AVINZA Pharmacokinetic Study Published in Leading Pain Journal Demonstrates that New Drug has More Stable and Consistent PK Profile than MS Contin.

Business Editors & Health/Medical Writers

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SAN DIEGO--(BW HealthWire)--May 1, 2002

Ligand's new once-daily pain product, AVINZA(TM) (morphine sulfate extended-release capsules), approached maximum plasma concentrations of morphine quicker, maintained these concentrations longer, and generated less fluctuation in plasma levels over a 24-hour period than twice-daily MS Contin(R), according to a pharmacokinetic study published in The Journal of Pain and Symptom Management (Vol. 23, No. 4, 2002).

Once-daily AVINZA was approved in March by the U.S. Food and Drug Administration for the relief of moderate-to-severe pain in patients requiring continuous, around-the-clock opioid therapy for an extended period of time. Ligand plans to launch AVINZA this quarter.

In the pharmacokinetic study, 10 patients were stabilized on a twice-daily dose of MS Contin(R) (MSC; morphine sulfate controlled-release, Purdue Frederick) for a minimum of seven days, then switched to once-daily AVINZA for a minimum of 10 days. Twenty-four-hour, steady-state pharmacokinetic profiles were obtained on the last day of each treatment period. Nine patients completed the study.

The study showed that once-daily AVINZA and twice-daily MSC provided similar total systemic exposure to morphine over a 24-hour period, but that the two formulations have distinct PK profiles that reflect their divergent extended-release technologies. The authors note that in the study, AVINZA once-daily provided more stable and consistent morphine concentrations over a 24-hour period than did MS Contin twice-daily, and that MS Contin produced two distinct peak-to-trough fluctuations, whereas AVINZA displayed more of a plateau-like profile with an initial rapid release of morphine. The authors also suggest that larger controlled studies are warranted to determine whether the different plasma profiles yield reliable clinical distinctions.

In the study, AVINZA approached maximum plasma morphine concentrations more quickly than MSC. Specifically, once-daily AVINZA achieved 55% higher concentrations 30 minutes after dosing. In addition, AVINZA maintained target morphine concentrations longer over a 24-hour period. For example, AVINZA maintained plasma morphine levels of at least 50% of maximum for 18.8 hours (compared to 10.1 hours with MSC). Finally, AVINZA once-daily yielded lower maximum levels of morphine and higher minimum levels of morphine, resulting in less peak-to-trough fluctuation in blood levels. Specifically, maximum morphine levels with AVINZA were 19% lower and minimum levels were 66% higher. As a result, the peak-to-trough fluctuation index was 44% lower with once-daily AVINZA than with twice-daily MSC.

In this study, AVINZA and MSC produced comparable safety and efficacy profiles. Adverse events were similar to those typically seen with opioid therapy, and included nausea, constipation and dry mouth. The overall incidence of side effects was comparable between patients taking AVINZA and MSC, and all side effects were considered mild to moderate. One patient withdrew from the MS Contin treatment period due to drowsiness in the morning and insomnia in the evening.

Other Recent AVINZA Publications

Recently published articles on AVINZA (formerly Morphelan(TM)) include:

Jacques Caldwell, M.D., et al, "Efficacy and Safety of a Once-Daily Morphine Formulation in Chronic, Moderate-to-Severe Osteoarthritis Pain: Results from a Randomized, Placebo-Controlled, Double-Blind Trial and an Open-Label Extension," Journal of Pain and Symptom Management, Vol. 23, No. 4, 2002.

Lise Eliot, Ph.D., et al, "Pharmacokinetic Evaluation of a Sprinkle-Dose Regimen of a Once-Daily, Extended-Release Morphine Formulation," Clinical Therapeutics, Vol. 24, No. 2, February 2002.

Lise Eliot, Ph.D., et al, "Steady-state pharmacokinetic comparison of a new once-daily, extended-release morphine formulation (Morphelan(TM)) and OxyContin(R) twice daily," Journal of Oncology Pharmacy Practice, Vol. 7, 2001.

Lise Eliot, Ph.D., et al, "Evaluation of Two Loading-Dose Regimens of Morphelan(TM) in Healthy Volunteers," The Journal Of Applied Research, Vol. 2, No. 1, Winter 2002.

About Ligand

Ligand discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, 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 (IRs) and Signal Transducers and Activators of Transcription (STATs).

Caution Regarding Forward-Looking Statements

This news release may contain certain forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from Ligand's expectations. For example, there can be no assurance that results of subsequent studies of AVINZA will confirm results presented here, or that patient and physician acceptance AVINZA will be achieved. Additional information concerning these and other risk factors affecting Ligand's business can be found in prior press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission, available via Ligand's internet site at www.ligand.com. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

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