Results Reinforce Efficacy of Recordati’s Isturisa in Cushing’s Disease

Posted on June 22, 2022 by MaryO

Recordati Rare Diseases, a US biopharma that forms part of the wider Italian group, has presented multiple positive data sets on Isturisa (osilodrostat) at the annual ENDO 2022 meeting in Atlanta, Georgia.

Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Among the data presented, the Phase III LINC 4 study demonstrated that Isturisa maintained normal mean urinary free cortisol long-term in patients with Cushing’s disease while the Phase III LINC 3 study found adrenal hormone levels changed during early treatment with the drug while stabilizing during long-term treatment.

The ILLUSTRATE study also showed patients treated with a prolonged titration interval tended to have greater persistence with therapy.

Mohamed Ladha, president and general manager for North America, Recordati Rare Diseases, said: “The data from these studies reinforces the efficacy and safety of Isturisa as a treatment for patients with Cushing’s disease.

“We are pleased to share these data with the endocrine community and are excited to provide patients with a much-needed step forward in the management of this rare, debilitating, and potentially life-threatening condition.”

Cushing’s disease is a rare, serious illness caused by a pituitary tumor that leads to overproduction of cortisol by the adrenal glands. Excess cortisol can contribute to an increased risk of morbidity and mortality. Treatment for the condition seeks to lower cortisol levels to a normal range.

Isturisa, which was approved by the US Food and Drug Administration in March 2020, works by inhibiting 11-beta-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

From https://www.thepharmaletter.com/article/results-reinforce-efficacy-of-recordati-s-isturisa-in-cushing-s-disease

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Medications Used to Treat Cushing’s

Posted on June 13, 2022 by MaryO

Dr. Friedman uses several medications to treat Cushing’s syndrome that are summarized in this table. Dr. Friedman especially recommends ketoconazole. An in-depth article on ketoconazole can be found on goodhormonehealth.com.

 

 

 Drug How it works Dosing Side effects
Ketoconazole  (Generic, not FDA approved in US) blocks several steps in cortisol biosynthesis Start 200 mg at 8 and 10 PM, can up titrate to 1200 mg/day • Transient increase in LFTs
• Decreased testosterone levels
• Adrenal insufficiency
Levoketoconazole (Recorlev) L-isomer of Ketoconazole Start at 150 mg at 8 and 10 PM, can uptitrate up to 1200 mg nausea, vomiting, increased blood pressure, low potassium, fatigue, headache, abdominal pain, and unusual bleeding
Isturisa (osilodrostat) blocks 11-hydroxylase 2 mg at bedtime, then go up to 2 mg at 8 and 10 pm, can go up to 30 mg  Dr. Friedman often gives with spironolactone or ketoconazole. • high testosterone (extra facial hair, acne, hair loss, irregular periods)  • low potassium
• hypertension
Cabergoline (generic, not FDA approved) D2-receptor agonist 0.5 to 7 mg • nausea,  • headache  • dizziness
Korlym (Mifepristone) glucocorticoid receptor antagonist 300-1200 mg per day • cortisol insufficiency (fatigue, nausea, vomiting, arthralgias, and headache)
• increased mineralocorticoid effects (hypertension, hypokalemia, and edema
• antiprogesterone effects (endometrial thickening)
Pasireotide (Signafor) somatostatin receptor ligand 600 μg or 900 μg twice a day Diabetes, hyperglycemia, gallbladder issues

For more information or to schedule an appointment with Dr. Friedman, go to goodhormonehealth.com

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Osilodrostat Resolves Most Physical Signs of Cushing’s Disease

Posted on May 18, 2022 by MaryO

— More than half of patients saw physical manifestations fully resolve by week 72

by Kristen Monaco, Staff Writer, MedPage Today May 16, 2022

SAN DIEGO — Osilodrostat (Isturisa) improved many physical features associated with Cushing’s disease, according to additional findings from the phase III LINC-3 study.

Among 137 adults with Cushing’s disease, a 39.5% improvement in central obesity scores was observed from baseline to week 72 with osilodrostat, reported Alberto Pedroncelli, MD, PhD, of Recordati AG in Basel, Switzerland.

Not only was central obesity the most common physical manifestation associated with hypercortisolism among these Cushing’s disease patients, but it was also more frequently rated as severe at baseline, Pedroncelli explained during the American Association of Clinical Endocrinology (AACE) annual meeting.

Osilodrostat treatment also led to a 34.9% improvement in proximal muscle atrophy at week 72, along with a 34.4% improvement in hirsutism scores.

By week 72, nearly all physical manifestations of hypercortisolism saw significant improvement — marked by more than 50% of patients scoring these physical traits as nonexistent:

  • Dorsal fat pat: 50.6%
  • Central obesity: 30.6%
  • Supraclavicular fat pad: 51.8%
  • Facial rubor: 64.7%
  • Hirsutism in women: 53.1%
  • Proximal muscle atrophy: 61.2%
  • Striae: 63.5%
  • Ecchymoses: 87.1%

Most of these physical manifestation improvements were notable soon after treatment initiation with osilodrostat, Pedroncelli pointed out.

