard to give a firm date while you're still recruiting, but our expectation is that we will, for sure, complete enrollment of that trial in the first quarter, which means that a midyear readout is still possible for the small molecule program.

因此，當你仍在招募時，總是很難給出一個確定的日期，但我們的期望是，我們肯定會在第一季度完成該試驗的註冊，這意味著對於小型企業來說，年中讀數仍然是可能的。

Great. And then maybe just as one final question. The opportunity for HO in Japan is something that you've talked about in the past. Can you just give us a sense of how the HO opportunity is likely to emerge there? And is this something that you still feel confident that it is something that Rhythm can take on, on its own?

偉大的。然後也許只是最後一個問題。您過去曾談到 HO 在日本的機會。您能否讓我們了解那裡可能會如何出現 HO 機會？您是否仍然相信 Rhythm 可以獨自承擔這項任務？

Yes. So like we said we're at ObesityWeek. I met with Dr. Tanaka, who is the lead investigator in Japan today. As I highlighted in my script, our expectation is that we'll complete enrollment of the 12 Japanese patients required by the end of this year.

是的。就像我們說的，我們在肥胖週。我今天會見了田中博士，他是日本的首席研究員。正如我在腳本中所強調的那樣，我們的期望是在今年年底前完成所需的 12 名日本患者的招募。

He was very positive again, about how this is going. The sites are working well together. So if you're asking about our optimism about Japan, I think it's not at all diminished, if anything, it's increased.

他對事情的進展再次非常樂觀。這些網站合作良好。因此，如果你問我們對日本的樂觀情緒，我認為它根本沒有減少，甚至增加。

Can we handle that? Again, I think rare diseases, if you have the right people -- and again, it's not so much a function of the size of the country necessarily. But if you have the right people, and I think we do as a starting point, you can go it alone. And so that's still our plan today.

我們可以處理嗎？再說一遍，我認為罕見疾病，如果你有合適的人的話——再說一次，這並不一定是國家大小的函數。但如果你有合適的人，而且我認為我們以此為起點，你就可以單獨行動。這仍然是我們今天的計劃。

Congrats on the quarter.

恭喜本季。

Dae Gon Ha, Stifel.

大貢河，斯蒂菲爾。

And congrats on all the data this week. I guess I'll just focus more on the hypothalamic obesity side. Just a couple of questions there. for 718 Part C data, before you go in there, is there any intention from you guys to share the Phase I healthy volunteer, just so we can get a sense for the PK as well as the hyperpigmentation side of the profile?

祝賀本週所有數據。我想我會更關注下丘腦肥胖方面。只是有幾個問題。對於718 C部分的數據，在你進入那裡之前，你們是否打算分享第一階段的健康志願者，這樣我們就可以了解PK以及配置文件的色素沉著過度方面？

As we think about the bivamelagon. I guess when you think about the trial itself, how much of an overlap is there between the trial participating in -- I guess, sites participating in that bivamelagon SIGNAL trial versus the Phase III hypothalamic obesity? I recall it was overenrolled. And so I would imagine some of that could bleed into, if you will, and perhaps fast track the bivamelagon enrollment?

當我們想到雙美拉貢。我想，當你考慮試驗本身時，參與的試驗——我想，參加 bivamelagon SIGNAL 試驗的站點與 III 期下丘腦肥胖試驗的站點之間有多少重疊？我記得是超額錄取的。因此，我想如果你願意的話，其中一些可能會滲透到雙瓦美拉康的註冊中，也許可以快速追蹤雙瓦美拉康的註冊情況？

And then I guess, lastly, just thinking about the broader opportunity, going back to Phil's question, DAYBREAK and M&A, just wanted to get your sense on sort of the commercial opportunity here. Are you guys thinking about hypothalamic obesity and maybe going after something like a profitability goal first? Or would you be looking after more expansion opportunities by going after M&A than DAYBREAK subsets that might be promising.

最後，我想，只是考慮更廣泛的機會，回到菲爾的問題，黎明和併購，只是想了解這裡的商業機會。你們是否正在考慮下視丘肥胖，並可能先追求諸如獲利目標之類的目標？或者，您是否會透過併購來尋找更多的擴張機會，而不是可能有希望的 DAYBREAK 子集。

Okay. I may come back to the last one, just -- so your first question was about 718, Part C. Will we share the A and B parts? We haven't made any plans for that. I'm not saying we won't.

好的。我可能會回到最後一個問題，只是 - 所以你的第一個問題是關於 718 的 C 部分。我們還沒有為此制定任何計劃。我並不是說我們不會。

I have to think a little bit about where we would do that in terms of the meeting. But given the delay, I think it's perfectly -- given the delay in Part C, it's a perfectly reasonable question. So I'll defer and come back to you on that.

我必須考慮我們在會議上應該在哪裡做到這一點。但考慮到延遲，我認為這是完美的——考慮到 C 部分的延遲，這是一個完全合理的問題。所以我會推遲一下，然後再回覆你。

On your second question, for the bib and the overlap of the sites, I'm going to plead ignorance here. We have a number of sites which were not part of the original or not part of our Phase III HO trial. As you said, we did over enroll. But most of these sites are new, but I can't tell you for sure that we don't have some overlap there. So maybe we can get back to you offline.

關於你的第二個問題，對於圍兜和網站的重疊，我將在這裡表示不知情。我們有許多站點不屬於原始或不屬於我們的 III 期 HO 試驗的一部分。正如你所說，我們確實超額招生了。但大多數這些網站都是新的，但我不能肯定地告訴你我們在那裡沒有一些重疊。所以也許我們可以離線回覆您。

I can probably take third on. I think the question of a trade-off between investment in a registrational strategy for M&A and DAYBREAK and profitability, it's a little early to speculate on because it presumes both that we've established a firm timeline to when we would invest in those and what the revenue that we would be generating from HO at that time would be.

我大概可以拿第三。我認為，在併購和DAYBREAK 的註冊策略投資與盈利能力之間進行權衡的問題，現在推測還為時過早，因為它假設我們已經制定了明確的時間表來確定何時投資這些以及投資哪些內容。

So there's a lot of moving parts. We consistently try to evaluate them prospectively, but I think it's a little too early to say.

所以有很多移動部件。我們一直試圖對它們進行前瞻性評估，但我認為現在說還為時過早。

What I would say is, as we've said repeatedly, we are very dilution-sensitive as a company. We're all shareholders here. And at the same time, we recognize that the biggest opportunity for the company is to maximize the area under the curve in terms of generating cash flow for our shareholders. So we're trying to optimize all those parts of the best we can.

我想說的是，正如我們一再說過的那樣，作為一家公司，我們對稀釋非常敏感。我們都是這裡的股東。同時，我們也意識到，公司最大的機會是最大化曲線下面積，為股東創造現金流。因此，我們正在盡力優化所有這些部分。

Great congrats again. Yes, sounds good.

再次恭喜。是的，聽起來不錯。

Whitney Ijem, Canaccord Genuity.

惠特尼·艾傑姆，Canaccord Genuity。

Just one follow-up on the -- can you guys still hear me, okay?

只是一個後續──你們還能聽到我說話嗎？

Yes.

是的。

Okay. Sorry. Follow-up on the Japan opportunity. Can you remind us -- I know you said the filing in Japan is based on the analysis of the overall study plus the Japanese cohort. Is it the full Japanese cohort out to a year of follow up? Or is there a potential for an interim cut with less follow-up of the Japanese cohort in particular?

好的。對不起。跟進日本機會。您能否提醒我們 - 我知道您說過在日本提交的申請是基於對整體研究以及日本隊列的分析。這是為期一年的追蹤的全部日本隊列嗎？或者是否有可能進行臨時削減，特別是對日本群體採取較少的後續行動？

Yes, it's the former. So it's -- what we've been clear about is the first 120 patients will form the basis for the EU and the US filing. And then there's an additional 11 patients, which was the over-enrollment plus the 12 Japanese patients. When they finish and the Japanese patients will be gating in that, that will be -- so it's the last Japanese patient out at a year, that's the filing.

是的，是前者。所以我們已經明確的是，前 120 名患者將構成歐盟和美國申請的基礎。然後還有另外 11 名患者，這是超額入組加上 12 名日本患者。當他們完成時，日本患者將進入該中心，這將是 - 所以這是一年中最後一個出院的日本患者，這就是備案。

Jeff Hung, Morgan Stanley.

傑夫洪，摩根士丹利。

The French real-world study suggests that patients who had a resection over a decade ago could still derive a benefit from setmelanotide. Are you seeing any patterns on BMI or hunger score that correlates with time since resection? And if not, do you think that setmelanotide would be an ideal therapy regardless of time since resection? And then I have a follow-up.

