PepGen Inc (PEPG) 2023 Q4 法說會逐字稿

Good afternoon, and welcome to PepGen's fourth quarter and full year 2023, earnings call to discuss its financial results and recent corporate developments.

下午好，歡迎參加 PepGen 的第四季度和 2023 年全年財報電話會議，討論其財務業績和最近的公司發展。

(Operator Instructions) As a reminder, this call is being recorded today, Thursday, March 6, 2024.

（操作員說明）謹此提醒，本次通話將於今天（2024 年 3 月 6 日星期四）錄音。

I would now like to turn the conference call over to Emiko Bryant, Chief of Staff of PepGen.

我現在想將電話會議轉給 PepGen 的參謀長 Emiko Bryant。

Emiko, please go ahead.

惠美子，請繼續。

Thank you, operator.

謝謝你，接線生。

Good afternoon, everyone, and thank you for joining today's call.

大家下午好，感謝您參加今天的電話會議。

Earlier today, we released our financial results for the fourth quarter and full year 2023, and provided an update on recent corporate developments.

今天早些時候，我們發布了 2023 年第四季和全年的財務業績，並提供了近期公司發展的最新資訊。

The press release and our 10-K filed with the SEC this afternoon outlining our financial results are both available on our website at pepgen.com.

今天下午向 SEC 提交的新聞稿和 10-K 概述了我們的財務業績，均可在我們的網站 pepgen.com 上取得。

Joining me on the call today are James McArthur, PhD, President and Chief Executive Officer; Dr. Michelle Mellion, Senior Vice President, Head of Clinical Development; and Noel Donnelly, Chief Financial Officer.

今天和我一起參加電話會議的是總裁兼執行長 James McArthur 博士； Michelle Mellion 博士，資深副總裁、臨床開發主管；和財務長諾埃爾唐納利。

As a reminder, we will be making forward-looking statements regarding our financial outlook in addition to regulatory and product development plans and research activities.

提醒一下，除了監管和產品開發計劃以及研究活動之外，我們還將就我們的財務前景做出前瞻性陳述。

These statements are subject to risks and uncertainties that may cause actual results to materially differ from those forecasted.

這些陳述存在風險和不確定性，可能導致實際結果與預測有重大差異。

A description of these risks can be found in our most recent 10-K on file with the SEC.

這些風險的描述可以在我們向 SEC 提交的最新 10-K 中找到。

PepGen does not undertake any obligation to publicly update its forward-looking statements as a result of new information, future events or changes in its expectations.

PepGen 不承擔因新資訊、未來事件或預期變更而公開更新其前瞻性聲明的任何義務。

I will now turn the call over to our CEO, James McArthur.

我現在將把電話轉給我們的執行長詹姆斯·麥克阿瑟。

James?

詹姆斯？

Thank you, Emiko, and good afternoon, everyone.

謝謝惠美子，大家午安。

PepGen made meaningful progress over the course of 2023, including the initiation of our first inpatient clinical trials evaluating programs derived from PepGen Enhanced Delivery Oligonucleotide, or EDO, cell-penetrating peptide platform in two neuromuscular diseases with high unmet medical need.

PepGen 在2023 年取得了有意義的進展，包括啟動了我們的第一個住院臨床試驗，評估源自PepGen 增強遞送寡核苷酸（EDO）細胞穿透肽平台的項目，用於治療兩種醫療需求未被滿足的神經肌肉疾病。

Our lead clinical program, PGN-EDO51 or EDO51 is designed for the treatment of patients with Duchenne Muscular Dystrophy, also known as DMD, whose disease is amenable to an exon 51-skipping approach.

我們的主要臨床項目 PGN-EDO51 或 EDO51 旨在治療杜氏肌肉營養不良症（也稱為 DMD）患者，這種疾病適合外顯子 51 跳躍方法。

As a reminder, an estimated 13% people with DMD or approximately 4,200 individuals in the US and EU have a mutation amenable to an exon 51-skipping approach.

提醒一下，在美國和歐盟，估計有 13% 的 DMD 患者或大約 4,200 人具有適合外顯子 51 跳躍方法的突變。

Our second clinical program, PGN-EDODM1 or EDODM1 is designed for the treatment of Myotonic Dystrophy Type 1, or DM1.

我們的第二個臨床計畫 PGN-EDODM1 或 EDODM1 旨在治療 1 型強直性肌肉營養不良或 DM1。

We estimate that DM1 affects more than 100,000 people in the US and Europe for whom there are currently no approved disease-modifying treatments.

我們估計，美國和歐洲有超過 10 萬人受到 DM1 的影響，目前尚無核准的疾病緩解治療方法。

Here at PepGen, developing potentially transformative medicines is the foundation of our mission and long-term vision for building the company.

在 PepGen，開發具有潛在變革性的藥物是我們建立公司的使命和長期願景的基礎。

We believe that both our DMD and DM1 programs have the potential to be disease-modifying and meaningfully improve outcomes for patients.

我們相信，我們的 DMD 和 DM1 計畫都有潛力改變疾病並顯著改善患者的治療結果。

Our team is committed to advancing these important programs through the clinic with a sense of urgency to get them to the people living with these diseases as quickly as possible.

我們的團隊致力於透過診所推動這些重要的項目，並懷著緊迫感，盡快將這些項目帶給患有這些疾病的人。

We believe our recent stock offering puts us in a strong financial position for our team to execute on this commitment.

我們相信，我們最近的股票發行使我們處於強大的財務狀況，使我們的團隊能夠履行這項承諾。

The net proceeds from this offering, together with our existing cash and cash equivalent, extend our projected cash runway into 2026.

此次發行的淨收益加上我們現有的現金和現金等價物，將我們預計的現金跑道延長至 2026 年。

Turning to the latest updates and highlights from our clinical programs, we are pleased to announce we have completed enrollment for cohort 1 in CONNECT1-EDO51, evaluating the 5 mg per kg dose in DMD patients in our first Phase II clinical trial.

談到我們臨床計畫的最新更新和亮點，我們很高興地宣布我們已經完成了CONNECT1-EDO51 隊列1 的入組，在我們的第一個II 期臨床試驗中評估了DMD 患者每公斤5 毫克的劑量。

Following the review of the safety data of the 5 mg per kg dose cohort by our Data Safety Monitoring Board, and assuming an acceptable emerging safety profile, we plan to escalate to the second cohort at 10 mg per kg of EDO51.

