Interleukine-2 (IL-2) Plus Semaglutide in Alzheimer's Disease

A Phase Ib Clinical Trial, Using Interleukin-2 (IL-2) and Semaglutide in Patients With Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of dementia. Despite major research efforts, effective treatments that slow or stop disease progression remain limited. Growing evidence suggests that inflammation in the brain and the body plays a key role in the onset and progression of AD. In particular, immune cells called regulatory T cells (Tregs), which normally help control inflammation, are impaired in AD individuals. This leads to increased activity of harmful immune pathways that worsen brain injury. Interleukin-2 (IL-2) is a drug that can restore the function of Tregs. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are a class of drugs currently used to treat diabetes and obesity. Beyond their metabolic effects, GLP-1RAs also reduce inflammation, protect brain cells, and improve cellular energy balance. Laboratory studies, including our own, show that combining IL-2 with semaglutide has stronger effects than either drug alone. Together, they enhance Treg function, dampen harmful inflammatory responses, and improve cell survival. These findings support testing IL-2 plus semaglutide as a novel combination therapy for AD. We now propose a clinical trial to evaluate the safety, feasibility, and biological effects of this strategy. The study will enroll 30 individuals with AD, ages 50 to 86, who have a confirmed diagnosis by amyloid PET brain imaging and a Mini-Mental State Exam score between 16 and 26. Participants will be randomly assigned to one of three groups: (1) placebo, (2) low-dose IL-2 alone, or (3) IL-2 combined with semaglutide. Throughout the trial, participants will undergo regular medical exams, blood tests, and safety monitoring. We will measure how the treatment affects Tregs and other immune cells, inflammatory markers in blood and CSF, and established Alzheimer's biomarkers such as amyloid beta, tau, and neurofilament light chain. Cognitive and functional assessments will also be conducted to explore potential benefits on memory and daily living skills. If successful, this study will provide the first evidence that a dual immunotherapeutic strategy can safely modify disease-related processes in AD. Such findings would lay the foundation for larger clinical trials and could open the door to a new, multimodal approach to slowing or preventing Alzheimer's progression.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Dementia (AD)
• Intervention / Treatment: Drug: Placebo; Drug: IL-2 (Aldesleukin); Drug: Semaglutide Plus IL-2

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Alireza Alireza, MD; Phone Number: 713-441-1150; Email: afaridar@houstonmethodist.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Research Institute
      • Contact: Alireza Faridar, MD; Phone Number: 713-441-1150; Email: afaridar@houstonmethodist.org
      • Contact: Email: afaridar@houstonmethodist.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of probable Alzheimer disease according to National Institute on Aging-Alzheimer's Association (NIA-AA) criteria13.
• Male or female age 50 to 86 years
• MMSE between 16-26
• Albumin greater than or equal to 3.0mg/dL
• White Blood Count (WBC) >3,500/mm3; platelets >100,000/mm3; hematocrit (HCT) >32%.
• INR<1.4
• If on medications affecting cognition (rivastigmine, galantamine, donepezil, memantine), participants must be on stable dosage for at least 4 weeks prior to screening and should remain at a stable dosage during the course of the study.
• English language speaking
• Formal education of eight or more years
• Stable pharmacological treatment of any other chronic conditions for at least 30 days prior to screening
• A family member or caretaker who is expected to be consistently available, administer study drugs of IL-2 and attend study visits throughout the study.
• For AD patients with limited decision-making capacity, the legally authorized representative (LAR) should be present and consent based on the patient's best interest.

Exclusion Criteria:

• Any untreated bacterial, fungal or viral infection
• Renal dysfunction indicated by serum creatinine greater than 1.5 mg/dL
• Hepatic impairment indicated by Alanine aminotransferase level (ALT) and aspartate aminotransferase (AST) greater than two times normal
• Clinically significant pulmonary dysfunction, including a history of chronic pulmonary disease (e.g., chronic obstructive pulmonary disease [COPD]) associated with functional limitation, or FEV₁ < 75% of predicted for age and height when pulmonary function testing indicated to evaluate ongoing respiratory symptoms
• Clinically significant cardiac dysfunction, including a history of uncontrolled cardiac arrhythmias, prior cardiac tamponade, or unstable angina or myocardial infarction within 3 months prior to screening, or clinically significant abnormalities on baseline electrocardiogram (ECG). LVEF< 40% in echocardiography if clinically indicated based on ongoing cardiac symptoms or abnormal ECG findings
• Hypersensitivity or allergy to IL-2
• History of severe gastrointestinal disease Hospitalization or change of chronic concomitant medication within one month prior to screening.
• History of hemorrhage or infarct or > 3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (e.g., abscess or brain tumor with the exception of small incidental meningiomas) in prior CT or MRI.

