预约演示
更新于：2025-11-17
DTaP vaccine(Sanofi)
吸附无细胞百白破联合疫苗(赛诺菲)
更新于：2025-11-17
概要
基本信息
非在研机构- |
最高研发阶段批准上市 |
最高研发阶段(中国)临床3期 |
特殊审评- |
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关联
41
项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的临床试验NCT06803524
Antibody Persistence and Safety and Immunogenicity of a Second Booster Dose 10 Years After a First Booster Vaccination With a Single Dose Vaccination of aP Vaccine in Adults: A Phase IV, Open-label, Non-randomized, Follow-up Study
This is a phase IV, open-label, non-randomized study to demonstrate superior immunogenicity and safety of a second booster dose of Pertagen® as compared to Adacel® at 10 years after the first booster vaccination and to evaluate the long-term persistence of specific antibodies induced by BioNet's recombinant aP (Pertagen®) and TdaP (Boostagen®) vaccines and a chemically-detoxified Tdap vaccine (Adacel®) at 10 years after the first booster in participants who were vaccinated in the phase II/III trial (Protocol No. TDA202).
开始日期2025-05-13 |
申办/合作机构  Mahidol University [+1] |
NCT05662852
A Clinical Study of the Safety and Antibody Responses of Plasma Donors Vaccinated With a Licensed Tdap Vaccine for a Hyperimmunization Program
The goal of this clinical trial is to investigate the safety and tetanus antibody response to a Tdap vaccine in healthy plasma donors. The main question it aims to answer are:
* Is it safe to give this vaccine multiple times over one year to plasma donors since the package insert for this vaccine indicates that it should administered once every 10 years?
* What is the tetanus antibody response over time in these donors after receiving the vaccine multiple times during the study?
Participants will receive a Tdap vaccination every 3 months ±2 weeks for 12 months (5 vaccinations) with a 6 month follow-up after the last vaccination. After obtaining informed consent and screening for eligibility including plasmapheresis donor eligibility, subjects will have other baseline assessments performed and if eligible, will receive the scheduled vaccinations, will be assessed for adverse events (AEs) and have plasma samples collected for antibody titers each month thereafter for 11 months, and then at 1 and 6 months after the last vaccination. As these subjects are participating in a standard donor plasmapheresis donor program, assessments for donor eligibility and routine plasmapheresis will be performed; however, only the data specifically required to meet the objectives of this study will be collected.
* Is it safe to give this vaccine multiple times over one year to plasma donors since the package insert for this vaccine indicates that it should administered once every 10 years?
* What is the tetanus antibody response over time in these donors after receiving the vaccine multiple times during the study?
Participants will receive a Tdap vaccination every 3 months ±2 weeks for 12 months (5 vaccinations) with a 6 month follow-up after the last vaccination. After obtaining informed consent and screening for eligibility including plasmapheresis donor eligibility, subjects will have other baseline assessments performed and if eligible, will receive the scheduled vaccinations, will be assessed for adverse events (AEs) and have plasma samples collected for antibody titers each month thereafter for 11 months, and then at 1 and 6 months after the last vaccination. As these subjects are participating in a standard donor plasmapheresis donor program, assessments for donor eligibility and routine plasmapheresis will be performed; however, only the data specifically required to meet the objectives of this study will be collected.
开始日期2023-05-05 |
申办/合作机构 |
NCT05264662
Pertussis Vaccination Among HIV-infected and HIV-uninfected Pregnant Women
Pertussis (also known as whooping cough) is a highly contagious, vaccine-preventable respiratory tract disease, caused by the bacteria Bordetella pertussis. It can affect people of all ages, however young unimmunised or partially immunised infants are the most vulnerable group with the highest rates of complications and death. Recent surveillance data and an increase in the number of pertussis outbreaks being reported nationally, indicate an increase in the incidence of pertussis disease in South Africa.To date there is no data on the effect of vaccinating HIV-infected pregnant women with pertussis-containing vaccines, although there is no reason to think that vaccinating these women would be harmful for them or their foetus. The knowledge gaps on the immunogenicity, safety and VE of pertussis vaccination of HIV-infected pregnant women should be addressed. Adacel which is a registered and licensed vaccine manufactured by Sanofi Pasteur, will be tested in this study.
开始日期2022-03-08 |
申办/合作机构 |
100 项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的临床结果
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100 项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的转化医学
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100 项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的专利（医药）
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101
项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的文献（医药）2025-09-01·IJID regions
Should Japanese athletes undergo booster vaccination for pertussis?
Article
作者: Hagiya, Hideharu
Pertussis, a highly contagious respiratory infection caused by Bordetella pertussis, has demonstrated a global resurgence in the post-COVID-19 era, with the emergence of macrolide-resistant strains. In Japan, the routine immunization schedule for pertussis remains limited compared with international standards, leaving young populations under-immunized and at elevated risk of infection. Despite international recommendations for booster vaccinations during adolescence, Japan currently provides only a four-dose primary series during infancy, without subsequent boosters. This immunization gap possibly increases the vulnerability of Japanese athletes to pertussis. Persistent cough can significantly impair athletic performance for weeks to months, posing substantial challenges to professional sports teams. To protect athletes' health and performance capacity and prevent team-wide outbreaks, it is imperative to consider pertussis booster immunizations in Japan, especially for elite athletes. However, DTaP (diphtheria, tetanus, and acellular pertussis) (TRIBIKⓇ) is the only available vaccine in Japan, which contains higher antigen concentrations than the internationally used Tdap (tetanus, diphtheria, pertussis) vaccines (ADACEL™ and BOOSTRIXⓇ): the antigen contents of pertussis toxin, filamentous hemagglutinin, and diphtheria toxin in TRIBIKⓇ, ADACEL™, and BOOSTRIXⓇ are 23.5 µg/23.5 µg/≤15 µg, 2.5 µg/5 µg/2 µg, and 8 µg/8 µg/2.5 µg, respectively. These differences result in more severe local adverse effects in vaccinees and would complicate booster strategies in Japan. Aligning Japan's immunization policies with international practices represents a critical step toward ensuring individual health and public safety in increasingly globalized sports environments.
2025-03-01·VACCINE
Pertussis vaccination campaign among health care workers and validity of recall of previous adverse events following immunization
Article
作者: Fritschi, Nora ; Heininger, Ulrich
BACKGROUND:
To minimize Bordetella pertussis transmission, health care workers (HCW) should be regularly vaccinated against pertussis, e.g. every 10 years. Therefore, the previous 2012/2013 vaccination campaign in our hospital was repeated in 2023. Here we describe our findings of the campaign and a nested study on the reliability of recall of adverse events (AE) after 10 years.
METHODS:
This was a prospective observational study including all HCW with patient contact. Those who had their last pertussis vaccination ≥10 years ago or with unknown date were offered a booster dose of Tdap (Adacel®) or Tdap-IPV (Adacel-Polio®) vaccine and were asked to report reactogenicity for seven days following vaccination. Those HCW who had participated in the 2012/2013 campaign were asked to report recall of vaccine tolerability back then.
RESULTS:
Of 916 eligible HCW, 705 (77.0 %) responded and 191 (27.1 %) of them were not up to date. Of these, 150 (78.5 %) plus 6 who were still up-to-date were vaccinated (Tdap-IPV: N = 91, 58.3 %, Tdap: N = 65; 41.7 %). After the vaccination campaign 684 (74.7 %) of all eligible HCW were up to date with their pertussis immunization status, including 63.4 % of nurses and 76.9 % of physicians. The most common adverse events in 133 (88.1 %) HCW were pain (66.7 %, day two), swelling (27.3 %, day two) and exhaustion (21.5 %, day two). Of 52 HCW who were vaccinated in both campaigns, 13 had ≥ 1 documented AE back in 2012/2013, of which only one remembered that the vaccination had not been well tolerated back then (Cohen's Kappa -0.04 for AE, -0.11 for swelling, -0.03 for redness and 0 for fever).
CONCLUSION:
We achieved an up-to date pertussis vaccination status in the majority of HCW. However, vaccinating all eligible HCW remains challenging in the absence of mandatory immunization. The recall of previous AE following immunization was poor.
2024-10-01·REPRODUCTIVE TOXICOLOGY
Erroneous statement
Letter
作者: Decker, Michael D
In the recent paper by Lee et al. 1 reporting reproductive toxicity testing of BVN008, a newly developed tetanus, diphtheria, and acellular pertussis vaccine, the statement is made "BVN008 is a booster vaccine identical to the current Tdap vaccines, Boostrix (GSK) and Adacel (Sanofi)." However, as the authors report, the acellular pertussis portion of BVN008 was provided by BIKEN (Japan). The composition of the BIKEN acellular pertussis product differs in important ways from the compositions of the acellular pertussis components of Boostrix and Adacel.2 Accordingly, the statement cited above is incorrect. A more appropriate statement might have been, "BVN008 is a booster vaccine similar in concept to the current Tdap vaccines, Boostrix (GSK) and Adacel (Sanofi)."
