RECORDATI: ISTURISA® (Osilodrostat) Phase III LINC-4 Trial Meets Its Primary Endpoint In Cushing’s Disease

Source: RECORDATI

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RECORDATI: ISTURISA® (OSILODROSTAT) PHASE III LINC-4 TRIAL MEETS ITS PRIMARY ENDPOINT IN CUSHING’S DISEASE

Isturisa® (osilodrostat) demonstrates significant and sustained benefit over placebo at normalizing mean urinary free cortisol (mUFC) levels in patients with Cushing’s disease

Milan, 17 June 2020 – Recordati today announces positive results from the large Phase III LINC-4 study of Isturisa® (osilodrostat) for the treatment of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Data from the LINC-4 study demonstrate that a significantly higher proportion of patients receiving Isturisa® achieve normal mUFC, the primary treatment goal for Cushing’s disease, after 12 weeks of treatment versus placebo (77% vs 8%; P<0.0001). Improvements in mUFC levels are sustained over 36 weeks of treatment (81% of patients). Isturisa® is well tolerated and has a manageable safety profile, with the most common adverse events in LINC-4 being arthralgia, decreased appetite, fatigue, and nausea. The findings from LINC-4, the first Phase III study of a medical therapy in Cushing’s disease to contain an upfront placebo-controlled phase, builds on existing clinical evidence and affirms the effectiveness of Isturisa® in this hard-to-treat patient population.1-3

“Cushing’s disease is a chronic and debilitating condition that can be extremely challenging to manage and, if left inadequately treated, can have a significant impact on patients’ quality of life and increase the risk of mortality”, said Richard Feelders, MD, Professor of Endocrinology at the Erasmus University Medical Centre, Rotterdam. “Data from this important Phase III study show that Isturisa® (osilodrostat) is an effective and well-tolerated therapy for Cushing’s disease, which significantly reduces and normalizes mUFC levels in most patients. These data are encouraging given the high unmet medical need for patients with this rare disorder”.

“The compelling topline LINC-4 data confirm the effectiveness of Isturisa® for the treatment of this rare, potentially life-threatening disease”, stated Andrea Recordati, CEO. “We are deeply grateful to the patients, investigators, clinicians and study staff whose ongoing participation in the clinical development of Isturisa® has helped bring this therapy to patients in need.”

Data from the LINC 4 study reinforce the clinical benefits of Isturisa® as an effective and generally well‑tolerated oral treatment option for patients with Cushing’s disease. Isturisa® has recently received marketing authorization in the European Union (January 2020) and United States (March 2020) for the treatment of Cushing’s syndrome and Cushing’s disease, respectively.

About Cushing’s syndrome

Cushing’s syndrome is caused by an inappropriate and chronic exposure to excessive levels of cortisol. The source of this excess of cortisol can be endogenous or exogenous (ie medication). When the excess cortisol production is triggered by a pituitary adenoma (ie a tumor of the pituitary gland located in the brain) secreting excess adrenocorticotropic hormone (ACTH), the condition of the patient is defined as Cushing’s disease and comprises about 70% of Cushing’s syndrome cases.4 It is a rare, serious and difficult-to-treat disease that affects approximately one to two patients per million per year.5 Prolonged exposure to elevated cortisol levels is associated with considerable morbidity, mortality and impaired quality of life as a result of complications and comorbidities.6 Normalization of cortisol levels is therefore a primary objective in the treatment of Cushing’s syndrome.7

About LINC-4

LINC-4 is a large randomized, double-blinded, multicentre, 48-week trial with an initial 12-week placebo-controlled period to evaluate the safety and efficacy of osilodrostat in patients with Cushing’s disease. The primary endpoint in the LINC-4 trial is the proportion of patients randomized to Isturisa® and placebo, separately, with a mUFC ≤ULN at the end of the 12-week placebo-controlled period. The key secondary endpoint is the proportion of patients in both arms combined with a mUFC ≤ULN after 36 weeks. LINC-4 involved 73 patients with persistent or recurrent Cushing’s disease or those with de novo disease who were not candidates for surgery.

About Isturisa®

Isturisa® is a potent oral, reversible inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that catalyses the final step of cortisol biosynthesis in the adrenal gland and is authorized in the EU and US for the treatment of adult patients with Cushing’s syndrome and Cushing’s disease, respectively.8,9 Isturisa® will be available as 1 mg, 5 mg and 10 mg film‐coated tablets. Please see prescribing information for detailed recommendations for the use of this product.8,9

  1. Bertagna X et al. J Clin Endocrinol Metab 2014;99:1375–83
  2. Fleseriu M et al. Pituitary 2016;19:138–48
  3. Biller BMK et al. Abstract OR16-2. Oral presentation at the Endocrine Society Annual Congress 2019
  4. Nieman LK et al. Am J Med 2005;118:1340–6
  5. Signifor® and Signifor® LAR Summary of Product Characteristics, June 2018
  6. Pivonello R et al. Lancet Diabetes Endocrinol 2016;4:611–29
  7. Nieman LK et al. J Clin Endocrinol Metab 2015;100:2807–31
  8. Isturisa® Summary of Product Characteristics. May 2020
  9. Isturisa® Prescribing Information. March 2020

About the 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 a number of 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.

For further information:

Recordati website:  http://www.recordati.com

Investor Relations                                                                 Media Relations
Marianne Tatschke                                                                Studio Noris Morano
(39)0248787393                                                                    (39)0276004736, (39)0276004745
e-mail: investorelations@recordati.it                                  e-mail: norismorano@studionorismorano.com

Statements contained in this release, other than historical facts, are “forward-looking statements” (as such term is defined in the Private Securities Litigation Reform Act of 1995). These statements are based on currently available information, on current best estimates, and on assumptions believed to be reasonable. This information, these estimates and assumptions may prove to be incomplete or erroneous, and involve numerous risks and uncertainties, beyond the Company’s control. Hence, actual results may differ materially from those expressed or implied by such forward-looking statements. All mentions and descriptions of Recordati products are intended solely as information on the general nature of the company’s activities and are not intended to indicate the advisability of administering any product in any particular instance.

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From https://www.globenewswire.com/news-release/2020/06/17/2049265/0/en/RECORDATI-ISTURISA-OSILODROSTAT-PHASE-III-LINC-4-TRIAL-MEETS-ITS-PRIMARY-ENDPOINT-IN-CUSHING-S-DISEASE.html

Patients With Cushing Have New Nonsurgical Treatment Option

Cushing syndrome, a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol, has a new pharmaceutical treatment to treat cortisol overproduction.

Osilodrostat (Isturisa) is the first FDA approved drug who either can’t undergo pituitary gland surgery or have undergone the surgery but still have the disease. The oral tablet functions by blocking the enzyme responsible for cortisol synthesis, 11-beta-hydroxylase.

“Until now, patients in need of medications…have had few approved options, either with limited efficacy or with too many adverse effects. With this demonstrated effective oral treatment, we have a therapeutic option that will help address patients’ needs in this underserved patient population,” said Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health Sciences University.

Cushing disease is caused by a pituitary tumor that releases too much of the hormone that stimulates cortisol production, adrenocorticotropin. This causes excessive levels of cortisol, a hormone responsible for helping to maintain blood sugar levels, regulate metabolism, help reduce inflammation, assist in memory formulation, and support fetus development during pregnancy.

The condition is most common among adults aged 30-50 and affects women 3 times more than men.

Cushing disease can lead to a number of medical issues including high blood pressure, obesity, type 2 diabetes, blood clots in the arms and legs, bone loss and fractures, a weakened immune system, and depression. Patients with Cushing disease may also have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks), or weak muscles.

Side effects of osilodrostat occurring in more than 20% of patients are adrenal insufficiency, headache, nausea, fatigue, and edema. Other side effects can include vomiting, hypocortisolism (low cortisol levels), QTc prolongation (heart rhythm condition), elevations in adrenal hormone precursors (inactive substance converted into hormone), and androgens (hormone that regulated male characteristics).

Osilodrostat’s safety and effectiveness was evaluated in a study consisting of 137 patients, of which about 75% were women. After a 24-week period, about half of patients had achieved normal cortisol levels; 71 successful cases then entered an 8-week, double-blind, randomized withdrawal study where 86% of patients receiving osilodrostat maintained normal cortisol levels, compared with 30% who were taking a placebo.

In January 2020, the European Commission also granted marketing authorization for osilodrostat.

From https://www.ajmc.com/newsroom/patients-with-cushing-have-new-nonsurgical-treatment-option

FDA Approves New Treatment for Adults with Cushing’s Disease

The U.S. Food and Drug Administration today approved Isturisa (osilodrostat) oral tablets for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. Cushing’s disease is a rare disease in which the adrenal glands make too much of the cortisol hormone. Isturisa is the first FDA-approved drug to directly address this cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis.

“The FDA supports the development of safe and effective treatments for rare diseases, and this new therapy can help people with Cushing’s disease, a rare condition where excessive cortisol production puts them at risk for other medical issues,” said Mary Thanh Hai, M.D., acting director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “By helping patients achieve normal cortisol levels, this medication is an important treatment option for adults with Cushing’s disease.”

Cushing’s disease is caused by a pituitary tumor that releases too much of a hormone called adrenocorticotropin, which stimulates the adrenal gland to produce an excessive amount of cortisol. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Cushing’s disease can cause significant health issues, such as high blood pressure, obesity, type 2 diabetes, blood clots in the legs and lungs, bone loss and fractures, a weakened immune system and depression. Patients may have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks) and weak muscles.

Isturisa’s safety and effectiveness for treating Cushing’s disease among adults was evaluated in a study of 137 adult patients (about three-quarters women) with a mean age of 41 years. The majority of patients either had undergone pituitary surgery that did not cure Cushing’s disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 milligrams (mg) of Isturisa twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of patients had cortisol levels within normal limits. After this point, 71 patients who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received Isturisa or a placebo (inactive treatment). At the end of this withdrawal period, 86% of patients receiving Isturisa maintained cortisol levels within normal limits compared to 30% of patients taking the placebo.

The most common side effects reported in the clinical trial for Isturisa were adrenal insufficiency, headache, vomiting, nausea, fatigue and edema (swelling caused by fluid retention). Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking Isturisa.

Isturisa is taken by mouth twice a day, in the morning and evening as directed by a health care provider. After treatment has started, a provider may re-evaluate dosage, depending upon the patient’s response.

Isturisa received Orphan Drug Designation, which is a special status granted to a drug intended to treat a rare disease or condition.

The FDA granted the approval of Isturisa to Novartis.

Media Contact: Monique Richards, 240-402-3014
Consumer InquiriesEmail, 888-INFO-FDA

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

SOURCE U.S. Food and Drug Administration

Related Links

http://www.fda.gov

From https://www.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-cushings-disease-301019293.html

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