Nektar Therapeutics (NKTR) 2023 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Nektar Therapeutics First Quarter 2023 Financial Results Conference Call. (Operator Instructions) Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Vivian Wu. Please go ahead.

美好的一天，感謝您的支持。歡迎參加 Nektar Therapeutics 2023 年第一季度財務業績電話會議。 （操作員指示）請注意，今天的會議正在錄製中。現在我想把會議交給今天的發言人 Vivian Wu。請繼續。

Thank you, Crystal, and good afternoon, everyone. Thank you for joining us today. With us on the call are Howard Robin, our President and CEO; Dr. Jonathan Zalevsky, our Chief of Research and Development; Dr. Mary Tagliaferri, our Chief Medical Officer; and Sandra Gardiner, our acting Chief Financial Officer. .

謝謝克里斯托，大家下午好。感謝您今天加入我們。與我們一起參加電話會議的是我們的總裁兼首席執行官霍華德·羅賓 (Howard Robin)；我們的研發主管 Jonathan Zalevsky 博士； Mary Tagliaferri 博士，我們的首席醫療官；以及我們的代理首席財務官桑德拉·加德納 (Sandra Gardiner)。 。

On today's call, we expect to make forward-looking statements regarding our business, including statements regarding the therapeutic potential of and future development plans for drug candidates and research programs, the timing of the initiation of clinical studies and the availability of clinical data for drug candidates, the timing and plans for future clinical data presentations, the formation -- future development plans or success of our collaboration arrangements. The expectations following our corporate restructuring and reorganization, financial guidance and certain other statements regarding the future of our business. Because forward-looking statements relate to the future, they are subject to uncertainties and risks that are difficult to predict and many of which are outside of our control.

在今天的電話會議上，我們希望就我們的業務做出前瞻性陳述，包括有關候選藥物和研究項目的治療潛力和未來開發計劃、候選藥物臨床研究啟動時間和臨床數據可用性、未來臨床數據展示的時間和計劃、我們合作安排的未來開發計劃或成功的陳述。我們的公司重組和重組、財務指導以及有關我們業務未來的某些其他聲明之後的預期。由於前瞻性陳述涉及未來，因此它們受到難以預測的不確定性和風險的影響，其中許多是我們無法控制的。

Our actual results may differ materially from these statements. Important risks and uncertainties are set forth in our Form 10-K that was filed on February 28, 2023, which is available at sec.gov. We undertake no obligation to update any of these forward-looking statements, whether as a result of new information, future developments or otherwise. A webcast of this call will be available on the IR page of Nektar's website at nektar.com. With that said, I would like to hand the call over to our President and CEO, Howard Robin. Howard?

我們的實際結果可能與這些陳述存在重大差異。我們於 2023 年 2 月 28 日提交的 10-K 表格中列出了重要的風險和不確定性，該表格可在 sec.gov 上獲取。我們沒有義務更新任何這些前瞻性陳述，無論是由於新信息、未來發展還是其他原因。本次電話會議的網絡直播將在 Nektar 網站 nektar.com 的 IR 頁面上提供。話雖如此，我想將電話轉交給我們的總裁兼首席執行官霍華德羅賓。霍華德？

Thank you, Vivian, and thank you all for joining us today. As you know, a few weeks ago, we announced our plans to implement a new strategic plan and cost restructuring at Nektar. And I'm pleased to report today that we enacted the plan quickly and that we will begin to see ongoing expense savings starting in the third quarter of this year. The new plan focuses our company more clearly on immunology and importantly, also extends our cash runway through at least the middle of 2026. A core element of our new pipeline focus and plan is on the advancement of REZPEG, and we intend to move quickly to initiate a well-powered randomized Phase IIb study for REZPEG in patients with atopic dermatitis. We were incredibly pleased to have regained the rights to this first-in-class regulatory T cell program from Lilly. Importantly, there are no royalties owed to Lilly for this transfer and REZPEG now becomes a wholly owned asset of Nektar's.

謝謝你，維維安，也感謝大家今天加入我們。如您所知，幾週前，我們宣布了在 Nektar 實施新戰略計劃和成本重組的計劃。我今天很高興地向大家報告，我們迅速制定了該計劃，並且從今年第三季度開始我們將開始看到持續的費用節省。新計劃更明確地將我們公司的重點放在免疫學上，重要的是，還將我們的現金跑道至少延長到 2026 年中期。我們新的管道重點和計劃的核心要素是 REZPEG 的進展，我們打算迅速採取行動，啟動一項針對特應性皮炎患者的 REZPEG 的強有力的隨機 IIb 期研究。我們非常高興能夠從禮來公司重新獲得這一一流的調節性 T 細胞項目的權利。重要的是，此次轉讓無需向禮來公司支付任何特許權使用費，REZPEG 現在成為 Nektar 的全資資產。

Atopic dermatitis, as a target indication for REZPEG, is attractive to us for several reasons, not the least of which is the strength of the data that has been generated for REZPEG in patients with atopic dermatitis. The nontopical biologic treatment landscape is significantly growing. The approvals of DUPIXENT and other IL-13 based biologics have driven this growth. In the U.S. alone, approximately 16 million people are living with atopic dermatitis with 3 out of 4 of these affected by moderate to severe disease.

特應性皮炎作為 REZPEG 的目標適應症，對我們有吸引力有幾個原因，其中最重要的是 REZPEG 在特應性皮炎患者中產生的數據的強度。非外用生物治療領域正在顯著增長。 DUPIXENT 和其他基於 IL-13 的生物製劑的批准推動了這一增長。僅在美國，就有約 1600 萬人患有特應性皮炎，其中四分之三患有中度至重度疾病。

In 2021, biologic sales for atopic dermatitis were close to $5 billion and sales continue to grow. That being said, atopic dermatitis is a disease area where there is still a very high unmet need for novel biologic treatment options. Most notably, the mechanisms available to patients today after they fail topical treatments overlap and fall into either the category of IL-13 based mechanisms or JAK inhibitor. Both mechanisms have limitations on efficacy and both have some notable safety challenges, which include black box warnings with the JAK inhibitor class.

2021年，特應性皮炎生物製劑銷售額接近50億美元，且銷售額持續增長。話雖這麼說，特應性皮炎是一個對新型生物治療方案的需求仍然非常未得到滿足的疾病領域。最值得注意的是，當今患者在局部治療失敗後可用的機制重疊，屬於基於 IL-13 的機製或 JAK 抑製劑的類別。這兩種機制的功效都有局限性，並且都存在一些顯著的安全挑戰，其中包括 JAK 抑製劑類的黑框警告。

Even with the growth in the adoption of these mechanisms, at least 50% of patients don't respond to these therapies at all, and many patients see a rebound in their disease after coming off these therapies. This opens a real opportunity for REZPEG to be introduced as the first regulatory T cell mechanism that is differentiated from these overlapping existing mechanisms. The Phase Ib data for REZPEG was compelling and set the stage for us to measure the potential for REZPEG to be a remittive therapy with longer-term disease control and less frequent maintenance dosing. JZ will review the data reported for REZPEG in a few minutes, including the quality and durability of responses we saw in patients.

即使這些機制的採用不斷增加，至少 50% 的患者對這些療法根本沒有反應，而且許多患者在停止這些療法後病情出現反彈。這為 REZPEG 作為第一個不同於這些重疊的現有機制的調節性 T 細胞機制提供了真正的機會。 REZPEG 的 Ib 期數據令人信服，為我們衡量 REZPEG 作為緩解療法的潛力奠定了基礎，該療法具有長期疾病控制和較低頻率的維持劑量。 JZ 將在幾分鐘內審查 REZPEG 報告的數據，包括我們在患者中看到的反應的質量和持久性。

Now as we mentioned in our reprioritization plan with a focus on immunology, we'll also continue the development of our IL-15 program, NKTR-255 in cancer, while we explore strategic partnership options. NKTR-255 is being developed in combination with cell therapies, and we believe it could be a valuable adjuvant therapy for companies focused in the area of cell therapy. Our Phase II study of NKTR-255 in combination with approved cell therapies, BREYANZI and Yescarta, as well as the Phase II JAVELIN Bladder Medley study with Merck KGaA will continue while we seek a development partner.