4
项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的新闻（医药）2025-09-13
·药时空
▲2004页2025 WCLC摘要集免费领取！摘要：百日咳作为一种严重的呼吸道传染病，虽在全细胞疫苗（wP）问世后发病率大幅下降，但随着无细胞疫苗（aP）的广泛应用，其发病率却出现回升。本文从百日咳疫苗的发展现状出发，详细介绍了现有疫苗的抗原成分、联合疫苗的种类，深入分析了疫苗效果不佳的原因，重点探讨了新型佐剂在提升疫苗免疫效果方面的作用，包括不同类型佐剂的作用机制、临床前研究成果等，同时还涉及疫苗稳定性及未来发展方向，为新一代百日咳疫苗的研发提供全面且易懂的参考。
一、百日咳与疫苗的 “前世今生”
百日咳是由百日咳杆菌引起的一种严重传染性呼吸道疾病，对婴儿、儿童和成人都有威胁。回顾历史，1948 年全细胞百日咳（wP）疫苗的研发是一个重要里程碑。在这之前，1940 年百日咳的发病率为每 10 万人 157 例，而到了 1973 年，这一数字降至每 10 万人 1 例，足见 wP 疫苗的显著效果。
然而，wP 疫苗虽有效，但安全性方面存在不足。相比之下，无细胞百日咳（aP）疫苗凭借更好的安全记录逐渐占据主导地位。但近年来，百日咳疫情的反弹令人担忧。2020 - 2022 年期间，由于新冠疫情期间广泛的公共卫生措施，百日咳报告病例数和发病率有所下降，2022 年全球报告病例为 62646 例。但 2023 年，全球百日咳病例数增至 158910 例，截至 2024 年 11 月 30 日，美国报告的百日咳病例数是 2023 年同期的六倍多。
百日咳卷土重来的原因众多。首先是疫苗覆盖率存在地区差异；其次，自然感染或接种疫苗获得的免疫力会随时间逐渐下降；再者，一些百日咳杆菌菌株不再产生某些疫苗抗原（如 PRN），这使其在接种aP疫苗的人群中更易存活；另外，疫苗中缺乏像腺苷酸环化酶毒素这样能诱导保护性免疫反应的毒力因子，且某些抗原（如丝状血凝素）的免疫调节活性有限，会促进免疫抑制性细胞因子的产生等。还有一个关键因素是，aP 疫苗替代 wP 疫苗后，无法提供最佳的免疫增强效果和长期保护，这与两种疫苗使用铝佐剂所引发的不同免疫刺激密切相关。二、无细胞百日咳疫苗的抗原成分
百日咳杆菌是一种感染呼吸道的人类病原体，在宿主的黏膜表面会产生多种毒力因子，这些毒力因子常被纳入 aP 疫苗，在预防百日咳感染中发挥关键作用。（一）百日咳毒素（PT）
PT 是一种分泌到细胞外的毒素，也是百日咳杆菌的关键毒力因子，在百日咳的发病机制中处于核心地位，被广泛认为是导致百日咳临床症状的主要因素。疫苗诱导产生的血清中 PT 特异性 IgG 水平与对百日咳的保护作用密切相关，因此 PT 是目前所有 aP 疫苗中最具代表性的抗原。
PT 遵循经典的细菌毒素 A/B 模型，A 组分具有酶活性，B 组分负责与靶细胞受体结合。在小鼠鼻内感染模型中，PT 会特异性地靶向气道驻留巨噬细胞，促进百日咳杆菌在呼吸道的早期定植，同时还会抑制中性粒细胞的募集，帮助细菌逃避早期免疫攻击。多项研究表明，抗 PT 抗体能有效保护小鼠免受脑内（IC）攻击。1997 年，丹麦批准了一种含过氧化氢灭活 PT 的单组分 aP 疫苗，该疫苗用于婴儿初次接种（DTaP - IPV）和儿童加强剂量接种（TdaP 和 TdaP - IPV），尽管仅以 PT 为唯一抗原，但丹麦的百日咳负担与使用多组分 aP 疫苗的邻国相当。（二）丝状血凝素（FHA）
与细菌毒素 PT 不同，FHA 主要参与细菌对气管上皮细胞的黏附，它是一种螺旋状蛋白质，可释放到细胞外环境中。FHA 内的多个结构域有助于其与巨噬细胞和呼吸道上皮细胞结合。
木村等人的研究显示，通过腹腔或肌肉注射 FHA 免疫小鼠后，小鼠会产生 FHA 特异性抗体，气管和肺部的细菌定植量减少。在一项人体研究中，日本的一种含 PT 和 FHA 的双组分疫苗在 3 年多的时间里提供了比单组分 PT 疫苗更好的长期保护。瑞典的一项临床试验评估了单组分（仅 PT，JNIH - 7）和双组分（PT + FHA，JNIH - 6）疫苗在 5 - 11 个月大婴儿中的疗效。在第二次接种后 30 天开始的 15 个月随访中，单组分疫苗组有 27 人确诊百日咳，双组分疫苗组有 18 人，估计保护效力分别为 54% 和 69%。重要的是，进一步的随访表明，与单独使用 PT 相比，加入 FHA 能显著降低百日咳杆菌感染的发生率。（三）百日咳黏附素（PRN）
PRN 是一种与细菌表面相关的蛋白质，通过其精氨酸 - 甘氨酸 - 天冬氨酸基序和富含脯氨酸的结构域促进对气管上皮细胞的吸附。在小鼠模型中，PRN 通过抑制中性粒细胞介导的清除作用促进发病，并引发炎症，从而增加细菌的脱落和传播。研究表明，用 PRN 免疫可抑制肺部细菌增殖，有助于感染的早期清除。（四）菌毛（FIM）
FIM 是细菌表面表达的丝状聚集蛋白质结构，作为黏附素促进细菌与宿主组织的黏附。主要有两种血清型，FIM2 和 FIM3，代表不同的菌毛结构。
Holuboval 等人证明，FHA 和 FIM 介导的共黏附对于鼻定植、分泌物诱导、脱落以及随后的宿主间传播至关重要。小鼠研究显示，增加 aP 疫苗中 FIM 的含量可增强保护作用，且不会增加反应原性。瑞典的临床试验比较了双组分、三组分和五组分 aP 疫苗与全细胞百日咳（wP）疫苗的效果，发现双组分疫苗的效力显著较低。五组分、三组分 aP 疫苗以及 wP 疫苗在预防至少持续 21 天的阵发性咳嗽的培养确诊百日咳方面具有相当的保护作用，但三组分疫苗对轻度疾病的保护作用相对较弱，这表明 FIM 在减少感染和传播方面有一定作用。
图 1：百日咳杆菌及其毒力因子的示意图百日咳杆菌产生多种毒力因子，包括百日咳毒素（PT）、腺苷酸环化酶毒素（ACT）、气管细胞毒素（TCT）、皮肤坏死毒素（DNT）、丝状血凝素（FHA）、菌毛（FIM）、百日咳黏附素（PRN）、博德特氏菌抗杀伤抗原（BrkA）和气管定植因子（TCF）。三、无细胞百日咳联合疫苗
这些百日咳抗原通常与破伤风和白喉毒素联合使用。FDA 批准的人类联合疫苗包括用于儿童的 INFANRIX（葛兰素史克生物制品公司）和 DAPTACEL（赛诺菲巴斯德公司），以及用于青少年和成人的 BOOSTRIX（葛兰素史克生物制品公司）和 Adacel（赛诺菲巴斯德公司）。青少年和成人疫苗中百日咳抗原和白喉类毒素的含量低于儿童疫苗，而破伤风类毒素的含量大致相同。
DAPTACEL（赛诺菲巴斯德公司）和 Adacel（赛诺菲巴斯德公司）是五组分疫苗制剂，含有磷酸铝佐剂；而 INFANRIX（葛兰素史克生物制品公司）和 BOOSTRIX（葛兰素史克生物制品公司）是三组分疫苗制剂（不含 2 型和 3 型 FIM）。Susanna Esposito 和 Nicola Principi 对 Greco 和 Gustafsson 的研究总结指出，三组分和五组分疫苗的效力似乎相似。然而，Carvalho 等人报告称，接种三抗原（aP3）aP 疫苗的儿童比接种 wP 疫苗的儿童更易感染百日咳，而在初次接种中接种五抗原（aP5）aP 疫苗的儿童感染百日咳的风险与接种 wP 疫苗的儿童相似。
除了传统的破伤风 - 白喉 - 百日咳疫苗外，联合疫苗还可能包含其他抗原。例如，FDA 批准的疫苗 KINRIX（葛兰素史克生物制品公司）和 Quadracel（赛诺菲巴斯德公司）与脊髓灰质炎病毒抗原联合使用，分别使用氢氧化铝佐剂和磷酸铝佐剂。PEDIARIX（葛兰素史克生物制品公司）与乙肝抗原和脊髓灰质炎病毒抗原联合使用，白喉和破伤风类毒素以及百日咳抗原（PT、FHA 和 PRN）吸附在氢氧化铝上，乙肝成分吸附在磷酸铝上。为预防 B 型流感嗜血杆菌（Hib）引起的侵袭性疾病，VAXELIS（MCM 疫苗公司）和 Pentacel（赛诺菲巴斯德公司）中添加了蛋白质结合的多核糖基核糖醇磷酸（PRP）以增强免疫原性。PRP 是侵袭性 Hib 疾病的主要毒力因子，是一种具有良好保护效果的高度免疫原性抗原。VAXELIS 中包含 PRP 与 B 群脑膜炎奈瑟菌外膜蛋白复合物（OMPC）的共价结合物，吸附在无定形羟基磷酸铝硫酸盐上，乙肝也吸附在无定形羟基磷酸铝硫酸盐上，而白喉和破伤风类毒素以及百日咳抗原分别吸附在磷酸铝上。Pentacel 中包含 PRP 与破伤风类毒素的共价结合物，以及吸附在磷酸铝上的白喉、破伤风类毒素和百日咳抗原。
表 1：FDA 批准的含百日咳抗原的人用疫苗
四、无细胞百日咳联合疫苗的佐剂
为增强免疫原性，aP 疫苗通常会添加佐剂。佐剂用于灭活疫苗、亚单位疫苗和重组疫苗中，以刺激先天和适应性免疫反应，从而获得最佳且持久的免疫原性。
过去人们认为百日咳杆菌是一种特殊的胞外病原体，含铝盐佐剂的 aP 疫苗诱导的强大体液免疫足以预防百日咳杆菌感染。但后来发现，百日咳杆菌能感染并存活于人类肺泡巨噬细胞和小鼠支气管肺泡灌洗液细胞中，细胞免疫在预防百日咳中可能起着至关重要的作用。Mills 等人发现，即使没有可检测到的血清抗体反应，CD4 + T 细胞也能介导细菌清除，且自然百日咳感染诱导的主要 T 细胞是分泌 IL - 2 和 IFN - γ 的 CD4 + T 细胞，IFN - γ 可激活巨噬细胞以清除细胞内的百日咳杆菌。
在小鼠中，Th1 细胞介导的细胞免疫反应对于抵抗呼吸道感染引起的百日咳至关重要（图 2）。Ross 等人在自然感染百日咳的小鼠肺部发现了大量百日咳杆菌特异性 Th17 细胞，他们发现过继转移百日咳杆菌特异性 Th1 或 Th17 细胞能有效保护小鼠免受百日咳杆菌感染，尤其是当这两种细胞群一起转移时。Th1 和 Th17 免疫都有助于小鼠对百日咳杆菌感染的自然免疫（图 2）。wP 疫苗也能刺激 Th1 和 Th17 细胞，在小鼠中提供由 IFN - γ 介导的保护性免疫，IL - 17A 也有一定作用，尽管程度较轻。然而，IL - 17A 在 aP 疫苗诱导的保护性免疫中很重要，它通过募集巨噬细胞和中性粒细胞来增强肺部百日咳杆菌的清除。
在狒狒模型中也证实了 Th1 和 Th17 反应的重要性，能刺激 Th1 和 Th17 记忆反应的 wP 疫苗能更快地清除感染。与在小鼠中诱导 Th2/Th17 免疫反应不同，在狒狒中诱导 Th1/Th2 反应的 aP 疫苗清除感染较慢，且无法有效预防百日咳杆菌在呼吸道的定植和传播。这是因为 wP 疫苗含有大量抗原和潜在佐剂，而 aP 疫苗仅使用单一佐剂和有限的抗原组合，从而引发不同且更局限的免疫反应，这与近年来百日咳的复发有关。因此，除了铝盐佐剂外，旨在诱导 Th1 和 Th17 反应的新型佐剂，如 MF59、AS04、AS01、CpG ODN、Poly（I:C）、TLR7 激动剂、脂蛋白、脂质体等，在新型百日咳疫苗中也显示出发展潜力（图 3），且在临床前研究中取得了一定成果（表 2）。
图 2：小鼠对百日咳杆菌自然免疫的机制示意图百日咳杆菌初次呼吸道感染后，局部树突状细胞（DCs）捕获百日咳杆菌抗原，迁移至引流淋巴结，在特定细胞因子的作用下刺激初始 CD4 + T 细胞分化为 Th1 和 Th17 细胞。分泌 IFN - γ 的 Th1 细胞激活肺泡巨噬细胞，清除呼吸道中的百日咳杆菌。Th17 细胞释放的 IL - 17 有助于中性粒细胞募集到肺部。初始 CD4 + T 细胞也可分化为效应记忆 T（TEM）细胞，迁移至鼻组织和肺部，并作为组织驻留记忆 T（TRM）细胞保留在那里。再次感染时，IL - 17 + CD4 + TRM 细胞扩增并募集唾液酸结合 Ig 样凝集素（Siglec）- F + 中性粒细胞，这些中性粒细胞在鼻咽部形成中性粒细胞胞外陷阱（NETs）（NETosis）的潜力更高，有助于细菌清除。B 细胞在 DCs 和辅助性 T 细胞的刺激下分化为浆细胞并分泌抗体。分泌的二聚体 IgA 与 polymeric 免疫球蛋白受体结合，以分泌型 IgA 的形式释放到受感染的呼吸道组织中。
图 3：百日咳疫苗中具有免疫潜力的佐剂多种佐剂可用于百日咳疫苗，包括明矾、脂质体、MF59、CpG ODN、TLR7 激动剂、Poly（I:C）、脂蛋白、AS04 等。（一）铝盐佐剂
铝盐佐剂被选用于百日咳疫苗，是因为其历史悠久、符合监管要求，且在联合疫苗的应用中具有后勤优势。传统上认为，铝盐佐剂具有 depot 效应，能在注射部位持续释放抗原。铝盐与抗原的结合可促进抗原呈递细胞（APCs）的摄取和呈递。此外，铝佐剂还能激活 NLRP3 炎症小体，促进 IL - 1β 和 IL - 18 的产生。铝佐剂可促进抗体产生和 Th2 反应，这与体液免疫有关。
研究表明，铝佐剂的类型会影响免疫反应，氢氧化铝和磷酸铝均常被用于增强免疫反应。在无细胞百日咳疫苗中，三组分疫苗 InfanrixTM 或 PediarixTM（抗原吸附在氢氧化铝上）以及五组分疫苗 PediacelTM 或 PentacelTM（抗原吸附在磷酸铝上）被广泛使用（表 1）。Morel 等人比较了含有 PT、PRN 和 FHA 三种抗原的 DTaP3 与 DTaP5 的效果，发现 DTaP3 比 DTaP5 制剂提供更好的保护和持久性。PediacelTM 在启动体液反应方面不如 InfanrixTM 有效，这可能与佐剂类型有关。疫苗抗原与磷酸铝的结合较松散，会影响抗原反应。Denoël 等人还证明，PRN 更容易从磷酸铝佐剂上解吸，影响 PRN 抗原反应和小鼠肺部清除活性。这表明制剂工艺在刺激免疫反应中很重要。
在吸附疫苗的生产中，除了铝佐剂的类型外，多种因素会影响抗原与佐剂的吸附。溶液的 pH 值决定了被吸附抗原和佐剂的表面电荷，当 pH 值介于佐剂和抗原的等电点之间时，可通过静电相互作用发生吸附。溶液中离子的存在，如磷酸盐和柠檬酸盐，容易导致抗原解吸。对于 aP 疫苗这类多抗原吸附疫苗，吸附顺序（如顺序吸附、竞争性吸附和单独吸附）也会影响吸附行为。（二）TLR9 激动剂
含胞嘧啶-硫代磷酸酯-鸟嘌呤（CpG）基序的寡脱氧核苷酸（ODN）可通过 TLR9 直接刺激抗原呈递细胞，从而加速免疫反应。CpG ODN 作为一种强效佐剂，可诱导 Th1 反应，促进细胞毒性 T 淋巴细胞（CTL）的大量产生和 IFN-γ 的分泌，增强对抗原的特异性体液和细胞免疫反应。
CpG ODN 1018 被批准用于乙肝疫苗 HEPLISAV-B，CpG ODN 2006 被批准用于炭疽疫苗 CYFENDUS。Sugai等人将 CpG-ODN 加入白喉-百日咳-破伤风（DPT）疫苗中，评估明矾和 CpG-ODN 联合佐剂的免疫效果。接种含 CpG-ODN 的 DPT 疫苗（DPT-明矾/ODN）的小鼠血清总 IgE 水平显著降低，血清抗 PT 特异性 IgG2a 滴度升高。此外，还研究了接种后对口服卵清蛋白（OVA）的抗体反应，在接受 DPT-明矾/ODN 的组中，血清中 OVA 特异性 IgE 的产生减少。
DeJong 等人将 CpG 1018 添加到 Tdap 中，诱导更多的 Th1 抗体，增强下呼吸道的保护作用和细菌清除率。此外，无论百日咳杆菌菌株是否表达 PRN，Tdap + CpG 1018 都能提供保护，缓解了人们对 PRN 突变体可能抵抗疫苗介导的免疫反应的担忧。Dynavax 进行的 1 期试验评估了试验性破伤风/白喉/无细胞百日咳疫苗与 CpG 1018 佐剂联合在成人和青少年中的安全性和免疫原性，结果显示安全性和耐受性良好。Tdap-1018 3000μg 诱导的免疫反应与目前市售的成人和青少年用 Boostrix 相当或更强。
尽管 CpG 未用于特殊人群的百日咳疫苗，但与三剂铝佐剂乙肝疫苗相比，两剂含 CPG1018 的乙肝疫苗在老年人中产生更高的血清保护水平，且在怀孕期间未观察到不良妊娠结局增加。（三）TLR7 激动剂
TLR7 激动剂具有佐剂活性，可在多种传染病中诱导 Th1/Th17 反应。小分子 TLR7 激动剂与铝佐剂联合使用可减轻全身炎症，减少细胞因子释放到血液中，提高其作为佐剂的安全性。
Misiak 等人将 TLR7a（Toll 样受体 7 激动剂）添加到含明矾佐剂的 aP 疫苗中，可将其从诱导 Th2 反应的疫苗转变为诱导 Th1/Th17 反应的疫苗，从而具有更强的保护能力。明矾 - TLR7a 佐剂疫苗比明矾佐剂疫苗更有效，可促进 Th1 极化反应，且抗原剂量显著降低。铝 - TLR7a 佐剂增加了 PT 中和抗体的产生，抑制了 FHA 与肺上皮的结合，并增强了小鼠气溶胶攻击模型的保护性免疫。（四）TLR4 激动剂
TLR4 激动剂 LPS 是百日咳杆菌外膜的天然成分，存在于 wP 疫苗中，可作为天然佐剂帮助诱导保护性免疫。3'- O - 脱酰基单磷酰脂质 A（MPL）是一种脱毒的 LPS 衍生物，可与 TLR4 结合并促进先天免疫反应。MPL 与氢氧化铝佐剂的组合形成 AS04，已被批准用于乙肝病毒疫苗 FENDRIX 和人乳头瘤病毒疫苗 CERVARIX。
Geurtsen 等人使用两种 LPS 类似物（MPL 和脑膜炎奈瑟菌 LpxL2LPS）替代 DTaP 疫苗中的铝佐剂，发现将 LPS 类似物纳入疫苗可减少肺部定植，诱导更高的 Ptx 特异性 IgG 水平，使反应更具 Th1 型反应特征，并减少Ⅰ型超敏反应。Agnolon 等人评估了乳剂佐剂 MF59 和 TLR4 激动剂单磷酰脂质 A（MPLA）与氢氧化铝（明矾）的组合，添加 MPLA 和 MF59 可增加 IgG2a 抗体滴度，刺激 IgG2a/Th1 反应，增强 DT 的中和活性，并阻断 FHA 与人类肺上皮细胞的结合。
Mitchell 等人认为，百日咳杆菌的 TLR4 刺激功能是 wP 疫苗转变为内毒素含量极低的 aP 疫苗时丢失的特性之一，而 TLR4 对免疫至关重要。MPL 具有改良百日咳疫苗可能需要的佐剂特性，包括抑制反应性、提供更持久的免疫力和减少 Th2 偏向。此外，AS04 具有良好的安全性，在受孕前 60 天至分娩期间接种 AS04 - HPV - 16/18 疫苗不会增加致畸风险，AS04 佐剂非常适合用于百日咳疫苗。（五）TLR2 激动剂
百日咳杆菌表达多种脂蛋白，作为 TLR2 激动剂，同时也具有抗原特性。Dunne 等人从百日咳杆菌中纯化出一种新型 TLR2 激活脂蛋白 BP1569，表明相应的合成脂肽 LP1569 能有效刺激免疫系统，具有佐剂特性，可诱导 Th1 和 Th17 反应。在预防小鼠百日咳杆菌定植方面，它比铝基疫苗更有效。（六）MF59
MF59 由角鲨烯、聚山梨酯 80、山梨糖醇三油酸酯和脱水柠檬酸三钠组成，已在 30 个国家的许可产品中使用，主要用于流感疫苗。MF59 促进抗原在注射部位的吸收和免疫细胞的募集，增强抗原向引流淋巴结的运输，并加强 Th1 和 Th2 的免疫反应。
Agnolon 等人发现，MF59 与 MPLA 和明矾的组合相似，均能增加 IgG2a 抗体滴度，刺激 Th1 反应，并通过血清抗体阻断 FHA 与人类肺上皮细胞的结合。与 MPLA 和明矾的组合相比，MF59 被证明是 TT 和 PRN 抗原最有效的佐剂。
MF59 已用于 65 岁以上人群的 Flaud® 流感疫苗，在诱导老年人强烈免疫反应方面显示出巨大潜力。对接受 Focetria®（MF59 佐剂 A/H1N1 大流行性流感疫苗）的孕妇的研究表明，MF59 佐剂 A/H1N1 大流行性流感疫苗在怀孕期间是安全的。这表明 MF59 也可能在成人百日咳疫苗的加强接种中发挥作用。
表 2：aP 疫苗中新型佐剂的临床前研究
五、aP 疫苗的黏膜佐剂
百日咳影响上呼吸道，因此呼吸道黏膜免疫在预防百日咳感染中至关重要。人类百日咳感染会在鼻腔分泌物中产生 IgA，尽管没有证据表明 IgA 缺乏与百日咳感染有关，但恢复期患者鼻腔洗液中的抗百日咳分泌型 IgA（sIgA）和血清 IgA 已被证明能抑制百日咳杆菌对人类呼吸道上皮细胞的黏附。
除了 IgA，组织驻留记忆 T（TRM）细胞在黏膜免疫中也起着关键作用。在小鼠模型中，分泌 IL - 17 的 CD4 + TRM 细胞在初次感染时迁移至鼻组织，随后介导 Siglec - F + 中性粒细胞的募集。此外，再次感染时 IL - 17 - CD4 + TRM 细胞在局部扩增，有助于从鼻腔清除百日咳杆菌（图 2）。肌肉注射含铝佐剂的 aP 疫苗可诱导 Th2 免疫，但不会促进呼吸道中的 sIgA 或 TRM 细胞。因此，黏膜免疫可能在预防鼻腔定植和感染方面更有效。开发新型佐剂的目的是促进鼻内免疫，以预防细菌在鼻腔定植和肺部感染。
霍乱毒素（CT）、大肠杆菌热不稳定肠毒素（LT）及其基因解毒突变体常用作黏膜佐剂。Ryan 等人将 aP 疫苗与无毒突变体 LKT63 或部分酶活性 LTR72 突变体联合用于鼻内免疫，发现两者都能增强抗原特异性血清 IgG 和分泌型 IgA，并加速肺部细菌清除。无毒突变体 LTK63 可增强 Th1 和 Th2 反应，而部分酶活性 LTR72 突变体更倾向于 Th2 反应。
尽管 LT 可以增强鼻内 aP 疫苗的免疫反应，但 CT 作为百日咳疫苗佐剂的免疫效果并不理想。Herland Berstad 等人发现，CT 与百日咳杆菌联合鼻内免疫未能增强 IgA 反应，反而显著降低了它，这可能是由于 CT 与鼻上皮相互作用，与百日咳杆菌制剂的成分竞争所致。Isaka 等人还发现，当重组霍乱毒素 B 亚单位（rCTB）与 DPT 疫苗联合用于鼻内免疫时，对百日咳类毒素（PTd）和福尔马林处理的丝状血凝素（fFHA）的黏膜佐剂作用不显著。
Orr 等人研究了百日咳杆菌的腺苷酸环化酶毒素（CyaA）作为黏膜佐剂经鼻内给予小鼠时的免疫效果。具有酶活性的 CyaA 和缺乏腺苷酸环化酶活性的 CyaA（CyaA*）与 Prn 共同给药可显著增强血清 IgG 反应。与 Prn 和 CyaA 相比，Prn 和 CyaA * 免疫导致肺部抗 Prn IgA 反应显著改善。然而，这两种佐剂都不如 LKT63 有效。
尽管 CT 和 LT 的佐剂活性已被广泛研究和认可，但它们可能导致贝尔氏麻痹，这限制了它们在人类疫苗中的使用。目前正在开发更安全有效的黏膜佐剂。Shi 等人将基于食品级乳酸乳球菌的新型细菌样颗粒（BLP）黏膜佐剂引入百日咳抗原（如 PT、FHA 和 PRN）中，进行腹腔和鼻内免疫，发现与明矾相比，鼻内免疫 BLPs 在鼻冲洗液中产生显著的抗 PT IgA 和抗 FHA IgA，在预防细菌定植和肺损伤方面更有效。
