ABCG2

Submission is based on 2-year confirmatory results from the Phase 3 PROTECT Study in which FILSPARI demonstrated a significant reduction in proteinuria, preservation of kidney function and a generally well-tolerated safety pro with active control irbesartan SAN DIEGO, March 11, 2024 (GLOBE NEWSWIRE) -- Travere Therapeutics, Inc. (Nasdaq: TVTX) today announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for conversion of the existing U.S. accelerated approval of FILSPARI® (sparsentan) in IgA nephropathy (IgAN) to full approval. In February 2023, the FDA granted accelerated approval to FILSPARI as the first and only non-immunosuppressive treatment targeting glomerular injury in the kidney to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression. The sNDA is based on 2-year confirmatory results from the Phase 3 PROTECT Study, the only head-to-head study in IgAN versus an active comparator. “Since being introduced under accelerated approval, FILSPARI has positively impacted the lives of many people living with IgAN. The submission of the sNDA is an important step toward potentially gaining full approval in IgAN in support of reaching more people living with this devastating rare kidney disease,” said Eric Dube, Ph.D., president and chief executive officer of Travere Therapeutics. “FILSPARI is at the forefront of emerging new treatment options providing hope for a delay in kidney transplant or dialysis. The results from the pivotal Phase 3 PROTECT Study show that by directly targeting glomerular injury in the kidney with FILSPARI, patients can achieve sustained proteinuria reduction and long-term kidney function preservation. We look forward to working with the FDA throughout the upcoming review process.” FILSPARI is a once-daily, oral medication that directly targets glomerular injury in the kidney by blocking two critical pathways of IgAN disease progression (endothelin-1 and angiotensin II). FILSPARI is also the first and only non-immunosuppressive therapy approved for the treatment of this rare kidney disease. The sNDA submission is supported by results from the Phase 3 PROTECT Study that showed that FILSPARI demonstrated long-term kidney function preservation and achieved a significant reduction in proteinuria and a clinically meaningful difference in eGFR slope versus an active comparator. The FDA has 60 days from the receipt of the application to determine whether to accept it for review. The Company expects to receive notice regarding the acceptance for review of the sNDA submission as well as the timeline for sNDA review from the FDA in the second quarter of 2024. In addition to the sNDA submission to the FDA, the Company and its European commercial partner CSL Vifor recently announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the conditional marketing authorization (CMA) for sparsentan for the treatment of IgA nephropathy (IgAN) in Europe. A decision by the European Commission is expected in the second quarter of 2024. If approved, sparsentan would receive a CMA in all member states of the European Union, as well as in Iceland, Liechtenstein, and Norway. About IgA Nephropathy IgA nephropathy (IgAN), also called Berger's disease, is a rare progressive kidney disease characterized by the buildup of immunoglobulin A (IgA), a protein that helps the body fight infections, in the kidneys. The deposits of IgA cause a breakdown of the normal filtering mechanisms in the kidney, leading to blood in the urine (hematuria), protein in the urine (proteinuria) and a progressive loss of kidney function. Other symptoms of IgAN may include swelling (edema) and high blood pressure. IgAN is the most common type of primary glomerulonephritis worldwide and a leading cause of kidney failure due to glomerular disease. IgAN is estimated to affect up to 150,000 people in the U.S. and is one of the most common glomerular diseases in Europe and Japan. About the PROTECT Study The PROTECT Study is one of the largest interventional studies to date in IgA nephropathy (IgAN) and the only head-to-head trial in this rare kidney disease. It is a global, randomized, multicenter, double-blind, parallel-arm, active-controlled clinical trial evaluating the safety and efficacy of 400 mg of sparsentan, compared to 300 mg of irbesartan, in 404 patients ages 18 years and up with IgAN and persistent proteinuria despite receiving at least 50% of max label dose and maximally tolerated ACE or ARB therapy. In August 2021, the Company announced the PROTECT Study met its pre-specified interim primary efficacy endpoint with statistical significance. Based on the pre-specified, primary analyses set, after 36 weeks of treatment, patients receiving sparsentan achieved a mean reduction in proteinuria from baseline of 49.8%, compared to a mean reduction in proteinuria from baseline of 15.1% for irbesartan-treated patients (p<0.0001). The study’s confirmatory secondary endpoint in the U.S. is estimated glomerular filtration rate (eGFR) total slope from day 1 to week 110 of treatment. The