STAINES-UPON-THAMES, United
Kingdom, Nov. 11, 2019
/PRNewswire/ -- Mallinckrodt
plc (NYSE: MNK), a global biopharmaceutical company, today
announced results from its pivotal Phase 3 CONFIRM study to assess
the efficacy and safety of its investigational agent terlipressin
in adults with hepatorenal syndrome type 1 (HRS-1). HRS-1 is an
acute and life-threatening syndrome involving acute kidney failure
in people with cirrhosis.1 Results were reported during
a late-breaking abstract presentation today at The Liver
Meeting® 2019, the annual meeting of the American
Association for the Study of Liver Diseases (AASLD), in
Boston. The CONFIRM abstract was
also selected by AASLD for inclusion in its prestigious "Best of
the Liver Meeting" educational program in the portal
hypertension/cirrhosis category.
In the 35-month study period, 300 patients from the U.S. (89
percent) and Canada (11 percent)
participated in the largest-ever prospective, multi-center
randomized controlled clinical trial in HRS-1. Patients in
the study were critically ill, as indicated by assessments of their
liver and kidney function at the start of the trial. Patients in
the trial had a mean Model for End-Stage Liver Disease (MELD) score
of 33; a mean serum creatinine (SCr) level of 3.5 mg/dL; and 61
percent were categorized as Child-Pugh Class C.2
The study met its primary endpoint of Verified HRS Reversal
(VHRSR), which is defined as renal function improvement, avoidance
of dialysis and short-term survival. 29.1 percent (58/199) of
patients administered terlipressin plus albumin achieved
Verified HRS Reversal versus 15.8 percent (16/101) on placebo plus
albumin (p=0.012). In order to achieve Verified HRS Reversal,
patients had to have two consecutive SCr values ≤1.5 mg/dL, at
least two hours apart by day 14 or hospital discharge, and be alive
without intervening renal replacement therapy (RRT) for at least 10
days following discharge or treatment.2
"HRS-1 is a rapidly progressing and often fatal disease that is
extremely difficult to diagnose and treat, and many patients don't
live beyond a few weeks without treatment. The results from the
CONFIRM trial are very encouraging, and show terlipressin, if
approved, has the potential to reverse the course of HRS-1 as
measured by renal function improvement, avoidance of dialysis and
short-term survival," said presenting author Florence Wong, MBBS, MD, FRACP, FRCPC,
hepatologist at Toronto General
Hospital, and professor of Medicine at the University of Toronto. "These results provide
important information that may help the healthcare community better
manage this critically ill and underserved patient population."
HRS-1 has a median survival time of less than two weeks and
greater than 80 percent mortality within three months if left
untreated.3,4 At present, there are no approved
drug therapies for HRS-1 in the U.S.
or Canada.5 HRS-1 is estimated to affect
between 30,000 and 40,000 patients in the U.S.
annually.6,7 Terlipressin is
an investigational product and its safety and effectiveness have
not yet been established by the U.S. FDA or Health Canada. The
company plans to submit a New Drug Application to the U.S.
Food and Drug Administration (FDA) in the first half of
2020.
"We are grateful to all the patients and investigators who
participated in the CONFIRM trial and greatly encouraged by the
positive results, which demonstrated that terlipressin may have a
potential impact on the progressively worsening kidney function
that is the hallmark of HRS-1," said Steven Romano, M.D., Executive Vice President
and Chief Scientific Officer at Mallinckrodt. "Today marks
the culmination of a long clinical development journey led by our
passionate, dedicated clinical development team. The results from
this largest-ever prospective phase 3 clinical trial in HRS-1
provide meaningful insight into the management of HRS-1 in clinical
practice."
CONFIRM Study Key Findings2
- The study met its primary endpoint of Verified HRS
Reversal, defined as two consecutive SCr values ≤1.5 mg/dL, at
least two hours apart by day 14 or discharge, with subjects alive
without RRT for at least 10 days after the second SCr ≤1.5
mg/dL.
-
- 29.1 percent (n=58) of patients treated with terlipressin plus
albumin compared to 15.8 percent (n=16) of patients treated with
placebo plus albumin (p=0.012) achieved Verified HRS Reversal.