Boehm 等人配制了含 curdlan 佐剂（一种来自粪产碱菌的 1,3β 葡聚糖）的 DTaP 疫苗，curdlan 佐剂促进 DTaP 颗粒在上呼吸道的定位。与原始 DTaP 疫苗相比，curdlan 佐剂虽然没有增强对 FHA 和 PT 的抗体反应，但经鼻内免疫的含 curdlan 佐剂的疫苗在肺匀浆中诱导 IL - 17A 显著增加。无论腹腔还是鼻内给予含 curdlan 佐剂的疫苗，肺中都没有观察到 TRM 细胞的显著扩增。经鼻内给予的 DTaP 疫苗联合 curdlan 佐剂也能从呼吸道清除百日咳杆菌。
Galeas - Pena 等人开发了一种由 aP 抗原和 T - vant（一种来自细菌外膜囊泡的新型佐剂）组成的鼻内疫苗，该疫苗经鼻内给药时可促进 Th1 和 Th17 免疫反应，扩增 CD4 + T 细胞（可能是常规 TRM 细胞），并清除肺和鼻咽部的百日咳杆菌，此外，它还能诱导黏膜 IgA 和血清 IgG。
脂质体佐剂、STING 和 TLR 激动剂及其组合也可作为黏膜佐剂。Asokanathan 等人证明，当氢氧化铝与 CpG - ODN 联合使用时，百日咳疫苗可增加血清 PT、FHA 和 PRN 特异性 IgG 抗体。巨噬细胞或脾脏上清液中 NO 和 IFN - γ 的水平显著增加，表明免疫反应转向 Th1。
基于合成脂肽 LP1569 的研究，Allen 等人随后继续使用一种新的佐剂 LP - GMP，其中包含 LP1569 和 c - di - GMP。c - di - GMP 作为细胞内干扰素基因受体刺激因子（STING）。LP - GMP 能够激活小鼠和人类的 DCs，促进有效的 Th1 和 Th17 免疫。当与百日咳抗原共同免疫时，LP - GMP 可预防百日咳杆菌引起的鼻腔定植和肺部感染，并且在鼻内接种时比腹腔免疫诱导更多的呼吸道 TRM 细胞，其中很大一部分是分泌 IL - 17 的肺组织驻留 CD4 + 细胞。
Jiang 等人发现，鼻内给予激动剂 c - di - GMP 作为 aP 疫苗的佐剂可诱导 Th1 和 Th17 免疫，并显著增加肺中的 CD4 + TRM 细胞。含 c - di - GMP 佐剂的 aP 疫苗组比其他组（包括含氢氧化铝的 aP 疫苗）表现出更好的保护效果。此外，肺部炎症细胞浸润减少，呼吸道细菌负荷也减少。
Aibna 等人将 PRN、FHA 2/3 和百日咳毒素突变体与三重佐剂（包括 Toll 样受体（TLR）- 3 激动剂 poly（I:C）、宿主先天防御肽（IDR - 1002）、聚磷腈载体系统（PCEP）和阳离子 DDAB/DOPE 脂质体）联合用于鼻内免疫。这种疫苗可促进 Th1 型免疫，产生高 IgG2a 和 IgA 血清抗体滴度，单次给药后产生鼻腔分泌的 sIgA 抗体。六、百日咳联合疫苗的稳定性
如上所述，百日咳联合疫苗通常包括白喉、破伤风类毒素、百日咳杆菌纯化亚单位蛋白、灭活脊髓灰质炎病毒抗原等。这种联合疫苗通常需要多次注射，且制成液体制剂，这对疫苗在长期储存过程中的稳定性提出了很高的要求。
联合疫苗的稳定性相当复杂，取决于各组分之间的相互作用。当疫苗中含有佐剂时，百日咳抗原、白喉类毒素和乙肝抗原会竞争佐剂上的结合位点，导致其他抗原经常取代白喉类毒素，从而降低白喉类毒素的效力。
Kalbfleisch 等人研究表明，近 90% 的单价抗原 DT、TT 和 FHA 可吸附在磷酸铝上，而 PRN、PT 和 FIM 的吸附率较低。与磷酸铝吸附后，DT 和 TT 比其他抗原表现出更明显的结构变化。Duprez 等人对含基因修饰百日咳毒素（gdPT）和 TLR 激动剂（E6020 和 CpG）且吸附于 AlOOH 佐剂的无细胞百日咳疫苗 Tdap 进行了表征，与 Tdap-AlOOH 和 Tdap-E6020（TLR4 激动剂）-AlOOH 相比，Tdap-CPG-AlOOH 表现出更好的热稳定性，且 FTIR 分析表明，与 PT 相比，gdPT 被 AlOOH 吸附后其二级结构基本保持不变。
抗原在铝佐剂上的解吸动力学会影响储存稳定性。以 Al (OH)₃为基础的 Infanrix 疫苗在 4°C 下储存长达 3 年时，所有批次的 PT、FHA 和 PRN 解吸率分别低于 3%、0.8% 和 0.1%。当抗原吸附在 AlPO₄上时，18-24 个月后 PT 的最大损失为 11-12%，而 PRN 在 2 年后逐渐解吸至 60% 的水平。吸附在磷酸铝上可能导致对小鼠鼻内百日咳攻击的保护效果较差。
此外，防腐剂的存在和极端温度会影响百日咳联合疫苗的稳定性。白喉和破伤风类毒素在较高温度下往往相对稳定，而疫苗效力在冷冻条件下更易降低。高温和冷冻温度都会对百日咳疫苗产生影响，但冷冻的影响更为显著。百日咳成分在 22-25°C 下储存 2-8 周仍能保持 80% 的初始效力，而疫苗在 - 20°C 下保存 15 天，百日咳成分的效力会降低约 50%。
研究表明，疫苗的冷冻损伤与铝盐佐剂有关。铝盐佐剂的存在增加了疫苗对冷冻温度的敏感性。冷冻铝盐会破坏疫苗，且冷冻引起的铝佐剂表面羟基损伤会减少铝颗粒之间的排斥力，促进聚集体的形成，从而导致疫苗效力下降。Xue 等人发现，在 DTaP 和 DTwP 疫苗中添加丙二醇赋形剂可以保护疫苗免受冷冻损伤，且不影响疫苗的 pH 值、粒径分布和效力。
总体而言，在百日咳联合疫苗中，破伤风和白喉的成分比百日咳的成分更稳定，疫苗的整体稳定性受温度、赋形剂、佐剂等多种因素的影响。由于联合疫苗的复杂性，目前尚未得出明确的结论。七、结论与展望
本文全面概述了当前含百日咳抗原的联合疫苗，探讨了通过加入促进 Th1 和 Th17 反应的佐剂来增强 aP 疫苗免疫原性的方法，讨论了百日咳联合疫苗中一些有前景的佐剂（如 CpG-ODN、MPL 和 LPS）的实例，为 aP 疫苗制剂中新佐剂的选择提供了见解。此外，从肌肉注射转向鼻内接种百日咳疫苗可能进一步提高效力，本文总结了各种黏膜佐剂在百日咳疫苗中的应用，强调了它们增强免疫反应的潜力。
理想的佐剂应具有广泛的安全性，易于制造和施用，能有效激活体液和细胞免疫反应，并将不良反应降至最低。本文概述了各种在临床前动物试验中显示出保护作用的新型 aP 疫苗佐剂。其中，CpG、TLR7a、LP1569 和 MPL 在肌肉注射或腹腔注射时可防止百日咳杆菌在肺部或气管定植，而鼻内施用的黏膜佐剂如 LP-GMP 和 c-di-GMP 甚至可诱导鼻腔黏膜免疫并减少细菌负荷。在 Tdap 疫苗中对 MF59 与氢氧化铝 + MPLA 的比较表明，氢氧化铝 + MPLA 诱导的免疫反应起效更快。
此外，新型佐剂在百日咳疫苗中尚未直接进行比较。然而，先前的研究表明，大多数 TLR 激动剂可诱导抗原特异性 CD4 T 细胞，但只有更强的 TLR7/8 和 TLR3 激动剂可诱导 CD8 细胞毒性 T 细胞。除免疫效果外，佐剂生产的复杂性、稳定性以及诱导免疫耐受的可能性都需要进一步评估，以避免临床限制。在临床试验和市售疫苗中测试的 TLR 激动剂表现出稳定的化学性质和较低的生产成本，使其成为有前景的开发候选物。与传统的铝佐剂不同，TLR 激活剂不需要与抗原吸附，这似乎降低了开发复杂性。然而，对抗原 - 佐剂相互作用产生的稳定性和免疫原性的研究仍然至关重要。多种佐剂的联合使用为未来 aP 疫苗的开发提供了另一条有前景的途径。我们认为，在百日咳疫苗中使用 TLR 激动剂，特别是已证明安全的 CpG 和 AS04，将成为一种普遍趋势。值得注意的是，虽然新型佐剂有助于诱导免疫增强和长期保护，但尚不清楚它是否能克服抗原缺陷菌株的选择压力，这方面还需要更多的研究。
传统上，新型佐剂的发现和选择依赖于对候选化合物的经验性筛选和优化，对其免疫机制的理解有限。此外，必须仔细考虑新型佐剂与其他疫苗成分的相互作用。这些传统方法通常成本高昂、耗时，并且在对佐剂机制和毒性缺乏清晰了解的情况下，难以符合疫苗安全性和有效性标准。因此，开发含新型佐剂的 aP 联合疫苗仍然是一个复杂而漫长的过程。
人工智能（AI）的最新进展为佐剂的发现和选择开辟了新途径。AI 利用虚拟评估，根据候选化合物的化学结构评估其生物活性，并预测它们与特定靶点的相互作用，从而能够快速识别活性佐剂。此外，AI 可以通过定量结构 - 活性关系（QSAR）模型研究佐剂的理化性质与生物活性之间的关系，促进佐剂制剂的合理优化。尽管 AI 技术尚未广泛应用于 aP 疫苗新型佐剂的开发，但其改变这一领域的潜力是不可否认的。AI 的整合必将推动 aP 疫苗设计和优化的重大进展。
此外，必须努力提高发展中国家的百日咳疫苗覆盖率，降低婴儿死亡率。在资源有限的偏远地区维持百日咳疫苗的稳定性需要对冷链基础设施进行大量投资。通过赋形剂、佐剂和制剂技术的进步来提高疫苗稳定性，有助于确保资源受限的发展中国家更好地获得有效的疫苗。
理想的百日咳疫苗应具有优异的安全性和稳定性，能引发体液和细胞免疫，提供长期保护，且不干扰其他疫苗成分的效力。深入了解百日咳联合疫苗中佐剂的成分、机制和类型，可以加速改进型百日咳疫苗的开发和临床应用。通过应对这些挑战，我们可以更接近实现高效且全球可及的百日咳疫苗。
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疫苗临床研究
2022-08-24
Lung Association educates adults living with chronic lung disease about the importance of pertussis vaccination
CHICAGO, Aug. 24, 2022 /PRNewswire/ -- Pertussis, commonly referred to as whooping cough, is a serious and highly contagious respiratory illness. There is a vaccine available for whooping cough, however only 30% of adults in the U.S. received it in the past 10 years. The American Lung Association, in collaboration with Sanofi, are working to educate adults living with asthma and chronic obstructive pulmonary disease (COPD) about the potential dangers of pertussis and the importance of vaccination.
"Here in the U.S., there are approximately 21.1 million adults living with asthma and 12.5 million adults living with COPD. For these people, whooping cough can lead to severe, sometimes life-threatening health challenges including exacerbation of their chronic medical conditions," said Harold Wimmer, National President and CEO for the American Lung Association. "Thankfully, there is a vaccine available, Tdap, which is specifically developed for adults and helps protect against tetanus, diphtheria and pertussis."
Vaccination is the best way to help protect against pertussis. Preventing pertussis helps reduce the risk of hospitalization and severe outcomes for high-risk individuals.
The Lung Association's Pertussis Educational Campaign includes online resources with key facts about pertussis, an online assessment and targeted outreach to raise awareness about the disease to high-risk individuals.
If you are living with COPD or asthma, visit Lung.org/Pertussis to learn more and speak with your healthcare provider about getting a vaccination to help protect against pertussis.
About the American Lung Association
The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease through education, advocacy and research. The work of the American Lung Association is focused on four strategic imperatives: to defeat lung cancer; to champion clean air for all; to improve the quality of life for those with lung disease and their families; and to create a tobacco-free future. For more information about the American Lung Association, which has a 4-star rating from Charity Navigator and is a Gold-Level GuideStar Member, or to support the work it does, call 1-800-LUNGUSA (1-800-586-4872) or visit: Lung.org.
American Lung Association • 55 W. Wacker Drive, Suite 1150 • Chicago, IL 60601
1331 Pennsylvania Ave. NW, Ste. 1425 North • Washington, D.C. 20004
1-800-LUNGUSA (1-800-586-4872) Lung.org
CONTACT: Jill Dale | American Lung Association
P: 312-940-7001 C:720-438-8289 E: [email protected]
SOURCE American Lung Association
疫苗
2021-10-28
Paris, October 28, 2021
Strong Q3 performance drives guidance upgrade to around 14% business EPS growth at CER(1)
Q3 2021 sales grew double digit to €10.4 billion (up 10.1%) due to strong growth from Dupixent®, Vaccines and CHC
Specialty Care sales increased 20.2% with strong contribution from Dupixent® (+54.6% to €1,410 million)
Vaccines up 16.5%, with record quarterly sales driven by differentiated flu vaccines and meningitis franchise recovery
CHC increased 11.1% driven by growth of Pain care and Digestive Wellness categories
General Medicines sales down 1.7% while transformation of business model supports core assets growth (up 4.5%)
Q3 2021 business EPS(2) growth of 19.1% at CER driven by sales performance and efficiencies
Business EPS(2) was €2.18, up 19.1% on a reported basis
BOI margin reached 34.1% up 2.2 ppts reflecting improvement in Gross margin and continued expense management
IFRS EPS was €1.85 (up 19.4 %)
Progress on Corporate Social Responsibility strategy
Carbon neutrality target accelerated to 2030; a 2050 net zero objective established
Sanofi ranked #1 in the European pharma sector by ESG rating agency Vigeo Eiris (part of Moody’s ESG Solutions)
Key milestone and regulatory achievements on R&D transformation
Positive pivotal phase 3 readouts for Dupixent® in chronic spontaneous urticaria and infant atopic dermatitis (6 months to 5 years)
Nexviazyme® approvals in U.S. and Japan
Submissions of sutimlimab in the U.S. and olipudase alfa in Japan under the Sakigake pathway
Acquisition of Translate Bio completed, first positive clinical data read-out validating the mRNA platform
Full-year 2021 business EPS guidance revised upward(1)
Sanofi now expects 2021 business EPS(2) to grow around 14% at CER(3), barring unforeseen major adverse events. Applying average October 2021 exchange rates, the currency impact on 2021 business EPS is estimated to be between -3.5% to -4.5%
Sanofi Chief Executive Officer, Paul Hudson, commented:
“Sanofi has delivered outstanding financial results in the third quarter. Double-digit sales growth in the period was driven by the remarkable performance of Dupixent®, record sales of Vaccines and business momentum in Consumer Healthcare, all in line with our strategic priorities. As a result of our sales performance and strong earnings, we have upgraded our full-year EPS guidance growth to around 14% at CER. In R&D, our growing pipeline of potentially transformative therapies has progressed, including the most recent positive readouts for Dupixent® in Eosinophilic esophagitis and Prurigo nodularis as well as the U.S. approval and launch of Nexviazyme® in Pompe disease. With higher R&D investment behind our pipeline assets and the two targeted bolt-on acquisitions of Translate Bio and Kadmon, we have further increased our commitment to bring innovative medicines to patients and drive future growth. Aligned with our contract with society and leading up to COP 26, we have set ourselves new ambitious ESG targets to reduce carbon emissions and accelerate our actions in fighting global climate change.”
