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	1		Estradiol/drospirenone - Bayer Schering Pharma Angeliq^®; Angeliq^® Low Dose; Estradiol/drospirenone (800014148)


Estradiol/drospirenone - Bayer Schering Pharma	800014148

At A Glance



Alternate names	Angeliq^®; Angeliq^® Low Dose; Estradiol/drospirenone
Originator	Bayer Schering Pharma
Highest development phase	Launched (Belgium, Denmark, European Union, Finland, Germany, Netherlands, Sweden, United Kingdom, USA)
Active Development - indications	Hypertension, Menopausal syndrome, Postmenopausal osteoporosis
Class	Androstenes, Estradiol-congeners, Estrenes, Progesterone-congeners, Small-molecules
Mechanism of action	Aldosterone antagonists, Estrogen receptor agonists

Organisations


ORIGINATOR	Country	Type	Ownership
Bayer Schering Pharma	Germany	Large Pharma, Pharmaceutical	Public

Brand Names


Organisation	Country	Indication	Brand Name
Bayer HealthCare Pharmaceuticals	USA	Menopausal syndrome	Angeliq®
Bayer Schering Pharma	European Union	Menopausal syndrome	Angeliq® Low Dose

Development Status

Phase Of Development


Phase	Indication	Country	Route
III	Hypertension	USA	PO

Development Overview

Introduction

Schering AG (formerly Berlex and now Bayer Schering Pharma) has developed an oral preparation of estradiol and drospirenone [Angeliq^®] for hormone replacement therapy (HRT) among women for menopausal syndrome and postmenopausal osteoporosis prevention. Angeliq^® once-daily tablets contain 1mg estradiol and 2mg drospirenone; the tablets are taken continuously over a cycle of 28 days. The product is available in certain European countries and also launched in the US. In addition, estradiol/drospirenone is under clinical evaluation for hypertension, since it also appears to have positive effects on blood pressure among postmenopausal women.

In June 2006, Schering AG was acquired by Bayer and was subsequently renamed as Bayer Schering Pharma AG¹².

Key Development Milestones

In September 2005, the US FDA approved Angeliq^® tablets (estradiol/drospirenone 1mg/0.5mg) for the treatment of moderate-to-severe menopausal syndrome. Angeliq^® was launched in the US around the middle of 2006³⁴. This followed on the approvable letter issued by the FDA to Berlex in September 2004 arising from the refiled NDA in March 2004. The resubmission was accompanied by additional manufacturing data requested by the FDA. Since drospirenone's lowest effective dose was established to be 0.5mg, Berlex withdrew higher doses of drospirenone from the NDA for Angeliq^®, pending completion of trials evaluating its potential blood pressure lowering effects⁵⁶⁷. Previously, Berlex received a 'non-approvable' letter from the US FDA in October 2002 following initial NDA filing for Angeliq^® in December 2001. Schering actively consulted the agency regarding concerns raised in order to continue progress of product approval for the US market⁸.

Schering AG (now Bayer Schering Pharma) announced in June 2005 that Angeliq^® is currently launched in all major European markets⁶. The product is available in the UK for the treatment of menopausal syndrome and the prevention of postmenopausal osteoporosis, according to the June 2005 issue of the UK Monthly Index of Medical Specialities (MIMS). Angeliq^® has also been available in certain European countries since the fourth quarter of 2003, according to Schering's Annual Report for 2003; the company confirmed in September 2004 that the product is available in the Netherlands, Belgium, Germany, Denmark, Sweden, Finland and Iceland with additional European countries to follow⁹. This rollout followed on the successful conclusion of the Mutual Recognition Procedure (MRP) during July 2003 for Angeliq^® in the treatment of menopausal syndrome and the prevention of postmenopausal osteoporosis. The Netherlands acted as the Reference Member State for the MRP, where the product was approved in December 2002¹⁰¹¹. Applications for marketing approval were filed in Europe during December 2001, following completion of phase III trials with Angeliq^® in the US.

Additionally, Schering announced in September 2004 that Angeliq^® is available in South Africa⁹.

Hypertension: phase III results presented at Schering's 2003 R&D Day for Angeliq^® showed additional positive effects with a reduction of blood pressure among postmenopausal women with mild hypertension in a multicentre, double-blind, randomised, placebo-controlled study. Schering plans to use this data for further submissions relating to Angeliq^®¹². Berlex has presented further trial findings of estradiol/drospirenone in the presence of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) among hypertensive postmenopausal women¹³.