現在，正如我們在重點關注免疫學的重新優先順序計劃中提到的，我們還將繼續開發癌症領域的 IL-15 項目 NKTR-255，同時探索戰略合作夥伴選擇。 NKTR-255正在與細胞療法結合開發，我們相信它對於專注於細胞療法領域的公司來說可能是一種有價值的輔助療法。我們的 NKTR-255 與已批准的細胞療法 BREYANZI 和 Yescarta 相結合的 II 期研究，以及與 Merck KGaA 的 II 期 JAVELIN Bladder Medley 研究將繼續進行，同時我們正在尋找開發合作夥伴。

We continue to see great value in NKTR-255 and early data showed its promise as a potentiator of cell therapies that could benefit patients suffering from very difficult-to-treat cancers. Our goal is to find a strategic co-development partner this year. As I've stated earlier, our primary focus is on immunology. And to that end, we have 2 preclinical candidates advancing, a TNFR2 antibody program and a PEG-CSF1 program, which JZ will discuss in a moment. Our goal is to have an IND ready in 2024 for at least 1 of these programs. We're deeply grateful to our employees for their commitment and dedication to Nektar and the patients we aim to serve.

我們繼續看到 NKTR-255 的巨大價值，早期數據顯示其作為細胞療法增強劑的前景，可以使患有非常難以治療的癌症的患者受益。我們今年的目標是找到戰略共同開發合作夥伴。正如我之前所說，我們的主要關注點是免疫學。為此，我們有 2 個臨床前候選藥物正在推進，即 TNFR2 抗體項目和 PEG-CSF1 項目，JZ 稍後將討論這些項目。我們的目標是在 2024 年為其中至少 1 個項目準備好 IND。我們非常感謝我們的員工對 Nektar 和我們旨在服務的患者的承諾和奉獻。

The decisions over the past month to further reduce our head count have been difficult, but we believe these are the right decisions to maximize the success of REZPEG and our immunology programs. We're confident that our focus on immunology is the best path forward to bring important potential therapies to patients and to create value for our shareholders. And now I'll pass the call to JZ to review the programs in more detail.

過去一個月進一步減少員工人數的決定很困難，但我們相信這些是正確的決定，可以最大限度地提高 REZPEG 和我們的免疫學項目的成功。我們相信，我們對免疫學的關注是為患者帶來重要的潛在療法並為股東創造價值的最佳途徑。現在我將把電話轉給 JZ，以更詳細地審查這些計劃。

Thanks, Howard. Starting with REZPEG. This is a unique molecule that has shown promising efficacy in multiple clinical trials as a single agent. Our goal with this program is to address the underlying Treg deficiencies and consequent overactivity of effector T cells in these diseases by selectively activating and expanding Tregs. REZPEG is uniquely positioned as the most advanced IL-2-based Treg mechanism in the clinic with opportunity and potential in a number of autoimmune disease indications.

謝謝，霍華德。從 REZPEG 開始。這是一種獨特的分子，作為單一藥物在多項臨床試驗中顯示出有希望的功效。我們這個項目的目標是通過選擇性激活和擴展 Tregs 來解決這些疾病中潛在的 Treg 缺陷以及隨之而來的效應 T 細胞過度活躍的問題。 REZPEG 具有獨特的定位，是臨床上最先進的基於 IL-2 的 Treg 機制，在許多自身免疫性疾病適應症中具有機會和潛力。

Now Howard touched on one of these indications, atopic dermatitis. Management of atopic dermatitis has a few main goals. The first goal is the rapid efficacious treatment of the acute phase of the flare. And second, this is a far more challenging control of the chronic disease in the long term. And given that most patients with moderate to severe disease need medication for many years, the safety profile is also critically important. The current treatment landscape for patients with moderate to severe disease that requires systemic therapy has 2 major classes of medicines currently approved for standard of care.

現在霍華德談到了這些適應症之一：特應性皮炎。特應性皮炎的治療有幾個主要目標。第一個目標是快速有效地治療急性發作期。其次，從長遠來看，這是對慢性疾病的更具挑戰性的控制。鑑於大多數患有中度至重度疾病的患者需要多年的藥物治療，安全性也至關重要。目前對於需要全身治療的中度至重度疾病患者的治療格局有兩類主要藥物目前已批准用於標準護理。

One class of these target key cytokines that drive the Th2 inflammation pathway. The flagship in this class is DUPIXENT or dupilumab, which blocks the IL-4 and IL-13 pathways. Lebrikizumab which is expecting approval later this year and the recently approved Adbry both target and block IL-13 only. While DUPIXENT is a very successful drug, there is now real-world data that describes some of its limitations. One real-world evidence study shows the lack of durable efficacy in that 79% of patients that discontinued DUPIXENT lost disease control after an average of 4 months and needed to restart therapy. Another real-word study showed that 27% of patients taking DUPIXENT developed moderate to severe conjunctivitis, requiring treatment with anti-inflammatory eye drops or appointments.

其中一類靶向驅動 Th2 炎症通路的關鍵細胞因子。該類別中的旗艦產品是 DUPIXENT 或 dupilumab，它可阻斷 IL-4 和 IL-13 途徑。 Lebrikizumab 預計在今年晚些時候獲得批准，而最近批准的 Adbry 則僅靶向和阻斷 IL-13。雖然 DUPIXENT 是一種非常成功的藥物，但現在有現實世界的數據描述了它的一些局限性。一項真實世界的證據研究表明，79% 的停用 DUPIXENT 的患者在平均 4 個月後失去了疾病控制，需要重新開始治療，缺乏持久療效。另一項真實研究表明，27% 服用 DUPIXENT 的患者出現中度至重度結膜炎，需要使用抗炎滴眼液或預約治療。

The other major class of therapies for atopic dermatitis are the JAK inhibitors. These interfere with T cell activation and thus suppress inflammation in the dermis. JAK inhibitors show impressive efficacy in atopic dermatitis, but they carry multiple black-box warnings making them less attractive for chronic use. Because the JAK inhibitors are associated with these multiple safety risks, the FDA has only granted a label for the JAK inhibitors in patients whose disease is not adequately controlled with other systemic drug products, including biologics.

特應性皮炎的另一類主要療法是 JAK 抑製劑。它們會干擾 T 細胞活化，從而抑制真皮炎症。 JAK 抑製劑在特應性皮炎方面顯示出令人印象深刻的功效，但它們帶有多個黑框警告，這使得它們對長期使用的吸引力較低。由於 JAK 抑製劑與這些多重安全風險相關，FDA 僅在疾病無法通過其他全身性藥物產品（包括生物製劑）得到充分控制的患者中授予 JAK 抑製劑標籤。

In the clinic, because of the black-box warnings, dermatologists acknowledge that JAK inhibitors are not suited for many of their patients, including individuals greater than 65 years old or those with the comorbidities associated with the black-box warning. Like DUPIXENT, patients that discontinue JAK inhibitors also quickly lose disease control and relapse. Unlike IL-13 blockers and JAK inhibitors, which both block their respective pathways, REZPEG is designed to target the IL-2 receptor complex and stimulate the expansion and function of Treg cells. These in turn suppress the harmful T cells that are driving the underlying pathology of atopic dermatitis. REZPEG aims to restore homeostasis in the immune system through the proliferation of Treg cells rather than just blocking effector cells.

在診所中，由於黑框警告，皮膚科醫生承認 JAK 抑製劑不適合他們的許多患者，包括 65 歲以上的患者或患有與黑框警告相關的合併症的患者。與 DUPIXENT 一樣，停用 JAK 抑製劑的患者也會很快失去疾病控制並複發。與 IL-13 阻滯劑和 JAK 抑製劑不同，REZPEG 旨在靶向 IL-2 受體複合物並刺激 Treg 細胞的擴張和功能。這些反過來又會抑制導致特應性皮炎潛在病理的有害 T 細胞。 REZPEG 旨在通過 Treg 細胞的增殖來恢復免疫系統的穩態，而不僅僅是阻斷效應細胞。

And consequently, REZPEG provides a completely different mechanism of action compared to the other drugs that are currently approved or under development in the atopic dermatitis space. The Phase Ib data from our first initial proof-of-concept study in moderate to severe atopic dermatitis reinforces our conviction in REZPEG. The 12-week Phase Ib study conducted by Lilly tested 2 doses of REZPEG compared to placebo and then followed patients for 36 additional weeks after the last dose of therapy.

因此，與目前在特應性皮炎領域已批准或正在開發的其​​他藥物相比，REZPEG 提供了完全不同的作用機制。我們首次針對中度至重度特應性皮炎的初步概念驗證研究的 Ib 期數據增強了我們對 REZPEG 的信心。禮來公司進行的為期 12 週的 Ib 期研究測試了 2 劑 REZPEG 與安慰劑的比較，然後在最後一劑治療後又對患者進行了 36 週的隨訪。

Last September, we presented the interim data from this trial. REZPEG demonstrated a dose-dependent reduction in eczema area and severity index scores in patients, also known as the EASI score with approximately a 70% reduction in scores at week 12 at the highest dose tested.

去年九月，我們公佈了該試驗的中期數據。 REZPEG 證明患者濕疹面積和嚴重程度指數評分（也稱為 EASI 評分）呈劑量依賴性降低，在最高測試劑量下，第 12 週時評分降低約 70%。

We also saw a dose-dependent improvement in the investigator global assessment for atopic dermatitis and itch responder rates through week 12 of treatment. Consistent with the REZPEG mechanism of action, total Tregs and CD25bright Tregs increased versus placebo through week 12. The efficacy observed at 12 weeks of treatment with REZPEG is in line with efficacy observed after 16 weeks of treatment with DUPIXENT.

我們還發現，在治療第 12 週，研究者對特應性皮炎和瘙癢反應率的整體評估出現了劑量依賴性改善。與 REZPEG 的作用機制一致，第 12 週時總 Tregs 和 CD25bright Tregs 與安慰劑相比有所增加。REZPEG 治療 12 週時觀察到的療效與 DUPIXENT 治療 16 週後觀察到的療效一致。

But clearly, the most fascinating observation from the study was that when we looked at patients 36 weeks after we stopped dosing REZPEG, their skin scores and other measurements of disease activity remained very low. And this is an effect that is not observed with DUPIXENT. This has us and KOLs very enthusiastic about the potential for long-lasting responses and infrequent maintenance dosing with REZPEG in the setting of atopic dermatitis. We have now received the final data for this study from Eli Lilly, and the study results positively extend the interim results previously reported. In addition, these data include additional efficacy endpoints that were not covered in last year's EADV presentation.

但顯然，該研究中最令人著迷的觀察結果是，當我們在停止服用 REZPEG 36 週後觀察患者時，他們的皮膚評分和其他疾病活動測量值仍然非常低。這是 DUPIXENT 中未觀察到的效果。這讓我們和 KOL 對 REZPEG 在特應性皮炎中產生持久反應和不頻繁維持劑量的潛力充滿熱情。我們現已收到禮來公司這項研究的最終數據，該研究結果積極擴展了之前報告的中期結果。此外，這些數據還包括去年 EADV 演示中未涵蓋的其他療效終點。

To briefly touch on some of these, we observed a dose-dependent decrease in the percentage of body surface area involved with atopic dermatitis, also known as BSA in patients treated with REZPEG, with patients at the highest dose level reaching a 72% reduction in BSA at week 12. As a reminder, BSA continuous measurement that correlates with EASI. We also observed dose-dependent reductions in 2 patient-reported outcome measures, the Dermatology Life Quality Index, also known as DLQI, and the patient-oriented eczema measure or POEM. In addition, the final data set has data for more patients completing the 36-week observation period. We are very excited about the data obtained in this study. REZPEG showed efficacy across all measures of physician-reported disease activity and patient-reported outcomes. And these effects were durable and maintained after patients stopped REZPEG administrations at week 12.

為了簡要討論其中的一些問題，我們觀察到，在接受 REZPEG 治療的患者中，特應性皮炎（也稱為 BSA）所涉及的體表面積百分比呈劑量依賴性下降，最高劑量水平的患者在第 12 週時 BSA 減少了 72%。需要提醒的是，BSA 連續測量與 EASI 相關。我們還觀察到 2 種患者報告的結果指標（皮膚病生活質量指數，也稱為 DLQI）和以患者為導向的濕疹指標（POEM）呈劑量依賴性下降。此外，最終數據集還有更多患者完成36週觀察期的數據。我們對這項研究中獲得的數據感到非常興奮。 REZPEG 在醫生報告的疾病活動和患者報告的結果的所有指標上都顯示出有效性。在患者在第 12 週停止 REZPEG 給藥後，這些效果是持久的並得以維持。

We look forward to (inaudible) in the coming months. When we developed REZPEG at Nektar, our hypothesis was that restoring Treg populations in patients with autoimmune disease would restore the normal balance of the immune system and potentially provide a disease-modifying therapy. We are excited to see the long duration of sustained response observed in the atopic dermatitis study, consistent with this hypothesis. These collective data demonstrate REZPEG's potential as a remittive therapy and supports the quick advancement of REZPEG to move into a Phase IIb study in atopic dermatitis later this year.

我們期待（聽不清）未來幾個月。當我們在 Nektar 開發 REZPEG 時，我們的假設是恢復自身免疫性疾病患者的 Treg 群體將恢復免疫系統的正常平衡，並有可能提供一種疾病緩解療法。我們很高興看到在特應性皮炎研究中觀察到的長期持續反應，與這一假設一致。這些集體數據證明了 REZPEG 作為緩解療法的潛力，並支持 REZPEG 在今年晚些時候快速進入特應性皮炎的 IIb 期研究。

We are now finalizing the Phase IIb study, which will give the industry standard Phase II study design similarly to Phase II work conducted for approved IL-13 and other agents. This will allow us to evaluate multiple dose regimens of REZPEG in a 16-week induction period followed by a 28-week maintenance period. We believe the study design will enable data to be better compared to prior Phase II studies at a 16-week primary endpoint readout at the end of the induction period. We have assembled a scientific steering committee for this trial and we are pleased to announce that Dr. Jonathan Silverberg from the George Washington University School of Medicine and Health Sciences will be the Chair of this committee. We are truly excited for REZPEG's potential as a first-in-class Treg stimulator, and we look forward to initiating this Phase IIb study in patients with moderate-to-severe atopic dermatitis this year.

