Clinical Data Analysis on Terlipressin Presented at The Liver Meeting®

-- Data Show Small Improvements in Serum Creatinine (SCr) Associated with Increased Survival of Hepatorenal Syndrome Type 1 (HRS-1) Patients --

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Mallinckrodt plc

Nov 16, 2016, 04:30 ET

CHESTERFIELD, United Kingdom, Nov. 16, 2016 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today announced results of a post-hoc analysis of terlipressin clinical trial data presented at The Liver Meeting^®1 — the 67th Annual Meeting of the American Association for the Study of Liver Diseases, held Nov. 11–15, 2016 in Boston, Mass.

Terlipressin is being investigated for the treatment of HRS-1, an acute, rare and life-threatening condition requiring hospitalization, with currently no approved therapy in the U.S. or Canada. Terlipressin is approved for use in countries outside the U.S., including several in Europe.^2,3,4,5

The Mallinckrodt-sponsored analysis, titled "Time for a New, More Inclusive Endpoint for Treatment of HRS-1? Small Changes in SCr of >20% Are Equivalent to HRS Reversal in Predicting Survival and Need for Renal Replacement Therapy During Treatment of HRS-1 With Terlipressin and Albumin," analyzed findings from the largest prospective data set from two previously completed [and published] studies evaluating terlipressin used in patients with HRS-1.^6,7 Data were available for 308 patients with well-characterized HRS-1 from the two studies.

"Patients diagnosed with HRS-1 typically have a very poor prognosis, and there is a significant unmet need for an approved treatment," said Steven Romano, M.D., Chief Scientific Officer and Executive Vice President, Mallinckrodt. "This analysis underscores the clinical relevance of improvement in renal function in HRS-1 patients and supports our ongoing CONFIRM clinical trial,⁸ which is evaluating terlipressin as a potentially important therapy for U.S. patients."

Study Methods
Data were analyzed for the predictive value of HRS-1 reversal (20% or 30% improvement in SCr) for survival and the use of Renal Replacement Therapy (RRT). Positive predictive value (PPV), negative predictive value (NPV), accuracy, sensitivity, and specificity were determined using standard definitions. Receiver operator curves (ROCs) were generated for overall survival by improvement in SCr from baseline to the end of treatment and HRS-1 reversal by improvement in SCr from baseline to end of treatment. Youden's index as an estimate of optimal cutoff for the ROCs was derived using the standard formula (Youden index = sensitivity + specificity – 1).⁹

Study Results
Improvement in SCr had similar PPV, NPV, sensitivity, and specificity as HRS-1 reversal in predicting survival; HRS-1 reversal and improvement in SCr were similarly accurate in predicting the use of RRT. The number of patients achieving at least a 20% improvement in SCr was twice that of those achieving HRS-1 reversal in these two large studies. Small improvements in SCr of 15% were associated with increased survival; an improvement in SCr of 40% was the optimal cutoff for achieving HRS-1 reversal. More specific analysis results follow:

64 patients (21%) achieved HRS-1 reversal and 118 patients (38%) had at least a 20% fall in SCr.
A 20% reduction in SCr gave predictive, sensitivity and specificity values that were similar to HRS-1 reversal for survival; 30% improvement in SCr did not increase accuracy.
For RRT, results were similar; HRS-1 reversal was somewhat more accurate in predicting the use of RRT.
HRS-1 reversal or improvement in SCr reduced the use of RRT from 50‒56% to 9‒12%.
The number of patients achieving ≥20% improvement in SCr was twice that of those achieving HRS-1 reversal in these two large studies.
The highest values for the Youden index for overall survival was 0.353, suggesting an optimal cutoff of 15% improvement in SCr from baseline to end of treatment. The highest value of the Youden index for HRS-1 reversal was 0.896, suggesting an optimal cutoff of 40% improvement in SCr from baseline to end of treatment.

Study Limitations
This study is a post-hoc analysis of completed clinical trials.

The study abstract can be accessed here (abstract 2071). The poster is available on the Mallinckrodt website.

About Hepatorenal Syndrome
HRS type 1 is characterized by a rapid, progressive renal impairment and has a very poor prognosis, with >80% mortality within three months. HRS is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease and portal hypertension. At present, there are no approved drug therapies for HRS type 1 in the U.S. or Canada. The only curative treatment for HRS type 1 and the underlying end-stage cirrhosis is liver transplantation. However, more patients will not survive long enough to receive a liver transplant.

About Terlipressin
Terlipressin is a synthetic vasopressin analogue in development for the treatment of HRS type 1 in the U.S. and Canada.

ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical and biopharmaceutical products and therapies, as well as nuclear imaging products. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and hemostasis products; and central nervous system drugs. The company's core strengths include the acquisition and management of highly regulated raw materials and specialized chemistry, formulation and manufacturing capabilities. The company's Specialty Brands segment includes branded medicines; its Specialty Generics segment includes specialty generic drugs, active pharmaceutical ingredients and external manufacturing; and the Nuclear Imaging segment includes nuclear imaging agents. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

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¹ Copyright & Trademark. The American Association for the Study of Liver Diseases (AASLD). Available at: http://www.aasld.org/copyright-trademark. Accessed November 15, 2016.
² Nadim, M., et al. Management of the critically ill patient with cirrhosis: A multidisciplinary perspective. Journal of Hepatology. 2016, vol. 64, 717–735.
³ Angeli, P., et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites. Journal of Hepatology. 2015, vol. 62, 968–974.
⁴ Nadim, M., et al. Hepatorenal syndrome: the 8th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2012 16:R23.
⁵ European Association for the Study of the Liver clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology. 2010, vol. 53, 397–417.
⁶ Boyer TD, Sanyal AJ, Wong F, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150:1579-1589.
⁷ Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368.
⁸ A Study To Confirm Efficacy and Safety of Terlipressin in HRS Type 1. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02770716. Accessed November 15, 2016.
⁹ ROC Curves in NCSS. NCSS Statistical Software Web Site. Available at: https://www.ncss.com/software/ncss/roc-curves-ncss/. Accessed November 15, 2016.