BOSTON--(BUSINESS WIRE)--Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, announced an update on its PRMT5 program. Based on positive data from the dose escalation and early dose expansion cohorts of the TNG462 phase 1/2 clinical trial, the Company has selected TNG462 to move forward into full development.

。根据TNG462 1/2期临床试验剂量递增和早期剂量扩展队列的积极数据，该公司选择TNG462进行全面开发。

TNG908, an MTA-cooperative brain penetrant PRMT5 inhibitor, is clinically active and well-tolerated in non-CNS solid tumors including NSCLC and pancreatic cancer. However, TNG908 did not meet the pharmacokinetic exposure threshold for clinical efficacy in glioblastoma (GBM) in the phase 1/2 trial. Thus, the Company is introducing TNG456, a next-generation brain penetrant MTA-cooperative PRMT5 inhibitor with enhanced potency and selectivity for the treatment of GBM, NSCLC and selected other solid tumors.

TNG908是一种MTA协同脑渗透剂PRMT5抑制剂，在非中枢神经系统实体瘤（包括NSCLC和胰腺癌）中具有临床活性且耐受性良好。然而，在1/2期试验中，TNG908不符合胶质母细胞瘤（GBM）临床疗效的药代动力学暴露阈值。因此，该公司正在引入TNG456，这是一种新一代脑渗透剂MTA协同PRMT5抑制剂，具有增强的治疗GBM，NSCLC和选定的其他实体瘤的效力和选择性。

TNG908 enrollment is being stopped in order to fully resource TNG462 and TNG456..

为了充分利用TNG462和TNG456的资源，正在停止TNG908注册。。

“Early data from the TNG462 phase 1/2 clinical trial demonstrate activity, durability and tolerability, with the potential to be a best-in-class molecule. In this ongoing clinical trial, patients remain on treatment with a current median of 24 weeks and is still increasing,” said Adam Crystal, M.D., Ph.D., President, Research and Development of Tango Therapeutics.

Tango Therapeutics研究与开发总裁Adam Crystal博士说：“TNG462 1/2期临床试验的早期数据显示活性、耐久性和耐受性，有可能成为同类最佳分子。在这项正在进行的临床试验中，患者仍在接受治疗，目前中位数为24周，并且仍在增加。”。

“In addition, we are introducing TNG456, our next-generation brain-penetrant molecule, which is anticipated to enter the clinic in the first half of next year. Given the increased potency, selectivity and predicted brain penetrance of TNG456, we expect CNS exposure to be in the range needed for meaningful efficacy in glioblastoma and brain metastases.

“此外，我们正在引入下一代脑渗透分子TNG456，预计它将于明年上半年进入临床。鉴于TNG456的效力，选择性和预测的脑渗透性增加，我们预计中枢神经系统暴露在胶质母细胞瘤和脑转移瘤有意义疗效所需的范围内。

While it’s disappointing that, unlike in other solid tumors, TNG908 is not active in GBM, we believe this is due to lower-than-predicted central nervous system exposure. We remain steadfastly committed to bringing an effective treatment to people with glioblastoma and we are strongly positioned to achieve our goal of reaching as many patients as possible with MTAP-deleted cancers.”.

虽然令人失望的是，与其他实体瘤不同，TNG908在GBM中不活跃，但我们认为这是由于中枢神经系统暴露低于预期。我们仍然坚定地致力于为胶质母细胞瘤患者提供有效的治疗，我们有能力实现尽可能多的MTAP缺失癌症患者的目标。”。

“Clinical data from the phase 1/2 trial demonstrate that TNG462 has potentially best-in-class characteristics including clinical activity across multiple tumor types included in the trial, substantive durability, and a good safety and tolerability profile, thus we are moving rapidly into the next phase of development.

“1/2期试验的临床数据表明，TNG462具有潜在的同类最佳特征，包括试验中包括的多种肿瘤类型的临床活性，实质性的耐久性以及良好的安全性和耐受性，因此我们正在迅速进入下一个发展阶段。

This includes clinical evaluation of TNG462 as a monotherapy and in multiple combinations of both targeted and standard of care agents to begin in 1H 2025, in preparation for registrational trials in NSCLC and pancreatic cancer. It also includes building key capabilities within Tango to bring TNG462 to a broad range of patients in the coming years.

这包括将TNG462作为单一疗法进行临床评估，并将其作为靶向和标准治疗药物的多种组合，于2025年上半年开始，为NSCLC和胰腺癌的注册试验做准备。它还包括在探戈中建立关键能力，以便在未来几年将TNG462带给广泛的患者。

As part of this effort, we have entered into a clinical collaboration with Revolution Medicines under which we plan to conduct the first combination trials of an MTA-cooperative PRMT5 inhibitor with the exciting class of RAS(ON) tri-complex inhibitors. Given that nearly all MTAP-deleted pancreatic cancers have a co-occurring RAS mutation, we believe this could be a powerful approach to changing the treatment landscape for this challenging cancer,” said Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics..

