Efficacy, Safety, and Tolerability of Subcutaneous Folate-Based Liposomes Encapsulating Methotrexate in Rheumatoid Arthritis Patients

Trial ID: 2023-510258-17-00
Protocol: FBL-MTX-201
Sponsor: Solfarcos Solucoes Farmaceuticas E Cosmeticas Lda.

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Diseases & Conditions

Rheumatoid arthritis

Objectives

The primary objective of this study is to evaluate the **efficacy** of Folate-based Liposomes Encapsulating Methotrexate (FBL-MTX) administered via the subcutaneous (SC) route in patients with moderate-to-severe active **rheumatoid arthritis** (RA). This is clinically relevant as it aims to determine the potential of FBL-MTX as a disease-modifying antirheumatic drug (DMARD) in patients who are either DMARD-naïve or have shown an inadequate response or intolerance to oral methotrexate (MTX).

Secondary objectives include:

Evaluating the **safety** and tolerability of FBL-MTX when administered subcutaneously in RA patients.
Assessing the pharmacokinetics of FBL-MTX following a 2.5 mg dose via the SC route in RA patients.
Determining the efficacy of FBL-MTX after an additional 12 weeks of administration in patients who achieve significant therapeutic gain after the initial 14 weeks, contingent upon the research physician's assessment and patient consent to continue the study medication.

Participants

The clinical trial focuses on evaluating the efficacy of FBL-MTX administered subcutaneously in patients with **rheumatoid arthritis**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a body mass index (BMI) ranging from 18.5 to 35.0 kg/m². The trial includes individuals with at least moderately active disease, as defined by a DAS28-CRP score greater than 3.2, and a documented history of positive rheumatoid factor and/or cyclic citrullinated peptide antibody test. Participants must be either DMARD-naïve or have an inadequate response or intolerance to oral methotrexate. The trial population was selected based on specific inclusion criteria, such as the absence of clinically relevant diseases other than rheumatoid arthritis, stable regimens of oral corticosteroids or NSAIDs if applicable, and negative test results for significant infections like HIV and hepatitis. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is a **Phase IIa** proof-of-concept study designed to evaluate the efficacy, safety, and tolerability of subcutaneous injection of folate-based liposomes encapsulating **methotrexate** (FBL-MTX) in patients with moderate-to-severe active **rheumatoid arthritis** (RA). The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The study is expected to last until July 31, 2025, with recruitment starting on June 1, 2024. Participants will be involved in the study for a maximum treatment period of 12 weeks, with the possibility of early termination if they experience significant adverse events or fail to comply with study procedures.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, disease activity, and medical history. Participants must provide written informed consent and meet specific health requirements, including stable corticosteroid and NSAID regimens if applicable. Following the screening, participants will undergo baseline assessments before randomization. Subsequent follow-up visits are scheduled at Weeks 4, 8, 12, and 14 to monitor changes in disease activity scores, assess the incidence of treatment-emergent adverse events, and evaluate pharmacokinetic parameters. The primary endpoint is the change from baseline in the Disease Activity Score for 28-joint count using C-reactive protein (DAS28-CRP) at Week 14. Secondary endpoints include the incidence of adverse events and changes in laboratory parameters and health assessment scores.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the overall efficacy and safety of the treatment. Participants may be withdrawn from the study if they develop clinically significant infections, fail to adhere to contraceptive requirements, or exhibit any exclusion criteria during the trial. The study aims to provide valuable insights into the potential of FBL-MTX as a treatment option for RA, contributing to the advancement of therapeutic strategies for this condition.

Treatment

The clinical trial involves the administration of **Methotrexate**, a chemical-origin medication, formulated as a **dispersion for injection**. The active substance, methotrexate, is encapsulated in folate-based liposomes for enhanced delivery. The pharmaceutical form is specifically designed for subcutaneous injection, ensuring targeted delivery to patients. The maximum daily dose of methotrexate is 2.5 mg, with a total maximum dose of 30 mg over the treatment period. The treatment duration is set for a maximum of 12 weeks, with dosing schedules adjusted based on a treat-to-target strategy. Participant compliance is monitored through regular assessments to ensure adherence to the dosing regimen.

In this study, methotrexate is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial focuses on evaluating the efficacy, safety, and tolerability of the subcutaneous administration of methotrexate in patients with moderate-to-severe active rheumatoid arthritis who are either DMARD-naïve or have shown an inadequate response or intolerance to oral methotrexate. The study aims to provide insights into the potential benefits of this novel formulation in improving patient outcomes.

Efficacy

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include changes from baseline in the Disease Activity Score for 28-joint count using **C-reactive protein** (DAS28-CRP) at Weeks 4, 8, 12, and 14, as well as the number of subjects achieving remission (DAS28-CRP <2.6) and low disease activity (DAS28-CRP <3.2) at these same time points. Additionally, the trial will evaluate the number of subjects achieving American College of Rheumatology (ACR) 20%, 50%, and 70% responses at Weeks 4, 8, 12, and 14. Changes from baseline in the Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Health Assessment Questionnaire - Disability Index (HAQ-DI) score, and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) at specified weeks will also be measured.