When stratified according to testosterone levels, hirsutism scores remained either stable or improved in the majority of patients who had normal or above normal testosterone levels. More women with normal testosterone levels over time experienced improvements in hirsutism versus those with levels above the upper limit of normal, who mostly remained stable.

Osilodrostat is an oral agent that was first FDA approved in March 2020 for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. Available in 1 mg, 5 mg, and 10 mg film-coated tablets, the drug acts as a potent oral 11-beta-hydroxylase inhibitor — the enzyme involved in the last step of cortisol synthesis.

Osilodrostat is taken orally twice daily, once in the morning and once in the evening.

Approval was based upon findings from the LINC-3 and LINC-4 trials, which found osilodrostat was able to normalize cortisol levels in 53% of patients, based on mean 24-hour urinary free cortisol (UFC) concentrations. During an initial 10-week randomization phase, 86% of patients maintained their complete cortisol response if they remained on osilodrostat versus only 29% of those who were switched to placebo.

As expected, 77.4% of the 137 adults included in the trial were women. The median participant age was 40 and about 47 months had passed since their initial diagnosis. A total of 87.6% underwent previous pituitary surgery and 16.1% underwent previous pituitary irradiation. At baseline, median and mean 24-hour UFC levels were 3.5 nmol and 7.3 nmol, respectively, based on two or three urine samples.

Participants had an average body weight of 176.4 lb, body mass index (BMI) of 30, and 41 in waist circumference at baseline. Throughout the trial, all measures dropped, reaching the nadir at week 72: body weight of 165 lb, BMI of 27, and 37.8 in waist circumference.

The most common side effects reported with the agent include adrenal insufficiency, fatigue, nausea, headache, and edema.

  • author['full_name']

    Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.

Disclosures

The study was supported by Recordati AG.

Pedroncelli reported employment with Recordati.

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Recordati Rare Diseases Announce Publication in the Journal of Clinical Endocrinology & Metabolism of the Phase III LINC 4 Study Confirming the Efficacy and Safety of Isturisa® (Osilodrostat) in Patients With Cushing’s Disease

Posted on April 2, 2022 by MaryO

The LINC 4 study demonstrated superiority of Isturisa® (osilodrostat) over placebo in achieving cortisol normalisation during the 12-week, double-blind, randomised phase (77% vs 8%, P<0.0001).

Isturisa provided rapid and sustained control of cortisol secretion in the majority of patients throughout the 48-week core phase of the study.

PUTEAUX, France, March 29, 2022–(BUSINESS WIRE)–Recordati Rare Diseases announce today the publication of positive results from the Phase III LINC 4 study of Isturisa in The Journal of Clinical Endocrinology & Metabolism.1 These data reinforce Isturisa as 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 augments the efficacy and safety data for Isturisa in patients with Cushing’s disease, confirming the results from the Phase III LINC 3 study. This study in 73 adults is the first Phase III study of a medical treatment in patients with Cushing’s disease to include an upfront, randomised, double-blind, placebo-controlled period during which 48 patients received Isturisa and 25 received placebo for the first 12 weeks, followed by an open-label period during which all patients received Isturisa until week 48; thereafter, patients could enter an optional extension phase.

Key findings published in the manuscript entitled ‘Randomised trial of osilodrostat for the treatment of Cushing’s disease’ include:1

  • LINC 4 met the primary endpoint: Isturisa was significantly superior to placebo at normalising mUFC at the end of a 12-week randomised, double-blind period (77% vs 8%; P<0.0001).
  • Effects of Isturisa were rapid. Over one-quarter of patients randomised to Isturisa achieved normal mUFC as early week 2 and 58% achieved control by week 5.
  • The key secondary endpoint was also met, with 81% of all patients in the study having normal mUFC at week 36.
  • Improvements in cardiovascular and metabolic parameters of Cushing’s disease, including blood pressure and blood glucose metabolism, were seen by week 12 and were maintained throughout the study.
  • Physical features of hypercortisolism improved during Isturisa treatment, including fat pads, facial rubor, striae, and muscle wasting. Improvements were observed by week 12, with continued improvement throughout the study to week 48.
  • Patient-reported QoL scores (CushingQoL and Beck Depression Inventory) also improved during Isturisa treatment.
  • Isturisa was well tolerated in the majority of patients, with no unexpected adverse events (AEs). The most common AEs overall were decreased appetite, arthralgia, fatigue and nausea.

“These results show convincingly 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 lowered cortisol excretion to normal in most patients with Cushing’s disease and maintained normal levels throughout the core phase of the study. Importantly, this normalisation 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 & Endocrinology in 2020,4 demonstrating that Isturisa enables most patients with Cushing’s disease to gain rapid control of their cortisol levels, which in turn provides relief from a host of undesirable symptoms,” said Alberto Pedroncelli, Clinical Development & Medical Affairs Lead, Global Endocrinology, Recordati AG. “Recordati Rare Diseases is committed to improving the lives of patients with this rare, debilitating and life-threatening condition. I would like to thank everyone who has contributed to LINC 4 and the LINC clinical programme.”

“I had Cushing’s disease for 8 years without being diagnosed,” said Thérèse Fournier from L’association “Surrénales”. “I was trapped in a vicious circle of missed diagnoses and worsening physical and psychological symptoms that became life-threatening. I lost everything – my job, my house, my partner, my friends – I was isolated. When I finally received my diagnosis, I was relieved because I knew the truth. Since my surgery, I have been learning to live again, enjoying the moments that make a life. I am still on the path to remission, but I feel deeply happy, even if I carry this journey that nobody can understand.”

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.5 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.5,6 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 QoL and increase the risk of mortality.3,6 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.8

About LINC 4
LINC 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 an mUFC ≤ULN at week 36.1,9

About Isturisa®
Isturisa® is an oral inhibitor of 11β-hydroxylase (CYP11B1), which catalyses the final 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® was granted marketing authorisation by the European Commission on 9 January 2020. For detailed recommendations on the appropriate use of this product, please consult the summary of product characteristics.2

References

1. Gadelha M, Bex M, Feelders RA et al. Randomised trial of osilodrostat for the treatment of Cushing’s disease. J Clin Endocrinol Metab 2022; dgac178, https://doi.org/10.1210/clinem/dgac178.
2. Isturisa® summary of product characteristics. May 2020.
3. Ferriere A, Tabarin A. Cushing’s syndrome: Treatment and new therapeutic approaches. Best Pract 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 multicentre phase III study with a double-blind, randomised 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: An Endocrine Society clinical practice guideline. 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 headquarter offices in Milan, Italy.

For a full list of products, please click here: www.recordatirarediseases.com/products.

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 in Europe, Russia and the other C.I.S. countries, Ukraine, 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 2021 was € 1,580.1 million, operating income was € 490.2 million and net income was € 386.0 million.

For further information:

Recordati website: www.recordatirarediseases.com

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 advertising.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220325005169/en/

Contacts

Celine Plisson, MD
Medical Affairs Director
Telephone: +33(0)147739463
Email: PLISSON.C@recordati.com

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More Gradual Dose Titration Could Reduce Hypocortisolism Risk with Osilodrostat in Cushing’s Disease

Posted on June 3, 2021 by MaryO

Data from LINC3 and LINC4 provide insight into the impact of dosing titration schedules on risk of hypocortisolism-related adverse events associated with osilodrostat use in patients with Cushing’s disease.

Data from a pair of phase 3 studies presented at the American Academy of Clinical Endocrinology’s 30th Annual Meeting (AACE 2021) is providing insight into the effect of dose titration schedules with use of osilodrostat (Isturisa) in patients with Cushing’s disease.

Presented by Maria Fleseriu, MD, of Oregon Health and Science University, the analysis of the LINC3 and LINC4 demonstrated the more gradual titration occurring in LINC4 resulted in a lower proportion of hypocortisolism-related adverse events, suggesting up-titration every 3 weeks rather than every 2 weeks could help lower event risk without compromising mean urinary free cortisol (mUFC) control.

“For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response/tolerability aimed at normalizing cortisol levels,” concluded investigators.

With approval from the US Food and Drug Administration in March 2020 for patients not eligible for pituitary surgery or have undergone the surgery but still have the disease, osilodrostat became the first FDA-approved therapy address cortisol overproduction by blocking 11β-hydroxylase. Based on results of LINC3, data from the trial, and the subsequent LINC4 trial, provide the greatest available insight into use of the agent in this patient population.

The study presented at AACE 2021 sought to assess whether slow dose up titration might affect rates of hypocortisolism-related adverse events by comparing titration schedules from both phase 3 trials. Median osilodrostat exposure was 75 (IQR, 48-117) weeks and 70 (IQR, 49-87) weeks in LINC3 and LINC4, respectively. The median time to first mUFC equal to or less than ULN was 41 (IQR, 30-42) days in LINC3 and 35 (IQR, 34-52) days in LINC4.

Adverse events potentially related to hypocortisolism were more common among patients in LINC3 (51%, n=70) than LINC4 (27%, n=20). Upon analysis of adverse events, investigators found the most commonly reported type of adverse event was adrenal insufficiency, which included events of glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased urinary free cortisol.

Results incited the majority of hypocortisolism-related adverse events occurred during the dos titration periods of each trial. In LINC3, 54 of the 70 (77%) hypocortisolism-related adverse events occurred by week 26. In comparison, 58% of hypocortisolism-related adverse events occurring in LINC4 occurred prior to week 12. Investigators noted most of events that occurred were mild or moderate and managed with dose interruption or reduction of osilodrostat or concomitant medications.

This study, “Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients with Cushing’s Disease (CD): Results from Two Phase III Trials (LINC3 and LINC4),” was presented at AACE 2021.

From https://www.endocrinologynetwork.com/view/fda-panels-votes-to-support-teplizumab-potential-for-delaying-type-1-diabetes

Filed under: AACE 2021, American Academy of Clinical Endocrinology, Cushing's, Helpful Doctors, pituitary, Treatments | Tagged: , , , , , , , , | Leave a comment »

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