Q3 2021
Change
Change
at CER
9M 2021
Change
Change
at CER
IFRS net sales reported
€10,432m
+10.1%
+10.1%
€27,767m
+4.2%
+8.2%
IFRS net income reported(4)
€2,317m
+18.7%
_
€5,093m
-54.7%
—
IFRS EPS reported
€1.85
+19.4%
_
€4.07
-54.6%
—
Free cash flow(5)
€2,202m
+16.9%
_
€5,555m
+1.9%
—
Business operating income
€3,558m
+17.5%
+17,3%
€8,461m
+9.7%
+15.0%
Business net income(2)
€2,736m
+19.0%
+18.8%
€6,484m
+11.4%
+16.9%
Business EPS(2)
€2.18
+19.1%
+19.1%
€5.18
+11.6%
+17.2%
Changes in net sales are expressed at constant exchange rates (CER) unless otherwise indicated (definition in Appendix 7)
(1) Sanofi already raised its full-year 2021 business EPS growth guidance to around 12% at CER on July 29; (2) In order to facilitate an understanding of operational performance, Sanofi comments on the business net income statement. Business net income is a non-GAAP financial measure (definition in Appendix 7). The consolidated income statement for Q3 2021 is provided in Appendix 3 and a reconciliation of reported IFRS net income to business net income is set forth in Appendix 4; (3) 2020 restated business EPS was €5.86; (4) 9M 2021 IFRS net income reported reflected capital gain from sales of Regeneron shares in Q2 2020; (5) Free cash flow is a non-GAAP financial measure (definition in Appendix 7)
2021 third-quarter and first nine months Sanofi sales
----------------------------
Unless otherwise indicated, all percentage changes in sales in this press release are stated at CER1
----------------------------
In the third quarter of 2021, Sanofi sales were €10,432 million, up 10.1% on a reported basis. Exchange rate movements had a neutral effect, the negative impact of the U.S. dollar, Japanese yen and Turkish lira was offset by the increase of the Chinese Yuan and some other currencies.
In the first nine months Sanofi sales reached €27,767 million, up 4.2% on a reported basis. Exchange rate movements had a negative effect of 4.0 percentage points. At CER, company sales were up 8.2%.
Global Business Units
Third-quarter 2021 operating income
Third-quarter business operating income (BOI) increased 17.5% to €3,558 million. At CER, BOI increased 17.3%. The ratio of BOI to net sales increased 2.2 percentage points to 34.1% (34.0% at CER). In the first nine months, BOI increased 9.7% to €8,461 million. At CER, BOI increased 15.0%. The ratio of business operating income to net sales increased 1.6 percentage points to 30.5% (30.8% at CER).
Pharmaceuticals
Third-quarter 2021 Pharmaceutical sales increased 7.8% to €6,855 million, mainly driven by the Specialty Care portfolio (up 20.2%) with continued strong performance of Dupixent® while sales in General Medicines decreased 1.7%. In the first nine months, Pharmaceuticals sales increased 7.7% to €20,051 million reflecting the strong performance of Specialty Care and General Medicines core assets.
Specialty Care
Dupixent
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Total Dupixent®
1,410
+54.6
%
3,700
+52.5
%
In the third quarter, Dupixent® (collaboration with Regeneron) sales increased 54.6% to €1,410 million. In the U.S., Dupixent® sales of €1,061 million (up 47.7%) were driven by continued strong demand in atopic dermatitis (AD) in adults, adolescents, and children aged 6 to 11 years, and continued uptake in asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Dupixent® total prescriptions (TRx) increased 45% (year-over-year) and new-to-brand prescriptions (NBRx) grew 23% despite fewer in-person physician visits, which remain slightly below the pre-COVID level. In Europe, third-quarter Dupixent® sales grew 78.4% to €173 million reflecting continued growth in AD in key countries and additional launches in asthma in European markets. In Japan, sales were €78 million (up 68.8%). In the first nine months, Dupixent® sales reached €3,700 million, up 52.5%.
Neurology and Immunology
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Aubagio®
483
-3.8
%
1,477
-1.7
%
Lemtrada®
20
-16.7
%
63
-27.2
%
Kevzara®
83
+42.4
%
196
+15.3
%
Total Neurology and Immunology
586
+0.3
%
1,736
-1.4
%
In the third quarter, Neurology and Immunology sales remained stable to €586 million, reflecting strong Kevzara® sales which were offset by lower Aubagio® sales. In the first nine months, Neurology and Immunology sales were down 1.4% reflecting decreased sales of Lemtrada® and Aubagio.
Aubagio® sales decreased 3.8% in the third quarter to €483 million due to lower sales in the U.S. reflecting increased competition which was partially offset by higher sales in Europe and the Rest of the World.
Third-quarter Kevzara® (collaboration with Regeneron) sales increased 42.4% to €83 million due to an increase in global demand for IL-6 receptor blockers and the temporary tocilizumab shortage.
Rare Disease
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Myozyme® / Lumizyme®
266
+10.4
%
749
+8.4
%
Fabrazyme®
209
+3.4
%
621
+5.7
%
Cerezyme®
159
+0.6
%
502
+1.1
%
Aldurazyme®
57
+5.5
%
180
+7.3
%
Cerdelga®
64
+5.0
%
187
+10.9
%
Others Rare Disease
24
+4.3
%
69
+10.8
%
Total Rare Disease
779
+5.4
%
2,308
+6.1
%
In the third quarter, Rare Disease sales increased 5.4% to €779 million driven by Pompe franchise performance. In the first nine months, sales of Rare Disease increased 6.1% reflecting growth across all three geographic regions.
Third-quarter Myozyme®/Lumizyme® sales increased 10.4% to €266 million supported primarily by new patient accruals across geographic regions.
Third-quarter Fabrazyme® sales increased 3.4% to €209 million driven by higher demand in Europe and the Rest of the World region, reflecting new patient accruals and improved treatment compliance.
Sales of the Gaucher franchise (Cerezyme® + Cerdelga®) increased 1.8% (to €223 million) in the third quarter. Over the period, Cerezyme® sales increased 0.6% to €159 million, reflecting growth in the U.S. and Rest of World region. In Europe Cerezyme® sales were down 4.8% as Cerdelga® sales were up 5.0% globally driven by new patient accruals in Europe.
Oncology
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Jevtana®
105
-20.9
%
345
-10.9
%
Sarclisa®
48
+276.9
%
122
+605.6
%
Fasturtec®
37
-9.5
%
111
+1.8
%
Libtayo®
35
+61.9
%
94
+95.8
%
Total Oncology
225
+8.1
%
672
+19.3
%
Third-quarter and first-nine months sales of Oncology increased 8.1% (to €225 million) and 19.3%, respectively, driven by the Sarclisa® and Libtayo® launches which more than offset the impact of Jevtana® generic competition in Europe.
Third-quarter Jevtana® sales decreased 20.9% to €105 million following the entry of generic competition in certain European markets (down 58.3%) at the end of March. In the U.S., sales were up 1.6%, where the Jevtana® composition of matter patent has expired in September 2021. However, Sanofi has filed patent infringement suits against generic on Jevtana® under Hatch-Waxman in the U.S. District Court for the District of Delaware asserting three method of use patents, two of which (US 10,583,110 and US 10, 716,777) expire in October 2030 and the other one (US 8,927,592) expires in April 2031 including 6-month pediatric exclusivities. Sanofi has reached settlement agreements with some of the defendants and the suit against the remaining defendants is ongoing. No trial dates has been scheduled and the remaining defendants have agreed not to launch any generic cabazitaxel product until the earlier of a district court decision in favor of the defendants or four months after the completion of the post-trial briefing. Separately, Jevtana® has been granted a data exclusivity on the CARD clinical study results which expires in December 2023.
Third-quarter Sarclisa® sales were €48 million (versus €13 million in the third quarter of 2020) driven by additional country launches in Europe (€17 million), higher sales in the U.S (€18 million) and in the Rest of the world region (€13 million) driven by the uptake in Japan.
Libtayo® (collaboration with Regeneron) sales were €35 million (up 61.9%) in the third quarter driven by increased demand in metastatic cutaneous squamous cell carcinoma (CSCC) as well as additional country launches. Libtayo® sales in the U.S. are reported by Regeneron.
Rare Blood Disorders
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Eloctate®
144
-4.6
%
422
-7.3
%
Alprolix®
101
-6.4
%
301
-4.8
%
Cablivi®
42
+32.3
%
126
+56.6
%
Total Rare Blood Disorders
287
-1.4
%
849
-0.4
%
In the third quarter, Rare Blood Disorders franchise sales decreased 1.4% (€287 million). Excluding industrial sales to Sobi, third-quarter sales were up 7.1% mainly driven by Cablivi®. Alprolix® and Eloctate® industrial sales to Sobi are expected to be significantly lower in 2021 than in 2020 due to a change in the supply agreement. In the first nine months sales of Rare Blood Disorders decreased 0.4% and were up 9.8.% when excluding industrial sales to Sobi.
Eloctate® sales were €144 million in the third quarter, down 4.6%. Excluding industrial sales to Sobi, Eloctate sales were up 2.2% driven by higher U.S. sales (+3.7%) which benefited from buying patterns in the quarter . Sales in the Rest of the World were down 25.0% reflecting lower industrial sales to Sobi (which are recorded in this region).
Third-quarter Alprolix® sales were down 6.4% to €101 million. Excluding industrial sales to Sobi, Alprolix® sales were up 6.3% driven by U.S. sales (up 5.0%) which benefited from buying patterns in the quarter. Sales in the Rest of the World were down 37.9% reflecting lower industrial sales to Sobi (which are recorded in this region).
Cablivi® generated sales of €42 million (up 32.3%) in the third quarter driven by launches in Europe (up 120.0% to €22 million). In the U.S., sales of the product were €19 million, down 9.5% reflecting the impact of the COVID-19 environment on treatment initiations with Cablivi® at the hospital level.
General Medicines
Third quarter General Medicines sales decreased 1.7% to €3,568 million. The growth of core assets2 (up 4.5% to €1,437 million and up 5.6% excluding Praluent® U.S. sales) was more than offset by the non-core assets sales decrease (down 6.3% to €1,923 million) mainly reflecting lower Lantus® sales in the U.S., portfolio streamlining (-1.3 ppt impact) and a decline in Aprovel®/Avapro® sales. Third-quarter Industrial sales3 were €208 million up 2.5%. Excluding portfolio streamlining, third quarter General Medicines sales were down 0.7% (- 1.0 ppt impact).
In the first nine months, General Medicines sales were down 0.6% to €10,786 million. During the same period, sales of the core assets were €4,339 million up 6.8%, driven by strong performance of Lovenox®, Toujeo® and Thymoglobulin®. Non-core assets sales were €5,859 million, down 5.8% reflecting portfolio streamlining (-2.0 ppt), as well as lower Lantus® and Aprovel®/Avapro® sales. Over the same period, Industrial sales were €588 million up 4.2%. Excluding portfolio streamlining, General Medicines sales were up 0.5 % (-1.1 ppt impact).
Diabetes
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Lantus®
622
-5.9
%
1,911
-4.1
%
Toujeo®
239
+11.1
%
739
+7.9
%
Total glargine
861
-1.7
%
2,650
-1.0
%
Soliqua®
51
+27.5
%
141
+28.7
%
Other diabetes
211
-6.6
%
653
-3.7
%
Total Diabetes
1,123
-1.7
%
3,444
-0.6
%
In the third quarter, global Diabetes sales decreased 1.7% to €1,123 million. Sales growth in the Rest of the Word (up 9.3%) was more than offset by lower sales in the U.S. (down 13.4%) and Europe (down 3.2%). In the first nine months, Diabetes sales were down 0.6% mainly as a result of lower Lantus® sales partially offset by growth from Toujeo® and Soliqua®.
Third-quarter Toujeo® sales increased 11.1% to €239 million reflecting growth across all geographies and strong growth in the Rest of World region (up 20.0%).
Lantus® sales were €622 million, down 5.9% in the third quarter, reflecting lower sales in the U.S. and Europe due to a continued decline in average U.S. net price, increasing use of Toujeo® and biosimilar glargine competition. In the Rest of World region, Lantus® sales were up 10.1% driven by China.
Third-quarter Soliqua® sales increased 27.5% to €51 million driven by growth in all three geographic regions. In the Rest of World region, third-quarter Soliqua® sales grew 40.0% mainly due to new launches.
Cardiovascular and Established Rx Products
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Lovenox®*
383
+4.4
%
1,151
+19.1
%
Plavix®*
222
+6.3
%
707
+1.0
%
Aprovel®/Avapro®
107
-21.8
%
307
-29.4
%
Thymoglobulin®
91
+4.6
%
263
+16.1
%
Multaq®
79
0.0
%
230
+4.3
%
Praluent®
59
+18.0
%
163
-15.8
%
Mozobil®
60
+7.1
%
170
+13.5
%
Generics
172
-10.9
%
566
-0.3
%
Other
1,064
-4.0
%
3,197
-5.0
%
Total Cardiovascular and Established Rx Products
2,237
-2.1
%
6,754
-1.0
%
*Excluding Auto generics
In the third quarter, Cardiovascular andEstablished Rx Products sales decreased 2.1% to €2,237 million. The performance of the core assets including Lovenox®, Plavix®, Thymoglobulin®, Mozobil® and Praluent® was more than offset by lower sales of Aprovel®/Avapro® and generics as well as the impact of the divestments of non-core products. In the first nine months, Cardiovascular and Established Rx Products sales were down 1.0% (up 0.1% excluding Praluent® U.S. sales) mainly due to lower Aprovel®/Avapro® sales and the divestments which offset strong growth of several core assets.
Third-quarter Lovenox® sales increased 4.4% to €383 million, driven by strong sales in Rest of World region (up 9.5%). COVID-19 related demand continued to be strong (guidelines recommending the use of low molecular weight heparins in hospitalized COVID-19 patients). However, growth performance was impacted by a comparable high base in the third quarter of 2020, supply limitations and biosimilar competition in Europe (down 1.8%).
Plavix® sales were up 6.3% in the third quarter to €222 million due to higher sales in Rest of World (up 9.2%) driven by China (up 16.7% to €90 million) largely offsetting lower sales in Japan and Europe.
Third-quarter Aprovel®/Avapro® sales were down 21.8% to €107 million reflecting supply constraints.
Third-quarter Praluent® sales increased 18.0% to €59 million, reflecting the restructuring of the collaboration with Regeneron effective April 1, 2020. Sanofi has sole responsibility for Praluent® outside the U.S. while Regeneron has sole responsibility for Praluent® in the U.S. Excluding U.S. sales in the comparable quarter last year, higher Praluent® sales (up 63.9%) were driven by the launch in China and strong performance in Europe.
Multaq® third quarter sales were stable at €79 million, reflecting U.S. sales growth which was offset by lower sales in Europe.
Pharmaceuticals business operating income
In the third quarter, business operating income (BOI) of Pharmaceuticals increased 2.8% to €2,409 million (up 1.7% at CER). The ratio of BOI to net sales decreased by 1.7 percentage points to 35.1%. At CER, the ratio decreased 2.0 percentage points reflecting Regeneron MAbs alliance and increased R&D expenses in priority assets and commercial expenses in Specialty Care growth drivers, despite an improvement of the gross margin ratio. In the first nine months, business operating income of Pharmaceuticals decreased 1.2% to €7,320 million (up 3.1% at CER). The ratio of BOI to net sales decreased by 1.7 percentage points to 36.5% (36.6% at CER).
Vaccines
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Polio/Pertussis/Hib vaccines
(incl. Hexaxim® / Hexyon®, Pentacel®, Pentaxim® and Imovax®)
563
+1.8
%
1,616
+3.1
%
Influenza vaccines
(incl. Vaxigrip®, Fluzone HD®, Fluzone® & Flublok®)
1,339
+25.5
%
1,535
+23.9
%
Meningitis/Pneumo vaccines
(incl. Menactra®)
253
+18.7
%
567
+36.2
%
Adult Booster vaccines (incl. Adacel®)
158
+4.6
%
364
+8.7
%
Travel and other endemic vaccines
82
+16.9
%
215
-1.3
%
Other vaccines
27
+8.7
%
62
+18.5
%
Total Vaccines
2,422
+16.5
%
4,359
+13.8
%
Third-quarter Vaccines sales grew 16.5% to €2,422 million driven by influenza vaccines performance and meningitis vaccination recovery in the U.S. In the first nine months, Vaccines sales grew 13.8% due to the strong performance of the influenza vaccines franchise and a recovery of meningitis vaccines more than offsetting the negative COVID-19 impact on the travel vaccines.
In the third quarter, Polio/Pertussis/Hib (PPH) vaccines sales increased 1.8% to €563 million. In Europe, PPH sales decreased 11.2% reflecting unfavorable phasing effect and lower birth rates due to the pandemic. In Rest of World, PPH sales were up 3.5% supported by Pentaxim® in China and Polio vaccines which largely offset the impact of lower birth rates. In the U.S., PPH sales increased 6.8% due to positive inventory fluctuation. VaxelisTM, the first and only hexavalent combination vaccine approved in the U.S., was launched in the U.S. in June 2021. Developed as part of a joint-partnership between Sanofi and Merck, VaxelisTM in-market sales are not consolidated and the profits shared equally between the two parties. As Vaxelis™ is expected to partly replace Pentacel® sales, PPH sales in the U.S. are expected to decrease going forward.
Influenza vaccines sales increased 25.5% in the third quarter to €1,339 million as a result of earlier shipments in the U.S and a strong increase in differentiated influenza vaccines in Europe driven by Germany which adopted a preferential recommendation for Efluelda® for people above 60 years old. Influenza vaccines sales in the U.S and in Europe grew 18.1% (to €982 million) and 87.8% (to €247 million), respectively.
Third-quarter Meningitis sales were up 18.7% to €253 million mainly with the recovery of meningitis vaccination in the U.S. and in Middle East in conjunction with the U.S. launch of MenQuadfi® in March 2021.
Adult Booster vaccines sales grew 4.6% in the third quarter to €158 million, due to the gradual recovery of Adacel® vaccinations in the U.S.