- The four pre-specified secondary endpoints of the study
were:
-
- HRS reversal: 36.2 percent (n=72) of patients in the
terlipressin group demonstrated HRS reversal, defined as the
percentage of participants with a SCr value no more than 1.5 mg/dL
by day 14 or discharge versus 16.8 percent (n=17) on placebo
(p<0.001).
- Durability of/maintaining HRS reversal: 31.7 percent of
patients receiving terlipressin (n=63) maintained HRS reversal
without RRT/dialysis up to day 30 versus 15.8 percent (n=16) in the
placebo group (P<0.003).
- HRS reversal in the systemic inflammatory response syndrome
(SIRS) subgroup: 33.3 percent (28/84) of patients with SIRS in
the terlipressin arm achieved Verified HRS reversal versus 6.3
percent (3/48) in the placebo arm (p<0.001).
- Verified HRS Reversal without HRS recurrence by day 30:
24.1 percent (n=48) of patients on terlipressin and 15.8 percent
(n=16) of patients in the placebo group (p=0.092) achieved Verified
HRS Reversal without recurrence by day 30.
- Adverse events (AEs) were similar in both groups. Serious AEs
were reported in 65 percent (n=130) of subjects in the terlipressin
group and 60.6 percent (n=60) in the placebo group. The most
commonly reported serious AEs included respiratory failure, which
occurred in 10 percent of the terlipressin group and 3 percent of
the placebo group; and abdominal pain, which occurred in 5 percent
of the terlipressin group and 1 percent of the placebo group. The
most commonly reported AEs included abdominal pain, which occurred
in 19.5 percent of the terlipressin group and 6.1 percent of the
placebo group; and nausea, which occurred in 16 percent of the
terlipressin group and 10.1 percent of the placebo group.
Ischemia-associated AEs occurred in 4.5 percent of the terlipressin
group and 0 percent in the placebo group. No new or unexpected AEs
were reported.
About the Pivotal Phase 3 CONFIRM Study (multi-center,
randomized, placebo-controlled, double-blind trial in the U.S. and
Canada):2
- The trial was designed to confirm efficacy and safety of
terlipressin for the treatment of HRS-1
- CONFIRM is the largest prospective trial ever conducted (n=300)
in HRS-1 patients
- Eligibility criteria included adults with liver cirrhosis and
ascites with rapidly worsening renal function and no response to
diuretic withdrawal or volume expansion with albumin
- Subjects were randomized in a 2:1 ratio to receive terlipressin
plus albumin (n=199) or placebo plus albumin (n=101)
- The primary endpoint of Verified HRS Reversal evaluated renal
function improvement, avoidance of dialysis and short-term
survival.
Find out more information about the CONFIRM
trial here on the ClinicalTrials.gov website.
About Terlipressin
Terlipressin is a potent, vasopressin analogue selective for V1
receptors being investigated for the treatment of HRS-1 in the U.S.
and Canada. It is an investigational product in these
countries as the 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.
ABOUT MALLINCKRODT
Mallinckrodt is a global business consisting of multiple
wholly owned subsidiaries that develop, manufacture, market and
distribute specialty pharmaceutical products and therapies. The
company's Specialty Brands reportable segment's 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. Its Specialty Generics
reportable segment includes specialty generic drugs and active
pharmaceutical ingredients. 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 with regard to
terlipressin and the study described in this release, including its
potential impact on patients. 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.
CONTACT
For Trade Media Inquiries
Caren Begun
Green Room Communications
201-396-8551
caren@greenroompr.com
For Financial/Dailies Media Inquiries
Daniel Yunger
Kekst CNC
212-521-4879
mallinckrodt@kekstcnc.com
Investor Relations
Daniel J. Speciale, CPA
Vice President, Investor Relations and IRO
314-654-3638
daniel.speciale@mnk.com
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.
©2019 Mallinckrodt. US-1901762 11/19
References
1 National Organization for Rare Disorders.
Hepatorenal Syndrome. Available
at: https://rarediseases.org/rare-diseases/hepatorenal-syndrome/.
Accessed April 9, 2019
2 Data on file. Mallinckrodt Hospital Products, Inc.
3 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.
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 C Pant, B S Jani, M Desai, A Deshpande,
Prashant Pandya, Ryan Taylor, R Gilroy, M Olyaee. Hepatorenal
syndrome in hospitalized patients with chronic liver disease:
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Med 2016;64:33–38.
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