RECORDATI: POSITIVE RESULTS FROM THE PHASE III LINC 4 STUDY
PRESENTED AT THE ENDOCRINE SOCIETY’S ANNUAL MEETING REINFORCE THE
EFFICACY AND SAFETY OF ISTURISA® (OSILODROSTAT) IN CUSHING’S
DISEASE
RECORDATI:
POSITIVE RESULTS FROM THE PHASE III LINC 4
STUDY PRESENTED AT THE ENDOCRINE SOCIETY’S ANNUAL MEETING REINFORCE
THE EFFICACY AND SAFETY OF ISTURISA®
(OSILODROSTAT) IN CUSHING’S DISEASE
Statistically significant results from
the pivotal Phase III LINC 4 study demonstrate that Isturisa®
(osilodrostat) provides rapid and sustained normalisation of mean
urinary free cortisol levels in the majority of patients. These
data provide further evidence of the benefits of Isturisa® as an
effective and well-tolerated oral treatment option for patients
with Cushing’s disease.
Milan, 23 March 2021 – Recordati Rare Diseases
announces that positive results from the Phase III LINC 4 study of
Isturisa® were presented on March 22 at the Endocrine Society’s
Annual Meeting. 1
Results from LINC 4, the first Phase III study
in patients with Cushing’s disease to include an upfront,
double-blind, randomised, placebo-controlled period, demonstrated
that Isturisa® provided rapid and sustained normalisation of mean
urinary free cortisol (mUFC) levels. 1
Normalising mUFC levels represents an important
treatment goal that can potentially reduce morbidity, improve
quality of life and restore the life expectancy of patients with
Cushing’s disease towards that of the general
population. 2
The Phase III LINC 4 study enrolled adult
patients with persistent, recurrent or de novo Cushing’s disease
who had mUFC >1.3 x upper limit of normal (ULN). Seventy-three
patients received randomised treatment with Isturisa® or placebo
(2:1) during the initial 12-week, double-blind, placebo-controlled
period; 48 patients were included in the Isturisa® arm and 25
patients in the placebo arm. All patients received open-label
Isturisa® after week 12 until the end of the core study (week
48).
The primary endpoint of the LINC 4 study was
met: a significantly higher proportion of patients achieved normal
mUFC levels with Isturisa® than with placebo at the end of the
initial 12week placebo-controlled phase (77% vs 8%; P<0.0001).
Median time to first controlled mUFC response (mUFC ≤ULN) was 35
days.
The key secondary endpoint was also met, with
the majority (81%) of patients having normal mUFC levels at week
36. The rapid and sustained reductions in mUFC levels were
accompanied by improvements in cardiovascular and metabolic-related
parameters, including systolic and diastolic blood pressure and
glycated haemoglobin (HbA1c) at both week 12 and the end of the
core study.
“The exciting data presented today further
emphasise the efficacy and tolerability of Isturisa® and build on
the positive findings from the LINC 3 pivotal study, which was
published in The Lancet Diabetes & Endocrinology in July 2020.
Importantly, treatment with Isturisa® was effective in normalising
mUFC levels in the majority of patients from the start of
treatment, improved clinical signs of hypercortisolism and
cardiovascular-related risk factors, and was well tolerated,” said
Mônica Gadelha, MD, PhD, Professor of Endocrinology at Universidade
Federal do Rio de Janeiro. “I feel privileged to present these
additional important findings at the Endocrine Society’s Annual
Meeting, which represent a meaningful step forward in the optimal
management of patients experiencing this life-threatening,
devastating disease.”
Isturisa® was well tolerated in LINC 4, further
supporting the manageable safety profile established in previous
studies. 3 The most common adverse events (AEs) reported
up to data cut-off were arthralgia (45%), decreased appetite (45%),
fatigue (38%), nausea (37%) and headache (33%).
Hypocortisolism-related AEs were reported in 27% of patients. Most
hypocortisolism-related AEs were of mild or moderate severity, were
managed with dose reduction, dose interruption, and/or additional
therapy, and did not require discontinuation of Isturisa®
treatment.
“We are delighted that the positive and
statistically significant data from the LINC 4 study have been
presented at the Endocrine Society’s Annual Meeting. These data add
to the robust body of evidence supporting Isturisa® as an effective
and well-tolerated treatment for patients with Cushing’s disease,”
said Andrea Recordati, CEO. “Recordati is committed to improving
the lives of patients with this serious yet underserved condition.
On behalf of Recordati, I would like to thank all the patients,
their families and carers, the investigators and the study
collaborators who have contributed to LINC 4 and the Isturisa®
clinical programme.”