confirmatory secondary endpoint in the EU is eGFR chronic slope from week 6 to week 110 of treatment, following the initial acute effect of randomized treatment. Following the 110-week blinded treatment period, treatment with study medication was discontinued for 4 weeks -- at this time, the investigator resumed standard of care treatment. In September 2023, the Company announced topline two-year confirmatory secondary endpoint results from the PROTECT Study of sparsentan in IgAN. Sparsentan demonstrated long-term kidney function preservation and achieved a clinically meaningful difference in eGFR total and chronic slope versus irbesartan, narrowly missing statistical significance in eGFR total slope while achieving statistical significance in eGFR chronic slope for purposes of regulatory review in the EU. Patients who completed the PROTECT double-blind portion of the study on treatment were eligible to participate in the open-label extension of the trial. About Travere Therapeutics At Travere Therapeutics, we are in rare for life. We are a biopharmaceutical company that comes together every day to help patients, families and caregivers of all backgrounds as they navigate life with a rare disease. On this path, we know the need for treatment options is urgent – that is why our global team works with the rare disease community to identify, develop and deliver life-changing therapies. In pursuit of this mission, we continuously seek to understand the diverse perspectives of rare patients and to courageously forge new paths to make a difference in their lives and provide hope – today and tomorrow. For more information, visit travere.com FILSPARI® (sparsentan) U.S. Indication FILSPARI is an endothelin and angiotensin II receptor antagonist indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a UPCR ≥1.5 g/g. This indication is granted under accelerated approval based on reduction in proteinuria. It has not been established whether FILSPARI slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. FILSPARI® (sparsentan) Important Safety Information BOXED WARNING: HEPATOTOXICITY AND EMBRYO-FETAL TOXICITY Because of the risks of hepatotoxicity and birth defects, FILSPARI is available only through a restricted program called the FILSPARI REMS. Under the FILSPARI REMS, prescribers, patients and pharmacies must enroll in the program. Hepatotoxicity Some Endothelin Receptor Antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3-times the Upper Limit of Normal (ULN) have been observed in up to 2.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3x ULN. FILSPARI should generally be avoided in patients with elevated aminotransferases (>3x ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity FILSPARI can cause major birth defects if used by pregnant patients based on animal data. Therefore, pregnancy testing is required before the initiation of treatment, during treatment and one month after discontinuation of treatment with FILSPARI. Patients who can become pregnant must use effective contraception before the initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI. Contraindications: FILSPARI is contraindicated in patients who are pregnant. Do not coadminister FILSPARI with angiotensin receptor blockers (ARBs), ERAs, or aliskiren. Warnings and Precautions Hepatotoxicity: Elevations in ALT or AST of at least 3-fold ULN have been observed. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment, monthly for the first 12 months, then every 3 months during treatment. Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended. Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity. Avoid initiation of FILSPARI in patients with elevated aminotransferases (>3x ULN) prior to drug initiation. Embryo-Fetal Toxicity: FILSPARI can cause fetal harm. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test and advise patients who can become pregnant to use effective contraception prior to, during, and one month after discontinuation of FILSPARI treatment. FILSPARI REMS: FILSPARI is available only through a restricted program under a REMS called the FILSPARI REMS. Important requirements include: — Prescribers must be certified with the FILSPARI REMS by enrolling and completing training. — All patients must enroll in the FILSPARI REMS prior to initiating treatment and comply with monitoring requirements. — Pharmacies that dispense FILSPARI must be certified with the FILSPARI REMS and must dispense only to patients who are authorized to receive FILSPARI. Further information is available at or 1-833-513-1325. Hypotension: There was a greater incidence of hypotension-associated adverse events, some serious, including dizziness, in patients treated with FILSPARI compared to irbesartan. In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status. If hypotension develops, consider a dose reduction or dose interruption of FILSPARI. Acute Kidney Injury: Monitor kidney function periodically. Patients whose kidney function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute kidney injury on FILSPARI. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on FILSPARI. Hyperkalemia: Monitor serum potassium periodically and treat appropriately. Patients with advanced kidney disease, taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia. Dosage reduction or discontinuation of FILSPARI may be required. Fluid Retention: Fluid retention may occur with ERAs, and has been observed with FILSPARI. If clinically significant fluid retention develops, after evaluation, consider modifying the dose of FILSPARI. Most common adverse reactions (5%) with FILSPARI are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia. Drug interactions Renin-Angiotensin System (RAS) Inhibitors and ERAs: Do not coadminister FILSPARI with angiotensin receptor blockers (ARBs), ERAs, or aliskiren. Strong and Moderate CYP3A Inhibitors: Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors. Strong CYP3A Inducers: Avoid concomitant use with a strong CYP3A inducer. Antacids and Acid Reducing Agents: Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H2 receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: Monitor for signs of worsening renal function. CYP2B6, 2C9, and 2C19 Substrates: Monitor for efficacy of the concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. P-gp and BCRP Substrates: Avoid concomitant use of sensitive substrates of P-gp and BCRP with FILSPARI. Agents Increasing Serum Potassium: Monitor serum potassium frequently. Concomitant use of FILSPARI with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia. Use in specific populations Pregnancy / Females and Males of Reproductive Potential: FILSPARI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy. Pregnancy Testing / Contraception: Verify the pregnancy status and effective method of contraception prior to, during, and one month after discontinuation of FILSPARI treatment. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. Lactation: Advise patients not to breastfeed during treatment with FILSPARI. Hepatic Impairment: Avoid use of FILSPARI in patients with any hepatic impairment (Child-Pugh class A-C). Please see Full Prescribing Information for FILSPARI here. Forward Looking Statements This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, these statements are often identified by the words “on-track,” “positioned,” “look forward to,” “will,” “would,” “may,” “might,” “believes,” “anticipates,” “plans,” “expects,” “intends,” “potential,” or similar expressions. In addition, expressions of our strategies, intentions or plans are also forward-looking statements. Such forward-looking statements include, but are not limited to, references to: statements and expectations regarding the FDA’s potential acceptance for filing of the sNDA submission for FILSPARI in IgAN and the anticipated timeline and outcome of the FDA’s review of the sNDA; statements regarding the potential conditional marketing authorization of sparsentan for the treatment of IgAN in the European Union, Iceland, Liechtenstein and Norway and the anticipated timing thereof, including the potential timing and outcome of the European Commission’s decision; and the potential for emerging new treatment options for IgAN that have the potential to provide hope for a delay in kidney transplant or a dialysis. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks and uncertainties associated with the regulatory review and approval process, as well as risks and uncertainties associated with the Company’s business and finances in general, the success of its commercial products and risks and uncertainties associated with the Company’s preclinical and clinical stage pipeline. Specifically, the Company faces risks associated with market acceptance of its commercial products including efficacy, safety, price, reimbursement, and benefit over competing therapies, as well as risks associated with the successful development and execution of commercial strategies for such products, including FILSPARI. The risks and uncertainties the Company faces with respect to its preclinical and clinical stage pipeline include risk that the Company’s clinical candidates will not be found to be safe or effective and that current or anticipated future clinical trials will not proceed as planned. Specifically, the Company faces risks related to the timing and potential outcome of the FDA’s potential acceptance for filing and review of the sNDA submission for full approval of FILSPARI in IgAN, and the timing and potential outcome of the European Commission’s decision regarding conditional marketing authorization of sparsentan for IgAN. There is no guarantee that the FDA will accept the sNDA submission for filing, that the European Commission will grant conditional marketing authorization of sparsentan for IgAN, or that regulators will grant full approval of sparsentan for IgAN. The Company also faces the risk that it will be unable to raise additional funding that may be required to complete development of any or all of its product candidates, including as a result of