Inhaled mRNA therapy:Sanofi to Acquire Translate Bio

新闻原文见最后,都是官话,Biotech acquisitions since 2020

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1 概况

看这家公司的介绍还是挺有意思的:对于mRNA创新,目前还只是第一波,也就是针对感染性疫苗,后浪门还包括第二波的蛋白替换疗法、细胞因子、癌症疫苗,第三波mRNA编码抗体,第四波mRNA编码的蛋白降解及基因编辑等等

先驱:未修饰mRNA,针对多个组织的自主专利LNP,08年开始搭建专利池

聚焦三个主要领域:1)囊性纤维化(CF),首个吸入式mRNA治疗性药物MRI 5005,目前处于Ph1/2,下一代CF药物正在准备IND;2)其他肺部疾病;3)感染性疾病疫苗,与Sanofi Pasteur合作的COVID-19、流感等,2项处于临床

R&D 策略

  • 治疗领域:1)肺部疾病:充分利用肺部递送的创新和领先;2)肝脏疾病:下一代的创新的递送复合物;3)后浪:新的疾病领域,工业界与学术界的合作;4)疫苗:拓展在感染性疾病的能力和核心技术

  • 平台:1)保持在肺部疾病、肝脏疾病和LNP技术的领先;2)生产的优化的mRNA载体可以被快速全面评估和选定

主要管线

  • 肺部疾病:采取吸入式给药,进展最快的是治疗CF的MRT5005

  • 肝脏疾病:静脉注射,适应症未披露

  • 感染性疾病的预防疫苗:都是和赛诺菲合作,进展最快的是新冠领域的MRT5500和流感领域的MRT5400及MRT5401,剩余2个预防的病原分别是某病毒和某细菌

2 肺部疾病领域

囊性纤维化(cystic fibrosis, CF)是一种影响肺部、消化系统、汗腺和生殖道的多系统疾病,CF患者中氯离子和钠离子跨分泌上皮转运异常,导致支气管、胆道、胰腺、肠道和生殖系统出现稠厚的黏性分泌物。虽然CF为系统性疾病,但进行性肺病仍是大多数CF患者发病和死亡的主要原因。患者病程差异极大,从出生后数月期间到出数十年间,个体将最终发展为一系列典型菌群的慢性呼吸道感染,从而导致进行性呼吸功能不全并最终出现呼吸衰竭。

CF是常染色体7q31位置上CFTR基因的突变导致,该基因编码囊性纤维化跨膜传导调节因子(cystic fibrosis transmembrane conductance regulator, CFTR)蛋白,是一种存在于上皮细胞膜上的氯离子通道,它将氯离子运出上皮,而到达内脏中各种通道的黏液中,从而维持黏液的正常的稀薄流动;CF 患者中氯离子分泌的途径被异常突变的 CFTR 阻断,导致通道中的黏液异常粘稠;如果在皮肤汗管中氯化钠不能被重吸收,导致产生非常咸的汗液;如果在肺部导致异常浓稠的粘液堆积,从而引起许多患者慢性肺部感染和进行性肺损伤,最终导致死亡。

CF在高加索白人中上常见的致命性常染色体隐性遗传病,欧美患病率高于亚洲,在欧美及加澳合计约8.65万患者人群。

治疗上目前没有可以治愈的疗法或者手段,虽然有许多不同类型的 CFTR 突变可以导致该疾病,但绝大多数CF患者至少有一个F508del突变,目前像Vertex公司的Trikafta(elexacaftor/ivacaftor/tezacaftor,elexacaftor是新一代CFTR蛋白矫正用于恢复携带F508del突变的CFTR蛋白的功能,vacaftor可以通过延长细胞表面CFTR蛋白的开放时间来提高缺陷型CFTR蛋白的功能,tezacaftor可以通过增加CFTR蛋白转运到细胞表面的水平来增强CFTR蛋白功能)已经批准用于至少有一个F508del突变、或CFTR基因中有特定突变且基于体外数据对Trikafta治疗有反应的6-11岁CF患者,而更早的Kalydeco(ivacaftor)也被批准用于特定突变的患者,总的来说还是缺乏治疗,比如mRNA治疗。

mRNA疗法可以不再考虑CFTR基因的突变状态

  • 向肺部递送编码完整功能CF蛋白的mRNA

  • 整个CFTR mRNA LNP 雾化吸入

  • 可以根据CFTR蛋白表达水平来确定给药频次

  • 如果安全性和耐受性支持可以慢性长期给药

  • 最终便捷的自行雾化配药

CF开发策略就是针对活性、可耐受性及给药进行优化:

