The FDA has granted fast track designation to NG-350A, an investigational oncolytic immunotherapy developed by Akamis Bio, for the treatment of patients with mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC). This regulatory milestone recognizes the significant unmet medical need in this patient population and aims to expedite the development of potentially transformative treatments.
Addressing a Growing Clinical Challenge
"The NG-350A fast track designation from the FDA is a recognition of the significant unmet need for new therapies to treat LARC," stated Dr. Oliver Rosen, chief medical officer at Akamis Bio. "The global incidence of LARC continues to rise, with a particularly alarming increase of this cancer among younger populations."
The designation is particularly significant given that patients with pMMR tumors account for approximately 90% of LARC cases. According to the company, this population has the greatest need for evolution in the standard of care to include treatments that may enable patients to avoid surgical interventions.
Novel Mechanism of Action
NG-350A represents a clinical-stage T-SIGn® therapy delivered intravenously and engineered to encourage intratumoral expression of a CD40 agonist monoclonal antibody. This mechanism stimulates activation of antigen-presenting cells (APCs) within solid tumors and their draining lymph nodes. The activated APCs then draw T cells to the tumor site, introducing a strong antitumor immune response.
Clinical Development Program
FORTRESS Trial Design
The therapy is currently being explored in combination with chemoradiotherapy in the phase 1b FORTRESS trial (NCT06459869), which began enrolling patients in April 2025. This open-label, single-arm, multicenter study plans to enroll approximately 30 patients aged 18 years or older with histologically confirmed adenocarcinoma of the rectum with locally advanced disease and microsatellite stable or pMMR status.
The trial is being conducted at four locations: Ohio State University Comprehensive Cancer Center in Columbus, The University of Texas MD Anderson Cancer Center in Houston, and two locations in the United Kingdom, in London and Sutton. The study has an estimated primary completion date of February 28, 2026, and an expected study completion date of approximately January 30, 2029.
Patients enrolled in FORTRESS will receive NG-350A plus oral capecitabine and long-course intensity-modulated radiotherapy during a 12-week active study treatment period. The primary outcome measure is the proportion of patients achieving a clinical complete response at week 12, while secondary outcome measures include incidence and severity of adverse effects, clinical response outcomes, and MRI-based tumor regression grade.
Early Clinical Evidence
Data from a phase 1a/1b study (NCT03852511) in heavily pretreated patients with metastatic or advanced epithelial tumors (n = 25) demonstrated that NG-350A was well tolerated regardless of administration approach. The study evaluated both intravenous administration, comprising 4 dose levels each with infusions on days 1, 3, and 5 of 57-day periods, and intratumoral injection approaches.
Key findings from this early study included:
- Continued persistence of the drug in blood samples up to 7 weeks following the last dose, especially with higher IV dose levels
- A dose-dependent pattern with IV infusion, with 4 patients positive for vector DNA in biopsies at day 57
- Transgene messenger RNA from replicating NG-350A identified in 5 of 12 patients who received the agent IV and in 1 of 9 patients who had intratumoral administration
- Sustained boosts in inflammatory cytokines after dosing, particularly at higher IV dose levels
- No evidence of transgene-related or off-target viral toxicity
Broader Development Pipeline
Beyond FORTRESS, NG-350A is being investigated in the open-label, nonrandomized, multicenter, phase 1a/1b FORTIFY study (NCT05165433), which explores the combination of NG-350A and pembrolizumab (Keytruda) in patients with metastatic or advanced epithelial tumors.
"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," Rosen noted. "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."
Disease Burden and Market Context
Colorectal cancer represents the third most common cancer diagnosed in both men and women in the United States, with approximately 145,000 people being newly diagnosed every year. Among this population, approximately 45,000 people are diagnosed with rectal cancer, of which around 60% have locally advanced disease, meaning it has spread to nearby tissues or lymph nodes. Nearly all of these patients, or approximately 90%, have mismatch repair-proficient tumors, which are tumors that have a functional DNA repair system.
