CES1

这种递送系统由于设计了CES1特异性剪切片段，可以有效在肝细胞的胞质内响应CES1酶切，释放Cas9-mRNA 启动Cas9蛋白表达，在核定微信号肽（NLS肽）引导下携带sgRNA入核进行基因编辑。 心血管疾病是高患病率、高致残率和高死亡率的常见病，降脂抗炎的药物治疗是心血管疾病的主要治疗方式。以CRISPR-Cas9为代表的基因组编辑技术由于其简单、灵活和高效性，有望实现一次性治愈遗传疾病。此外，基于CRISPR基因编辑技术的细胞疗法和靶向肝脏的降脂疗法也已经进入临床试验阶段。然而，如何将CRISPR-Cas9组分安全有效地递送和释放到靶器官、细胞及细胞核中，仍然是基因组编辑介导的疾病治疗中面临的主要挑战，这将直接影响该系统的成功和治疗应用。 近日，重庆医科大学于超教授团队在 Advanced Science 期刊发表了题为：CES1‐Triggered Liver‐Specifi Cargo Release of CRISPR/Cas9  Elements  by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration 的研究论文。 该研究建立了一种全新的大分子核酸递送体系，实现了复杂的CRISPR-Cas9基因编辑RNA成分的稳定加载、安全递送和靶向释放。这种新型递送系统，拓展了CRISPR-Cas9基因编辑技术在心血管疾病治疗药物研发领域的应用，突破该类技术的瓶颈，为进一步临床应用奠定了理论基础。 该研究针对PCSK9蛋白靶点设计的CRISPR-Cas9基因编辑的两种RNA组分（Cas9-mRNA和sgRNA）高效稳定地递送进肝细胞，并在胞质内有效释放，首先合成了新型肝细胞特异性的肝酯酶（CES1）响应二甲双胍衍生三元共聚物（mPEG-b-P(Met/n-PMA），该共聚物带有正电荷，通过与带负电荷的Cas9-mRNA/sgRNA自组装形成稳定的纳米递送系统。 这种递送系统由于设计了CES1特异性剪切片段，可以有效在肝细胞的胞质内响应CES1酶切，释放Cas9-mRNA 启动Cas9蛋白表达，在核定微信号肽（NLS肽）引导下携带sgRNA入核进行基因编辑。 研究结果显示，mPEG-b-P(Met/n-PMA)/Cas9-mRNA/sgPCSK9纳米粒在肝细胞中有效积累，显著抑制PCSK9蛋白的表达，并有效降低小鼠血清中低密度脂蛋白胆固醇和总胆固醇水平。 重庆医科大学药学院博士研究生赵云飞、博士后王帆，脂质中心博士后李韵为论文共同第一作者；重庆医科大学药学院于超教授为该文主要通讯作者。

这项研究首次清晰地证明了BACE1可以切割gp130产生sgp130，抑制BACE1的活性会导致BACE1对神经元上gp130的裂解减少，增加神经元上gp130的含量并减少大脑中sgp130的含量，这 阿尔茨海默病（AD）是导致痴呆的重要因素，随着人口老龄化的不断加重，AD已经成为近在眼前的危机。 经典理论认为Aβ沉积是AD的病理原因之一，因此针对性地开发了多款药物。β分泌酶BACE1是将淀粉样前体蛋白（APP）转变为Aβ的催化酶之一，抑制BACE1的活性能够减少Aβ蛋白的产生。 已有多款BACE1抑制剂进入临床试验，它们可以有效地抑制BACE1的活性，并减少大脑以及脑脊液中的Aβ蛋白，但是由于存在包括非进展性认知衰退在内的副作用[1-3]，多数药物止步于2/3期临床试验。目前还不清楚为何BACE1抑制剂会引起患者认知衰退。 近期，由德国神经退行性疾病中心的Stefan F. Lichtenthaler领衔的研究团队，在Molecular Neurodegeneration上发表最新研究成果[4]，揭示了BACE1不为人知的新功能。 他们发现，在非人类灵长类动物以及人类中，BACE1可以切割IL-6受体β亚基（gp130），从而影响神经元中IL-6的信号转导。由于可溶性gp130（sgp130）在健康状态下可以作为一种缓冲体系，防止过度的IL-6信号对神经元造成不利影响，因此长期抑制BACE1使得接受治疗的个体对IL-6信号的不利影响更为敏感。 论文首页截图 由于不同分子结构的BACE1抑制剂均可以引起认知衰退，并且这些药物对中枢神经系统BACE1的活性抑制可以达到75%以上，Lichtenthaler团队猜测这可能是由于过强地抑制了BACE1对某一个或某几个底物的裂解，从而引起神经系统的副作用。 为了寻找可能被BACE1裂解的蛋白，他们收集了3只猕猴在口服BACE1抑制剂MBI-4前后的脑脊液样品，利用质谱寻找差异蛋白质。他们发现服用BACE1抑制剂后，脑脊液中SEZ6、IL6ST（gp130）、VCAM1胞外结构域的丰度以剂量依赖的方式显著降低。其中，SEZ6是已知的BACE1底物；IL6ST是细胞因子受体gp130，已有的研究认为它可能是BACE1底物[5,6]。 为了进一步确认上述的发现，他们又进行了一次独立实验，给猕猴服用正在进行临床试验的BACE1抑制剂verubecestat，检测其脑脊液中含量变化的蛋白质。结果显示，服用verubecestat后，脑脊液中的SEZ6、CACHD1、LRRN1、L1CAM和sgp130表现出剂量依赖性的减少。 以上两次实验均表明，抑制BACE1的活性能够减少sgp130，提示gp130是一种潜在的BACE1底物。 gp130可能是BACE1的底物 为了探究上述现象在人类中是否也存在，Lichtenthaler团队收集了健康年轻人服用BACE1抑制剂verubecestat前后的脑脊液样品，通过WB以及ELISA检测脑脊液中的SEZ6以及sgp130的含量。 结果显示，服用verubecestat后，人类脑脊液中SEZ6以及sgp130的含量显著减少。这些数据提示，SEZ6和sgp130可以作为BACE1的药效学活性标记物。 既然来自非人灵长类以及人类志愿者的数据均表明gp130可能是BACE1的底物，那么接下来就是要证实BACE1是否真能够切割gp130。通过体外实验，Lichtenthaler团队直接地证实BACE1确实能够切割膜结合型gp130产生sgp130。 基于小鼠原代神经元的实验也表明，在活体神经元中BACE1确实可以切割gp130产生sgp130。 BACE1对gp130的体外切割作用 由于gp130介导IL-6的下游信号转导，且sgp130能够抑制IL-6的反式信号，因此Lichtenthaler团队想知道抑制BACE1的活性，是否会通过影响sgp130的丰度，从而影响神经元对IL-6的应答。 为此，他们使用小鼠原代神经元进行实验，使用IL-6和IL6R复合物（H-IL-6）刺激神经元，通过添加C3来抑制BACE1的活性。结果显示，抑制BACE1后，IL-6下游的STAT3磷酸化水平显著升高。 这可能是因为抑制BACE1活性后，细胞膜上的gp130增加，因此增强了IL-6的下游信号转导。如果将H-IL-6与sgp130共孵育一段时间再添加至培养基中，神经元中STAT3的磷酸化水平会显著降低，这表明sgp130可以与膜结合型gp130竞争性结合H-IL-6，从而阻碍神经元响应IL-6刺激。 在兴奋性毒性以及生长因子缺乏的情况下，gp130信号对神经元具有保护作用，因此研究团队使用不完全培养基培养小鼠原代神经元，比较添加或不添加BACE1抑制剂C3的情况下，H-IL-6对神经元的保护作用。结果显示，抑制BACE1提高了神经元对H-IL-6的敏感性，使更多的神经元存活下来。 