Meeting News

Pirfenidone promising for unclassifiable ILD

Pirfenidone treatment was associated with improvement in several outcomes among patients with progressive fibrosing unclassifiable interstitial lung disease, according to a new study.

Unfortunately, the multicenter, double-blind, randomized, placebo-controlled phase 2 trial — which was presented at the European Respiratory Society International Congress and simultaneously published in The Lancet Respiratory Medicine — faced technical issues with home spirometry that prevented analysis of data for the primary endpoint. Positive findings for secondary endpoints, however, were encouraging, the researchers noted.

“Further research is needed to address the challenges encountered with this outcome measure. However, the results from several of the key secondary and exploratory outcomes, including lung function and exercise capacity, suggest that pirfenidone could be an effective treatment for patients with progressive fibrotic unclassifiable ILD over 24 weeks, with an acceptable safety and tolerability profile, and these results warrant further investigation,” they wrote.

Potentially slower disease progression

From 2017 to 2018, the researchers randomly assigned adults aged 18 to 85 years with fibrosing unclassifiable ILD to 2,403 mg per day oral pirfenidone (Esbriet, Genentech; n = 127) or placebo (n = 126).

As previously mentioned, technical issues with home spirometry recordings precluded application of the planned statistical analysis to data for the primary endpoint of mean change in FVC as assessed by home spirometry, according to the researchers. They reported, though, that the predicted median change in FVC measured by home spirometry was –87.7 mL in the pirfenidone group vs. –157.1 mL in the placebo group.

When assessed using spirometry in the clinic, the predicted mean change in FVC over 24 weeks was lower in patients in the pirfenidone group than in the placebo group, with a treatment difference of 95.3 mL (95% CI, 35.9-154.6). Additionally, patients in the pirfenidone group were less likely than those in the placebo group to have a decline in FVC of more than 5% (OR = 0.42; 95% CI, 0.25-0.69) or more than 10% (OR = 0.44; 95% CI, 0.23-0.84).

Results also showed that, at 24 weeks, the mean change in diffusing capacity of the lung for carbon monoxide (DLCO) from baseline was –0.7% for those taking pirfenidone and –2.5% for those taking placebo and that the mean change in 6-minute walk distance from baseline was –2 m for the pirfenidone group and –26.7 m for the placebo group. Rank analysis of covariance (ANCOVA) results predicted that percent DLCO did not favor pirfenidone, but the prespecified exploratory analysis of the proportion of patients with a more than 15% categorical decline in percent predicted DLCO did show a treatment benefit, according to the researchers. Conversely, rank ANCOVA results for 6-minute walk distance favored pirfenidone, but the prespecified exploratory analysis of the proportion of patients with a more than 50-m categorical decline did not.

There were no differences between treatment groups in progression-free survival or in patient-reported outcomes, including University of California Shortness of Breath Questionnaire score, Leicester Cough Questionnaire score, cough visual analogue scale and St. George’s Respiratory Questionnaire score, with changes from baseline being similar in both groups.

Due to the small number of events, the analysis of acute exacerbations, hospital admissions and time to death from respiratory causes during the study yielded meaningful results.

In terms of adverse events, most patients in the pirfenidone (94%) and the placebo groups (81%) reported treatment-emergent adverse events, with 14% of the pirfenidone group and 16% of the placebo group reporting serious events. The most frequently reported treatment-related treatment-emergent events were gastrointestinal disorders (pirfenidone vs. placebo, 47% vs. 26%), fatigue (13% vs. 10%) and rash (10% vs. 7%).

‘Encouraging’ results

In an accompanying editorial, Justin M. Oldham, MD, MS, from the department of internal medicine and the division of pulmonary and critical care medicine at the University of California, Davis, in Sacramento, discussed some of the technical issues experienced with home spirometry that prevented the researchers from analyzing the study’s primary endpoint.

