A Biomarker-directed Study of XPro1595 in Patients With Mild to Moderate Alzheimer's

• ClinicalTrials.gov Identifier: NCT03943264
• Recruitment Status: Completed
• First Posted: May 9, 2019
• Last Update Posted: February 17, 2022
• Sponsor: Inmune Bio, Inc.
• Collaborator: Alzheimer's Association
• Information provided by (Responsible Party): Inmune Bio, Inc.

Study Description

Brief Summary:

The purpose of this study is to evaluate safety and target engagement of XPro1595 in Alzheimer's patients with biomarkers of inflammation.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: XPro1595	Phase 1

Detailed Description:

The study is designed as a multicentre, phase 1b open-label study. The objectives of this study are to determine the safety, tolerability, and efficacy of XPro1595 in patients with mild to moderate Alzheimer's disease and elevated blood levels of the inflammatory biomarker high sensitivity c-reactive protein (hs-CRP).

XPro1595 is a second-generation inhibitor of tumor necrosis factor (TNF) that selectively neutralizes soluble TNF, an inflammatory factor implicated in Alzheimer's pathology.

A key element of this study is to identify Alzheimer's patients that are most likely to benefit from XPro1595 treatment. Enrollment is limited to patients with evidence of peripheral inflammation using elevated blood inflammatory biomarkers. For instance, hs-CRP is an inflammatory biomarker elevated in the blood of some Alzheimer's patients and elevated CRP has been shown to predict response to TNF inhibitors in multiple other diseases.

Alzheimer's patients with elevated blood inflammatory biomarkers will be enrolled in a 12-week study to determine the safety and the ability of XPro1595 to reduce neuroinflammation using a combination of invasive and non-invasive biomarkers of inflammation. The study will identify the dose of XPro1595 to be used in a larger Phase II disease modification study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1b Open-Label, Dose-Identification Study of XPro1595 in Patients With Mild to Moderate Alzheimer's Disease With Elevated High Sensitivity C-reactive Protein in Blood
• Actual Study Start Date: November 20, 2019
• Actual Primary Completion Date: June 30, 2021
• Actual Study Completion Date: September 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 0.3 mg/kg XPro1595; 0.3 mg/kg of XPro1595 will be administered via subcutaneous injection once a week for 12 weeks.	Drug: XPro1595; XPro1595 will be delivered by subcutaneous injection once a week; Other Name: INB03, DN-TNF, XENP345
Experimental: 1.0 mg/kg XPro1595; 1.0 mg/kg of XPro1595 will be administered via subcutaneous injection once a week for 12 weeks.	Drug: XPro1595; XPro1595 will be delivered by subcutaneous injection once a week; Other Name: INB03, DN-TNF, XENP345
Experimental: 3.0 mg/kg XPro1595; 3.0 mg/kg of XPro1595 will be administered via subcutaneous injection once a week for 12 weeks.	Drug: XPro1595; XPro1595 will be delivered by subcutaneous injection once a week; Other Name: INB03, DN-TNF, XENP345

Outcome Measures

Primary Outcome Measures :

1. The number of patients with a treatment-emergent adverse event throughout 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   Adverse events will be assessed by clinical and laboratory measures
2. The percentage of patients with a treatment-emergent adverse event throughout 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   Adverse events will be assessed by clinical and laboratory measures

Secondary Outcome Measures :

