Frank Gilberg

Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial

BACKGROUND Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. METHODS In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. FINDINGS Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0-72·3) in treatment group A and 54·0% (43·6-64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. INTERPRETATION Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. FUNDING F Hoffmann-La Roche.

Safety of Nintedanib Added to Pirfenidone Treatment for Idiopathic Pulmonary Fibrosis

We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) in patients with idiopathic pulmonary fibrosis (IPF). This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day−1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. 89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF. Combined pirfenidone and nintedanib was tolerated by the majority of patients with IPF, encouraging further study http://ow.ly/1Iq030kaZuD

Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study – Rationale and study design

BACKGROUND Pulmonary hypertension (PH) is commonly observed in patients with advanced idiopathic pulmonary fibrosis (IPF). Despite the availability of therapies for both IPF and PH, none are approved for PH treatment in the context of significant pulmonary disease. This study will investigate the use of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH, who represent a group with a high unmet medical need. METHODS This Phase IIb, randomised, double-blind, placebo-controlled trial is actively enrolling patients and will study the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and intermediate or high probability of Group 3 PH who are receiving a stable dose of pirfenidone. Patients with advanced IPF (diffusing capacity for carbon monoxide ≤40% predicted) and risk of Group 3 PH (defined as mean pulmonary arterial pressure ≥20 mm Hg with pulmonary arterial wedge pressure ≤15 mm Hg on a previous right-heart catheterisation [RHC], or intermediate/high probability of Group 3 PH as defined by the 2015 European Society of Cardiology/European Respiratory Society guidelines) are eligible. In the absence of a previous RHC, patients with an echocardiogram showing a peak tricuspid valve regurgitation velocity ≥2.9 m/s can enrol if all other criteria are met. The primary efficacy endpoint is the proportion of patients with disease progression over a 52-week treatment period. Safety will be evaluated descriptively. DISCUSSION Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials

Introduction Temporary dose modifications, such as reductions or interruptions, may allow patients to better manage adverse events (AEs) associated with pirfenidone use and continue treatment for idiopathic pulmonary fibrosis (IPF). However, the impact of such dosing adjustments on efficacy and safety is uncertain. Methods Patients randomised to receive treatment with pirfenidone 2403 mg/day or placebo in the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY (Study 004 (NCT00287716)) and Study 006 (NCT00287729))) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND (Study 016 (NCT01366209)) trials were included in the analysis (n=1247). Descriptive statistics and a linear mixed-effects model (slope analysis) for annual rate of decline in forced vital capacity (FVC) by dose intensity were performed. Treatment-emergent AEs (TEAEs) were summarised and grouped by dose intensity or body size. Results Dose reductions and interruptions occurred in 76.9% (95% CI 73.4% to 80.1%) and 46.5% (95% CI 42.6% to 50.6%) of patients receiving pirfenidone vs 72.0% (95% CI 68.3% to 75.4%) and 31.1% (95% CI 27.5% to 34.9%) of patients receiving placebo, respectively. Dose interruptions tended to occur during the first 6 months of treatment, whereas dose reductions exhibited more variability. Less FVC decline from baseline was observed in patients receiving pirfenidone versus placebo at >90% dose intensity (p<0.001) or ≤90% dose intensity (p=0.0191), showing treatment benefit in both subgroups of dose intensity. No meaningful relationship between weight and TEAEs was observed. Conclusion Dose interruptions, which may be required to manage TEAEs, mostly occurred during the first 6 months of treatment. Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on pirfenidone, without compromising its treatment effect compared with placebo. Trial registration numbers NCT00287729, NCT00287716, NCT01366209.

M27 Effect of pirfenidone on breathlessness as measured by the ucsd-sobq score in patients with idiopathic pulmonary fibrosis (ipf) with moderate lung function impairment

Introduction Treatment of IPF with pirfenidone slows disease progression as measured by changes in forced vital capacity (FVC), independent of baseline FVC values. In a previous analysis of patients with limited vs more advanced lung function impairment, increases in University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) scores were more pronounced in patients with Gender Age Physiology index (GAP) stage II/III vs GAP stage I and in patients with baseline FVC <80% vs FVC ≥80%0.1 We examined the effect of pirfenidone on UCSD-SOBQ in these subpopulations. Methods 1247 patients in ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) were randomised to pirfenidone 2403 mg/d or placebo. Patients were stratified by GAP stage I vs stage II/III and by baseline%–predicted FVC. The effect of pirfenidone on UCSD-SOBQ score was assessed by continuous and categorical changes from baseline over 12 months, and by multiples of the minimal clinically important difference of 5 points for UCSD-SOBQ. Results Pirfenidone-treated patients with GAP stage II/III had higher UCSD-SOBQ scores after 12 months than those with GAP stage I (median increase from baseline: 9.4 vs 5.0); similar Results occurred with placebo (12.5 vs 4.3). GAP stage II/III patients treated with pirfenidone had less increase in median UCSD–SOBQ score at 12 months compared with those receiving placebo (9.4 vs 12.5; median difference −3.5, 95% CI −6.2,–0.5; p=0.0161) with the curves diverging after 3 months (figure 1). Evaluation of categorical change for patients with GAP stage II/III demonstrated that pirfenidone reduced the proportion of patients with UCSD-SOBQ score increases of ≥15 points (45.6% vs 38.4%; p=0.0449) and ≥20 points (37.7% vs 28.6%; p=0.0089) at 12 months compared with placebo; increases of ≥5 or≥10 points were similar between treatment groups. Results in patients with%FVC ≤80% were comparable to GAP stage II/III. Conclusions In patients with IPF with moderate lung function impairment, pirfenidone reduced the progression of breathlessness compared with placebo. Patients receiving pirfenidone showed less change from baseline in UCSD-SOBQ score and a lower proportion of patients had more pronounced increases in UCSD-SOBQ scores at 12 months. Reference . Albera C et al. Eur Respir J2016;48:843–851. Abstract M27 Figure 1 Median increase in UCSD-SOBQ scores from baseline in patients with GAP stage II/III.