macroeconomic conditions; risks relating to the Company’s dependence on contractors for clinical drug supply and commercial manufacturing; uncertainties relating to patent protection and exclusivity periods and intellectual property rights of third parties; risks associated with regulatory interactions; and risks and uncertainties relating to competitive products, including current and potential future generic competition with certain of the Company’s products, and technological changes that may limit demand for the Company’s products. The Company also faces additional risks associated with global and macroeconomic conditions, including health epidemics and pandemics, including risks related to potential disruptions to clinical trials, commercialization activity, supply chain, and manufacturing operations. You are cautioned not to place undue reliance on these forward-looking statements as there are important factors that could cause actual results to differ materially from those in forward-looking statements, many of which are beyond our control. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investors are referred to the full discussion of risks and uncertainties, including under the heading “Risk Factors”, as included in the Company’s most recent Form 10-K, Form 10-Q and other filings with the Securities and Exchange Commission. Contact Info Media: 888-969-7879 mediarelations@travere.com Investors: 888-969-7879 IR@travere.com

抗体偶联药物（ADC）是一种极具潜力的癌症治疗方式，可以选择性地向肿瘤递送高细胞毒性有效载荷。但ADC正面临耐药性、肿瘤异质性和治疗相关不良反应等一系列挑战。如何解决这些挑战？一方面，ADC各组分（即抗体、连接子、有效载荷）的进步是提高药物疗效和安全性的关键；另一方面，目前几种新兴的ADC形式，如双特异性ADC、条件激活型抗体前药偶联物（也称为probody–drug conjugates, PDC）、免疫刺激ADC（immune-stimulating antibody conjugates, ISAC）、蛋白质降解ADC和双药ADC等都有各自的优势，能应对不同的挑战：1）双特异性ADC和双药ADC具有对抗耐药性和肿瘤异质性的双重潜力；2）将免疫刺激ADC和蛋白质降解ADC与当前的治疗方案相结合，可能通过几种不同的作用机制实现多模式治疗。近日，Nature Reviews Clinical Oncology发表了一篇综述文章，深入探讨了ADC分子的设计，以及每种组分如何影响药物的特性。此外，文章还重点介绍了处于临床前/临床早期阶段的上述ADC新兴形式（双特异性ADC、PDC、ISAC、蛋白质降解ADC和双药ADC）的代表药物。来源：Nature Reviews Clinical OncologyADC分子设计如图1a所示，ADC由单抗、有效载荷和连接子组成，这种设计结合了抗体的特异性和有效载荷的高细胞毒性。ADC设计的原理是通过优化每个结构组分（抗体、有效载荷和连接子）而发展起来的。图1. ADC的组分、分子特性和新设计抗体、靶点的选择ADC的抗体通常选用经人源化改造，或直接是人源的免疫球蛋白G（IgG）。ADC设计时会优先使用IgG1抗体，一方面，IgG1在体循环中总体稳定，并且能与先天免疫细胞产生协同作用（如NK细胞、巨噬细胞）；另一方面，使用人IgG1还有助于降低ADC的整体免疫原性，从而将超敏反应和抗药物抗体（ADAs）形成的风险降至最低。目前大多数ADC结构中会连接N-聚糖，以实现FcγR的结合。然而，聚糖可能会导致肝细胞非特异性摄取ADC，导致肝脏毒性，未来可能会使用非糖基化单抗。理想情况是，抗体能够识别在癌细胞表面特异性表达、在健康组织中完全不表达的抗原。但大多数ADC靶点（如HER2和TROP2）都在一定程度上在健康组织中表达。因此，靶标依赖性和靶标非依赖性毒性仍然可能发生。目前已经有研究在探索能够特异性识别肿瘤中的结构变异的抗原对应的抗体。此外，ADC内化和更新率对疗效也有重要影响。结合亲和力的优化也是ADC功效最大化的关键一步。但矛盾的是，过强的抗原结合会导致ADC分子滞留在肿瘤细胞表面，限制了组织渗透的程度。因此，ADC的抗体骨架要考虑到不同的参数，以确保最佳性能。有效载荷目前FDA批准的ADC的有效载荷包括抗有丝分裂剂（MMAE、MMAF、美坦素衍生物DM1和DM4）、DNA损伤剂（卡奇霉素和pyrolobenzodiazepine二聚体）、拓扑异构酶I抑制剂（CN-38、DXd）等。其他正在评估中的药物还包括微管蛋白抑制剂、DNA烷基化剂、拓扑异构酶II抑制剂、RNA聚合酶II抑制剂。此外，免疫调节剂、蛋白质降解招募分子也逐渐成为有希望的新型有效载荷。大多数有效载荷分子具有中等至高水平的疏水性。疏水有效载荷可以从靶表达的肿瘤细胞扩散到邻近的靶表达有限甚至没有靶表达的细胞，这种现象被称为旁观者效应。由于异质性肿瘤中表达抗原的细胞与未表达抗原的细胞共存，所以旁观者效应对于成功根除异质肿瘤至关重要。但疏水有效载荷也会对ADC的有效性产生负面影响：1）疏水有效载荷可以作为多药耐药蛋白（如MDR1、MRP1和BCRP）的良好底物，从而降低某些ADC对表达这些转运蛋白的肿瘤的效力；2）疏水ADC倾向于形成聚集体，可能会被迅速清除，且可能具有免疫原性；3）过度疏水性可促进肝脏摄取，并引起肝毒性。因此，在保证旁观者效应的前提下，需要调节ADC的疏水性。目前策略之一是降低DAR，但降低DAR会导致抗肿瘤活性的降低，所以需要对每个有效载荷类别的DAR进行微调，以平衡功效和毒性的重要性。另一种解决策略是插入如长聚乙二醇（PEG）等亲水性掩膜基团，这样可以构建高DAR的ADC，同时避免高疏水性的一些不必要的影响。连接子如图1b所示，连接子在使细胞毒性有效载荷保持附着在抗体上直到达到靶标方面起着关键作用。连接子分为两类：不可切割型和可切割型。不可切割的连接子由稳定的化学键组成，抵抗蛋白质水解降解，能在体循环中提供极好的稳定性，但这种ADC药物中，有效载荷的释放需要抗体的完全内吞和消化。相比之下，可切割连接子应用更广。可切割连接子能被肿瘤相关因子（如与大多数肿瘤或细胞内蛋白酶相关的酸性和/或还原条件）降解。这些连接子使有效载荷在内化到癌细胞后有效释放，从而产生细胞毒性，最大化ADC效力，并促进旁观者效应。但可切割的连接子存在有效载荷过早释放的风险，会导致系统毒性和有效载荷递送效率降低。因此，如何在稳定性和有效性之间取得平衡至关重要。同质性除了上面讨论的结构成分外，实现偶联的同质性也至关重要。如图1c所示，传统ADC多使用半胱氨酸-马来酰亚胺烷基化、赖氨酸-酰胺偶联来构建，但这些随机的偶联方法会得到有效载荷附着位点和DAR变化的ADC异质混合物。ADC的异质性通常导致有效载荷递送效率降低，因此需要严格控制生产，以尽量减少这种变化。目前已经有很多用于生成具有特定DAR的ADC的偶联技术，如链间二硫化合物的全烷基化（用于T-DXd和sacituzumab govitecan）、THIOMAB技术、非天然存在的活性氨基酸的结合、半胱氨酸再桥接、Fc亲和标签以及使用各种酶（如工程糖苷酶、谷氨酰胺转胺酶、甲酰基甘氨酸生成酶和分选酶）的位点特异性偶联。双特异性ADC如前所述，肿瘤异质性和耐药性会限制针对单靶点ADC的抗肿瘤活性。为了解决这一挑战，双特异性抗体作为一种能够同时结合两种不同的靶分子和/或细胞的方法出现了（图2）。图2. 代表性双特异性ADC双位ADC先前有研究表明，使用两种结合不同表位的抗HER2抗体可以导致内吞作用、溶酶体运输和靶受体的下调，所以研究人员假设，靶向HER2中两个不同表位的多价双异位ADC可能改善结合亲和力，提高有效载荷递送。为了验证这一假设，研究人员通过将曲珠单抗的单链可变片段与另一种抗HER2 IgG1抗体39S的N端融合，生成了四价HER2靶向ADC MEDI4276（图2a）。正如预期的那样，与曲妥珠单抗或亲本39S抗体相比，这种同质双异位ADC具有更快的内化动力学和溶酶体运输。尽管在临床前模型中具有高水平的活性，但在临床测试中MEDI4276并未表现出良好的疗效-安全性平衡。在乳腺癌患者中ORR较低（9.4%）。MEDI4276的最大耐受剂量（MTD）确定为每3周0.75mg/kg，但接受该剂量的12例患者中，有7例有一个或多个临床严重和/或3级以上不良事件。Zanidatamab zovodotin（也称为ZW49）是另一种双位HER2 ADC（图2a），与MEDI4276的四价结合不同，ZW49的不对称结构使HER2能够二价结合。尽管结合方式存在差异，但ZW49也能诱导HER2的受体聚集和快速内化。一项测试ZW49的I期剂量研究显示，ZW49具有可控的安全性，并且在大量预处理的患者中具有良好的抗肿瘤活性。靶向两种不同抗原的双特异性ADC双特异性ADC能同时靶向两种不同的抗原，具有多重优势：1）可以识别和杀死更广泛的肿瘤细胞，包括来自异质肿瘤的细胞；2）靶点合适的话，双特异性ADC具有更强的肿瘤特异性结合能力，可将健康组织中的毒性风险降至最低；3）多种抗原和/或细胞同时参与可能会产生协同效应。如图2b所示，研究人员创建了双特异性ADC AZD9592，可以靶向EGFR和MET（一种在肿瘤细胞表面优先与EGFR共表达的分子）。该药物在EGFR突变型和野生型NSCLC以及头颈部鳞状细胞癌的PDX模型中显示出良好的单药治疗，及与奥西替尼联合治疗的活性。而且AZD9592在猴子中耐受性良好。这些积极的临床前结果推动了其I期试验（NCT05647122）。M1231是另一种双特异性ADC，可靶向MUC1和EGFR，有效载荷是SC209。临床前数据表明，与单特异性二价ADC相比，PDX模型在非小细胞肺癌和食管鳞状细胞癌（ESCC）中的内化、溶酶体运输和治疗活性更强。此外，BL-B01D1是一款可靶向EGFR和HER3的四价双特异性ADC，有效载荷是喜树碱衍生物ED04，通过全半胱氨酸偶联连接，DAR为8，临床前评估证实了该化合物在胰腺或结直肠癌小鼠异种移植模型中的抗肿瘤活性，目前已进入III期临床。