Astellas Bets $1.34 Billion on Preclinical IL-12 Fusion With No Human Proof

Astellas Secures Option for Audax's Novel Immuno-Oncology Candidate DAX-044

Astellas Pharma Inc. and Audax Biosciences Pty Ltd have announced an exclusive option and license agreement for DAX-044, Audax’s lead immuno-oncology AVIKINE® candidate. This agreement grants Astellas an exclusive option for a worldwide license to develop, manufacture, and commercialize DAX-044, while Audax retains an option to co-fund and co-promote the drug in Australia and New Zealand. The total potential transaction value is up to US$1.34 billion, excluding royalties. Audax will receive US$285 million in upfront and option exercise payments and will advance DAX-044 into a Phase 1 study, expected to commence in 2027. DAX-044 is an investigational immune-targeted IL-12 antibody-cytokine fusion designed to selectively activate anti-tumor immune responses in solid tumors.

• Astellas has entered a strategic partnership with Audax Biosciences for DAX-044, an immuno-oncology candidate, with a total potential transaction value of up to US$1.34 billion. This includes US$285 million in upfront and option exercise payments, up to US$1.05 billion in development and commercial milestones, and tiered double-digit royalties on worldwide net sales.
• DAX-044 is an investigational immune-targeted interleukin-12 (IL-12) antibody-cytokine fusion, leveraging AVIKINE® technology. It is designed to concentrate IL-12's immune-activating activity within the tumor microenvironment, aiming to overcome the systemic toxicity challenges historically associated with IL-12-based therapies and demonstrating potential best-in-class therapeutic index in preclinical studies.
• Audax Biosciences will fund and continue the development of DAX-044 into a Phase 1 clinical study, anticipated to begin in 2027. Upon Astellas' exercise of its option, it will assume sole global responsibility for development, manufacturing, and commercialization, with Audax retaining an option to co-fund and co-promote DAX-044 in Australia and New Zealand.

How DAX-044's IL-12 Fusion Compares in Solid Tumors

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Astellas' Strategic Focus on Emerging Immuno-Oncology MoAs

Recent literature converges on DNA damage response modulation, next-generation immune checkpoint expansion, and tumor-targeted cytotoxic delivery as key directions for solid tumors. Strategies focus on widening therapeutic window through targeted delivery, optimized scheduling, and biomarker-guided patient selection.

• Tumor-targeted topoisomerase I delivery with gapped PARP inhibition: CRLX101, a nanoparticle topoisomerase I inhibitor, combined with olaparib using gapped scheduling in trial NCT02769962 in 24 patients with advanced solid tumors. Maximum tolerated dose was CRLX101 12 mg/m² every two weeks and olaparib 250 mg twice daily on days 3-13 and 17-26. Pharmacokinetics were consistent with monotherapy of each agent, and γH2AX kinetics revealed elevated DNA damage with combination versus CRLX101 alone. Among 19 evaluable patients, 2 had partial responses and 6 had stable disease, with median overall survival 6.06 months, progression-free survival 2.34 months, and duration of response 7.95 months.

• WEE1 checkpoint inhibition: Azenosertib (ZN-c3), a selective and orally bioavailable WEE1 inhibitor, blocks WEE1-dependent cell cycle checkpoints. Antiproliferative activity is exemplified by reduction of pY15-CDK1 levels and increases in DNA damage markers, allowing cancer cells to prematurely enter mitosis leading to mitotic catastrophe and apoptosis. Preclinical models show robust tumor growth inhibition and delayed tumor regrowth after cessation of treatment, with Phase I monotherapy showing preliminary clinical activity in advanced solid tumors.

• ATR and broader DNA damage response inhibition: Berzosertib 240 mg/m² intravenously twice per week tested in four cohorts: T1 ATRX-mutant leiomyosarcoma, T2 ATM-mutant solid tumors, T3 solid tumors with mutations in replication stress-associated genes, and T4 SDH-deficient gastrointestinal stromal tumors (GIST). Patients with SDH-mutant GIST had longest median progression-free survival (229 days) with stable disease as best response, with decreased pS345-CHK1 indicating target engagement and increases in γ-H2AX and pKAP1 in a subset. Increased SLFN11 expression on treatment correlated with clinical benefit (HR = 0.045; 95% confidence interval, 0.005-0.400). Related approaches target ATR, ATM and DNA-dependent protein kinase to potentiate immunogenic cell death and prime adaptive immune response.

