– Findings from two clinical study presentations in adults with
HRS involving rapid reduction in kidney function1
provide insight into the appropriate use of terlipressin for the
care of critically ill patients2,3 –
DUBLIN, May 8, 2023
/PRNewswire/ -- Mallinckrodt
plc (NYSE American: MNK), a global specialty pharmaceutical
company, today announced the presentation of results from two
clinical studies for adults with hepatorenal syndrome (HRS) with
rapid reduction in kidney function1 treated with
TERLIVAZ® (terlipressin) for injection at Digestive
Disease Week® (DDW) 2023, taking place in Chicago, Ill. from May
6-9. Mallinckrodt's pooled
analysis of three North American Phase III studies on the incidence
of adverse events (AEs) related to bradycardia and arrhythmias in
adults with HRS treated with terlipressin was awarded Poster of
Distinction status from DDW, and was presented on Sunday, May 7, 2023, 12:30 – 1:30 p.m. CDT.2 Additionally,
Mallinckrodt's subgroup analysis of the
CONFIRM Phase III study to assess terlipressin treatment outcomes
in adults with HRS compounded by alcoholic hepatitis (AH) will be
presented in an oral lecture session today, May 8, 2023, 10:30 – 10:45
a.m. CDT.3
TERLIVAZ is the first and only FDA-approved product indicated
for the treatment of adults with HRS involving rapid reduction in
kidney function,1 an acute and life-threatening
condition requiring hospitalization.4 Terlipressin is
recommended by the American Association for the Study of Liver
Diseases (AASLD) guidance5 and the American College of
Gastroenterology (ACG) guidelines.6
Please see Limitation of Use and Important Safety
Information, including Boxed Warning, below.
Presented by Jasmohan S. Bajaj, School of Internal Medicine,
Virginia Commonwealth University,
Richmond, Va., the pooled analysis
(DDW Poster of Distinction: Su1535) used the
largest-to-date prospective database of three North American Phase
III, randomized, placebo-controlled trials (OT-0401, REVERSE,
CONFIRM) to evaluate the incidence of reported bradycardia and
arrhythmias in adult patients with HRS treated with terlipressin
vs. placebo. All three studies excluded patients with prior
arrhythmias and significant cardiovascular disease, and statistical
analysis was determined using a Fisher's Exact
test.2
Khurram Jamil, Vice President
& Head, Hepatology, Clinical Development & Critical Care at
Mallinckrodt, said, "We are
excited to share the results from this pooled analysis of the
largest HRS patient data set to-date, selected as a DDW 2023
Poster of Distinction, which bolsters our overall understanding
of TERLIVAZ® (terlipressin) for injection's
risk-benefit profile and the significance of adverse events such as
bradycardia and arrhythmias,2 to ultimately provide
continued support for the use of this treatment in appropriate
patients with HRS with rapid reduction in kidney
function.1"
The pooled safety population included 598 patients, of which 349
received terlipressin and 249 received placebo. The incidence of
episodes of bradycardia was higher in terlipressin-treated patients
(6.3%; n=22) compared with placebo-treated patients (0.8%; n=2;
P<0.001), and none of these episodes were considered serious.
Bradycardia was classified as severe per investigator assessment in
68.2% (n=15/22) of patients in the terlipressin group and in 100%
(n=2/2) of patients in the placebo group, and most patients did not
require a change in treatment dose (terlipressin: 72.7%; n=16/22
vs. placebo: 50%; n=1/2; P=0.507). One patient treated with
terlipressin had a dose interruption, and there were no treatment
discontinuations.2
Further, no differences were observed between treatment groups
(terlipressin: arrhythmia [0%, n=0/349,]; nodal arrhythmia [0%,
n=0/349]; ventricular fibrillation [0%, n=0/349] vs. placebo:
arrhythmia [0.8%, n=2/249, P=0.173]; nodal arrhythmia [0.4%, n=
1/249, P=0.416]; ventricular fibrillation [0.4%, n=1/249, P=0.416].
Atrial fibrillation was the most reported arrhythmia across the
pooled safety population (total: 4.0%, n=24/598; terlipressin:
3.7%, n=13/349; placebo: 4.4%, n=11/249; P=0.678).2
To be presented by Kevin
Korenblat, Washington University
School of Medicine, St. Louis,
Mo., the key findings of a subgroup analysis (DDW Oral
Lecture: 651) of the CONFIRM Phase III study aim to
evaluate efficacy of terlipressin treatment in patients with HRS
compounded by AH. Diagnosis of baseline AH was via investigator
assessment, and data was retrospectively analyzed in patients with
AH for verified HRS reversal (defined as the percentage of patients
with 2 serum creatinine (SCr) values of ≤1.5 mg/dL ≥2 hours apart,
while on treatment up to 72 hours after the last dose of study
drug), admission to the intensive care unit (ICU), length of ICU
stay, and incidence of renal replacement therapy (RRT) by Day
30.3
"The findings of this subgroup analysis of the CONFIRM Phase III
study build upon the growing body of evidence supporting the use of
TERLIVAZ® (terlipressin) for injection as a
treatment option among critical care patients with HRS, including
its therapeutic ability to drive meaningful clinical outcomes for a
significant population of patients with comorbid conditions, such
as alcoholic hepatitis,3" added Peter Richardson, MRCP (UK), Executive Vice
President & Chief Scientific Officer at Mallinckrodt. "As TERLIVAZ uptake and use among
U.S. hospitals continues following FDA approval in 2022, our
research at DDW 2023 reflects our ongoing commitment to critically
ill patients by pursuing research that provides physicians with the
most up-to-date treatment considerations to help inform patient
care decisions."