在我們的資料安全監測委員會審查了每公斤 5 毫克劑量組的安全資料後，並假設新出現的安全性可以接受，我們計劃升級到每公斤 10 毫克 EDO51 的第二組。

The same process will take place prior to advancing to cohort 3.

在進入第 3 組之前，將進行相同的過程。

In parallel, earlier this week, we announced we received clearance from the MHRA in the UK to initiate CONNECT2-EDO51, our Phase II study of EDO51 in people with DMD amenable to an exon 51-skipping therapy.

同時，本週早些時候，我們宣布獲得英國 MHRA 的批准，啟動 CONNECT2-EDO51，這是我們針對接受外顯子 51 跳躍療法的 DMD 患者進行 EDO51 的 II 期研究。

We currently expect to be initiating dosing in cohort 1 evaluating the 5 mg per kg dose level in patients in the UK in the third quarter of 2024.

目前，我們預計將於 2024 年第三季開始在隊列 1 中開始給藥，評估英國患者每公斤 5 毫克的劑量水平。

Following CONNECT1's preliminary data readout for the 5 mg per kg cohort, we expect to open trial sites for CONNECT2 in other geographies, including the US, subject to regulatory authorizations.

在 CONNECT1 讀取每公斤 5 毫克隊列的初步數據後，我們預計在獲得監管授權的情況下，在包括美國在內的其他地區開設 CONNECT2 試驗點。

We anticipate reporting preliminary data for the CONNECT1, 5 mg per kg cohort in mid-2024, including safety, exon skipping and dystrophin production.

我們預計在 2024 年中期報告 CONNECT1（每公斤 5 毫克）隊列的初步數據，包括安全性、外顯子跳躍和肌肉營養不良蛋白的產生。

Based upon externally available data and using our own clinical and nonclinical work for internal modeling assumptions, PepGen expects treatment with EDO51 in DMD patients to produce high levels of dystrophin protein.

根據外部可用數據並使用我們自己的臨床和非臨床工作進行內部建模假設，PepGen 預計 EDO51 對 DMD 患者的治療將產生高水平的肌肉營養不良蛋白。

At the 5 mg per kg dose level, we expect to see greater than 1% of normal levels of dystrophin protein above background levels in the CONNECT1-EDO51 trial as measured by Western Blot analysis following four repeat doses of EDO51 in DMD patients.

在5 mg/kg 劑量下，我們預期CONNECT1-EDO51 試驗中的抗肌肉營養不良蛋白正常水準會高於背景水準1% 以上，這是透過DMD 患者四次重複劑量EDO51 後透過蛋白質印跡分析進行測量的。

For our 10 mg per kg dose cohort, if EDO51 were to achieve dystrophin levels of greater than 7%, this would be the highest level of dystrophin production achieved by a DMD exon-skipping therapy to date.

對於我們的 10 mg/kg 劑量組，如果 EDO51 達到大於 7% 的肌肉營養不良蛋白水平，這將是迄今為止 DMD 外顯子跳躍療法實現的肌肉營養不良蛋白產生的最高水平。

Our modeling projections for this dose level suggests the possibility that we could potentially achieve greater than 9% of normal levels of dystrophin protein.

我們對此劑量水平的模型預測表明，我們有可能達到超過正常水平 9% 的肌肉營養不良蛋白。

The combined safety and dystrophin expression data package from CONNECT1 and CONNECT2 is designed to support a potential path towards accelerated approval, assuming alignment with regulatory authorities.

CONNECT1 和 CONNECT2 的組合安全性和肌肉營養不良蛋白表達資料包旨在支持加速批准的潛在途徑（假設與監管機構保持一致）。

Turning to our DM1 development program, we were pleased that the clinical hold on EDODM1 was lifted by the FDA in October 2023.

談到我們的 DM1 開發計劃，我們很高興 FDA 於 2023 年 10 月取消了 EDODM1 的臨床擱置。

Following discussions with regulatory authorities, we are advancing our EDODM1 therapy at the same dose level starting at 5 mg per kg across all countries, including the US, in the Phase I FREEDOM-DM1 clinical trial for people living with DM1.

經過與監管機構的討論，我們正在所有國家（包括美國）以相同的劑量水平推進 EDODM1 療法，從 5 毫克/公斤開始，針對 DM1 患者進行 I 期 FREEDOM-DM1 臨床試驗。

Just last month, EDODM1 was granted fast track designation by FDA.

就在上個月，EDODM1 被 FDA 授予快速通道資格。

This designation is designed to facilitate the development, and expedite the review of potential therapies designed to treat serious diseases and conditions with clear unmet medical needs.

該頭銜旨在促進開發並加快審查旨在治療明顯未滿足醫療需求的嚴重疾病和病症的潛在療法。

Importantly, fast track designation allows for early and more frequent communication with the FDA, which can potentially lead to earlier drug approval and access for patients.

重要的是，快速通道指定允許與 FDA 進行早期和更頻繁的溝通，這可能會導致患者更早獲得藥物批准和使用。

In December 2023, PepGen announced the first patient was dosed in the Phase I FREEDOM-DM1, single ascending dose clinical trial, and we expect to report preliminary data, including safety, splicing correction and functional outcome measures from at least 5 mg per kg dose cohort in the second half of 2024.

2023 年12 月，PepGen 宣佈在I 期FREEDOM-DM1 單次劑量遞增臨床試驗中對第一位患者進行了給藥，我們預計將報告初始數據，包括安全性、剪接校正和功能結果測量，劑量至少為5 mg/kg 2024 年下半年的隊列。

We expect both the 5 mg per kg dose and 10 mg per kg dose evaluated in the FREEDOM-DM1 clinical study to be pharmacologically active and believe that 10 mg per kg dose could exhibit meaningful splicing correction and myotonia correction.

我們預期 FREEDOM-DM1 臨床研究中評估的 5 mg/kg 劑量和 10 mg/kg 劑量均具有藥理活性，並相信 10 mg/kg 劑量可以表現出有意義的剪接校正和肌強直校正。

In addition to our FREEDOM-DM1 trial, we expect to open our FREEDOM2-DM1, placebo-controlled multiple ascending dose clinical trial in DM1 patients in the second half of 2024.