综合上述数据，抑制BACE1的活性不仅可以减少gp130的切割，增强神经元向下游转导IL-6信号的能力，还能够减少sgp130的产生，减少对IL-6反式信号的抑制。这两方面的作用都能够提高神经元对IL-6信号的敏感性。 然而，IL-6对神经系统来说是一把双刃剑，虽然在正常发育过程中IL-6可以促进神经发生并促进神经元存活，但是IL-6信号的过度激活会对神经系统造成损伤[7]。考虑到AD患者血清中IL-6的浓度高于健康人，抑制BACE1提高神经元对IL-6的敏感性对AD患者来说可能并不一定是一件好事。 抑制BACE1能够影响神经元中IL-6反式信号转导 总的来说，这项研究首次清晰地证明了BACE1可以切割gp130产生sgp130，抑制BACE1的活性会导致BACE1对神经元上gp130的裂解减少，增加神经元上gp130的含量并减少大脑中sgp130的含量，这会导致神经元对IL-6信号更加敏感。 考虑到已有的研究显示，IL-6信号的过度激活与AD的认知功能下降有关[7]，因此，BACE1活性的强烈抑制可能会通过增强神经元对IL-6信号的敏感性，而导致患者认知能力受损。 Lichtenthaler团队的这一发现，对于BACE1抑制剂的临床开发具有重大意义。例如，可以将临床3期试验中脑脊液或者血液中sgp130减少的程度，与患者的认知衰退幅度进行联合分析，借此寻找到一个安全的sgp130含量范围，针对性地减少BACE1抑制剂的用量。而且，已经有临床前研究表明，将BACE1的活性降低50%或者更少仍然能够减少淀粉样斑块的增加[9]。 因此，或许可以找到一个用药方案，既能减少淀粉样斑块也能避免治疗带来的严重副作用。 参考文献： 1. McDade E, Voytyuk I, Aisen P , Bateman RJ, Carrillo MC, De Strooper B, et al The case for low‑level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021;17(11):703–14. 2. Henley D, Raghavan N, Sperling R, Aisen P , Raman R, Romano G. Prelimi‑ nary results of a trial of Atabecestat in preclinical Alzheimer’s disease. N Engl J Med. 2019;380(15):1483–5. 3. Wessels AM, Lines C, Stern RA, Kost J, Voss T, Mozley LH, et al Cognitive outcomes in trials of two BACE inhibitors in Alzheimer’s disease. Alzhei‑ mers Dement. 2020;16(11):1483–92. 4. Müller SA, Shmueli MD, Feng X, et al. The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener. 2023;18(1):13. Published 2023 Feb 21. doi:10.1186/s13024-023-00596-6 5. Stutzer I, Selevsek N, Esterhazy D, Schmidt A, Aebersold R, Stoffel M.Systematic proteomic analysis identifies beta‑site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta‑cells. J Biol Chem. 2013;288(15):10536–47. 6. Hemming ML, Elias JE, Gygi SP , Selkoe DJ. Identification of β‑secretase (BACE1) substrates using quantitative proteomics. PLoS One.2010;4(12):e8477. 7. Lyra ESNM, Goncalves RA, Pascoal TA, Lima‑Filho RAS, Resende EPF , Vieira ELM, et al Pro‑inflammatory interleukin‑6 signaling links cogni‑ tive impairments and peripheral metabolic alterations in Alzheimer’s disease. Transl Psychiatry. 2021;11(1):251 8. McDade E, Voytyuk I, Aisen P , Bateman RJ, Carrillo MC, De Strooper B, et al The case for low‑level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021;17(11):703–14

Low risk for drug-drug interactions with bemnifosbuvir based upon results from in vitro metabolism and transporter studies Bemnifosbuvir retains activity against all SARS-CoV-2 variants of concern evaluated as well as other human coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-1 Favorable absorption, distribution, metabolism, and excretion profile demonstrated for bemnifosbuvir Synergistic antiviral effect observed for the combination of bemnifosbuvir and ruzasvir against HCV in vitro BOSTON, March 14, 2023 (GLOBE NEWSWIRE) -- Atea Pharmaceuticals, Inc. (Nasdaq: AVIR) (“Atea”), a clinical-stage biopharmaceutical company engaged in the discovery and development of oral direct acting therapeutics for serious viral diseases, today announced the presentation of new Phase 1, in vitro and in vivo data that demonstrate key profile attributes of Atea’s lead drug candidate, bemnifosbuvir, for the treatment of COVID-19 and hepatitis C (HCV). Additionally, new data for AT-752 for dengue and a nucleotide analogue are being presented. These results are being presented at the 36th International Conference on Antiviral Research (ICAR 2023) taking place March 13-17, 2023 in Lyon, France. Key highlights of the presentations include results from a Phase 1 human absorption, distribution, metabolism, and excretion (ADME) study for bemnifosbuvir demonstrating a favorable ADME profile supportive of the dosing regimen used in SUNRISE-3, a global, multicenter Phase 3 registrational trial for the treatment of COVID-19. In vitro metabolism and transporter interaction studies showed bemnifosbuvir has a low risk for interactions with medicines commonly prescribed to patients at risk for COVID-19 progression and for those with HCV infection. In vitro studies also demonstrated advantages of bemnifosbuvir’s mechanism of action, which targets conserved regions of the viruses that cause COVID-19 and HCV infection. These advantages include a higher barrier to resistance and maintenance of antiviral activity in the presence of COVID-19 variants. Additionally, the combination of bemnifosbuvir and ruzasvir for the treatment of HCV demonstrated potent in vitro synergistic antiviral activity and in vivo preclinical safety without adverse interactions. “As COVID-19 becomes endemic, it is essential to have new oral antiviral medicines that are safe, well tolerated and address the current limitations of existing treatments,” said Bruno Canard, Ph.D., lead investigator of the in vitro studies of bemnifosbuvir conducted at Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille University. “The data presented at ICAR demonstrate bemnifosbuvir’s unique metabolic activation pathway and how it inhibits enzymes essential to the viral replication of COVID-19 and HCV and its potential to play an important role in the treatment of these serious viral diseases.” Bemnifosbuvir is an investigational, oral, direct-acting antiviral being evaluated in the Phase 3 SUNRISE-3 trial for the treatment of COVID-19 in non-hospitalized patients at high risk for disease progression, and in Phase 2 development for the treatment of HCV in combination with ruzasvir, an oral NS5A inhibitor. “As we continue to advance late-stage development of bemnifosbuvir, these data demonstrate that our lead compound has the potential to improve the current standard of care and address key unmet needs and limitations for patients with COVID-19 and HCV,” said Jean-Pierre Sommadossi, PhD, Chief Executive Officer and Founder of Atea Pharmaceuticals. “These data support a favorable safety and drug interaction profile of bemnifosbuvir to treat these conditions and to provide vulnerable patients with another therapeutic option.” COVID-19 Oral Presentation Number: 019 Date/Time: Wednesday, March 15 from 10:35 am-10:45 am CET Title: Bemnifosbuvir (BEM, AT-527) a Potent Inhibitor of SARS-CoV-2 Variants of Concern (VOC), and a Promising Oral Antiviral with a High Resistance Barrier for Treatment of COVID-19 and other Coronaviruses Infections In vitro results demonstrate that bemnifosbuvir is a potent inhibitor of all tested SARS-CoV-2 