  • mRNA设计:利用全新的密码子优化算法提升蛋白表达

  • 递送:优化全新的LNP来保证效率、可耐受性、体内分布、代谢和穿透黏液

  • 雾化:通过雾化来优化递送效率

  • 配方:制成干粉制剂

  • 内部专业技术:除了在肺生物学及药学领域,还包括雾化器械团队

  • 临床前数据:用改进的检测方法和体内转化模型来提供全方面评估潜在疗效的能力

临床设计

  • 每个Cohort按照3:1采取随机双盲安慰剂对照

  • 主要评估MRT5005通过雾化给药单次或多次提升剂量后的安全性及可耐受性

  • 入组标准:≥18yrs、每秒用力呼吸量百分比(ppFEV1) 50-90%、携带2个I类 and/or II类突变

  • 患者背景:1)Part A单次提升剂量(SAD):16例患者中15例至少携带1个F508del突变 ,9/16接受过CFTR调节剂治疗;2)Part B多次提升剂量(MAD):14例患者中10例至少携带1个F508del突变 ,7/14接受过CFTR调节剂治疗;

  • 除了Part A和B,还有8例患者接受了连续5天的4mg QD剂量

初步结果支持推进mRNA疗法用于肺部疾病

  • 既是首个吸入式的mRNA疗法,也是首个可以多次吸入的mRNA疗法

  • 安全性:整体上安全可耐受

  • 肺功能:ppFEV1没有恶化,也没有增加——这个应该是弱了

  • 免疫原性:未检测到抗CFTR抗体、抗PEG抗体或是T细胞对CFTR的敏化

  • 递送:血液中可检测到mRNA和脂质,表面MRT5005可以穿透粘膜层递送到肺部

下一代的开发

  • 历史数据显示只要CFTR功能提升≥20%就能带来临床获益

  • 目前针对下一代CFTR mRNA的优化已经产生多个强效的候选,提升>1.5x

  • 用全新的可吸入LNP包装这些mRNA分子会有可能进一步增强活性

  • 活性提升允许更低的剂量更短的雾化时间

下一代优化的CFTR蛋白体内表达提升很明显

多个新型脂质可以将目标蛋白在肺部的表达提升超过50倍

将来继续推进mRNA疗法用于治疗CF

  • 目前基本完成了MRT5005的Ph1/2,MAD部分增加20mg剂量组,另外增加了单日连续给药的Cohort(4mg QD x 5 days)

  • 继续推进下一代CFTR mRNA候选药物筛选及用于IND的研究

  • 继续MRT5005级下一代CFTR mRNA候选药物的转化及临床前研究,以优化剂量/给药频次、配方及雾化策略

  • 内外协作

下面看原发性纤毛运动障碍(Primary Ciliary Dyskinesia, PCD),属于常染色体隐性遗传,由基因突变引起纤毛结构或功能缺陷:

  • 纤毛是一种微小的鞭状结构,排列在呼吸系统中,功能正常时协同跳动,有助于推进粘液通过呼吸系统到达咽喉区,从而可以通过咳嗽排出体外。如果纤毛不移动或移动不正确,肺部粘液难以清除,感染的可能性也会增加

  • 目前发现了30个相关基因,其中任意一个突变都会引起纤毛功能的缺失,其中DNAI1突变占到已确诊PCD案例的5-10%

  • 美国确诊患者!1.6万

  • 慢性炎症、肺部感染风险会加剧不可逆转的肺损伤,严重影响生活质量,引起呼吸衰竭,可能需要肺移植

  • 没有治愈手段,主要针对症状,延缓疾病进展

mRNA疗法可以通过提供野生型蛋白来恢复纤毛功能,比如表达正常功能的DNAl1,目前在小鼠中注射mRNA可以在假复层纤毛柱状上皮的顶面检测到表达的PCD蛋白,目标在21H2将候选mRNA药物推进到IND-enabling研究

DNAl1在空间上的正确分布:表达遍布肺部的假复层纤毛柱状上皮

按周给药可以引起DNAl1蛋白的蓄积

  • 单剂给药第8天就可以检测到DNAl1表达

  • 多剂给药后蛋白表达升高,表明更多的多纤毛柱状上皮细胞表达DNAl1

  • 最后1次给药停药后14天依旧可以检测到DNAl1

3 和赛诺菲的合作

合作历程

明细

传染性疾病的mRNA疫苗

在食蟹猴中可以诱导体液免疫:强效的结合抗体,高滴度的中和抗体

金黄地鼠模型的病毒挑战实验证明了MRT5500的保护

5 Anticipated Milestones in 2021


Sanofi to acquire Translate Bio; advances deployment of mRNA technology across vaccines and therapeutics development 

  • Accelerates development of current Sanofi licensed programs in vaccines and potential to explore other therapeutic areas

  • Fast tracks establishment of Sanofi’s recently announced mRNA Center of Excellence

  • Full integration upgrades drug formulation capabilities and enhances US talent in a promising new technology

PARIS and LEXINGTON, Mass – August 3, 2021 – As part of Sanofi’s endeavor to accelerate the application of messenger RNA (mRNA) to develop therapeutics and vaccines, the company has entered into a definitive agreement with Translate Bio (NASDAQ: TBIO), a clinical-stage mRNA therapeutics company, under which Sanofi will acquire all outstanding shares of Translate Bio for $38.00 per share in cash, which represents a total equity value of approximately $3.2 billion (on a fully diluted basis). The Sanofi and Translate Bio Boards of Directors unanimously approved the transaction.

