Summary of completed clinical trials
| Lung disease/documented PDGF-PDGFR involved in pathogenesis | Drug | Completed clinical study, study phase, study design and number of patients | Patient population | Intervention | Primary outcome | Results |
| IPAH PDGF-BB PDGFR-β | Imatinib mesylate | IMPRES [24] Phase 3, 24 weeks, multicentre, randomised, double blind, placebo controlled (n=202) | PVR ≥800 dyn·s·cm−5 symptomatic on ≥2 PAH therapies | Randomised to receive imatinib 200 mg once daily or placebo | Change in 6MWD | Mean treatment effect on 6MWD 32 m; p=0.002 PVR decreased by 379 dyn·s·cm−5 p<0.001 Serious AEs were more frequent with imatinib compared to placebo (44% versus 30%) |
| Sorafenib | Gomberg-Maitland et al. [25] Phase 1b, 16 weeks, single centre, open label (n=22) | Advanced but stable PAH on parenteral prostanoids (with or without oral sildenafil) | Received sorafenib started at 200 mg daily then escalated to 400 mg twice daily | Safety and tolerability | Sorafenib was well tolerated at 200 mg twice daily AEs: moderate skin reactions on the hands and feet and alopecia | |
| NSCLC PDGF-A/B PDGFR-α/β | Imatinib mesylate (in combination with paclitaxel) | Bauman et al. [26] Phase 2, multicentre, single stage, open label (n=34) | Age ≥70 years with untreated, stage IIIB/IV NSCLC and ECOG performance status 0–2 | Received up to six 28-day cycles of imatinib and paclitaxel | RR | Met primary end-point; however, no improvement in overall survival and PFS. Regimen not recommended for further study |
| Linifanib (in combination with carboplatin and paclitaxel) | Ramalingam et al. [27] Phase 2, multinational, open label (n=139) | Stage IIIB/IV nonsquamous NSCLC | Received carboplatin and paclitaxel plus placebo, linifanib 7.5 mg or linifanib 12.5 mg | PFS | Improved PFS. Higher incidence of AEs known to be associated with VEGF/PDGF inhibition | |
| Nintedanib (BIBF 1120) with pemetrexed | Ellis et al. [28] Phase 1, multicentre, open label (n=26) | Metastatic, unresectable, or locally advanced NSCLC and had to have relapsed during or following one prior platinum-based chemotherapy regimen | Received BIBF 1120 starting dose of 100 mg twice daily (days 2–21) with pemetrexed 500 mg·m−2 (day 1) over a 21-day cycle BIBF 1120 dose was escalated until the MTD was determined | Safety, tolerability and MTD | The MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg twice daily BIBF 1120 in this combination was tolerable, with promising signs of efficacy | |
| Nintedanib (in combination with docetaxel) | LUME-Lung 1 [29] Phase 3, multicentre, double blind, randomised, placebo controlled (n=1314) | Stage IIIb/IV recurrent NSCLC progressing after first-line chemotherapy | Randomised to docetaxel 75 mg·m−2 by i.v. infusion on day 1 plus nintedanib 200 mg twice daily orally or placebo on days 2–21, every 3 weeks Treatment was continued until unacceptable AEs or disease progression | PFS | PFS was significantly improved after a median follow-up of 7.1 months Improved overall survival in all patients with adenocarcinoma (12.6 versus 10.3 months); more pronounced in the subgroup of patients who progressed within 9 months after start of first-line therapy (10.9 versus 7.9 months) AEs: diarrhoea, reversible increase in ALT and AST, gastrointestinal side-effects | |