除了 FREEDOM-DM1 試驗外，我們預計 2024 年下半年 DM1 患者中進行 FREEDOM2-DM1、安慰劑對照多劑量遞增臨床試驗。

An important differentiator of our PGN-EDODM1 is that it is designed to selectively target the pathogenic DMPK RNA with the CUG repeat expansion rather than degrading both the normal as well as pathogenic DMPK RNA.

我們的 PGN-EDODM1 的一個重要區別在於，它被設計為透過 CUG 重複擴增選擇性地靶向致病性 DMPK RNA，而不是降解正常和致病性 DMPK RNA。

As a result of this selectivity, and based on our preclinical data, we believe that EDODM1 has the potential to achieve superior correction of splicing events at a well-tolerated dose levels, which could lead to improved functional outcomes for patients.

由於這種選擇性，並且根據我們的臨床前數據，我們相信 EDODM1 有潛力在耐受良好的劑量水平下實現剪接事件的卓越校正，這可能會改善患者的功能結果。

In addition to our clinical programs, our research team continues to advance and evaluate our preclinical candidates in key areas of focus for neuromuscular and neurologic disorders.

除了我們的臨床計畫外，我們的研究團隊還繼續推進和評估神經肌肉和神經系統疾病關鍵領域的臨床前候選藥物。

PGN-EDO53 is our lead preclinical program designed to skip exon 53 of the dystrophin transcript, a therapeutic target for approximately 8% of patients with DMD.

PGN-EDO53 是我們的主要臨床前項目，旨在跳過肌肉營養不良蛋白轉錄物的外顯子 53，這是約 8% 的 DMD 患者的治療標靶。

We previously reported superior exon skipping in repeat dose studies in nonhuman primates, and our team is commencing IND and CTA-enabling studies in 2024.

我們先前在非人類靈長類動物的重複劑量研究中報告了優異的外顯子跳躍，我們的團隊將於 2024 年開始 IND 和 CTA 支持研究。

We look forward to providing more details as we progress.

隨著我們的進展，我們期待提供更多詳細資訊。

I will now turn the call over to Dr. Michelle Mellion, PepGen's Head of Clinical Development, to provide an in-depth review of the trial designs, of the ongoing clinical trials in DMD and DM1 that I just mentioned.

我現在將把電話轉給 PepGen 臨床開發主管 Michelle Mellion 博士，對試驗設計以及我剛才提到的正在進行的 DMD 和 DM1 臨床試驗進行深入審查。

Michelle?

米歇爾？

Thank you, James.

謝謝你，詹姆斯。

Starting with our clinical trials in DMD, CONNECT1 is a Phase II 13-week open-label, multiple-ascending dose clinical trial that is enrolling both ambulatory and non-ambulatory boys and young men living with DMD amenable to an exon 51-skipping approach.

從我們的 DMD 臨床試驗開始，CONNECT1 是一項為期 13 週的開放標籤、多劑量遞增的 II 期臨床試驗，招募接受外顯子 51 跳躍方法的患有 DMD 的流動和非流動男孩和年輕男性。

Each of the DMD patients must be at least eight years of age to enroll and will provide a muscle biopsy pre-dose and on week 13.

每位 DMD 患者必須年滿 8 歲才能報名，並將在服藥前和第 13 週提供肌肉活檢。

The dosing of EDO51 will occur once every four weeks for 12 weeks.

EDO51 的給藥將每四週進行一次，持續 12 週。

We will evaluate safety data from three subjects in the 5 mg per kg dose cohort with the DSMB before progressing to the 10 mg per kg dose cohort.

在進入 10 mg/kg 劑量隊列之前，我們將使用 DSMB 評估 5 mg/kg 劑量隊列中三名受試者的安全性數據。

We will evaluate further dose escalations based upon the evaluation of safety data from prior dose cohorts.

我們將根據先前劑量組的安全性數據評估來評估進一步的劑量遞增。

CONNECT2 is a multinational Phase II 26-week double-blind, placebo-controlled multiple ascending dose clinical trial that will enroll both ambulatory and non-ambulatory boys and young men living with DMD amenable to an exon 51-skipping therapy who are at least six years old.

CONNECT2 是一項為期26 週的多國II 期雙盲、安慰劑對照多劑量遞增臨床試驗，將招募患有DMD 並接受外顯子51 跳躍治療且年齡至少為6 歲的流動和非流動男孩和年輕男性歲了。

Participants will provide a muscle biopsy at baseline and then at week 25.

參與者將在基線和第 25 週進行肌肉活檢。

ED051 will be administered every four weeks for six months.

ED051 將每四週施用一次，持續六個月。

The DSMB will review the data before we proceed to the next dose cohort.

DSMB 將在我們進行下一個劑量組之前審查數據。

In February, we received authorization from the MHRA for our CTA to initiate CONNECT2 in the UK and are planning to open the study in the EU and the US later this year following regulatory clearance.

今年 2 月，我們的 CTA 獲得了 MHRA 的授權，在英國啟動 CONNECT2，並計劃在獲得監管許可後於今年稍後在歐盟和美國開展這項研究。

Turning to our EDODM1 development plan, we are pleased to have dosed the first patient in our FREEDOM-DM1 global Phase I single ascending dose randomized, double-blind, placebo-controlled trial of EDODM1 in DM1 patients in December 2023.

談到我們的EDODM1 開發計劃，我們很高興於2023 年12 月在DM1 患者中進行的FREEDOM-DM1 全球I 期單劑量遞增隨機、雙盲、安慰劑對照試驗中對第一位患者進行了給藥。

FREEDOM-DM1 will enroll a total of 24 DM1 patients randomized three to one in favor of drug versus placebo, evaluating 5, 10 and up to 20 mg per kg with dose escalation following review of safety data from prior dose cohorts.

FREEDOM-DM1 將招募總共24 名DM1 患者，隨機分為三對一，選擇藥物與安慰劑，在審查先前劑量組的安全性數據後，評估每公斤5 毫克、10 毫克和最高20 毫克的劑量，並逐步增加劑量。

The subjects will provide a muscle biopsy at baseline followed by a single infusion of EDODM1 with muscle biopsies taken again at day 28 and week 16.