Third-quarter Travel and other endemic vaccines sales increased 16.9% versus a low 2020 basis.
Vaccines business operating income
In the third quarter, business operating income (BOI) increased 29.8% to €1,359 million reflecting the strong sales growth. At CER, BOI increased 29.5%. The ratio of BOI to net sales was 56.1% (versus 50.4% in the third quarter of 2020) reflecting a favorable product mix driven by influenza vaccines and Meningitis vaccines as well as good industrial performance. In the first nine months, BOI increased 30.7% (up 33.0% at CER) to €1,957 million reflecting strong sales performance as well as the payment from Daiichi Sankyo in the first quarter of 2021. The ratio of BOI to net sales increased 6.6 percentage points to 44.9% (44.7% at CER).
Consumer Healthcare
Net sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
Allergy
142
+17.4
%
485
+2.2
%
Cough, Cold and Flu
94
+4.4
%
204
-30.9
%
Pain Care
290
+18.2
%
818
+7.3
%
Digestive Wellness
282
+16.0
%
855
+21.8
%
Physical Wellness
85
-7.7
%
244
-5.7
%
Mental Wellness
53
+8.2
%
160
+16.8
%
Personal Care
135
+5.4
%
387
+2.8
%
Non-Core / Others
74
+4.2
%
204
-5.8
%
Total Consumer Healthcare
1,155
+11.1
%
3,357
+4.2
%
In the third quarter, Consumer Healthcare (CHC) sales increased 11.1% to €1,155 million driven by growth in all three geographic regions and the performance of the Digestive Wellness category, as well as the Pain Care category which also benefited from COVID-19 vaccinations. In the first nine months CHC sales increased 4.2% mainly due to the growing sales in Digestive Wellness, Pain Care and Mental Wellness categories which more than offset a weak cough and cold season last winter and the divestments of non-core products (-0.6 ppt impact).
In the U.S., third-quarter CHC sales increased 16.4% to €289 million driven by strong growth of Pain Care, Personal Care (driven by Gold bond) and Digestive Wellness categories as well as Allergy which benefited from a low base for comparison.
In Europe, third-quarter CHC sales increased 3.1% to €335 million mainly reflecting growth of Pain Care and Digestive categories which more than offset lower sales from the Cough, Cold and Flu category due to the impact of social distancing measures.
In Rest of World, third-quarter CHC sales increased 13.9% to €531 million, supported by strong growth of Pain Care and Digestive Wellness categories as well as higher sales from the Allergy category.
CHC business operating income
In the third quarter, business operating income (BOI) of CHC increased 44.1% (44.4% at CER) to €464 million reflecting higher sales and a strict control of operational expenses. The ratio of BOI to net sales increased 9.3 percentage point to 40.2% versus the prior year and included a €77 million capital gain related to divestment of non-strategic assets. In the first nine months of 2021, BOI of CHC increased 8.0% (up 14.5% at CER) to €1,195 million. The ratio of BOI to net sales increased 2.7 percentage points to 35.6% (36.1% at CER).
Company sales by geographic region
Sanofi sales (€ million)
Q3 2021
Change
at CER
9M 2021
Change
at CER
United States
4,477
+13.4
%
10,565
+13.4
%
Europe
2,483
+8.9
%
6,955
+5.3
%
Rest of the World
3,472
+6.7
%
10,247
+5.0
%
of which China
782
+12.8
%
2,162
+8.5
%
of which Japan
423
+13.3
%
1,253
+2.1
%
of which Brazil
198
+14.8
%
651
+16.7
%
of which Russia
139
-0.7
%
439
-3.8
%
Total Sanofi sales
10,432
+10.1
%
27,767
+8.2
%
Third-quarter sales in the U.S. increased 13.4% to €4,477 million supported by the strong performance of Dupixent® and double-digit growth of Vaccines and CHC. In the first nine months, U.S. sales grew 13.4%, mainly reflecting Dupixent® and Vaccines performance.
In Europe sales increased 8.9% in the third quarter to €2,483 million mainly driven by strong Vaccines growth and Dupixent® performance. In the first nine months, European sales increased 5.3% due to the growth of Specialty Care products driven by Dupixent® and Vaccines which more than offset lower sales of General Medicines and CHC.
In Rest of World sales increased 6.7% to €3,472 million in the third quarter, driven by the performance of Dupixent®, General medicine and CHC. Sales in China increased 12.8% to €782 million mainly sustained by Dupixent®, Vaccines, CHC and General Medicines performance. In Japan, third-quarter sales increased 13.3% to €423 million reflecting the strong performance of Dupixent® and Sarclisa®. In Rest of World first-nine months sales increased 5.0% mainly supported by growth of Dupixent®, Oncology, General Medicines and CHC.
R&D update at the end of the third quarter 2021
Regulatory update
The U.S. Food and Drug Administration (FDA) approvedNexviazyme® (avalglucosidase alfa) for the treatment of patients one year of age and older with late-onset Pompe disease. Nexviazyme® was also approved in Japan. Nexviazyme® is a long-term enzyme replacement therapy targeting the mannose-6-phosphate receptor, the key pathway for cellular uptake of enzyme replacement therapy, to effectively clear glycogen build-up in muscle cells. The approval was based on the Phase 3 COMET study, showing clinically meaningful improvements in respiratory function and movement endurance measures in people with late-onset Pompe disease.
The European Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Nexviazyme® (avalglucosidase alfa), for the treatment of Pompe disease. However, they considered that avalglucosidase alfa does not qualify as a New Active Substance (NAS), leading Sanofi to be requesting a re-examination of the CHMP opinion in relation to the NAS conclusion.
The FDA accepted the resubmission of the Biologics License Application (BLA) for sutimlimab, its investigational therapy for the treatment of hemolysis in adult patients with cold agglutinin disease (CAD). The FDA is reviewing the BLA under priority review with a PDUFA action date of February 5, 2022. Sutimlimab has previously received Breakthrough Therapy Designation (BTD) and Orphan Drug Designations (ODD) from the FDA.
Olipudase alfa, an investigational recombinant human acid sphingomyelinase for the treatment of Acid Sphingomyelinase Deficiency (ASMD), was submitted in Japan on September 30th, through the Sakigake regulatory pathway.
The FDA accepted for priority review of the supplemental Biologics License Application (sBLA) for PD-1 inhibitor Libtayo® (cemiplimab) to treat patients in 2L with recurrent or metastatic cervical cancer.
The FDA approvedfexinidazole, the first 10-day once-a-day oral treatment for Trypanosoma brucei gambiensesleeping sickness, in patients 6 years of age and older and weighing at least 20 kg. Both first stage and second stage of the disease are targeted, in which the parasites have crossed the blood-brain barrier, causing patients to suffer from neuropsychiatric symptoms.
The China National Medical Products Administrations (NMPA) approved the use of Dupixent® (dupilumab), for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
The FDA granted Fast-Track Designation for SAR443820, a RIPK1 inhibitor currently in Phase 1, for the amyotrophic lateral sclerosis (ALS) indication.
The FDA granted ODD for SAR445088 (formerly known as BIVV020), a complement C1s inhibitor currently in Phase 2, for the treatment of Chronic inflammatory demyelinating polyneuropathy (CIDP).
Portfolio update
Phase 3:
Dupixent®met its primary and all key secondary endpoints in Study A (the first of two trials) of the pivotal LIBERTY CUPID clinical program, showing a nearly doubled reduction in itch and urticaria activity scores, compared to antihistamines (standard-of-care treatment), in patients with moderate-to-severe chronic spontaneous urticaria (CSU). Study B of the clinical trial evaluates Dupixent® in adults and adolescents who remain symptomatic despite standard-of-care treatment and are intolerant or incomplete responders to an anti-IgE therapeutic (omalizumab). This study is expected to read out in H1 2022. CSU is an inflammatory skin disease, affecting more than 300,000 patients in the U.S. alone.
The pivotal trial evaluating Dupixent® (dupilumab) for the treatment of children aged 6 months to 5 years with moderate-to-severe atopic dermatitis, met its primary and all secondary endpoints. The data show adding Dupixent® to standard of care topical corticosteroids (TCS) significantly reduced the overall disease severity and improved the skin clearance, itch and health-related quality of life measures at 16 weeks compared to TCS alone.
Detailed data from the MELODY study for nirsevimab to prevent respiratory illness caused by RSV (Respiratory Syncytial Virus) in infants was presented at the IDWeek congress showing a 74.5% reduction in medically attended LRTI (Lower Respiratory Tract Infections) after 5 months of follow up.
The study evaluating Libtayo® in combination with platinum-doublet chemotherapy was stopped early after meeting its overall survival primary endpoint, compared to chemotherapy alone, in first-line treatment of patients with advanced non-smallcell lung cancer(NSCLC), with metastatic or locally advanced disease and tumors with either squamous or non-squamous histology and across all PD-L1 expression levels. Results were presented at the 2021 European Society of Oncology (ESMO) congress.
The PEGASUS phase 3 trial, evaluating rilzabrutinib, a BTK inhibitor for the treatment of pemphigus, a rare autoimmune skin condition, did not meet its primary or key secondary endpoints. The proportion of patients meeting the primary endpoint on Rilzabrutinib, was not significantly different from placebo. Rilzabrutinib continues to be investigated in a Phase 3 trial for the treatment of immune thrombocytopenia, a rare blood disorder, and in a Phase 2 study for the autoimmune condition IgG4-related disease. Additional Phase 2 studies in immunological and rare blood disorders diseases including asthma, atopic dermatitis, chronic spontaneous urticaria and warm autoimmune hemolytic anemia are planned to start in 2021.
A potential filing date for fitusiran, a small interference RNA therapy in development for the treatment of people with hemophilia A or B, with or without inhibitors, has been moved to 2024 due the introduction of a lower dose cohort in the ongoing phase 3 studies. The lower dose may be available to those patients currently on 50 mg every other month with anti-thrombin levels below the lower threshold of 15% and may enable them to continue to receive prophylactic treatment with fitusiran.
A new phase 3 study evaluating the safety pro Nexviazyme® in infantile-onset Pompe Disease was initiated in children from 6 months to 17 years.
Patient enrollment is ongoing in EU and ROW in the phase 3 multicenter, open-label ELIKIDS study of Cerdelga® in pediatric patients with Gaucher Disease Type 1 and Type 3, under the pediatric investigation plan (PIP) as part of the overall clinical development plan. Submission is currently planned for 2025. Given the integral nature of the project it is not detailed anymore on the overall Sanofi pipeline chart.
MenQuadfi®, a quadrivalent ACWY vaccine, met all primary and secondary endpoints, demonstrating the induced superior immune responses to serogroup C based on geometric mean antibody titers (GMTs) compared to NeisVac-C (monovalent C vaccine) - standard-of-care vaccine- , in healthy toddlers. The data also showed superior immune responses to serogroup C based on seroprotection rates and GMTs compared to Nimenrix® (quadrivalent ACWY vaccine) in this population. MenQuadfi is approved in Europe for use as a single dose in individuals 12 months of age and older for the prevention of invasive meningococcal ACWY disease. In the US it is licensed for the prevention of invasive meningococcal disease in individuals 2 years of age and older.
Phase 2
Positive results from a Phase 2a study evaluating the safety and efficacy of amlitelimab in patients with moderate-to-severe atopic dermatitis, were presented as a late-breaker at the European Academy of Dermatology and Venerology (EADV) 2021 Virtual Congress. Amlitelimab, formerly known as KY1005, is a human monoclonal antibody targeting immune system regulator OX40-Ligand At week 16, the data demonstrated that when dosed intravenously every four weeks an 80% improvement in average EASI from baseline for the low dose and a 70% improvement in average EASI from baseline for the high dose was achieved, compared to 49% for the placebo group indicating a consistent pharmacological effect of blocking OX40-L. A Phase 2b dose ranging study is about to start, including lower doses and subcutaneous injection.
SAR444727 (formerly known as PRN473), a topically administered BTK inhibitor, entered Phase 2a study, evaluating safety, tolerability, and pharmacokinetics in patients with mild-to-moderate atopic dermatitis.
Data of tolebrutinib, an oral brain penetrant BTK inhibitor, were published in Lancet Neurology. The Phase 2b trial showed both safety and efficacy in relapsing multiple sclerosis. The treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, leading to a reduction of acute inflammation, while the drug was well tolerated. The phase 3 clinical trials in patients with relapsing and progressive forms of multiple sclerosis are currently enrolling.
SAR444245 (formerly known as THOR707), a novel non-alpha IL-2, entered a phase 2 basket trial in combination with Libtayo® for the treatment of various advanced skin cancers.
A phase 2 study cohort evaluating safety and efficacy of Sarclisa® in combination with atezolizumab in 1L mCRC was terminated.
A phase 2 study evaluating the safety and efficacy of Sarclisa®, in Adults with Warm Autoimmune Hemolytic Anemia (wAIHA) was initiated.
The phase 1/2 study of SP0254, an mRNA-based COVID-19 vaccine candidate, delivered positive interim results confirming the company’s platform robust capabilities and strategy in mRNA. Taking into account public health needs and given sufficient mRNA COVID-19 vaccines supply can be expected going forward, the development of SP0254 will not be further continued.
Phase 1
SAR443216, an anti-CD3xCD28xHER2 trispecific antibody, entered phase 1 study for the treatment of metastatic gastric cancers with HER2 low expression or HER2 mutation.
SAR443726, a novel IL13/OX40L nanobody entered a first-in-human, three-part, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult participants and in adult participants with moderate-to-severeatopic dermatitis.
Sangamo and Sanofi are continuing to advance the zinc finger genome editing program (SAR445136, formerly known as BIVV003) for sickle cell disease. The companies recently obtained manufacturing requirements guidance from FDA in preparation for further clinical studies and expect to share preliminary data from the sickle cell program at an upcoming meeting. The parties agreed to terminate the program addressing transfusion-dependent β-thalassemia (ST400) while focusing resources on the sickle cell disease indication.
Acquisitions
On September 14, Sanofi completed the acquisition of Translate Bio, acquiring all of their outstanding shares for $38.00 per share in cash, representing a total equity value of approximately $3.2 billion. Translate Bio is a clinical-stage mRNA therapeutics company, having already signed a collaboration with Sanofi in 2018, to develop mRNA vaccines which was further expanded in 2020 to broadly address current and future infectious diseases. The acquisition builds on Sanofi’s establishment of a first-of-its kind vaccines mRNA Center of Excellence.
On September 8, Sanofi entered into a definitive agreement to acquire Kadmon Holdings4 for $9.50 per share in cash, which represents a total equity value of approximately $1.9 billion. The acquisition supports Sanofi’s strategy to continue to grow its General Medicines core assets and will immediately add Rezurock™(belumosudil) to its transplant portfolio. This latter, a Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, has been recently FDA-approved, first-in-class treatment for chronic graft-versus-host disease (cGVHD) for adult and pediatric patients 12 years and older who have failed at least two prior lines of systemic therapy.
An update of the R&D pipeline as of September 30, 2021, is available on our website.
Progress on implementation of the Corporate Social Responsibility strategy
Sanofi is accelerating its efforts to address climate change and intends to achieve net zero5 greenhouse gas (GHG) emissions across all operations (scope 1 & 2) and the entire value chain (scope 3) by 2050. In alignment with the 1.5°C pathway, this new commitment will be building on years of work to reduce the environmental footprint of its products and activities through its Planet Mobilization program.
In this journey, the company has also set an interim target to reach by 2030 carbon neutrality6 across all scopes of emissions, 20 years ahead of its previous commitment made in 2015 after the COP21 and the Paris Agreement.
Sanofi’s carbon footprint (scope 1 and 2) has decreased by –27% between 2015 and 2020. As per today, renewable electricity represents 50% of total electricity consumption, on track to reach 100% of renewable electricity supply in 2030, and its RE1007 commitment.
As a result of an eco-driving policy and the renewal of the car fleet, the eco fleet represents 22% of total car fleet today with the objective to reach 100% by 2030.
The company will continue to report on progress annually to ensure its efforts are on track.
Finally, in the run-up to the 26th UN Climate Change Conference of the Parties (COP26), Sanofi has joined the UN’s 'Race to Zero' initiative. This global campaign mobilizes cities, regions, investors and 20% of the major companies by revenue committing to net zero carbon emissions by 2050. The COP26 will take place in Glasgow (UK) from October 31 until November 12, 2021.
In recognition of Sanofi’ ESG strategy implementation, Sanofi is ranked #1 in the European pharmaceutical sector in the latest international ESG ranking issued by Vigeo Eiris (V.E), published late August 2021. V.E, which is part of Moody’s ESG Solutions, is an independent international ESG rating agency. Its assessment is based on information covering 28 areas of interest ranging from climate change, health, safety, and environmental issues to human and labor rights.
VE's ESG scores measure the degree to which companies factor and manage material Environmental, Social and Governance factors. Across the pharmaceutical sector globally, Sanofi scored of 62/100 points moving up from its fourth place in the ranking one year ago.
Embedded in Sanofi's long-term Play to Win strategy, the company’s ESG strategy is based on four essential pillars.
Sanofi Global Health, a newly formed nonprofit unit within the company, will provide thirty of Sanofi's medicines across a wide range of therapeutic areas to patients in 40 of the lowest income countries. Sanofi Global Health will also fund the training of healthcare professionals and the development of sustainable care systems.
