Horizon Pharma Announces U.S. FDA Acceptance of LODOTRA® NDA for Review for the Treatment of RA

Horizon Pharma, Inc. has announced that the United States Food and Drug Administration (FDA) has accepted for filing and review its New Drug Application (NDA) for LODOTRA®, a proprietary modified (delayed)-release formulation of low-dose prednisone, for the treatment of rheumatoid arthritis (RA) in adults, and set a PDUFA date of July 26, 2012, based on the standard 10 month review.

LODOTRA is currently approved for marketing in 16 European countries.

"The acceptance of the LODOTRA NDA for review is an important milestone as we continue our commitment to bringing new therapeutic options to patients suffering from arthritis, pain and inflammatory diseases," said Timothy P. Walbert, chairman, president and chief executive officer, Horizon Pharma.

Walbert continued, "We are confident in the data from the Phase 3 program and believe that if approved, LODOTRA will address an unmet treatment need for patients with rheumatoid arthritis."

The LODOTRA NDA submission was primarily based on results from the Circadian Administration of Prednisone in RA (CAPRA-2) trial, a pivotal, 12-week, double-blind, randomized, placebo-controlled Phase 3 trial involving 350 RA patients (N=231 on LODOTRA, N=119 on placebo).

Both treatment groups in the trial continued to receive standard of care RA treatment with a disease-modifying anti-rheumatic drug (DMARD). Results from CAPRA-2 demonstrated:

• A statistically significant improvement in American College of Rheumatology (ACR)20 response criteria, the primary study endpoint, for patients who were treated with LODOTRA compared to the placebo group (48.0% vs. 29.4%; p-value = 0.0007).
• A statistically significant improvement in ACR50 response compared to placebo (22.3% vs. 10.1%; p-value = 0.0063) and an improvement in the more stringent ACR70 response criteria (7.0% vs. 2.5%; p-value = 0.0955).
• A statistically significant reduction in the duration of morning stiffness compared to patients in the placebo group (median relative change: 55.2% vs. 34.6%; p-value = 0.0015).

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

Additional data in the NDA submission included results from the CAPRA-1 study, which was a 12 week, double-blind, randomized, active comparator-controlled study in Europe involving 288 RA patients.

CAPRA-1 compared the night-time administration of LODOTRA (N=144) with the morning administration of immediate release prednisone (N=144) at the same individual dose (average dose of 6.7 mg). Results from CAPRA-1 demonstrated:

• A statistically significant reduction in the duration of morning stiffness compared to patients in the immediate release prednisone group, the primary outcome of the trial, (22.7% for LODOTRA compared to 0.4% for immediate release prednisone (p-value = 0.045)).
• Patients treated with LODOTRA had a reduction in IL-6 levels of approximately 29% (relative median change), which was statistically significant, while corresponding IL-6 levels following treatment with immediate release prednisone remained constant.

The most commonly reported treatment-emergent adverse events were a flare in RA-related symptoms (7.6% for LODOTRA compared to 9.0% for immediate release prednisone), abdominal pain (3.5% for LODOTRA compared to 5.6% for immediate release prednisone), nasopharyngitis (2.8% for LODOTRA compared to 5.6% for immediate release prednisone), headache (4.2% for LODOTRA compared to 2.8% for immediate release prednisone) and flushing (2.8% for LODOTRA and 4.2% for immediate release prednisone).

Following the 12-week CAPRA-1 study, patients were followed in a nine-month, open-label extension study, which included 249 RA patients, 219 of whom completed the extension study.

Results showed that patients who continued treatment with LODOTRA experienced a 55% reduction in the duration of morning stiffness.

Further, patients newly assigned to LODOTRA exhibited a 45% reduction in the duration of morning stiffness over the nine-month course of this extension study.

These patients also experienced a 50% median reduction in IL-6 levels that also corresponded to improvements in the duration of morning stiffness following daily administration of LODOTRA.

The most commonly reported treatment-emergent adverse events in the extension study were a flare in RA-related symptoms (14.5%), flushing (5.2%), upper respiratory tract infections (2.8%), back pain (2.8%) and weight increase (2.8%).

Adverse events indicative of aggravated hypothalamic-pituitary adrenal, or HPA, axis suppression, typical of high dose prednisone administration, were not observed.