Ligand Pharmaceuticals Incorporated (Pink Sheets:LGND) announced the final data from three studies of its pain product AVINZA(R) presented in poster sessions at the American Pain Society annual meeting today in San Antonio. In the first study, AVINZA showed better around the clock control of chronic pain and improved sleep in a large randomized study comparing AVINZA given once daily to oxycodone CR(1) given twice daily in patients with low back pain. A second study demonstrated AVINZA's ability to provide better sleep as well as improved pain control for patients with moderate-to-severe chronic osteoarthritis. In the third study conducted in patients with chronic, non-cancer, moderate-to-severe pain, AVINZA was shown to improve pain, sleep, and physical functioning.

"The collective studies being presented at the American Pain Society involving more than 900 patients provide important new, mutually-supportive information to the medical community about the ability of AVINZA, as a once-a-day product, to afford sustained, around-the-clock pain control and improved sleep, cognitive functions and quality of life," said Andres Negro-Vilar, M.D. Ph.D., Ligand's Executive Vice President for Research and Development and Chief Scientific Officer. The large comparator study of AVINZA once a day versus oxycodone CR(1) twice a day clearly illustrates the advantages of a true once-a-day sustained-release opioid in different parameters of efficacy providing better around the clock pain control which, combined with a comparable safety profile, contribute significantly to overall patient benefit."

The ACTION Study: AVINZA results in better around the clock pain control than oxycodone CR(1) in patients with chronic low back pain

The first study, currently scheduled for publication in a forthcoming issue of Journal of Opioid Management, and referred to as ACTION (AVINZA Comparator Trials in Opioid Naive patients) is a randomized, multi-center, parallel-group study which enrolled 392 patients with moderate to severe chronic back pain treated for up to seven months. The study included a titration phase to allow patients to achieve pain control with an acceptable safety profile, an eight-week evaluation phase, followed by a four-month extension phase to collect long-term pain control comparator information. It compared once-daily AVINZA (morphine sulfate extended-release capsules) to twice-daily OxyContin(R) (oxycodone hydrochloride controlled-release). In the eight-week evaluation phase of the study (Poster 813), with 266 evaluable patients (132 in the AVINZA arm and 134 in the oxycodone CR(1) arm) the study showed that at lower mean morphine-equivalent doses (69.9 mg AVINZA to 91.0 mg oxycodone CR(1)), patients receiving AVINZA once daily demonstrated statistically significant better pain control (evaluated using the Brief Pain Inventory), statistically significant better quality of sleep (evaluated using the Pittsburgh Sleep Quality Index), and a statistically significant reduction in the number of rescue medications used to control breakthrough pain.

Regarding around-the-clock pain control, the study results showed that in addition to maintaining a steady level of baseline pain control during the entire eight-week evaluation period, AVINZA showed additional pain control benefit throughout the day. The measurements at frequent intervals during Weeks 1, 4 and 8, provided clear evidence of AVINZA's advantage as a once-a-day treatment showing statistically significant pain control benefit over oxycodone CR(1) at 6 hours (p = 0.03), 9 hours (p = 0.005), and 12 hours (p = 0.002).

Overall use of rescue medication over the entire eight-week evaluation period was significantly lower for AVINZA than for oxycodone CR(1) (p less than 0.0001), again reinforcing the ability of AVINZA to maintain 24-hour pain control with fewer episodes of breakthrough pain.

Patients treated with AVINZA enjoyed a statistically significant improvement in overall quality of sleep over baseline and when compared with oxycodone CR(1) (p = 0.02 at Week 4, p = 0.006 at Week 8, and p = 0.013 for Weeks 1-8).

Side effects (incidence and severity) were recorded throughout the evaluation period. AVINZA and oxycodone CR(1) showed a similar profile of side effects, indicating that the advantages of 24-hour pain control observed with AVINZA were obtained without an increase in the nature and number of patient-reported side effects.

The extension phase (Poster 820) involved 174 patients and lasted up to four additional months. Patients treated in the AVINZA arm required lower daily dose of opioid, with the mean morphine-equivalent doses of 86 mg for AVINZA versus 119 mg for oxycodone, (p less than 0.05). Pain control was better in the AVINZA group over the 4-month period, showing a significant difference at Month 2 (p = 0.029) and Month 3 (p = 0.023). Sleep was also better in the AVINZA group over the 4-month period with a significant difference at Month 1 (p = 0.0004). In measuring patient satisfaction at the end of the study, 68% of AVINZA patients expressed that they were "Extremely Satisfied" with their therapy compared to 57% for oxycodone patients. There were no differences on safety between the two opioids.

Poster 827 summarized the data for the entire duration of the study and showed that AVINZA was consistently better than oxycodone CR(1) in terms of pain relief, quality of sleep, daily opioid dose, rescue medications used, and a comparable safety profile between the 2 study medications.

"In a large, randomized, prospective comparative trial once-daily AVINZA provided excellent pain relief for patients suffering from chronic low back pain," stated the study's lead investigator, Dr. Richard L. Rauck of Wake Forest University Health Sciences. "Compared to sustained release oxycodone, AVINZA demonstrated significant analgesic advantages in several categories and improved sleep characteristics. Impressively, these results were durable and still present 7 months later as shown in one of the first long-term follow up studies of its kind." Dr. Rauck continued, "I expect to see medicines like AVINZA used more frequently in this population of chronic back pain sufferers when stable pain control and improved quality of life combined with relatively low doses are required for prolonged periods."