Sanofi continues its efforts to fight polio and sleeping sickness, two of its historical programs that address global health issues. Sanofi is the only pharmaceutical company that keeps developing and supplying treatments for sleeping sickness. It has committed itself alongside the WHO to eliminate this neglected tropical disease in humans by 2030. Over the years, Sanofi has supplied billions of polio vaccine doses, including hundreds of millions of donated doses to support the global polio eradication effort.
To contribute to better resource conservation, Sanofi plans to remove all pre-formed plastic packaging (blister packs) for its vaccines by 2027. In addition, the company is committed to ecodesigning all its new products by 2025. To reduce its greenhouse gas emissions by 55% by 2030, all Sanofi sites will use 100% renewable electricity and the company has set a target of a carbon-neutral car fleet, both by 2030.
As a global company, Sanofi is committed to ensuring that its leaders reflect the communities and patients it serves. The company is committed to continue fostering an organization where all employees have equal opportunities to reach positions of responsibility within the company.
Sanofi also keeps its commitment to making a strong contribution to current global public health priorities, with the supply of half a billion doses of authorized vaccines. Sanofi is the only company leveraging its worldwide manufacturing capacity and expertise for the supply of three different authorized COVID-19 vaccines from BioNTech / Pfizer, Moderna, and Johnson & Johnson. Manufacturing teams on three industrial sites of the company in France, Germany and the U.S. are mobilized, with 30 million doses released by end September.
At the same time, Sanofi continues its efforts in the fight against the COVID-19 pandemic with its adjuvanted recombinant protein candidate vaccine, developed in partnership with GSK. In parallel to its ongoing Phase 3 efficacy and safety study, Sanofi has expanded its development program to include a study of the vaccine as a potentially broadly protective booster to address evolving public health needs. First data readout is expected before year-end.
2021 third-quarter and the first nine months financial results
Business Net Income8
In the third quarter of 2021, Sanofi generated net sales of €10,432 million, an increase of 10.1% (on a reported basis and at CER). In the first nine months, net sales were €27,767 million up 4.2% (up 8.2% at CER).
Third-quarter other revenues decreased 0.7% (up 0.2% at CER) to €397 million, reflecting decreased VaxServe sales of non-Sanofi products (€336 million, down 5.3% at CER). In the first nine months, other revenues increased 2.0% (up 8.1% at CER) to €993 million, including higher VaxServe sales of non-Sanofi products (€790 million, up 0.8% at CER).
Third-quarter Gross Profit increased 13.0% (on a reported basis and at CER) to €7,591 million. The gross margin ratio increased 1.9 percentage points to 72.8% versus the third quarter of 2020. This improvement mainly reflected efficiency gains in Industrial Affairs, favorable impact of growing weight of Specialty Care (the Pharmaceuticals gross margin ratio improved from 73.5% to 75.2%), positive product mix of Vaccines (Vaccines gross margin ratio increased 3.7 percentage point to 72.0% which more than offset lower CHC gross margin ratio (64.7% versus 66.6%). In the first nine months, the gross margin ratio increased 0.9 percentage point to 72.0% (72.1% at CER).
Research and Development (R&D) expenses increased 9.2% (up 9.3% at CER) to €1,443 million in the third quarter, reflecting increase in priority assets development and early pipeline as well as recent acquisitions partly offset by efficiencies. In the first nine months, R&D expenses increased 2.3% to €4,106 million and were up 4.9% at CER as increased investment behind key assets were partly offset by the benefits of terminating diabetes and cardiovascular care related projects recorded in 2020.
Third-quarter selling general and administrative expenses (SG&A) increased 3.9% to €2,267 million. At CER, SG&A expenses were up 3.6%, reflecting increased commercial investments in Specialty Care growth drivers which were partially offset by continued streamlining of General and Administrative expenses (G&A). In the third quarter, the ratio of SG&A to sales decreased 1.3 percentage points to 21.7% compared to the prior year. In the first nine months, SG&A expenses increased 0.1% to €6,797 million (up 3.6% at CER). In the first nine months, ratio of SG&A to sales was 1.0 percentage point lower at 24.5% compared to the prior year.
Third-quarter operating expenses were €3,710 million, an increase of 5.9% and 5.7% at CER. In the first nine months operating expenses were €10,903 million, an increase of 0.9% and an increase of 4.1% at CER.
Third-quarter other current operating income net of expenses was -€289 million versus -€182 million in the third quarter of 2020. Other current operating income net of expenses included an expense of €399 million (versus an expense of €229 million in the third quarter of 2020) corresponding to the share of profit to Regeneron of the monoclonal antibodies Alliance, reimbursement of development costs by Regeneron and the reimbursement of commercialization-related expenses incurred by Regeneron. In the first nine months, other current operating income net of expenses was -€589 million versus -€437 million in the same period of 2020.
The share of profit from associates was -€5 million versus €1 million in Q3 2020 and included the share of U.S profit related to VaxelisTM.
Third-quarter business operating income8 (BOI) increased 17.5% to €3,558 million. At CER, BOI increased 17.3%. The ratio of BOI to net sales was 34.1% versus 31.9% in Q3 2020 reflecting seasonal contribution of flu vaccines, gross margin ratio improvement as well as SG&A ratio improvement. In the first nine months, business operating income was €8,461 million, up 9.7% (up 15.0% at CER) and the ratio of business operating income to net sales increased 1.6 percentage points to 30.5% (30.8% at CER).
Net financial expenses were €85 million in the third quarter versus €76 million in the same period of 2020.
Third-quarter and the first-nine months 2021 effective tax rate was 21.0% versus 22% in the prior year. Sanofi expects its effective tax rate to be around 21% in 2021, everything being equal in the U.S.
Third-quarter business net income8 increased 19.0% to €2,736 million and increased 18.8% at CER. The ratio of business net income to net sales increased 1.9 percentages points to 26.2% versus the third quarter of 2020. In the first nine months, business net income increased 11.4% to €6,484 million and increased 16.9% at CER. The ratio of business net income to net sales increased 1.6 percentage points to 23.4% versus the same period of 2020.
In the third quarter of 2021, business earnings per share8 (EPS) was €2.18, up 19.1% on a reported basis (and at CER). The average number of shares outstanding was 1,254.5 million versus 1,255.7 million in third quarter 2020. In the first nine months of 2021, business earnings per share8 was €5.18, up 11.6% on a reported basis and up 17.2% at CER. The average number of shares outstanding was 1,251.7 million in the first nine months of 2021 versus 1,253.0 million in the first nine months 2020.
Reconciliation of IFRS net income reported to business net income (see Appendix 4)
In the first nine months of 2021, the IFRS net income was €5,093 million. The main items excluded from the business net income were:
An amortization charge of €1,160 million related to fair value remeasurement on intangible assets of acquired companies (primarily Genzyme: €380 million, Bioverativ: €238 million, Boehringer Ingelheim CHC business: €148 million and Ablynx: €126 million) and to acquired intangible assets (licenses/products: €70 million). These items have no cash impact on the Company.
An impairment of intangible assets of €177 million mainly related to sutimlimab (termination of ITP).
Restructuring costs and similar items of €494 million related to streamlining initiatives.
A €440 million tax effect arising from the items listed above, mainly comprising €320 million of deferred taxes generated by amortization and impairments of intangible assets and €121 million associated with restructuring costs and similar items (see Appendix 4).
Capital Allocation
In the first nine months of 2021, free cash flow before restructuring, acquisitions and disposals increased by 21.0% to €6,968 million, after net changes in working capital (+€218 million) and capital expenditures (-€953 million). After acquisitions9 (-€1,093 million of which Kiadis -€319 million, Tidal Therapeutics -€135 millions), proceeds from disposals9 (+€461 million), and payments related to restructuring and similar items (-€781 million), free cash flow10 increased 1.9% to €5,555 million, reflecting recent acquisitions to strengthen the long-term pipeline and less proceeds compared to last year as Seprafilm was divested in Q1 2020 (€311 million). After the acquisition of Translate Bio (-€ 2,397 million) and Kymab (-€922 million) and the dividend paid by Sanofi (-€4,008 million), net debt increased from €8,790 million at December 31, 2020 to €10,427 million at September 30, 2021 (amount net of €9,785 million cash and cash equivalents).
Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects”, “anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, risks related to Sanofi’s ability to complete the proposed transaction with Kadmon Holdings, Inc. on the proposed terms or on the proposed timeline, including the receipt of required regulatory approvals, the possibility that competing offers will be made, other risks associated with executing business combination transactions, as well as other risks related to Sanofi’s business, including the ability to grow sales and revenues from existing products and to develop, commercialize or market new products, competition, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such product candidates, the fact that product candidates if approved may not be commercially successful, the future approval and commercial success of therapeutic alternatives, Sanofi’s ability to benefit from external growth opportunities, to complete related transactions and/or obtain regulatory clearances, risks associated with intellectual property and any related pending or future litigation and the ultimate outcome of such litigation, trends in exchange rates and prevailing interest rates, volatile economic and market conditions, cost containment initiatives and subsequent changes thereto, and the impact that COVID-19 will have on us, our customers, suppliers, vendors, and other business partners, and the financial condition of any one of them, as well as on our employees and on the global economy as a whole. Any material effect of COVID-19 on any of the foregoing could also adversely impact us. This situation is changing rapidly and additional impacts may arise of which we are not currently aware and may exacerbate other previously identified risks. The risks and uncertainties also include the uncertainties discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2020. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements.
Appendices
List of appendices
Appendix 1:
2021 third-quarter and first nine months sales by GBU, franchise, geographic region and product
Appendix 2:
2021 third-quarter and first nine months business net income statement
Appendix 3:
2021 third-quarter and first nine months consolidated income statement
Appendix 4:
Reconciliation of IFRS net income reported to business net income
Appendix 5:
Change in net debt
Appendix 6:
Currency sensitivity
Appendix 7:
Definitions of non-GAAP financial indicators
Investor Relations: (+) 33 1 53 77 45 45 - E-mail: IR@sanofi.com - Media Relations: (+) 33 1 53 77 46 46 - E-mail: MR@sanofi.com
Website:
Appendix 1: 2021 third-quarter net sales by GBU, franchise, geographic region and product
Q3 2021 (€ million)
Total Sales
% CER
% reported
United States
% CER
Europe
% CER
Rest of the world
% CER
Dupixent
1,410
54.6
%
53.6
%
1,061
47.7
%
173
78.4
%
176
82.3
%
Aubagio
483
-3.8
%
-4.4
%
328
-6.8
%
122
1.7
%
33
10.0
%
Lemtrada
20
-16.7
%
-16.7
%
9
-35.7
%
7
-14.3
%
4
66.7
%
Kevzara
83
42.4
%
40.7
%
49
75.0
%
24
33.3
%
10
-15.4
%
Neurology & Immunology
586
0.3
%
-0.3
%
386
-2.0
%
153
4.8
%
47
6.5
%
Cerezyme
159
0.6
%
-1.9
%
45
4.7
%
59
-4.8
%
55
3.5
%
Cerdelga
64
5.0
%
6.7
%
33
0.0
%
26
13.0
%
5
0.0
%
Myozyme
266
10.4
%
10.4
%
103
13.2
%
105
6.1
%
58
13.5
%
Fabrazyme
209
3.4
%
2.5
%
101
0.0
%
53
3.9
%
55
9.8
%
Aldurazyme
57
5.5
%
3.6
%
13
7.7
%
20
0.0
%
24
9.1
%
Rare Disease
779
5.4
%
4.6
%
296
5.7
%
264
3.5
%
219
7.2
%
Jevtana
105
-20.9
%
-21.6
%
63
1.6
%
20
-58.3
%
22
-4.3
%
Fasturtec
37
-9.5
%
-11.9
%
22
-17.9
%
12
9.1
%
3
0.0
%
Libtayo
35
61.9
%
66.7
%
—
0.0
%
28
47.4
%
7
200.0
%
Sarclisa
48
276.9
%
269.2
%
18
111.1
%
17
750.0
%
13
550.0
%
Oncology
225
8.1
%
7.1
%
103
6.0
%
77
-3.8
%
45
46.7
%
Alprolix
101
-6.4
%
-7.3
%
83
5.0
%
—
0.0
%
18
-37.9
%
Eloctate
144
-4.6
%
-5.3
%
111
3.7
%
—
0.0
%
33
-25.0
%
Cablivi
42
32.3
%
35.5
%
19
-9.5
%
22
120.0
%
1
0.0
%
Rare Blood Disorder
287
-1.4
%
-1.7
%
213
2.9
%
22
120.0
%
52
-30.1
%
Specialty Care
3,287
20.2
%
19.4
%
2,059
21.4
%
689
17.2
%
539
19.6
%
Lantus
622
-5.9
%
-5.3
%
199
-20.9
%
113
-11.1
%
310
10.1
%
Toujeo
239
11.1
%
10.6
%
72
9.1
%
96
6.7
%
71
20.0
%
Soliqua/iGlarLixi
51
27.5
%
27.5
%
30
25.0
%
7
16.7
%
14
40.0
%
0thers Diabetes
211
-6.6
%
-7.0
%
39
-23.1
%
61
-3.2
%
111
-0.9
%
Diabetes
1,123
-1.7
%
-1.5
%
340
-13.4
%
277
-3.2
%
506
9.3
%
Lovenox
383
4.4
%
4.9
%
9
14.3
%
166
-1.8
%
208
9.5
%
Plavix
222
6.3
%
8.3
%
2
-33.3
%
28
-6.9
%
192
9.2
%
Multaq
79
0.0
%
0.0
%
70
1.4
%
5
-16.7
%
4
0.0
%
Praluent
59
18.0
%
18.0
%
—
-100.0
%
41
36.7
%
18
200.0
%
Aprovel
107
-21.8
%
-19.5
%
4
-42.9
%
19
-13.0
%
84
-22.3
%
Mozobil
60
7.1
%
7.1
%
33
3.1
%
16
7.1
%
11
20.0
%
Thymoglobulin
91
4.6
%
4.6
%
52
1.9
%
9
0.0
%
30
11.5
%
Generics
172
-10.9
