Paxalisib

Data identify nuclear PD-L1 as a previously unaddressed driver of immunotherapy resistance and metastatic progression Jan. 30, 2026 -- Kazia Therapeutics (NASDAQ: KZIA), an oncology-focused pharmaceutical company developing novel therapies for difficult-to-treat cancers, today announced compelling preclinical and translational data supporting the development of NDL2, a potentially first-in-class protein degrader that is designed to selectively eliminate nuclear PD-L1, a previously unrecognized intracellular driver of immunotherapy resistance and metastatic progression that is not addressed by currently approved PD-1/PD-L1 antibodies. Across multiple preclinical models and patient-derived samples, NDL2 demonstrated reversal of immune exhaustion, suppression of metastatic biology, and enhanced anti-tumor activity, including in combination with anti-PD-1 therapy. By applying targeted protein degradation to one of the most clinically validated targets in oncology (PD-L1), Kazia aims to address a fundamental limitation of current immunotherapies while advancing a program aligned with growing strategic interest in protein degraders. The data were generated by Professor Sudha Rao and her team at QIMR Berghofer and collectively support nuclear PD-L1 as a mechanistically distinct and therapeutically actionable driver of immune evasion, disease progression, and metastasis. Potentially first-in-class Nuclear PD-L1 degrader: Targets a newly discovered epigenetically regulated intracellular PD-L1 species driving immune evasion, metastasis, and resistance to checkpoint inhibitors. Clear mechanistic differentiation: Unlike PD-1/PD-L1 antibodies that block extracellular signalling, NDL2 is designed to target nuclear PD-L1 proteins that are linked to aggressive and therapeutically resistant mesenchymal and stem-like cancer phenotypes. In murine triple-negative breast cancer (TNBC) preclinical models, NDL2 reduced primary tumor volume by 49% as monotherapy and 73% in combination with anti-PD-1, with 50% reduction in lung metastases in the combination setting. Favorable preclinical safety and pharmacokinetics (PK) profile: No observed toxicity, no hemolysis, preserved immune checkpoint function at the cell surface, and favorable plasma stability. Despite the transformative impact of immune checkpoint inhibitors, most solid tumors develop primary or acquired resistance, frequently accompanied by metastatic progression. Kazia's collaborators identified nuclear PD-L1 as a transcriptionally active regulator that promotes: Epithelial (benign) to Mesenchymal (aggressive) Transition (EMT) Cancer stem-like phenotypes Metastatic dissemination Immune exhaustion and evasion Nuclear PD-L1 was shown to be enriched in immunotherapy-resistant tumor cells, metastatic lesions, and circulating tumor cells (CTCs), and to regulate gene programs associated with invasion, survival, and immune suppression. Importantly, this intracellular PD-L1 pool is not addressed by existing PD-1/PD-L1 antibodies, representing a previously inaccessible resistance mechanism. Using an advanced epigenetic digital pathology and liquid biopsy platform, researchers demonstrated that: Nuclear PD-L1 is selectively enriched in resistant and metastatic tumors, including TNBC, melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer. Distinct nuclear versus cytoplasmic PD-L1 post-translational modification states can be reliably quantified in circulating tumor cells. Longitudinal liquid biopsy analysis showed that reductions in nuclear PD-L1 preceded radiographic tumor responses, supporting its potential utility as an early predictive biomarker