受試者將在基線時進行肌肉活檢，然後單次輸注 EDODM1，並在第 28 天和第 16 週再次進行肌肉活檢。

Our FREEDOM-DM1 study will inform our planned multinational Phase II trial in DM1, a multiple ascending dose clinical trial that is designed to support potential regulatory approvals subject to alignment with regulatory authorities.

我們的 FREEDOM-DM1 研究將為我們計劃的 DM1 跨國 II 期試驗提供信息，這是一項多劑量遞增臨床試驗，旨在支持潛在的監管批准，但須與監管機構保持一致。

We anticipate opening the Phase II trial of EDODM1 in the second half of 2024, following discussions with the regulators.

在與監管機構討論後，我們預計將於 2024 年下半年啟動 EDODM1 的 II 期試驗。

With that review of PepGen's clinical development plans, I will now hand the line to Noel Donnelly, our Chief Financial Officer, to review our latest financial results.

在審查了 PepGen 的臨床開發計劃後，我現在將電話交給我們的首席財務官諾埃爾·唐納利 (Noel Donnelly)，以審查我們最新的財務業績。

Noel?

諾埃爾？

Thank you, Michelle.

謝謝你，米歇爾。

My comments will reflect the high-level financial results of our fourth quarter and full year 2023, period.

我的評論將反映我們第四季和 2023 年全年的高階財務表現。

More details are provided in this afternoon's financial results press release and in the corresponding SEC filing.

今天下午的財務業績新聞稿和相應的 SEC 文件中提供了更多詳細資訊。

As of December 31, 2023, PepGen held $110.4 million in cash and cash equivalents compared to $181.8 million on December 31, 2022.

截至 2023 年 12 月 31 日，PepGen 持有現金及現金等價物 1.104 億美元，而 2022 年 12 月 31 日為 1.818 億美元。

As James mentioned previously, on February 9, 2024, PepGen successfully completed an underwritten stock offering of 7.53 million common shares for gross proceeds of approximately $80 million.

正如詹姆斯之前提到的，2024 年 2 月 9 日，PepGen 成功完成了 753 萬股普通股的承銷股票發行，總收益約為 8,000 萬美元。

Based on our current operating plans, PepGen's current cash and cash equivalents, including the proceeds of the offering are expected to fund operations into 2026.

根據我們目前的營運計劃，PepGen 目前的現金和現金等價物（包括此次發行的收益）預計將為 2026 年的營運提供資金。

Net loss for the fourth quarter of 2023, was $19.5 million.

2023 年第四季的淨虧損為 1,950 萬美元。

Our net loss for the full year 2023, was $78.6 million.

我們 2023 年全年的淨虧損為 7,860 萬美元。

Research and development expenses for the three months ended December 31, 2023, were $16.3 million.

截至2023年12月31日止三個月的研發費用為1,630萬美元。

For the full year 2023, research and development expenses were $68.1 million.

2023 年全年，研發費用為 6,810 萬美元。

The increase in research and development expenses in the fourth quarter of 2023, compared to the fourth quarter of 2022, was primarily attributable to costs associated with the advancement of the company's PGN-ED051 and PGN-EDODM1 programs, including preclinical, clinical and manufacturing costs related to our ongoing and future clinical trials.

與2022年第四季相比，2023年第四季研發費用增加，主要歸因於與公司PGN-ED051和PGN-EDODM1專案推進相關的成本，包括臨床前、臨床和製造成本與我們正在進行和未來的臨床試驗相關。

General and administrative expenses were $4.5 million for the three months ended December 31, 2023.

截至 2023 年 12 月 31 日止三個月的一般及行政費用為 450 萬美元。

General and administrative expenses for the full year 2023, were $16.6 million.

2023 年全年一般及行政費用為 1,660 萬美元。

The increase in general and administrative expenses was primarily due to an increase in personnel-related costs.

一般及行政費用的增加主要是由於人員相關成本的增加。

Finally, as of February 29, 2024, PepGen had approximately 32.4 million shares outstanding.

最後，截至 2024 年 2 月 29 日，PepGen 已發行股票約 3,240 萬股。

And with that, I will turn the call back to James.

然後我會把電話轉回給詹姆斯。

Thank you, Noel.

謝謝你，諾埃爾。

I'm very proud of our team's ability to advance multiple clinical programs in 2023, and look forward to continuing the successful operational execution over the course of 2024, and beyond.

我對我們的團隊在 2023 年推進多個臨床項目的能力感到非常自豪，並期待在 2024 年及以後繼續成功的營運執行。

This year is an important time for PepGen as we will have multiple upcoming clinical data readouts from our ongoing clinical trials in DMD and DM1 patients, making the first inpatient clinical data from our proprietary EDO platform.

今年對PepGen 來說是一個重要的時刻，因為我們將從我們正在進行的DMD 和DM1 患者臨床試驗中獲得多個即將發布的臨床數據，從而從我們專有的EDO 平台獲取第一個住院患者臨床數據。

To quickly review our anticipated data announcements for the year.

快速回顧我們今年預期的數據公佈。

In the middle of 2024, we expect to report preliminary data from the 5 mg per kg dose cohort in CONNECT1-EDO51, the multiple ascending dose trial in boys with DMD.

2024 年中期，我們預計將報告 CONNECT1-EDO51（針對患有 DMD 的男孩的多次遞增劑量試驗）中每公斤 5 毫克劑量隊列的初步數據。

We plan to provide safety, exon 51-skipping and dystrophin production data.

我們計劃提供安全性、外顯子 51 跳躍和肌肉營養不良蛋白生產數據。

For the multinational FREEDOM-DM1 Phase I trial of EDODM1 in patients with DM1, we anticipate reporting preliminary safety, splicing correction and functional outcome measures from at least the 5 mg per kg dose cohort in the second half of 2024.

對於 DM1 患者的 EDODM1 跨國 FREEDOM-DM1 I 期試驗，我們預計在 2024 年下半年報告至少 5 mg/kg 劑量組的初步安全性、剪接校正和功能結果測量。

With that, I will open the call for questions.

接下來，我將開始提問。

Operator?

操作員？

Thank you.

謝謝。

(Operator Instructions) Joseph Schwartz, Leerink Partners.