Other formulations: according to Schering's 2003 Annual Report, the company has further plans to develop another version of Angeliq^® with an ultra-low dose of estradiol. Angeliq^® Low Dose is being investigated with an estradiol dosage of 0.5mg in combination with drospirenone.

Schering has also developed a combination of drosperinone and ethinylestradiol for use as an oral contraceptive [see separate profile: Ethinylestradiol/drosperinone].

Drug Properties


Class:	Androstenes, Estradiol-congeners, Estrenes, Progesterone-congeners, Small-molecules
Mechanism of Action:	Aldosterone antagonists; Estrogen receptor agonists
Route of Administration:	PO
Pharmacodynamics:	Displays aldosterone antagonist activity in the presence of ACE inhibitors or ARBs among postmenopausal women with hypertension
ATC Codes
- WHO ATC code	C02K (Other Antihypertensives), G03F-A (Progestogens and estrogens, fixed combinations), M05 (Drugs for Treatment of Bone Diseases)
- EphMRA ATC code	C2 (Antihypertensives), G3F (Oestrogen with Progestogen Combinations, Excluding G3A), M5X (All Other Musculoskeletal Products)

Adverse events


Occasional	Breast pain, Headache, Vaginal bleeding

Scientific Summary

Adverse Events

Data from several large-scale clinical trials indicated that estradiol/drospirenone [Angeliq^®] was associated with high rates of acceptability and compliance among ≥ 1,759 postmenopausal women with menopausal syndrome. There was a low discontinuation rate due to mild and transient side effects that were similar to those of seen with other hormonal therapies. The most common adverse events included vaginal bleeding, breast pain and headaches³⁴.

Pharmacodynamics
Hypertension

Women treated with estradiol/drospirenone [Angeliq^®] maintained constant body weight or lost weight, compared with women receiving estradiol monotherapy, who reported increased weight. The difference between the two test groups was significant. Women receiving estradiol/drospirenone showed significant increases in HDL-C and reductions in total cholesterol, LDL-C, VLDL-C and apolipoprotein B¹⁴.

Clinical studies: estradiol/drospirenone [Angeliq^®] displayed aldosterone antagonist activity in the presence of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in postmenopausal women with hypertension in a randomised, placebo-controlled trial (n = 230). Despite this observation, estradiol/drospirenone was not associated with any significant changes in renal function or potassium balance versus placebo in the high risk subgroups of subjects with renal impairment and aged > 60 years¹³.

Therapeutic Trials
Hypertension

Estradiol/drospirenone [Angeliq^®] significantly lowered blood pressure in postmenopausal women with hypertension when compared to estradiol monotherapy (-8.9 to -12.7mm Hg)¹⁴.

Estradiol/drospirenone [Angeliq^®] significantly lowered systolic and diastolic blood pressures in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) among hypertensive postmenopausal women in a multicentre, randomised, placebo-controlled trial (n = 230). Overall, estradiol/drospirenone significantly reduced systolic/diastolic blood pressures versus placebo by −8.8/−5.8 versus −3.7/−2.9 mmHg, respectively¹³.

Women's Health

Menopausal syndrome: data from several large-scale clinical trials among ≥ 1,759 postmenopausal women showed that estradiol/drospirenone [Angeliq^®] provided endometrial protection with an acceptable bleeding profile and rapidly provided relief from moderate-to-severe vasomotor symptoms, such as hot flushes, night sweats and vulvovaginal atrophy. Such clinical benefits were generally apparent within 4 weeks of therapy initiation³⁴.