但是，双特异性ADC的应用也存在潜在的挑战。例如，两种靶抗原在不同肿瘤和患者中的表达比例可能有所不同，这可能增加了识别和选择潜在治疗响应者的复杂性。因此，对靶点的表位、结合方式及其潜在生物学特性的仔细评估对于双特异性ADC的有效治疗至关重要。这要求研究人员在开发双特异性ADC时综合考虑各种生物学和临床因素，以优化治疗策略。条件激活型抗体前药偶联物（PDC）传统ADC不仅靶向肿瘤细胞上表达的受体，也靶向某些健康组织的受体，导致了不可避免的靶外肿瘤毒性。PDC可以解决这个问题（图3），这一概念的灵感来自于与小分子药物的前药。PDC的前体抗体分子是IgG，它们要么在N端通过可裂解的间隔子与自我掩蔽（self-masking）基团融合，要么被设计为pH依赖性构象变化的抗原结合位点，从而降低了IgG的靶点结合亲和力。当到达肿瘤微环境时，这些抗体或通过移除自我掩蔽基团，或通过响应特定肿瘤相关因素（如蛋白酶丰度和酸性条件）而改变抗原结合位点的构象，从而在局部恢复其原始的靶点结合亲和力及有效载荷的释放。这种创新方法有望提高ADC的治疗指数。图3. 条件激活型抗体前药偶联物具有蛋白酶敏感自掩蔽基团的PDC一项研究显示，抗CD71-PDC CX-2029及其ADC等价物（都含了MMAE有效载荷，DAR~2）在各种实体瘤的小鼠异种移植模型中具有相当水平的抗肿瘤活性。PDC和其等效ADC在非人灵长类动物中的临床前MTDs分别为6和0.6mg/kg，说明掩蔽片段的引入使治疗指数提高了约10倍。基于这一理念，研究人员开发了几款first-in-class PDCs，包括CX-2051（I期临床）、praluzatamab ravtansine（II期临床）和CX-2029（I/II期临床）等。Praluzatamab ravtansine含有微管抑制剂DM4和抗CD166抗体。CD166在许多非恶性组织中广泛表达，因此为PDC提供了理想的靶点。临床I期研究中，由乳腺癌（46%）、上皮性卵巢癌（22%）和非小细胞肺癌（13%）组成的99例转移性实体肿瘤患者接受了praluzatamab ravtansine治疗，剂量≥4mg/kg时观察到肿瘤消退。CX-2029是一种具有MMAE有效载荷的抗CD71 PDC，目前正在进行I期临床试验，涉及各种晚期实体肿瘤患者，如NSCLC（20%）、HNSCC（18%）和结直肠癌（16%）。具有pH反应性抗原结合位点的PDC肿瘤组织（pH=6.0-6.8）通常比大多数健康组织（pH=7.3-7.4）略偏酸性。由于抗原结合位点的可逆构象变化，pH值的差异可用于使ADC有条件激活（图3b）。将弱碱性组氨酸残基结合到抗体的结合区域中是一种常见的赋予这种pH依赖性激活的方法。基于MMAE的EGFR靶向PDC HTI-1511是一个典型案例。HTI-1511亲本抗体在pH=6.0-6.5时对EGFR的结合亲和力比pH=7.4时高10倍以上。HTI-1511在食蟹猴中显示出高达8mg/kg剂量的良好耐受性，表明了潜在的临床安全性。总之，PDC平台在靶向抗原方面具有很大的前景，但使用PDC有效靶向的特定癌症亚型的种类仍需确定。免疫刺激ADC（ISAC）ISAC通过激活免疫系统来增强针对肿瘤的免疫反应。与携带细胞毒性有效载荷的传统ADC相比，ISAC具有以下潜在优势：1）ISAC介导的抗肿瘤反应能够针对多种与肿瘤相关的损伤相关分子模式（DAMPs）；2）ISAC介导的免疫刺激不仅能激活抗原呈递细胞，还可能激活其他肿瘤浸润免疫细胞，如T细胞；3）ISAC能够诱发贯穿整个细胞免疫反应的免疫记忆效应，从而提供持久的抗肿瘤效果，并减少复发风险。图4. 免疫刺激ADC具有TLR7/TLR8/TLR9激动剂有效载荷的ISAC在迄今为止确定的所有TLR中，TLR7、TLR8和TLR9是大多数ISAC的主要靶点，这些内体TLR的激活促进了APC对肿瘤相关DAMPs的呈现，通过激活先天和适应性免疫反应产生强大的抗肿瘤作用。2015年，研究人员公布了通过将TLR7激动剂与利妥昔单抗结合而开发的抗CD20 ISAC的活性，体外测试表明，结合不会损害利妥昔单抗的抗原结合能力或特异性，也不会损害激动剂的TLR刺激活性。这项早期研究为开发各种激活TLR7/8的ISAC铺平了道路。但HER2 TLR8 ISAC SBT6050的I期研究（NCT04460456）和I/II期研究（NCT05091528）中，细胞因子相关的不良事件最终导致了研究的终止。另一种靶向HER22的ISAC NJH395包含一种TLR7激动剂，通过不可切割的连接子与抗HER2抗体结合，已在I期试验中进行评估（NCT03696771）。但由于疗效不足等原因，该研究也在完成单次上升剂量部分后停止。另一款靶向HER2的ISAC BDC-1001是一种基于曲妥珠单抗的ISAC，通过不可切割的连接剂配备了TLR7/8激动剂（图4b）。BDC-1001目前正在I/II期试验中进行测试。与SBT6050和NJH395不同，BDC-1001显示出了有希望的初步结果。具有STING激动剂有效载荷的ISAC暴露于来自微生物病原体和/或垂死肿瘤细胞的外源DNA时，cGAS-cGAMP-STING通路会被激活，导致I型干扰素的产生和先天免疫的激活。研究表明，STING信号传导对于诱导T细胞介导的抗肿瘤免疫反应，以及T细胞浸润到TME至关重要。靶向EGFR的ISAC将cGAMP类似物IMSA172偶联到抗EGFR抗体上，这些ISAC在EGFR表达的小鼠异种移植模型中具有良好的耐受性，每隔3天给药3次，剂量为200μg（约8-10mg/kg），抗肿瘤活性较好。这些ISAC的抗肿瘤活性通过与抗PD-L1抗体联合进一步增强。总之，ISAC所提供的多模式抗肿瘤免疫作用展现了减少获得性抗药性风险和/或推迟其发生的潜力。基于其独特的作用方式，ISAC有望成为在癌症治疗中应对复杂免疫环境的有力工具。蛋白质降解ADC（DAC）DAC利用细胞内的蛋白降解机制来靶向特定蛋白质，为癌症治疗提供了一种创新的提效方法，其设计理念源自于PROTAC技术。PROTACs是由两种配体通过连接子相连的异双功能分子，其中一个配体靶向特定的目标蛋白，另一个配体则结合E3泛素连接酶。与传统的抑制剂不同，这些配体与目标蛋白的结合不需要具有拮抗活性。这样的设计使得一些之前被认为是“不可成药”的蛋白质成为可能的治疗靶点。图5. 蛋白质降解ADCGNE-987是一款BET-PROTAC，由BRD4配体和VHL配体组成，在EOL-1细胞中表现出对BRD4的有效降解（DC50=0.03nM），在两个细胞系中表现出优异的体外效力（EOL-1中IC50=0.02nM，HL-60中IC50=0.03nM），但药物代谢和药代动力学导致其在体内模型中无效。为了解决这一问题，研究人员将GNE-987的羟基与6个半胱氨酸连接到抗CLL1抗体中，使用不稳定的碳酸盐连接，将GNE-987转化为均质DAC（图5b）。数据显示，在皮下移植的HL-60和EOL-1 AML小鼠模型中，单次静脉给药10mg/kg的DAC能够持续在体内暴露，并显著抑制肿瘤生长。除BRD4外，雌激素受体-α（ERα）、TGFβ受体2和染色质调节蛋白SMARCA2（也称为BRM）也被广泛应用为DAC的靶点。然而，DAC面临的挑战在于其有效载荷通常具有较高的疏水性，导致整体结构过度疏水。为了确保足够的细胞毒性，可能需要较高的药物抗体比（DAR），这会进一步加剧其疏水性，从而对这些药物的药代动力学和毒性特性产生不良影响。因此，开发新型连接子设计和改良降解剂分子以解决这些问题，可能会大大改善DAC在癌症治疗中的应用潜力。双药ADC双药ADC通过整合两种不同的有效载荷，联合多种细胞毒性药物的作用机制，来应对肿瘤的耐药性和异质性问题。这种策略可能对异质性肿瘤细胞群和耐药性克隆表现出增强的活性。双药ADC作为一种单一疗法，有可能产生协同效应，同时通过简化的给药方案，克服对治疗不敏感的肿瘤患者的抗药性。图6. 双药ADC研究人员首先假设使用两种有效载荷（MMAE和MMAF）同时递送会增强和协同活性，实验表明，这种双药ADC在表达CD30耐多药的间变性大细胞淋巴瘤（ALCL）的小鼠异种移植模型中显示出强大的活性，导致5只小鼠中的3只完全根除癌细胞。相比之下，DAR为8的、仅MMAF的ADC活性较低，仅在5只小鼠中有1只小鼠中根除了所有癌细胞，而等效的仅MMAE的ADC完全没有抗肿瘤活性。在具有异质CD30表达的小鼠霍奇金淋巴瘤异种移植模型中，双药ADC和仅MMAE的ADC都能完全抑制肿瘤生长，这可能是由于MMAE介导的旁观者细胞杀伤。相反，仅MMAF的等效ADC仅赋予肿瘤生长适度延迟。虽然双药ADC在克服肿瘤的异质性和抗药性方面显示出潜在的优势，但也必须警惕其可能引发的协同毒性。为此，研究人员已开发出多种正交偶联策略，以制造出具有高均一性和明确药物抗体比的双药ADC。这些策略不仅确保了两种有效载荷的有效整合，而且优化了它们的共同作用，以最大化治疗效果并减少不良反应。参考资料：Kyoji Tsuchikama et al. Exploring the next generation of antibody–drug conjugates. Nature Reviews Clinical Oncology（2024）ADC是2023年中国创新药最炙手可热的赛道，license out交易频出并不断刷新记录，为时下略显低迷的创新药行业注入了资金和信心。这种热度能够持续多久？ADC企业的竞争力在哪？医药魔方3月28日举办的2024医药投融资交易大会暨第二届医药魔方TOP15榜单发布大会将会有ADC投资交易相关话题讨论，敬请关注！Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

FOSTER CITY, Calif., & RAHWAY, N.J.--( BUSINESS WIRE )--Gilead Sciences, Inc. (Nasdaq: GILD) and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the Phase 2 clinical study evaluating the investigational combination of islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, and lenacapavir, a first-in-class capsid inhibitor. These late-breaking data were presented during an oral session at the 31st Conference on Retroviruses and Opportunistic Infections ( CROI ). Prior to the late-breaker oral presentation, the key findings were featured in a CROI press conference. At 24 weeks, the novel investigational combination maintained a high rate (94.2%) of viral suppression (HIV-1 RNA <50 copies/mL), which is a secondary endpoint of the study. Results of the primary endpoint (HIV-1 RNA ≥50 copies/mL (c/mL) showed that one participant (1.9%) treated with islatravir and lenacapavir had a viral