In CONFIRM (n=300), 41% (81/199) of patients in the terlipressin
group and 39% (39/101) of the patients in the placebo group had AH
at baseline. In the subgroup of patients with AH (n=120), the
median Maddrey discriminant function score was similar across
treatment groups (terlipressin: 96.9 vs. placebo: 97.7; P=0.681).
Verified HRS reversal was achieved in 30.9% (n=25/81) of patients
in the terlipressin group vs. 7.7% (n=3/39) in the placebo group
(P=0.005).3
Additionally, admission to the ICU was similar for patients in
the terlipressin and placebo groups (17.3%, n=14 vs. 17.9%, n=7),
whereas mean length of stay in the ICU was shorter for terlipressin
(6.9 days) vs. the placebo group (12.4 days). There was a numerical
decrease in RRT by Day 30 in the terlipressin group vs. the placebo
group (21%, n=17 vs. 25.6%, n= 10).3
These studies were sponsored by Mallinckrodt
Pharmaceuticals:
Presented Sunday, May 7, 2023; 12:30 – 1:30 p.m. CDT:
- Poster Su1535*: Low Incidence of Clinically
Significant Bradycardia and Arrhythmia in Patients with Hepatorenal
Syndrome Following Terlipressin Treatment: A Pooled Analysis of 3
North American Phase III Clinical Studies2
-
- Presenter: Jasmohan S. Bajaj, School of Internal
Medicine, Virginia Commonwealth
University, Richmond,
Va.
*Poster of Distinction
To be presented Monday, May 8, 2023; 10:30 – 10:45 a.m. CDT;
South Level, 402:
- Oral Lecture 651: Clinical Responses to Terlipressin
in the Subgroup of Patients with Hepatorenal Syndrome Further
Compounded by Alcoholic Hepatitis: Analysis of the CONFIRM Phase
III Study3
-
- Presenter: Kevin Korenblat, Washington University School of Medicine,
St. Louis, Mo.
Find more information on the Digestive Disease Week (DDW) 2023
Meeting website.
About Digestive Disease Week®
Digestive
Disease Week® (DDW) is the largest international
gathering of physicians, researchers and academics in the fields of
gastroenterology, hepatology, endoscopy and gastrointestinal
surgery. Jointly sponsored by the American Association for the
Study of Liver Diseases (AASLD), the American Gastroenterological
Association (AGA) Institute, the American Society for
Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of
the Alimentary Tract (SSAT), DDW is an in-person and online meeting
from May 6-9, 2023. The meeting showcases more than 3,100 abstracts
and hundreds of lectures on the latest advances in GI research,
medicine and technology. More information can be found at
www.ddw.org.
About Hepatorenal Syndrome (HRS)
Hepatorenal syndrome
(HRS) involving rapid reduction in kidney function1 is
an acute and life-threatening condition that occurs in people with
advanced liver disease.4 HRS is classified into two
distinct types – a rapidly progressive type that leads to acute
renal failure where patients are typically hospitalized for their
care and a more chronic type that progresses over weeks to
months.4 HRS involving rapid reduction in kidney
function1 is estimated to affect between 30,000 and
40,000 Americans annually.7,8 If left untreated,
HRS with rapid reduction in kidney function1 has a
median survival time of approximately two weeks and greater than 80
percent mortality within three months.9
INDICATION AND LIMITATION OF USE
TERLIVAZ is indicated to improve kidney function in adults with
hepatorenal syndrome with rapid reduction in kidney function.
- Patients with a serum creatinine >5 mg/dL are unlikely to
experience benefit.
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS OR FATAL RESPIRATORY FAILURE
- TERLIVAZ may cause serious or fatal respiratory failure.
Patients with volume overload or with acute-on-chronic liver
failure (ACLF) Grade 3 are at increased risk. Assess oxygenation
saturation (e.g., SpO2) before initiating TERLIVAZ.
- Do not initiate TERLIVAZ in patients experiencing hypoxia
(e.g., SpO2 <90%) until oxygenation levels improve.
Monitor patients for hypoxia using continuous pulse oximetry during
treatment and discontinue TERLIVAZ if SpO2 decreases
below 90%.
Contraindications
TERLIVAZ is contraindicated:
- In patients experiencing hypoxia or worsening respiratory
symptoms.
- In patients with ongoing coronary, peripheral, or mesenteric
ischemia.
Warnings and Precautions
- Serious or Fatal Respiratory Failure: Obtain baseline
oxygen saturation and do not initiate TERLIVAZ in hypoxic patients.
Monitor patients for changes in respiratory status using continuous
pulse oximetry and regular clinical assessments. Discontinue
TERLIVAZ in patients experiencing hypoxia or increased respiratory
symptoms.
Manage intravascular volume overload by reducing or discontinuing
the administration of albumin and/or other fluids and through
judicious use of diuretics. Temporarily interrupt, reduce, or
discontinue TERLIVAZ treatment until patient volume status
improves. Avoid use in patients with ACLF Grade 3 because they are
at significant risk for respiratory failure.
- Ineligibility for Liver
Transplant: TERLIVAZ-related adverse reactions
(respiratory failure, ischemia) may make a patient ineligible for
liver transplantation, if listed. For patients with high
prioritization for liver transplantation (e.g., MELD ≥35), the
benefits of TERLIVAZ may not outweigh its risks.
- Ischemic Events: TERLIVAZ may cause cardiac,
cerebrovascular, peripheral, or mesenteric ischemia. Avoid use of
TERLIVAZ in patients with a history of severe cardiovascular
conditions or cerebrovascular or ischemic disease. Discontinue
TERLIVAZ in patients who experience signs or symptoms suggestive of
ischemic adverse reactions.
- Embryo-Fetal Toxicity: TERLIVAZ may cause fetal harm
when administered to a pregnant woman. If TERLIVAZ is used during
pregnancy, the patient should be informed of the potential risk to
the fetus.
Adverse Reactions
- The most common adverse reactions (≥10%) include abdominal
pain, nausea, respiratory failure, diarrhea, and dyspnea.
Please click here to see full Prescribing Information,
including Boxed Warning.
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, hepatology, nephrology,
pulmonology, ophthalmology, and oncology; immunotherapy and
neonatal respiratory critical care therapies; analgesics; cultured
skin substitutes 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 contains forward-looking statements,
including with regard to TERLIVAZ and 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
Media Inquiries
Heather
Guzzi
Senior Vice President, Green Room Communications
973-524-4112
hguzzi@grcomms.com
Investor Relations
Daniel J.
Speciale
Global Corporate Controller & Chief Investor Relations
Officer
314-654-3638
daniel.speciale@mnk.com
Derek Belz
Vice President, Investor Relations
314-654-3950
derek.belz@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.
©2023 Mallinckrodt. US-2300189
5/23
References
1 TERLIVAZ® (terlipressin) for
injection. [Prescribing Information]. Mallinckrodt Hospital
Products Inc.
2 Bajaj JS, et al. Low Incidence of Clinically
Significant Bradycardia and Arrhythmia in Patients with Hepatorenal
Syndrome Following Terlipressin Treatment: A Pooled Analysis of 3
North American Phase III Clinical Studies. Abstract Presented at
Digestive Disease Week (DDW) 2023. May
2023.
3 Korenblat, K et al. Clinical Responses to Terlipressin
in the Subgroup of Patients with Hepatorenal Syndrome Further
Compounded by Alcoholic Hepatitis: Analysis of the CONFIRM Phase
III Study. Abstract to be Presented at Digestive Disease
Week (DDW) 2023. May 2023.
4 National Organization for Rare Disorders.
Hepatorenal Syndrome. Available
at: https://rarediseases.org/rare-diseases/hepatorenal-syndrome/.
Accessed April 18, 2023.
5 Biggins SW, Angeli P, Garcia-Tsao G, et al.
Diagnosis, evaluation, and management of ascites, spontaneous
bacterial peritonitis and hepatorenal syndrome: 2021 practice
guidance by the American Association for the Study of Liver
Diseases. Hepatology. 2021;74(2):1014-1048.
doi:10.1002/HEP.31884.
6 Bajaj JS, O'Leary JG, Lai JC, et al. Acute-on-chronic
liver failure clinical guidelines. Am J Gastroenterol.
2022;1-28.
7 C Pant, B S Jani, M Desai, A Deshpande,
Prashant Pandya, Ryan Taylor, R Gilroy, M OIyaee. Heptorenal
syndrome in hospitalized patients with chronic liver disease:
results from the Nationwide Inpatient Sample 2002-2012. J of
Investig Med. 2016; 64:33-38.
8 United States Census Bureau: Quick Facts.
Available
at: https://www.census.gov/quickfacts/fact/table/US/PST045218.
Accessed April 18, 2023.
9 Flamm SL, Brown K, Wadei HM., et al. The Current
Management of Hepatorenal Syndrome–Acute Kidney Injury in
the United States and the
Potential of Terlipressin. Liver Transpl.
2021;27:1191-1202. https://doi.org/10.1002/lt.26072.
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