作为这项努力的一部分，我们与Revolution Medicines进行了临床合作，根据该合作，我们计划进行MTA合作PRMT5抑制剂与令人兴奋的RAS（ON）三复合物抑制剂的首次联合试验。Tango Therapeutics总裁兼首席执行官芭芭拉·韦伯（BarbaraWeber）医学博士说：“鉴于几乎所有MTAP缺失的胰腺癌都有共同发生的RAS突变，我们认为这可能是改变这种具有挑战性的癌症治疗格局的有力方法。”。。

TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor

TNG462，一种潜在的最佳MTA协同PRMT5抑制剂

TNG462 dose escalation began in July 2023 and enrollment in the dose expansion cohorts began in June 2024. With a data cutoff of 20 October 2024, a total of 59 patients have been enrolled, 39 evaluable patients across 13 histologies at active doses (160-300 mg QD).

TNG462剂量递增始于2023年7月，剂量扩展队列的登记始于2024年6月。数据截止日期为2024年10月20日，共招募了59名患者，其中39名患者在13种组织学中以活性剂量（每天160-300毫克）进行评估。

TNG462 is active and well-tolerated across multiple tumor types, including NSCLC and pancreatic cancer, with a current median time on treatment of 24 weeks, and is still increasing.

TNG462在多种肿瘤类型（包括NSCLC和胰腺癌）中具有活性且耐受性良好，目前治疗的中位时间为24周，并且仍在增加。

As has been reported with other MTA-cooperative PRMT5 inhibitors, tumors continue to shrink over time in multiple tumor types. Median time to response is 16 weeks (8-32 weeks) and ~60% of patients with partial responses were initially assessed with stable disease.

正如其他MTA协同PRMT5抑制剂所报道的那样，随着时间的推移，多种肿瘤类型的肿瘤继续缩小。中位反应时间为16周（8-32周），约60%的部分反应患者最初评估为疾病稳定。

While there is not yet a sufficient number of evaluable patients and follow-up to accurately estimate ORR for most cancer types, we have enrolled seven cholangiocarcinoma patients and observed confirmed partial responses in 3/7 of these patients (ORR 43%). 4/7 cholangiocarcinoma patients are ongoing with a median time on study of 24 weeks, and is still increasing..

虽然尚未有足够数量的可评估患者和随访来准确估计大多数癌症类型的ORR，但我们招募了7名胆管癌患者，并在其中3/7的患者中观察到确诊的部分反应（ORR 43%）。。。

TNG462 has a good safety profile and is well-tolerated at active doses, with thrombocytopenia as the dose limiting toxicity. Other adverse events reported for the class, including nausea, vomiting, diarrhea, and fatigue, occurred in less than 20% of patients and were predominantly grade 1. Dysgeusia has not been reported with the doses being evaluated in expansion..

TNG462具有良好的安全性，并且在活性剂量下耐受性良好，血小板减少症是剂量限制性毒性。该类报告的其他不良事件，包括恶心，呕吐，腹泻和疲劳，发生率不到20%，主要是1级。目前还没有关于扩大剂量评估的味觉障碍的报道。。

TNG462 efficacy and tolerability continue to be evaluated at 200 mg, 250 mg and 300 mg daily, predominantly in NSCLC and pancreatic cancer. The next clinical update is planned for 2025.

TNG462的疗效和耐受性继续以每天200 mg，250 mg和300 mg的剂量进行评估，主要在NSCLC和胰腺癌中进行。下一次临床更新计划于2025年进行。

Development plans for TNG462 being implemented include targeted combinations with two RAS(ON) inhibitors – RAS(ON) multi-selective inhibitor, RMC-6236, and RAS(ON) G12D-selective inhibitor, RMC-9805 (Revolution Medicines) – osimertinib (AstraZeneca) and pembrolizumab (Merck), with enrollment planned to start in 1H 2025..

。。

Combinations of TNG462 and standard of care chemotherapy for NSCLC and pancreatic cancer also are being planned as potential paths to approval in the first line setting and we are initiating conversations with the FDA in preparation for multiple registrational studies.

。

TNG908, a blood-brain barrier penetrant, MTA-cooperative PRMT5 inhibitor

TNG908，血脑屏障渗透剂，MTA协同PRMT5抑制剂

TNG908 dose escalation began in August 2022 and enrollment in the dose expansion cohorts began in April 2024. With a data cutoff of 20 October 2024, a total of 103 patients have been enrolled, 70 non-CNS patients across 24 histologies and 33 glioblastoma patients.

TNG908剂量递增始于2022年8月，剂量扩展队列的登记始于2024年4月。。

TNG908 is active and well-tolerated across multiple non-CNS solid tumors, including NSCLC and pancreatic cancer, with a median time on study of 16 weeks.

TNG908在多种非中枢神经系统实体瘤（包括NSCLC和胰腺癌）中具有活性且耐受性良好，研究的中位时间为16周。

Of the 70 patients with non-CNS solid tumors, 31 were treated at active doses (400-600 mg BID) and had at least one tumor assessment. Four partial responses were observed. Responses occurred in pancreatic cancer (2/9), NSCLC (1/4) and urothelial cancer (1/1).

在70例非中枢神经系统实体瘤患者中，31例接受了活性剂量（400-600 mg BID）治疗，并至少进行了一次肿瘤评估。观察到四个部分反应。胰腺癌（2/9），NSCLC（1/4）和尿路上皮癌（1/1）发生反应。

Of note, there were a total of nine evaluable pancreatic cancer patients, two with partial responses (ORR 22%) and five with stable disease as best response to date. The five ongoing pancreatic cancer patients have been on study for an average of 24 weeks, the longest for 72 weeks.

值得注意的是，迄今为止，共有9名可评估的胰腺癌患者，其中2名部分缓解（ORR 22%），5名疾病稳定，是最佳反应。这五名正在进行的胰腺癌患者平均接受了24周的研究，最长持续了72周。

Of the 33 patients with glioblastoma, 23 were treated at active doses (400-600 mg BID) and had at least one tumor assessment. No partial responses by RANO criteria were observed and median time on study was less than 8 weeks.

在33例胶质母细胞瘤患者中，23例接受了活性剂量（400-600 mg BID）治疗，并至少进行了一次肿瘤评估。没有观察到RANO标准的部分反应，研究的中位时间少于8周。

In preclinical primate studies of TNG908, cerebral spinal fluid (CSF) exposure was 50-70% of plasma exposure. In CSF samples from three glioblastoma patients on study, exposure was ~30% of plasma exposure and below the threshold required for efficacy.

在TNG908的临床前灵长类动物研究中，脑脊液（CSF）暴露为血浆暴露的50-70%。在研究的三名胶质母细胞瘤患者的脑脊液样本中，暴露量约为血浆暴露量的30%，低于疗效所需的阈值。

Dose-limiting toxicities were elevated creatine kinase and aspartate aminotransferase in one patient and altered mental status in a second patient, both at 900 mg BID. Nausea and fatigue were reported in ~40% of patients at 600 mg BID, the expansion dose.

剂量限制性毒性是一名患者的肌酸激酶和天冬氨酸转氨酶升高，另一名患者的精神状态改变，均为900 mg BID。据报道，约40%的患者在600 mg BID（扩展剂量）时出现恶心和疲劳。

While TNG908 is an active and well-tolerated MTA-cooperative PRMT5 inhibitor in non-CNS solid tumors, enrollment is being stopped to allow full resourcing of TNG462 as a potential best-in-class molecule. In particular, the notably longer time on treatment observed – 24 weeks and still increasing for TNG462 versus 16 weeks for TNG908 – the superior target coverage and the safety and tolerability profile all support selection of TNG462 for further development..

虽然TNG908在非中枢神经系统实体瘤中是一种活性且耐受性良好的MTA协同PRMT5抑制剂，但正在停止招募，以使TNG462作为潜在的同类最佳分子得到充分资源。特别是，观察到的治疗时间明显更长（TNG462为24周，仍在增加，而TNG908为16周），优越的目标覆盖率以及安全性和耐受性都支持选择TNG462进行进一步开发。。

TNG456, a next-generation, brain penetrant MTA-cooperative PRMT5 inhibitor

TNG456，下一代脑渗透MTA协同PRMT5抑制剂

TNG456 is a novel, brain-penetrant MTA-cooperative PRMT5 inhibitor that is 55X selective for MTAP deletion with 20 nM potency (GI50) in preclinical studies.

TNG456是一种新型的脑渗透性MTA协同PRMT5抑制剂，在临床前研究中对MTAP缺失具有55倍的选择性，效力为20 nM（GI50）。

Based on primate CSF exposure that is 50%-110% of plasma levels and the markedly increased potency and selectivity of TNG456 compared to TNG908 (GI50 120 nM, 15X MTAP-deleted selectivity), TNG456 CNS exposure is predicted to be in the range needed for efficacy in glioblastoma and brain metastases.

基于灵长类动物脑脊液暴露量为血浆水平的50%-110%，并且与TNG908相比，TNG456的效力和选择性显着增加（GI50 120 nM，15X MTAP缺失选择性），预计TNG456中枢神经系统暴露量在胶质母细胞瘤和脑转移瘤疗效所需的范围内。

TNG456 will be evaluated in glioblastoma, NSCLC and select other solid tumors as a monotherapy and in combination with the brain-penetrant CDK4/6 inhibitor abemaciclib (Lilly). The combination with abemaciclib is based on the co-deletion of CDKN2A and MTAP in essentially all MTAP-deleted cancers and on strong synergy observed in preclinical models..