| Nintedanib (in combination with premetrexed) | LUME-Lung 2 [30] Phase 3, multicentre, double blind, randomised, placebo controlled (n=713) | Stage IIIb/IV or recurrent NSCLC previously treated with chemotherapy. ECOG performance score of 0–1 | Randomised to pemetrexed 500 mg·m−2 i.v. on day 1, combined with either oral nintedanib 200 mg twice daily or placebo, given on days 2–21, every 3 weeks | PFS | Stopped early. ITT analysis of PFS favoured the treatment arm (median 4.4 months versus 3.6 months; HR 0.83, 95% CI 0.70–0.99; p=0.0435) | |
| IPF PDGF-AA, -BB and -CC | Imatinib mesylate (Gleevec) | Daniels et al. [31] Phase 2, 96 weeks, multicentre, randomised, double blind, placebo controlled (n=119) | Mild to moderate IPF diagnosed within 3–36 months of screening with clinical worsening in the past year (10% decline in FVC % pred or worsening chest radiograph or worsening dyspnoea) | Randomised to receive imatinib mesylate 600 mg (six tablets) orally once daily or placebo | Combined measure of disease progression (defined as 10% decline from baseline FVC) or death | No effect on survival or lung function |
| Nintedanib (BIBF 1120) | TOMORROW [32] Phase 2, 12 months, multicentre, randomised, double blind, placebo controlled (n=432) | Age ≥40 years with <5 years diagnosis of IPF, FVC ≥50% pred, DLCO 30–79% pred, PaO2 ≥55 mmHg at <1500 m altitude or ≥50 mmHg at >1500 m altitude | Randomisation to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day or 150 mg twice a day) or placebo | Annual rate of decline in FVC | Compared to placebo, BIBF 1120 at a dose of 150 mg twice daily was associated with: a trend toward a reduction in the decline in lung function (0.06 versus 0.19 L·year-1); fewer acute exacerbations (2.4 versus 15.7 per 100 patient-years, p=0.02); preserved quality of life (−0.66 versus 5.46, p=0.007); gastrointestinal AEs, which led to more discontinuation in the 150 mg BIBF 1120 twice a day group; increase in liver aminotransferase levels | |
| INPULSIS-1 and 2 [33] Phase 3, 52 weeks, multicentre, randomised double blind, placebo controlled (n=1061) | Age ≥40 years with <5 years diagnosis of IPF, FVC ≥50% pred, DLCO 30–79% pred, | Randomised to receive 150 mg nintedanib twice daily or placebo | Annual rate of decline in FVC | INPULSIS-1 No difference in time to first acute exacerbation (HR 1.15, 95% CI 0.54–2.42) Comparable proportion of patients with at least one investigator-reported acute exacerbation (6.1% versus 5.4%, respectively, in the nintedanib and placebo groups) INPULSIS-2 Significant increase in time to first acute exacerbation (HR 0.38, 95% CI 0.19–0.77) Lower proportion of patients with at least one investigator-reported acute exacerbation in the nintedanib group (3.6%) compared with placebo (9.6%) Most common AEs: diarrhoea followed by nausea | ||
| Pirfenidone | ASCEND [34] Phase 3, 52 weeks, multicentre, double blind, placebo-controlled (n=555) | Age 40–80 years, centrally confirmed diagnosis of IPF | Randomised to receive pirfenidone 2403 mg per day or placebo | Change in FVC or death at week 52 | 47.9% relative reduction in the proportion of patients who had an absolute decline of ≥10% of FVC % pred or who died No significant difference in dyspnoea scores (p=0.16) No significant difference in rates of death from any cause (p=0.10) or from IPF (p=0.23) | |
| CAPACITY 004 [35] Phase 3, 72 weeks, multicentre, double blind, placebo randomised controlled trial (n=435) | Age 40–80 years, diagnosis of IPF in the previous 48 months, FVC ≥50% and ≤90% pred, DLCO ≥35% and ≤90% pred 6MWT≥150 m | Randomised to receive pirfenidone 2403 mg·day−1, or pirfenidone 1197 mg·day−1 or placebo | Change in percentage of FVC % pred from baseline to week 72 | Significant reduction in decline of FVC (p=0.001). Mean FVC change at week 72 was –8·0±16.5% in the pirfenidone 2403 mg·day−1 group and –12.4±18.5% in the placebo group (difference 4.4%, 95% CI 0.7–9.1). Outcomes in the pirfenidone 1197 mg·day−1 group were intermediate to the pirfenidone 2403 mg·day−1 and placebo groups AEs: patients in the pirfenidone 2403 mg·day−1 group had higher incidences of nausea, dyspepsia, vomiting, anorexia, photosensitivity and dizziness | ||