of treatment benefit. These findings support a precision-guided development strategy, integrating therapy and diagnostics from the outset. Spatial transcriptomic and proteomic profiling revealed that NDL2 treatment was able to drive a coordinated shift toward a less aggressive tumor state and a more active anti-tumor immune response in preclinical models, including: Suppressed aggressive mesenchymal phenotype and metastasis-associated gene programs (including VIM, ZEB1, FN1); Reduced oncogenic PI3K/AKT and MAPK signalling; Increased intratumoral CD8+ cytotoxic T-cell infiltration and Granzyme B expression; and Reduced markers of T-cell exhaustion, including TIM-3 and LAG-3. In combination with anti-PD-1 therapy, these effects translated into meaningful reductions in metastatic burden in the preclinical models evaluated, supporting the potential of NDL2 to address one of the most significant limitations of current immunotherapies. Targeted protein degradation has emerged as a strategically important area of innovation in oncology, with large pharmaceutical companies increasingly prioritizing degrader-based approaches to address therapeutic resistance and intracellular targets not readily accessible through conventional modalities. Importantly, recent strategic acquisitions and collaborations in this space have been predominantly focused on research-stage and preclinical programs, reinforcing the industry's willingness to invest meaningfully in degrader technologies well ahead of clinical proof-of-concept. Against this backdrop, NDL2 uniquely combines an innovative approach with one of the most clinically validated targets in oncology. PD-L1 underpins multiple FDA-approved therapies across numerous tumor types and indications globally. By selectively degrading the nuclear, resistance-associated form of PD-L1, Kazia's approach applies a novel and differentiated mechanism to a well-established biological pathway, positioning the program favorably for future strategic partnerships and long-term value creation. NDL2 is a bicyclic peptide-based degrader, a modality that combines the selectivity of biologics with the tissue penetration, manufacturability, and pharmacokinetic advantages of small molecules. Future development of the program is supported by scalable synthetic manufacturing, favorable stability and PK characteristics, and absence of off-target nuclear effects observed to date. Initial clinical development is expected to prioritize immunotherapy-refractory solid tumors where PD-L1 biology, metastatic progression, and resistance to immune checkpoint inhibitors are well established. Based on the underlying mechanism and preclinical data, these may include triple-negative breast cancer and melanoma, with potential expansion into larger PD-1/PD-L1-treated populations such as lung and colorectal cancers. Kazia and its collaborators are advancing IND-enabling studies, with the objective of initiating first-in-human clinical trials in 2027, subject to regulatory review. Kazia also plans to present elements of this dataset at an upcoming oncology-focused scientific meeting in the second quarter of 2026, where additional details on the underlying biology, translational findings, and therapeutic rationale for nuclear PD-L1 degradation are expected to be shared. Further program updates, including expanded preclinical and translational insights, are expected to be included in the Company's next corporate presentation update scheduled for the first quarter 2026. "The pharmaceutical industry is clearly signalling that targeted protein degradation represents a transformational opportunity in oncology," said