Evaluation of Axatilimab Efficacy, Safety, and Tolerability in Idiopathic Pulmonary Fibrosis: A 26-Week Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2022-502954-15-00
Protocol: SNDX-6352-0506
Sponsor: Syndax Pharmaceuticals Inc.

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Diseases & Conditions

Idiopathic pulmonary fibrosis

Objectives

The primary objective of this study is to evaluate the effect of **axatilimab** compared to placebo on lung function in subjects with **idiopathic pulmonary fibrosis** (IPF) from baseline to Week 26. This is clinically relevant as IPF is a progressive lung disease characterized by declining lung function, and assessing the impact of axatilimab could provide insights into potential therapeutic benefits for patients.

Secondary objectives include:

Assessing the effect of axatilimab compared to placebo on disease progression from baseline to Week 26.
Evaluating changes in additional parameters of lung function from baseline to Week 26.
Assessing the impact on quality-of-life measures from baseline to Week 26.
Evaluating the effect on gas exchange from baseline to Week 26.

Participants

The clinical trial involves a total of **87 participants** diagnosed with **idiopathic pulmonary fibrosis** (IPF). The study population includes both male and female subjects aged 40 years and older. Participants were selected based on their documented diagnosis of IPF, confirmed through high-resolution computed tomography (HRCT) and, if necessary, lung biopsy. The trial includes individuals who are either treatment-naïve or have been on a stable dose of IPF medications such as nintedanib or pirfenidone for at least 12 weeks prior to screening. Participants are required to have a forced vital capacity (FVC) of at least 45% of the predicted normal value and a forced expiratory volume in 1 second (FEV1)/FVC ratio of 0.7 or higher. The study also considers lifestyle factors, requiring participants to agree to use highly effective contraception methods during the study and for a specified period afterward. The trial population includes vulnerable groups, and all participants must have an estimated minimum life expectancy of at least 12 months for non-IPF-related conditions. The selection process ensures that participants can comply with the study protocol and have considered all medicinal treatment options and potential lung transplantation before enrolling in the study.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **axatilimab** in subjects with **idiopathic pulmonary fibrosis** (IPF). The trial will span a duration of 26 weeks, with the primary objective being to assess the effect of axatilimab compared to placebo on lung function from baseline to Week 26. The study will involve multiple centers and will include a placebo group for control purposes. Participants will be randomly assigned to receive either axatilimab or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including a documented diagnosis of IPF and specific lung function parameters. Following successful screening, participants will undergo regular follow-up visits to monitor their health status, adherence to the study protocol, and any adverse events. The end-of-study visit will occur at the conclusion of the 26-week period, where final assessments will be conducted to evaluate the primary and secondary endpoints, such as the annualized rate of decline in forced vital capacity (FVC) and time to disease progression.

Participant involvement is expected to last for the entire 26-week duration of the trial. However, conditions that may lead to early termination from the study include significant non-compliance with the study protocol, withdrawal of consent, or the occurrence of serious adverse events that, in the opinion of the investigator, warrant discontinuation of the study drug. The trial aims to provide valuable insights into the potential benefits of axatilimab for individuals with IPF, contributing to the understanding of treatment options for this condition.

Treatment

The clinical trial involves the administration of **Axatilimab**, an investigational medication, to evaluate its efficacy, safety, and tolerability in subjects with **Idiopathic Pulmonary Fibrosis (IPF)**. Axatilimab is provided as a **solution for infusion** and is administered via **intravenous infusion**. The dosing regimen is based on a milligram per kilogram (mg/kg) body weight basis, although specific dosage amounts are not detailed in the provided data. The treatment period for Axatilimab is set for a maximum of 26 weeks. Axatilimab is a monoclonal antibody targeting the colony-stimulating factor 1 receptor (CSF1R) and is developed by Syndax Pharmaceuticals, Inc. The active substance is derived from a protein of other origin, and it is also known by synonyms such as UCB-6352 and SNDX-6352.