（操作員說明）Joseph Schwartz，Leerink Partners。

Hi, everyone.

大家好。

This is Jenny on for Joe. I was just wondering if you could talk a little bit more about the mechanism of PGN-EDODM1?

這是珍妮替喬代言。我只是想知道您是否可以多談談 PGN-EDODM1 的機制？

And if you expect a blocking risk approach to result in a more specific profile and how that might read through to splicing correction and any implications for safety?

如果您期望阻塞風險方法產生更具體的概況，以及如何解讀剪接校正以及對安全性的任何影響？

Thank you.

謝謝。

Thank you, Jenny.

謝謝你，珍妮。

Our mechanism, unlike other approaches, which are seeking to degrade both the pathogenic DMPK as well as the non-pathogenic DMPK, is targeting the CUG repeat.

與尋求降解致病性 DMPK 和非致病性 DMPK 的其他方法不同，我們的機制針對的是 CUG 重複。

And we've been able to demonstrate in cell-based models that we can liberate MBNL1 as well as reduce the number of toxic foci and nuclei of patient cells as well as dramatically correct this splicing in patient cells.

我們已經能夠在基於細胞的模型中證明，我們可以釋放 MBNL1，減少患者細胞的毒性灶和細胞核的數量，並顯著糾正患者細胞中的這種剪接。

And in those models, we're also similarly able to correct splicing and importantly, correct both the electrophysiologic as well as the observable myotonia in the mouse model.

在這些模型中，我們也同樣能夠修正剪接，重要的是，矯正小鼠模型中的電生理學以及可觀察到的肌肉強直。

This is a very profound response, and we were able to do this at dose levels, which we were able to demonstrate achievable with our EDO051 technology in healthy volunteers, which employs the same EDO peptide and conjugation chemistry to the PMO.

這是一個非常深刻的反應，我們能夠在劑量水平上做到這一點，我們能夠在健康志願者中證明我們的EDO051 技術可以實現這一目標，該技術採用與PMO 相同的EDO 肽和綴合化學。

As such, we believe that we are specifically targeting the toxic species that drive this disease and coupling it to our EDO platform technology, which has been demonstrated to reduce the highest level of exon 51-skipping following a single dose in humans as well as robust delivery in nonhuman primates and mice coupled with excellent exon skipping.

因此，我們相信，我們專門針對導致這種疾病的有毒物質，並將其與我們的EDO 平台技術相結合，該技術已被證明可以降低人類單劑量後外顯子51 跳躍的最高水平，並且具有強大的效果在非人類靈長類動物和小鼠中的遞送以及出色的外顯子跳躍。

As such, we believe that at doses that we say (inaudible) we can achieve robust levels of splicing correction that will allow us to demonstrate correction of myotonia and improvement in strength.

因此，我們相信，在我們所說的劑量（聽不清楚）下，我們可以實現強大的剪接校正水平，這將使我們能夠證明肌強直的校正和力量的提高。

Although it's not been demonstrated, that (inaudible) efficiency is a toxicologic challenge in this disease by indiscriminately knocking down DMPK, we believe that we will be able to avoid this by targeting the RNA species that is pathogenic and drives the fundamentals of this disease.

儘管尚未證明，透過不加區別地敲低DMPK，（聽不清楚）效率是這種疾病的毒理學挑戰，但我們相信，透過針對致病性並驅動這種疾病的基本原理的RNA 種類，我們將能夠避免這種情況。

Paul Matteis, Stifel.

保羅馬蒂斯，斯蒂菲爾。

This is James on for Paul.

這是詹姆斯對保羅的回應。

Thanks for taking our question.

感謝您提出我們的問題。

I just had one as it relates to the upcoming readout.

我剛剛收到了一份，因為它與即將到來的讀數有關。

Just as it relates to dystrophin specifically, there's been some discussions recently about different cuts of dystrophin, including an adjusted figure that accounts for muscle fat content.

正如它與肌肉營養不良蛋白特別相關一樣，最近有一些關於肌肉營養不良蛋白的不同削減的討論，包括考慮肌肉脂肪含量的調整數字。

And you mentioned for your study at 5 mg per kg, you're looking for greater than 1% dystrophin in that.

您在研究中提到每公斤 5 毫克，您正在尋找其中超過 1% 的肌肉營養不良蛋白。

For 10 mg per kg, hoping to get above 9%, I guess, one, are these unadjusted dystrophin measures?

對於每公斤10毫克，希望達到9%以上，我猜，一，這些是未經調整的肌肉營養不良蛋白測量嗎？

And then two, just how much above 1% dystrophin do we need to see initial readout to have confidence that we can get to 9% plus at the next dose?

然後第二個問題，我們需要看到初始讀數高於 1% 多少肌肉營養不良蛋白才能有信心在下一次劑量達到 9% 以上？

Thanks so much.

非常感謝。

Great.

偉大的。

I appreciate the question.

我很欣賞這個問題。

So you're correct that we are planning on reporting dystrophin levels above background.

所以你是對的，我們計劃報告高於背景的肌肉營養不良蛋白水平。

The reason why this is important is an individual enters the study with 0.5% endogenous levels of dystrophin and one can only elevate it by 0.3%.

這一點之所以重要，是因為個體進入研究時內源性肌肉營養不良蛋白水平為 0.5%，但只能提高 0.3%。

It's really a net of 0.3% gain of dystrophin.

這其實是肌肉營養不良蛋白淨增加了 0.3%。

And so we are looking to see at least a 1% gain over background in terms of dystrophin levels at the 5 mg per kg dose level, but we have the possibility to go and see higher levels still.

因此，我們希望在每公斤 5 毫克的劑量水平下，肌肉營養不良蛋白水平至少比背景增加 1%，但我們仍有可能看到更高的水平。

The reason why this 1% would give us confidence that at 10 mg per kg, we could produce 9% or better levels of dystrophin in patients is that when we looked in our nonhuman primate studies, we've observed that a single dose at a low level of 20 mg per kg, produces approximately 2% dystrophin.

為什麼這1% 會讓我們相信，在每公斤10 毫克的劑量下，我們可以在患者體內產生9% 或更高水平的肌肉營養不良蛋白，因為當我們查看非人類靈長類動物研究時，我們觀察到單劑量每公斤 20 毫克的低水平，產生約 2% 的肌肉營養不良蛋白。

But following four monthly doses of EDO51 in nonhuman primates, this has increased to almost 35% exon skipping.