• Clinical or laboratory findings consistent with:

  1. Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeld-Jakob Disease(CJD), Down's syndrome, etc.)
  2. Other neurodegenerative condition (Parkinson's disease, amyotrophic lateral sclerosis, etc.)
  3. Seizure disorder
  4. History of infectious, metabolic or systemic diseases affecting the central nervous system (syphilis, vitamin B12 or folate deficiency, other laboratory values, etc.)
  5. Clinically significant abnormal T4 or TSH

• Clinically significant, advanced or unstable disease that may interfere with outcome evaluations, such as:

  1. Respiratory insufficiency
  2. Bradycardia (<45/min.) or tachycardia (>100/min.)
  3. Poorly managed hypertension (systolic >160 mm Hg and/or diastolic >95 mm Hg) or hypotension (systolic <90 mm Hg and/or diastolic <60 mm Hg)
  4. Uncontrolled diabetes defined by HbA1c >8%
• History of cancer within 3 years of screening with the exception of fully excised non-melanoma skin cancers or non-metastatic prostate cancer that has been stable for at least 6 months.
• History of acute/chronic hepatitis B or C and/or carriers of hepatitis B
• History of organ allografts
• Current treatment with insulin or insulin secretagogues (including sulfonylureas or meglitinides)
• Prior GLP-1 RA administration or natural GLP1 supplements intake within the past 6 months
• Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulty, etc.).
• Within 4 weeks of screening visit or during the course of the study, concurrent treatment with antipsychotic agents (except risperidone ≤1.5 mg/day, quetiapine ≤100 mg/day, olanzapine ≤5 mg/day, and aripiprazole ≤10 mg/day), antiepileptics (except lamotrigine, gabapentin and pregabalin for nonseizure indications), centrally active anti-hypertensive drugs (e.g., clonidine, l-methyl dopa, guanidine, guanfacine, etc.), opiate analgesics, systemic corticosteroids, psychostimulants, antiparkinsonian medications (except for non-parkinsonian indications) and mood stabilizers (e.g., valproate, lithium), sedatives, and anxiolytics with the exception that use of short- to medium-acting benzodiazepines for treatment of insomnia is permitted, however, use of sedatives or hypnotics should be avoided for 8 hours before administration of cognitive tests.
• Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors and memantine.
• Use of concomitant CYP-metabolized medications with a narrow therapeutic index including warfarin, calcineurin inhibitors, or theophylline)
• Suspected or known drug or alcohol abuse, i.e., more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) indicated by elevated MCV significantly above normal value at screening
• Suspected or known allergy to any components of the study treatments.
• Intake of investigational drug within the previous 30 days or five half-lives of the investigational drug, whichever is longer.
• Contraindication to undergoing an LP including, but not limited to: inability to tolerate an appropriately flexed position for the time necessary to perform an LP; INR >1.4 or other coagulopathy; platelet count of <100,000/μL; infection at the desired lumbar puncture site; taking anti-coagulant medication within 90 days of screening (Note: low dose aspirin is permitted); suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma.
• Any condition, which in the opinion of the investigator makes the patient unsuitable for inclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo Administration	Drug: Placebo; Placebo
Active Comparator: Low-dose recombinant human IL-2 (LD IL-2) monotherapy; Low-dose recombinant human IL-2 (LD IL-2) monotherapy (aldesleukin) administered subcutaneously once daily for 5 consecutive days, repeated every 4 weeks for six cycles.	Drug: IL-2 (Aldesleukin); aldesleukin administered subcutaneously once daily for 5 consecutive days, repeated every 4 weeks for six cycles
Active Comparator: IL-2 Plus Semaglutide combination therapy; Combination therapy with LD IL-2 on the same schedule as Arm B plus subcutaneous semaglutide, administered with stepwise dose escalation administered once weekly	Drug: Semaglutide Plus IL-2; Combination therapy with LD IL-2 plus subcutaneous semaglutide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety and the tolerability of IL-2 plus Semaglutide in AD patients	Number of participants with adverse events and with abnormal laboratory findings (serum chemistry, hematology).	6 months treatment phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the impact of IL-2 plus Semaglutide administration on the blood Treg population	Change in Treg percentage out of total # of CD4 cells from baseline to month 6	6 months treatment phase

Collaborators and Investigators

• Sponsor: The Methodist Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 10, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Semaglutide; Immunotherapy; inflammation; IL-2
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Pathological Conditions, Signs and Symptoms; Alzheimer Disease; Inflammation; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukins; Lymphokines; Interleukin-2; semaglutide; aldesleukin
• Other Study ID Numbers: PRO00042175

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No