我們現在正在完成 IIb 期研究，這將提供行業標準的 II 期研究設計，類似於為批准的 IL-13 和其他藥物進行的 II 期工作。這將使我們能夠在 16 週的誘導期和隨後的 28 週的維持期中評估 REZPEG 的多劑量方案。我們相信，與之前的 II 期研究相比，該研究設計將使誘導期結束時 16 週主要終點讀數的數據更好。我們為本次試驗組建了一個科學指導委員會，我們很高興地宣布，喬治華盛頓大學醫學與健康科學學院的 Jonathan Silverberg 博士將擔任該委員會的主席。我們對 REZPEG 作為一流 Treg 刺激劑的潛力感到非常興奮，我們期待今年在中重度特應性皮炎患者中啟動這項 IIb 期研究。

The Phase II top line data reported in lupus earlier this year also demonstrated clinically meaningful improvements as compared to placebo across key secondary end points, including BICLA and LLDAS at the mid-dose level. And since we reported the data, we have had time to meet with many thought leaders in the field of lupus. Their reaction to our study results has been positive and provided us with many insights. In their feedback, the thought leaders focused on REZPEG's rapid onset of BICLA and LLDAS response as well as the magnitude of the effect on these endpoints that was observed. There is agreement that the Phase IIb data provides ample evidence to design a Phase III registrational study around these approvable end points.

今年早些時候報告的狼瘡 II 期頂線數據也表明，與安慰劑相比，在關鍵次要終點（包括中等劑量水平的 BICLA 和 LLDAS）方面取得了具有臨床意義的改善。自從我們報告數據以來，我們有時間會見了狼瘡領域的許多思想領袖。他們對我們的研究結果反應積極，並為我們提供了許多見解。在他們的反饋中，思想領袖重點關注 REZPEG 快速起效的 BICLA 和 LLDAS 反應以及觀察到的對這些終點的影響程度。人們一致認為，IIb 期數據為圍繞這些可批准終點設計 III 期註冊研究提供了充足的證據。

While we remain very interested in lupus, to be clear, we are prioritizing first the Phase IIb study in atopic dermatitis because it will allow us to rapidly reach a definitive result in a randomized study. We may have the opportunity to revisit a development strategy in lupus once we get the results from this atopic dermatitis study. We are extremely excited about REZPEG now being a wholly owned component of our pipeline. While our near-term focus is on atopic dermatitis, we continue to believe that REZPEG has broad potential in multiple indications. As development of this program progresses, we will continue to evaluate further opportunities and indications for REZPEG.

雖然我們對狼瘡仍然非常感興趣，但需要明確的是，我們首先優先考慮特應性皮炎的 IIb 期研究，因為它將使我們能夠在隨機研究中快速得出明確的結果。一旦我們得到特應性皮炎研究的結果，我們可能有機會重新審視狼瘡的發展策略。我們對 REZPEG 現在成為我們管道的全資組成部分感到非常興奮。雖然我們近期的重點是特應性皮炎，但我們仍然相信 REZPEG 在多種適應症方面具有廣泛的潛力。隨著該計劃開發的進展，我們將繼續評估 REZPEG 的進一步機會和適應症。

Moving to NKTR-255. We are evaluating strategic partnership options for the asset, while we continue our NEKTR-sponsored Phase II study of NKTR-255 in combination with cell therapies and the Phase II JAVELIN Bladder Medley Study with our partner, Merck KGaA. NKTR-255 is an agent that engages the full biology of the IL-15 pathway to provide functional activation and homeostatic control of IL-15 responses of immune cells, mainly natural killer cells, CD8 T cells and immune memory subsets. As the full agonist of the IL-15 pathway, it can signal through both cis and trans-presentation of the trimeric IL-15 receptor complex. NKTR-255 can be combined with multiple mechanisms ranging from targeted therapies to cell therapies, including CAR-Ts and even TCR therapies and checkpoint inhibitors to potentially improve the efficacy of these agents.

轉向 NKTR-255。我們正在評估該資產的戰略合作夥伴選擇，同時繼續由 NEKTR 贊助的 NKTR-255 與細胞療法相結合的 II 期研究，以及與我們的合作夥伴 Merck KGaA 進行的 II 期 JAVELIN 膀胱混合研究。 NKTR-255 是一種參與 IL-15 通路完整生物學的藥劑，為免疫細胞（主要是自然殺傷細胞、CD8 T 細胞和免疫記憶亞群）的 IL-15 反應提供功能激活和穩態控制。作為 IL-15 通路的完全激動劑，它可以通過三聚體 IL-15 受體複合物的順式和反式呈遞來發出信號。 NKTR-255可以與從靶向療法到細胞療法的多種機制相結合，包括CAR-T，甚至TCR療法和檢查點抑製劑，以潛在地提高這些藥物的療效。

While we continue to see great value in this program with NKTR-255 showing broad potential applicability across oncology indications, we believe prioritizing our immunology programs provides great opportunity to create value for our shareholders. We believe further development of NKTR-255 with the strategic partner is, therefore, the best path forward for our program, and our goal is to find a partner this year.

雖然我們繼續看到該項目的巨大價值，因為 NKTR-255 在腫瘤學適應症中顯示出廣泛的潛在適用性，但我們相信優先考慮我們的免疫學項目為我們的股東創造價值提供了絕佳的機會。因此，我們相信與戰略合作夥伴進一步開發 NKTR-255 是我們項目的最佳前進道路，我們的目標是今年找到合作夥伴。

With this reprioritization, the NKTR-255 study is in combination with DARZALEX FASPRO in multiple myeloma and in combination with cetuximab in solid tumors are wrapping up as we prioritize the cell therapy in bladder cancer studies.

隨著優先順序的重新調整，NKTR-255 與 DARZALEX FASPRO 聯合治療多發性骨髓瘤的研究以及與西妥昔單抗聯合治療實體瘤的研究正在結束，同時我們在膀胱癌研究中優先考慮細胞治療。

Now turning to our preclinical research programs. We are advancing our research pipeline with a focus on autoimmune disease. The first program we are working on is our new PEG colony-stimulating factor, also known as CSF1 program. PEG-CSF1 is the polyethylene glycol or PEG-modified version of the CSF1 protein. This molecule was engineered to optimize their receptor interaction and the exposure to selectively modulate the resolution processes of inflammation. We believe this program has applications in a number of therapeutic indications, including acute and chronic inflammation as well as fibrosis. And we are excited to be ramping up the program.

現在轉向我們的臨床前研究項目。我們正在推進我們的研究管線，重點關注自身免疫性疾病。我們正在進行的第一個項目是新的 PEG 集落刺激因子，也稱為 CSF1 項目。 PEG-CSF1 是 CSF1 蛋白的聚乙二醇或 PEG 修飾版本。該分子經過精心設計，可優化其受體相互作用和暴露，從而選擇性地調節炎症的消退過程。我們相信該計劃可應用於許多治療適應症，包括急性和慢性炎症以及纖維化。我們很高興能夠加強該計劃。

Our second preclinical program is our TNFR2 agonist antibody being developed in collaboration with biologic design. TNFR2 is highly expressed on Tregs, neuronal cells and endothelial cells, and TNFR2 agonism has been shown to potentiate the suppressive effect and overall functional properties of Tregs. If absent, it is associated with CNS autoimmunity. While its presence has been associated with protective effects for neuronal cells as well as other cell populations and tissues in the body. The lead antibodies we have identified shows selective Treg binding and signaling, which enables them to be developed specifically for autoimmune disease. We are very excited about this program and its potential to suppress inflammation and promote immune resolution.

我們的第二個臨床前項目是與生物設計合作開發的 TNFR2 激動劑抗體。 TNFR2 在 Tregs、神經元細胞和內皮細胞上高表達，並且 TNFR2 激動已被證明可以增強 Tregs 的抑製作用和整體功能特性。如果不存在，則與中樞神經系統自身免疫有關。它的存在與神經元細胞以及體內其他細胞群和組織的保護作用有關。我們鑑定的先導抗體顯示出選擇性 Treg 結合和信號傳導，這使得它們能夠專門針對自身免疫性疾病進行開發。我們對這個項目及其抑制炎症和促進免疫消退的潛力感到非常興奮。

We plan to file an IND for at least one of these programs in 2024 and look forward to keeping you updated on our progress as these programs mature. And with that, I will turn the call over to Sandy for a review of our cost restructuring plan and financial guidance.

