PUTEAUX, France–(BUSINESS WIRE)–Recordati Rare Diseases today announces the publication of positive results from the Phase III LINC 4 study of Isturisa in The Journal of Clinical Endocrinology and Metabolism.1 These data confirm that Isturisa is an effective and well-tolerated oral therapy for patients with Cushing’s disease. Isturisa is indicated in the EU for the treatment of adult patients with endogenous Cushing’s syndrome,2 a rare and debilitating condition of hypercortisolism that is most commonly caused by a pituitary adenoma (Cushing’s disease).3
The LINC 4 study increases the efficacy and safety data of Isturisa in patients with Cushing’s disease, confirming the results of the phase III LINC 3 study. This study involving 73 adults is the first phase III study of medical treatment in patients with Cushing’s disease to include an initial, randomized, double-blind, placebo-controlled period in which 48 patients received Isturisa and 25 received placebo during the first 12 weeks. , followed by an open-label period in which all patients received Isturisa through week 48; thereafter, patients could enter an optional extension phase.
Key findings published in the manuscript titled “Randomized Trial of Osilodrostat for the Treatment of Cushing’s Disease” include:1
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LINC 4 met the primary endpoint: Isturisa was significantly superior to placebo for mCFU normalization at the end of a randomized, double-blind 12-week period (77% vs. 8%; P
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The effects of Isturisa were quick. More than a quarter of patients randomized to Isturisa achieved normal mUFC at the start of week 2 and 58% achieved control at week 5.
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The key secondary endpoint was also met, with 81% of all patients in the study having normal mUFC at week 36.
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Improvements in cardiovascular and metabolic parameters of Cushing’s disease, including blood pressure and blood glucose metabolism, were observed at week 12 and were maintained throughout the study.
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Physical features of hypercortisolism improved during treatment with Isturisa, including fat pads, facial chafing, striae, and muscle wasting. Improvements were seen at week 12, with continued improvement throughout the study through week 48.
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Patient-reported quality of life scores (CushingQoL and Beck Depression Inventory) also improved during treatment with Isturisa.
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Isturisa was well tolerated in the majority of patients, with no unexpected adverse events (AEs). Overall, the most common side effects were decreased appetite, arthralgia, fatigue, and nausea.
“These results provide compelling evidence that osilodrostat is an effective treatment for Cushing’s disease,” said Peter J. Snyder MD, professor of medicine at the University of Pennsylvania. “Osilodrostat rapidly returned cortisol excretion to normal in most patients with Cushing’s disease and maintained normal levels throughout the central phase of the study. Importantly, this normalization was accompanied by improvements in cardiovascular and metabolic parameters, which increase morbidity and mortality in Cushing’s disease.
“These compelling data build on the positive Phase III LINC 3 study, published in The Lancet Diabetes and Endocrinology in 2020,4 demonstrating that Isturisa enables most patients with Cushing’s disease to rapidly control their cortisol levels, which in turn relieves a host of adverse symptoms,” said Alberto Pedroncelli, Head of Clinical Development and Medical Affairs. , Global Endocrinology, Recordati AG. “Recordati Rare Diseases is committed to improving the lives of patients with this rare, debilitating and life-threatening disease. I would like to thank everyone who contributed to CLIC 4 and the CLIC clinical program.
“I had Cushing’s disease for 8 years without being diagnosed,” says Thérèse Fournier of the “Surrénales” association. “I was trapped in a vicious cycle of missed diagnoses and worsening physical and psychological symptoms that put my life at risk. I lost everything – my job, my home, my partner, my friends – I I was isolated. When I finally received my diagnosis, I was relieved because I knew the truth. Since my operation, I am learning to live again, to enjoy the moments that make a life. I am still on the road to remission , but I feel deeply happy, even if I carry this journey that no one can understand.