Dr. John Friend, M.D., Chief Executive Officer of Kazia Therapeutics. "Recent high-profile acquisitions of preclinical protein degrader programs underscore the strategic value being placed on this modality. What differentiates NDL2 is that we are applying protein degradation to PD-L1 as one of the most clinically validated targets in cancer, while addressing a resistance mechanism not reached by existing therapies. Unlike programs focused on narrow biology, PD-L1 protein degraders offers multiple shots on goal across tumor types and treatment settings, which we believe creates a broad strategic partnering opportunity." Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, an investigational brain penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. A completed Phase 2/3 study in glioblastoma (GBM-Agile) was reported in 2024, and discussions are ongoing for designing and executing a pivotal registrational study in pursuit of a standard approval. Other clinical trials involving paxalisib are ongoing in advanced breast cancer, brain metastases, diffuse midline gliomas, and primary central nervous system lymphoma, with several of these trials having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the U.S. Food and Drug Administration (FDA) in February 2018, and Fast Track Designation (FTD) for glioblastoma by the FDA in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumor brain metastases harboring PI3K pathway mutations in combination with radiation therapy. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA for diffuse intrinsic pontine glioma in August 2020, and for atypical teratoid / rhabdoid tumors in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumor types and has provided evidence of synergy with immuno-oncology agents. In addition to its clinical-stage programs, Kazia is advancing NDL2, a potentially first-in-class nuclear PD-L1 protein degrader program targeting a newly identified mechanism of immunotherapy resistance and metastatic progression, currently in preclinical development. 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2025年被证明是神经肿瘤学具有里程碑意义的一年，多项临床突破和监管动态为部分最具挑战性、侵袭性最强的脑肿瘤带来了全新的治疗前景。尤其是在胶质母细胞瘤（GBM）这一致死率高且耐药性强的肿瘤领域，取得了多项关键进展。随着这些突破不断重塑治疗格局并改善患者预后，以下为2025年脑肿瘤领域最具代表性的五项重要进展。 FDA释放Paxalisib有望获批用于胶质母细胞瘤的信号 在一次Type C会议后，美国食品药品监督管理局（FDA）表示，paxalisib用于胶质母细胞瘤的总生存期（OS）数据可能支持其获得常规批准，但不太可能满足加速批准的要求。该判断基于GBM-AGILE II/III期临床试验的次要OS分析结果。数据显示，在MGMT启动子未甲基化的新诊断GBM患者中，paxalisib可使OS延长3.8个月。该药物耐受性良好，未观察到新的安全性信号。Kazia Therapeutics已与FDA就关键性III期研究的设计达成一致，以进一步评估paxalisib在该人群中的疗效。 FDA授予新型胶质母细胞瘤治疗药物孤儿药资格 9月，FDA授予BA-101孤儿药资格。BA-101是一种用于胶质母细胞瘤的在研小分子治疗药物。该认定将为其开发提供包括税收抵免、费用减免以及获批后7年市场独占期在内的多项激励措施，以促进这一高未满足医疗需求领域的药物研发。BA-101靶向异常的一氧化氮信号通路，该通路在GBM肿瘤增殖和治疗耐受中发挥重要调控作用。临床前研究显示，BA-101可抑制肿瘤细胞生长，并增强替莫唑胺这一现行标准治疗的疗效。 声动力疗法在胶质母细胞瘤治疗中展现潜力 发表于Journal of Neuro-Oncology的一项研究显示，声动力疗法（SDT）可在保留正常脑组织的同时安全性地破坏胶质母细胞瘤细胞。该无创治疗方式通过低强度超声联合口服5-ALA实现，患者在单次给药后未出现不良事件。在另一项针对复发性高级别胶质瘤的I/II期临床试验中，SDT使中位OS从历史对照的6-8个月显著延长至15.7个月。该疗法能够覆盖整个大脑半球内的浸润区域，具有突破性意义。目前，针对新诊断GBM患者的随机对照试验已进入筹备阶段。 胶质瘤治疗的新希望，Dordaviprone获FDA批准 FDA于2025年8月加速批准dordaviprone用于治疗携带K27M突变的成人及儿童弥漫性中线胶质瘤患者。这是首个获FDA批准用于该侵袭性、罕见脑肿瘤的全身治疗药物，具有重要里程碑意义。支持该批准的临床试验显示，dordaviprone的客观缓解率为22%，且耐受性良好，采用每周一次口服给药方案。在相关专题访谈中，丹娜法伯癌症研究所的Patrick Wen博士深入解读了该批准的意义，并指出神经肿瘤疗效评估在方法学上的复杂性。与此同时，正在开展的III期ACTION研究仍是验证其临床获益的关键。 新型免疫治疗方案在复发性胶质母细胞瘤中显示前景 一种不含化疗的新型联合方案在复发性GBM中显示出显著潜力。该方案结合了nogapendekin alfa inbakicept-pmln、自然杀伤（NK）细胞治疗及肿瘤电场治疗。在一项纳入5例患者的探索性研究中，该方案实现了100%的疾病控制率，并获得3例客观缓解，其中2例接近完全缓解。该治疗策略通过白介素-15激动剂激活免疫细胞，从而克服肿瘤诱导的免疫抑制。初步数据显示，所有受试者的淋巴细胞减少状态均得到逆转。目前，一项2期临床试验正在招募患者，以进一步评估该免疫增强联合方案的安全性和疗效。 Reference 1.https://www.targetedonc.com/view/the-top-brain-cancer-news-of-2025