Secondary endpoints will include the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), with clinically relevant abnormalities in vital signs, 12-lead ECG, and laboratory parameters reported as adverse events. Pharmacokinetic parameters such as Cmax, time of occurrence of Cmax, and area under the concentration versus time curve (AUC) will be analyzed. Changes from baseline in DAS28-CRP and SF-36 will be assessed every 4 weeks. The efficacy parameters will be collected and analyzed at the specified time points using validated scales and laboratory tests to ensure accurate and reliable data collection throughout the trial.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Free written informed consent prior to any procedure required by the study.
Willingness to accept and comply with all study procedures and restrictions.
DMARD-naïve RA patient or RA patient with an inadequate response or intolerance to oral MTX.
Male or female participant ≥ 18 years, at the time of signing the informed consent.
Body mass index (BMI) of 18.5 to 35.0 kg/m2, inclusive.
Diagnosis of RA according to the 2010 classification criteria of the ACR/EULAR, with a Total Score ≥ 6/10.
At least moderately active disease, as defined by DAS28-CRP >3.2 at Screening and Baseline, including: a) Tender joint count (TJC) ≥ 4; b) Swollen joint count (SJC) ≥ 4; c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.
Chest X-ray performed in the previous 3 months not suggestive of tuberculosis.
If under NSAIDs therapy, must be able to be in a stable dosing regimen from at least 2 weeks before baseline up to EoS.
If under oral corticosteroid therapy (≤ 10mg per day of prednisone or equivalent), must be able to be on a stable regimen from at least 4 weeks before baseline up to up to EoS.
Eligible to start treatment with an immunomodulator.
No clinically relevant diseases other than RA captured in medical history.
No clinically relevant findings other than RA-related captured on physical examination.
No clinically relevant abnormalities on vital signs.
No clinically relevant abnormalities on 12-lead ECG.
No clinically relevant abnormalities on clinical laboratory tests.
No evidence of clinically significant active infection.
Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab).
Negative results from either the hepatitis B or C serology based on hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, total hepatitis B core antibody (IgM will be measured if total anti-hepatitis B core antibody is positive), and hepatitis C virus (HCV) antibody (anti-HCVAb) markers, except for vaccinated subjects or subjects with past resolved hepatitis.
A female participant is eligible if she meets one of the following criteria: a) is of non-childbearing potential; or b) is of childbearing potential and agrees to use an highly effective contraceptive method from at least 4 weeks prior to admission to study period until at least 6 months after the last investigational product administration.
A male participant who is sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from admission until at least 90 days following the last investigational product administration.
A male participant must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception
A male participant must be willing not to donate sperm from admission until 90 days following the last investigational product administration.
At least moderately active disease, as defined by DAS28-CRP >3.2, including: a) Tender joint count (TJC) ≥ 4 b) Swollen joint count (SJC) ≥ 4 c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.

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Exclusion Criteria

Known hypersensitivity / allergy reaction to MTX or any of the excipients.
Positive Interferon-Gamma Release Assay (IGRA), in the previous 3 months, unless the patient received previous treatment for tuberculosis (with documented evidence) or presents conditions and is willing to initiate latent tuberculosis treatment (to guarantee, at least, 4 weeks of treatment before baseline).
Known severe hypersensitivity reaction to any other drug.
Any medical condition (e.g., gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g., cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or participant safety.
History of drug or alcohol abuse.
History of short QT syndrome, long QT syndrome, or clinically significant cardiac arrhythmia.
Family history of sudden death before 40 years old, short, or long QT syndrome.
Resting heart rate < 50 bpm in ECG.
Baseline QTcF interval > 450 msec if man or > 470 msec if woman, or < 350 msec.
History of liver impairment (Child-Pugh B or C).
Systolic Blood Pressure (SBP) < 90 mmHg and/or Diastolic Blood Pressure (DBP) <45 mmHg.
SBP > 160 mmHg and/or DBP > 95 mmHg.
Estimated renal creatinine clearance (CLCr) below the lower limit of normal range (60 mL/min), based on CLCr calculation by the Cockcroft-Gault formula and normalized to an average body surface area of 1.73 m2
Positive result in drugs-of-abuse and ethanol tests.
Use of a depot injection or an implant of any drug (except for contraceptives) within the previous 6 months.
Previous treatment with any of following: a) oral or injectable gold within 4 weeks prior to Day 1; b) sulfasalazine within 4 weeks prior to Day 1; c) azathioprine within 4 weeks prior to Day 1; d) D penicillamine within 4 weeks prior to Day 1; e) cyclosporine within 8 weeks prior to Day 1; f) MTX within 4 weeks prior to Day 1; g) leflunomide within 8 weeks prior to Day 1 or a minimum 4 weeks prior to Day 1, if after 11 days of standard cholestyramine therapy; h) any cytotoxic agent, including chlorambucil, cyclophosphamide, nitrogen mustard, and other alkylating agents; i) any JAK inhibitor or other small molecule immunomodulator; j) potent Pg-p inducer (e.g. rifampin, phenytoin, carbamazepine, and St. John's wort) within 3 weeks prior to Day 1; k) metamizole and other hematotoxic drugs, anticonvulsants, and 5-fluorouracil within 4 weeks prior to admission; l) substances that may have adverse effects on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine) within 4 weeks prior to Day 1.
Participation in any clinical trial within the previous 4 weeks or 5 half-lives of the investigational medicinal product (IMP).
Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
Veins unsuitable for IV puncture on either arm (for patients in the pharmacokinetics group).
If woman of childbearing potential (WOCBP), positive pregnancy test.
If woman, she is breast-feeding.
Any other condition that the Investigator considers to render the participant unsuitable for the study.
Any recent disease or condition or treatment that, according to the Investigator, would put the participant at undue risk due to study participation.
Positive result in drugs-of-abuse and ethanol tests.
If WOCBP, positive urinary pregnancy test.
Any other condition that the Investigator considers to render the participant unsuitable for the study period.