Pharmaceutical giant, Boehringer Ingelheim (BI), is poised to begin a Phase III trial of its idiopathic pulmonary fibrosis (IPF) drug, Ofev (nintedanib) as a treatment for systemic sclerosis-related interstitial lung disease (SSc-ILD). Ofev initially gained approval by the Food and Drug Administration (FDA) in October 2014 and by the European Medicines Agency (EMA) in January 2015. Roche and Genentech’s Esbriet, arguably BI’s closest competitor in the field, is more widely known than Ofev. Despite being available in Europe since 2011, Esbriet gained FDA approval on the same day as Ofev.
SSc is an autoimmune disease which triggers progressive fibrosis of the skin and internal organs as well as vasculopathy. ILD, and other forms of lung disease, is the lead cause of death in patients with SSc. With patients already having limited options for treatment of this disease, SSc has become a major health concern. The usual standard of care is to treat the patient’s symptoms (which normally include vasculopathy), as well as treat fibrotic disease early on with immunosuppressive agents. The choice of immunotherapy can often depend on any additional symptoms they may carry. For instance, methotrexate is preferred for patients with arthritis, while cyclophosphamide or mycophenolate mofetil is preferred for patients with ILD. However, even with early immunosuppressive therapy, the effects are likely minimal at best.
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Esbriet and Ofev have been shown to prevent the decline in lung function that is inevitable in IPF patients, as determined by the forced vital capacity (FVC). Although SSc-ILD is a similar form of pulmonary fibrosis to IPF, and there is great interest among physicians in treating SSc with Ofev and Esbriet, few patients with SSc-ILD have access to these therapies. There are additional safety concerns in SSc patients, and though there is likely an overlapping pathophysiology in these two forms of ILD, there are a few key differences. First, the etiology of IPF and SSc-ILD is unknown, and the mechanisms of lung damage and repair leading to fibrosis are not completely understood. Secondly, the morphological pattern that is typical of fibrosis in IPF is known as usual interstitial pneumonia (UIP), while the pattern in SSc-ILD is typically non-specific interstitial pneumonia (NSIP). There is some overlap, where SSc-ILD patients display the UIP pattern, and vice versa. Despite this overlap, SSc-ILD patients generally do not have access to Ofev and Esbriet, due to reimbursement restrictions, except for a very limited number of cases of SSc-ILD with UIP. More research is necessary to determine whether SSc-ILD responds to these IPF therapies, which will be necessary for their regulatory approval and widespread reimbursement.
Esbriet was investigated in a Phase II safety and tolerability trial for SSc-ILD, known as the LOTUSS trial. The trial reported the drug to be safe for use in SSc patients, but additional research with a focus on efficacy is warranted. Although the Phase III trial of Ofev aims to determine the drug’s efficacy in SSc-ILD, with FVC as a primary endpoint, rheumatologists interviewed by GlobalData are also interested in understanding whether these IPF therapies are effective beyond the treatment of lung disease. Specifically, the Ofev trial includes several exploratory endpoints, including a secondary endpoint to measure the modified Rodnan skin score (mRSS. The mRSS is a measure of skin fibrosis, but it is commonly used in SSc as a surrogate endpoint for the overall function of the patient, as serial measures can determine whether a patient is at risk of rapid progression of disease. Positive results for the mRSS would likely be viewed favorably by specialists in SSc, as this would provide evidence for drug efficacy beyond an improvement in lung function.
In terms of their mechanisms of action, it stands to reason that these novel medicines would be effective as systemic anti-fibrotics, although many unanswered questions remain. Ofev is the newest member of a class of tyrosine-kinase inhibitors (TKIs), which are typically investigated for their use in oncology, and is also considered to be an anti-fibrotic agent. Although other TKIs, such as imatinib, have been investigated in fibrosis, none have shown a favorable safety and efficacy profile that could support a regulatory filing for pulmonary fibrosis. Although the anti-fibrotic properties of Esbriet have been studied extensively, its precise mechanism of action is unknown. Within the field of IPF, Ofev and Esbriet were shown to prevent the decline in lung function, and while the mechanism is believed to be due to inhibition of fibrosis, this has not been conclusively shown. Furthermore, it is unknown whether these drugs reverse fibrosis or simply prevent it.
In order to obtain regulatory approval in SSc, Ofev and Esbriet will need to be proven effective in ILD. Rheumatologists are hopeful that the benefits will go beyond use in ILD, and that these novel agents will prevent or treat fibrosis of the skin and other organs. As these drugs do not target the immune system, rheumatologists interviewed by GlobalData suggested that they may be used in combination with immunosuppressive agents for greater efficacy. Although trials are in their infancy for SSc, GlobalData believes that Esbriet and Ofev hold potential to radically change the SSc treatment landscape and fulfill a major unmet need.
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By GlobalData*This article first appeared on GlobalData on 4 December 2015
