Phase 3 Data Demonstrate Efficacy and Tolerability of Paliperidone Palmitate, an Investigational Long-Acting Therapy for the Treatment of Schizophrenia

Results of Two Trials Identify Potential Initiation Dosing Regimen

Titusville, NJ . - Paliperidone palmitate, an investigational long-acting therapy (LAT) demonstrated statistically significant symptom control compared with placebo according to the results of a 13-week study presented today 1. Statistical significance was evidenced at all doses tested (25, 100, and 150 mg equivalent [eq.a]), when given every 4 weeks with a 150 mg eq. initiation dose. A separate 53-week non-inferiority trialb evaluating paliperidone palmitate using only a 50 mg eq. initiation dose, and subsequent doses of 25, 50, 75, and 100 mg eq., showed that while paliperidone palmitate reduced symptoms, non-inferiority relative to risperidone LAT was not demonstrated. Safety findings in both trials were similar to those from previously published studies of paliperidone extended-release (ER) tablets in the treatment of schizophrenia 2,3. Based on these results, an additional phase III study is being conducted to further assess the higher initiation dosing regimen of paliperidone palmitate 150 mg eq. followed by a second injection of 100 mg eq. with subsequent injections every four weeks.

Paliperidone palmitate, an investigational LAT, is a formulation of the oral antipsychotic paliperidone ER, used for the acute and maintenance treatment of schizophrenia. Because of the delivery systems used, LAT formulations may produce more consistent levels of the drug in the blood and provide healthcare professionals with reassurance that patients are receiving their medication as scheduled. The two studies add more information to the body of evidence for paliperidone palmitate in the treatment of schizophrenia.

In the 13-week trial, patients were randomly assigned to receive either paliperidone palmitate 25, 100 or 150 mg eq. injection or placebo. On day 1, all patients randomly assigned to any of the paliperidone palmitate treatment groups received a 150 mg eq. injection in the deltoid muscle. On day 8 and every 4 weeks for the duration of the trial they received the randomly assigned fixed dose (25, 100 or 150 mg eq.) in the deltoid or gluteal muscle. The primary endpoint of the trial was change in PANSS© total score from baseline to endpoint.

The results showed that with the 150 mg eq. initiation dose, patients taking paliperidone palmitate at any of the three doses (25, 100, or 150 mg eq.) had significantly improved symptoms, based on the primary outcome parameter of change in PANSS total scores, compared to patients on placebo (p is less than or equal to 0.034). Symptoms improved with increased dosage, with those taking the 150 mg eq. dose showing the greatest improvement. Overall treatment-emergent adverse events (TEAEs) occurred at similar rates among the paliperidone palmitate (60-63%) and placebo (65%) groups. The number of patients who reported serious TEAEs was higher in the placebo group (14%) than in any of the paliperidone palmitate groups (25 mg eq. 9.4%; 100 mg eq. 13.3%; 150 mg eq. 8.0%). Common TEAEs occurring greater than or equal to 2% more frequently in the total paliperidone palmitate group compared to the placebo group were injection site pain (placebo, 3.7% vs 7.6% with paliperidone palmitate), dizziness (placebo 1.2% vs 2.5% with paliperidone palmitate), sedation (placebo 0.6% vs 2.3% with paliperidone palmitate), pain in extremity (placebo 0% vs 1.6% with paliperidone palmitate) and myalgia (placebo 0% vs 1.0% with paliperidone palmitate). The overall safety profile was similar to previously published studies of paliperidone ER in the treatment of schizophrenia1,2.

The authors concluded that using a 150 mg eq. deltoid initiation dose followed by subsequent injections every 4 weeks of 25-150 mg eq. of paliperidone palmitate produced statistically significant symptom control as measured by the PANSS total score.

In the 53-week non-inferiority trial, patients were randomly assigned to receive flexible dose paliperidone palmitate plus orally supplemented placebo (PP+Pbo) or flexible dose risperidone LAT plus orally supplemented risperidone (LAT RIS+RIS). All injections were administered in the gluteal muscle. Patients in the PP+Pbo group received two 50 mg eq. injections one week apart, followed by injections of 25, 50, 75 or 100 mg eq. every 4 weeks. Patients in the LAT RIS+RIS group received a placebo injection on day 1, 25 mg risperidone LAT on days 8 and 22 and injections every 2 weeks of 25, 37.5 or 50 mg. The primary endpoint was the change in PANSS total score from baseline to endpoint. Non-inferiority was planned to be demonstrated if paliperidone palmitate was no worse than risperidone LAT, as measured by a 95% confidence interval of more than -5 points in the change in PANSS total score.

Although patients receiving both paliperidone palmitate and risperidone LAT had similar improvements in PANSS scores at the end of the 53 week trial, the difference between paliperidone palmitate and risperidone LAT in the least square adjusted mean change in PANSS score was -2.6 points, with a 95% confidence interval (CI) of (-5.84, 0.61). As the lower limit (-5.84) of the CI was less than -5, non-inferiority of paliperidone palmitate versus risperidone LAT was not demonstrated using this dosing regimen. Comparative plasma concentrations of paliperidone in the PP+Pbo group were consistently lower than concentrations of active moiety in the LAT RIS+RIS group until day 260. Although non-inferiority was not demonstrated using this dosing regimen, it is not possible to conclude superiority of LAT RIS+RIS over PP+Pbo using the results from this study. Overall rates of adverse events were similar in both groups: 76% for paliperidone palmitate and 79% for risperidone LAT. The most common (more than 10% in either group) TEAEs among the reported psychiatric disorders were insomnia (both groups 15%), psychotic disorder (PP+Pbo 14%; RIS+RIS 12%) schizophrenia (PP+Pbo 12%; RIS+RIS 9%) and anxiety (PP+Pbo 10%; RIS+RIS 15%). Adverse events leading to discontinuation occurred in 7% of PP+Pbo patients and 6% of LAT RIS+RIS patients. Based on these results, an additional phase III study is being conducted to further assess the dosing regimen of paliperidone palmitate 150 mg eq. followed by a second injection of 100 mg eq. with subsequent injections every four weeks, compared with risperidone LAT.

“These findings will help us determine the best dosing strategy for paliperidone palmitate in the treatment of schizophrenia,” said lead author, Professor Wolfgang Fleischhacker, Dept of Psychiatry and Psychotherapy, Medical University Innsbruck*. “This could provide a valuable option for healthcare professionals to help people who are struggling with this illness.”

INVEGA® (paliperidone) Extended-Release Tablets, the oral formulation of paliperidone, was first approved in 2006 in the U.S. for the acute treatment of schizophrenia. In March 2007, INVEGA was approved for the maintenance treatment of schizophrenia in the U.S. It was also approved for the treatment of schizophrenia in the European Union in June 2007.

Worldwide, it is estimated that one person in every 100 develops schizophrenia, one of the most serious types of mental illness4. An estimated 2.4 million Americans have schizophrenia, with men and women affected equally5. The disease is marked by positive symptoms (hallucinations and delusions) and negative symptoms (depression, blunted emotions, and social withdrawal), as well by disorganized thinking, speech and behavior.

The study was sponsored by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD). Once approved, Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. will market paliperidone palmitate in the U.S.

* Professor Wolfgang Fleischhacker has been a consultant, served on advisory boards and received research grants from J&JPRD and Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.