load of >50 copies/mL at Week 24; the participant later suppressed on islatravir and lenacapavir at Week 30. The potent antiviral activities, along with pharmacokinetic profiles of islatravir and lenacapavir, support their development as an investigational once-weekly oral combination regimen. Single-tablet daily oral therapies have helped to transform HIV care, but options that allow for less frequent dosing have the potential to address adherence, stigma and other challenges faced by some individuals taking daily oral antiretroviral therapy. “ HIV treatment is not one size fits all – developing once-weekly treatment options could help meet the needs of each individual, aiming toward maximizing long-term outcomes for people with HIV,” said Jared Baeten, Vice President, MD, PhD, HIV Clinical Development, Gilead Sciences. “ These promising data presented at CROI help bring us one step closer to our goal of providing a wide range of options that may help transform the HIV treatment landscape.” In this open-label, active-controlled study ( NCT05052996 ), virologically suppressed adults (n=104) on Biktarvy ® (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, B/F/TAF) were randomly allocated in a 1:1 ratio to receive either oral islatravir 2 mg and lenacapavir 300 mg once a week (n=52) or to continue daily oral Biktarvy (n=52). The median age of participants was 40 years. Eighteen percent of participants were assigned female at birth, 50% were non-white, and 29% were Hispanic or Latinx. Results of the primary endpoint, measured as HIV-1 RNA ≥50 copies/mL (c/mL) at Week 24 per FDA Snapshot algorithm, showed that one participant (1.9%) treated with islatravir and lenacapavir had a viral load of more than 50 copies/mL at Week 24; the participant later suppressed on islatravir and lenacapavir at Week 30. No participants in the Biktarvy group had a viral load of more than 50 copies/mL at Week 24. Results of the secondary endpoint, as measured by the proportion of individuals with HIV-1 RNA < 50 c/mL at Week 24, showed that participants who switched to treatment with once-weekly islatravir and lenacapavir or continued Biktarvy both maintained comparable high rates of HIV suppression at Week 24 (94.2% v. 94.2%). Grade 1 and 2 treatment-related-adverse events (TRAEs) reported in the islatravir and lenacapavir group included dry mouth and nausea (each 3.8%). No grade 1 and 2 TRAEs were reported in the Biktarvy group. No grade 3 or 4 TRAEs related to study drug in either treatment group were reported. Two participants discontinued islatravir and lenacapavir due to adverse events unrelated to the drug. In addition, no differences were seen between treatment groups for changes in CD4+ T cell counts or absolute lymphocyte counts. “ Our strategies for managing and treating HIV must evolve with the needs of the HIV community and we are excited to have these promising first data from the Phase 2 study for islatravir and lenacapavir presented at CROI,” said Dr. Elizabeth Rhee, vice president, global clinical development, Merck Research Laboratories. “ Gilead and Merck remain committed to this collaboration and to the development of a potential once-weekly oral therapy for people living with HIV who may need additional options to help maintain viral suppression.” The Phase 2 study will continue in an open-label fashion through Week 48. Longer-term data will be presented at a future scientific conference. Islatravir, alone or in combination with lenacapavir, is investigational and not approved anywhere globally. The safety and efficacy of the combination of islatravir and lenacapavir have not been established. Lenacapavir, marketed as Sunlenca ® , is approved in Australia, Canada, the European Union, Israel, Japan, Switzerland, the United Arab Emirates, the United Kingdom and the United States for the treatment of people with multi-drug resistant HIV in combination with other antiretroviral(s). Please see below for the U.S. Indication and Important Safety Information for Sunlenca. Please also see below for U.S. Indication and Important Safety Information, including Boxed Warning, for Biktarvy. There is currently no cure for HIV or AIDS. About islatravir (MK-8591) Islatravir (MK-8591) is Merck’s investigational nucleoside reverse transcriptase translocation inhibitor under evaluation for the treatment of HIV-1 in combination with other antiretrovirals. For an overview of Merck’s HIV treatment and prevention clinical development program, please click here . About Sunlenca ® Sunlenca (300 mg tablet and 463.5 mg/1.5 mL injection) [(lenacapavir)] is a first-in-class, long-acting HIV capsid inhibitor indicated for the treatment of HIV infection, in combination with other antiretroviral(s), in adults with multi-drug resistant HIV who are heavily treatment-experienced. Sunlenca is the only HIV treatment option administered twice-yearly. Sunlenca tablets are approved for oral loading during initiation of Sunlenca treatment, prior to or at the time of the first long-acting lenacapavir injection