New drugs tested to treat Pulmonary Fibrosis. Report on the use of Enbrel at the Keck School of Medicine, University of Southern California

April 9, 2003 -- Los Angeles, California -- Entanercept (Enbrel®) for the treatment of I.P.F. Patients have been continued on therapy on a compassionate basis beyond the one year study period. Patients have been on therapy 4-5 years to date.

Usual Interstitial Pneumonia (UIP)/Idiopathic Pulmonary Fibrosis (IPF) is a diffuse interstitial lung disease characterized by chronic inflammation and progressive fibrosis of unknown etiology. It is not uncommon, occurring in 28 per 100,000 population. Untreated, the disease is insidiously progressive. It responds poorly to currently available therapy. Only 10% of patients respond to corticosteriod therapy with an additional 15-25% response to cyclophosphamide or azathiaprine/corticosteroid combination therapy. Median survival from time of diagnosis is 5.5 years. In summary, IPF is not an uncommon disease in need for more effective therapy. To date, there are no established sensitive markers for disease activity and response to therapy. Serial spirometry/DLCO and arterial blood gases are currently the best way to monitor disease activity and response to therapy.

Lung biopsy is the only definitive method to establish a diagnosis of UIP. The histopathologic findings are heterogeneous from normal lung, to intra-alveolar and interstitial inflammation with fibroblastic foci to fibrosis with distortion of lung parenchyma. Transbronchial biopsies often provide insufficient tissue to establish a diagnosis of UIP.

Recent studies in animals and humans have demonstrated an association and possible cause/effect between lung tumor necrosis factor (TNF) and pulmonary inflanimationlfibrosis. There are two distinct cell surface receptors (TNFR) for TNF. Soluble TNFR’ s are shed forms of the extracellular portion of the receptor and occur naturally in humans. Soluble TNFR binds TNF and inhibits its activity. TNFR:Fc (Enbrel ~, Etanercept) has binding affinity for TNF equivalent to cell-surface TNFR. TNFR:Fc binds both TNF and LTcc, which are inflammatory mediators released by activated macrophages and T cells.

The study was designed to determine whether TNFR: Fe could reverse and/or prevent further loss of lung function (vital capacity, DLco and A-a02 gradient) in patients with UIP. In addition we wanted to determine the safety of TNFR: Fe therapy in such a patient population. Nine consecutive patients with pathologically confirmed UIP by open lung biopsy (one patient) or transthoracic core needle biopsy (eight patients) with a Franldin Silverman needle (Fig 1) were enrolled to study the clinical response to TNFR: Fe therapy. All patients had failed to respond to prednisone (eight patients) or prednisone/cyclophosphamide (one patient) prior to entering the study. Severity of lung dysfunction was not a criteria for exclusion. Four of the nine patients had end stage disease. There were five males and four females aged 40 — 76 years (Ave. 56.Syrs). Degree of dyspnea was evaluated by a Dyspnea Scale (ATS): 0= no dyspnea to 4 + = dyspnea at rest. Initial dyspnea ranged between 1+ and 4 + with an average of 2.75+. Initial vital capacity ranged between 29% and 75% predicted normal (Ave 45.8%) . Initial diffusing capacity ranged between 11 % -55% predicted normal (Ave. 30.5%). The initial A-a02 gradient ranged between 19-93 mm Hg. (Ave. 48.6 mm Hg).

Patients were treated with TNFR: Fe 25mgm S.C. biw and predmsone 10 mgn daily. In addition to clinical and physiologic evaluations, a CBC, blood chemistries including liver function tests and urinalyses were obtained

Nine patients have been followed for 6 to 22 months with follow-up evaluations at monthly intervals. For five patients, the Dyspnea Scale improved by one with associated increased physical activity. For two patients the Dyspnea Scale was unchanged but they were able to increase their physical activity. For two patients there was no change in Dyspnea Scale or physical activity. Improvement, or decline in physiologic function was defined as > 15% change in test results. The Vital Capacity has improved in two patients and has remained unchanged in seven patients with an average improvement of 8% (Table II-V). The diffusing capacity has improved in five patients, was unchanged in one patient, reduced in two patients and unable to obtain in one patient with an average improvement of 22%. (Table III-IV). The A-a 02 gradient was improved in five patients and unchanged in four patients with an average improvement of 27%. (Table IV-V).

All patients tolerated therapy well. There were no adverse events. Three patients each had single episodes of acute bronchitis responding immediately to antibiotic therapy. The acute episodes of bronchitis were not considered to be a result of TNFR: Fe therapy. One patient (AM) died at one year. At time of entry she had an acute exacerbation of her disease. The patient improved symptomatically with therapy but did not physiologically improved. One patient (FG) who responded well to therapy died of unrelated cause.

Despite severity of disease present at the time treatment was initiated, TNFR: Fe appears to reverse or reduce loss of lung function of patient with UIP. The results support the need for a large scale, double blind study of UIP patients with early to moderate loss of lung function to determine the role of TNFR: FC for the treatment of a disease with such a poor prognosis. For more information contact: