Since 2008, the CSRF has been tracking the progress of a dual release glucocorticoid (cortisol) replacement medication developed by DuoCort Pharma that more closely mimics the natural secretion of cortisol over 24 hours. The original article appeared in the Spring, 2008 issue of the CSRF newsletter and discussed how the medication worked. A second article discussing some Phase II/III data in patients with adrenal insufficiency appeared in the Summer, 2009 issue. Both of these articles are available on the CSRF website (www.CSRF.net) under Doctor’s Articles. Since those articles appeared, the dual release product has been trademarked “Plenadren” and in early November, the European Commission granted European Marketing Authorization for Plenadren. Also, DuoCort Pharma has been acquired by the American company ViroPharma who anticipates that Plenadren will be commercially available in the EU in approximately one year. No further information is available at this time regarding availability in the US. The CSRF has received many requests to provide updated information as it became available. This article reviews further data that is now available from presentations at an annual meeting of The Endocrine Society and in a recent publication on Phase II/III trial results in the Journal of Clinical Endocrinology & Metabolism.

Introduction

To briefly review, what are the issues with cortisol replacement in individuals who are adrenal insufficient? In a normal individual, cortisol is 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 repeatedly been reported in the literature that patients with adrenal insufficiency have a decreased quality of life as well as a higher prevalence of obesity, glucose intolerance, diabetes, muscle wasting, cardiovascular disease and osteoporosis. Presumably this is due to long term replacement that does not mimic the diurnal rhythm. In order to assess how patients perceived replacement medication, a worldwide survey of 1200 adrenal insufficiency patients was undertaken. Some CSRF members participated in this survey.

• Over 60% of patients report that current replacement therapy results in reduced and compromised quality of life necessitating changes to physical activity, social life, work life and family life.
• Three quarters are concerned about long term side effects of their replacement therapy such as osteoporosis, obesity, fatigue and cardiovascular morbidity, in that order.
• Multiple dosing throughout the day was perceived as a problem by 38%
• 40% reported being absent from work in the three months preceding their participation in the survey and 29% of those reported more than 3 weeks absence.

These data demonstrate a need for improvement in glucocorticoid replacement therapy. (1) In order to make a safe and improved new therapy and in an effort to mimic the diurnal rhythm, Plenadren was formulated with dual release properties. The outside coating of the tablet is for immediate release and serves to quickly increase the cortisol concentration in the blood. The inside core 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, Plenadren only needs to be taken once per day in the morning in order to be able to produce a robust physiological profile.

Results

Phase II/III trials were completed in Europe in December, 2008. The Phase II/III trial was a trial in which 64 patients with adrenal insufficiency were studied for 12 weeks on 3 times daily dosing of standard replacement and 12 weeks on once daily Plenadren. After completion of this study, patients were allowed to continue Plenadren for an additional 24 weeks. Extensive measurements of blood cortisol were made on both replacement regimens and cortisol exposure over a 24 hour period was shown to be approximately 20% lower with Plenadren than with the standard 3x daily dosing. Most importantly, the profile demonstrated sustained cortisol for the first 4 hours after dosing with decreasing levels throughout the day, particularly in the afternoon and nighttime where elevated cortisol levels are thought to be the most detrimental. The data from this trial was recently published and is summarized below(2).

Weight Loss – Patients on replacement medication generally feel that it is difficult to lose weight while on replacement. In this study while on Plenadren, body weight decreased over the 12 weeks by an average of .7 kg or about 1.5 lbs., while those on traditional 3x/day replacement showed a slight weight gain over the 12 week period. For those continuing on Plenadren for the 24 week extension , the weight loss trend continued such that the total weight loss at the end of the 24 weeks was .9 kg or about 2 lbs.

Blood pressure – In this study, systolic blood pressure (the top number) while on Plenadren was reduced by 5.5 mm Hg compared to 3x/day replacement. Diastolic blood pressure (the bottom number) was reduced by 2.3 while on Plenadren, compared with 3x daily dosing. These lower blood pressure values were maintained during the 24 week extension.

Glucose – Fasting morning blood glucose was similar with both replacement regimens, but HbA1c (a measure of glucose exposure over time) decreased substantially by .6% in diabetic patients while on Plenadren compared to 3x daily dosing.

Bone – It is also well known that excess glucocorticoid exposure over a period of time, encourages bone loss leading to osteoporosis. Blood levels of Osteocalcin and S-PINP (circulating markers of bone formation) can be used to assess bone status. Small increases in both of these measurements were observed after 12 weeks on Plenadren compared to 3x daily dosing indicating increased bone formation.

Quality of Life – During the Phase II/III trial, quality of life was measured using three different questionnaires at standard dosing (three time daily), 4 weeks after changing to the once daily product and 12 weeks after changing to the once daily product. After 4 weeks on once daily product, there was a trend for reduced quality of life as compared with the 3 times daily dose. This is most likely due to change in therapy as a similar change was seen before the trial when some patients were switched from 2- 3 times hydrocortisone per day. After 12 weeks, however, Plenadren was associated with a perceived improvement in cognitive function, psychosocial function, and a trend for improvement in fatigue. Well-being improved and patients reported less afternoon moodiness. At the conclusion of the 12 weeks, patients were asked which replacement regimen they preferred and 85 % preferred the once daily dosing with Plenadren. Also, when offered Plenadren for an additional 24 weeks, 92% chose to continue on Plenadren.

Conclusions

Thus, in this trial, the dual release, once daily replacement regimen with Plenadren and its resultant serum cortisol profile was safe, well accepted and tolerated. This was also accompanied by improvements in body weight, blood pressure, quality of life, well-being and was overall preferred by patients. It is not known at this time whether this regimen could be beneficial for Cushing’s patients during the replacement tapering stage following successful surgery.

Authors: Karen Campbell and Dr. Gudmundur Johannsson, MD, PhD (Spring, 2011)

Editor’s Note: Karen Campbell is a Director with the CSRF and editor of the newsletter. Dr. Gudmundur Johannsson, MD, PhD, is Senior Consultant at the Department of Endocrinology, Sahlgrenska University Hospital, and Professor at University of Gothenburg, Sweden. Dr. Johannsson’s research interest in long-term outcomes for patients with adrenal insufficiency led him, along with other scientists, to found DuoCort AB, a Swedish endocrinology company to develop an improved therapy. DuoCort has since been acquired by ViroPharma. DuoCort is now being marketed (2013) in Europe under the brand name Plenadren.

References

(1) The Endocrine Society Abstracts (2010) P3-644 and P3-646

(2) Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation, Johannsson G., et al, JCEM on-line ahead of print November 23, 2011 as doi:10.1210/jc.2011-1926. (To appear in print JCEM February 2012, 97(2).)