A 26-Week, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Efficacy, Safety, and Tolerability of Axatilimab in Subjects with Idiopathic Pulmonary Fibrosis (IPF)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Syndax Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

21 Jun 2024 → ongoing

Decision date (initial)

2024-08-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Syndax Pharmaceuticals, Inc.

External identifiers

EU CT number

2022-502954-15-00

ClinicalTrials.gov

NCT06132256

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Others

To assess the effect of axatilimab compared to placebo on lung function in subjects with IPF from baseline to Week 26

Secondary objectives 4

1. To assess the effect of axatilimab compared to placebo on disease progression from baseline to Week 26
2. To assess the effect of axatilimab compared to placebo on change in additional parameters of lung function from baseline to Week 26
3. To assess the effect of axatilimab compared to placebo in quality-of-life measures from baseline to Week 26
4. To assess the effect of axatilimab compared to placebo on gas exchange from baseline to Week 26

Conditions and MedDRA coding

Idiopathic pulmonary fibrosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Male or female subject aged ≥40 years on the day of signing the Informed Consent Form (ICF).
2. 2. 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).
3. 3. 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.
4. 4. 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).
5. 5. 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.
6. 6. 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).
7. 7. Estimated minimum life expectancy of at least 12 months for non-IPF-related disease in the opinion of the Investigator.
8. 8. 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.
9. 9. Subject, according to the Investigator’s best judgment, can comply with the requirements of the protocol.
10. 10. Subject is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
11. 11. Subject and Investigator considered all medicinal treatment options and/or possibly lung transplantation prior to considering participation in the study.

Exclusion criteria 31

1. 1. 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).
2. 2. 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.
3. 3. 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.
4. 4. 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).
5. 5. 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.
6. 6. 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.
7. 7. Receiving nintedanib in combination with pirfenidone.
8. 8. Receiving systemic corticosteroids equivalent to prednisone >10 mg/day or equivalent within 2 weeks prior to Screening.
9. 9. 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.
10. 10. 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.
11. 11. Class IV New York Heart Association chronic heart failure.
12. 12. 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
13. 13. 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.
14. 14. History of cigarette smoking or vaping within the previous 3 months.
15. 15. Recent history (<6 months) of alcohol or substance abuse disorder.
16. 16. 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).
17. 17. Major surgery within 3 months prior to Screening, during screening or have major surgery planned during the study period.
18. 18. 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.
19. 19. Moderate to severe hepatic impairment (Child-Pugh B or C).
20. 20. Amylase or lipase >1.5 x ULN; creatine phosphokinase (CPK) >2 x ULN. Retesting is allowed once.
21. 21. 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.
22. 22. History of acute pancreatitis in the prior 12 months or ≥2 episodes in past 3 years.
23. 23. Subject with acquired immune deficiency syndrome.
24. 24. 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.]
25. 25. An active coronavirus disease 19 (COVID-19) infection within 4 weeks prior to Screening.
26. 26. 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]).
27. 27. Female subject who is pregnant or breastfeeding.
28. 28. Previous exposure to study intervention or known allergy/sensitivity to study drug and/or its excipients.
29. 29. 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.
30. 30. Inadequate IV access.
31. 31. Positive for human immunodeficiency virus (HIV) antibodies.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The annualized rate of decline in morning pre dose trough forced vital capacity (FVC) (mL) over 26 weeks

Secondary endpoints 4

1. Time to disease progression. Disease progression is defined as absolute FVC percent predicted decline of ≥10%, or occurrence of lung transplant or all-cause death prior to Week 26.
2. The annualized rate of decline in FVC percent predicted over 26 weeks.
3. Change in St. George’s Respiratory Questionnaire (SGRQ) from baseline to Week 26.
4. The mean change in diffusion capacity for carbon monoxide (DLCO % of predicted, corrected for hemoglobin) from baseline to Week 26.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Syndax Pharmaceuticals Inc.

Sponsor organisation

Syndax Pharmaceuticals Inc.

Address

730 3rd Avenue Floor 9

City

New York

Postcode

10017-3206

Country

United States

Scientific contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

DevPro Biopharma: Colin Reisner

Public contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

DevPro Biopharma: Jane E. Fitzpatrick

Third parties 17

Locations

8 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 109 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

29 submissions — initial application plus substantial / non-substantial modifications