%
-10.9
%
26
-40.5
%
3
0.0
%
143
-2.7
%
Others
1,064
-4.0
%
-2.9
%
96
-10.2
%
335
-9.2
%
633
0.2
%
Cardiovascular & Established Rx Products
2,237
-2.1
%
-1.2
%
292
-12.5
%
622
-4.8
%
1,323
2.0
%
Industrial Sales
208
2.5
%
2.0
%
9
-60.0
%
186
13.4
%
13
-25.0
%
General Medicines
3,568
-1.7
%
-1.1
%
641
-14.3
%
1,085
-1.6
%
1,842
3.6
%
Pharmaceuticals
6,855
7.8
%
7.8
%
2,700
10.5
%
1,774
4.9
%
2,381
6.9
%
Polio / Pertussis / Hib
563
1.8
%
1.8
%
124
6.8
%
79
-11.2
%
360
3.5
%
Adult Booster Vaccines
158
4.6
%
4.6
%
105
14.1
%
36
-7.7
%
17
-15.0
%
Meningitis / Pneumonia
253
18.7
%
18.2
%
218
19.7
%
—
0.0
%
35
12.9
%
Influenza Vaccines
1,339
25.5
%
25.7
%
982
18.1
%
247
87.8
%
110
5.9
%
Travel and Other Endemic Vaccines
82
16.9
%
15.5
%
34
100.0
%
12
200.0
%
36
-26.0
%
Vaccines
2,422
16.5
%
16.6
%
1,488
18.5
%
374
41.8
%
560
0.0
%
Allergy
142
17.4
%
17.4
%
92
13.6
%
8
-11.1
%
42
35.5
%
Cough, Cold and Flu
94
4.4
%
4.4
%
—
0.0
%
45
-10.2
%
49
22.0
%
Pain Care
290
18.2
%
17.4
%
53
23.3
%
127
9.5
%
110
27.3
%
Digestive Wellness
282
16.0
%
16.0
%
29
16.0
%
97
9.0
%
156
20.9
%
Physical Wellness
85
-7.7
%
-6.6
%
—
0.0
%
7
0.0
%
78
-8.3
%
Mental Wellness
53
8.2
%
8.2
%
11
0.0
%
23
4.3
%
19
20.0
%
Personal Care
135
5.4
%
4.7
%
101
9.7
%
1
0.0
%
33
-8.3
%
Non-Core / Others
74
4.2
%
4.2
%
3
-233.3
%
27
-16.1
%
44
2.3
%
Consumer Healthcare
1,155
11.1
%
11.0
%
289
16.4
%
335
3.1
%
531
13.9
%
Company
10,432
10.1
%
10.1
%
4,477
13.4
%
2,483
8.9
%
3,472
6.7
%
Appendix 1: 2021 first nine months net sales by GBU, franchise, geographic region and product
First 9M 2021 (€ million)
Total Sales
% CER
% reported
United States
% CER
Europe
% CER
Rest of the world
% CER
Dupixent
3,700
52.5
%
45.0
%
2,801
46.3
%
462
70.1
%
437
85.0
%
Aubagio
1,477
-1.7
%
-6.1
%
994
-6.2
%
386
10.0
%
97
8.7
%
Lemtrada
63
-27.2
%
-31.5
%
29
-36.7
%
18
-32.0
%
16
5.6
%
Kevzara
196
15.3
%
11.4
%
99
13.0
%
65
18.2
%
32
17.2
%
Neurology & Immunology
1,736
-1.4
%
-5.7
%
1,122
-6.0
%
469
8.6
%
145
10.1
%
Cerezyme
502
1.1
%
-5.3
%
128
2.3
%
183
-2.1
%
191
3.3
%
Cerdelga
187
10.9
%
6.9
%
97
7.2
%
77
13.2
%
13
30.0
%
Myozyme
749
8.4
%
5.0
%
283
11.5
%
305
4.5
%
161
10.5
%
Fabrazyme
621
5.7
%
0.6
%
291
0.6
%
164
10.1
%
166
11.3
%
Aldurazyme
180
7.3
%
1.7
%
39
7.7
%
63
6.8
%
78
7.6
%
Rare Disease
2,308
6.1
%
1.4
%
839
5.6
%
794
5.2
%
675
8.0
%
Jevtana
345
-10.9
%
-14.8
%
182
4.3
%
95
-32.1
%
68
-8.9
%
Fasturtec
111
1.8
%
-2.6
%
65
-4.1
%
34
9.7
%
12
20.0
%
Libtayo
94
95.8
%
95.8
%
—
0.0
%
76
76.7
%
18
260.0
%
Sarclisa
122
605.6
%
577.8
%
46
250.0
%
44
2100.0
%
32
1600.0
%
Oncology
672
19.3
%
14.9
%
293
14.7
%
249
15.3
%
130
41.7
%
Alprolix
301
-4.8
%
-10.1
%
245
8.3
%
—
0.0
%
56
-38.3
%
Eloctate
422
-7.3
%
-12.4
%
327
1.8
%
—
0.0
%
95
-29.3
%
Cablivi
126
56.6
%
51.8
%
62
22.2
%
62
113.8
%
2
0.0
%
Rare Blood Disorder
849
-0.4
%
-5.7
%
634
6.0
%
62
113.8
%
153
-32.1
%
Specialty Care
9,265
19.2
%
13.6
%
5,689
19.6
%
2,036
19.5
%
1,540
17.4
%
Lantus
1,911
-4.1
%
-7.9
%
628
-7.8
%
359
-11.8
%
924
2.1
%
Toujeo
739
7.9
%
3.8
%
192
-2.4
%
291
4.7
%
256
21.3
%
Soliqua/iGlarLixi
141
28.7
%
22.6
%
83
23.9
%
21
23.5
%
37
44.4
%
0thers Diabetes
653
-3.7
%
-7.6
%
126
-11.2
%
191
-3.5
%
336
-0.6
%
Diabetes
3,444
-0.6
%
-4.5
%
1,029
-5.3
%
862
-4.2
%
1,553
5.0
%
Lovenox
1,151
19.1
%
15.7
%
24
13.6
%
534
15.0
%
593
23.1
%
Plavix
707
1.0
%
-0.8
%
7
0.0
%
88
-7.4
%
612
2.3
%
Multaq
230
4.3
%
-1.3
%
202
4.9
%
17
-5.6
%
11
10.0
%
Praluent
163
-15.8
%
-16.8
%
5
-92.7
%
116
34.9
%
42
53.6
%
Aprovel
307
-29.4
%
-30.1
%
7
-63.2
%
66
-11.8
%
234
-31.4
%
Mozobil
170
13.5
%
9.7
%
93
8.9
%
45
10.0
%
32
36.0
%
Thymoglobulin
263
16.1
%
11.4
%
153
16.4
%
25
13.6
%
85
16.2
%
Generics
566
-0.3
%
-7.8
%
96
-12.8
%
7
0.0
%
463
2.7
%
Others
3,197
-5.0
%
-7.6
%
254
-14.0
%
1,032
-11.2
%
1,911
0.1
%
Cardiovascular & Established Rx Products
6,754
-1.0
%
-4.1
%
841
-10.3
%
1,930
-2.0
%
3,983
1.8
%
Industrial Sales
588
4.2
%
2.1
%
33
-32.7
%
521
15.8
%
34
-45.6
%
General Medicines
10,786
-0.6
%
-3.9
%
1,903
-8.2
%
3,313
-0.2
%
5,570
2.1
%
Pharmaceuticals
20,051
7.7
%
3.5
%
7,592
11.1
%
5,349
6.5
%
7,110
5.1
%
Polio / Pertussis / Hib
1,616
3.1
%
0.2
%
365
29.3
%
224
-10.4
%
1,027
-1.1
%
Adult Booster Vaccines
364
8.7
%
5.8
%
218
21.3
%
102
-9.7
%
44
2.3
%
Meningitis / Pneumonia
567
36.2
%
30.6
%
425
43.1
%
1
0.0
%
141
18.9
%
Influenza Vaccines
1,535
23.9
%
23.4
%
982
16.3
%
265
94.1
%
288
11.8
%
Travel and Other Endemic Vaccines
215
-1.3
%
-4.4
%
70
23.3
%
25
-40.5
%
120
0.0
%
Vaccines
4,359
13.8
%
11.4
%
2,114
24.3
%
618
13.6
%
1,627
2.6
%
Allergy
485
2.2
%
-3.4
%
292
5.8
%
42
-6.7
%
151
-1.9
%
Cough, Cold and Flu
204
-30.9
%
-32.2
%
—
0.0
%
91
-42.4
%
113
-18.2
%
Pain Care
818
7.3
%
2.8
%
144
8.5
%
377
5.3
%
297
9.2
%
Digestive Wellness
855
21.8
%
16.5
%
90
57.4
%
297
6.4
%
468
27.3
%
Physical Wellness
244
-5.7
%
-7.9
%
—
0.0
%
20
5.3
%
224
-6.5
%
Mental Wellness
160
16.8
%
11.9
%
34
5.9
%
78
15.9
%
48
27.5
%
Personal Care
387
2.8
%
-3.0
%
292
3.3
%
3
50.0
%
92
0.0
%
Non-Core / Others
204
-5.8
%
-9.3
%
7
700.0
%
80
-26.2
%
117
6.8
%
Consumer Healthcare
3,357
4.2
%
-0.2
%
859
10.0
%
988
-4.6
%
1,510
7.2
%
Company
27,767
8.2
%
4.2
%
10,565
13.4
%
6,955
5.3
%
10,247
5.0
%
Appendix 2: Business net income statement
Third Quarter 2021
Pharmaceuticals
Vaccines
Consumer Healthcare
Other(1)
Total Group
€ million
Q3 2021
Q3 2020
Change
Q3 2021
Q3 2020
Change
Q3 2021
Q3 2020
Change
Q3 2021
Q3 2020
Change
Q3 2021
Q3 2020
Change
Net sales
6,855
6,361
7.8%
2,422
2,077
16.6%
1,155
1,041
11.0%
—
—
—%
10,432
9,479
10.1%
Other revenues
44
28
57.1%
339
359
-5.6%
14
13
7.7%
—
—
—%
397
400
-0.7%
Cost of Sales
(1,744)
(1,715)
1.7%
(1,017)
(1,018)
-0.1%
(422)
(361)
16.9%
(55)
(65)
-15.4%
(3,238)
(3,159)
2.5%
As % of net sales
(25.4)%
(27.0)%
(42.0)%
(49.0)%
(36.5)%
(34.7)%
(31.0)%
(33.3)%
Gross Profit
5,155
4,674
10.3%
1,744
1,418
23.0%
747
693
7.8%
(55)
(65)
-15.4%
7,591
6,720
13.0%
As % of net sales
75.2%
73.5%
72.0%
68.3%
64.7%
66.6%
72.8%
70.9%
Research and development expenses
(1,104)
(980)
12.7%
(185)
(178)
3.9%
(35)
(37)
-5.4%
(119)
(126)
-5.6%
(1,443)
(1,321)
9.2%
As % of net sales
(16.1)%
(15.4)%
(7.6)%
(8.6)%
(3.0)%
(3.6)%
(13.8)%
(13.9)%
Selling and general expenses
(1,281)
(1,151)
11.3%
(198)
(193)
2.6%
(327)
(330)
-0.9%
(461)
(508)
-9.3%
(2,267)
(2,182)
3.9%
As % of net sales
(18.7)%
(18.1)%
(8.2)%
(9.3)%
(28.3)%
(31.7)%
(21.7)%
(23.0)%
Other current operating income/expenses
(329)
(190)
2
(2)
77
(3)
(39)
13
(289)
(182)
Share of profit/loss of associates* and joint ventures
(5)
(1)
(3)
2
3
—
—
—
(5)
1
Net income attributable to non controlling interests
(27)
(8)
(1)
—
(1)
(1)
—
—
(29)
(9)
Business operating income (2)
2,409
2,344
2.8%
1,359
1,047
29.8%
464
322
44.1%
(674)
(686)
-1.7%
3,558
3,027
17.5%
As % of net sales
35.1%
36.8%
56.1%
50.4%
40.2%
30.9%
34.1%
31.9%
Financial income and expenses
(85)
(76)
Income tax expenses
(737)
(652)
Tax rate**
21.0%
22.0%
Business net income
2,736
2,299
19.0%
As % of net sales
26.2%
24.3%
Business earnings / share(in euros)***
2.18
1.83
19.1%
* Net of tax.
** Determined on the basis of Business income before tax, associates, and non-controlling interests.
*** Based on an average number of shares outstanding of 1,254.5 million in the third quarter of 2021 and 1,255.7 million in the third quarter of 2020.
(1) Other includes the cost of global support functions (Finance, Human Resources, Information Solution & Technologies, Sanofi Business Services, etc…).
(2) The 2020 items have been represented in order to take into account the reallocation of certain expenses, in particular the IT costs related to the new Digital organization, which were previously allocated to the Pharmaceuticals, Vaccines and Consumer Health Care segments and are now accounted for under "Other".
9 months 2021
Pharmaceuticals
Vaccines
Consumer Healthcare
Other(1)
Total Group
€ million
9M 2021
9M 2020
Change
9M 2021
9M 2020
Change
9M 2021
9M 2020
Change
9M 2021
9M 2020
Change
9M 2021
9M 2020
Change
Net sales
20,051
19,381
3.5%
4,359
3,913
11.4%
3,357
3,365
(0.2)%
—
—
—
27,767
26,659
4.2%
Other revenues
152
98
55.1%
800
833
(4.0)%
41
43
(4.7)%
—
—
—
993
974
2.0%
Cost of Sales
(5,147)
(5,121)
0.5%
(2,271)
(2,194)
3.5%
(1,175)
(1,142)
2.9%
(186)
(209)
(11.0)%
(8,779)
(8,666)
1.3%
As % of net sales
(25.7)%
(26.4)%
(52.1)%
(56.1)%
(35.0)%
(33.9)%
—%
(31.6)%
(32.5)%
Gross Profit
15,056
14,358
4.9%
2,888
2,552
13.2%
2,223
2,266
(1.9)%
(186)
(209)
(11.0)%
19,981
18,967
5.3%
As % of net sales
75.1%
74.1%
66.3%
65.2%
66.2%
67.3%
—
72.0%
71.1%
Research and development expenses
(3,145)
(3,045)
3.3%
(501)
(497)
0.8%
(104)
(106)
(1.9)%
(356)
(365)
(2.5)%
(4,106)
(4,013)
2.3%
As % of net sales
(15.7)%
(15.7)%
(11.5)%
(12.7)%
(3.1)%
(3.2)%
—
(14.8)%
(15.1)%
Selling and general expenses
(3,761)
(3,539)
6.3%
(557)
(562)
(0.9)%
(1,027)
(1,074)
(4.4)%
(1,452)
(1,614)
(10.0)%
(6,797)
(6,789)
0.1%
As % of net sales
(18.8)%
(18.3)%
(12.8)%
(14.4)%
(30.6)%
(31.9)%
—
(24.5)%
(25.5)%
Other current operating income/expenses
(795)
(340)
123
2
100
18
(17)
(117)
(589)
(437)
Share of profit/loss of associates* and joint ventures
8
3
5
2
8
7
—
—
21
12
Net income attributable to non controlling interests
(43)
(25)
(1)
—
(5)
(5)
—
—
(49)
(30)
Business operating income (2)
7,320
7,412
(1.2)%
1,957
1,497
30.7%
1,195
1,106
8.0%
(2,011)
(2,305)
(12.8)%
8,461
7,710
9.7%
As % of net sales
36.5%
38.2%
44.9%
38.3%
35.6%
32.9%
30.5%
28.9%
Financial income and expenses
(246)
(243)
Income tax expenses
(1,731)
(1,647)
Tax rate**
21.0%
22.0%
Business net income
6,484
5,820
11.4%
As % of net sales
23.4%
21.8%
Business earnings / share(in euros)***
5.18
4.64
11.6%
* Net of tax.
** Determined on the basis of Business income before tax, associates, and non-controlling interests.
*** Based on an average number of shares outstanding of 1,251.7 million in the first nine months of 2021 and 1,253 million in the first nine months of 2020.
(1) Other includes the cost of global support functions (Finance, Human Resources, Information Solution & Technologies, Sanofi Business Services, etc…).
(2) The 2020 items have been represented in order to take into account the reallocation of certain expenses, in particular the IT costs related to the new Digital organization, which were previously allocated to the Pharmaceuticals, Vaccines and Consumer Health Care segments and are now accounted for under "Other".
Appendix 3: Consolidated income statements
€ million
Q3 2021
Q3 2020
9M 2021
9M 2020
Net sales
10,432
9,479
27,767
26,659
Other revenues
397
400
993
974
Cost of sales
(3,238)
(3,176)
(8,779)
(8,719)
Gross profit
7,591
6,703
19,981
18,914
Research and development expenses
(1,443)
(1,321)
(4,106)
(4,013)
Selling and general expenses
(2,267)
(2,182)
(6,797)
(6,789)
Other operating income
259
242
668
523
Other operating expenses
(548)
(424)
(1,257)
(1,117)
Amortization of intangible assets
(385)
(404)
(1,160)
(1,287)
Impairment of intangible assets (1)
1
(2)
(177)
(325)
Fair value remeasurement of contingent consideration
5
22
1
76
Restructuring costs and similar items
(167)
(110)
(494)
(868)
Other gains and losses, and litigation (2)
(4)
—
(4)
136
Gain on Regeneron investment as result of transaction completed on May 29th, 2020 (3)
—
—
—
7,382
Operating income
3,042
2,524
6,655
12,632
Financial expenses
(87)
(91)
(276)
(289)
Financial income
2
15
30
46
Income before tax and associates and joint ventures
2,957
2,448
6,409
12,389
Income tax expense
(609)
(490)
(1,291)
(1,484)
Share of profit/(loss) of associates and joint ventures
(5)
1
21
355
Net income
2,343
1,959
5,139
11,260
Net income attributable to non-controlling interests
26
7
46
27
Net income attributable to equity holders of Sanofi
2,317
1,952
5,093
11,233
Average number of shares outstanding (million)
1,254.5
1,255.7
1,251.7
1,253.0
IFRS Earnings per share (in euros)
1.85
1.55
4.07
8.96
(1) In 2021 and 2020, mainly related to Sutimlimab impairments.
(2) In 2020, includes mainly the gain on the sale of operations related to the Seprafilm product to Baxter.
(3) In 2020, this line includes the pre-tax income from the sale of Regeneron shares following the public offer for sale and Regeneron's repurchase on May 29, 2020. This amount includes the gain related to the remeasurement at fair value of the 400,000 retained shares that could be used to finance the R&D collaboration under the letter of agreement dated 2018.
Appendix 4: Reconciliation of Net income attributable to equity holders of Sanofi to Business net income
€ million
Q3 2021
Q3 2020
9M 2021
9M 2020
Net income attributable to equity holders of Sanofi
2,317
1,952
5,093
11,233
Amortization of intangible assets (1)
385
404
1,160
1,287
Impairment of intangible assets (2)
(1)
2
177
325
Fair value remeasurement of contingent consideration
(5)
(22)
(1)
(76)
Expenses arising from the impact of acquisitions on inventories
—
17
—
53
Restructuring costs and similar items
167
110
494
868
Other gains and losses, and litigation (3)
4
—
4
(136)
Gain on sale of Regeneron shares on May 29, 2020 (4)
—
—
—
(7,225)
Tax effect of the items listed above:
(129)
(162)
(440)
(163)
Amortization and impairment of intangible assets
(90)
(122)
(320)
(424)
Fair value remeasurement of contingent consideration
(1)
(1)
2
1
Expenses arising from the impact of acquisitions on inventories
—
(3)
—
(8)
Restructuring costs and similar items
(37)
(29)
(121)
(261)
Gain on sale of Regeneron shares on May 29, 2020
—
—
—
475
Other tax effects
(1)
(7)
(1)
54
Share of items listed above attributable to non-controlling interests
(2)
(2)
(3)
(3)
Restructuring costs of associates and joint ventures, and expenses arising from the impact of acquisitions on associates and joint ventures
—
—
—
(30)
Effect of discontinuation of use of equity method for Regeneron investment (5)
—
—
—
(313)
Business net income
2,736
2,299
6,484
5,820
IFRS earnings per share (6) (in euros)
1.85
1.55
4.07
8.96
(1) Of which related to amortization expense generated by the remeasurement of intangible assets as part of business combinations: €361 million in the third quarter of 2021 and €383 million in the third quarter of 2020.
(2) In 2021 and 2020, mainly related to Sutimlimab impairments.