• PARP inhibition plus immune checkpoint blockade: PARP-based therapies work through inhibition of single-strand DNA repair leading to DNA damage, increased tumor mutational burden, and enhancing PD-L1 expression. Efficacy demonstrated in breast, ovarian, and prostate cancers predominately in BRCA-mutated tumors, with moderate overall response or disease control rates in wildtype BRCA and gastrointestinal tumors. GUIDANCE trial evaluates chemotherapy-free maintenance with durvalumab 1500 mg every 4 weeks and olaparib 300 mg twice daily in HRD-positive extensive disease small-cell lung cancer without progression after first-line platinum, etoposide and durvalumab, with primary endpoint progression-free survival by RECIST 1.1.

• Novel immune checkpoints and combinations: New generation inhibitors target T cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte activating gene 3 (LAG-3), and Ig V domain suppressor for T cell activation (VISTA). Rationale is combining multiple inhibitors to overcome resistance to inhibitors targeting PD-1/PD-L1 and/or CTLA-4 through inhibition of multiple pathways and immune checkpoints.

• Topoisomerase II-directed and isoform-selective strategies: Clinically important TOP2-targeted drugs including etoposide, doxorubicin, and mitoxantrone interfere with the TOP2 catalytic cycle resulting in DNA damage and cell death, with efficacy in leukemias, lymphomas, and solid tumors such as breast, lung, ovarian, and testicular cancers. Advances focus on distinct roles of TOP2A and TOP2B isoforms, TOP2 poisons versus catalytic inhibitors, resistance pathways, structure-based drug design, isoform-selective inhibitors and targeted protein degradation technologies.

• Antibody-drug conjugates with topoisomerase I and PBD payloads: MTX-13, a PTK7-directed conjugate of antibody Ab13 to eight molecules of exatecan through T1000 self-immolative moiety, causes cytotoxic activity through DNA damage and apoptosis induction with bystander killing, with highest non-severely toxic dose ≥30 mg/kg in monkeys. GenSci139, an EGFR×HER2 bispecific ADC conjugated via hydrophilic peptide-cleavable linker to topoisomerase I inhibitor payload, induced DNA damage, apoptosis, and hallmarks of immunogenic cell death. ITC-6102RO, a B7-H3-targeting ADC conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine, using Ortho Hydroxy-Protected Aryl Sulfate linkers, induced S phase arrest, DNA damage, and apoptosis.

• Epigenetic killing via DNMT1 inhibition: Azacytidine and decitabine act via DNA hypomethylation rather than DNA damage via DNA methyltransferase 1 inhibition, compared to non-DNA-damaging DNMT1 inhibitor GSK-3685032 across over 600 human cancer models. Histone deubiquitinase USP48 is recruited to newly hypomethylated CpG islands and deubiquitinates non-canonical histones, with loss of USP48 sensitizing hematologic and solid tumors to DNMT1 inhibition in vitro and in vivo.

• Microbiome-metabolite and mitochondria-centered modulation: Pro-carcinogenic metabolites such as secondary bile acids and bacterial genotoxins like colibactin drive malignancy through chronic inflammation, direct DNA damage, and oncogenic signaling, while protective metabolites predominantly short-chain fatty acids like butyrate counteract progression through immune modulation, selective apoptosis, and epigenetic regulation. Mitochondria-targeted radiotherapy sensitization modulates mitochondrial ROS production and antioxidant defenses, with release of damage-associated molecular patterns such as mitochondrial DNA, ATP, and cytochrome c promoting dendritic cell maturation and antitumor immunity. Au and TiO nanoparticles provide physical or chemical dose enhancement with hydroxyl radicals to overcome hypoxic radioresistance.

