Elagolix, an oral human gonadotropin releasing hormone (GnRH) antagonist, has just completed phase II development for endometriosis and is newly partnered with Abbott. The path through phase II was difficult, as Neurocrine struggled to find the appropriate yardsticks with which to measure the effect of treatment on disease-associated pain. The drug clearly suppresses estradiol and interrupts the menstrual cycle -- the intended pharmacological effects suggested by its mechanism of action. However, the goal of showing that therapy consistently relieves disease-associated pain was more elusive. The last trial in the series, Daisy PETAL, demonstrated robustly positive results. This report explores the basic question of whether these results can be duplicated in phase III trials. That is, has Neurocrine identified a winning endpoint, dose, and population for use in phase III, or will the difficulties seen throughout the earlier trials continue to affect trial results. In addition, we review the market and competition in endometriosis, and whether elagolix's safety profile can translate into a greater market share.

Published: June 29th, 2010

Number of pages: 38

Authors: Dr. Ellen Brady and Dr. Ilana Fogelman


TABLE OF CONTENTS:
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INTRODUCTION
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1. Endometriosis often presents with chronic pelvic pain
2. The disease has a variable course and elusive cause
3. The therapeutic rationale for GnRH antagonists is biologically plausible

CLINICAL DATA
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1. Study 405 showed depression of estradiol levels
2. Pilot phase II studies (501 and 504) suggested activity and safety
3. PETAL (Study 603) assessed bone density - a key safety consideration
4. Lilac PETAL (Study 702) further explored dose and endpoint issues
5. Tulip PETAL (Study 703) used Eastern European sites and a positive control
6. Daisy PETAL (Study 901) aimed to address failings in the revised pain scales

CLINICAL AND REGULATORY DISCUSSION
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1. In summary, what has available data taught us?
2. Are the reasons for the failed trials plausible and have they been resolved?
− Do excessive placebo responses explain adverse outcomes or pose an ongoing risk?
− Issues related to the measurement of pain are complex and not easily resolved.
3. Are there regulatory precedents that are relevant for planning phase III?
− Pfizer’s NDA for Depot sub-Q Provera provides some regulatory precedent
− A “white paper” provides insight trial design issues
4. What about bone density?
5. Is general safety acceptable?

MARKET ISSUES
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1. Endometriosis is common, but disease progression and treatment vary
2. Main competitors and elagolix’s distinguishing attributes
3. What is elagolix future potential in other indications?

SUMMARY OPINION
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