NKGen Continues Progress Evaluating SNK01 NK Cell Therapy for Alzheimer Disease

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The phase 1/2 trial is proceeding to its phase 2 trial after safety was demonstrated in its first phase.

SNK01 is an autologous, not genetically engineered, natural killer cell therapy with enhanced cytotoxicity and activating receptor expression that is being developed by NKGen Biotech for the potential treatment of Alzheimer disease.

The company is assessing SNK01 in a phase 1/2a trial (NCT06189963) at a dose of 6 billion SNK01 cells administered every 3 years for 1 year. The phase 1 portion enrolled 3 patients in which the therapy was seen to be well-tolerated. A safety review committee evaluated data from the first portion of the trial and an internal review board subsequently cleared the program to continue in May 2024.1 The randomized, double-blind phase 2 trial will further assess efficacy and safety in a planned 30 participants with moderate Alzheimer disease.

“I am encouraged by the continued promise of NKGen’s SNK01 NK cell therapy in a difficult to treat disease such as Alzheimer,” Jesse Carr, MD, Medical Director, Behavioral Research Specialists, Glendale, California, who is independently overseeing the trial site, said in a statement.“We are seeing remarkable preliminary clinical benefit in all patients without treatment-related adverse events (AEs), including apparent improvements in cognitive function, increases in daily living activities and overall quality of life. I look forward to the potential that this novel drug candidate holds as we continue to progress the trial.”

Altogether, the phase 1/2 trial has a planned enrollment of 36 participants. The study is enrolling individuals that can provide written informed consent and comply with study requirements. A reliable caregiver, in close contact with the participant and able to communicate in the assessment language, must also be available to assist with functional endpoint evaluations and sign a separate consent form. Participants should be aged 40 to 85, have a diagnosis of Alzheimer dementia based on 2011 National Institute on Aging-Alzheimer Association guidelines, possess at least 6 years of formal education, and be fluent in the test language. Female participants of childbearing potential must have a negative pregnancy test at screening and the first visit, and both male and female participants of reproductive potential must agree to abstinence or effective contraception during the study and for 30 days after the final dose. Participants must also have positive amyloid PET evidence of Alzheimer disease within the past 6 months and a CDR-SB score between 9.5 and 16.0.

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Participants will be excluded from the study if they have significant cerebrovascular disease (Fazekas Grade 3), a history of stroke or intracranial hemorrhage related to cognitive impairment, or any substance use disorder not in remission for at least 12 months. Exclusion also applies to those with a history of cancer (excluding basal cell carcinoma) within the last 5 years, uncontrolled cardiovascular conditions, recent cerebrovascular incidents or unexplained loss of consciousness, significant pulmonary or ischemic heart diseases, liver disease or elevated liver enzymes, and gastrointestinal disorders. Immunological disorders, unstable hematological conditions, neurological or psychiatric disorders impacting cognitive function, recent history of major depression or anxiety, seizures in the past 3 years, and uncontrolled endocrine diseases also disqualify participants. Additionally, severe renal impairment, infections like HIV or hepatitis, current anticoagulant treatment (except low-dose aspirin), unstable doses of Alzheimer's medications, contraindications for MRI or PET scans, any medically unstable conditions, recent suicidal behavior or ideation, and any other condition deemed a risk by the investigator are exclusion criteria.

The study’s primary outcome measures include assessing the number of participants experiencing dose-limiting toxicity (DLT) within 3 weeks by reviewing labs, physical exams, and AEs to determine the maximum tolerated dose and the recommended phase 2 dose (RP2D). The number of participants with treatment-related AEs will be evaluated over 1 year using the CTCAE v5.0 criteria to assess the safety and tolerability of SNK01. Additionally, preliminary efficacy will be measured through changes in cognitive assessment scores from baseline over 1 year using various scales, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe (ADCS-ADL-Severe), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

The study’s secondary outcome measures assess changes in cerebrospinal fluid (CSF) and plasma biomarkers, including phosphorylated tau 181 (pTau 181), amyloid-beta 42/40 (Aβ42/40), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), over the course of one year, comparing these levels to baseline to evaluate the impact of the treatment.

“We are excited to announce another important clinical milestone in our mission to advance SNK01 as the first potential disease modifying treatment of its kind for patients with more advanced Alzheimer’s disease,” Paul Y. Song, MD, Chairman and CEO, NKGen, added.1 “The Phase 2 trial will utilize our cryopreserved SNK01 product given at the highest dose we have ever delivered, and for a full year duration. To date, SNK01 has been found to be well-tolerated with no reported drug-related adverse events (AEs). We are also very encouraged with the clinical progress we have made to date in moderate Alzheimer’s disease research and look forward to generating additional significant clinical and biomarker data from our randomized placebo-controlled Phase 2 trial.”

SNK01 as manufactured by an older manufacturing process was assessed in the proof-of-concept phase 1 ASK-AD trial (NCT04678453). The study was an open label, 3+3 dose escalation study which demonstrated that 4 doses of 1, 2, or 4 billion SNK01 cells administered intravenously were safe and crossed the blood brain barrier to reduce amyloid, tau, and alpha-synuclein proteins. Investigators also observed a dose-dependent decrease in neuroinflammation and 90% of patients had improvements or maintenance in cognitive function as assessed by Alzheimer's disease composite score (ADCOMS).2

The FDA also recently cleared NKGen Biotech’s investigational new drug application (IND) for SNK01 to be evaluated in people with Parkinson disease. NKGen expects to dose the first of 30 planned patients in a phase 1/2a clinical trial in the second half of 2024.3

REFERENCES
1. NKGen Biotech’s SNK01 NK Cell Therapy Cleared to Start Phase 2 Clinical Trial in Alzheimer’s Disease. News release. NKGen Biotech. May 20, 2024. https://www.globenewswire.com/news-release/2024/05/20/2884834/0/en/NKGen-Biotech-s-SNK01-NK-Cell-Therapy-Cleared-to-Start-Phase-2-Clinical-Trial-in-Alzheimer-s-Disease.html
2. NKGen Biotech Presents Updated NK Cell Therapy Data for Neurodegenerative Disease at the 12th Annual Alzheimer’s & Parkinson’s Drug Development Summit. News release. NKGen Biotech, Inc. April 25, 2024. https://nkgenbiotech.com/nkgen-biotech-presents-updated-nk-cell-therapy-data-for-neurodegenerative-disease-at-the-12th-annual-alzheimers-parkinsons-drug-development-summit/
3. NKGen Biotech announces FDA clearance of investigational new drug (IND) application for SNK01 NK cell therapy in Parkinson’s disease. News release. NKGen Biotech, Inc. April 30, 2024. Accessed April 30, 2024. https://nkgenbiotech.com/nkgen-biotech-announces-fda-clearance-of-investigational-new-drug-ind-application-for-snk01-nk-cell-therapy-in-parkinsons-disease/
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