1. Changes from baseline in high sensitivity C-reactive protein in the blood and cerebral spinal fluid following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   To compare changes in high sensitivity C-reactive protein
2. Changes from baseline in inflammatory cytokines in the blood and cerebral following 12 weeks of treatment with XPro1595 spinal fluid [ Time Frame: 12 weeks ]
   To compare changes in Inflammatory cytokines; including but not limited to tumor necrosis factor, interleukin-1, and interleukin-6
3. Changes from baseline in blood and cerebral spinal fluid levels of amyloid beta following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   To compare changes in amyloid in cerebral spinal fluid
4. Changes from baseline in cerebral spinal fluid levels of tau following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   To compare changes in tau in cerebral spinal fluid
5. Change from baseline in FreeWater content (edema) using magnetic resonance imaging following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   To compare changes in FreeWater content as a proxy of neuroinflammation following 12 weeks of treatment with XPro1595
6. Change from baseline in the Mini-Mental State Examination (MMSE) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   The Mini-Mental State Examination (MMSE) provides a comprehensive measure of cognitive function. The maximum possible score is 30 and patients scoring below 23 are classified as having cognitive impairment as follows, mild (19 to 23), moderate (10 to 18), severe (below 9).
7. Change from baseline in the Digit Symbol Substitution Test (DSST) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   The Digit Symbol Substitution Test (DSST) is a cognitive test that consists of digit-symbol pairs. The patient records the corresponding symbol to each presented digit in 90 seconds. The total number of correct symbols is counted to provide a score between 0 and 133. Higher scores indicate better cognitive functioning.
8. Change from baseline in the Verbal Fluency Test following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   In the Verbal Fluency Test, patients are given a letter and asked to name as many words as they can that begin with that letter in 60 seconds. The number of correct responses is counted. A higher number of responses indicates better cognitive functioning.
9. Change from baseline in the Neuropsychiatric Inventory (NPI) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   Neuropsychiatric Inventory (NPI) is a measure of frequency and severity of common psychiatric symptoms related to dementia using a 12-question measure. For each question, a score is given for frequency, severity and caregiver distress. Total scores range from 0 to 144. A higher score means greater neuropsychiatric disturbance.
10. Change from baseline in the Bristol Activities of Daily Living Scale (BALDS) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
    Bristol Activities of Daily Living Scale (BADLS) is a questionnaire that measures the impact of Alzheimer's disease on daily activities using a 20-item questionnaire. Total scores range from 0 to 60. A higher score indicates a greater disturbance in daily living.
11. Change from baseline in the Memory-Enhanced Retrospective Evaluation of Treatment Observer Reported Global Impression of Improvement (MERET OBSRO-C) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
    Memory-Enhanced Retrospective Evaluation of Treatment Observer Reported Global Impression of Improvement (MERET OBSRO-C) evaluates caregivers' self-reports of treatment efficacy with self-prompted memory aids regarding their clinical experiences obtained prior to treatment initiation.
12. Evaluate changes in the Memory-Enhanced Retrospective Evaluation of Change from baseline Global Impression of Improvement (MERET PGI-C) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
    Memory-Enhanced Retrospective Evaluation of Treatment Patient Global Impression of Improvement (MERET PGI-C) evaluates patients self-reports of treatment efficacy with self-prompted memory aids regarding their clinical experience obtained prior to treatment initiation. Patient's global impression of (PGI-I) ratings will be obtained using a web-based interface prior to and following playback of impromptu patient recordings obtained prior to the start of treatment (MERET).

Other Outcome Measures:

1. Change from baseline in Breath volatile organic compounds (BVOCs) following 12 weeks of treatment with XPro1595 [ Time Frame: 12 weeks ]
   Breath volatile organic compounds (BVOCs) is a non-invasive method of measuring biological processes in exhaled breath that can be used to inform on disease and treatment-related states.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Aged 18 years and above at screening;
2. Diagnosed with probable AD defined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria;
3. Has hsCRP levels ≥1.5mg/L,OR HbA1c ≥ 6DCCT %, OR Erythrocyte Sedimentation Rate (ESR) ≥10 mm/h, OR APOE4 positive (at least one APOE4 allele);
4. Female of childbearing potential (FCBP) must have confirmed negative urine pregnancy test at Screening;
5. All female of childbearing potential (FCBP) and male patients who are sexually active with a female of childbearing potential must agree to use a highly effective contraception during the treatment period and until 90 days after the last dose of treatment for sexually active males whose partners are FCBP or until 30 days after the last dose of treatment for FCBP.
6. Consents to having lumbar punctures;
7. Consents to apolipoprotein E (APOE) genotyping(if status unknown);
8. Provide written informed consent prior to any study procedures being performed;
9. Has a caregiver who either lives in the same household or interacts withthe patient at least 4 hours per day and at least 4 days per week, who is knowledgeable about the participant's daytime and night-time behaviours and who canbe available to attend all clinic visits in personat which caregiver assessments are performed.Patients with caregivers that do not meet this criterionbut are determined by the investigator as able to provide an adequate assessment of the patient may also participate with prior approval from the sponsor.