The study also includes a **placebo** as a comparator treatment to assess the effect of Axatilimab on lung function in subjects with IPF. The placebo is used in a double-blind manner, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The placebo is administered in a similar pharmaceutical form and route as Axatilimab, although specific details regarding its composition and administration are not provided. The use of a placebo is critical in maintaining the study's integrity by providing a baseline to compare the effects of the experimental treatment.

Efficacy

The efficacy of axatilimab in subjects with **Idiopathic Pulmonary Fibrosis (IPF)** will be assessed through a series of predefined endpoints over a 26-week period. The primary endpoint is the annualized rate of decline in morning pre-dose trough forced vital capacity (FVC) measured in milliliters over the 26 weeks. This will provide a quantitative measure of lung function deterioration or stabilization in response to the treatment.

Secondary endpoints include several additional measures to evaluate disease progression and patient quality of life. These include the time to disease progression, defined as an absolute FVC percent predicted decline of ≥10%, the occurrence of lung transplant, or all-cause death prior to Week 26. The annualized rate of decline in FVC percent predicted over the 26 weeks will also be assessed. Furthermore, changes in the St. George’s Respiratory Questionnaire (SGRQ) from baseline to Week 26 will be evaluated to assess the impact on respiratory health-related quality of life. Lastly, the mean change in diffusion capacity for carbon monoxide (DLCO % of predicted, corrected for hemoglobin) from baseline to Week 26 will be measured to provide additional insights into pulmonary function changes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female subject aged ≥40 years on the day of signing the Informed Consent Form (ICF).
Documented diagnosis of IPF per the 2018 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society Clinical Practice Guideline (Raghu 2018).
HRCT confirming the diagnosis of IPF based on radiographic findings, as follows: Chest HRCT performed within 12 months prior to Screening Visit 1 and according to the minimum requirements for IPF diagnosis by central review based on subject's HRCT only (if no lung biopsy is available) or based on both HRCT and lung biopsy (with application of the different criteria in either situation). If an evaluable HRCT <12 months prior to Screening is not available, an HRCT can be performed at Screening Visit 1 to determine eligibility, according to the same requirements as the historical HRCT. If a subject has an indeterminate usual interstitial pneumonia (UIP) pattern and their HRCT is >6 months old, if in the opinion of the Investigator their disease has progressed, an additional HRCT may be obtained and reviewed for eligibility.
Subjects are eligible if they meet either of the following criteria: a. UIP or probable UIP pattern determined by at least 2 reviewers (see Appendix 3), or b. Indeterminate UIP with an accompanying biopsy supporting UIP or probable UIP histopathology pattern. The pathology report from a locally certified pathologist will provide documentation of histopathologic criteria (see Appendix 3).
Meeting one of the following criteria for background IPF medication use: a. Subjects may be treatment-naïve to nintedanib or pirfenidone for reasons such as contraindication to nintedanib or pirfenidone or subject refusal. (Note: Initiation of nintedanib or pirfenidone and consideration of other therapies for IPF should be discussed by Investigator before study enrollment.) b. Subjects receiving pirfenidone or nintedanib for IPF must have been at a stable dose for at least 12 weeks before Screening. c. If subjects have previously taken and discontinued nintedanib or pirfenidone for any reason (eg, side effect, no therapeutic benefit, refusal of these medications by the subject), they must have discontinued such treatment ≥4 weeks prior to Screening Visit 1. Note: Discontinuation of nintedanib or pirfenidone for the sole purpose of enrollment in this study is not allowed.
Meeting all of the following criteria during the Screening Period: a. FVC ≥45% of predicted normal at Screening Visit 1 or Visit 2, (optional if Screening Visit 1 occurred between 6 AM and 12 PM and the subject meets the PFT criteria in this inclusion criterion #6) b. Forced expiratory volume in 1 second (FEV1)/FVC ≥0.7 or ≥ age-adjusted lower limit of normal Global Lung Function Initiative (GLI) values (Quanjer et al, 2012) at Screening Visit 1 or Visit 2, (optional, as above) c. DLCO ≥30% and ≤90% of predicted, corrected for hemoglobin at Screening Visit 1, d. Acceptability: Subject can perform acceptable PFTs (ie, meet ATS/ERS acceptability criteria [Appendix 2] at Screening Visits 1, 2, (optional, as above), and 3). e. Repeatability: Subject can perform technically acceptable PFTs meeting repeatability criteria for FVC at Screening Visits 1, 2, (optional, as above), and 3 (Appendix 2).
Estimated minimum life expectancy of at least 12 months for non-IPF-related disease in the opinion of the Investigator.
Male subjects and female subjects of childbearing potential (defined as females who are fertile, following menarche and until becoming post-menopausal unless permanently sterile) agree to use highly effective contraception measures from the time of first dose of study drug (for the male subject) or the signing of the ICF (for the female subject), during the study, and until 90 days after the last dose of study drug. Subjects agree not to donate eggs or sperm during the same period. Male subjects must use a condom and female partners of male subjects who are of childbearing potential must use a highly effective method of contraception, defined below: a. A highly effective method of contraception is one that results in a low failure rate (ie, <1% per year) when used consistently and correctly. The acceptable methods of contraception include: sexual abstinence (defined as refraining from heterosexual intercourse during the entire treatment and follow-up periods), a vasectomized partner, bilateral tubal occlusion, any effective intrauterine device/hormone-releasing system, and progesterone-only (oral, injectable, or implantable) or combined (estrogen- and progesterone-containing; oral, intravaginal, or transdermal) hormonal contraception associated with inhibition of ovulation. Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. b. The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced. Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.
Subject, according to the Investigator’s best judgment, can comply with the requirements of the protocol.
Subject is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Subject and Investigator considered all medicinal treatment options and/or possibly lung transplantation prior to considering participation in the study.

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Exclusion Criteria

History of malignancy within the past 5 years unless previously treated with curative intent and approved by Medical Monitor (e.g. carcinoma in situ of the uterine cervix, basal cell carcinoma of the skin that has been treated with no evidence of recurrence, low risk prostate cancer [confined to prostate] that has been managed medically through active surveillance or watchful waiting or definitively treated more than 12 months ago with no evidence of recurrence, squamous cell carcinoma of the skin if fully resected, non-invasive ductal carcinoma in situ of the breast, and melanoma in situ).
Abnormalities detected on ECG of either rhythm or conduction that in the opinion of the Investigator are clinically significant. Note: • Subjects with implantable cardiovascular devices (eg, pacemaker) affecting the QT interval time may be enrolled in the study based upon Investigator judgment following cardiologist consultation if deemed necessary. • Atrial fibrillation that has been clinically stable for at least 6 months and that has been appropriately treated with anticoagulants and controlled with a rate control strategy (eg, selective beta blocker, calcium channel blocker, digoxin or ablation therapy) for at least 6 months is allowed for inclusion. In such subjects, if atrial fibrillation is present at Visit 1, resting ventricular rate must be <100 beats per minute.
Emphysema present on ≥50% of the HRCT, or the extent of emphysema is greater than the extent of fibrosis, according to central review of the HRCT.
Interstitial lung disease associated with known primary diseases (eg, connective tissue disease, sarcoidosis and amyloidosis), exposures (eg, radiation, silica, asbestos, and coal dust), or drugs (eg, amiodarone).
Subjects who cannot meet protocol-specified baseline stability criteria. Forced vital capacity baseline stability is defined as the FVC assessments at Visit 4 (Week 0/Day 1/Randomization) being within ±15% of the mean of the FVC assessments obtained at 2 preceding screening visits. At Visit 4, if the pre-dose FVC is outside of ±15% range, the subject will not be randomized and will be considered a screen failure.
Acute IPF exacerbation within 3 months prior to screening. The definition of an acute IPF exacerbation is as follows: Previous or concurrent diagnosis of IPF; Acute worsening or development of dyspnea typically <1-month duration; Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with usual interstitial pneumonia pattern and deterioration not fully explained by cardiac failure, fluid overload or by a defined cause.
Receiving nintedanib in combination with pirfenidone.
Receiving systemic corticosteroids equivalent to prednisone >10 mg/day or equivalent within 2 weeks prior to Screening.
Use of any of the following therapies within 4 weeks prior to Screening and during the Screening Period, or planned during the study: imatinib, ambrisentan, azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine A, tacrolimus, bosentan, methotrexate, inhaled treprostinil, phosphodiesterase-5 inhibitors, including sildenafil (unless for occasional use), prednisone at steady dose >10 mg/day or equivalent, or other investigational therapy.