法國的真實世界研究表明，十多年前接受過切除術的患者仍然可以從塞黑諾肽中受益。您是否發現 BMI 或飢餓評分有任何與切除後時間相關的模式？如果不是，您認為無論切除後的時間如何，setmelanotide 都是理想的治療方法嗎？然後我有一個後續行動。

Yes. No, thanks, Jeff. And you're highlighting what I think is the most amazing part about this. It's -- I do think it's exactly what you said, which is that time doesn't seem to make a difference. The drop in hunger and the BMI changes are perfectly consistent with what we saw in the HO trial, despite the fact that the original Phase II trial was 13 pediatric patients out of the 17.

是的。不，謝謝，傑夫。你強調了我認為最令人驚奇的部分。我確實認為這正是你所說的，那就是時間似乎沒有帶來什麼影響。飢餓感的下降和體重指數的變化與我們在 HO 試驗中看到的情況完全一致，儘管最初的 II 期試驗是 17 名兒童患者中的 13 名。

So yes, I think it says it doesn't matter. It's the defect. The biology of the defect, no matter when you had it, you've interrupted somehow impaired signaling to the MC4 pathway and MC4 agonist seems to be the solution.

所以是的，我認為它說沒關係。這就是缺陷從生物學角度來看，無論您何時出現這種缺陷，都會以某種方式中斷 MC4 通路受損的訊號傳導，而 MC4 激動劑似乎是解決方案。

Great. And then a few weeks ago, you announced the partnership with Axovia in BBS. Can you just talk about what you hope to gain from it? And will that help you gain greater access to the UK registry to reach additional BBS patients?

偉大的。幾週前，你們在 BBS 上宣布與 Axovia 建立合作關係。您能簡單談談您希望從中獲得什麼嗎？這會幫助您更好地訪問英國登記處以接觸更多 BBS 患者嗎？

I'm going to let Yann comment on the access to the UK registry. What we announced the week ago is a -- so we know Phil Beales very well. We work closely with him. Obviously, he's one of the leading experts in the world.

我將讓 Yann 評論英國註冊中心的訪問權限。我們一週前宣布的是——所以我們非常了解菲爾·比爾斯。我們與他密切合作。顯然，他是世界領先的專家之一。

And he's doing work now trying to develop a treatment for the eye findings in Bardet-Biedl. So one, we wanted to support that. Two, we have a shared interest in terms of understanding the epidemiology of BBS. So it made sense to work together.

他現在正在努力開發一種針對 Bardet-Biedl 眼部症狀的治療方法。因此，我們想支持這一點。第二，我們在了解 BBS 的流行病學方面有著共同的興趣。所以一起工作是有意義的。

And yes, he's got deep data, which I don't think he would deny us, but this is an opportunity to put it together. But Yann, maybe a couple of comments just on your thoughts on that.

是的，他擁有深入的數據，我認為他不會否認我們，但這是將這些數據整合在一起的機會。但是 Yann，也許我想就你對此的想法發表一些評論。

No, I can just add that we already support --

不，我可以補充一點，我們已經支持--

Speak up a little bit, Yann. You've got to speak into your phone.

說一點點，Yann。你必須對著手機說話。

Okay. Is it good now?

好的。現在好了嗎？

Yes.

是的。

Sorry. No, I just -- I can add that we already support the BBS registry. Phil Beales and his team have worked on it for many years in collaboration with the BBS UK patient association, and we have started to support this effort maybe, I would say, one year ago now, and we will continue to do so.

對不起。不，我只是——我可以補充一點，我們已經支持 BBS 註冊表。Phil Beales 和他的團隊已經與英國 BBS 患者協會合作多年，我們可能在一年前就開始支持這項工作，而我們將繼續這樣做。

Tazeen Ahmad, Bank of America Securities.

塔津‧艾哈邁德，美國銀行證券公司。

In terms of the Phase III data that you're expecting for HO, I think you've given a little bit of a broad guidance for the first half of 2025. Should we be expecting that timeline to be condensed maybe early next year some time? Or is that the guidance that you're going to maintain? And what's going to need to happen in order for that time line to condense?

