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

Changes in the mean Forced Vital Capacity (FVC) from baseline at Week 24. Normal FVC-- Healthy males 20 to 60 years: 4.75 to 5.5 L; healthy females 20 to 60 years: 3.25 to 3.75 L

Time frame: 24 weeks

Population: Analysis was performed using randomized population. Available data for change from baseline at Week 24 have been reported.

Changes in the mean Forced Vital Capacity (FVC)% Predicted from baseline at Week 24. Normal FVC%: 80% to 120%

Time frame: 24 weeks

Population: Analysis was performed using randomized population. Available data for change from baseline at Week 24 have been reported.

Percentage of subjects with deaths by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related.

Time frame: Up to 96 weeks (Weeks 24, 8, and 96) of treatment with belumosudil. Subjects randomized to BSC also had the option of crossing over to treatment with belumosudil at 24 weeks.

Population: All subjects treated in study.

Percentage of subjects with non-serious TEAEs by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Severity of TEAEs were measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 22.1 (Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal).

Time frame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC had the option of crossing over at 24 weeks.

Population: All subjects treated in study.

Percentage of subjects with serious TEAEs by relationship to treatment with belumosudil and/or BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC and crossing over also up to 24 weeks of BSC.

Population: All subjects treated in study.

Percentage of subjects with treatment-emergent adverse events (TEAEs) leading to subjects discontinuing from treatment. Investigators assessed whether TEAEs leading to discontinuation were related to study drug (possibly, probably, or definitely), belumosudil 400 mg PO QD.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil

Population: Subjects who received belumosudil 400 mg PO QD were included. Subjects who only received BSC and did not cross over to treatment with belumosudil were not included.

The categorical changes of lung fibrosis using subjective visual assessments by radiologists from sequential scans at baseline, Week 24, Week 48, and Week 96. Changes were categorized as: (1) much better; (2) slightly better; (3) same; (4) slightly worse; and (5) much worse. This categorization is simplified as Better (Much or Slightly); Same; and Worse (Slightly or Much).

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects.

The change in Data-driven Texture Analysis (DTA) Lung Fibrosis mean score using sequential scans from Radiologist's Visual Reads from baseline to Weeks 24, 48, and 96. The change in DTA Lung Fibrosis mean score was measured using sequential scans from Radiologist's Visual Reads from baseline at Weeks 24, 48, and 96. DTA fibrosis score was computed as the number of Region of Interests (ROIs) classified as fibrotic divided by the total number of ROIs sampled from the lung segmentation volume. The DTA fibrosis score ranged from 0 - 100%, where higher scores indicated worsening of disease.

Time frame: Up to 96 Weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

Acute exacerbation of IPF was defined by the following symptoms within 1 month that could not be explained by other reasons: (1) aggravated dyspnea; (2) newly discovered chest interstitial lung abnormality (by radiograph or HRCT); (3) SpO2 decrease to \< 88%. Acute exacerbation was diagnosed if Items #1 and #2 were present or if Items #1 and #3 were present and the following AEs did not occur: (A) any AE with the Preferred Term containing the word infection or cardiac failure; (B) pulmonary embolism; (C) pneumothorax.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

Probability of first-related hospitalization defined as any AE where the high-level group term contained the terms respiratory and the AE resulted in a hospitalization. Subjects randomized and received BSC were censored on crossover. Note: The hazard ratios for Belumosudil-R vs. BSC-NC and for Belumosudil-WC vs. BSC-NC were not calculable.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: Analysis was of the Modified Intent-to-Treat (mITT) Population, defined as consisting of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post-baseline assessment.

Progression of IPF exacerbation was defined as the probability of a subject exhibiting IPF time from baseline to any of the following: (1) probability of first respiratory-related hospitalization; (2) probability of respiratory-related death; absolute decline in FVC% Predicted value of ≥ 10% vs. FVC %; probability of predicted value recorded at baseline; and (4) probability of absolute decline in DLCO, adjusted for hemoglobin (Hb), Percent of predicted value of ≥ 15% vs. DLCO at baseline. Subjects randomized to and received BSC were censored on crossover.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

Probability of respiratory-related death, defined as any AE where the high-level group term contained the term respiratory and the AE resulted in a death. Subjects randomized to and who received BSC were censored on crossover.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: Analysis was of the Modified Intent-to-Treat (mITT) Population, defined as consisting of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post-baseline assessment.

The mean change in the 6-mile Walking Distance (6MWD), i.e., the distance a subject can walk in 6 minutes, from baseline to Week 24, to Week 48, and to Week 96. Positive change = improvement; negative change = worsening

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

Change in the mean ratio of Forced Expiratory Volume in 1 Second (FEV1) divided by the Forced Vital Capacity (FVC) at Week 24, Week 48, Week 96, and End-of-Treatment (EOT) Normal FEV1: 80% to 120% FEV1/FVC = Within 5% of predicted ratio

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

The diffusing capacity for carbon dioxide (DLCO) is a measure of the conductance of gas transfer from inspired gas to the red blood cells. Normal DLCO is \> 75% of predicted up to 140%. Severity is generally rated as: * Mild: 60% to lower limit of normal * Moderate: 40% to 60% * Severe: \< 40%

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

Changes in the mean Forced Vital Capacities (FVC) at Week 24 by Gender/Age/Physiology (GAP) Stage and by the previous use of pirfenidone and/or nintedanib prior to the study for Belumosudil-WC compared to BSC-NC. Normal FVC--Healthy males 20 to 60 years: 4.75 to 5.5 L; healthy famles 20 to 60 years: 3.25 to 3.75 L GAP is measured by points as follows: (G) Gender: Female = 0 points; Male = 1 point (A) Age: ≤ 60 years = 0 points; 61-65 years = 1 point; \> 65 years = 2 points (P) Physiology: * FVC% Predicted: \> 75% = 0 points; 50-75% = 1 point; ≤ 50% = 2 points * DLCO% (diffusing lung capacity of carbon monoxide by % predicted) Predicted: \> 55% = 0 points; 36-55% = 1 point, ≤ 35% = 2 points; cannot perform = 3 points GAP Stage: * Stage I Index = 0 to 3 points * Stage II Index= 4 to 5 points * Stage III Index = 6 to 8 points

Time frame: 24 weeks

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

Changes in the mean Forced Vital Capacity (FVC) from baseline at Weeks 48 and 96, and End-of-Treatment (EOT) Normal FVC: Healthy males 20 to 60 years: 4.75 to 5.25 L; healthy females 20 to 60 years: 3.25 to 3.75 L

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

Changes in the mean Forced Vital Capacities (FVC)% Predicted at Week 24 by Gender/Age/Physiology (GAP) Stage and by the previous use of pirfenidone and/or nintedanib prior to the study for Belumosudil-WC compared to BSC-NC. GAP is measured by points as follows: (G) Gender: Female = 0 points; Male = 1 point (A) Age: ≤ 60 years = 0 points; 61-65 years = 1 point; \> 65 years = 2 points (P) Physiology: * FVC% Predicted: \> 75% = 0 points; 50-75% = 1 point; ≤ 50% = 2 points * DLCO% (diffusing lung capacity of carbon monoxide by % predicted) Predicted: \> 55% = 0 points; 36-55% = 1 point, ≤ 35% = 2 points; cannot perform = 3 points GAP Stage: * Stage I = 0 to 3 points * Stage II = 4 to 5 points * Stage III = 6 to 8 points

Time frame: 24 weeks

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

The St. George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in subjects with obstructive airways disease consisting of 2 parts: (1) symptoms component (frequency & severity) with a 3-month recall; and (2) activities that cause or are limited by breathlessness. Impact components (social functioning, psychological disturbances resulting from airways disease) refer to current state as the recall. Changes were assessed from baseline at Week 24, at Week 48, and at Week 96. The SGRQ scores range from 0 to 100, with higher scores indicating greater limitations. Based on empirical data and interviews with subjects, a mean change score of 4 units is associated with slightly efficacious treatment, 8 units for moderately efficacious change, and 12 units for very efficacious treatment

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: All randomized subjects

The change in Total Lung Fibrosis mean score from baseline at Weeks 24, 48, and 96. Measurements using quantitative high-resolution computerized tomography (HRCT) and include (1) extent of fibrotic abnormality; (2) fibrosis score; (3) ground glass opacity; (4) honeycombing score; (5) kurtosis of lung voxel intensity; (6) skewness of lung voxel intensity; (7) standard deviation of voxel; (8) CT total lung volume; (9) normal lung; (10) reticular score; and (11) evaluation of change on sequential scans. The Quantitative Lung Fibrosis (QLF) score measures the extent of reticular patterns with architectural distortion due to fibrosis using a support vector machine classifier. Range: 0 to 100. Higher scores imply greater impairment.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The mITT Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline FVC assessment.

Percentage of subjects who exhibited at least a 10% decrease in Forced Vital Capacity (FVC)% Predicted from baseline at Week 24, at Week 48, and at Week 96

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

The percentage of subjects who have at least a 50 meter improvement in the 6-mile Walking Distance (6MWD), i.e., the distance a subject can walk in 6 minutes, from baseline to Week 24, Week 48, and Week 96.

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

Percentage of the number of subjects who exhibit less than a -15% decrease in diffusing capacity of carbon monoxide (DLCO), measured as % from baseline at Week 24, Week 48, and Week 96 The diffusing capacity for carbon dioxide (DLCO) is a measure of the conductance of gas transfer from inspired gas to the red blood cells. Normal DLCO is \> 75% of predicted up to 140%. Severity is generally rated as: * Mild: 60% to lower limit of normal * Moderate: 40% to 60% * Severe: \< 40%

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.

Percentage of subjects exhibiting at least a 5% decrease in Forced Vital Capacity (FVC)% Predicted from baseline at Week 24, at Week 48, and at Week 96

Time frame: Up to 96 weeks (Weeks 24, 48, and 96)

Population: The Modified Intent-to-Treat (mITT) Population was used which consisted of all subjects in the Safety Population who had an evaluable baseline and ≥ 1 evaluable post baseline assessment.