To briefly review, what are the issues with cortisol replacement in individuals who are adrenal insufficient? In normal individuals, cortisol is the highest in the morning and the lowest around mid-night. While replacement doses of hydrocortisone, taken 2 or 3 times daily, provide the body with needed cortisol, the replacement dose does not mimic the normal diurnal variation throughout the day. This can lead to highs and lows throughout the day, and may require higher replacement doses than are actually needed. It has been reported numerous times in the literature that patients with adrenal insufficiency have a decreased quality of life as well as a higher prevalence of obesity, difficulty loosing weight, glucose intolerance, diabetes, muscle wasting, cardiovascular disease and osteoporosis. Presumably this is due to long-term replacement that does not mimic the diurnal rhythm. Also, a patient survey of over 1200 patients with adrenal insufficiency conducted by DuoCort (1) again found that patients experienced a lower quality of life with needs to alter their physical activity, social life, work and family life due to their illness. The most common complaints were early morning and afternoon fatigue. This survey data is in line with previously reported data that reported that over 10% are unable to work due to their illness. (2)

In an effort to mimic the diurnal rhythm, the new product from DuoCort was formulated with dual release properties. The outside of the tablet is for rapid release and serves to quickly increase the cortisol concentration in the blood. The inside of the tablet is an extended release form that tapers off gradually throughout the day and provides a cortisol free interval during the nighttime hours. Thus, DuoCort only needs to be taken once per day in the morning in order to be able to produce a robust physiological profile.

Phase I clinical trials have been completed in Europe and the safety data and serum cortisol profiles were recently reported (3). During the Phase I trial, DuoCort was found to increase serum cortisol levels to a biologically active level after about 20 minutes, about half the time compared to standard hydrocortisone replacement. This should give patients an earlier effect in the morning. The levels were also found to highly mimic the diurnal variation, which avoids the daily ups and downs. DuoCort provides increased exposure during the first 4 hours and decreased exposure in the late afternoon, resulting in overall less exposure throughout the day compared to 3 times daily dosing using conventional hydrocortisone tablets. The extended release should minimize afternoon fatigue often reported by patients on traditional replacement.

Phase II/III trials were completed in Europe in December, 2008. The Phase II/III trial was a trial in which patients with adrenal insufficiency were studied for 12 weeks on 3 times daily dosing of standard replacement and 12 weeks on once daily DuoCort. Data from this trial was presented at the Endocrine Society Meeting in June, 2009. (4) In 63 patients studied for 12 weeks, body weight increased .14 ± 1.8 kg (~.3 ± 4 lbs) in patients on 3x daily dosing and decreased .6 ± 1.6 kg (~ 1.3 ± 3.5 lbs) while on DuoCort. Also in this study, systolic blood pressure (the top number) was reduced by 5.5 ± 11.3 mmHg and diastolic blood pressure (the bottom number) was reduced by 2.3 ± 8mmHg while on DuoCort compared with 3x daily dosing. Fasting blood glucose was similar with both medications, but HbA1c (a measure of glucose exposure over time) decreased a mean of .1% in non-diabetic patients and a mean of .5% in diabetic patients. The data is highly encouraging given the short time of study. Further data from the Phase II/III trial will be forth coming.

With normal regulatory reviews and approval times, DuoCort might be available in Europe sometime in 2010. DuoCort has received orphan drug status from the FDA in the US. While orphan drug status encourages companies to develop drugs for rare disorders, this does not mean that DuoCort has been FDA approved. FDA approval and availability in the US will require FDA review of the Phase I and II/III data generated in Europe and it is not known if clinical trials will be required in the US. It is hoped that the DuoCort product will be available in the US in the next few years.

Author: Maria Forss (Summer, 2009)

Editor’s Note: Maria Forss is the Project Manager for DuoCort. DuoCort has been acquired by ViroPharma and in 2012, DuoCort became commercially available in Europe under the brand name Plenadren.

References

1) www.DuoCort.com—Patient Survey

2) British Endocrine Societies Joint Meeting Abstracts, 2005, 9 P142.

3) European Journal of Endocrinology (2009) 161 119-130

4) The Endocrine Society Abstracts (2009) P3-614, Johannsson, et al