“A single daily spirometry was required, with the aim of optimizing patient adherence and minimizing discomfort; however, this approach resulted in highly variable FVC values not being detected since spirometer quality control safeguards required repeated daily measures for activation,” he wrote. “This experience will inform the design of future clinicals using this novel technology and supports adaptive trial designs to allow technical problems to be identified during a trial.”

Oldham also highlighted potential opportunities for further investigation, such as stratification by reason for unclassifiable ILD classification or identification of minimum diagnostic confidence thresholds, as some patients were diagnosed with a low level of confidence.

Nevertheless, he too found the results of this study promising.

“Although their trial was disappointing in terms of the primary endpoint, and the secondary endpoints should be interpreted with caution, these findings are nonetheless encouraging and provide hope that effective therapies are within reach for an increasing number of patients with fibrotic ILD. This work supports ongoing investigation of pirfenidone and other antifibrotic medications for the treatment of fibrotic ILD, whether classifiable or not,” Oldham wrote. – by Melissa Foster

References:

Maher TM, et al. ALERT: Abstracts leading to evolution in respiratory medicine trials: Interstitial lung disease and pulmonary hypertension. Presented at: European Respiratory Society International Congress; Sept. 28-Oct. 2, 2019; Madrid.

Maher TM, et al. Lancet Respir Med. 2019;doi:10.1016/S2213-2600(19)30341-8.

Oldham JM. Lancet Respir Med. 2019;doi:10.1016/S2213-2600(19)30343-1.

Disclosures: This study was funded by F. Hoffmann-La Roche. Maher reports he has received grants from AstraZeneca, GlaxoSmithKline and UCB via his institution; he has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galapagos, GlaxoSmithKline, Indalo, Novartis, Pliant, ProMetic, Respivant, F. Hoffmann-La Roche, Samumed and UCB; and he owns stock options in Apellis. Please see the study for all other authors’ relevant financial disclosures. Oldham reports he has received grants from the NIH and American College of Chest Physicians, and he has received personal fees from Boehringer Ingelheim and Genentech.

Pirfenidone treatment was associated with improvement in several outcomes among patients with progressive fibrosing unclassifiable interstitial lung disease, according to a new study.

Unfortunately, the multicenter, double-blind, randomized, placebo-controlled phase 2 trial — which was presented at the European Respiratory Society International Congress and simultaneously published in The Lancet Respiratory Medicine — faced technical issues with home spirometry that prevented analysis of data for the primary endpoint. Positive findings for secondary endpoints, however, were encouraging, the researchers noted.

“Further research is needed to address the challenges encountered with this outcome measure. However, the results from several of the key secondary and exploratory outcomes, including lung function and exercise capacity, suggest that pirfenidone could be an effective treatment for patients with progressive fibrotic unclassifiable ILD over 24 weeks, with an acceptable safety and tolerability profile, and these results warrant further investigation,” they wrote.

Potentially slower disease progression

From 2017 to 2018, the researchers randomly assigned adults aged 18 to 85 years with fibrosing unclassifiable ILD to 2,403 mg per day oral pirfenidone (Esbriet, Genentech; n = 127) or placebo (n = 126).

As previously mentioned, technical issues with home spirometry recordings precluded application of the planned statistical analysis to data for the primary endpoint of mean change in FVC as assessed by home spirometry, according to the researchers. They reported, though, that the predicted median change in FVC measured by home spirometry was –87.7 mL in the pirfenidone group vs. –157.1 mL in the placebo group.

When assessed using spirometry in the clinic, the predicted mean change in FVC over 24 weeks was lower in patients in the pirfenidone group than in the placebo group, with a treatment difference of 95.3 mL (95% CI, 35.9-154.6). Additionally, patients in the pirfenidone group were less likely than those in the placebo group to have a decline in FVC of more than 5% (OR = 0.42; 95% CI, 0.25-0.69) or more than 10% (OR = 0.44; 95% CI, 0.23-0.84).

