Akari Therapeutics Reports Promising Preclinical Data for AKTX-101 in K-Ras Mutant Pancreatic Cancer
核心洞察
Akari Therapeutics announced preclinical data showing AKTX-101, a Trop2 (搜索)-targeting ADC with novel spliceosome-modulating payload PH1 (搜索), demonstrated single-digit nanomolar cytotoxic potency against K-Ras G12V (搜索) mutated pancreatic cancer (搜索) cell lines.
The K-Ras G12V (搜索) mutation drives one-third of all pancreatic ductal adenocarcinoma (搜索) cases, representing a significant unmet medical need with median overall survival of only 1.4 years.
AKTX-101 outperformed daraxonrasib, an investigational K-Ras (搜索) inhibitor from Revolution Medicines, in multiple pancreatic cancer (搜索) cell lines during preclinical testing.
Akari Therapeutics announced key preclinical data demonstrating the therapeutic potential of its novel antibody-drug conjugate AKTX-101 in pancreatic cancer (搜索) driven by K-Ras (搜索) mutations, targeting one of the deadliest and most treatment-resistant forms of cancer. The data highlights AKTX-101's ability to kill K-Ras G12V (搜索) mutated cancer cell lines in preclinical models, potentially addressing a cancer with the lowest survival rates.
Addressing Critical Unmet Need in Pancreatic Cancer
Pancreatic cancer (搜索) represents one of the most lethal malignancies, characterized by late-stage diagnosis, resistance to standard chemotherapy, and high mortality rates. In the United States, approximately 60,000 people are diagnosed annually with pancreatic cancer, and about 50,000 die from this aggressive disease. The most common form, pancreatic ductal adenocarcinoma (搜索) (PDAC (搜索)), accounts for the vast majority of cases and has few effective treatment options, particularly for tumors driven by the K-Ras G12V (搜索) mutation.
The K-Ras G12V (搜索) mutation serves as the oncogenic driver for one-third of all PDAC (搜索) cases, with median overall survival of just 1.4 years. Current standard of care treatments include 5-fluorouracil (5-FU) containing chemotherapy regimens such as FOLFIRINOX (overall survival of 1.5 years) or gemcitabine plus nab-paclitaxel (overall survival of 1.3 years), which offer poor outcomes, significant toxicities, and poor quality of life.
Novel Mechanism of Action
AKTX-101 is an antibody-drug conjugate that delivers a novel RNA spliceosome modulating payload, PH1 (搜索), into cancer cells expressing Trop2 (搜索), a protein commonly found at high levels in pancreatic and other hard-to-treat solid tumors. Once inside the tumor, the PH1 payload disrupts normal RNA splicing, a fundamental process cancer cells depend on to survive, grow, and spread.
Trop2 (搜索) is ubiquitously expressed at high levels in PDAC (搜索) and represents a potentially good ADC target in pancreatic cancer (搜索), having been validated in other solid tumors including lung and breast cancers. Within pancreatic cancer, K-Ras (搜索) mutated PDAC is associated with higher levels of Trop2 protein compared to PDAC with normal K-Ras, making a Trop2 ADC like AKTX-101 a potential precision therapeutic for this specific tumor mutation.
Promising Preclinical Results
The latest data for AKTX-101 in K-Ras G12V (搜索) PDAC (搜索) builds on preclinical evidence disclosed earlier in a patent filing. In the new study, AKTX-101 exhibited single-digit nanomolar cytotoxic potency in all K-Ras G12V PDAC cell lines tested. Significantly, AKTX-101 outperformed daraxonrasib in multiple PDAC cell lines. Daraxonrasib is an investigational therapy being developed by Revolution Medicines to treat patients with cancers driven by K-Ras (搜索) mutations.
"These preclinical data provide a rationale for Akari to develop AKTX-101 in areas of severe unmet need and historically very difficult cancers, such as K-Ras (搜索) mutant PDAC (搜索)," said Abizer Gaslightwala, President and Chief Executive Officer of Akari Therapeutics. "We aspire to tackle hard-to-treat cancers and are excited to see our novel spliceosome-modulating payload PH1 (搜索), conjugated to an ADC, demonstrate activity against aggressive cancers like K-Ras mutant tumors."
Clinical Development Timeline
The company plans to present this preclinical data at an upcoming scientific conference and is currently advancing AKTX-101 towards a first-in-human trial, expected to initiate in late 2026, with preliminary safety and efficacy data anticipated in 2027. In parallel, Akari is pursuing discussions with potential partners on developing the PH1 (搜索) payload for new ADCs targeting other antigens expressed in a range of cancer tumors.
Differentiated ADC Platform
Unlike current ADCs that use tubulin inhibitors and DNA damaging agents as their payloads, PH1 (搜索) is a novel spliceosome modulator designed to disrupt RNA splicing within cancer cells. This splicing modulation has been shown in preclinical animal models to induce cancer cell death while activating immune cells to drive robust and durable activity. In preclinical studies, AKTX-101 has shown significant activity and prolonged survival relative to ADCs with traditional payloads.
Additionally, AKTX-101 has the potential to be synergistic with checkpoint inhibitors and has demonstrated prolonged survival as both a single agent and in combination with checkpoint inhibitors, compared to appropriate controls. The company believes AKTX-101 may have therapeutic potential to control an aggressive form of untreatable pancreatic cancer (搜索), with preliminary data supporting K-Ras G12V (搜索)-mutated PDAC (搜索) as another high unmet need opportunity for the drug candidate.