variants of concern as well as other human coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-1. Results from an in vitro resistance study conducted with the surrogate virus HCoV-229E in Huh7 cells suggest that bemnifosbuvir may have a high barrier to drug resistance during treatment of COVID-19 and other coronavirus infections. Bemnifosbuvir Oral Presentation Number: 047Date/Time: Thursday, March 16 from 5:20-5:30 pm CETTitle: Five Cellular Enzymes in the Activation Pathway of Bemnifosbuvir, a Drug Candidate Against SARS-CoV-2 Infections Results from this in vitro study showed that bemnifosbuvir required a minimal set of 5 cellular enzymes (Cat/CES1, HINT1, ADALP1, GUK1, and NDPK) to be metabolized to its active triphosphate form, AT-9010, with an obligate order of reactions, as demonstrated by functional and structural data at each step. In vitro, AT-9010 inhibits enzymes essential to viral replication such as the SARS-CoV-2 bi-functional nsp12 RNA polymerase/nucleotidyltransferase, the dengue virus bi-functional NS5 RNA polymerase/RNA methyltransferase, and the HCV NS5B RNA polymerase. Poster Number: 537Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: Low Risk of Drug-Drug Interactions (DDIs) for Bemnifosbuvir (BEM) Based Upon In Vitro Metabolism and Transporter Interaction Studies Results from these in vitro studies suggest that bemnifosbuvir has a low risk of drug-drug interactions when co-administered with drugs that are substrates of CYP450 enzymes, UGT1A1 or ABC/SLC transporters. The enzymes that support metabolic activation of bemnifosbuvir are of high capacity and are not likely to be inhibited by commonly prescribed drugs. The observations from these in vitro studies have been subsequently validated with Phase 1 clinical drug-drug interaction studies. Poster Number: 549Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: Pharmacokinetics and Metabolism of [14C]-Bemnifosbuvir in Healthy Male Participants Results from a Phase 1, open-label, single-dose, mass balance study demonstrated that bemnifosbuvir 550 mg was well absorbed and nearly completely recovered in urine and feces. The data showed bemnifosbuvir and its metabolites did not accumulate in red blood cells, with similar exposure in plasma and whole blood, and that bemnifosbuvir underwent rapid and extensive metabolic activation to the intracellular active triphosphate metabolite and thereafter entered general circulation mostly as nucleoside metabolites. AT-273, the nucleoside metabolite considered a surrogate of the intracellular phosphates, exhibited a long half-life in plasma, supporting once- and twice-daily dosing. Hepatitis C Poster Number: 411Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15 pm-2:15 pm CETTitle: The Combination of Bemnifosbuvir (BEM) and Ruzasvir (RZR), the HCV NS5B and NS5A Inhibitors, Demonstrates Potent In Vitro Synergistic Antiviral Activity and In Vivo Preclinical Safety Without Adverse Interactions In vitro, the combination of bemnifosbuvir and ruzasvir demonstrated greater inhibition of HCV replication compared to the sum of inhibition of each agent alone in HCV replicon cells, suggesting a