我們計劃在 2024 年至少為其中一個項目提交 IND，並期待隨著這些項目的成熟向您通報我們的最新進展。接下來，我將把電話轉給桑迪，以審查我們的成本重組計劃和財務指導。

Thank you, JZ, and good afternoon, everyone. I'd like to first outline the actions we are taking currently in the second quarter as part of our cost restructuring plan to reduce operating expenses. And then I will provide 2023 financial guidance. We ended the first quarter with approximately $457 million in cash and investments with no debt on our balance sheet. As we announced in April, we have reduced our San Francisco-based workforce by approximately 60%. Costs related to the restructuring will be paid by the end of June in the second quarter. We now have approximately 55 employees based in San Francisco going forward.

謝謝你，JZ，大家下午好。我想首先概述一下我們目前在第二季度採取的行動，作為我們減少運營費用的成本重組計劃的一部分。然後我將提供 2023 年的財務指導。第一季度末，我們擁有約 4.57 億美元的現金和投資，資產負債表上沒有債務。正如我們在 4 月份宣布的那樣，我們已將舊金山的員工人數減少了約 60%。重組相關費用將於第二季度6月底前支付。今後，我們將在舊金山擁有大約 55 名員工。

On an annual run rate basis, the reduction to personnel represents approximately $30 million a year in operating expense reductions. We will have quarterly savings beginning in the third quarter of 2023, and we expect to fully realize these annual savings in 2024.

按年運行率計算，人員減少意味著每年運營費用減少約 3000 萬美元。我們將從 2023 年第三季度開始實現季度節省，並預計在 2024 年完全實現這些年度節省。

With these reductions in annual operating expenses, as Howard stated, our plan allows for Nektar to have a cash runway through at least the middle of 2026 with our existing cash on hand. Any cash brought in from partnering or other strategic activities would further extend this runway and bolster the balance sheet.

正如霍華德所說，隨著年度運營費用的減少，我們的計劃允許 Nektar 至少在 2026 年中期利用我們現有的現金擁有現金跑道。從合作或其他戰略活動中帶來的任何現金都將進一步擴大這條跑道並加強資產負債表。

Before I move on to 2023 financial guidance, I will note a few noncash items that were recorded during the first quarter of 2023. First, we recorded a onetime noncash charge of $76.5 million to impair the goodwill that was previously recorded on our balance sheet, primarily from 2 acquisitions made over 17 years ago, the 2001 acquisition of Share Water Corporation and the 2005 acquisition of Aerogen. In Q1, we also recorded a $13.2 million noncash impairment primarily for leased assets. These aggregate noncash impairment charges of $89.7 million contributed $0.48 to our net loss per share in Q1 2023.

在談到 2023 年財務指引之前，我要指出 2023 年第一季度記錄的一些非現金項目。首先，我們記錄了 7650 萬美元的一次性非現金費用，以損害之前記錄在我們資產負債表上的商譽，主要來自 17 年前的兩次收購，即 2001 年收購 Share Water Corporation 和 2005 年收購 Aerogen。第一季度，我們還記錄了 1,320 萬美元的非現金減值，主要針對租賃資產。這些總計 8970 萬美元的非現金減值費用為我們 2023 年第一季度的每股淨虧損貢獻了 0.48 美元。

Excluding these noncash impairment charges, net loss on a non-GAAP basis for the first quarter of 2023 was $47.3 million or $0.25 basic and diluted loss per share. I'll now review our 2023 financial guidance. We expect to end 2023 with at least $315 million in cash and investments. In the second quarter of 2023, we will have nonrecurring cash payments of approximately $8 million in connection with our reduction in head count. We expect our net cash usage to decrease in the second half of the year after these payments are made in June.

不包括這些非現金減值費用，2023 年第一季度按非 GAAP 計算的淨虧損為 4730 萬美元，即每股基本虧損和攤薄虧損 0.25 美元。我現在將回顧我們的 2023 年財務指引。我們預計到 2023 年底將擁有至少 3.15 億美元的現金和投資。 2023 年第二季度，我們將因裁員而支付約 800 萬美元的非經常性現金付款。我們預計在 6 月份支付這些款項後，下半年我們的淨現金使用量將減少。

As I said earlier, this reduction in net cash utilization extends our cash runway through at least the middle of 2026. Our GAAP revenue for full year 2023 is expected to be between $80 million and $90 million. This revenue includes $65 million to $70 million in noncash royalties and $15 million to $20 million in product sales. We anticipate full year 2023 GAAP R&D operating expenses will range between $105 million and $115 million, which includes approximately $15 million to $20 million of noncash depreciation and stock compensation expense. We expect G&A operating expense for full year 2023 to be between $75 million and $80 million, which includes approximately $15 million to $20 million of noncash depreciation and stock compensation expense.

正如我之前所說，淨現金利用率的減少將我們的現金跑道至少延長到 2026 年中期。我們 2023 年全年的 GAAP 收入預計在 8000 萬美元至 9000 萬美元之間。該收入包括 6500 萬至 7000 萬美元的非現金特許權使用費和 1500 萬至 2000 萬美元的產品銷售收入。我們預計 2023 年全年 GAAP 研發運營費用將在 1.05 億美元至 1.15 億美元之間，其中包括約 1500 萬美元至 2000 萬美元的非現金折舊和股票補償費用。我們預計 2023 年全年的 G&A 運營費用將在 7500 萬美元至 8000 萬美元之間，其中包括約 1500 萬美元至 2000 萬美元的非現金折舊和股票補償費用。

For the full year 2023, we expect to recognize restructuring, impairment and costs of terminated programs of approximately $30 million to $35 million, $13.2 million of which is a noncash impairment that I mentioned earlier and was recognized in Q1 2023. Our full year 2023 noncash interest expense is expected to be between $20 million and $25 million. And with that, we'll now open the call for questions. Operator?

對於 2023 年全年，我們預計將確認約 3000 萬至 3500 萬美元的重組、減值和終止計劃成本，其中 1320 萬美元是我之前提到的非現金減值，並於 2023 年第一季度確認。我們 2023 年全年非現金利息支出預計在 2000 萬至 2500 萬美元之間。現在，我們將開始提問。操作員？

(Operator Instructions) Our first question will come from Chris Shibutani from Goldman Sachs.

（操作員說明）我們的第一個問題將來自高盛的 Chris Shibutani。

This is Charlie on for Chris. I understand the excitement for having REZPEG back in-house. But just wondering, as we're thinking about the restructuring efforts going forward, are you open to the opportunity to potentially partnering REZPEG with another pharma partner at some point? Or are you happy to keep it in-house at this point? And then I have a quick follow-up.

這是查理為克里斯代言的。我理解 REZPEG 重返公司的興奮之情。但只是想知道，當我們考慮未來的重組工作時，您是否願意在某個時候與 REZPEG 與另一家製藥合作夥伴合作？或者您現在願意將其保留在內部嗎？然後我會進行快速跟進。

Yes. Good. This is Howard. Good question. At this point, I have no plans to partner with anybody else. This is Nektar's program. I think it's a great opportunity for us to see this through to completion. I do see from the data that we should be able to complete a Phase IIb trial in atopic dermatitis with success. And it will be the first mechanism of its kind and, I think, set the stage for a new way to treat autoimmune disease. So for now, it's our drug. I hope that answers it.

是的。好的。這是霍華德。好問題。目前，我沒有與其他人合作的計劃。這是內克塔爾的計劃。我認為這對我們來說是一個很好的機會來完成這個任務。我確實從數據中看到，我們應該能夠成功完成特應性皮炎的 IIb 期試驗。這將是同類機制中的第一個，我認為，它為治療自身免疫性疾病的新方法奠定了基礎。所以現在，這是我們的藥物。我希望這能回答這個問題。

Yes, that's very helpful. And then just quickly, if we think about the timeline for the Phase IIb in atopic dermatitis that has kind of played out just now, should we be expecting those data to maybe be like a mid-2024 sort of time line?

是的，這非常有幫助。然後很快，如果我們考慮一下剛剛結束的特應性皮炎 IIb 期的時間表，我們是否應該期望這些數據可能類似於 2024 年中期的時間表？

Yes. Look, we're going to -- look, we're going to start that study as soon as we can. It's going to take a few more months to finalize the design and get sites set up. I would say that you're looking at somewhere in the range of 14 to 18 months to complete that study from the time we start. So as soon as we start it, we'll give everybody a more thorough update.

是的。聽著，我們將——聽著，我們將盡快開始這項研究。還需要幾個月的時間才能完成設計並建立站點。我想說的是，從我們開始時起，您需要 14 到 18 個月的時間來完成這項研究。因此，一旦我們開始，我們就會為大家提供更全面的更新。

Our next question comes from Jerry Gong from Mizuho.

我們的下一個問題來自瑞穗的傑瑞·龔。

This is Jerry Gong for Mara Goldstein. Just two quick ones from us. For the Phase IIb study in atopic derm, are you planning conducting differential analysis for different patients with probably DUPIXENT, JAK, other cytokine use? And one quick one on NKTR-255. Can you give any color on the type of partnership that I can look for? Like would a Lilly type of deal be interesting?

我是瑪拉·戈德斯坦的傑瑞·龔。我們只有兩個快的。對於特應性皮膚的 IIb 期研究，您是否計劃對可能使用 DUPIXENT、JAK 或其他細胞因子的不同患者進行差異分析？還有 NKTR-255 的快速介紹。您能否說明我可以尋找的合作夥伴類型？像禮來公司這樣的交易會有趣嗎？

Well, okay, let me take the second half first, and then I'll give it over to JZ to answer your first part of your question. I think look, we're focused -- right now, I think we're -- we need to focus. We need to make sure our cash runway runs through at least the middle of '26. I'm comfortable that we can do that. And that means we're going to focus right now on atopic dermatitis because it's an enormous market. Certainly much larger than the cell therapy market. And I do think that that's where we need to focus. And I think REZPEG has not just the potential to treat atopic dermatitis. But if we're successful there, the potential for that type of mechanism in various autoimmune disorders is kind of exciting.

好吧，讓我先講後半部分，然後我將把它交給JZ來回答你問題的第一部分。我認為看，我們現在很專注，我認為我們需要專注。我們需要確保我們的現金跑道至少能持續到 26 年中期。我很高興我們能做到這一點。這意味著我們現在將重點關注特應性皮炎，因為這是一個巨大的市場。當然比細胞治療市場大得多。我確實認為這就是我們需要關注的地方。我認為 REZPEG 不僅具有治療特應性皮炎的潛力。但如果我們在這方面取得成功，那麼這種機制在各種自身免疫性疾病中的潛力是令人興奮的。

I do think for NKTR-255, I can't tell you what that will look like yet. Obviously, it will be in combination with a cell therapy, whereas obviously, what we're doing with REZPEG is active as a single agent. So we have to explore carefully what that deal would look like. I think it could be a joint collaboration. It could be a license deal. Don't know yet. Certainly, all the cell therapy companies are talking to us because I do believe they feel that IL-15 is going to be important in potentiating cell therapies. So lots of discussion, lots of potential. It could be a collaboration, could be a license, don't know yet.

我確實認為對於 NKTR-255，我還不能告訴你它會是什麼樣子。顯然，它將與細胞療法結合使用，而顯然，我們正在使用 REZPEG 作為單一藥物進行治療。因此，我們必須仔細探討這筆交易會是什麼樣子。我認為這可能是一次聯合合作。這可能是一項許可協議。還不知道。當然，所有細胞治療公司都在與我們交談，因為我確實相信他們認為 IL-15 在增強細胞治療方面將發揮重要作用。有很多討論，有很多潛力。可能是合作，可能是許可，目前還不知道。

Okay. Jerry, this is JZ. So in response to your first question, the study design is being finalized now and where we still have to wait for the feedback that we get from the health authorities. But I can give you a little bit of color. We're planning to enroll approximately 280 patients. We will have multiple dose regimens that we'll evaluate in the induction phase. And then in the maintenance phase, we'll also be looking at very infrequent dosing regimens. And the purpose of this design is really to springboard from the things that we learned in the Phase Ib study. So there, we saw that strong and long durability of effect which we believe in the maintenance arm can allow us to access very, very low-frequency dosing, which would be highly differentiating.

好的。傑瑞，這是 JZ。因此，針對你的第一個問題，研究設計現在正在最終確定，我們仍然需要等待衛生當局的反饋。但我可以給你一點顏色。我們計劃招募大約 280 名患者。我們將有多種劑量方案，我們將在誘導階段進行評估。然後在維持階段，我們還將研究非常不頻繁的給藥方案。這個設計的目的實際上是從我們在 Ib 期研究中學到的東西作為跳板。因此，我們看到了強大而持久的效果，我們相信維護臂可以讓我們獲得非常非常低的頻率給藥，這將是高度差異化的。

I guess all of the other agents in the class that require either a twice monthly or monthly kind of a dosing regimen. And as we get closer to -- later this year, closer to kicking off the study, we will give another update where we'll unveil the design of the study. Some of the key endpoints that we're measuring and all of the additional features. So please stay tuned for that. It will be coming up soon.

我猜想該類中的所有其他藥物都需要每月兩次或每月一次的給藥方案。隨著今年晚些時候，接近啟動這項研究，我們將提供另一次更新，公佈該研究的設計。我們正在測量的一些關鍵端點以及所有附加功能。所以請繼續關注。很快就會出現。

Our next question will come from Jessica Fye from JPMorgan.

我們的下一個問題將來自摩根大通的傑西卡·菲伊。

This is JL for Jess. So a couple of questions from us. First of all, for your kind of strategic decision to partner on 255, just wondering is this something new after you kind of regain the full right of REZPEG? Or was it always on the table for 255? And then on your cash runway, is there any extra color that you could kind of can set right for us, for example, does your current cash run rate to at least mid-2023 kind of budget in completing the full Phase IIb study for REZPEG? And does it also kind of budget in your 255 study, right? With cell therapy in Phase II, I believe, that's currently active. And I think you kind of announced some new programs just now and how much cash runway have you budgeted for those preclinical studies, assuming some of them can move into the clinic?

這是 Jess 的 JL。我們有幾個問題。首先，對於你們在255上合作的戰略決策，我想知道這是你們重新獲得REZPEG的全部權利後的新事物嗎？或者它總是以 255 美元的價格出現在桌面上？然後，在您的現金跑道上，您是否可以為我們設置任何額外的顏色，例如，您當前的現金運行率是否至少達到 2023 年中期完成 REZPEG 完整 IIb 期研究的預算？這也是你 255 研究中的預算吧？我相信，第二階段的細胞療法目前正在積極開展。我認為您剛才宣布了一些新項目，假設其中一些可以進入臨床，您為這些臨床前研究預算了多少現金跑道？

Okay. Good. Very good questions. Look, we were -- look, when we've been working -- as an immuno-oncology company and an company, of course, 255 was important component of our portfolio, and I still think NKTR-255, IL-15 has an important role in immuno-oncology. That said, we need to focus and we need to focus where the opportunities are the largest and the opportunities of to have a novel mechanism are available to us. And that's REZPEG. So will we keep working on 255? Yes. But I do want -- I do think we've changed our mind at this point over the past years and have decided that as an immunology company, we would like to find a strategic partner for NKTR-255. And that's to allow us to fully exploit our skills in immunology.