但在非人類靈長類動物中每月注射 4 劑 EDO51 後，外顯子跳躍率已增加至近 35%。

I apologize, I misspoke.

我道歉，我說錯話了。

It was 2% exon skipping going to 35% exon skipping.

從 2% 的外顯子跳躍到 35% 的外顯子跳躍。

Obviously, higher levels of exon skipping will produce higher levels of dystrophin production.

顯然，更高水平的外顯子跳躍將產生更高水平的抗肌營養不良蛋白。

But it gives us a good sense that going from low single-digit levels we have the potential to see much higher levels of exon skipping and dystrophin production.

但這讓我們有一個很好的感覺，即從低個位數水平開始，我們有可能看到更高水平的外顯子跳躍和肌肉營養不良蛋白產生。

This is also supported, as I mentioned in the call by our modeling work based on both, primary work in cells in the mouse model, nonhuman primates.

正如我在電話會議中提到的，我們基於小鼠模型和非人類靈長類動物細胞中的主要工作的建模工作也支持了這一點。

And of course, the work we have done in healthy volunteers.

當然，還有我們在健康志工身上所做的工作。

Thanks very much.

非常感謝。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

Great.

偉大的。

Thanks so much for taking my questions.

非常感謝您回答我的問題。

Just two quick ones on DMD.

就 DMD 而言，只有兩個簡短的內容。

For the 10 mg per kg cohort, have you already started the process of identifying patients for that?

對於每公斤 10 毫克的隊列，您是否已經開始識別患者的過程？

And based on your timeline for when to expect the 5 mg data, do you think it would be a reasonable expectation to expect data from the 10 mg cohort this year as well?

根據您預計何時獲得 5 毫克數據的時間表，您認為今年也能獲得 10 毫克隊列的數據是合理的預期嗎？

Thank you, Tazeen.

謝謝你，塔津。

So we see a lot of enthusiasm from our clinical investigators for the CONNECT1 clinical study and we anticipate seeing robust recruitment of this study.

因此，我們看到臨床研究人員對 CONNECT1 臨床研究表現出極大的熱情，我們預計研究的招募工作將大量進行。

As I've mentioned, we've already recruited cohort 1 of 5 mg per kg cohort and we anticipate reporting out that data set mid- of this year.

正如我所提到的，我們已經招募了每公斤 5 毫克的隊列 1，我們預計將在今年年中報告該數據集。

As soon as we have an update for you in terms of recruitment, we will give more guidance in terms of the timing of the 10-mg per kg data readout, but we anticipate being able to report that in a timely fashion based on the enthusiasm we're seeing for those patients as well as investigators in the study.

一旦我們為您提供了招募方面的最新消息，我們將在每公斤 10 毫克數據讀出的時間方面提供更多指導，但我們預計能夠根據熱情及時報告這一點我們正在為這些患者以及研究中的研究人員觀察。

Laura Chico.

勞拉·奇科.

Wedbush.

韋德布希。

Hey.

嘿。

Good afternoon, guys.

下午好，夥計們。

Thanks very much for taking the questions.

非常感謝您提出問題。

I have two for you.

我有兩個給你。

So with respect to CONNECT1 data.

因此對於 CONNECT1 數據而言。

James, I'm wondering if you could spend a moment discussing a little bit more about the preliminary kinetics and the pace of exon skipping that you're seeing with initial doses.

詹姆斯，我想知道您是否可以花一點時間討論您在初始劑量中看到的初步動力學和外顯子跳躍的速度。

I think in the nonhuman primates, if I'm not mistaken, there was kind of a maximal effect or a plateauing, which occurred over time.

我認為在非人類靈長類動物中，如果我沒記錯的話，隨著時間的推移，會出現一種最大的效應或穩定狀態。

I'm curious if you kind of anticipate seeing that in the patient samples.

我很好奇您是否預計會在患者樣本中看到這一點。

I guess what's the expectation that the magnitude of skipping can increase over time?

我想隨著時間的推移，跳躍的幅度會增加多少？

And then I have a quick follow-up for you.

然後我會為您進行快速跟進。

Terrific.

了不起。

I appreciate the question, Laura.

我很欣賞這個問題，勞拉。

You're correct.

你是對的。

When we look at our nonhuman primate data for both our 51 as well as our 53 program, we got to observe some of the greatest increase that we've seen in terms of exon skipping is occurring from dose one to dose two, a smaller level from dose two to dose three and a smaller increase still from dose three to dose four, And it does appear that we are reaching these very high levels of exon skipping by dose four, and there may not be incrementally that much more that one can achieve.

當我們查看 51 和 53 計劃的非人靈長類動物數據時，我們觀察到外顯子跳躍方面的一些最大增加發生在從第一劑量到第二劑量，較小的水平從第2 劑到第3 劑，從第3 劑到第4 劑仍有較小的增加，而且看起來我們確實在到第4 劑時達到了非常高的外顯子跳躍水平，並且可能不會逐漸達到人們可以達到的水平。

As such, we do anticipate seeing better than 7% and very likely above 9% dystrophin production based on the level of exon skipping and the modeling work that we've done, based on the extrapolation we've done from prior work of other companies where we compare our single-dose exon skipping in humans to their single-dose exon skipping in humans.

因此，根據外顯子跳躍的水平和我們所做的建模工作，以及根據我們從其他公司之前的工作中所做的推斷，我們確實預計肌營養不良蛋白的產量會超過7%，很可能超過9%我們將人類的單一劑量外顯子跳躍與人類的單一劑量外顯子跳躍進行比較。

And then lastly, based on the very extensive nonhuman primate modeling work we've done looking at both single and multiple doses.

最後，基於非常廣泛的非人類靈長類動物建模工作，我們研究了單劑量和多劑量。

So as such, we do expect to see very robust levels of exon skipping following four doses.

因此，我們確實預計在四次劑量後會看到非常強勁的外顯子跳躍水平。

And this will be reflective of what we're able to achieve, we believe, long term.

我們相信，這將反映我們長期能夠實現的目標。

Okay, that's helpful.