Overcoming Current Limitations in Solid Tumor Treatment

Current treatment approaches for solid tumors face limitations rooted in both assessment frameworks and tumor biology. Response criteria oversimplify treatment failure, while heterogeneity, immunosuppression, and drug resistance constrain durable efficacy across modalities.

• Response assessment oversimplifies progression biology. Progression in oncology trials is most often defined by Response Evaluation Criteria in Solid Tumors (RECIST), a framework that standardizes response assessment but oversimplifies the biological complexity of treatment failure. Efforts such as immune RECIST (iRECIST) have adapted these criteria for atypical response patterns seen with immunotherapy, yet the velocity of disease spread, the tropism or organ site of failure, and the burden of progression each carry prognostic and therapeutic significance and remain underexplored in trial endpoints.

• Immunotherapy delivers low response rates and acquired resistance. The overall response rate (ORR) of immunotherapy in patients with EC is lower than 30%, and most patients initially treated with immunotherapy are likely to develop acquired resistance (AR) over time. Insufficient clinical response rate, acquired drug resistance, and immune-related adverse reactions have limited its wide application, which is closely related to the immunosuppressive network formed by the dynamic evolution of the tumor microenvironment (TME) during the treatment process.

• Intratumoral heterogeneity and immune escape drive therapy failure. Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion, with tumor cells evolving to reduce neoantigen generation and the mutational burden to escape the anti-tumor response.

• Chemotherapy resistance and cross-resistance limit efficacy. Approximately 50% of CRC patients fail to respond to one or more drugs in either regimen, in many cases due to inherent or acquired drug resistance. Primary and metastatic tumors expressing EDR to 5FU + FA demonstrated up to 58% cross-resistance to a variety of chemotherapy agents, and approximately 20% of tumors showed EDR to either FULFOX or FOLFIRI.

• Biomarker and data standardization gaps impede progress. Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Prospective, standardized collection of lesion-level and temporal data is essential to validate these approaches and mitigate biases inherent to retrospective analyses.

Astellas's Bold Bet on Next-Gen IL-12 Immuno-Oncology

Astellas Pharma's substantial investment in Audax Biosciences' DAX-044 marks a significant strategic maneuver within the fiercely competitive immuno-oncology landscape. This exclusive option and license agreement, valued at up to US$1.34 billion, with a considerable US$285 million in upfront and option exercise payments, underscores Astellas's commitment to expanding its oncology pipeline with next-generation immune-targeted therapies. By backing an investigational IL-12 antibody-cytokine fusion, Astellas is making a high-stakes bet on a novel mechanism designed for selective activation of anti-tumor immune responses in solid tumors. This approach aims to harness the potent anti-cancer effects of IL-12 while potentially mitigating broader systemic challenges, a critical area of innovation in oncology.

For Audax, this partnership provides crucial validation for its proprietary AVIKINE® platform and secures the necessary capital to advance DAX-044 into a Phase 1 study, anticipated in 2027. This early-stage collaboration highlights a growing trend of large pharmaceutical companies seeking innovative assets from biotech partners to replenish and diversify their pipelines.

However, several considerations accompany this promising development:

• Early-stage attrition: DAX-044 is still in preclinical development, with Phase 1 trials not expected until 2027. The journey from early-stage research to market approval is fraught with high attrition rates, and many promising candidates fail to demonstrate sufficient safety or efficacy in human trials.

• Competitive pressure: The immuno-oncology field is already crowded with numerous approved therapies and a robust pipeline of emerging treatments. DAX-044 will need to establish a clear differentiation in its therapeutic profile to carve out a meaningful market position.

• Translational risk: As a novel immune-targeted fusion protein, the successful translation of preclinical data into a favorable clinical safety and efficacy profile in humans remains a key hurdle.

Ultimately, this deal positions Astellas to potentially capture a share of the evolving immuno-oncology market with a differentiated asset, while providing Audax with the resources and expertise to bring its innovative science closer to patients. The success of DAX-044 will hinge on its ability to navigate the complexities of clinical development and demonstrate a compelling therapeutic advantage.