Acute respiratory or systemic bacterial, viral, or fungal infection requiring systemic treatment either during Screening or prior to Screening and not successfully resolved 4 weeks prior to Screening Visit 1.
Class IV New York Heart Association chronic heart failure.
Significant pulmonary hypertension (PH) defined by any of the following: a. Previous clinical or echocardiographic evidence of significant right heart failure b. History of right heart catheterization showing a cardiac index ≤2 L/min/m² c. PH requiring parenteral therapy with epoprostenol/treprostinil
Cardiopulmonary rehabilitation program based on exercise training that has been completed within 6 weeks prior to Screening or planned to start within the first 6 weeks of the subject's enrollment in this study.
History of cigarette smoking or vaping within the previous 3 months.
Recent history (<6 months) of alcohol or substance abuse disorder.
Unstable cardiovascular, pulmonary (other than IPF), or other disease within 6 months prior to Screening or during the Screening Period (eg, acute coronary disease, heart failure, and stroke).
Major surgery within 3 months prior to Screening, during screening or have major surgery planned during the study period.
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN) or total bilirubin ≥1.5 x ULN. Retesting is allowed once.
Moderate to severe hepatic impairment (Child-Pugh B or C).
Amylase or lipase >1.5 x ULN; creatine phosphokinase (CPK) >2 x ULN. Retesting is allowed once.
Abnormal renal function defined as estimated creatinine clearance of <30 mL/min, calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula (Inker 2021). Retesting is allowed once.
History of acute pancreatitis in the prior 12 months or ≥2 episodes in past 3 years.
Subject with acquired immune deficiency syndrome.
A history of tuberculosis in the prior 6 months, or subjects with active or latent tuberculosis, confirmed by a positive test during Screening (interferon gamma release assay). [The interferon gamma release assay may be substituted with local tuberculosis test or local tuberculosis test results determined within 6 months prior to Screening Visit 1.]
An active coronavirus disease 19 (COVID-19) infection within 4 weeks prior to Screening.
Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, with positive HBV deoxyribonucleic acid [DNA], or HBV positive core antibody alone with positive HBV DNA. Hepatitis C (defined as positive hepatitis C [HCV] antibody with positive HCV ribonucleic acid [RNA]).
Female subject who is pregnant or breastfeeding.
Previous exposure to study intervention or known allergy/sensitivity to study drug and/or its excipients.
Receiving an investigational non-biologic treatment within 28 days before randomization or receiving an investigational biologic treatment within 28 days or 5 half-lives of randomization, whichever is longer. Any AE related to prior investigational biologic treatment must have resolved to baseline severity or ≤ Grade 1.
Inadequate IV access.
Positive for human immunodeficiency virus (HIV) antibodies.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	30 Apr 2024	10
Czechia	Not Recruiting	30 Apr 2024	5
France	Not Recruiting	30 Apr 2024	20
Germany	Not Recruiting	30 Apr 2024	32
Italy	Not Recruiting	30 Apr 2024	24
Poland	Not Recruiting	30 Apr 2024	14
Romania	Not Recruiting	30 Apr 2024	12
Spain	Not Recruiting	30 Apr 2024	24