就您期望的 HO 第三階段數據而言，我認為您已經為 2025 年上半年提供了一些廣泛的指導。我們是否應該期待這個時間表可能會在明年初的某個時候被壓縮？或者這是您要維持的指導方針？為了縮短時間線，需要發生什麼？

And then secondly, as you think about HO and the use of setmelanotide there, what have doctors told you about the desire to be able to combine GLP-1s with that drug? And I know you're not doing studies on that per se, but commercially speaking, would that be a good size?

其次，當您考慮 H2O 和 setmelanotide 的使用時，醫生告訴您什麼關於將 GLP-1 與該藥物結合的願望？我知道你並沒有對此本身進行研究，但從商業角度來看，這個尺寸合適嗎？

So your first question, which is totally fair. I mean, what we've said, which is just -- we've given you as best we could, the math. So last patient dosed literally at the first day of February. It's a 60-week trial, last patient last out, so you can do the math on 60 weeks from then.

所以你的第一個問題是完全公平的。我的意思是，我們所說的只是——我們已經盡我們所能地為您提供了數學。所以最後一位患者其實是在二月的第一天服藥的。這是一項為期 60 週的試驗，最後一名患者最後退出，因此您可以從那時起計算 60 週。

And then you've got to close the trial out and the like. So we'll be working as aggressively as we can to close it out efficiently, but it's not an instantaneous. So I don't think we're going to be able to update it a lot better than that. I think we -- it's not going to be June 30. I think you can all do the math on that and conclude that's not the case.

然後你必須結束試驗等等。因此，我們將盡可能積極地工作，以有效地結束它，但這不是瞬間的。所以我認為我們無法比這更好地更新它。我想我們——不會是 6 月 30 日。我想你們都可以計算一下並得出結論事實並非如此。

I'm not sure we'll be able to refine it publicly much more than that, but I don't know. I'm not helping you very much there beyond the math, to be honest. Your second question was on the HO -- the combination therapies, and there is interest. I mean the whole world is focused on combos in general. In our world, as we've discussed, I think we gain weight for different reasons.

我不確定我們能否公開改進它，但我不知道。老實說，除了數學之外，我並沒有給你太多幫助。你的第二個問題是關於 HO——聯合療法，大家很感興趣。我的意思是整個世界都專注在連擊。正如我們所討論的，在我們的世界中，我認為我們體重增加的原因各有不同。

So any given patient who has a deficit in their MC4R pathway signaling and does well on setmelanotide, they may plateau. They may also have gained weight for other reasons, which may be amenable to another drug, a GLP-1, for example. And anecdotally, we know that GLP-1s have been added to patients who have been on setmelanotide.

因此，任何 MC4R 通路訊號傳導缺陷但服用 setmelanotide 效果良好的患者，其病情可能會趨於穩定。他們也可能因其他原因而體重增加，這可能適合另一種藥物，例如 GLP-1。有趣的是，我們知道 GLP-1 已被添加到服用 setmelanotide 的患者中。

In some of those cases, they've had incremental weight loss, which I think is consistent with that hypothesis. So I think your last question was, is that a good thing? To me, a good thing is anything that gets the patient a better outcome. And we know that the medications can be used together. We know in a mouse model, they were additive.

在其中一些案例中，他們的體重減輕了，我認為這與該假設是一致的。所以我認為你的最後一個問題是，這是一件好事嗎？對我來說，任何能讓患者獲得更好結果的事情都是好事。我們知道這些藥物可以一起使用。我們知道在小鼠模型中，它們是相加的。

So it makes sense from that standpoint. There's a little bit of overlap in the toxicity. They both have nausea, GI complaints as part of that. And so using the two drugs together,it's a little more work that may be the case, but it can be done.

所以從這個角度來看這是有道理的。毒性有一點重疊。他們都有噁心、腸胃不適等症狀。因此，同時使用這兩種藥物可能需要更多的工作，但這是可以完成的。

Joseph Stringer, Needham & Company.

約瑟夫‧斯金格，李約瑟公司。

Just back on the BBS launch, you're seeing pretty steady growth in new patient adds, another 100 US. TRx were in the quarter. Just wondering if you can describe the BBS patients that are new to drug at this point in the launch. Are the vast majority newly diagnosed? Where and how are they being identified and/or diagnosed? Any color on this would be helpful.