好的，這很有幫助。

And then maybe one quick question on DM1 and I'll hop back in the queue here.

然後可能會問一個關於 DM1 的簡單問題，然後我會回到這裡的隊列。

With respect to kind of the magnitude of splicing correction that you're looking for, I'm wondering if you could kind of share any more color around what you think would be a meaningful level and if you could just remind us with respect to FREEDOM1, what's the extent of functional assessments that we will be getting in the second half update?

關於您正在尋找的拼接校正的幅度，我想知道您是否可以分享更多關於您認為有意義的水平的顏色，以及您是否可以提醒我們有關 FREEDOM1 的信息，下半年更新我們會得到什麼程度的功能評估？

Thanks very much.

非常感謝。

Let me first speak to the splicing correction work that we've done pre-clinically and then I'll hand it over to Michelle Mellion to speak to the outcome measures that we'll be looking at in FREEDOM1.

讓我先談談我們在臨床前完成的剪接校正工作，然後我將把它交給 Michelle Mellion 來談談我們將在 FREEDOM1 中研究的結果測量。

So in terms of the preclinical work that we have conducted, we've observed that with higher and higher levels of splicing correction in the mouse model, which is granted an engineered animal model, we can go and see higher and higher levels of myotonia correction, both from the standpoint of the dragging the high [lens] as we observed in this model as well as measurement by electrophysiology.

因此，就我們進行的臨床前工作而言，我們觀察到，隨著小鼠模型（被授予工程動物模型）中越來越高水平的剪接校正，我們可以看到越來越高水平的肌強直校正，無論是從我們在該模型中觀察到的拖曳高[鏡頭]的角度來看，還是從電生理學的測量角度來看。

As such, if we're looking at 30%, 40% splicing correction at that level in the mouse model, we're beginning to see robust levels of correction of myotonia.

因此，如果我們在小鼠模型中觀察到該水平的 30%、40% 剪接校正，我們將開始看到肌強直校正的穩健程度。

And as we approach 60% at higher levels of splicing correction, we can begin to approach 70%, 80% correction of the myotonia.

當我們在更高層次的剪接校正上接近 60% 時，我們可以開始接近 70%、80% 的肌強直校正。

So we do believe it's important to be able to demonstrate better than 25%-plus splicing correction to see really robust changes in terms of the physiology and the pathology of this disease.

因此，我們確實相信，能夠證明超過 25% 以上的剪接校正對於看到這種疾病的生理學和病理學方面真正強勁的變化非常重要。

With that I'll turn it over to Michelle to speak to the outcome metrics that we'll be looking at in FREEDOM1.

接下來，我將把它交給 Michelle，讓她談談我們將在 FREEDOM1 中查看的結果指標。

So in FREEDOM 1, our clinical outcome measures include a full assessment of symptoms related to DM1.

因此，在 FREEDOM 1 中，我們的臨床結果測量包括對 DM1 相關症狀的全面評估。

And this assessment includes the vHoT, which is an assessment of myotonia that I believe most are now familiar with as well as strength assessments of several different muscles, including risk and other functional outcome measures such as the 10-meter walk test and the (inaudible) and these will be done at different endpoints or time points during the study to assess the impact of splicing correction on these assessments.

此評估包括 vHoT，這是一種我相信大多數人現在都熟悉的肌強直評估，以及幾種不同肌肉的力量評估，包括風險和其他功能結果測量，例如 10 公尺步行測試和（聽不清楚） ）並且這些將在研究期間的不同終點或時間點進行，以評估剪接校正對這些評估的影響。

And I just want to add to what Michelle said.

我只想補充一下米歇爾所說的內容。

As was mentioned earlier, the FREEDOM1 clinical study is a single ascending dose clinical study and we expect both based on our work as well as the work of others that following a single dose, we can reasonably expect to see both robust splicing correction as well as changes in terms of myotonia.

如同前面所提到的，FREEDOM1 臨床研究是一項單次劑量遞增的臨床研究，我們期望根據我們的工作以及其他人的工作，在單次劑量後，我們可以合理地預期看​​到穩健的剪接校正以及肌強直方面的變化。

Some of the other assessments that Michelle mentioned that we will be looking at maintain multiple doses before we start seeing a meaningful change there.

米歇爾提到的其他一些評估表明，在我們開始看到有意義的變化之前，我們將考慮維持多次劑量。

But we will get a very good sense from the data that we'll be presenting this year on the power of the EDODM1 molecule to go and really change the pathology of this disease.

但我們將從今年將提供的數據中充分認識到 EDODM1 分子真正改變這種疾病的病理學的力量。

Thanks very much.

非常感謝。

Appreciate it.

欣賞它。

(Operator Instructions) Ananda Ghosh, H.C. Wainwright & Company.

（操作員說明）Ananda Ghosh, H.C.溫賴特公司。

Hi, James.

嗨，詹姆斯。

Thanks for the opportunity.

感謝您提供的機會。

I had two questions, one on DMD and that is with respect to the recent SRP-5051 data.

我有兩個問題，一個是關於 DMD 的，另一個是關於最近的 SRP-5051 數據的。

What does that data tell you about your program concerning the platform and the EDO51?

這些數據告訴您有關平台和 EDO51 的程序的哪些資訊？

And then I have one follow-up question on the DM1 program.

我還有一個關於 DM1 計劃的後續問題。

Thank you, Ananda.

謝謝你，阿難。

I appreciate the question.

我很欣賞這個問題。

So we have done a cross-trial comparison of the ability of EDO51 to mediate exon 51 skipping in humans following a single dose.

因此，我們對 EDO51 在單次劑量後介導人類外顯子 51 跳躍的能力進行了交叉試驗比較。

And there, we were able to observe six fold higher levels of exon 51 skipping compared to a single dose of the 5051 molecule at 20 mgs per kg. 20 mg per kg 5051 was relatively well tolerated at 10 mg per kg, ED051, demonstrated following the single dose in humans only grade 1 reversible transient adverse events.

在那裡，我們能夠觀察到與單劑量 20 毫克/公斤的 5051 分子相比，外顯子 51 跳躍水平高出六倍。 20 mg/kg 5051 在 10 mg/kg ED051 下的耐受性相對較好，在人類單一劑量給藥後僅出現 1 級可逆性短暫不良事件。

So very, very well tolerated drug.

