Mallinckrodt Presents Terlipressin Clinical Data at The Liver Meeting® 2018

- In Post-Hoc Pooled Analysis of North American Studies, Investigational Agent Terlipressin Associated With Improvement in Survival in Patients with Hepatorenal Syndrome Type 1 with Low Baseline Mean Arterial Pressure -

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Mallinckrodt plc

Nov 09, 2018, 08:09 ET

STAINES-UPON-THAMES, United Kingdom, Nov. 9, 2018 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today announced results of a pooled analysis¹ of terlipressin clinical trial data in patients with hepatorenal syndrome type 1 (HRS-1) at The Liver Meeting^®2018, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), held Nov. 9-13 in San Francisco.

The post-hoc pooled analysis of data from two previously completed Phase 3, randomized, double-blind, placebo-controlled studies conducted in North America showed that treatment with terlipressin was associated with improved overall and transplant-free survival in HRS-1 patients with lower baseline mean arterial pressure (MAP). This effect was seen independent of HRS reversal, and may relate to a marked improvement in MAP and renal function in this patient group following administration of terlipressin.

MAP is calculated using systolic and diastolic blood pressure, and can ascertain whether there is enough blood flow, resistance and pressure to supply blood to all major organs. Low MAP is common in patients with decompensated cirrhosis and HRS-1 in the absence of overt shock, and indicates a more progressed liver disease.

Terlipressin is being investigated for the treatment of HRS-1, a rare, acute, rapidly progressing and life-threatening complication of liver cirrhosis that leads to renal failure. The safety and effectiveness of terlipressin have not yet been established by the U.S. Food and Drug Administration (FDA). There are no currently approved drug therapies for HRS-1 in the U.S. or Canada.

"Patients with HRS-1 have an extremely poor prognosis and often progress to life-threatening renal failure within days,² and we remain committed to investigating the potential clinical utility of terlipressin for these patients," said Steven Romano, M.D., Chief Scientific Officer and Executive Vice President, Mallinckrodt. "This pooled analysis of data from these two previously completed Phase 3 studies of more than 300 patients provides additional insights regarding the potential effect of terlipressin on key outcomes in patients with low baseline MAP. We also continue to evaluate terlipressin in our ongoing Phase 3 trial, the CONFIRM study."

"Terlipressin Treatment Is Associated With Significantly Increased Survival in Patients With Hepatorenal Syndrome Type 1 (HRS-1) and Low Baseline Mean Arterial Pressure (MAP), Independent of HRS Reversal" – the Mallinckrodt-sponsored analysis – sought to characterize the relationship between low baseline MAP and improved survival in patients with HRS-1 treated with terlipressin in the REVERSE and OT-0401 trials, which both showed that terlipressin improved renal function when administered concomitantly with albumin compared with placebo plus albumin in patients with HRS-1 and cirrhosis. Low MAP was defined as < 65mmHg.

Study Methods
Data from the two Phase 3 studies, REVERSE and OT-0401, of 307 patients with HRS-1 were pooled and analyzed. In both studies, patients received terlipressin or placebo plus albumin intravenously every six hours for up to 14 days. This pooled analysis compared terlipressin and placebo in two groups of patients: one with MAP <65 mm Hg; and a second group with MAP ≥65 mm Hg. The analysis included an assessment of overall survival; transplant-free survival; HRS reversal, defined as serum creatinine (SCr) value of ≤1.5 mg/dl; and change in SCr from baseline through end of treatment.

Key Findings
The pooled analysis of REVERSE and OT0401 clinical data showed:

Overall survival at 90 days in the MAP <65 mm Hg group was significantly higher among patients receiving terlipressin (17/25 [68.0%]) versus placebo (6/25 [24.0%]): survival estimate was 0.680 versus 0.209, respectively; P=.005.
No difference in overall survival at 90 days was observed between terlipressin (66/128 [51.6%]) and placebo (72/129 [55.8%]) in the MAP ≥65 mm Hg group: survival estimate was: 0.515 versus 0.554, respectively; P=.429.
Transplant-free survival at 90 days in the MAP <65 mm Hg group was significantly higher among patients receiving terlipressin (17/25 [68.0%]) versus placebo (7/25 [28.0%]): transplant-free survival estimate was: 0.618 versus 0.083, respectively; P=.015.
In the MAP ≥65 mm Hg group, no difference in transplant-free survival at 90 days was observed between terlipressin (67/128 [52.3%]) and placebo (76/129 [58.9%]): transplant-free survival estimate was: 0.404 versus 0.444, respectively; P=.291.
Rates of HRS reversal among patients receiving terlipressin were similar between the MAP <65 mm Hg and ≥65 mm Hg groups; the proportion of patients with HRS reversal in the MAP ≥65 mm Hg group was significantly higher among patients receiving terlipressin than among those receiving placebo.
Improvement in SCr from baseline to end of treatment was significantly greater with terlipressin than with placebo in both MAP groups; however, the degree of improvement was lower in the MAP ≥65 mm Hg group.

Study Limitations
This study is a post-hoc pooled analysis of completed clinical trials. Results were based on a statistical model that was not specified before the data were seen. Appropriately designed randomized, prospective studies are needed to determine the efficacy of terlipressin in this patient population, such as the company's ongoing Phase 3 study of terlipressin in HRS-1, known as The CONFIRM Study. Details on The CONFIRM Study can be found on clinicaltrials.gov.

Find The Liver Meeting study abstract online (abstract #959). Details on the analysis can be found on Mallinckrodt's website.

About Hepatorenal Syndrome Type 1
Hepatorenal Syndrome Type 1 (HRS-1) is a rare condition characterized by the development of rapid kidney failure in patients with advanced chronic liver disease.³ HRS-1 has a very poor prognosis, with a median survival time of less than two weeks and greater than 80 percent mortality within three months.^2,4 At present, there are no approved drug therapies for HRS-1 in the U.S. or Canada.⁵ The only curative treatment for the underlying end-stage liver disease (cirrhosis) is liver transplantation.³ However, many patients will not survive long enough to receive a liver transplant.⁶

About Terlipressin
Terlipressin is a V1 selective vasoconstrictor being investigated for the treatment of HRS-1 in the U.S. and Canada. Safety and efficacy have not been established with, nor has approval been granted by regulatory authorities in either country. Terlipressin is approved for use outside the U.S. and Canada, including in Europe, Latin America, Asia and Australia.

ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. 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 gastrointestinal products. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.

CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS
This release includes forward-looking statements concerning terlipressin, including potential benefits associated with its use. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.

CONTACTS
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Meredith Fischer
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Investor Relations
Daniel J. Speciale, CPA
Investor Relations and Strategy Officer
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Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners.

¹ Pappas SC, Wong F, Escalante S, Teuber P, Jamil K. Terlipressin Treatment Is Associated With Significantly Increased Survival in Patients With Hepatorenal Syndrome Type 1 (HRS-1) and Low Baseline Mean Arterial Pressure (MAP), Independent of HRS Reversal. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) (The Liver Meeting^® 2018), November 9-13, 2018, San Francisco, CA. https://plan.core-apps.com/tristar_aasld18/abstract/3b9b2f3af8aefb4e9fba71511d9ba603
² Colle I and Laterre PF. Hepatorenal syndrome: the clinical impact of vasoactive therapy, Expert Review of Gastroenterology & Hepatology. (2018) 12:2, 173-188, DOI: 10.1080/17474124.2018.1417034.
³ National Organization for Rare Disorders. Hepatorenal Syndrome. Available at: https://rarediseases.org/rare-diseases/hepatorenal-syndrome/. Accessed October 29, 2018.
⁴ Gines P, Sola E, Angeli P, et al. Hepatorenal syndrome. Nature Reviews. (2018) 4:23.
⁵ Boyer TD, Medicis JJ, Pappas SC, et al. A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access Journal of Clinical Trials 2012:4. https://www.dovepress.com/a-randomized-placebo-controlled-double-blind-study-to-confirm-the-reve-peer-reviewed-article-OAJCT.
⁶ Rice JB, White AG, Galebach P, et al. The burden of hepatorenal syndrome among commercially insured and Medicare patients in the United States, Current Medical Research and Opinion (2017), DOI: 10.1080/03007995.2017.1331211.