回到 BBS 發佈時，您會看到新增患者數量相當穩定地成長，又增加了 100 名美國患者。TRx 在本季。只是想知道您是否可以描述一下在發佈時剛接觸藥物的 BBS 患者。絕大多數是新確診的嗎？他們在哪裡以及如何被識別和/或診斷？任何顏色都會有幫助。

Okay. So we'll start with Jennifer. And then Yann, if you have any thoughts on international, you can go there, but Jennifer?

好的。我們將從詹妮弗開始。然後Yann，如果你對國際有什麼想法，你可以去那裡，但Jennifer？

Yes. So I think it's a mix in general. I think that our teams overall are doing a lot of outreach to physicians, they have been in contact with over time and through the education and back and forth, those physicians for a rare disease. It's being aware and heightened just in terms of as patients come their way, to actually get that patient [to spec] understanding the various different symptoms and actually getting that patient to a diagnosis.

是的。所以我認為總的來說這是一個混合體。我認為我們的團隊總體上正在與醫生進行大量的外展活動，隨著時間的推移，他們透過教育和來回與那些治療罕見疾病的醫生進行了接觸。它只是隨著患者的到來而意識到並加強，以真正讓患者[規範]了解各種不同的症狀並真正讓患者得到診斷。

So it -- as these patients are more educated and they're more in tune, it becomes easier for them also to potentially [suspect] patients to get to diagnosis. So this is how, as I explained, we have some initial first-time prescribers where they have finally gotten to a patient diagnosis and understand the value of IMCIVREE as well as repeat prescribers as well. Both are contributing.

因此，隨著這些患者受過更多的教育並且他們更加適應，他們也更容易潛在地[懷疑]患者獲得診斷。正如我所解釋的，這就是我們最初的首次處方者以及重複處方者最終獲得患者診斷並了解 IMCIVREE 價值的方式。兩者都在做出貢獻。

Yes, maybe we'll leave it there. Is that good?

是的，也許我們會把它留在那裡。這樣好嗎？

Great.

偉大的。

Raghuram Selvaraju, H.C. Wainwright & Company.

塞爾瓦拉朱 (Raghuram Selvaraju)，H.C.溫賴特公司。

Just wanted to see if you could comment at all on activities that are planned in congenital hyperinsulinism. Over the course of 2025, if we should expect any updates on that front? And also, if you could give us some additional color on where you anticipate there might be additional reimbursed early access programs instituted for setmelanotide over the course of 2025?

只是想看看您是否可以對先天性高胰島素血症計劃的活動發表評論。2025 年，我們是否應該期待這方面的任何更新？另外，您是否可以給我們一些額外的信息，說明您預計在 2025 年期間可能會為 setmelanotide 制定額外的報銷早期訪問計劃？

Okay. So for the second part of your question, Yann, I don't know if you've got any other countries where you would want to highlight at this point. But I'll come back to you in just a minute. The first question was on congenital causes. And I think I would put this in the category, the earlier question we got about rate -- oh, congenital hyperinsulinism.

好的。因此，對於你問題的第二部分，Yann，我不知道你現在是否想強調任何其他國家。但我一會兒就回你。第一個問題是關於先天原因的。我想我會把它歸類在我們之前收到的關於比率的問題——哦，先天性高胰島素血症。

Thank you. CHI, I just got clarification. Apologies on that. So on our CHI program, which we have not spoken about, as I said, and we are waiting to develop a molecule, get our lead molecule identified. We've made good progress. And so I will commit to updating in 2025. We won't have further updates here in 2024, but we are making good progress and our interest remains high in the CHI.

謝謝。CHI，我剛剛得到澄清。對此表示歉意。因此，在我們的 CHI 計劃中，正如我所說，我們尚未談論該計劃，我們正在等待開發一種分子，並確定我們的先導分子。我們已經取得了很好的進展。因此我將承諾在 2025 年進行更新。2024 年我們不會再有進一步的更新，但我們正在取得良好進展，我們對 CHI 的興趣仍然很高。

With that, Yann, any other sort of additional early access countries where we would be looking at? You got to go back to your phone.

那麼，Yann，我們還會考慮哪些其他類型的早期訪問國家/地區嗎？你必須回到你的手機前。

I am very close from my laptop. Is it better now?

我離我的筆記型電腦很近。現在好點了嗎？

Yes.

是的。

Okay. Sorry. So yes, thank you for your question. So not so many countries, in fact, but for good reasons. First, we are, as I said earlier, already in more than 15 countries ex-US. And a good chunk of these countries are countries where we have early access programs or paid early access.

