Phase 3 U.S. registration study of LODOTRA shows improvement in patients with RA

Horizon Pharma, Inc., announced today that data from the Phase 3 U.S. registration study of LODOTRA®, a circadian cytokine modulator and novel modified-release, low-dose prednisone tablet, showed a statistically significant improvement in American College of Rheumatology (ACR) response criteria in patients with rheumatoid arthritis (RA).  These data, along with 12-month efficacy data from the company's Phase 3 European registration study, were presented at the 11th Annual Congress of the European League Against Rheumatism (EULAR) in Rome, Italy.

"Conditions like rheumatoid arthritis follow a very distinct circadian rhythm, in which symptoms are more severe at a specific time of day.  In the case of RA, many patients feel stiff when they wake up and it has the potential to negatively impact their quality of life," said Frank Buttgereit, M.D., senior consultant and deputy head of the Department of Rheumatology and Clinical Immunology, Charite Hospital, Berlin.  "The results from this second, Phase 3 study demonstrate that compared to placebo, LODOTRA shows clinically and statistically higher response in reducing symptoms, such as tender and swollen joint counts and morning stiffness associated with RA, which may provide some needed relief for these patients when their symptoms may be at their worst."

CAPRA-2 Results Demonstrate Statistically Significant Efficacy Versus Placebo

The 350 patient CAPRA-2 (Circadian Administration of Prednisone in Rheumatoid Arthritis-2) U.S. registration study was a 12-week, double blind, placebo-controlled trial evaluating LODOTRA compared to placebo in patients with active RA who were receiving ongoing disease-modifying anti-rheumatic drug (DMARD) therapy.  The primary endpoint of the study was ACR 20 response rate, which signifies a 20 percent improvement in tender and swollen joint counts, as well as other criteria, at week 12.  The secondary endpoint was relative reduction of morning stiffness associated with RA at week 12.  

ACR 20 responses were statistically significant for patients treated with LODOTRA (48.5 percent) compared to patients treated with placebo (28.6 percent,>

In this study, the most commonly reported treatment-emergent adverse events reported with LODOTRA were arthralgia or joint pain (10.4 percent for LODOTRA compared to 20.2 percent for placebo), RA flare (6.5 percent for LODOTRA compared to 9.2 for placebo), nasopharyngitis (4.8 percent for LODOTRA compared to 3.4 percent for placebo) and headache (3.9 percent for LODOTRA compared to 4.2 percent for placebo).

Sustained Efficacy Demonstrated in European CAPRA-1 Study

Twelve-month follow-up data from the open-label, double-blind, placebo-controlled, CAPRA-1 (Circadian Administration of Prednisone in Rheumatoid Arthritis-1) European registration study was also presented today during the EULAR Congress.  The trial evaluated 288 patients with active RA randomized to receive an evening dose of approximately 6 mg of LODOTRA or a morning dose of approximately 6 mg of immediate-release (IR) prednisone.  Of the 288 patients enrolled in the initial three-month CAPRA-1 trial, 249 continued on to an open label study for up to nine additional months, during which time all patients received an average evening dose of approximately 6.8 mg of LODOTRA.

At the conclusion of the three-month, double-blind phase, patients treated with LODOTRA showed a statistically significant reduction in morning stiffness duration compared to those in the IR prednisone treatment group (22.7 percent compared to 0.4 percent, respectively, mean relative change to baseline;>

In the open-label phase, at 12 months, the mean relative reduction in morning stiffness reached 55 percent in LODOTRA patients who continued on the drug from the double-blind phase compared to 45 percent in the patient group who had switched from IR prednisone to LODOTRA.  Both groups of patients achieved a clinically relevant reduction in the Disease Activity Score (DAS) 28 score, a measurement of pain and swelling in 28 joints typically impacted by RA.  At 12 months, both the LODOTRA group and the IR prednisone group who had subsequently received LODOTRA also showed a reduction in pain intensity by 11 and 13 mm, respectively on the 100mm-Visual Analog Scale (VAS), a tool used to measure the amount of pain a patient feels. In both groups, the median reduction in IL-6 levels was about 50 percent.  ACR 20 response at the end of the 12 month study period was achieved by 37.5 percent and 37.4 percent of LODOTRA patients and IR prednisone patients who had switched to LODOTRA, respectively.

In the double-blind phase of the study, the most commonly reported treatment-emergent adverse events were: RA flare (7.6 percent for LODOTRA compared to 9.0 percent for IR prednisone), abdominal pain (3.5 percent for LODOTRA compared to 5.6 percent for IR prednisone), nasopharyngitis (2.8 percent for LODOTRA compared 5.6 percent for IR prednisone), headache (4.2 percent for LODOTRA, 2.8 percent for IR prednisone) and flushing (2.8 percent for LODOTRA compared to 4.2 percent for IR prednisone).  In the open label phase, the most common adverse events reported were RA flare, flushing, upper respiratory tract infections, weight gain and back pain.

"The CAPRA-2 findings, along with the positive 12-month data from CAPRA-1, demonstrate that LODOTRA may be an important new option for patients who suffer from the symptoms related to RA," said Timothy P. Walbert, chairman, president and chief executive officer, Horizon Pharma.  "We anticipate submitting a New Drug Application for LODOTRA for the treatment of the signs and symptoms of RA to the U.S. FDA later this year."