The Polysomnography Study: AVINZA significantly improves quality and quantity of sleep in patients with osteoarthritic pain

Two posters present final data on a separate study that evaluated AVINZA's effects on various sleep parameters intended to validate and quantify objectively improvement of sleep reported in previous AVINZA trials. This is a 31-patient, placebo/baseline-controlled, single-blind study using both polysomnography (PSG) and subjective sleep measurements to assess and better quantify sleep parameters. Patients in the study had moderate-to-severe osteoarthritic pain with sleep disturbances not due to another primary sleep disorder. All patients were on pain medications prior to the run-in placebo phase but had not previously had sustained-release opioids.

The PSG studies were conducted in the sleep laboratory at California Clinical Trials in San Diego. The recordings included electroencephalograms and electro-oculograms to analyze multiple sleep parameters such as total sleep time, sleep efficiency, number of awakenings, latency to persistent sleep, sleep stages and shifts, number of stage shifts, and REM sleep. Additional recordings were made to monitor electrocardiogram, blood pressure, air flow, and muscle and limb movement.

The study results presented in Poster 795 show that subjects who have achieved stable pain control during 2 - 3 weeks of treatment after a placebo run-in period had an improved patient-reported pain control (p less than 0.05) and overall quality of sleep (p less than 0.05). The latter correlates with the quantitative PSG measurements which showed a significant (P less than 0.05) increase in total sleep time, decrease in latency time to REM sleep, decrease in number of awakenings, and increased sleep efficiency.

In addition to AVINZA's effect on pain and sleep, this study showed improvement in cognitive functions (Poster 865). Using a battery of validated tests, AVINZA was shown to improve significantly (P less than 0.05) assessments measuring immediate and short-term memory, as well as measures of attention, concentration, working memory, motor speed and manual dexterity.

In this study, the tolerability of AVINZA given at a daily dose of 30 or 60 mg was consistent with the AVINZA safety profile reported in previous studies as well as the safety profile of opioids in general. Two-thirds of the patients reported at least one adverse reaction, the most common being nausea (47%), sedation (35%), constipation (29%), vomiting (12%), and itching (12%).

"In this study, we have shown that AVINZA given at 30 or 60 mg daily, provided significant pain relief in chronic osteoarthritis patients (OA) previously treated with a variety of analgesics except long-acting opioids, and led to a significant improvement in sleep efficiency and an overall improvement in neurocognitive functioning," said the study Principal Investigator, Dr. Murray Rosenthal, Medical Director of California Clinical Trials. "To our knowledge, this is the first clinical trial that combined polysomnography and neurocognitive testing of OA patients to study the treatment effects of a long-acting opioid. The study also shows the importance of dose titration to achieve the full benefits of AVINZA in pain control, sleep parameters and quality of life," concluded Dr. Rosenthal.

The ACCPT Study: AVINZA significantly improves pain, sleep, and physical functioning in a large, real-world conditions trial

One poster (no. 825) presents final data on the ACCPT trial (AVINZA Clinical Chronic Pain Trial), an open-label, real-world condition trial with 491 patients with various types of non-cancer, moderate-to-severe chronic pain. A baseline followed by three monthly questionnaires measuring pain, sleep, AVINZA dose, and physical functioning were completed by the patients via phone or internet-based interviews. Compared to the baseline measurements, patients reported significant improvement in pain control (p less than 0.01), sleep (p less than 0.05), and physical functioning for moderate activities (p less than 0.05). At their final assessment of the study, 90% of patients reported that AVINZA was "Extremely Effective" or "Effective" in controlling their pain. The safety profile of AVINZA in this study was consistent with the findings of previous trials.

"In this large study conducted under real-world treatment conditions in patients with a variety of non-cancer chronic pain, AVINZA was shown to significantly improve pain symptoms, sleep, and physical functioning for moderate activities such as climbing a flight of stairs. These results were maintained for the 3-month study duration without increasing the dose of AVINZA once the initial dose titration was completed," stated Dr. Edgar E. Adams, Executive Director at Covance, describing the results of the study he had conducted while at the Harris-Interactive Health Care Division. "The number of patients that completed the study is consistent with observations derived from a large observational study of patients taking modified release opioids. Given the acknowledged undertreatment of pain, efforts should be made to educate patients on the importance of complying with their opioid treatment plan," added Dr. Adams.

About AVINZA

AVINZA (oral morphine sulfate extended-release capsules) is the first true once-a-day treatment for chronic moderate-to-severe pain in patients who require continuous, around-the-clock opioid therapy for an extended period of time. Approved by the FDA in March 2002, AVINZA consists of two components: an immediate-release component that rapidly achieves plateau morphine concentrations in plasma and an extended-release component that maintains plasma concentrations throughout a 24-hour dosing interval. Ligand co-promotes AVINZA with Organon Pharmaceuticals USA, Inc. in the United States.

About Ligand

Ligand discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, pain, skin diseases, men's and women's hormone-related diseases, osteoporosis, metabolic disorders, and cardiovascular and inflammatory diseases. Ligand's proprietary drug discovery and development programs are based on its leadership position in gene transcription technology, primarily related to intracellular receptors. For more information, go to www.ligand.com.