synergistic antiviral effect when bemnifosbuvir and ruzasvir are administered together. In a 13-week toxicity study in rats in which bemnifosbuvir and ruzasvir were administered alone or in combination at 500 mg/kg once daily, treatments were well tolerated, and no adverse events were observed. Results demonstrated that systemic exposures of bemnifosbuvir, its metabolites, and ruzasvir were similar when administered independently or in combination, suggesting no significant drug-drug interactions between bemnifosbuvir and ruzasvir. This synergistic activity and no significant drug-drug interactions, together with the previously demonstrated potent, pan-genotypic, antiviral activity of each agent alone, suggest the combination of bemnifosbuvir and ruzasvir has the potential to offer a differentiated, short duration, pan-genotypic, protease inhibitor-sparing regimen for patients with HCV, with or without cirrhosis. Dengue Oral Presentation Number: 046Date/Time: Thursday, March 16 from 4:50-5:00 pm CET Title: AT-752 Targets Multiple Sites and Activities on the Dengue Virus Replication Enzyme NS5 Results from this in vitro study demonstrated the mechanism of action of AT-752. AT-9010, the active triphosphate metabolite of AT-752, inhibited the essential DENV NS5 enzyme. AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. RNA synthesis inhibition occurred for all 4 DENV serotypes. These results illustrate at atomic resolution (1.97 Å) how RNA cap methylation was prevented by AT-9010. Nucleotide Analogue Poster Number: 504Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: A Non-Excisable Nucleotide Analogue Active against SARS-CoV-2AT-1000 is a 2'-ribose modified nucleotide analog, related to bemnifosbuvir but bearing a sulfur atom at its α-phosphate (i.e., α-thio). Results from this in vitro study show that AT-1000 exhibited potent anti-SARS-CoV2 activity, similar to bemnifosbuvir in human airway epithelial cells. Unlike bemnifosbuvir, neither the Sp or Rp isomer binds or inhibits the NiRAN domain nucleotidylation activity. The α-thio modification therefore creates a novel compound, exhibiting an original mechanism of action. These results suggest that this single atom modification may provide a general approach to potentiate a wide array of nucleotide analogues against RNA viruses carrying natural resistance to nucleotide analogue antivirals, such as highly pathogenic coronaviruses. About Bemnifosbuvir for COVID-19 Bemnifosbuvir, a nucleotide polymerase inhibitor, targets the SARS-CoV-2 RNA polymerase (nsp12), a highly conserved gene that is unlikely to change as the virus mutates and new variants continue to emerge. This gene is responsible for both replication and transcription of SARS-CoV-2. Bemnifosbuvir has a unique mechanism of action, with dual targets consisting of chain termination (RdRp) and nucleotityltransferase (NiRAN) inhibition, which has the potential to create a high barrier to resistance. In vitro data confirm that bemnifosbuvir is active with similar efficacy against all variants of concern and variants of interest that have been tested, including Omicron subvariants BA.4 and BA.5. Bemnifosbuvir