Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis Interstitial Lung Disease

Dinesh Khanna¹, Carlo Albera², Aryeh Fischer³, James R. Seibold⁴, Nader A. Khalidi⁵, Ganesh Raghu⁶, Lorinda Chung⁷, Elena Schiopu¹, Dan Chen⁸ and Eduard Gorina⁹, ¹University of Michigan, Ann Arbor, MI, ²University of Turin, Turin, Italy, ³National Jewish Health and University of Colorado, Denver, CO, ⁴Scleroderma Research Consultants LLC, Litchfield, CT, ⁵McMaster University, Hamilton, ON, Canada, ⁶University of Washington, Seattle, WA, ⁷Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ⁸Jazz Pharmaceuticals (formerly of InterMune), Palo Alto, CA, ⁹Formerly of InterMune, Brisbane, CA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: interstitial lung disease, randomized trials, Safety, systemic sclerosis and tolerance

Session Information

Date: Tuesday, November 10, 2015

Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud's - Clinical Aspects and Therapeutics II

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Interstitial lung disease (ILD) is a common and serious complication
of systemic sclerosis (SSc). Pirfenidone, a novel antifibrotic agent, has been shown
to be safe and effective in the treatment of idiopathic pulmonary fibrosis
(IPF). The LOTUSS study was designed to assess the safety and tolerability of
pirfenidone in patients with SSc-ILD.

Methods: This
is an open-label, 16-week study. Patients were randomized to a 2- or 4-week
titration to the target dose of 2403 mg/day. Eligibility required a diagnosis
of SSc ≤7 years from first non-Raynaud’s symptom, HRCT-confirmed ILD, FVC
≥50% and DL_co ≥40%, absence of clinically significant
pulmonary hypertension or severe GERD. Stable treatment with mycophenolate mofetil
(MMF) or oral cyclophosphamide was permitted. Safety assessments included collection
of treatment emergent adverse events (TEAEs), vital signs, ECGs and laboratory
tests. Though the study was not designed or powered to evaluate efficacy, FVC
%-predicted, DL_co %-predicted, modified Rodnan skin score (mRSS), Mahler
BDI/TDI, and UCLA SCTC GIT 2.0 were recorded at baseline and 4 months.

Results: Of
the 63 patients enrolled, the mean (SD) age was 50.6 (12.3) years; the majority
were female (82.5%) and white (76.2%). The mean (SD) SSc duration was 38.3 (26.0)
months. Forty patients (63.5%) were on MMF and the rest (36.5%) were not receiving
any immunosuppressants. The mean (SD) mRSS, %FVC and %DL_co at
baseline were 11.4 (9.6), 76.0 (14.2) and 59.7 (16.5), respectively.

The frequency and type of TEAEs were
similar for both titration groups. The safety results are summarized below. No
clinically significant changes in vital signs, ECGs, or laboratory tests were observed.

At week 16, the median change from baseline
in %FVC was -0.5% (range -42% to 12%); 10 patients (16.7%) had an increase
≥5% whereas 5 (8.3%) had a decrease >5% at week 16. Median change
from baseline in %DL_co was 1.5% (range -24.0% to 40.0%); 19 subjects
(31.7%) had an increase ≥5% vs. 10 (16.7%) had a decrease >5% at week
16. Minor changes (mean±SD) were observed in Mahler TDI (1.0±3.41) and mRSS
(-0.4±3.71). No change was noted in the GI symptoms on UCLA SCTC GIT 2.0.

Conclusion:
In the 16-week, open-label trial of pirfenidone in SSc-ILD, pirfenidone was
safe and generally well-tolerated in SSc-ILD patients, despite pre-existing
co-morbidities, including underlying GI disease, and concomitant use of MMF.
The AEs were expected and consistent with those previously seen in IPF trials.
The data support further investigation of pirfenidone in SSc-ILD.

Disclosure: D. Khanna, Bristol Myers-Squibb, EMD Serono, Genentech/Roche, NIH/NIAID-ACE, NIH/NIAMS-K24, PCORI and Scleroderma Foundation, 2,Bayer, Biogen, Cytori, EMD Serono, Forward, Genentech/Roche, Gilead, Lycera and Seattle Genetics, 5; C. Albera, InterMune, Roche, GlaxoSmithKline, Boehringer Ingelheim, and Baye., 5; A. Fischer, Roche-Genentech, 2,Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, Roche-Genentech, Gilead, GlaxoSmithKline and Seattle Genetics, 5; J. R. Seibold, Actelion, Aires, Apricus/Nexmed, Bayer, Boehringer Ingelheim, Covis, Cellgene, DART, Eiccose, Eiger, EMD Serono, FibroGen, Gilead, InterMune, Novartis, Pfizer, Sanofi-Aventis, Sigma Tau and United Therapeutics, 5; N. A. Khalidi, None; G. Raghu, Roche-Genentech and Boehringer Ingelheim, 5; L. Chung, Gilead, 4; E. Schiopu, InterMune, 2; D. Chen, None; E. Gorina, InterMune Inc, 3.

To cite this abstract in AMA style:

Khanna D, Albera C, Fischer A, Seibold JR, Khalidi NA, Raghu G, Chung L, Schiopu E, Chen D, Gorina E. Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis Interstitial Lung Disease [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/safety-and-tolerability-of-pirfenidone-in-patients-with-systemic-sclerosis-interstitial-lung-disease/. Accessed .

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