Drug Development History

Date	Comment
4 April 2007	Berlex Inc has been acquired by Bayer HealthCare (MR 9074204)
29 December 2006	Schering AG is now called Bayer Schering Pharma AG
10 July 2006	This compound is still in active development for hypertension
30 June 2006	Launched for Menopausal syndrome in USA (PO)
20 June 2006	Schering AG has been acquired by Bayer
14 October 2005	Data from the 16th Annual Meeting of the North America Menopause Society (NAMS-2005) have been added to the pharmacodynamics and Hypertension therapeutic trials sections ¹⁴
1 October 2005	Clinical data have been added to the adverse events and Women's Health therapeutic trials sections ³, ⁴
29 September 2005	Registered for Menopausal syndrome in USA (PO)
18 August 2005	Phase-III clinical trials in Hypertension in USA (PO)
7 July 2005	Data presented at the 15th European Meeting on Hypertension (ESH-2005) have been added to the Hypertension pharmacodynamics and therapeutic trials sections ¹³
21 June 2005	Launched for Menopausal syndrome in United Kingdom (PO)
21 June 2005	Launched for Postmenopausal osteoporosis prevention in United Kingdom (PO)
15 September 2004	Schering has received an approvable letter from the US FDA for Angeliq® in Menopausal syndrome ⁷
2 September 2004	Launched for Postmenopausal osteoporosis prevention in South Africa (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Sweden (PO)
2 September 2004	Launched for Menopausal syndrome in Belgium (PO)
2 September 2004	Launched for Menopausal syndrome in Denmark (PO)
2 September 2004	Launched for Menopausal syndrome in Finland (PO)
2 September 2004	Launched for Menopausal syndrome in Germany (PO)
2 September 2004	Launched for Menopausal syndrome in Iceland (PO)
2 September 2004	Launched for Menopausal syndrome in Netherlands (PO)
2 September 2004	Launched for Menopausal syndrome in South Africa (PO)
2 September 2004	Launched for Menopausal syndrome in Sweden (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Belgium (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Denmark (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Finland (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Germany (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Iceland (PO)
2 September 2004	Launched for Postmenopausal osteoporosis prevention in Netherlands (PO)
31 March 2004	Schering has refiled the NDA for Angeliq® with the US FDA for Menopausal syndrome ⁵
31 December 2003	First global launch for Menopausal syndrome in certain countries of the European Union (PO)
31 December 2003	First global launch for Postmenopausal osteoporosis prevention in certain countries of the European Union (PO)
8 July 2003	Registered for Menopausal syndrome in European Union (PO)
8 July 2003	Registered for Postmenopausal osteoporosis prevention in European Union (PO)
26 June 2003	Clinical trials in Hypertension in USA (PO)
17 December 2002	Registered for Menopausal syndrome in Netherlands (PO)
18 October 2002	Schering has received a non-approvable letter from the US FDA for Angeliq® in Menopausal syndrome ⁸
15 December 2001	Preregistration for Menopausal syndrome in Netherlands (PO)
15 December 2001	Preregistration for Menopausal syndrome in USA (PO)
3 July 2000	Phase-III clinical trials for Menopausal syndrome in USA (PO)
30 June 2000	New profile

References

1. Bayer AG.Takeover Offer Completed; Bayer Controls 92.4 Percent of Outstanding Schering Shares.www.bayer.com, 12 Jul 2006 Media Release

2. Bayer.Renaming of Schering entered in the commercial register: Bayer Schering Pharma AG officially launched.www.bayer.com, 29 Dec 2006 Media Release

3. Berlex Inc.FDA Approves ANGELIQ(R) to Treat Menopausal Symptoms.www.berlex.com, 29 Sep 2005 Media Release

4. Schering AG.Angeliq(R) Approved in the U.S. for Treatment of Menopausal Symptoms.www.schering.de, 29 Sep 2005 Media Release

5. Schering AG.Schering refiles for U.S. approval of Angeliq.www.schering.de, 07 Apr 2004 Media Release

6. Schering AG.Schering to Drive Profitability Through 2006 and Beyond.www.schering.de, 27 Jun 2005 Media Release

7. Berlex Inc.FDA Issues Approvable Letter to Berlex Laboratories for ANGELIQ(R).www.berlex.com, 15 Sep 2004 Media Release

8. Schering AG.Schering AG receives Not Approvable Letter for HRT-product in the US.www.schering.de, 18 Oct 2002 Media Release

9. Schering AG.Start of Angeliq Launch Throughout Europe.www.schering.de, 02 Sep 2004 Media Release

10. Schering AG.European Authorities Give the Go-Ahead to Schering′s Angeliq.www.schering.de, 08 Jul 2003 Media Release

11. Schering AG.Schering′s Novel HRT Product Angeliq(R) Receives First Approval in Europe.www.schering.de, 17 Dec 2002 Media Release

12. Schering AG.R&D Day 2003: Schering Presents Promising Product Pipeline.www.schering.de, 26 Jun 2003 Media Release

13. Preston RA, White WB, Pitt B, Norris PM, Hanes V.Effects of drospirenone/estradiol, a novel hormone therapy with aldosterone antagonist activity, on blood pressure, renal function, and potassium balance in high risk hypertension subgroups. Journal of Hypertension. 23 (Suppl. 2): 70, Jun 2005. USA. [English]. Clinical Trials Insight

14. Archer D, Thorneycroft I, Foegh M, Hanes V.Efficacy and safety of drospirenone-estradiol for hormone therapy: a randomized multicenter trial. 16th Annual Meeting of the North American Menopause Society. : abstr. S-16, 28 Sep 2005. Available from: URL: http://www.menopause.org.USA. [English].