is currently being evaluated in SUNRISE-3, a global multicenter Phase 3 registrational trial for the treatment of COVID-19. About Bemnifosbuvir and Ruzasvir for Hepatitis C VirusBemnifosbuvir has been shown to be approximately 10-fold more active than sofosbuvir (SOF) in vitro against a panel of laboratory strains and clinical isolates of HCV genotypes 1–5. In vitro studies demonstrated bemnifosbuvir remained fully active against SOF resistance-associated strains (S282T), with up to 58-fold more potency than SOF. The pharmacokinetic (PK) profile of bemnifosbuvir supports once-daily dosing for the treatment of HCV and bemnifosbuvir has been well tolerated at doses up to 550 mg for durations up to 8-12 weeks in healthy and HCV infected subjects. Ruzasvir (RZR), an oral NS5A inhibitor, has demonstrated highly potent and pangenotypic antiviral activity in preclinical (picomolar range) and clinical studies. RZR has been administered to over 1,200 HCV-infected patients at daily doses of up to 180 mg for up to 24 weeks and has demonstrated a favorable safety profile. RZR’s PK profile supports once-daily dosing. The combination of bemnifosbuvir and ruzasvir for the treatment of HCV is in Phase 2 development. About Atea PharmaceuticalsAtea is a clinical stage biopharmaceutical company focused on discovering, developing and commercializing oral therapies to address the unmet medical needs of patients with serious viral infections. Leveraging the Company’s deep understanding of antiviral drug development, nucleos(t)ide chemistry, biology, biochemistry and virology, Atea has built a proprietary nucleos(t)ide prodrug platform to develop novel product candidates to treat single stranded ribonucleic acid, or ssRNA, viruses, which are a prevalent cause of serious viral diseases. Atea plans to continue to build its pipeline of antiviral product candidates by augmenting its nucleos(t)ide platform with other classes of antivirals that may be used in combination with its nucleos(t)ide product candidates. Currently, Atea is focused on the development of orally-available antiviral agents for serious viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and hepatitis C virus (HCV). For more information, please visit www.ateapharma.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our expectations surrounding the potential of our product candidates, including bemnifosbuvir combination product candidates, and expectations regarding our pipeline, including trial design and development timelines. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the uncertainty around and costs associated with the clinical development of bemnifosbuvir as a potential treatment for COVID-19 and the combination of bemnifosbuvir and ruzasvir as a potential treatment for HCV. These and other important factors discussed under the caption “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2022 and our other filings with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. Contacts Jonae BarnesSVP, Investor Relations and Corporate Communications617-818-2985barnes.jonae@ateapharma.com Will O’ConnorStern Investor Relations 212-362-1200will.oconnor@sternir.com