depending on initiation option. The multi-stage mechanism of action of Sunlenca’s active pharmaceutical agent, lenacapavir, is distinguishable from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, Sunlenca is designed to inhibit HIV at multiple stages of its lifecycle and has no known cross resistance exhibited in vitro to other existing drug classes. Lenacapavir is being developed as a foundation for future HIV therapies developed by Gilead. The goal is to offer both long-acting oral and injectable options with various dosing frequencies in combination with other antiretroviral agents for treatment or as a single agent for prevention. This approach aims to help address the individual needs and preferences of people with HIV and people who could benefit from pre-exposure prophylaxis (PrEP). The use of lenacapavir for HIV prevention is investigational and the safety and efficacy of lenacapavir for this use has not been established. Lenacapavir is being evaluated as a potential long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Merck’s Commitment to HIV For more than 35 years, Merck has been committed to scientific research and discovery in HIV. Today, we are developing a series of antiviral options designed to help people manage HIV and protect people from HIV, with the goal of reducing the growing burden of infection worldwide. We remain committed to collaborating with others in the global HIV community to address the complex challenges that impede progress toward ending the epidemic. About Gilead Sciences in HIV For more than 35 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 12 HIV medications , including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce HIV infections, and the first long-acting injectable HIV treatment medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Gilead is committed to continued scientific innovation to provide solutions for the evolving needs of people affected by HIV around the world. Through partnerships , collaborations, and charitable giving, the company also aims to improve education, expand access and address barriers to care, with the goal of ending the HIV epidemic for everyone, everywhere. Gilead was recognized as the number one philanthropic funder of HIV-related programs in a report released by Funders Concerned About AIDS. Learn more about Gilead’s unique collaborations worldwide and the work to help end the global HIV epidemic. U.S. Indication for Sunlenca Sunlenca, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. U.S. Important Safety Information for Sunlenca Contraindications Coadministration: Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers. Warnings and precautions Immune reconstitution syndrome , including the occurrence of autoimmune disorders with variable time to onset, has been reported in patients treated with combination antiretroviral (ARV) therapy. Long-acting properties and potential associated risks with SUNLENCA: Residual concentrations of SUNLENCA may remain in the systemic circulation of patients for up to 12 months or longer. SUNLENCA may increase exposure, and potential risk of adverse reactions, to drugs primarily metabolized by CYP3A initiated within 9 months after last injection. Counsel patients regarding the dosing schedule because nonadherence could lead to loss of virologic response and development of resistance. If virologic failure occurs, switch to an alternative regimen if possible. If discontinuing SUNLENCA, begin alternate suppressive ARV regimen within 28 weeks from last injection. Injection site reactions may occur, and nodules and indurations may be persistent. Adverse reactions Most common adverse reactions (incidence ≥3%, all grades) are injection site reactions (65%) and nausea (4%). Drug interactions Prescribing information: Consult the full prescribing information for SUNLENCA for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that are strong or moderate inducers of CYP3A may significantly decrease the concentration of SUNLENCA. Drugs that strongly inhibit CYP3A, P-gp, and UGT1A1 together may significantly increase the concentration of SUNLENCA. SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A, when initiated within 9 months after the last injection of SUNLENCA, which may increase the potential risk of adverse reactions. Dosage and administration Dosage: Initiation with 1 of 2 options, followed by maintenance dosing once every 6 months. Tablets may be taken with or without food. Initiation Option 1: Day 1: 927 mg by subcutaneous injection and 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally (2 x 300-mg tablets). Initiation Option 2: Day 1: 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally (2 x 300-mg tablets). Day 8: 300 mg orally (1 x 300-mg tablet). Day 15: 927 mg by subcutaneous injection. Maintenance: 927 mg by subcutaneous injection every 26 weeks +/- 2 weeks from date of last injection. Missed Dose: During the maintenance period, if more than 28 weeks have elapsed since the last injection and if clinically