New Drug Application submitted to FDA for centrally acting analgesic tapentadol immediate release tablets

Aachen, Germany, January 25, 2008. The German pain specialist Grunenthal GmbH announces that a New Drug Application (NDA) has been submitted to the U.S. Food and Drug Administration (FDA) for tapentadol immediate release (IR) tablets by its co-development partner Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD). Tapentadol is an oral centrally acting analgesic and will be the first new substance in its class for more than 25 years after successful registration. In the European Union, tapentadol is currently in phase 3 of the development program for severe acute pain, and the Company plans to submit it for approval later this year.

Tapentadol acts by two mechanisms of action, combining mu-opioid receptor agonism and noradrenaline reuptake inhibition properties in a single molecule. It is in development as immediate-release and prolonged-release formulations. When approved, it will be used in hospital and outpatient settings.

According to the American Pain Foundation, more than 25 million Americans experience acute pain each year as a result of injuries or surgeries, and a recent study estimated that 42 percent of U.S. hospital emergency department visits were due to pain-related problems.1,2

Data from clinical phase 2 and phase 3 trials indicate that tapentadol has efficacy comparable to strong, centrally acting analgesics like oxycodone and morphine, whilst offering and at the same time an improved tolerability profile, especially with regard to nausea, vomiting and constipation.3,4

The U.S. clinical development program includes two double blind phase 3 multi-center studies vs. oxycodone IR that explored the efficacy and safety of multiple doses of the tapentadol IR formulation either for the treatment of acute pain in patients undergoing bunionectomy surgery or for patients with degenerative, end-stage joint disease of the hip or knee. Bunionectomy is a standard foot surgery. The predictable level of pain for several days make bunionectomy an excellent model for assessing the efficacy of potent analgesics.

Data were also submitted to FDA from an additional double blind phase 3 study that supported the safety and tolerability of multiple doses of tapentadol IR vs. oxycodone IR in the treatment of outpatients with low back pain or pain from osteoarthritis of the hip or the knee over a period of 90 days.

More than 1,800 patients have been treated with tapentadol in the clinical development program of the immediate release formulation.

This filing represents the ongoing commitment of both J&JPRD and Grunenthal to bring new and innovative products to patients and physicians for the treatment and management of pain.

Combined Mode of Action

Mu-opioid agonists are drugs that bind to mu-opioid receptors in the central nervous system. These drugs modify sensory and affective (mood) aspects of pain, inhibit the transmission of pain on the spinal cord level and affect activity in parts of the brain that control how pain is perceived.5 p. 37 Noradrenaline reuptake inhibitors are a type of central nervous system medication that increase the level of noradrenaline in the brain by inhibiting its reabsorption into nerve cells; these compounds have analgesic properties. 5 p. 45

Tapentadol Co-Development Partnership

Grunenthal discovered and began development of tapentadol. Grunenthal and J&JPRD are conducting the phase 2b and 3 development program for tapentadol for acute and chronic pain conditions. Grunenthal licensed marketing rights to tapentadol to Ortho-McNeil-Janssen Pharmaceutical,-, Inc., an affiliate of J&JPRD, for the U.S., Canada and Japan. Grunenthal maintains marketing rights in Europe and other parts of the world. Pending regulatory approval, PriCara, a division of Ortho-McNeil-Janssen Pharmaceutical, Inc. will market tapentadol in the United States. A trade name for the product has not yet been determined.

About GrunenthalGrunenthal is an expert in pain therapy and gynaecology and a pioneer in intelligent, user-friendly drug delivery technologies. Founded in 1946, the company employs 1,900 people in Germany and 4,800 worldwide. In 2006, Grunenthal achieved revenues of 813 million Euro. www.grunenthal.com


1 National Pain Survey (1999). The American Pain Foundation. Conducted for Ortho-McNeil Pharmaceutical. Reference to come.

2 Pletcher, M.J., Kertesz, S.G., Kohn, M.A., Gonzales R. (2008). Trends in Opioid Prescribing by Race/Ethnicity for Patients Seeking Care in U.S. Emergency Departments, JAMA, 299(1), 70-78.

3 Stegmann J.U., Weber H., Steup A., Upmalis D., Link A., Desjardins P.J. (2007). Efficacy and Tolerability of Tapentadol Immediate Release for the Treatment of Acute Pain Following Bunionectomy (Poster presented at the 4th World Congress of the World Institute of Pain). 4 Stegmann, J.U., Engels, C., Steup, A., Schwarz, H.J., Desjardins, P., Grond, S. (2006). Tapentadol, a Novel Centrally Acting Analgesic with a Dual Mode of Action: Efficacy and Safety in Clinical Acute Pain Models (Poster presented at the 5th congress of the EFIC).

5 National Pharmaceutical Council and Joint Commission on Accreditation of Healthcare Organizations (2001). Pain: Current Understanding of Assessment, Management and Treatment [Monograph]. National Pharmaceutical Council.