(3) In 2020, includes mainly the gain on the sale of operations related to the Seprafilm product to Baxter.
(4) This line includes the result of the sale of 13 million of Regeneron’s shares as part of the public offering and of the 9.8 million of its shares repurchased by Regeneron. The amount does not include the gain related to the remeasurement at fair value at this date of the 400,000 retained shares.
(5) Our non-GAAP indicator (Business Net Income) does not include the share of income related to equity accounting from Regeneron since it ceased to be an associate on May 29, 2020. As a result, this line reflects that exclusion up to this date.
(6) Q3: Based on an average number of shares outstanding of 1,254.5 million in the third quarter of 2021 and 1,255.7 million in the third quarter of 2020.
9M : Based on an average number of shares outstanding of 1,251.7 million in the first nine months of 2021 and 1,253 million in the first nine months of 2020.
Appendix 5: Change in net debt
€ million
9M 2021
9M 2020
(1)
Business net income
6,484
5,820
Depreciation & amortization & impairment of property, plant and equipment and software
1,102
1,125
Other items
117
592
Operating cash flow
7,703
7,537
Changes in Working Capital
218
(933)
Acquisitions of property, plant and equipment and software
(953)
(847)
Free cash flow before restructuring, acquisitions and disposals
6,968
5,757
Acquisitions of intangibles assets, investments and other long-term financial assets (2)
(1,093)
(447)
Restructuring costs and similar items paid
(781)
(660)
Proceeds from disposals of property, plant and equipment, intangible assets and other non-current assets net of taxes (2)
461
802
Free cash flow
5,555
5,452
Acquisitions of investments in consolidated undertakings including
assumed debt (3)
(3,385)
(5,767)
Proceeds from Sale of Regeneron Shares on May 29,2020 net of taxes
—
10,332
Issuance of Sanofi shares
175
194
Acquisition of treasury shares
(140)
(361)
Dividends paid to shareholders of Sanofi
(4,008)
(3,937)
Other items
166
(450)
Change in net debt
(1,637)
5,463
Beginning of period
8,790
15,107
Closing of net debt
10,427
9,644
(1) Excluding any effect of equity method accounting for Regeneron investment for comparison purposes.
(2) Free cash flow includes investments and divestments not exceeding a cap of €500 million per transaction (inclusive of all payments related to the transaction).
(3) Includes transactions that are above a cap of €500 million per transaction (inclusive of all payments related to the transaction).
Appendix 6: Currency sensitivity
2021 business EPS currency sensitivity
Currency
Variation
Business EPS Sensitivity
U.S. Dollar
+0.05 USD/EUR
-EUR 0.13
Japanese Yen
+5 JPY/EUR
-EUR 0.02
Chinese Yuan
+0.2 CNY/EUR
-EUR 0.02
Brazilian Real
+0.4 BRL/EUR
-EUR 0.01
Russian Ruble
+10 RUB/EUR
-EUR 0.02
Currency exposure on Q3 2021 sales
Currency
Q3 2021
US $
43.8
%
Euro €
20.1
%
Chinese Yuan
7.1
%
Japanese Yen
3.9
%
Brazilian Real
1.7
%
Canadian $
1.6
%
British Pound
1.5
%
Mexican Peso
1.3
%
Russian ruble
1.3
%
South Korean won
1.1
%
Others
16.6
%
Currency average rates
Q3 2020
Q3 2021
Change
9M 2020
9M 2021
Change
€/$
1.17
1.18
+0.8
%
1.12
1.20
+6.5
%
€/Yen
124.05
129.79
+4.6
%
120.84
129.80
+7.4
%
€/Yuan
8.09
7.63
-5.7
%
7.87
7.74
-1.60
%
€/Real
6.29
6.16
-2.0
%
5.71
6.38
+11.8
%
€/Ruble
86.28
86.60
+0.4
%
79.87
88.60
+10.9
%
Appendix 7: Definitions of non-GAAP financial indicators
Company sales at constant exchange rates (CER)
When we refer to changes in our net sales “at constant exchange rates” (CER), this means that we exclude the effect of changes in exchange rates.
We eliminate the effect of exchange rates by recalculating net sales for the relevant period at the exchange rates used for the previous period.
Reconciliation of net sales to Company sales at constant exchange rates for the third quarter and In the first nine months 2021
€ million
Q3 2021
9M 2021
Net sales
10,432
27,767
Effect of exchange rates
—
(1,075)
Company sales at constant exchange rates
10,432
28,842
Business net income
Sanofi publishes a key non-GAAP indicator. Following the Regeneron shares transaction that was completed on May 29, 2020, the definition of the non-GAAP financial measure “Business net income” has been revised such that Share of profit/(loss) from investments accounted for using the equity method excludes the effects of applying the equity method to the investment in Regeneron. The comparative periods of 2019 presented have been restated to reflect that adjustment.
Business net income is defined as net income attributable to equity holders of Sanofi excluding:
amortization of intangible assets,
impairment of intangible assets,
fair value remeasurement of contingent consideration related to business combinations or to disposals,
other impacts associated with acquisitions (including impacts of acquisitions on associates and joint ventures),
restructuring costs and similar items(1),
other gains and losses (including gains and losses on disposals of non-current assets(1)),
costs or provisions associated with litigation(1),
gain on Regeneron investment as a result of the transaction completed on May 29, 2020 (the amount does not include the gain related to the remeasurement at fair value at this date of the 400,000 retained shares),
tax effects related to the items listed above as well as effects of major tax disputes,
effect of equity method accounting for Regeneron investment (excluded from Business net income as a consequence of the sale of the entire equity investment in Regeneron (with the exception of 400,000 shares retained by Sanofi) on May 29th 2020,
net income attributable to non-controlling interests related to the items listed above.
(1) Reported in the line items Restructuring costsand similar items and Gains and losses on disposals, and litigation, which are defined in Notes B.19. and B.20. to our consolidated financial statements.
Free cash flow
Free cash flow is a non-GAAP financial indicator which is reviewed by our management, and which we believe provides useful information to measure the net cash generated from the Company’s operations that is available for strategic investments1 (net of divestments1), for debt repayment, and for capital return to shareholders. Free Cash Flow is determined from the Business Net Income adjusted for depreciation, amortization and impairment, share of profit/loss in associates and joint ventures net of dividends received, gains & losses on disposals, net change in provisions including pensions and other post-employment benefits, deferred taxes, share-based expense and other non-cash items. It comprises net changes in working capital, capital expenditures and other asset acquisitions2 net of disposal proceeds2, and payments related to restructuring and similar items. Free cash flow is not defined by IFRS and it is not a substitute measure for the IFRS aggregate net cash flows in operating activities.
1 Amount of the transaction above a cap of €500 million per transaction (inclusive of all payments related to the transaction).
2 Not exceeding a cap of €500 million per transaction (inclusive of all payments related to the transaction).
1See Appendix 7 for definitions of financial indicators.
2Sanofi has prioritized core assets in its General Medicines portfolio with differentiated and/or established profiles that have significant opportunity for growth in key markets. Core assets include Toujeo, Soliqua, Praluent, Multaq, Lovenox, Plavix and others for total sales of €5.6bn in 2020
3API and Drug Product manufacturing in Sanofi sites for third party
4 Announced on September 8, 2021; Subject to satisfaction or waiver of customary closing conditions, Sanofi expects to complete the acquisition in Q4 2021
5Net zero is achieved when company emissions of greenhouse gases to the atmosphere are balanced by removals elsewhere over a specified period.
6Carbon neutrality is achieved when company emissions of greenhouse gases to the atmosphere are balanced by reduction or avoidance elsewhere over a specified period.
7RE100 is a global initiative bringing together the world's most influential businesses committed to 100% renewable electricity
8See Appendix 3 for 2021 third-quarter consolidated income statement; see Appendix 7 for definitions of financial indicators, and Appendix 4 for reconciliation of IFRS net income reported to business net income.
9Not exceeding €500 million per transaction (inclusive of all payments related to the transaction).
10non-GAAP financial measure (definition in Appendix 7).
Attachment
Press Release Q3 2021
基因疗法财报抗体孤儿药突破性疗法
100 项与 吸附无细胞百白破联合疫苗(赛诺菲) 相关的药物交易
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研发状态
10 条最早获批的记录, 后查看更多信息
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| 白喉 | 奥地利 | 2002-06-12 | |
| 白喉 | 比利时 | 2002-06-12 | |
| 白喉 | 保加利亚 | 2002-06-12 | |
| 白喉 | 克罗地亚 | 2002-06-12 | |
| 白喉 | 捷克 | 2002-06-12 | |
| 白喉 | 丹麦 | 2002-06-12 | |
| 白喉 | 芬兰 | 2002-06-12 | |
| 白喉 | 法国 | 2002-06-12 | |
| 白喉 | 德国 | 2002-06-12 | |
| 白喉 | 希腊 | 2002-06-12 | |
| 白喉 | 匈牙利 | 2002-06-12 | |
| 白喉 | 冰岛 | 2002-06-12 | |
| 白喉 | 爱尔兰 | 2002-06-12 | |
| 白喉 | 意大利 | 2002-06-12 | |
| 白喉 | 卢森堡 | 2002-06-12 | |
| 白喉 | 挪威 | 2002-06-12 | |
| 白喉 | 波兰 | 2002-06-12 | |
| 白喉 | 罗马尼亚 | 2002-06-12 | |
| 白喉 | 斯洛伐克 | 2002-06-12 | |
| 白喉 | 斯洛文尼亚 | 2002-06-12 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床2/3期 | 110 | Tdap Vaccine | 選構餘鬱壓襯餘製鬱夢 = 壓獵糧壓繭築醖鹽蓋繭 鑰鬱膚艱鑰繭繭鹽製積 (艱積鏇鬱廠窪膚壓鹽築, 夢壓遞遞淵顧獵繭艱鑰 ~ 獵蓋簾網淵鹹窪選壓糧) 更多 | - | 2022-12-06 | ||
临床2期 | 1,715 | Meningococcal Polysaccharide (Serogroups A, C, Y, and W13 (Group 1: MenACYW Conjugate Vaccine) | 選夢壓鹽壓鹽齋艱構艱 = 獵網淵壓願鏇夢積網糧 窪築簾餘網襯範醖範簾 (夢製願鑰鹹範餘觸醖鏇, 鑰簾夢餘淵艱觸蓋廠範 ~ 襯餘襯願鹽廠鏇鑰積憲) 更多 | - | 2020-06-09 | ||
W135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine+Meningococcal (Groups A, C, Y and W135) Oligosaccharide (Group 2: MENVEO® Vaccine) | 選夢壓鹽壓鹽齋艱構艱 = 積夢膚壓顧鑰醖製鑰鹽 窪築簾餘網襯範醖範簾 (夢製願鑰鹹範餘觸醖鏇, 遞構衊醖齋範繭鏇遞齋 ~ 鹹願簾夢醖淵簾範鹹簾) 更多 | ||||||
临床4期 | 1,330 | Adacel Vaccine (Adacel Vaccine) | 鑰鹹醖衊淵遞遞衊鑰觸 = 願窪鑰遞簾鑰糧鏇繭積 夢獵壓繭獵襯獵鏇醖鬱 (繭觸餘淵夢衊範糧鬱製, 願糧遞鏇鑰窪鹹壓窪顧 ~ 範衊醖鹹齋醖齋糧窪觸) 更多 | - | 2017-10-09 | ||
Td (Td Adsorbed Vaccine) | 鑰鹹醖衊淵遞遞衊鑰觸 = 淵遞窪繭餘鬱遞願範糧 夢獵壓繭獵襯獵鏇醖鬱 (繭觸餘淵夢衊範糧鬱製, 醖膚構鑰壓蓋遞積獵簾 ~ 齋糧艱衊鹽齋構製鏇淵) 更多 | ||||||
临床4期 | 1,302 | (Participants 10 to <11 Years of Age) | 製鏇築繭鏇壓構壓繭觸(憲繭築膚遞窪願鹽鏇淵) = 鑰壓範憲簾築廠繭簾鑰 遞廠廠簾齋網衊構鹹鹽 (獵蓋膚齋蓋衊製鏇糧築, 鹹觸淵襯齋構廠鏇醖齋 ~ 廠觸積願範製膚襯窪簾) 更多 | - | 2016-04-08 | ||
(Participants 11 to <12 Years of Age) | 製鏇築繭鏇壓構壓繭觸(憲繭築膚遞窪願鹽鏇淵) = 構窪繭蓋鹽膚獵築積齋 遞廠廠簾齋網衊構鹹鹽 (獵蓋膚齋蓋衊製鏇糧築, 蓋餘夢製醖積遞構願製 ~ 願糧壓構遞鬱壓衊膚餘) 更多 | ||||||
临床3期 | 534 | 範顧壓淵鹹鬱願壓簾廠 = 鏇製窪築壓膚製顧衊範 積餘壓構衊夢淵鬱網膚 (範觸艱廠廠鹽鹹壓製鏇, 顧膚鹹製顧壓糧顧構壓 ~ 襯夢範鏇獵糧築淵範夢) 更多 | - | 2015-10-08 | |||
(DT Group) | 範顧壓淵鹹鬱願壓簾廠 = 衊壓鏇齋觸獵製糧壓網 積餘壓構衊夢淵鬱網膚 (範觸艱廠廠鹽鹹壓製鏇, 齋衊簾衊築鹽範觸醖鏇 ~ 廠艱顧鑰齋廠醖構網積) 更多 | ||||||
临床4期 | 769 | (Group 1: Previous Tdap or Tdap-IPV Recipients) | 淵餘衊餘構獵獵築鏇蓋 = 餘醖醖壓衊窪糧艱構憲 繭顧鬱廠觸網獵顧壓壓 (膚憲範艱繭淵鹹齋餘夢, 鑰觸獵鏇鹽觸觸鏇獵獵 ~ 繭鏇艱糧鬱夢齋齋鏇夢) 更多 | - | 2014-04-30 | ||
(Group 2: Tdap Vaccine-naïve) | 淵餘衊餘構獵獵築鏇蓋 = 艱鏇製簾鬱齋鑰鑰憲憲 繭顧鬱廠觸網獵顧壓壓 (膚憲範艱繭淵鹹齋餘夢, 鏇繭網獵糧遞鹹鹹獵觸 ~ 遞襯膚製糧蓋遞鬱醖範) 更多 | ||||||
临床1期 | 40 | ADACEL™ Vaccine (ADACEL™ Vaccine Group 1) | 壓鹽構範鹹鹽繭築網蓋 = 廠積網壓觸遞餘網網鹹 壓窪襯齋簾構獵醖積蓋 (鹽襯淵鹽築衊齋齋鹹醖, 觸網蓋簾窪餘願夢網襯 ~ 膚糧衊醖淵遞鏇顧壓淵) 更多 | - | 2014-04-21 | ||
ADACEL™ Vaccine (ADACEL™ Vaccine Group 2) | 壓鹽構範鹹鹽繭築網蓋 = 簾餘積壓壓鹹築範顧範 壓窪襯齋簾構獵醖積蓋 (鹽襯淵鹽築衊齋齋鹹醖, 窪壓襯夢鹹選遞構餘顧 ~ 鏇鏇簾窪壓鑰獵襯獵鏇) 更多 | ||||||
临床1/2期 | 43 | 憲遞鏇壓鹽糧築顧選繭 = 蓋夢積築鹹窪鬱遞夢獵 範艱鏇觸選簾製範夢鹹 (窪構糧醖蓋襯顧醖衊壓, 獵鹽鏇積鏇選獵艱衊繭 ~ 選淵繭醖範衊觸積襯糧) 更多 | - | 2014-02-21 | |||
临床4期 | 423 | (Adacel® Vaccine Group) | 構鑰艱蓋構餘膚顧鏇糧 = 構窪獵憲膚艱蓋鬱構鹽 醖齋餘遞鹽積艱齋鏇壓 (壓鬱艱範鬱選選鏇鏇壓, 窪獵鹹壓齋繭鏇願觸觸 ~ 選蓋網齋築淵糧鏇築繭) 更多 | - | 2013-10-21 | ||
(BOOSTRIX® Vaccine Group) | 構鑰艱蓋構餘膚顧鏇糧 = 簾構蓋醖壓鑰選積壓夢 醖齋餘遞鹽積艱齋鏇壓 (壓鬱艱範鬱選選鏇鏇壓, 夢簾鬱簾遞鏇鬱構構蓋 ~ 範淵遞構觸選構築範網) 更多 | ||||||
临床4期 | 1,564 | (ADACEL® Vaccine Group) | 齋醖網網衊簾鑰製願製(獵積鏇鏇積構鏇膚壓築) = 積獵鬱壓廠糧廠簾鏇簾 糧鏇憲衊淵範餘鏇獵糧 (顧遞醖齋簾製築鹹廠鏇, 窪築網壓憲餘鹽積蓋衊 ~ 願範範築網襯製餘廠鹹) 更多 | - | 2012-10-19 | ||
(DECAVAC® Vaccine Group) | 齋醖網網衊簾鑰製願製(獵積鏇鏇積構鏇膚壓築) = 窪餘選遞積遞遞願壓構 糧鏇憲衊淵範餘鏇獵糧 (顧遞醖齋簾製築鹹廠鏇, 鹽齋糧願艱積遞醖淵艱 ~ 蓋顧淵鏇淵範築壓廠餘) 更多 |
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