所以藥物的耐受性非常非常好。

We anticipate, as we extrapolate forward that we could be producing six fold higher levels of exon skipping and potentially dystrophin than what was observed in both the three month Momentum A and the six month Momentum B clinical studies with 5051.

我們預計，當我們向前推斷時，我們可能會產生比 5051 三個月 Momentum A 和六個月 Momentum B 臨床研究中觀察到的水平高六倍的外顯子跳躍和潛在肌肉營養不良蛋白。

This is what supports our contention that we have the potential to produce greater than 9% dystrophin levels in patients following four doses.

這支持了我們的論點，即我們有可能在四次給藥後使患者產生超過 9% 的肌肉營養不良蛋白水平。

And so we remain very confident, both based on the extrapolation in the cross-trial comparison to that clinical data, the work that we've done in animal modeling and nonhuman primates and the overall modeling work that has incorporated both mouse, nonhuman primate and human data with EDO051 that indeed, we'll be able to see better than 9% dystrophin in patients.

因此，我們仍然非常有信心，無論是基於與臨床數據的交叉試驗比較的推斷，還是我們在動物建模和非人靈長類動物方面所做的工作，以及結合了小鼠、非人類靈長類動物類動物和動物模型的整體建模工作。

If we could even achieve 7% dystrophin production with an exon skipping approach, this will be the highest level of dystrophin produced by any exon-skipping drug and projected to be produced by any exon-skipping drug.

如果我們甚至可以透過外顯子跳躍方法實現7% 的肌肉營養不良蛋白產量，這將是任何外顯子跳躍藥物產生的最高水平的肌肉營養不良蛋白，並且預計是任何外顯子跳躍藥物產生的肌肉營養不良蛋白。

And so we would be -- feel that to be a huge success but we believe based on all the work we've done, we have the potential to be greater than to produce later than 9% dystrophin in patients.

因此，我們認為這是一個巨大的成功，但我們相信，基於我們所做的所有工作，我們有潛力在患者體內產生超過 9% 的肌肉營養不良蛋白。

Got it.

知道了。

Thanks.

謝謝。

With respect to the DM1 program, there has been a debate in terms of what kind of primary endpoint the companies might see as the DM1 programs advance.

關於 DM1 項目，隨著 DM1 項目的推進，公司可能會看到什麼樣的主要終點一直存在爭議。

And so there have been a lot of discussions around the vHoT.

因此圍繞 vHoT 進行了很多討論。

So what is your take about the agency's view on primary endpoint in the DM1 program?

那麼您對該機構對 DM1 計畫主要終點的看法有何看法？

And my follow-up question to that is, is there a correlation between the splicing correction and the vHoT assay measurements?

我的後續問題是，剪接校正和 vHoT 測定測量之間是否存在相關性？

Perhaps I could start off, and then I'll ask Michelle Mellion to add to my thoughts.

也許我可以先開始，然後我會請 Michelle Mellion 來補充我的想法。

So these conversations with regulators are ongoing and so we cannot speak to what would be the approval end points from our FREEDOM2 and beyond clinical studies.

因此，與監管機構的對話仍在進行中，因此我們無法談論 FREEDOM2 及臨床研究之外的批准終點是什麼。

What we can say is that we believe that splicing is an important mechanistic underpinning of the EDODM1 program and with greater levels of slicing correction.

我們可以說的是，我們相信剪接是 EDODM1 程序的重要機制基礎，並且具有更高程度的切片校正。

We have, in animal models, seen greater levels of myotonia correction.

我們在動物模型中看到了更高水平的肌強直矯正。

And as such, we would expect to see with greater levels of slicing correction in patients, we would see greater levels of myotonia corrections and longer-term correction of many of the movement related topologies of this disease.

因此，我們期望看到患者得到更高水平的切片矯正，我們會看到更高水平的肌強直矯正以及這種疾病的許多運動相關拓撲的長期矯正。

So it is our anticipation that all of these will go into ultimately what would become an approvable endpoint.

因此，我們預計所有這些最終都將成為可批准的終點。

But let me allow Michelle to perhaps add to that.

但請容許米歇爾補充一下。

Yes, that's right, James.

是的，沒錯，詹姆斯。

I believe that we will learn from our FREEDOM-DM1 study, which is our single ascending dose study about the potential impact on several of these intermediate endpoints such as vHoT and potentially at later time points grip and strength.

我相信我們將從我們的 FREEDOM-DM1 研究中學習，這是我們的單次劑量遞增研究，了解對其中幾個中間終點的潛在影響，例如 vHoT 以及可能在稍後時間點的握力和力量。

And it is likely that looking at the totality of these endpoints taken together, the vHoT strength, grip and may be selected functional endpoints such as the 10 meter walk test, we'll be able to assess the full impact of placing correction over multiple doses in a future study on these endpoints to appreciate the potential impact on the disease that our therapies will have for this population.

很可能，透過綜合考慮這些終點、vHoT 強度、握力以及可能選擇的功能終點（例如 10 公尺步行測試），我們將能夠評估多次劑量進行矯正的全面影響在未來對這些終點的研究中，以了解我們的療法對該族群的疾病的潛在影響。

Got it.

知道了。

Thanks very much.

非常感謝。

Much appreciated.

非常感謝。

Thank you.

謝謝。

Thank you.

謝謝。

And I am showing no further questions.

我沒有提出任何進一步的問題。

I would now like to turn the call back over to James McArthur for closing remarks.

我現在想將電話轉回給詹姆斯·麥克阿瑟，讓其致閉幕詞。

Thank you, operator, and thank you, everybody, for participating in today's call.

謝謝接線員，也謝謝大家參加今天的電話會議。

If you have any questions or follow-up items, please do reach out to me or Noel.

如果您有任何疑問或後續事宜，請聯絡我或諾埃爾。

We look forward to connecting with all of you soon at upcoming investor conferences.

我們期待很快在即將舉行的投資者會議上與大家聯繫。

Have a great evening.

祝您有個美好的夜晚。

Thank you.

謝謝。

This concludes today's conference call.

今天的電話會議到此結束。

Thank you for participating.

感謝您的參與。

You may now disconnect.

您現在可以斷開連線。