Translate Bio adds an mRNA technology platform and strong capabilities to our research, further advancing our ability to explore the promise of this technology to develop both best-in-class vaccines and therapeutics,” said Paul Hudson, Sanofi Chief Executive Officer. A fully owned platform allows us to develop additional opportunities in the fast-evolving mRNA space. We will also be able to accelerate our existing partnered programs already under development. Our goal is to unlock the potential of mRNA in other strategic areas such as immunology, oncology, and rare diseases in addition to vaccines.”

“Sanofi and Translate Bio have a shared commitment to innovation in the mRNA space. With Sanofi’s long-standing expertise in developing and commercializing vaccines and other innovative medicines on a global scale, Translate Bio’s mRNA technology is now even better positioned to reach more people, faster,” said Ronald Renaud, Chief Executive Officer, Translate Bio. “The talented and dedicated Translate Bio team has built the foundation of a strong mRNA platform. Our expertise coupled with that of Sanofi has driven significant progress under the collaboration thus far, and we believe that this acquisition will strengthen the team’s ability to achieve the full potential of the mRNA technology.”

In June 2018, Sanofi and Translate Bio entered into a collaboration and exclusive license agreement to develop mRNA vaccines which was further expanded in 2020 to broadly address current and future infectious diseases. There are two ongoing mRNA vaccine clinical trials under the collaboration, the COVID-19 vaccine Phase 1/2 study with results expected in Q3 2021 and the mRNA seasonal influenza vaccine Phase 1 trial with results due in Q4 2021. The acquisition builds on Sanofi’s establishment of a first-of-its kind vaccines mRNA Center of Excellence.

On the therapeutic side, Translate Bio has an early-stage pipeline in cystic fibrosis and other rare pulmonary diseases. In addition, discovery work is ongoing in diseases that affect the liver, and Translate Bio’s MRTTM platform may be applied to various classes of treatments, such as therapeutic antibodies or vaccines in areas such as oncology. Sanofi’s recent acquisition of Tidal Therapeutics expanded the company’s mRNA research capabilities in both immuno-oncology and inflammatory diseases. The Translate Bio acquisition further accelerates Sanofi’s efforts to develop transformative medicines using mRNA technology.

Transaction Terms

Under the terms of the merger agreement, Sanofi will commence a cash tender offer to acquire all outstanding shares of Translate Bio common stock for $38.00 per share in cash reflecting a total equity value of Translate Bio of approximately $3.2 billion. The purchase price represents a premium of 56% to Translate Bio’s volume-weighted average price per share over the past 60 days.

To demonstrate their commitment to the transaction, the chief executive officer of Translate Bio and Translate Bio’s largest shareholder, The Baupost Group, L.L.C., have signed binding commitments to support the tender offer. These binding commitments, combined with the Translate Bio shares already owned by Sanofi or its affiliates, represent a total of approximately 30% of Translate Bio’s total shares outstanding.

The consummation of the tender offer is subject to customary closing conditions, including the tender of a number of shares of Translate Bio common stock that together with shares already owned by Sanofi or its affiliates represents at least a majority of the outstanding shares of Translate Bio common stock, the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, and other customary conditions. Following the successful completion of the tender offer, a wholly owned subsidiary of Sanofi will merge with Translate Bio and the outstanding Translate Bio shares not already owned by Sanofi or its affiliates that are not tendered in the tender offer will be converted into the right to receive the same $38.00 per share in cash paid in the tender offer. The tender offer is expected to commence later this month. Sanofi plans to fund the transaction with available cash resources. Subject to the satisfaction or waiver of customary closing conditions, Sanofi expects to complete the acquisition in the third quarter of 2021.

Morgan Stanley & Co. International plc is acting as exclusive financial advisor to Sanofi while Weil, Gotshal & Manges LLP is acting as legal counsel. Centerview Partners is acting as lead financial advisor to Translate Bio in the transaction, while Paul, Weiss, Rifkind, Wharton & Garrison LLP is acting as legal counsel. Evercore is also acting as a financial advisor in this transaction to Translate Bio. MTS Health Partners, LP is also giving financial advice to Translate Bio.

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