With the oral cortisol synthesis inhibitor osilodrostat
(Isturisa®), a new therapy option for medical treatment of adults
with endogenous Cushing’s syndrome is now available in Germany as
of July 15, 2020.1 Isturisa® can contribute to alleviate the high
burden of this rare but serious and potentially life-threatening
disease.2 Results of the pivotal, multicenter, randomised
withdrawal, double-blind phase III study LINC-3 show that
osilodrostat led to a rapid and sustained reduction of cortisol
levels accompanied by improvements in comorbidities, clinical
symptoms and quality of life. Furthermore osilodrostat was well
tolerated.1,3
Cortisol synthesis inhibitor
osilodrostat (Isturisa®) is now available in Germany as of July 15,
2020, as a promising new therapy option for medical treatment of
adult patients with endogenous Cushing’s syndrome (CS).1,4
Isturisa® was approved by the European Commission on January 9,
2020.
The approval of Isturisa® (osilodrostat) is based on the results
of the pivotal phase III study, LINC-3, in which the efficacy and
safety of osilodrostat in 137 patients with Cushing’s disease were
assessed. A significantly higher proportion of patients with
Cushing’s disease treated with Isturisa® maintained normal mean
urinary free cortisol (mUFC) at the end of the 8‐week randomized
withdrawal period (week 34) versus placebo (86% vs 29%). Cortisol
level control is the primary objective in the treatment of patients
with Cushing’s disease. Thus, the study successfully met its
primary and key secondary endpoint.1,3 Moreover, the results showed
that osilodrostat resulted in a rapid and sustained reduction of
mean free urine cortisol levels maintained during the 48-week
follow-up period. This was accompanied by improvements in clinical
symptoms, comorbidity and quality of life.
"Data from the LINC-3 study underline the efficacy and safety of
Isturisa® in a prospective setting and represent a significant
advance in the treatment of patients with Cushing’s disease, a
serious and potentially life-threatening rare disease," commented
Pr. Rosario Pivonello, Professor of Endocrinology at the Federico
II University of Naples (Italy). "I would like to thank all
patients who participated in the LINC-3 study and their families
who helped make this new and welcome therapy option available for
this underserved patient population."
The launch of Isturisa® is an
addition to the Recordati Rare Diseases endocrinology portfolio
which also includes Signifor®, subcutaneous and intramuscular
formulations, available across Europe, indicated for the treatment
of adult patients with Cushing’s disease for whom surgery is not an
option or for whom surgery has failed, and for adult patients with
acromegaly for whom surgery is not an option or has not been
curative and who are inadequately controlled on treatment with
another somatostatin analogue.5
High Burden of Disease and Impairment of Quality of Life
Cushing’s disease, the most common form of endogenous CS, is
associated with high morbidity and burden of disease.2 As a result,
those affected suffer from considerable impairments in their
quality of life. In addition, the disease is associated with a
large number of significant concomitant diseases as a result of the
excessively elevated cortisol levels.2 These include metabolic
syndrome, sleep disorders, osteoporosis, increased susceptibility
to infections and/or neuropsychiatric disorders such as depression
and anxiety.2 The mortality rate is correspondingly higher, in
particular due to cardio-vascular complications. Without proper
intervention to normalise cortisol levels, the mortality risk in
patients with Cushing’s disease is up to five times higher than in
the general population.2 Besides, there are indications that
negative physical and psychosocial consequences of chronic
hypercortisolism can persist a long time after remission.2 Because
of these potentially life-threatening risks, rapid diagnosis and
treatment are necessary.2,6
Multidisciplinary Treatment with a Need for Optimization
CS or Cushing’s disease require experienced multidisciplinary teams
and individual treatment.2,7 Therapy goals are normalization of
cortisol levels, improvement of clinical symptoms and quality of