TNG456将在胶质母细胞瘤，NSCLC中进行评估，并选择其他实体瘤作为单一疗法，并与脑渗透剂CDK4/6抑制剂abemaciclib（Lilly）联合使用。与abemaciclib的组合基于基本上所有MTAP缺失的癌症中CDKN2A和MTAP的共缺失以及在临床前模型中观察到的强协同作用。。

The Company plans to begin enrolling patients in the TNG456 phase 1/2 study in 1H 2025.

该公司计划在2025年上半年开始招募患者参加TNG456 1/2期研究。

About Tango Therapeutics

关于探戈疗法

Tango Therapeutics is a clinical-stage biotechnology company dedicated to discovering novel drug targets and delivering the next generation of precision medicine for the treatment of cancer. Using an approach that starts and ends with patients, Tango leverages the genetic principle of synthetic lethality to discover and develop therapies that take aim at critical targets in cancer.

Tango Therapeutics是一家临床阶段的生物技术公司，致力于发现新的药物靶标并提供下一代用于治疗癌症的精准药物。Tango采用以患者为起点和终点的方法，利用合成致死性的遗传原理来发现和开发针对癌症关键靶点的疗法。

This includes expanding the universe of precision oncology targets into novel areas such as tumor suppressor gene loss and their contribution to the ability of cancer cells to evade immune cell killing. For more information, please visit www.tangotx.com..

这包括将精确肿瘤学靶标的范围扩展到新的领域，例如肿瘤抑制基因的丢失及其对癌细胞逃避免疫细胞杀伤能力的贡献。有关更多信息，请访问www.tangotx.com。。

Forward-Looking Statements

前瞻性声明

Certain statements in this press release may be considered forward-looking statements. Forward-looking statements generally relate to future events, Tango’s future operating performance and goals, the anticipated benefits of therapies and combination therapies (that include a Tango pipeline product), as well as the expectations, beliefs and development objectives for Tango’s product pipeline and clinical trials.

本新闻稿中的某些声明可能被视为前瞻性声明。前瞻性陈述通常涉及未来事件，Tango未来的经营业绩和目标，治疗和联合治疗（包括Tango管道产品）的预期益处，以及Tango产品管道和临床试验的期望，信念和发展目标。

In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “goal”, “estimate”, “anticipate”, “believe”, “predict”, “designed,” “potential” or “continue”, or the negatives of these terms or variations of them or similar terminology. For example, implicit or explicit statements concerning the following include or constitute forward-looking statements: the Company is advancing TNG462 into clinical trials as a monotherapy and with multiple targeted and standard of care combinations, including two RAS(ON) tri-complex inhibitors from Revolution Medicines, Inc.; the Company believes the combination of TNG462 with RAS(ON) inhibitors could be a powerful approach to changing the treatment landscape for pancreatic cancer; potential combination strategies for PRMT5 inhibitors; the Company’s view that TNG462 has the potential to be a best-in-class MTA-cooperative PRMT5 inhibitor in multiple tumor types, including pancreatic and non-small cell lung cancers; the Company is moving TNG462 into full development; the Company expects cash runway into the third quarter of 2026; the Company expects to share another clinical update on TNG462 in 2025; the Company continues to advance TNG260 for cancers with STK11 loss-of-function mutations, with the phase 1/2 clinical trial ongoing; Tango is committed to discovering an.

在某些情况下，您可以通过诸如“可能”、“应该”、“期望”、“打算”、“意志”、“目标”、“估计”、“预期”、“相信”、“预测”、“设计”、“潜在”或“继续”等术语来识别前瞻性陈述，或者这些术语的否定或其变体或类似术语。例如，关于以下内容的隐含或明确陈述包括或构成前瞻性陈述：该公司正在将TNG462作为单一疗法和多种靶向和标准护理组合推进临床试验，包括来自Revolution Medicines的两种RAS（ON）三复合物抑制剂，Inc。；该公司认为TNG462与RAS（ON）抑制剂的组合可能是改变胰腺癌治疗前景的有力方法；PRMT5抑制剂的潜在组合策略；该公司认为，TNG462有可能成为多种肿瘤类型（包括胰腺癌和非小细胞肺癌）中最好的MTA合作PRMT5抑制剂；；该公司预计现金流将持续到2026年第三季度；该公司预计在2025年分享TNG462的另一个临床更新；该公司继续推进TNG260治疗STK11功能丧失突变的癌症，正在进行1/2期临床试验；Tango致力于发现。