| CAPACITY 006 [35] Phase 3, 72 weeks, multicentre, double blind, randomised, placebo controlled (n=344) | Age 40–80 years, diagnosis of IPF in the previous 48 months FVC ≥50% pred and ≤90% pred, DLCO ≥35% pred and ≤90% pred 6MWT ≥150 m | Randomised to receive pirfenidone 2403 mg·day−1 or placebo | Change in FVC % pred from baseline to week 72 | Significant reduction in decline of FVC. Mean change at week 72 was –9.0±19.6% in patients in the pirfenidone 2403 mg·day−1 group and –9.6±19.1% in patients in the placebo group AEs: same as CAPACITY 004 | ||
| HPS | Pirfenidone | Gahl et al. [36] 44 months, single centre, double blind, randomised controlled (n=21) | Confirmed diagnosis of HPS and FVC 40–75% pred All 21 subjects were Puerto Rican; 20 were homozygous for the 16-bp duplication in exon 15 of HPS1; one was homozygous for a 3904-bp deletion in HPS3 | Randomised to receive pirfenidone 800 mg three times daily or placebo | Average rate of decline of FVC, FEV1, TLC and DLCO, measured as % pred, in the two treatment groups | 5% difference in the yearly rate of FVC decline (p=0.001) In patients with an initial FVC >50% pred, pirfenidone slowed lost pulmonary function (FVC, FEV1, TLC and DLCO) at a rate of 8% per year, compared to placebo |
| O'Brien et al. [37] Single centre, double blind, randomised, placebo controlled (n=35) | HPS-1 or -4 confirmed by molecular analysis and FVC 51–85% pred, regardless of radiographic evidence of fibrosis on HRCT | Randomised to receive pirfenidone or placebo. A dosage escalation schedule was employed to reach 801 mg pirfenidone three times daily | Rate of decline in FVC | Stopped early (after 12 months) due to futility No significant safety concerns | ||
| Diffuse cutaneous systemic sclerosis | Nintedanib | Spiera et al. [38] Phase 2a, 12 months, single centre, single arm, open label (n=30) | Fulfilled the American College of Rheumatology classification criteria for systemic sclerosis and had the diffuse subtype. Stable MRSS of ≥16 points in the month between screening and baseline visits, and had disease duration of <10 years DLCO ≥30% pred | Imatinib 400 mg daily | Change in the MRSS after 12 months of treatment | Improved MRSS 6.6 points or 22.4% (p=0.001) FVC improved by 6.4% pred (p=0.008) |
PDGF: platelet-derived growth factor; PDGFR: PDGF receptor; IPAH: idiopathic pulmonary arterial hypertension; NSCLC: nonsmall cell lung cancer; IPF: idiopathic pulmonary fibrosis; HPS: Hermansky–Pudlak syndrome; PVR: pulmonary vascular resistance; PAH: pulmonary arterial hypertension; 6MWD: 6-min walking distance; AEs: adverse events; ECOG: Eastern Cooperative Oncology Group; RR: response rate; PFS: progression-free survival; VEGF: vascular endothelial growth factor; MTD: maximum tolerated dose; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ITT: intention to treat; FVC: forced vital capacity; % pred: % predicted; DLCO: diffusing capacity of the lung for carbon monoxide; PaO2: arterial oxygen tension; 6MWT: 6-min walk test; FEV1: forced expiratory volume in 1 s; TLC: total lung capacity; HRCT: high-resolution computed tomography; MRSS: modified Rodnan skin score.