Akamis Bio has announced the enrollment of the first patient in its Phase 1b FORTRESS trial, evaluating the novel immunotherapy NG-350A in patients with locally advanced rectal cancer (LARC). The proof-of-concept study will assess the efficacy and safety of NG-350A when combined with standard-of-care chemoradiotherapy in patients who have at least one risk factor for local or distant recurrence.
NG-350A is part of Akamis Bio's proprietary Tumor-Specific Immuno-Gene Therapy (T-SIGn®) platform. It is designed to be administered intravenously and selectively deliver a CD40 agonist monoclonal antibody to tumor sites, triggering activation of antigen-presenting cells (APCs) within the tumor microenvironment and draining lymph nodes.
"We have previously demonstrated that intravenously administered T-SIGn® therapeutics can reach both primary and metastatic tumor sites to drive local expression of immunotherapeutic payloads," said Dr. Oliver Rosen, Chief Medical Officer at Akamis Bio. "The results from prior clinical studies have provided what we believe is a clear roadmap for the design of the FORTRESS trial, where our aim is to demonstrate the safety and efficacy of NG-350A in LARC in order to advance a new therapeutic approach that can improve the current standard of care for patients living with this disease."
Trial Design and Objectives
The FORTRESS trial (NCT06459869) is a multi-center, open-label, single-arm study that plans to enroll approximately 30 adult patients with histologically confirmed adenocarcinoma of the rectum that is locally advanced (clinical stage II-III based on pelvic MRI). During the 12-week active treatment period, participants will receive NG-350A in combination with oral capecitabine and long-course intensity-modulated radiotherapy.
The primary endpoint of the study is the proportion of patients achieving a clinical complete response (cCR) at week 12. Secondary endpoints include the incidence and severity of adverse events, clinical response outcomes, and MRI-based tumor regression grade.
The FORTRESS trial builds upon Akamis Bio's earlier CEDAR study, which demonstrated significantly higher complete response rates in LARC patients treated with a combination of the company's first-generation immunotherapy and chemoradiotherapy compared to expected outcomes with standard-of-care chemoradiotherapy alone.
Mechanism of Action and Prior Clinical Evidence
NG-350A represents a next-generation approach to cancer immunotherapy. Once delivered to tumor sites, it drives the expression of CD40 agonist antibodies, which activate antigen-presenting cells. These activated APCs then recruit T cells to the tumor vicinity, potentially generating a potent anti-tumor immune response.
The therapy has already been evaluated in two clinical studies: the FORTITUDE study (as monotherapy) and the FORTIFY study (in combination with pembrolizumab) in patients with metastatic or advanced epithelial tumors. Across these studies, NG-350A has demonstrated a consistent safety and tolerability profile with no observed transgene-related or off-target toxicities. Importantly, these studies have provided strong evidence of tumor-selective delivery, replication, and transgene expression.
Addressing an Unmet Medical Need
Colorectal cancer ranks as the third most common cancer diagnosed in both men and women in the United States, with approximately 145,000 new cases annually. About 45,000 of these cases are specifically rectal cancer, and approximately 60 percent of those patients have locally advanced disease at diagnosis.
LARC is characterized by cancer that has spread to nearby tissues or lymph nodes. In these patients, tumors have either grown through muscle into the outermost layers of the rectum or, in more severe cases, penetrated the rectal wall where they may attach to other organs or structures and/or spread to lymph nodes.
Current standard-of-care treatment for LARC typically involves chemoradiotherapy followed by surgery. However, there remains a significant need for approaches that can improve complete response rates and potentially allow for organ preservation strategies.
Potential Clinical Impact
If successful, the FORTRESS trial could establish NG-350A as an important new component of treatment for patients with LARC. By leveraging the body's immune system to target cancer cells more effectively, this approach aims to improve upon current treatment paradigms.
The ability of T-SIGn® therapeutics to selectively target tumor tissue while sparing healthy cells represents a potential advantage over conventional therapies. Additionally, the systemic administration of NG-350A could address both the primary tumor and potential micrometastases that may not be visible on imaging.
As the FORTRESS trial progresses, oncologists and patients will be watching closely to see if this innovative approach can deliver on its promise of improving outcomes in locally advanced rectal cancer.
