A 2-Part, Phase 2 Open-label and Crossover Study of Belumosudil for Treatment of Idiopathic Pulmonary Fibrosis

A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of Belumosudil in Subjects With Idiopathic Pulmonary Fibrosis (IPF)

This Phase 2 study is to be conducted to evaluate the safety, tolerability, and activity of 400 mg of belumosudil orally (PO) once-daily (QD) compared to Best Supportive Care (BSC) in male and postmenopausal/surgically sterilized female subjects with Idiopathic Pulmonary Fibrosis (IPF). The primary objectives are to evaluate the:

• Change in Forced Vital Capacity (FVC) from baseline to 24 weeks after dosing with belumosudil 400 mg PO QD in subjects with IPF compared to BSC
• Safety and tolerability of belumosudil 400 mg PO QD when administered for 24 weeks to subjects with IPF compared to BSC

Study KD025-207 is a Phase 2, randomized, 2-part, open-label, crossover study in subjects with IPF.

The purpose of the study is to evaluate the safety, tolerability, and activity of 400 mg of belumosudil administered orally (PO) every day (QD) compared to Best Standard of Care (BSC) in subjects with IPF who have previously been treated with or declined treatment with pirfenidone or nintedanib.

The primary objectives are to evaluate the change in Forced Vital Capacity (FVC), and the safety and tolerability from baseline to 24 weeks in subjects with IPF after dosing with belumosudil 400 mg PO QD compared to BSC.

Part 1: Randomized, Open-label for 24 Weeks

Approximately 81 eligible subjects with IPF are to be enrolled, in 10 to 15 sites, and randomized in a 2:1 ratio (belumosudil:BSC) to 1 of the following 2 groups:

• Belumosudil-R (Investigational Group): Belumosudil 400 mg PO QD for 24 weeks
• BSC-R (Control Group): BSC for 24 weeks

The study plan is for 54 subjects to be entered into the Belumosudil-R Treatment Group and 27 subjects into the BSC-R Treatment Group. This sample size provides over 90% power at the 2-sided 0.05 significance level to detect a 20% difference between treatment groups at 24 weeks in percentage change from baseline in FVC assuming a standard deviation (SD) in percentage change from baseline in FVC of 17%. The sample size of 54 subjects receiving belumosudil provides over 90% probability of ≥ 1 subject in the study experiencing an AE that had an underlying rate of ≥ 5%.

Part 2: Continuation of Belumosudil Therapy or Crossover to Belumosudil Therapy Subjects in the Belumosudil-R group who complete 24 weeks of treatment with belumosudil 400 mg PO QD have the option of continuing therapy with belumosudil 400 mg PO QD up to an additional 72 weeks if there are no safety signals and if clinical progress continues. No subject in the Belumosudil-R group is to be permitted to receive therapy with belumosudil greater than a total of 96 weeks.

Subjects in control group BSC-R who complete 24 weeks of BSC have the option of crossing over to therapy with belumosudil 400 mg PO QD for up to 96 weeks if there are no safety signals and if clinical progress continues. No subject in control group BSC-R is to be permitted to receive belumosudil 400 mg PO QD therapy greater than 96 weeks.

Follow-up Period:

Follow-up Visits are to occur 30 days (± 3 days) after the last dose of belumosudil during which subjects are to undergo safety assessments. (A Follow-up Visit is not necessary for subjects receiving BSC.)

Duration of Study for Individual Subjects:

1. Subjects randomized to belumosudil: total up to 104 weeks (4-week screening, 96-week treatment with belumosudil, and 4-week follow-up)
2. Subject randomized to BSC: total up to 128 weeks (4-week screening; up to 24-week treatment with BSC, 96-week treatment with belumosudil, and 4-week follow-up)

Efficacy Assessments

• FVC
• FVC% Predicted
• 6-minute Walking Distance (6MWD)
• Diffusing Capacity of Carbon Monoxide (DLCO)
• Lung Fibrosis (by HRCT and Radiologist's Visual Assessments)
• Time to Acute Exacerbation
• Time to Progression of IPF
• Time to Respiratory-related Hospitalization
• Time to Respiratory-related Death
• St. Georges Respiratory Questionnaire (SGRQ)

Biomarker Assessments

• Matrix Metalloproteinase-7 (MMP7)
• Chemokine Ligand 18 (CCL18)
• Surfactant Protein-D (SPD)

Safety Assessments

• Adverse event (AE)
• Serious adverse event (SAE)
• Physical examination (PE)
• Vital signs (VS)
• Clinical laboratory evaluations (hematology, chemistry, and urinalysis)
• Electrocardiogram (ECG)
• Reason for treatment discontinuation due to toxicity

Analyses

Efficacy and safety are to be analyzed at the end of Part 1 (Week 24) and for the Entire Treatment Period (Parts 1 and 2). Analyses of study subjects are to be grouped and defined as follows:

• Belumosudil-R: subjects randomized to belumosudil
• BSC-R: subjects randomized to BSC
• Belumosudil-WC: subjects randomized to belumosudil plus subjects randomized to BSC and who cross over to treatment with belumosudil
• BSC-NC: subjects randomized to BSC and who cross over to treatment with belumosudil but have data censored by the date of crossover

Inclusion Criteria:

A subject had to meet all of the following criteria to be eligible for the study:

1. Adult male and postmenopausal/surgically sterilized female subjects at least 18 years of age (if female, was surgically sterilized [i.e., total hysterectomy, or bilateral salpingo-oophorectomy]).

2. Able to provide written informed consent before the performance of any study specific procedures.

3. IPF diagnosis within 5 years before study entry, proven according to the American Thoracic Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy. In the absence of a surgical lung biopsy, high-resolution computerized tomography (HRCT) consistent with usual interstitial pneumonitis.

4. Resting state pulse oximeter oxygen saturation (SpO2) ≥ 88% with or without supplemental oxygen, Forced Vital Capacity % (FVC%) ≥ 50% normal predicted value, and diffusing capcity (in the lung) of carbon monoxide (DLCO) ≥ 30% normal predicted value at baseline.

5. Men with partners of childbearing potential willing to use 2 medically acceptable methods of contraception during the trial and for 3 months after the last dose of study drug. Effective birth control includes:

   1. Intrauterine device plus 1 barrier method
   2. Stable doses of hormonal contraception for ≥ 3 months (e.g., oral, injectible, implant, transdermal) plus 1 barrier method
   3. 2 barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels containing a chemical to kill sperm)
   4. Vasectomy.

6. Have adequate bone marrow function:

   1. Absolute neutrophil count > 1500/mm^3
   2. Hemoglobin (Hb) > 9.0 g/L
   3. Platelets > 100,000/mm^3

7. Willing to complete all study measurements and assessments in compliance with protocol

8. Had either received pirfenidone and/or nintedanib or offered both treatments (with last dose administered at least 1 month before the expected start of study drug dosing). If either or both pirfenidone and nintedanib treatment had not been given, then documentation that the subject was offered both treatments must have been documented.

Exclusion Criteria:

A subject who met any of the following criteria was ineligible for the study:

1. Interstitial lung disease caused by conditions other than IPF

2. Severe concomitant illness limiting life expectancy (< 1 year)

3. DLCO < 30% predicted

4. Residual volume (RV) ≥ 120% predicted

5. Obstructive lung disease: Forced Expiratory Volume in 1 Second (FEV1/FVC ratio < 0.70)

6. Documented sustained improvement of the subject's IPF condition up to 12 months before study entry with or without IPF-specific therapy

7. Pulmonary infection or upper respiratory tract infection (URTI) within 4 weeks before study entry

8. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests [PFTs])

9. Chronic heart failure with New York Heart Association Class III/IV or known left ventricular ejection fraction < 25%

10. Moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C)

11. Estimated creatinine clearance < 30 mL/min

12. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.0 * upper limit of normal (ULN)

13. Hb < 75% of the lower limit of normal

14. Systolic blood pressure < 100 mmHg

15. Pregnant or breastfeeding female subject

16. Men whose partner is pregnant or breastfeeding

17. Current drug or alcohol dependence

18. Chronic treatment with the following drugs within 4 weeks of study entry and during the study:

    1. Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine
    2. Antifibrotic drugs including pirfenidone, nintedanib, D-penicillamine, colchicine, tumor necrosis factor-alpha blockers, imatinib, and interferon-γ
    3. Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day)
    4. Oral anticoagulants prescribed for IPF

19. Treatment with endothelin receptor antagonists within 4 weeks before study entry

20. Systemic treatment within 4 weeks before study entry with cyclosporine A or tacrolimus, everolimus, or sirolimus (calcineurin or mammalian target of rapamycin inhibitors)

21. Previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other Rho-associated protein kinase 2 (ROCK2) inhibitor

22. Planned treatment or treatment with another investigational drug within 4 weeks before study entry

23. Taking a medication with the potential for QTc prolongation

24. Taking a drug sensitive substrate of CYP enzymes

25. Taking a strong inducer of CYP3A4

26. Had consumed an herbal medication (e.g., St. John's Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1 Day 1 visit