好的。好的。非常好的問題。看，我們——看，當我們一直在工作時——作為一家免疫腫瘤學公司和一家公司，當然，255 是我們產品組合的重要組成部分，我仍然認為 NKTR-255、IL-15 在免疫腫瘤學中發揮著重要作用。也就是說，我們需要集中精力，我們需要集中精力在機會最大的地方，並且有機會建立一種新穎的機制。這就是 REZPEG。那麼我們會繼續開發255嗎？是的。但我確實希望——我確實認為我們在過去幾年中已經改變了主意，並決定作為一家免疫學公司，我們希望為 NKTR-255 尋找戰略合作夥伴。這就是為了讓我們能夠充分利用我們的免疫學技能。

Now to the second part of your question, our cash runway through at least '26 includes the full cost of a IIb study in atopic dermatitis. That full cost is in there, it's approximately $60 million. That is fully accounted for in there. As is the cost of continuing the NKTR-255 studies to gain a partnership as well as the IND filing for those 2 programs. So that's all in the cash runway through 2026. If we do any other deals or any other opportunities in there, that I'll just add -- as Sandra said earlier, that will just add to the length of our cash runway. I hope that answers it.

現在到你問題的第二部分，我們至少到 26 年的現金跑道包括特應性皮炎 IIb 研究的全部費用。全部成本都在裡面，大約是 6000 萬美元。那裡已經充分說明了這一點。繼續進行 NKTR-255 研究以獲得合作夥伴關係以及這兩個項目的 IND 申請的成本也是如此。這就是 2026 年現金跑道的全部內容。如果我們在那裡進行任何其他交易或任何其他機會，我會補充一點 - 正如桑德拉之前所說，這只會增加我們現金跑道的長度。我希望這能回答這個問題。

Our next question will come from Greg Harrison from Bank of America.

我們的下一個問題將來自美國銀行的格雷格·哈里森。

This is Mary Kate on for Greg. I guess in terms of the REZPEG program, how are discussions going with regulators regarding the development of REZPEG in atopic dermatitis? Maybe just looking at the program as a whole here, what other indications beyond AD and lupus do you think would benefit from this treatment?

這是格雷格的瑪麗·凱特。我想就 REZPEG 計劃而言，與監管機構就 REZPEG 在特應性皮炎中的開發進行的討論進展如何？也許只是從整體上看這個項目，您認為除了 AD 和狼瘡之外還有哪些其他適應症會從這種治療中受益？

Okay. Those are good questions. I will turn that over to JZ to give you a good answer.

好的。這些都是好問題。我會把這個問題交給JZ，給你一個好的答案。

Yes. Thanks, Howard. Yes, thank you for the question. So the agency, of course, has seen the totality of all of the studies that have been put forward so far. And that includes the Phase Ib study in atopic dermatitis or, of course, there was feedback on the protocol and multiple discussions with the FDA on that study. In terms of the Phase IIb study, as I mentioned earlier, so we're finalizing that study protocol. And we'll be seeking health authority feedback on that protocol very, very soon. So then we'll get that additional kind of information that will allow us to finalize the protocol and start the study later this year.

是的。謝謝，霍華德。是的，謝謝你的提問。因此，該機構當然已經了解了迄今為止提出的所有研究的全部內容。其中包括特應性皮炎的 Ib 期研究，當然，還有關於該研究方案的反饋以及與 FDA 就該研究進行的多次討論。就 IIb 期研究而言，正如我之前提到的，我們正在最終確定該研究方案。我們將很快尋求衛生當局對該協議的反饋。那麼我們將獲得額外的信息，使我們能夠最終確定協議並在今年晚些時候開始研究。

In terms of the scope of indications, so far, REZPEG has been evaluated in a number of indications. There was activity that we've seen in atopic dermatitis, as we've discussed. There was activity in a Phase Ib study in psoriasis. We saw clinical activity in lupus. In ulcerative colitis, the study was stopped early, so it was not efficacious in that indication. But one of the things that gives us insight in is a range of different kind of immunological settings where we know Tregs are important, and we know that either Treg dysfunction or the absence of a Treg compartment controlling conventional or effector T cells is a challenge.

從適應症範圍來看，迄今為止，REZPEG已在多項適應症中進行了評估。正如我們所討論的，我們在特應性皮炎中看到了一些活動。銀屑病 Ib 期研究正在進行中。我們看到了狼瘡的臨床活動。在潰瘍性結腸炎方面，該研究提前停止，因此對該適應症無效。但讓我們深入了解的一件事是一系列不同類型的免疫環境，我們知道 Treg 很重要，並且我們知道 Treg 功能障礙或控制常規或效應 T 細胞的 Treg 區室的缺失都是一個挑戰。

So there are a range of additional indications that we're thinking about. There's a number in the Th2 spectrum of diseases. Obviously, atopic dermatitis is a atopy of the skin. There are multiple other atopy conditions of other organs that are definitely something that we're thinking a lot about. There are some neuroinflammatory diseases that we think about as well and others. And so there's definitely a very wide spectrum, both biologically and with this novel mechanism, to consider multiple indications. As we reiterated on the call, and as Howard just mentioned, focus is critically important. So besides focusing on our immunology pipeline, we're prioritizing our Phase IIb study in atopic dermatitis. But as we move forward that study and as there's data from that study, we expect that in the future it will be expanding the program as well.

因此，我們正在考慮一系列其他跡象。 Th2 疾病譜中有許多疾病。顯然，特應性皮炎是皮膚的特應性。其他器官還有多種其他過敏性疾病，這絕對是我們正在思考的問題。我們也會考慮一些神經炎症疾病和其他疾病。因此，無論是生物學上還是這種新穎的機制，肯定有一個非常廣泛的範圍來考慮多種適應症。正如我們在電話會議中重申的那樣，以及霍華德剛才提到的，專注至關重要。因此，除了關注我們的免疫學管道外，我們還優先考慮特應性皮炎的 IIb 期研究。但隨著我們推進這項研究以及該研究的數據，我們預計未來它也會擴大該計劃。

(Operator Instructions) Our next question will come from Daina Graybosch from SVB Securities.

（操作員指令）我們的下一個問題將來自 SVB 證券的 Daina Graybosch。

I'd like to understand how you're thinking about the therapeutic window for REZPEG. Specifically, in the lupus study, you also had a dose response in tolerability or safety. And the highest dose, I think, is close to the dose where you saw the greatest Treg increases and efficacy in ATD and seem pretty intolerable in lupus. So how are you navigating that in your Phase IIb?

我想了解您如何看待 REZPEG 的治療窗口。具體來說，在狼瘡研究中，您還存在耐受性或安全性方面的劑量反應。我認為，最高劑量接近於 ATD 中 Treg 增加和功效最大的劑量，而在狼瘡中似乎相當難以忍受。那麼，您在 IIb 期中如何應對這一問題呢？

Well, I'll turn that over to JZ for a more thorough explanation, but the effects of these -- of a Treg mechanism is somewhat different in different diseases. And JZ, do you want to comment further on that?

好吧，我會將其交給 JZ 以獲得更徹底的解釋，但是 Treg 機制的這些作用在不同的疾病中有些不同。 JZ，您想對此發表進一步評論嗎？

Yes. Thanks, Daina, for the question. We've seen with even low-dose IL-2, and I know you're familiar with the literature, that across different disease indications, low-dose IL-2 has a different kind of performance. And there's different kinds of sensitivity of the underlying immune dysfunction and how low-dose IL-2 works. One of the things that we learned from the study in lupus patients, right, is that the high dose, which we've studied before in multiple settings, from healthy volunteers to patients with mild lupus to patients with psoriasis to patients with atopic dermatitis and patients with ulcerative colitis, we really didn't see systemic toxicities and issues with that dose level in those other patient populations. But in the moderate-to-severe lupus patients, we found more intolerability in that setting. .