好的。對不起。所以是的，謝謝你的提問。事實上，沒有那麼多國家，但有充分的理由。首先，正如我之前所說，我們已經在美國以外的超過 15 個國家開展業務。這些國家中有很大一部分是我們提供搶先體驗計畫或付費搶先體驗的國家。

Two, we pick our countries very carefully. So we could be in much more countries, but it would come with less time on more important countries first, and we also want to make sure that when we start somewhere, there will be some sustainability. So we pay really attention to where we go. So based on that and back to your questions, we will likely be in two or three additional countries in the next 12 months, but not more than that, again, by choice and by design.

第二，我們非常謹慎地選擇我們的國家。因此，我們可以進入更多的國家，但首先在更重要的國家會花費更少的時間，我們也希望確保當我們從某個地方開始時，會有一定的可持續性。所以我們非常關注我們去的地方。因此，基於此並回到您的問題，我們可能會在未來 12 個月內進入另外兩到三個國家，但不會超過這個數量，同樣是出於選擇和設計。

Jon Wolleben, Citizens JMP.

Jon Wolleben，公民 JMP。

This is [Katherine] on for Jon. I actually have two questions on reimbursement. The first question is, kind what was the current paid rate and how much more -- how much room is there to kind of improve upon this and what can be done to improve upon this and the cause of denials currently in the U.S.? And then just any color on early discussions with payers regarding HO and reimbursement there? And just kind of how to identify which patients can get the drug early, since you did -- have shown that it works in patients that have had diagnosis for years now.

這是喬恩的[凱瑟琳]。其實我有兩個關於報銷的問題。第一個問題是，目前的付費率是多少，還有多少——有多少改進的空間，可以採取哪些措施來改善這一點以及目前美國被拒絕的原因？那麼，與付款人就 HO 和報銷進行的早期討論有什麼不同嗎？就像如何確定哪些患者可以儘早獲得藥物一樣，因為您已經證明它對已經診斷多年的患者有效。

Hunter, do you want to comment on the paid rate?

亨特，您想對付費率發表評論嗎？

By the paid rate, are you speaking to -- what our coverage among payers where we've been pretty consistent is that we get essentially no coverage from Medicare by statute because we are an obesity med indicated for weight loss. And we have a high level of coverage from commercial -- close to full coverage from commercial, although there are many small commercial plans, which do not -- cannot afford or do not have coverage for expensive therapies.

就付費費率而言，您所說的是——我們在付款人中的承保範圍非常一致，我們基本上沒有根據法規獲得醫療保險的承保，因為我們是一種用於減肥的肥胖藥物。我們擁有高水準的商業承保——接近商業的全面承保，儘管有許多小型商業計劃，它們無法負擔或不承保昂貴的治療。

And then we have very high levels, plus -- 80% plus of covered lives in Medicaid. So that's kind of where we've been saying. We've said that the number of scripts that go to free -- sorry, the number of patients, the transition to free drug has been running about 20% of scripts.

然後我們的醫療補助覆蓋率非常高，超過 80%。這就是我們一直在說的。我們已經說過，免費的腳本數量——抱歉，患者數量，向免費藥物的過渡已經運行了大約 20% 的腳本。

And maybe one other thing if I understood the question was we don't -- a, we don't discount. And b, the price of the drug per se has not been the issue for denial. It's been more policy-related. Do they cover obesity drugs in general, for example, Medicare. That's the reason we don't get covered by Medicare.

如果我理解這個問題的話，也許另一件事是我們不——a，我們不打折。b，藥物本身的價格並不是否認的問題。這更與政策相關。它們是否涵蓋一般的肥胖藥物，例如醫療保險？這就是我們沒有享有醫療保險的原因。

So does that answer your question?

那麼這回答了你的問題嗎？

No, that's the answer to my question.

不，這就是我問題的答案。

Thank you. I would now like to turn the conference back over to Dr. Meeker for closing remarks.

謝謝。現在我想將會議轉回米克博士致閉幕詞。

Okay. Well, thanks again to everybody for tuning in here on a busy day and an unconventional end of the day earning call. Just excited where we are and look forward to our next update. Thanks.

好的。好吧，再次感謝大家在忙碌的一天和非傳統的一天結束時收看這裡。我們對現在的情況感到興奮，並期待我們的下一次更新。謝謝。

This concludes today's conference call. Thank you for your participation. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。