Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

Highland, Kristin B.; Distler, Oliver; Kuwana, Masataka; Allanore, Yannick; Assassi, Shervin; Azuma, Arata; Bourdin, Arnaud; Denton, Christopher P.; Distler, Jörg H W; Hoffmann-Vold, A. M.; Khanna, Dinesh; Mayes, Maureen D.; Raghu, Ganesh; Vonk, Madelon C.; Gahlemann, Martina; Clerisme-Beaty, Emmanuelle; Girard, M; Stowasser, Susanne; Zoz, Donald F.; Maher, Toby M.

doi:10.1016/s2213-2600(20)30330-1

Cited by 140 publications

(128 citation statements)

References 22 publications

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Section: Therapeutic Efficacy Of Nintedanibmentioning

confidence: 99%

“…The benefit of nintedanib over placebo for the annual rate of FVC decline was generally consistent across prespecified subgroups based on age, sex, race, region, ATA status, systemic sclerosis subtype (limited cutaneous vs diffuse cutaneous) and mycophenolate use at baseline [ 43 , 45 ]. The adjusted mean annual rate of FVC decline was − 40.2 mL/year with nintedanib versus − 66.5 mL/year with placebo in patients using mycophenolate at baseline and − 63.9 mL/year versus − 119.3 mL/year in patients not using mycophenolate at baseline [ 45 ]. Nintedanib also reduced annual FVC decline relative to placebo irrespective of the extent of lung fibrosis [ 46 ] or skin fibrosis [ 47 ] at baseline, FVC as a percentage of predicted value at baseline [ 48 ] or skin fibrosis progression over 52 weeks [ 49 ] (no significant treatment-by-time-by-subgroup interactions).…”

Section: Therapeutic Efficacy Of Nintedanibmentioning

confidence: 99%

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Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

Lamb

2021

Drugs

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Progressive fibrosing interstitial lung diseases (ILDs) involve similar pathophysiological processes, indicating the potential for common approaches to treatment. Nintedanib (Ofev ® ), an intracellular tyrosine kinase inhibitor (TKI) with antifibrotic properties, was one of the first drugs approved for use in idiopathic pulmonary fibrosis (IPF) and has more recently been approved for use in other chronic fibrosing ILDs with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). In multinational phase III trials, nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) in adults with IPF, other progressive fibrosing ILDs and SSc-ILD. Reductions in FVC decline with nintedanib in patients with IPF and severe gas exchange impairment were comparable to those in patients with milder disease. Real-world experience in patients with IPF supports the effectiveness of nintedanib in slowing ILD progression. Nintedanib had a manageable tolerability profile in patients with fibrotic ILDs in clinical trials and real-world studies. No new safety signals have emerged from global pharmacovigilance data. Nintedanib continues to represent an important therapeutic option in patients with IPF and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype or SSc-ILD, with these approvals expanding the range of fibrotic ILDs for which nintedanib can be prescribed. Plain language summaryTreatment options for fibrotic interstitial lung diseases (ILDs) that involve progressive lung function decline have historically been limited. Nintedanib (Ofev ® ) was one of the first antifibrotic drugs to be approved for use in idiopathic pulmonary fibrosis and is now also approved for use in other chronic fibrosing ILDs with a progressive phenotype and systemic sclerosisassociated ILD (SSc-ILD). Nintedanib reduced lung function deterioration in patients with idiopathic pulmonary fibrosis, other chronic fibrosing ILDs with a progressive phenotype and SSc-ILD in well-designed clinical trials. In patients with idiopathic pulmonary fibrosis, the clinical benefit of nintedanib was shown to persist over more than 4 years of treatment. The most common adverse events in nintedanib recipients were diarrhoea and nausea, which were manageable in the majority of patients. Real-world experience supports the effectiveness and acceptable safety of nintedanib. Nintedanib remains an important treatment option for patients with idiopathic pulmonary fibrosis and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype and SSc-ILD.

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Section: Therapeutic Efficacy Of Nintedanibmentioning

confidence: 99%

Section: Therapeutic Efficacy Of Nintedanibmentioning

confidence: 99%

Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

Lamb

2021

Drugs

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“…Although the change in FVC was small (absolute mean decline mean −52.4 mL per year in the nintedanib versus −93.3 mL per year in the placebo group), the mean decline reached a previously shown value of minimal clinically important difference (MCID) in the placebo group, but not in the nintedanib treated population [85]. This beneficial effect on FVC preservation was seen both in MMF and non-MMF cotreated patients, with a numerically lower decline in patients receiving the combination treatment [58]. In the SENSCIS study, Nintedanib showed a safety profile similar to the side effects seen in IPF, particularly affecting the gastrointestinal tract (75.7% of treated patients manifested diarrhea) and requiring dose-adjustment/temporary interruption in almost half of the treated patients [59].…”

Section: Anti-fibrotic Therapiesmentioning

confidence: 75%

“…In the SENSCIS study, Nintedanib showed a safety profile similar to the side effects seen in IPF, particularly affecting the gastrointestinal tract (75.7% of treated patients manifested diarrhea) and requiring dose-adjustment/temporary interruption in almost half of the treated patients [59]. Interestingly, the safety profile was similar in patients receiving or not receiving co-treatment with MMF, which itself carries a gastro-intestinal burden in terms of adverse events [58].…”

Section: Anti-fibrotic Therapiesmentioning

confidence: 91%

The Treatment of Lung Involvement in Systemic Sclerosis

et al. 2021

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Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.

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“…With regard to trial design and selected patients, it seems reasonable to position nintedanib as first-line for patients with established interstitial lung disease and lung fibrotic pattern both as monotherapy and in combination with mycophenolate mofetil. This has been recently further supported by the subgroup analysis of the SENSCIS trial on SSc-ILD patients who were on concomitant mycophenolate mofetil treatment at baseline where it has been shown that a smaller proportion of patients treated with nintedanib versus placebo (29% versus 40% respectively; odds ratio 0,61 [0,37–1,01]) had a decrease in %predicted FVC ≥ 3.3%, which has been estimated to be the minimal clinically important difference for worsening of FVC in SSc-ILD patients [ 65 ]. Nonetheless, with the hope of a larger effect to counteract interstitial lung disease, the question of the timing of combination will have to be addressed quickly: generalization of upfront combination?…”

Section: Discussionmentioning

confidence: 99%

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Campochiaro

Allanore

2021

Arthritis Res Ther

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New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

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Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

Cited by 140 publications

References 22 publications

Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

The Treatment of Lung Involvement in Systemic Sclerosis

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

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