是的。謝謝戴娜提出的問題。我們已經看到，即使是低劑量的 IL-2，我知道您也熟悉文獻，在不同的疾病適應症中，低劑量的 IL-2 也有不同的表現。潛在的免疫功能障礙以及低劑量 IL-2 的作用方式也存在不同的敏感性。我們從狼瘡患者的研究中了解到的一件事是，我們之前在多種環境中研究過高劑量，從健康志願者到輕度狼瘡患者，銀屑病患者，特應性皮炎患者和潰瘍性結腸炎患者，我們確實沒有在其他患者群體中看到該劑量水平的全身毒性和問題。但在中度至重度狼瘡患者中，我們發現在這種情況下有更多的不耐受性。 。

So one of the hypotheses that we have is really related to the nature of the disease. In the lupus patients, you have much more of a systemic Th1 disease, whereas in atopic dermatitis, it's different. It's a Th2 kind of a disease. So even though the same dose level was studied in both patient populations, we definitely saw very different profiles, both in terms of efficacy at that dose level as well as tolerability. Now one of the things that gives us comfort moving forward in the atopic dermatitis Phase IIb study is that we've already studied that same dose level at 24 micrograms per kilogram in the Phase Ib which is essentially analogous to the 1,800-microgram flat dose.

因此，我們的假設之一確實與疾病的性質有關。在狼瘡患者中，更多的是系統性 Th1 疾病，而在特應性皮炎中，情況有所不同。這是一種 Th2 疾病。因此，即使在兩個患者群體中研究了相同的劑量水平，我們也確實看到了非常不同的情況，無論是在該劑量水平的療效還是耐受性方面。現在，讓我們放心地在特應性皮炎 IIb 期研究中取得進展的一件事是，我們已經在 Ib 期研究了每公斤 24 微克的相同劑量水平，這基本上類似於 1,800 微克的固定劑量。

We've already studied that dose level in the Phase Ib study. And looking at the efficacy profile, relative to the tolerability profile, it looks like a very reasonable and encouraging, if not positive, kind of a risk benefit profile from that small study. So we're comfortable continuing using that dose level in patients with atopic dermatitis. And so it's really a patient population and disease indication difference. It's really not uncommon for many, many drugs.

我們已經在 Ib 期研究中研究了該劑量水平。從療效概況來看，相對於耐受性概況，它看起來是一項非常合理且令人鼓舞的（即使不是積極的）小型研究的風險效益概況。因此，我們很樂意繼續在特應性皮炎患者中使用該劑量水平。所以這實際上是患者群體和疾病適應症的差異。對於很多很多藥物來說，這確實並不罕見。

And our next question will come from Boris Peaker from TD Cowen.

我們的下一個問題將來自 TD Cowen 的 Boris Peaker。

This is Hangfei Fu for Boris Peaker. I have one for REZPEG. So when you decided to return the asset, just wonder if you could give a little color for the reasons behind. And also you had some feedback -- positive feedback from the key opinion leaders? And what does that make you feel confident to move forward with this asset?

我是鮑里斯·皮克 (Boris Peaker) 的傅航飛。我有一個用於 REZPEG 的。因此，當您決定歸還資產時，您是否可以為背後的原因提供一些說明。您還收到了一些反饋——來自關鍵意見領袖的積極反饋？是什麼讓您有信心繼續推進這項資產？

Okay. Good. Certainly a good question and pretty reasonable. Look, Lilly has other priorities in atopic dermatitis. And when we took the REZPEG data in both lupus and in atopic dermatitis to the various key opinion leaders, every key opinion leader that reviewed the data believed that REZPEG is a promising therapeutic and needs to be advanced in the clinic to help patients. So I think we were very comfortable when we went to some of the true thought leaders in atopic dermatitis and the true thought leaders in lupus and had them look at the data, they were very impressed with it, actually.

好的。好的。這當然是一個好問題，而且相當合理。看，禮來公司在特應性皮炎方面還有其他優先事項。當我們將狼瘡和特應性皮炎的 REZPEG 數據提供給各個關鍵意見領袖時，每個審查該數據的關鍵意見領袖都認為 REZPEG 是一種有前途的治療方法，需要在臨床上進行改進以幫助患者。因此，我認為當我們去找特應性皮炎和狼瘡領域的一些真正的思想領袖並讓他們查看數據時，我們感到非常自在，實際上，他們對此印象深刻。

I think Lilly -- we're very excited to get REZPEG back from Lilly. I think they made a business decision that doesn't reflect the inherent value of REZPEG. Instead, it really reflects their strategic direction where REZPEG would have been a potential competitor to their anticipated and soon likely to be approved other therapy in atopic dermatitis, so I think there's lots of reasons for them giving it back to us. But I wouldn't say lack of efficacy for the drug is one of them. I hope that answers your question.

我認為 Lilly——我們非常高興能從 Lilly 手中奪回 REZPEG。我認為他們做出的商業決策並沒有反映 REZPEG 的內在價值。相反，它確實反映了他們的戰略方向，即 REZPEG 將成為他們預期的潛在競爭對手，並且很快可能會被批准用於特應性皮炎的其他療法，所以我認為他們有很多理由將其歸還給我們。但我不會說該藥物缺乏療效是其中之一。我希望這能回答你的問題。

That's very helpful. My second question is just a general question. As your company now shifting to immunology folks to biotech, so what have you done in terms of your organization that you, expertise-wise, what have you done to make it possible or a successful transition?

這非常有幫助。我的第二個問題只是一個一般性問題。隨著您的公司現在將免疫學人員轉向生物技術，那麼您在組織方面做了什麼，從專業知識角度來看，您做了什麼來使其成為可能或成功過渡？

Okay. Since JZ is running that part of the organization, I'll let him answer that. Go ahead, JZ.

好的。由於 JZ 負責管理該組織的這一部分，所以我會讓他來回答這個問題。繼續吧，JZ。

Yes. So through the years, we've been bringing in staff with expertise in both drug discovery and drug development in immunology indications. So we've been actually bringing that in. And then when we have areas of either capability or another gap, then obviously we get help like others do from outside experts that help us reinforce some of our decision-making and thoughts. Besides that, collectively, within the team that's been developing the pipeline, there are many, many years of experience in working in the immunology fields across multiple diseases, multiple kinds of immunology settings. And that's across many companies and particularly in large pharma, where there was a lot of expertise there in the company. Thanks.

是的。因此，多年來，我們一直在引進具有免疫學適應症藥物發現和藥物開發方面專業知識的員工。所以我們實際上一直在引入這一點。然後，當我們在能力領域或其他領域存在差距時，顯然我們會像其他人一樣從外部專家那裡得到幫助，幫助我們強化我們的一些決策和想法。除此之外，總的來說，在開發產品線的團隊中，在多種疾病、多種免疫學環境的免疫學領域擁有多年的工作經驗。許多公司都是如此，尤其是大型製藥公司，公司裡有很多專業知識。謝謝。

And I am showing no further questions from our phone lines. I'd now like to turn the conference back over to Howard Robin for any closing remarks.

我的電話線路上沒有再提出任何問題。現在我想將會議轉回霍華德·羅賓（Howard Robin）發表閉幕詞。

Great. Thank you, everyone, for joining us today. And again, I want to thank our employees for their commitment and focus through some of these difficult and challenging times, which we all seem to be having in biotech these days. We look forward to sharing our progress in the development of REZPEG with everybody. So please stay tuned. I think there's a lot of potential for this molecule. Thank you very much.

偉大的。謝謝大家今天加入我們。再次，我要感謝我們的員工在這些困難和挑戰時期的奉獻和專注，這些日子我們似乎都在生物技術領域經歷過。我們期待與大家分享REZPEG的發展進展。所以請繼續關注。我認為這種分子有很大的潛力。非常感謝。

This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.

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。祝大家度過美好的一天。