life as well as reduction of comorbidity-related risks.8,9
The primary treatment for Cushing’s disease is the surgical
resection of the pituitary tumor. However, about a third of the
patients do not achieve remission or present with long-term
recurrences and, therefore, they require further therapy. Possible
therapeutic options are repeat surgery, radiotherapy, bilateral
adrenalectomy or medical treatments. The latter act either
centrally on the pituitary gland or peripherally on the adrenal
gland by inhibiting steroid synthesis. They are also used to bridge
the gap between diagnosis of the disease and surgery or
radiotherapy or its onset of action, or when surgical treatment is
not an option.2,6,8,9
However, these medical treatments can only be used to a limited
extent and/or can be associated with serious disadvantages and
risks. For example, up to 50% of patients with Cushing's syndrome
fail to reach normal cortisol levels with the currently available
medical treatments, which in up to 28% of cases leads to dose
adjustment or therapy discontinuation. Thus, there is an unmet need
for more effective pharmacological interventions.2,8,9
The introduction of osilodrostat has thus opened up new
therapeutic options. The data from prospective studies with a
well-planned design indicate that this active ingredient is a
promising, effective therapy option which is well tolerated.3,4
About Cushing’s Syndrome Cushing's syndrome (CS) is
caused by inappropriate and chronic exposure to excessive cortisol
levels. The source of this excessive cortisol can be endogenous or
exogenous (ie medication). Endogenous CS is most commonly caused
either by an adrenal gland tumor (approx. 15%), leading to an
excessive cortisol secretion, or by a pituitary adenoma (ie a tumor
of the pituitary gland located in the brain) secreting excessive
adrenocorticotropic hormone (ACTH), which accounts for about 70% of
cases. Remaining 15% of cases are of other (ectopic) origin.2,10,11
With a prevalence of 40 cases per million inhabitants and an
incidence of 1.2 to 2.4 per million per year Cushing’s disease is a
rare disease.2,11 Women are affected about three times more often
than men.2,7 The peak age is between the 4th and 6th decade of
life.11 The disease is characterized by various long-term effects
of glucocorticoids on organs and tissues and can, therefore, be
very heterogeneous. Clinical symptoms include stretch marks on the
skin (striae rubrae), obesity, muscle atrophy of the extremities,
moon-shaped face, general weakness, osteoporosis, glucose
intolerance, arterial hypertension, wound healing disorders,
increased bleeding tendency and thromboembolic complications.
However, many symptoms are non-specific and also appear in common
diseases such as alcohol addiction, obesity or (poorly controlled)
diabetes mellitus. Because of the low specificity of symptoms CS is
often diagnosed late in the course of disease.6,10
Chronically elevated cortisol levels can lead to serious
complications and comorbidities, severe impairment of quality of
life and increased mortality.2,6 Therefore, normalizing cortisol
levels is the main therapeutic goal.8,9 For most forms of CS
surgical resection of the causative tumor is the primary treatment
option. In case of a residual tumor or relapse irradiation is
possible. However, symptoms decrease with a delay of several months
to years. Medical treatments are used to bridge the gap between the
diagnosis of the disease and surgery or until radiotherapy begins
to work, as well as when there is no remission due to these
procedures. A distinction is made between steroid synthesis
inhibitors, which primarily act on adrenal gland, and substances,
acting centrally on pituitary gland.6,8
About LINC-3 LINC-3 is
a prospective 48-week, phase III, multi-center study to evaluate
the safety and efficacy of Isturisa® in patients (N = 137) with
persistent or recurrent Cushing’s disease or with De Novo disease,
who are not eligible for surgical therapy. The study consisted of a
12-week open-label dose titration period, followed by a 12-week
maintenant period and an 8-week double-blind, randomized withdrawal
phase in which eligible patients were randomized to receive 1: 1
osilodrostat or placebo, followed by another 14-week open-label
phase with osilodrostat. The primary endpoint was the proportion of
randomized patients who maintained complete response (mUFC ≤ULN
with no dose increase above the level at week 26) at the end of the
8-week randomized withdrawal period (week 34). The key secondary
endpoint was the proportion of patients with normal mUFC at week 24
and with no dose increase above the level established at week
12.1,3 The primary study
endpoint was reached: significantly more patients in the
osilodrostat group maintained a normal mUFC value without dose
increase than in the placebo group (86% vs. 29%; p < 0.001) at
the end of the 8-week randomized phase (week 34). More than half of
the patients (53%) reached the key secondary endpoint of a normal
mUFC value after the first 24 weeks of open therapy with
osilodrostat, without increasing the dose after week 12. Two thirds
(66%) of the patients had a normal mUFC at the end of the 48-week
study. The reduction in cortisol levels was accompanied by
improvements in cardiovascular and metabolic parameters (body
weight, waist size, HbA1c, blood pressure). At week 48, 86% of the
patients for whom data were available showed improvement in at
least one physical characteristic of M. Cushing.1,3
Osilodrostat was well tolerated.3 The most commonly observed side
effects in LINC-3 were nausea (42%), headache (34%), fatigue (44%)
and adrenal insufficiency (51%).1
About Isturisa Isturisa® is a potent inhibitor of
11β-hydroxylase (CYP11B1), the enzyme responsible for the final
step of cortisol synthesis in the adrenal gland. Isturisa® is taken
twice daily and is available as 1 mg, 5 mg and 10 mg film-coated
tablets. Please see the prescribing information for detailed
recommendations for the use of this product.1
About Recordati Rare Diseases The company’s
EMEA-headquarters is located in Puteaux, France, and its global
headquarters is based in Milan, Italy. For a complete list of
products, visit www.recordatirarediseases.com/products. You can
find more information on our website at www.recordati.com and
https://www.recordatirarediseases.com/ or follow us on LinkedIn or
Twitter for the latest company news.
About Recordati Group Recordati, established in 1926, is
an international pharmaceutical group, listed on the Italian Stock
Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271),
with a total staff of more than 4,300, dedicated to the research,
development, manufacturing and marketing of pharmaceuticals.
Headquartered in Milan, Italy, Recordati has operations throughout
the whole of Europe, including Russia, Turkey, North Africa, the
United States of America, Canada, Mexico, some South American
countries, Japan and Australia. An efficient field force of medical
representatives promotes a wide range of innovative
pharmaceuticals, both proprietary and under license, in several
therapeutic areas including a specialized business dedicated to
treatments for rare diseases. Recordati is a partner of choice for
new product licenses for its territories. Recordati is committed to
the research and development of new specialties with a focus on
treatments for rare diseases. Consolidated revenue for 2019 was €
1,481.8 million, operating income was € 465.3 million and net
income was € 368.9 million.
References:
1 Isturisa® Fachinformation, Mai 2020 2 Pivonello R et al.
Endocrine 2017; 56: 10–18 3 Biller BMK et al. Journal of the
Endocrine Society 2019; 3 (Supplement 1): OR16-2 4 Ferriere A,
Tabarin A. Best Pract Res Clin Endocrinol Metab 2020; 34 (2):
101381 5 Signifor® and Signifor® LAR Fachinformation, Juni 2018 6
Petersen S. Diagnostik und Therapie des Cushing-Syndroms. In:
Endokrinologie Informationen; Sonderheft März 2017: 38-43 7 Lacroix
A et al. Lancet 2015; 386: 913 8 Nieman LK et al. J Clin Endocrinol
Metab 2015; 100: 2807 9 Broersen LHA et al. Pituitary 2018; 21: 631
10 Nieman LK et al. Am J Med 2005; 118: 1340–1346 11 Pivonello R et
al. Endocrine Reviews 2015; 36: 385–486
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For additional information: Company Contact:
Claudia Limberger Franchise Head Endocrinology - Germany E-Mail:
limberger.c@recordati.com Tel.: +49 1522 8897110
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