appropriate to continue SUNLENCA treatment, restart the initiation dosage regimen from Day 1, Option 1 or Option 2. Pregnancy and lactation Pregnancy: There is insufficient human data on the use of SUNLENCA during pregnancy. An Antiretroviral Pregnancy Registry (APR) has been established. Lactation: Individuals infected with HIV-1 should be instructed not to breastfeed, due to the potential for HIV-1 transmission. U.S. Indication for Biktarvy Biktarvy is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 14 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known or suspected substitutions associated with resistance to bictegravir or tenofovir. U.S. Important Safety Information for Biktarvy BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue BIKTARVY. If appropriate, anti-hepatitis B therapy may be warranted. Contraindications Coadministration: Do not use BIKTARVY with dofetilide or rifampin. Warnings and precautions Drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during BIKTARVY therapy and monitor for adverse reactions. Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported. New onset or worsening renal impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)–containing products. Do not initiate BIKTARVY in patients with estimated creatinine clearance (CrCl) <30 mL/min except in virologically suppressed adults <15 mL/min who are receiving chronic hemodialysis. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue BIKTARVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Renal monitoring: Prior to or when initiating BIKTARVY and during therapy, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, assess serum phosphorus. Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including FTC and TDF. Discontinue BIKTARVY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse reactions Most common adverse reactions (incidence ≥5%; all grades) in clinical studies through week 144 were diarrhea (6%), nausea (6%), and headache (5%). Drug interactions Prescribing information: Consult the full prescribing information for BIKTARVY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that induce P-gp or induce both CYP3A and UGT1A1 can substantially decrease the concentration of components of BIKTARVY. Drugs that inhibit P-gp, BCRP, or inhibit both CYP3A and UGT1A1 may significantly increase the concentrations of components of BIKTARVY. BIKTARVY can increase the concentration of drugs that are substrates of OCT2 or MATE1. Drugs affecting renal function: Coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC and tenofovir and the risk of adverse reactions. Dosage and administration Dosage: Adult and pediatric patients weighing ≥25 kg: 1 tablet containing 50 mg bictegravir (BIC), 200 mg emtricitabine (FTC), and 25 mg tenofovir alafenamide (TAF) taken once daily with or without food. Pediatric patients weighing ≥14 kg to <25 kg: 1 tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. Renal impairment: For patients weighing ≥25 kg, not recommended in patients with CrCl 15 to <30 mL/min, or <15 mL/min who are not receiving chronic hemodialysis, or <15 mL/min who are receiving chronic hemodialysis and have no antiretroviral treatment history. For patients weighing ≥14 kg to <25 kg, not recommended in patients with CrCl <30 mL/min. Hepatic impairment: Not recommended in patients with severe hepatic impairment. Prior to or when initiating: Test patients for HBV infection. Prior to or when initiating, and during treatment: As clinically appropriate, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, assess serum phosphorus. Pregnancy and lactation Pregnancy: There is insufficient human data on the use of BIKTARVY during pregnancy. Dolutegravir, another integrase inhibitor, has been associated with neural tube defects. Discuss the benefit-risk of using BIKTARVY during pregnancy and conception. An Antiretroviral Pregnancy Registry (APR) has been established. Available data from the APR for FTC shows no difference in the rates of birth defects compared with a US reference population. Lactation: Women infected with HIV-1 should be instructed not to breastfeed, due to the potential for HIV-1 transmission. Gilead Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving Biktarvy and lenacapavir; uncertainties relating to regulatory applications and related filing and approval timelines, including potential applications for indications currently under evaluation; the possibility that Gilead may make a strategic decision to discontinue development of these programs and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). U.S. full Prescribing Information for Biktarvy, including BOXED WARNING , and U.S. full Prescribing Information for Sunlenca are available at www.gilead.com . Biktarvy, Sunlenca, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. All other marks are the property of their respective owners. For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on Twitter ( @Gilead Sciences ) and LinkedIn , or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.