Horizon Pharma, Inc announced results from the extended open label portion of The Circadian Administration of Prednisone in Rheumatoid Arthritis-1 (CAPRA-1) phase-3 European registration study of Lodotra, a programmed release formulation of low-dose prednisone, which showed sustained improvement in reducing the duration of morning stiffness in patients with Rheumatoid Arthritis (RA) over a 12 month period. The results were published in the July issue of the Annals of Rheumatic Diseases and were also recently presented at the European League Against Rheumatism (EULAR) Annual Congress.

"Symptoms of RA in patients, such as morning stiffness, show pronounced circadian rhythms with the highest severity in the early morning," said Frank Buttgereit, senior consultant and deputy head of the Department of Rheumatology and Clinical Immunology, Charité Hospital, Berlin and lead author of the study. "The results from the open label portion of the CAPRA-1 study showed that the efficacy of glucocorticoid therapy can be sustained by synchronizing the drug release with the circadian rhythm of the underlying inflammation and resulting symptoms."

The CAPRA-1 study of Lodotra evaluated 288 patients with active RA in a 12-week, randomized, double-blind, placebo-controlled trial comparing bedtime administration of Lodotra with morning administration of immediate release (IR) prednisone at the same individual dose (an average dose of 6.7 mg). Following the double-blind portion of the study, 249 patients continued on to an open label extension study for up to nine additional months, during which all patients received only an evening dose of Lodotra. Variables assessed included, among other things: (i) reduction in the duration of morning stiffness (MS) of the joints; (ii) disease activity scores (DAS 28), a measurement of pain and swelling in 28 joints typically impacted by RA; (iii) American College of Rheumatology (ACR) 20 response rate, which measures the percentage of patients who have achieved a 20 percent improvement in tender and swollen joint counts as well as a 20 per cent improvement in three of five other criteria of disease activity; and (iv) plasma levels of interleukin-6 (IL-6), a pro-inflammatory cytokine.

Following six months of treatment in the open label portion of the study, morning stiffness was reduced in those patients who were in the IR prednisone group during the double-blind portion by 54 per cent compared to 56 per cent for patients taking Lodotra in both portions of the study. At 12 months, the mean relative reduction in morning stiffness reached 55 per cent in patients treated with Lodotra who continued treatment from the double-blind phase compared to 45 per cent in the patient group who had switched from IR prednisone to Lodotra.

Of patients who completed a total of 12 months in the study (n=219), 37 percent achieved improvement in the ACR20 criteria. DAS 28 score was reduced from the mean 5.8 at baseline to 4.8 for those taking Lodotra and to 4.9 for the former IR prednisone group. IL-6 plasma levels were approximately 50 percent less in the Lodotra-treated patients compared to the IR prednisone-treated patients after both three and 12 months of treatment. Adverse events were observed in 51 percent of the patients enrolled in the open label portion of the study. The most commonly reported treatment-emergent adverse events were a flare in RA-related symptoms (14.5 per cent), upper respiratory tract infections (2.8 per cent), back pain (2.8 percent) and weight increase (2.8 per cent).

Adverse events indicative of aggravated hypothalamic-pituitary-adrenal axis suppression, typical of high dose prednisone administration, were not observed. Adverse events rated as being possibly related to study medication were upper abdominal pain (1.2 per cent), gastritis (1.6 per cent) and weight increase (2.4 per cent). A total of 12 patients (4.8 per cent) withdrew from the study due to an adverse event.

"The results of this study suggest that low-dose programmed-release Lodotra may offer significant benefits over IR prednisone for the treatment of RA, and those benefits are maintained for up to 12 months," said Jeffrey W. Sherman, executive vice president, development, regulatory affairs and chief medical officer of Horizon Pharma. "For RA patients struggling with the debilitating impact of morning stiffness, we believe this study provides continued evidence that a better treatment alternative is emerging."

Lodotra, a programmed release formulation of low-dose prednisone, was approved in Europe in March 2009 and has been initially launched in several European countries.

Horizon Pharma is a biopharmaceutical company that is developing and commercializing innovative medicines to target unmet therapeutic needs in arthritis, pain and inflammatory diseases.