About Cushing’s Syndrome
Cushing’s syndrome is a rare disease caused by chronic exposure to excessive levels of cortisol from either an exogenous source (eg a drug) or an endogenous source.5 Cushing’s disease is the most common cause of endogenous Cushing’s syndrome and results from excessive secretion of adrenocorticotropic hormone from a pituitary adenoma, a tumor of the pituitary gland.5.6 There is often a delay in the diagnosis of Cushing’s syndrome, which consequently leads to a delay in the treatment of patients.7 Patients who are exposed to excessive levels of cortisol for a prolonged period have increased comorbidities associated with the cardiovascular and metabolic systems, which consequently reduces quality of life and increases the risk of mortality.3.6 To alleviate the clinical signs associated with excessive cortisol exposure, the primary goal of treatment in Cushing’s syndrome is to return cortisol levels to normal.8
About CLICK 4
LINC 4 is a multicenter, randomized, double-blind, 48-week study with an initial placebo-controlled period of 12 weeks 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 de novo disease that were not eligible for surgery; 73 randomized patients were treated with Isturisa® (n=48) or a placebo (n=25).1 The primary endpoint of the study is the proportion of randomized patients with a complete response (mCFU ≤ 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 36.1.9
About Isturisa®
Isturisa® is an oral 11β-hydroxylase (CYP11B1) inhibitor, which catalyzes the last step of cortisol synthesis in the adrenal glands.2 Isturisa® is available as 1 mg, 5 mg and 10 mg film-coated tablets.2 Isturisa® is approved for the treatment of adult patients with endogenous Cushing’s syndrome in the EU and is now available in France, Germany, Greece and Austria.2
Isturisa® obtained marketing authorization from the European Commission on January 9, 2020. For detailed recommendations on the appropriate use of this product, please consult the summary of product characteristics.2
The references
1. Gadelha M, Bex M, Feelders RA et al. Randomized trial of osilodrostat for the treatment of Cushing’s disease. J Clin Endocrinol Metab 2022; dgac178, https://doi.org/10.1210/clinem/dgac178.
2. Summary of Isturisa® product characteristics. May 2020.
3. Ferriere A, Tabarin A. Cushing’s syndrome: treatment and new therapeutic approaches. Best Practice Res Clin Endocrinol Metab 2020;34:101381.
4. Pivonello R, Fleseriu M, Newell-Price J et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a phase III multicenter study with a randomized double-blind withdrawal phase. Lancet Diabetes Endocrinol 2020;8:748-61.
5. Lacroix A, Feelders RA, Stratakis CA et al. Cushing’s Syndrome. Lancet 2015;386:913-27.
6. Pivonello R, Isidori AM, De Martino MC et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol 2016;4:611-29.
7. Rubinstein G, Osswald A, Hoster E et al. Time to diagnosis in Cushing’s syndrome: a meta-analysis based on 5367 patients. J Clin Endocrinol Metab 2020;105:dgz136.
8. Nieman LK, Biller BM, Findling JW et al. Treatment of Cushing’s syndrome: a clinical practice guideline from the Endocrine Society. J Clin Endocrinol Metab 2015;100:2807-31.
9. ClinicalTrials.gov. NCT02697734; available at https://clinicaltrials.gov/ct2/show/NCT02697734 (accessed March 2021).
Recordati Rare Diseases, the company’s EMEA headquarters are located in Puteaux, France, with global headquarters offices in Milan, Italy.
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Registration, created 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 workforce of more than 4,300 people, dedicated to research, development, manufacturing and marketing of pharmaceutical products. Based in Milan, Italy, Recordati is present in Europe, Russia and other CIS countries, Ukraine, Turkey, North Africa, United States of America, Canada, Mexico, some South American countries, Japan and Australia. An effective field force of medical visitors promotes a wide range of innovative, proprietary and licensed pharmaceutical products in several therapeutic areas, including a specialist business dedicated to rare disease treatments. Recordati is a partner of choice for licensing new products for its territories. Recordati engages in the research and development of new specialties with an emphasis on treatments for rare diseases. Consolidated revenue for 2021 was €1,580.1 million, operating profit €490.2 million and net profit €386.0 million.
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