Results also showed that, at 24 weeks, the mean change in diffusing capacity of the lung for carbon monoxide (DLCO) from baseline was –0.7% for those taking pirfenidone and –2.5% for those taking placebo and that the mean change in 6-minute walk distance from baseline was –2 m for the pirfenidone group and –26.7 m for the placebo group. Rank analysis of covariance (ANCOVA) results predicted that percent DLCO did not favor pirfenidone, but the prespecified exploratory analysis of the proportion of patients with a more than 15% categorical decline in percent predicted DLCO did show a treatment benefit, according to the researchers. Conversely, rank ANCOVA results for 6-minute walk distance favored pirfenidone, but the prespecified exploratory analysis of the proportion of patients with a more than 50-m categorical decline did not.

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There were no differences between treatment groups in progression-free survival or in patient-reported outcomes, including University of California Shortness of Breath Questionnaire score, Leicester Cough Questionnaire score, cough visual analogue scale and St. George’s Respiratory Questionnaire score, with changes from baseline being similar in both groups.

Due to the small number of events, the analysis of acute exacerbations, hospital admissions and time to death from respiratory causes during the study yielded meaningful results.

In terms of adverse events, most patients in the pirfenidone (94%) and the placebo groups (81%) reported treatment-emergent adverse events, with 14% of the pirfenidone group and 16% of the placebo group reporting serious events. The most frequently reported treatment-related treatment-emergent events were gastrointestinal disorders (pirfenidone vs. placebo, 47% vs. 26%), fatigue (13% vs. 10%) and rash (10% vs. 7%).

‘Encouraging’ results

In an accompanying editorial, Justin M. Oldham, MD, MS, from the department of internal medicine and the division of pulmonary and critical care medicine at the University of California, Davis, in Sacramento, discussed some of the technical issues experienced with home spirometry that prevented the researchers from analyzing the study’s primary endpoint.

“A single daily spirometry was required, with the aim of optimizing patient adherence and minimizing discomfort; however, this approach resulted in highly variable FVC values not being detected since spirometer quality control safeguards required repeated daily measures for activation,” he wrote. “This experience will inform the design of future clinicals using this novel technology and supports adaptive trial designs to allow technical problems to be identified during a trial.”

Oldham also highlighted potential opportunities for further investigation, such as stratification by reason for unclassifiable ILD classification or identification of minimum diagnostic confidence thresholds, as some patients were diagnosed with a low level of confidence.

Nevertheless, he too found the results of this study promising.

“Although their trial was disappointing in terms of the primary endpoint, and the secondary endpoints should be interpreted with caution, these findings are nonetheless encouraging and provide hope that effective therapies are within reach for an increasing number of patients with fibrotic ILD. This work supports ongoing investigation of pirfenidone and other antifibrotic medications for the treatment of fibrotic ILD, whether classifiable or not,” Oldham wrote. – by Melissa Foster

References:

Maher TM, et al. ALERT: Abstracts leading to evolution in respiratory medicine trials: Interstitial lung disease and pulmonary hypertension. Presented at: European Respiratory Society International Congress; Sept. 28-Oct. 2, 2019; Madrid.

Maher TM, et al. Lancet Respir Med. 2019;doi:10.1016/S2213-2600(19)30341-8.

Oldham JM. Lancet Respir Med. 2019;doi:10.1016/S2213-2600(19)30343-1.

Disclosures: This study was funded by F. Hoffmann-La Roche. Maher reports he has received grants from AstraZeneca, GlaxoSmithKline and UCB via his institution; he has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galapagos, GlaxoSmithKline, Indalo, Novartis, Pliant, ProMetic, Respivant, F. Hoffmann-La Roche, Samumed and UCB; and he owns stock options in Apellis. Please see the study for all other authors’ relevant financial disclosures. Oldham reports he has received grants from the NIH and American College of Chest Physicians, and he has received personal fees from Boehringer Ingelheim and Genentech.