RECORDATI RARE DISEASES ANNOUNCES PUBLICATION OF LONG-TERM OUTCOMES FROM THE EXTENSION TO THE PHASE III LINC 3 STUDY OF ISTURISA® (OSILODROSTAT) IN PATIENTS WITH CUSHING'S DISEASE IN THE EUROPEAN JOURNAL OF ENDOCRINOLOGY

Long-term findings from the multicenter, international LINC 3 study demonstrated that treatment with ISTURISA® (osilodrostat) maintained cortisol normalization and was well tolerated in most patients with Cushing's disease.

LEBANON, N.J., Aug. 31, 2022 /PRNewswire/ -- Recordati Rare Diseases Inc. announces the publication of the long-term outcomes from the open-label extension period of the Phase III LINC 3 study of ISTURISA in The European Journal of Endocrinology.¹ These data support the long-term utility of ISTURISA in the maintenance treatment of patients with Cushing's disease and reinforce ISTURISA as an effective and well-tolerated oral therapy. ISTURISA is indicated in the United States for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.² Cushing's disease is a rare and debilitating condition of hypercortisolism that is caused by a pituitary adenoma.³

The Phase III LINC 3 study was the largest prospective trial of an adrenal steroidogenesis inhibitor to date. In total, 106 of the 113 patients who completed the 48-week core phase opted to continue receiving open-label ISTURISA during the extension phase, which ended after all patients completed ≥72 weeks of treatment or had discontinued the study. Median duration of exposure to ISTURISA from core study baseline to end of the extension was 130 weeks (range 1–245).

Key findings published in the manuscript entitled 'Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension' include:¹ 

• The normalization in mean urinary free cortisol (mUFC) achieved during the core phase was maintained, with mean mUFC ≤ upper limit of normal (ULN) throughout the extension; at
  week 72, 86/106 (81.1%) patients had mUFC ≤ULN
• The median average ISTURISA dose from core study start to end of the extension was
  7.4 mg/day (range 0.8–46.6); dose received stabilized during the extension, indicating that ISTURISA treatment provided a sustained response without need for up-titration over time.
• Observed improvements in most cardiovascular and metabolic-related parameters associated with Cushing's disease at the end of the core study were maintained or further improved with long-term treatment.
• Patient-reported quality of life (QoL) scores (CushingQoL and Beck Depression Inventory) also continued to improve during long-term treatment.
• Improvements in physician-rated severity scores for physical manifestations of hypercortisolism were evident within 12 weeks of ISTURISA treatment; the proportion of patients rated with an improvement was maintained or increased with longer follow-up, including improvement in hirsutism in female patients.
• In female patients, estradiol and testosterone levels tended to return to baseline levels with longer follow-up.
• ISTURISA was well tolerated in most patients, with no unexpected adverse events (AEs) compared with that observed in the core phase; AEs of special interest including hypocortisolism-related and adrenal hormone precursor-related AEs were generally less frequently reported during the extension phase than the core.
• The most common AEs regardless of study drug relationship were nausea (45.3%), headache, (36.5%) and fatigue (32.8%).

"Findings from our large trial, where patients with Cushing's disease opted to continue treatment with osilodrostat during the extension, support osilodrostat as an effective, long-term treatment option for patients with this chronic disease," said Maria Fleseriu, Professor of Medicine (Endocrinology) and Neurological Surgery and Director of the Pituitary Center at Oregon Health & Science University, Portland, OR, USA. "Importantly, as well as providing long-term normalization of cortisol, continued treatment with osilodrostat for over 72 weeks led to sustained improvements in clinical signs and physical manifestations of hypercortisolism and was generally well tolerated."

"These data support Isturisa as a viable long-term medical therapy option to maintain control of cortisol levels and signs and symptoms related to hypercortisolism in patients with Cushing's disease, building on the core phase of the positive Phase III LINC 3 study, published in The Lancet Diabetes & Endocrinology in 2020,⁴" said Alberto M. Pedroncelli, Clinical Development & Medical Affairs Head, Global Endocrinology, Recordati AG. "Recordati Rare Diseases is committed to improving the lives of patients with this rare, debilitating and life-threatening condition. On behalf of Recordati Rare Diseases, I would like to extend our thanks to all those who have contributed to LINC 3 and the LINC clinical development program."

The full publication can be found here.

Indications and usage 
ISTURISA (osilodrostat) 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.

• Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.

Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc). Monitor 24-hour urinary free cortisol, serum or plasma cortisol, and patient's signs and symptoms periodically during ISTURISA treatment.

Decrease or temporarily discontinue ISTURISA if urinary free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA. Please see section 5.1 of full Prescribing Information.

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

• QTc prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring. Please see section 5.2 of full Prescribing Information.

• Elevations in adrenal hormone precursors and androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur. Please see section 5.3 of full Prescribing Information.

• Most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.

• To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• CYP3A4 inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
• CYP3A4 and CYP2B6 inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.

• Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least 1 week after treatment.

Please refer to full Prescribing Information.

Cushing's disease is a form of Cushing's syndrome, in which chronically elevated cortisol levels is triggered by a pituitary adenoma secreting excess adrenocorticotropic hormone (ACTH).⁵ It is a rare, serious and difficult-to-treat disease that affects approximately one to two patients per million per year. Prolonged exposure to elevated cortisol levels is associated with considerable morbidity, mortality and impaired QoL as a result of complications and comorbidities.⁶ Normalization of cortisol levels is therefore a primary objective in the treatment of Cushing's disease.⁷

LINC 3 is a prospective, multicenter, 48-week trial with an 8-week, double-blind, randomized withdrawal phase, with optional extension phase to evaluate the safety and efficacy of ISTURISA in patients with Cushing's disease. Assessment of mUFC response rate, change in mUFC, change in cardiovascular and metabolic-related parameters, change in patient-reported outcomes, changes in physical manifestations of hypercortisolism as well as general AEs and AEs of special interest were included as secondary endpoints. LINC 3 enrolled 137 patients with persistent or recurrent Cushing's disease or those with de novo disease who were not candidates for surgery.⁴

ISTURISA is a cortisol synthesis inhibitor that works by inhibiting 11-beta-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. ISTURISA is 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.² In March 2020, the FDA granted marketing authorization for ISTURISA in the United States. For more information visit www.isturisa.com.

References

1. Fleseriu M, Newell-Price J, Pivonello R et al. Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension The European Journal of Endocrinology 2022.
2. Isturisa® US prescribing information. March 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. 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.

Recordati Rare Diseases Inc. is a biopharmaceutical company committed to providing often-overlooked orphan therapies to the underserved rare disease communities of the United States.

Recordati Rare Diseases is a part of 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. Recordati Rare Diseases' mission 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.

The company's U.S. corporate headquarters is located in Lebanon, NJ, with global headquarter offices located in Milan, Italy.

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

Recordati website: https://www.recordatirarediseases.com/us

Company contact
Peter Strauss
Vice President, Commercial Operations
(908) 721-1559
e-mail: [email protected]

Media contact
Michele Parisi
(925) 864-5028
e-mail: [email protected]

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.

PP-IST-US-0291

SOURCE Recordati Rare Diseases