Exclusion Criteria:

1. Patients taking cholinesterase inhibitors, memantine, or antidepressant medication for less than 45 days from Day 1 (i.e. must be on stable dose for at least 45 days prior to Day 1);
2. Have taken within the last 45 days from Day 1; corticosteroids or other immunosuppressive drugs, thalidomide or other TNF active drugs, minocycline.
3. Enrolled in another clinical trial where patients receive treatment with investigational drug or device or have received treatment on another AD clinical trial within the last 60 days from Day 1;
4. Unable to tolerate lumbar puncture or taking medicine where lumber punctures are contraindicated (anti-coagulants besides daily 100mg of aspirin);
5. A prior organ or stem cell transplant;
6. A major adverse cardiac event within 6 months before screening;
7. Lymphoma, leukaemia, or any malignancy within the past 5 years with the exception of malignancies with negligible risk of metastasis or death, such as basal cell or squamous cell carcinomas of the skin or cervical carcinoma in situ that have been resected with no evidence of metastatic disease for 3 years;
8. Jaundice, active hepatitis, or known hepatobiliary disease (except asymptomatic cholelithiasis);
9. Positive screening assessment for viral hepatitis B surface antigen or hepatitis C virus (HCV) antibody and positive HCV ribonucleic acid or human immunodeficiency virus, or a history of illicit drug injecting;
10. Seated blood pressure of ≥ 165/105 mmHg at screening;
11. Unable to comply with the study procedures and assessments;12.Known hypersensitivity to investigational product or its excipients;

Contacts and Locations

Locations

Australia, New South Wales

KaRa MINDS

Macquarie Park, New South Wales, Australia, 2113

Australia, Queensland

Mater Medical Research Institute

Brisbane, Queensland, Australia, 4101

Australia, South Australia

Central Adelaide Local Health Network

Woodville, South Australia, Australia, 5011

Australia, Victoria

Alfred Heath

Melbourne, Victoria, Australia, 3004

Eastern Clinical Research Unit

Melbourne, Victoria, Australia, 3128

Sponsors and Collaborators

Inmune Bio, Inc.

Alzheimer's Association

Investigators

• Principal Investigator: Terrence O'Brien, MD; The Alfred

More Information

Additional Information:

Related Info 

Part the cloud grant information - Alzheimer's Association 

Publications of Results:

McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis. 2009 Apr;34(1):163-77. doi: 10.1016/j.nbd.2009.01.006.

Cavanagh C, Tse YC, Nguyen HB, Krantic S, Breitner JC, Quirion R, Wong TP. Inhibiting tumor necrosis factor-alpha before amyloidosis prevents synaptic deficits in an Alzheimer's disease model. Neurobiol Aging. 2016 Nov;47:41-49. doi: 10.1016/j.neurobiolaging.2016.07.009. Epub 2016 Jul 25.

Sama DM, Mohmmad Abdul H, Furman JL, Artiushin IA, Szymkowski DE, Scheff SW, Norris CM. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One. 2012;7(5):e38170. doi: 10.1371/journal.pone.0038170. Epub 2012 May 29.

MacPherson KP, Sompol P, Kannarkat GT, Chang J, Sniffen L, Wildner ME, Norris CM, Tansey MG. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol Dis. 2017 Jun;102:81-95. doi: 10.1016/j.nbd.2017.02.010. Epub 2017 Feb 24.

• Responsible Party: Inmune Bio, Inc.
• ClinicalTrials.gov Identifier: NCT03943264
• Other Study ID Numbers: XPRO1595-AD; 18PTC-R-592167 ( Other Grant/Funding Number: Alzheimer's Association )
• First Posted: May 9, 2019
• Last Update Posted: February 17, 2022
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Inmune Bio, Inc.:

inflammation; Biomarker; TNF

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders