aKLmRNA-mediated Protein Replacement Therapy

Official title

A Randomized, Double-Blind, Placebo-controlled Phase 1b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (Protein Expression) of Multiple Administrations of Alpha Klotho mRNA (aKLmRNA), aKL003

Overview

This is a Phase 1b randomized, double-blind, placebo-controlled study to assess the safety and tolerability of a proprietary aKLmRNA formulated in lipid nanoparticles. Approximately 21 subjects will be enrolled. Each subject will receive a total of two injections during the study. The cohort will consist of approximately 21 subjects, with each receiving 0.5 mg aKLmRNA (AKL003) or placebo. Subjects will be randomized in a 2:1 ratio (active treatment:placebo). The placebo will be saline, matching the active treatment in both appearance and volume.

Detailed description

Systemic reactogenicity events, such as fever, headache, myalgia, fatigue, nausea/vomiting, diarrhea, and increased heart rate, will be assessed as adverse events using the WHO grading scale.

All subjects will be informed about potential clinical activity and reactogenicity, which may be influenced by increased aKL serum levels or the lipid nanoparticle formulation. Participants will be instructed to contact the study site to schedule an on-site visit in case of any unexpected adverse event (unscheduled visit, see Schedule of Activities table). All such occurrences will be documented as part of the drug candidate's safety evaluation.

Subjects will provide self-reported data on clinical activity, duration, and effects via a digital diary and in-person assessments during scheduled clinic visits. Additionally, they will be provided with an electronic memory aid for daily symptom tracking throughout the study. Participants will also complete a Quality-of-Life Impact Questionnaire (QOLIQ) at baseline and weekly throughout the study. Furthermore, continuous monitoring of heart rate, heart rate variability, and sleep quality will be conducted using a minimally invasive Oura ring.

Participants randomized to placebo who successfully complete the randomized Phase I study may be offered participation in an optional open-label extension to receive Klotho. The purpose of the open-label extension is to provide access to the investigational product and to collect additional safety and pharmacokinetic data. Participation in the open-label extension is voluntary and subject to predefined eligibility criteria and safety review. Data from the open-label extension will be analyzed separately and will not contribute to the primary analysis of the randomized Phase I study.

Participants randomized to placebo in the randomized Phase I study will not receive investigational product during the blinded treatment period. In order to provide eligible participants access to Klotho after completion of the randomized study phase and to collect additional safety and pharmacokinetic data, an optional open-label extension (OLE) is planned.

The open-label extension is not intended to evaluate efficacy and is not part of the primary analysis of the randomized Phase I study.

Interventions

• Drug aKLmRNA (AKL003)
  Each subject will be treated every 4 weeks for a total of 2 times with aKLmRNA via i.v.
• Other Placebo
  Each subject will be treated every 4 weeks for a total of 2 times with TRIS buffer

Primary outcome measures

• Overall incidence and severity of unsolicited AEs by treatment group [Time frame: From first dose through end of study (Day 60)]
• • Overall incidence and severity of solicited reactogenicity events by treatment group [Time frame: From first dose through end of study (Day 60)]

Secondary outcome measures (2)

• • Increase in serum aKL levels over the mean of the baseline values until end of study [Time frame: Baseline through Day 60]
• • aKL serum level by treatment group [Time frame: Baseline through Day 60]

Eligibility criteria

Subjects will only be included in the trial if they meet all following criteria:

• Written informed consent (ICF) signed and dated by the patient
• Ability and willingness to co-operate with the investigator and to comply with the requirements of the entire study.
• Healthy subjects, 25 50 to 75 90 years of age
• Sexually active females of childbearing potential and male partners of sexually active females of childbearing potential must use medically accepted form of contraception or be surgically sterile (hysterectomy or bilateral oophorectomy).
• Women of childbearing potential and men with female partners of childbearing potential must use an effective method of birth control during the course of the trial and for at least 90 days after the last dose in a manner such that risk of failure is minimized. Male participants should refrain from donating sperm during the intervention period and for at least 90 days after the last dose of study intervention (see additional considerations in section 5.3)
• Females of childbearing potential must have a negative pregnancy test at the time of enrollment (serum hCG test)

Exclusion criteria

Subjects will be excluded from the trial if they present one or more of the following conditions:

• Known of suspected allergy to IMP or related procedure
• Known or suspected allergy, or history of anaphylaxis, to vaccines or their excipients, if considered relevant by the Investigator
• Contraindications for the use of emergency treatments
• Clinically relevant findings at screening, e.g., active diseases of any kind particularly infections
• History of chronic alcohol or drug abuse/ dependence within the past 5 yearsUse of any prescription or over-the-counter medication within 7 days prior to first dosing or planned use during the study period, with the exception of medications considered medically necessary and administered at a stable dose and regimen. Stable medication is defined as medication for which no initiation, discontinuation, or dose adjustment has occurred for at least 3 monthsprior to first dosing and for which no change is anticipated during the study period. Occasional use of paracetamol (acetaminophen) and/or ibuprofen is permitted at the discretion of the investigator.
• Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub investigators, or study nurse) or employee of the Sponsor
• Known or suspected pregnancy, planned pregnancy of lactation
• Clinically significant unstable psychiatric illness in the past 6 months
• Presence of autoimmune disease, autoinflammatory syndrome, or immunological deficiency syndrome (including human immunodeficiency virus (HIV) infection)
• Relevant cardiovascular, hepatic, gastroenterological, respiratory, endocrinological, hematologic disease, or any other condition that, in the Investigator's opinion, could interfere with the analyses of safety and efficacy in this study, unless patient has been on stable doses of medication for any of these concurrent illnesses for at least 3 months prior to study entry
• Presence of end stage kidney failure (on dialysis)
• Current or anticipated use of immunosuppressive drugs such as, but not limited to, azathioprine, cyclosporine, methotrexate, tacrolimus, or mycophenylate within 2 months or any myelosuppressive or cytotoxic chemotherapies within the 12 months prior to the screening visit. Use of systemic corticosteroids equivalent to ≥20mg/week prednisone within the past 4 weeks before screening and during the course of the study (intranasal or inhaled steroids for allergies/asthma is allowed)
• History within the last 2 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment; or has a life expectancy of <2 years.
• Patients with long covid-19 showing long-term neurological sequelae within the past 12 months at the time of screening
• Has had a history within the last 5 years of a serious infectious disease affecting the brain, liver, lung and/or kidneys.
• Refractory epilepsy (has had seizures within the past 2 years)
• Hypothyroidism or vitamin B12 deficiency (patients with corrected hypothyroidism or vitamin B12 deficiency are eligible for the study provided that treatment has been stable for 3 months before study entry)
• Patient has hemochromatosis
• Pre-existing PEG antibodies of significant levels

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Honduras · 1 center

• GARM — Roatán

Identifiers

NCT: NCT07544420 · AKL003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