Isturisa® is indicated in the EU and the USA for
the treatment of adult patients with endogenous Cushing’s syndrome
and Cushing’s disease, respectively. 4,5
About Cushing’s syndrome
Cushing’s syndrome is a rare disorder caused by chronic exposure to
excess levels of cortisol from either an exogenous (eg medication)
or an endogenous source. 6 Cushing’s disease is the most
common cause of endogenous Cushing’s syndrome and arises as a
result of excess secretion of adrenocorticotropic hormone from a
pituitary adenoma, a tumour of the pituitary gland. 2,6
There is often a delay in diagnosing Cushing’s syndrome, which
consequently leads to a delay in treating patients. 7
Patients who are exposed to excess levels of cortisol for a
prolonged period have increased comorbidities associated with the
cardiovascular and metabolic systems, which consequently reduce
quality of life and increase the risk of mortality. 2,8
In order to alleviate the clinical signs associated with excess
cortisol exposure, the primary treatment goal in Cushing’s syndrome
is to reduce cortisol levels to normal. 9
About LINC 4LINC 4 is a
multicentre, randomised, double-blind, 48-week study with an
initial 12-week placebo-controlled period to evaluate the safety
and efficacy of Isturisa® in patients with Cushing’s disease. The
LINC 4 study enrolled patients with persistent or recurrent
Cushing’s disease or those with de novo disease who were ineligible
for surgery; 73 randomised patients were treated with Isturisa®
(n=48) or placebo (n=25). 1 The primary endpoint of the
study is the proportion of randomised patients with a complete
response (mUFC ≤ULN) at the end of the placebo-controlled period
(week 12). The key secondary endpoint is the proportion of patients
with mUFC ≤ULN at week 36. 1,10
About Isturisa®
Isturisa® is a potent oral inhibitor of
11β-hydroxylase (CYP11B1), the enzyme that catalyses the final step
of cortisol biosynthesis in the adrenal gland, and is authorised in
the EU and USA for the treatment of adult patients with Cushing’s
syndrome and Cushing’s disease, respectively. 4,5
Isturisa® is available as 1 mg, 5 mg and 10 mg
film‐coated tablets. 4,5 Please see the prescribing
information for detailed recommendations for the use of this
product. 4,5
Two pivotal Phase III trials, LINC 3 and LINC 4,
were designed to evaluate the efficacy and safety of Isturisa® in
patients with Cushing’s disease. 1,3 LINC 3 demonstrated
that a higher proportion of patients on Isturisa® achieved normal
mUFC compared with placebo during a randomised withdrawal
period. 3 LINC 4 is the first study to include a
placebo-controlled phase and complements the efficacy and safety
data from the LINC 3 study. 1 Both LINC 3 and LINC 4
studies include optional extension phases that will help understand
the efficacy and safety of long-term Isturisa®
treatment. 1,3
A Phase II study evaluated the efficacy and
safety of Isturisa® in adult Japanese patients with non-pituitary
causes of endogenous Cushing’s syndrome: adrenal adenoma, n=5;
ectopic adrenal corticotropic hormone syndrome, n=3;
adrenocorticotropin-independent macronodular adrenocortical
hyperplasia, n=1. Isturisa® decreased mUFC levels irrespective of
the aetiology of Cushing’s syndrome and normalised mUFC in most
(67%) patients at week 12. 11
References 1.
Gadelha M et al. Osilodrostat is an effective and well-tolerated
treatment for Cushing's disease (CD): results from a Phase III
study with an upfront, randomized, double-blind, placebo-controlled
phase (LINC 4); presented at ENDO 2021, March
2021.2.
Pivonello R et al. Lancet Diabetes Endocrinol
2016;4:611-29.3.
Pivonello R et al. Lancet Diabetes Endocrinol
2020;8:748-61.4.
Isturisa® summary of product characteristics. May
2020.5.
Isturisa® US prescribing information. March
2020.6.
Lacroix A et al. Lancet
2015;386:913-27.7.
Rubinstein G et al. J Clin Endocrinol Metab
2020;105:dgz136.8.
Ferriere A, Tabarin A. Best Pract Res Clin Endocrinol Metab
2020;34:101381.9.
Nieman LK et al. J Clin Endocrinol Metab
2015;100:2807-31.10.
ClinicalTrials.gov. NCT02697734; available at
https://clinicaltrials.gov/ct2/show/ NCT02697734 (accessed March
2021).11.
Tanaka T et al. Endocr J 2020;67:841-52.
About Recordati Rare Diseases,
Inc
Recordati Rare Diseases, Inc is a
biopharmaceutical company committed to providing often-overlooked
orphan therapies to underserved rare disease communities. Recordati
Rare Diseases, Inc is a part of the rare disease business within
the Recordati Group, a public international specialty
pharmaceutical company committed to the research and development of
new specialties with a focus on treatments for rare diseases.
The mission of Recordati Rare Diseases is to
reduce the impact of extremely rare and devastating diseases by
providing urgently needed therapies. We work side by side with rare
disease communities to increase awareness, improve diagnosis and
expand availability of treatments for people with rare
diseases.
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 2020 was € 1,448.9 million, operating income was € 469.0
million and net income was € 355.0 million.
For further information:
Recordati website: www.recordati.com
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This document contains forward-looking
statements relating to future events and future operating, economic
and financial results of the Recordati group. By their nature,
forward-looking statements involve risk and uncertainty because
they depend on the occurrence of future events and circumstances.
Actual results may therefore differ materially from those forecast
as a result of a variety of reasons, most of which are beyond the
Recordati group’s control. The information on the pharmaceutical
specialties and other products of the Recordati group contained in
this document is intended solely as information on the Recordati
group’s activities and therefore, as such, it is not intended as
medical scientific indication or recommendation, nor as
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