Clinical trial NCT06750432: PMN310 in Patients With Early Alzheimer's Disease (PRECISE-AD)
Official title: A Phase 1b, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PMN310 in Patients With Early Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Alzheimer Disease, Early Onset
Lead sponsor: ProMis Neurosciences, Inc
Sponsor class: INDUSTRY
First posted: 2024-12-27
Enrollment: 128
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: There will be 3 sequential escalating dose cohort groups. Dose groups are 350 mg, 700 mg, and 1400 mg administered as a single 60-minute infusion.
Primary purpose: TREATMENT

Brief summary: This Phase 1b study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple IV infusions of PMN310 in patients with early Alzheimer's disease.

Detailed description: This study is a Phase 1b, randomized, double-blind, placebo controlled, multi-ascending dose study of repeat doses of PMN310 to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of multiple intravenous infusions of PMN310 in patients with early Alzheimer's disease. This study will evaluate 3 dose levels (350 mg, 700 mg, and 1400 mg are planned). Patients will be randomly assigned 3:1, PMN310: placebo.

Each patient will receive PMN310 or placebo once every 28 days for a total of 12 infusions.

Eligibility criteria: Inclusion Criteria:

1. Patient and caregiver provide written informed consent.
2. Ambulatory male or female ≥ 50 years of age with adequate visual and auditory abilities to perform the cognitive and functional assessments in the opinion of the Investigator.
3. Meets all of the following clinical criteria for mild cognitive impairment (MCI) due to AD or mild AD dementia at Screening:

   1. National Institute on Aging-Alzheimer's Association criteria for MCI due to AD or mild AD dementia (Stage 3 and 4)
   2. Global Clinical Dementia Rating (CDR) of 0.5 1.0 and memory box score ≥ 0.5 at Screening and Baseline
   3. Objective impairment in episodic memory as indicated by at least 1 standard deviation (SD) below age-adjusted mean in the Wechsler Memory Scale IV-Logical Memory (subscale) II
   4. MMSE score between ≥ 20 and 28 inclusive at Screening, and
   5. Either a positive amyloid PET scan within 6 months of Screening consistent with AD, or a positive amyloid PET during Screening.
4. Body mass index between 18.5 and 35 kg/m2 inclusive.
5. Patients of childbearing potential must meet the following criteria:

   1. Male and female patients with reproductive potential must be willing to use an approved double barrier contraceptive method (e.g., condom plus intrauterine device, condom plus hormonal contraception, or double barrier device) during and for 120 days after the last dose of study drug
   2. Females of childbearing potential must have a negative serum pregnancy test during Screening, a negative urine pregnancy test prior to each dose, and not currently be breastfeeding.
6. Patients of non-childbearing potential must meet 1 of the following:

   1. Post-menopausal female (i.e., 12 consecutive months of spontaneous amenorrhea, age \> 51 years, and follicle-stimulating hormone \> 30 mIU/mL)
   2. Surgically sterile (i.e., bilateral oophorectomy or hysterectomy).
7. Has a reliable caregiver who agrees to accompany the patient at study visits, accurately report patient's status, provide feedback on functional and safety assessments, and ensure compliance to study requirements.
8. Confirmed to have acceptable venous access for blood collections and IV administration of study drug (i.e., PMN310 or placebo).
9. Patients taking Food and Drug Administration-approved acetylcholinesterase inhibitors or memantine are allowed as long as the dose has been stable for at least 3 months prior to Screening.

Exclusion Criteria:

1. Living in a continuous care or long-term care nursing facility. Patients in outpatient living at home or in an assisted living facility are eligible for the study.
2. Medical or neurological condition (other than AD; i.e., Parkinson's disease, Huntington's disease, frontal temporal dementia, dementia with Lewy bodies) judged to be contributing to the patient's cognitive impairment.
3. Laboratory and electrocardiogram (ECG) abnormalities:

   1. QT (QTcF) interval \> 450 msec (males) or \> 470 msec (females) during Screening
   2. Alanine aminotransferase ≥ 2 × upper limit of normal (ULN); aspartate aminotransferase ≥ 2 × ULN; total bilirubin ≥1.5 × ULN during Screening
   3. Creatinine clearance \< 30mL/min during Screening.
4. In the opinion of the Investigator, any clinically significant current or relevant history of physical or psychiatric illness (including suicidal risk, ideation, behavior, or suicide attempts), any medical disorder that may require treatment or make the patient unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures.
5. Clinically significant recurrent disease or unstable disease that could affect the action, absorption, or disposition of the investigational product, or could affect clinical or laboratory assessments, such as (but not limited to) the following:

   1. History of unstable angina, myocardial infarction, chronic heart failure, or clinically significant conduction abnormalities within 1 year prior to Screening
   2. Indication of clinically significant impairment of renal or liver function, including hepatitis B surface antigen, or hepatitis C virus antibody at Screening
   3. Poorly managed hypertension (systolic \> 160 mmHg and/or diastolic \> 95 mmHg) or hypotension (systolic \< 90 mmHg and/or diastolic \< 60 mmHg). Two repeated assessments during Screening are allowed
   4. Known uncontrolled diabetes defined by hemoglobin A1c \> 7.5 or insulin dependent diabetes.
6. Experienced a significant systemic illness, as judged by the Investigator, within 30 days of the first dose of study drug.
7. Seizure in the 3 years prior to Screening.
8. History of a clinically significant medical condition that would interfere with the patient's ability to comply with study instructions, would place the patient at increased risk, or might confound the interpretation of the study results.
9. History of prior malignancy (except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix).
10. Brain MRI with evidence of any of the following findings: \>4 microhemorrhages; \>1 lobar microhemorrhage; area of superficial siderosis; subarachnoid hemorrhage; any other hemorrhage \>10 mm; \>2 lacunar infarcts or cortical infarct; subjects with severe perivascular spaces or with what matter hyperintensities in a multisport pattern will require PI review prior to inclusion.
11. History of stroke or transient ischemic attack within 12 months prior to Screening.
12. Contraindication to PET or brain MRI.
13. Negative PET scan with any amyloid-targeting ligand within 6 months of Screening or during Screening.
14. Pregnant or breastfeeding.
15. History of alcohol abuse and/or other substance abuse within 12 months prior to dosing with study drug.
16. Positive test for alcohol (using an alcohol breath test) or illicit drugs of abuse at Screening.
17. Documented history of human immunodeficiency virus antibody.
18. Coronavirus disease 2019 (COVID-19) infection within 2 weeks of Screening or ongoing symptoms of COVID-19 at Screening.
19. Currently receiving an anti-amyloid treatment, either marketed (aducanumab, lecanemab, donanemab) or investigational or has received anti amyloid therapy within 9 months prior to Screening. In the case of investigational treatment, those known to have received placebo will not be excluded.
20. Contraindication to undergoing lumbar puncture (LP) including: sensitivity to local anesthetic, international normalized ratio (INR) \> 1.4 or other coagulopathy, platelet cell count of \< 120,000/µL, infection at the desired LP site, current use of anti-coagulant medication except for low dose aspirin, degenerative arthritis, spinal scoliosis, back surgery, suspected increased intracranial pressure on history or neurologic exam, non-communicating hydrocephalus or intracranial mass, or prior history of spinal mass or trauma and/or other known clinically significant spinal abnormalities.
21. Donated blood or blood products (e.g., plasma, platelets) within 56 days prior to first dose of study drug.
22. Received an investigational active agent (e.g., not placebo) within the last 30 days or 5 half-lives, whichever is longer (if known).
23. Known history of severe allergic reaction or hypersensitivity to any components of the PMN310 infusion.

Primary outcomes:
measure: Safety and tolerability of PMN310 following repeat intravenous infusions of PMN310
timeFrame: Up to Day 365
measure: Biomarker response to PMN310 following repeat intravenous infusions of PMN310
timeFrame: Up to Day 365
measure: Safety and tolerability of PMN310 following repeat intravenous infusions of PMN310
timeFrame: Up to Day 365
measure: Biomarker response to PMN310 following repeat intravenous infusions of PMN310
timeFrame: Up to Day 365
Secondary outcomes:
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Assessment of the immunogenicity of PMN310 following repeat intravenous infusions
timeFrame: Up to Day 365
measure: Assessment of biomarker response to PMN310
timeFrame: Up to Day 365
measure: Assessment of cortical and hippocampal volume
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on CDR-SB
timeFrame: Up to Day 365
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Pk profile of PMN310 with repeat dosing
timeFrame: Up to Day 365
measure: Assessment of biomarker response to PMN310
timeFrame: Up to Day 365
measure: Assessment of biomarker response to PMN310
timeFrame: Up to Day 365
measure: Assessment of biomarker response to PMN310
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on ADAS-Cog 14
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on ADCS-ADL
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on iADRS
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on CGI Scale
timeFrame: Up to Day 365
measure: Preliminary efficacy of repeat doses of PMN310 on MMSE
timeFrame: Up to Day 365
Other outcomes:
Locations:
city: Irvine
country: United States
facility: Irvine Center for Clinical Research
state: California
city: Long Beach
country: United States
facility: Healthy Brain Research
state: California
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Deerfield Beach
country: United States
facility: Quantum Laboratories
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Miami
country: United States
facility: Finlay Medical Research
state: Florida
city: Miami
country: United States
facility: Gonzalez MD and Aswad MD Health Services, Optimus U Corp
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Orlando
country: United States
facility: Charter Research
state: Florida
city: Stuart
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: The Villages
country: United States
facility: Charter Research
state: Florida
city: Wellington
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: Winter Park
country: United States
facility: Conquest Research, LLC
state: Florida
city: Columbus
country: United States
facility: Columbus Memory Center, LLC
state: Georgia
city: Decatur
country: United States
facility: CenExel iResearch, LLC
state: Georgia
city: Plymouth
country: United States
facility: Headlands Eastern MA LLC
state: Massachusetts
city: Toms River
country: United States
facility: Advanced Memory Research Institute of NJ
state: New Jersey
city: Albany
country: United States
facility: Alzheimer's Disease Research Center
state: New York
city: Matthews
country: United States
facility: Flourish Research
state: North Carolina
city: North Canton
country: United States
facility: Neuro Behavioral Clinical Research, Inc.
state: Ohio
city: Plymouth Meeting
country: United States
facility: Keystone Clinical Studies, LLC
state: Pennsylvania
city: Dallas
country: United States
facility: Kerwin Medical Center
state: Texas
Study officials:
References: