FDA Fast Tracks Innovative Cell Therapy Troculeucel for Alzheimer Disease

Paul Y. Song, MD

According to a new announcement, the FDA has granted fast track designation to NKGen Biotech’s troculeucel, a novel cell-based, patient specific ex vivo expanded autologous natural killer (NK) cell, immunotherapeutic candidate as a potential treatment for Alzheimer disease (AD). The company is currently enrolling patients with moderate AD for its phase 2a trial, with updated clinical data expected by the end of 2025.

Also known as SNK01, the novel NK cell manufacturing technology enables large-scale ex vivo production and expansion of NK cells. Expanded NK cells are an autologous biological product using the patient’s own cells that are cultivated and expanded outside the body and then reinfused into the same patient. The NK cell expansion process produces activated, fully functional non-genetically modified NK cells with both immunoregulatory and cytotoxic potential.

"We are pleased with the FDA’s decision to grant Fast Track designation for troculeucel. This decision underscores the significant unmet need for effective treatments for patients with moderate AD. We specifically targeted the moderate stage population as they represent about 30% of all Alzheimer cases and most, if not all, of the current focus has been on early/mild patients," Paul Y. Song, MD, chairman and chief executive officer at NKGen, said in a statement.

He added, "This designation comes after promising safety and efficacy results from our Phase 1 trial, which shows early signs of clinical benefit in patients treated with troculeucel. Receiving Fast Track designation will significantly accelerate the drug development process, bringing us one step closer to delivering this promising therapy to AD patients in need, and ensuring faster access to a potentially life-changing treatment."

Results from the phase 1 trial, which evaluated troculeucel in patients with either mild, moderate, or severe AD, were published in Alzheimer’s Research & Therapy shortly after the FDA’s fast track designation. The small-scale trial featured 11 patients with a median age of 79 years old (range, 56-85) who received troculeucel intravenously every 3 weeks for a total of 4 treatments using a 3 + 3 dose escalation design (1 x 10⁹, 2 x 10⁹, and 4 x 10⁹ cells).

The study’s primary end point was safety, as treatment with troculeucel resulted in no drug-related adverse events (AEs). Overall, the most common treatment-emergent AEs were puncture site pain (63.6%), vessel puncture pain (36.4%), anemia (36.4%), and hypertension (18.2%). One subject in Cohort 2 experienced Grade 3–5 adverse events, including multiple organ dysfunction syndrome, sepsis, and ulcers, leading to a fatal outcome five days after receiving a second infusion of 2 × 10⁹ cells. Ultimately, these events were attributed to underlying diabetes mellitus and not related to troculeucel.

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At week 11 of the study, 7 of the 10 subjects with available data demonstrated an improvement or remained stable on Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. The rest of the patients showed an increase in the sum of scores of 2.0 points and, thus, were considered to decline in function. At week 22, a point at which patients had been off of troculeucel for 12 weeks, 6 of 9 patients (66.7%) had stable or improved CDR-SB scores compared with baseline.

On Alzheimer’s Disease Assessment-Cognitive Subscale (ADAS-Cog), 3 of 10 (33.3%) patients showed an improvement of at least 4 points, considered MCID. Five patients (50%) were stable at week 11, and the remaining 2 patients showed a decline at week 11 of more than 3 or 4 points. At week 22, only 2 of 9 (22.2%) patients improved their final score compared with baseline, while 6 of the remaining 7 were said to remain stable.

In terms of biomarkers, 60-70% of participants showed decreases in α-synuclein and pTau181 levels and 40-50% demonstrated positive changes in cerebrospinal fluid (CSF) levels of amyloid-ß (Aß)-42, Aß42/40 ratio, total tau, and pTau217. Notably, these findings were observed fairly evenly across the 3 cohorts. Additionally, at week 11 and at the end of the study (week 22), investigators observed decreases in neuroinflammatory markers of glial fibrillary acidic protein (GFAP) and YKL-40 by 60% in treated patients.

At week 11, subjects with stable or decreased Alzheimer Disease Composite Score (ADCOMS) scores often showed decreases in pTau181, YKL-40, and, to a lesser extent, pTau217, α-synuclein, and GFAP. By week 22, these improvements persisted, with reduced neuroinflammation (GFAP/YKL-40) and lower tau/synuclein burden, while Aβ-42 and the Aβ42/Aβ40 ratio remained unaffected.

REFERENCES
1. NKGen Biotech Receives U.S. FDA Fast Track Designation for Troculeucel for the Treatment of Moderate Alzheimer’s Disease. News release. NKGen Biotech. February 12, 2025. Accessed February 13, 2025. https://www.globenewswire.com/news-release/2025/02/12/3024994/0/en/NKGen-Biotech-Receives-U-S-FDA-Fast-Track-Designation-for-Troculeucel-for-the-Treatment-of-Moderate-Alzheimer-s-Disease.html
2. Zúñiga CH, Acosta BI, Menchaca R, et al. Treatment of Alzheimer's Disease subjects with expanded non-genetically modified autologous natural killer cells (SNK01): a phase I study. Alzheim Research & Ther. 2025;17(40). doi:10.1186/s13195-025-01681-2