STAINES-UPON-THAMES, United
Kingdom, April 15, 2020
/PRNewswire/ -- Mallinckrodt
plc (NYSE: MNK), a global biopharmaceutical company, today
announced the publication of findings from its randomized,
placebo-controlled, double-blind Phase 4 study to assess the safety
and efficacy of Acthar® Gel (repository corticotropin
injection, or RCI) in patients with persistently active rheumatoid
arthritis (RA) despite treatment with stable background
disease-modifying antirheumatic drugs (DMARDs) and low-dose
glucocorticoids. Results of the study were recently published
online in Rheumatology and Therapy, an open access
peer-review journal. Preliminary findings from the study were
presented at the European Congress of Rheumatology 2019 (EULAR)
held in June.
Acthar Gel is a naturally sourced complex mixture of
adrenocorticotropic hormone analogs and other pituitary peptides.
Acthar Gel is approved by the U.S. Food and Drug Administration
(FDA) as adjunctive therapy for short-term administration (to tide
the patient over an acute episode or exacerbation) in RA, including
juvenile RA (selected cases may require low-dose maintenance
therapy).1 Please see Important Safety Information
for Acthar Gel below.
The study, titled "Repository Corticotropin Injection for Active
Rheumatoid Arthritis Despite Aggressive Treatment: A Randomized
Controlled Withdrawal Trial," enrolled 259 adult patients (≥18
years of age) with RA who were treated at 60 centers in four
countries between Nov. 7, 2016, and
Feb. 13, 2019. Results of the study
showed that Acthar Gel demonstrated the potential for effectiveness
in achieving low disease activity (LDA) as assessed by
DAS28-ESR2 in patients with active RA despite current
treatment with low-dose glucocorticoids and one or two DMARDs.
"The results of this study suggest that there could be a
reasonable risk-benefit for the short-term use of RCI over six
months in appropriate patients with persistently active RA despite
concurrent use of DMARDs and low-dose glucocorticoids. Many
patients achieved LDA by three months with the response persisting
for an additional three months in a majority of patients whether
discontinuing or continuing RCI. The adverse event profile was
similar in patients who continued and discontinued
RCI,i" said Dr. Roy
Fleischmann, Co-Medical Director of the Metroplex Clinical
Research Center and Clinical Professor of Medicine at the
University of Texas Southwestern Medical
Center in Dallas and the study's lead author.
"Rheumatoid arthritis is a common autoimmune disease that
can damage bone and joints and greatly impact daily functioning for
patients. The goal of treatment is remission or low disease
activity, but for a subset of underserved patients with
debilitating RA who don't achieve remission or LDA with standard
therapy, additional options are greatly needed," said
Tunde Otulana, M.D., Senior Vice
President and Chief Medical Officer at Mallinckrodt. "We are encouraged by the results
of this study that demonstrate Acthar Gel can be considered for
appropriate patients in this persistently active population, and
we're grateful to the patients, their families and clinicians who
participated in the study."
Key Findings3:
Open-label Period
- At week 12, 163 patients (62.9 percent, 95 percent Confidence
Interval 57.3–69.1 percent) achieved DAS28-ESR <3.2, the study's
primary endpoint (p<0.0001).
- The mean DAS28-ESR over time from baseline to week 12 decreased
by 2.75 (standard deviations (SD) 1.45, p<0.001) from a mean
baseline of 6.3.
- At week 12, 169 patients (65.3 percent) reached LDA as defined
by the Clinical Disease Activity Index (CDAI, score ≤10), a
composite measure of disease activity in patients with RA
(p<0.001).
- The proportion of patients (N=259) who achieved ACR 20, 50, and
70 response criteriaii at week 12 were as follows: 83.0
percent (n=215) achieved ACR20, 62.5 percent (n=162) achieved
ACR50, and 30.1 percent (n=78) achieved ACR70 (all
p<0.0001).
- 49 patients (18.9 percent) achieved DAS28-ESR < 2.6
(remission) at week 12.
- Significant decreases from baseline in the number of tender and
swollen joints were observed.
- In terms of patient-reported outcomes (PROs) at week 12,
significant improvements from baseline in Health Assessment
Questionnaire – Disability Index (HAQ-DI) and Functional Assessment
of Chronic Illness Therapy – Fatigue (FACIT-F) scores were
observed, as well as significant decreases from baseline in the
percentages of work time missed, impairment while working, overall
work impairment, and activity impairment, as assessed via the Work
Productivity and Activity Impairment (WPAI) questionnaire.
- Bone turnover markers, an exploratory endpoint, were stable
during the open-label period. At week 12, significant decreases in
levels of cartilage degeneration markers CTX-II (p<0.01) and
CTX-II CRT (p<0.001), as well as the bone formation marker PINP
(p<0.01) were observed, and bone degeneration markers CTX and
CTX-I showed no significant changes with Acthar Gel treatment in
this population. The clinical relevance of these data are unknown
as bone density assessments were not taken during this study.
- During the open-label period, 98 patients (37.8 percent)
reported adverse events (AEs), the most common were urinary tract
infection (3.9 percent, n=10), headache (3.5 percent, n=9) and
pharyngitis (2.7 percent, n=7). Three patients experienced serious
AEs.
Randomized, Placebo-Controlled, Blinded, Withdrawal
Period
- LDA as assessed by DAS28-ESR was maintained at week 24 in 47 of
77 (61.0 percent) of patients treated with Acthar Gel versus 32 of
76 (42.1 percent) of patients treated with placebo (p=0.019).
- Mean DAS28-ESR over time during the double-blind period did not
differ significantly between the Acthar Gel and placebo
groups.
- Mean time to disease activity flare during weeks 12 through 24
was 6.5 weeks (SD 2.61 weeks) for the placebo group and 8.2 weeks
(SD 2.92 weeks) for the Acthar Gel-treated group.
- At week 24, 66 patients (85.7 percent) treated with Acthar Gel
and 50 patients (65.8 percent) in the placebo group maintained LDA,
as defined by CDAI scores ≤ 10 (p=0.004).
- At week 24, ACR20 response achieved during the open-label
period was maintained through the double-blind period in the Acthar
Gel (91 percent, n=77) and placebo (84 percent, n=76) groups. ACR50
and ACR70 responses evaluated post hoc at week 24 of the
double-blind period were seen in 75 percent and 47 percent,
respectively, of patients treated with Acthar Gel and 70 percent
and 42 percent of patients who had discontinued Acthar Gel
therapy.
- At week 24, 23 patients (29.9 percent) treated with Acthar Gel
and 23 patients (30.3 percent treated with placebo achieved
DAS28-ESR remission (p=0.828) in this population with previously
highly active RA.
- As an exploratory endpoint, C-reactive protein values were
noted to be 12.1 µg/mL at baseline, 14.3 µg/mL at week 12 and 16.4
µg/mL at week 24 for the Acthar Gel group, and 21.8 µg/mL and
baseline, 16.9 µg/mL at week 12 and 20.0 µg/mL at week 24 for the
placebo group.
- The mean number of tender and swollen joints as derived for the
calculation of the DAS28-ESR remained decreased during the
double-blind period, with no significant differences between the
Acthar Gel and placebo groups noted.
- In terms of PROs, improvements on the HAQ-DI, FACIT-F, and WPAI
that were noted during the open-label period were generally
maintained in the Acthar Gel and placebo groups throughout the
double-blind period. There were no significant differences between
the Acthar Gel and placebo groups on these metrics.
- Levels of the osteoclast differentiation marker sRANKL
significantly increased from baseline to week 12 and week 24 (both
p<0.05) in the Acthar Gel group, but not in the placebo group.
All other bone turnover markers remained stable.
- 25 patients (32.5 percent) from the Acthar Gel group and 31
patients (40.3 percent) in the placebo group reported AEs during
the double-blind period, the most common being: headache (6.5
percent both groups, n=5), hypertension (3.9 percent, n=3 RCI; 0
placebo), hyperglycemia (3.9 percent, n=3 RCI; 2.6 percent, n=2
placebo) and diarrhea (1.3 percent, n=1 RCI; 3.9 percent, n=3
placebo).
Methods3:
- The study was a Phase 4, multicenter, two-part clinical study
assessing the efficacy and safety of Acthar Gel in adult patients
with RA with persistently active disease who were previously
treated with low-dose glucocorticoids and nonbiologic and/or
biologic DMARDs. The primary endpoint of the study was the
proportion of patients reaching LDA at 12 weeks.
- Part 1 of the study was an open-label period (259 patients were
enrolled and 235 completed part 1). Patients were assessed at
baseline and at weeks 4, 8 and 12.
- After 12 weeks of treatment with Acthar Gel, patients were
evaluated for treatment response using the DAS28-ESR. Participants
who achieved LDA as defined by DAS28-ESR <3.2 at week 12 in part
1 entered part 2, a double-blind withdrawal period. Patients who
did not achieve LDA at week 12 were discontinued from further study
participation.
- 154 patients entered part 2 of the study (77 in each treatment
group) and 127 patients completed part 2 of the study (Acthar Gel,
n=71; placebo, n=56).
- In part 2, patients were randomized in a 1:1 ratio to receive
either Acthar Gel 1 ml (80 U) or matching placebo twice weekly for
an additional 12 weeks.
Study Limitations3:
- All patients were aware that they were being treated with
Acthar Gel during the open-label period. This may have led to
higher responses to treatment.
- Sample bias may exist, limiting the extrapolation of the
results to the general population:
-
- >80 percent of study participants were of Hispanic or Latino
ethnicity
- Patients with other rheumatic autoimmune diseases, clinically
significant infections, or malignancies were excluded from the
study
- The results may not be solely attributed to Acthar Gel because
patients were on different stable background medications at the
start of the trial, and there were no washout periods. Acthar Gel
has not been formally studied in combination with other
treatments.
The study was funded by Mallinckrodt.
About Rheumatoid Arthritis
RA is an autoimmune
disease. It is a chronic condition that causes pain, stiffness, and
swelling of the joints—all symptoms and signs caused by
inflammation.4 An estimated 1.5 million U.S. adults are
living with RA.5 Treatment is aimed at stopping
inflammation to put the disease in remission and relieve
symptoms.6 Nonsteroidal anti-inflammatory drugs are used
to ease symptoms whereas glucocorticoids, and non-biologic and
biologic DMARDs are used to slow down the disease
activity.6
INDICATIONS
Acthar® Gel (repository corticotropin injection) is
indicated for:
- Treatment during an exacerbation or as maintenance therapy in
selected cases of systemic lupus erythematosus
- Treatment during an exacerbation or as maintenance therapy in
selected cases of dermatomyositis (polymyositis)
- Adjunctive therapy for short-term administration (to tide the
patient over an acute episode or exacerbation) in rheumatoid
arthritis, including juvenile rheumatoid arthritis (selected cases
may require low-dose maintenance therapy); ankylosing
spondylitis
- Adjunctive therapy for short-term administration (to tide the
patient over an acute episode or exacerbation) in psoriatic
arthritis
- The treatment of symptomatic sarcoidosis
IMPORTANT SAFETY INFORMATION
Contraindications
- Acthar should never be administered intravenously
- Administration of live or live attenuated vaccines is
contraindicated in patients receiving immunosuppressive doses of
Acthar
- Acthar is contraindicated where congenital infections are
suspected in infants
- Acthar is contraindicated in patients with scleroderma,
osteoporosis, systemic fungal infections, ocular herpes simplex,
recent surgery, history of or the presence of a peptic ulcer,
congestive heart failure, uncontrolled hypertension, primary
adrenocortical insufficiency, adrenocortical hyperfunction, or
sensitivity to proteins of porcine origin
Warnings and Precautions
- The adverse effects of Acthar are related primarily to its
steroidogenic effects
- Acthar may increase susceptibility to new infection or
reactivation of latent infections
- Suppression of the hypothalamic-pituitary-adrenal (HPA) axis
may occur following prolonged therapy with the potential for
adrenal insufficiency after withdrawal of the medication. Adrenal
insufficiency may be minimized by tapering of the dose when
discontinuing treatment. During recovery of the adrenal gland
patients should be protected from the stress (e.g. trauma or
surgery) by the use of corticosteroids. Monitor patients for
effects of HPA suppression after stopping treatment
- Cushing's syndrome may occur
during therapy but generally resolves after therapy is stopped.
Monitor patients for signs and symptoms
- Acthar can cause elevation of blood pressure, salt and water
retention, and hypokalemia. Blood pressure, sodium, and potassium
levels may need to be monitored
- Acthar often acts by masking symptoms of other
diseases/disorders. Monitor patients carefully during and for a
period following discontinuation of therapy
- Acthar can cause GI bleeding and gastric ulcer. There is also
an increased risk for perforation in patients with certain
gastrointestinal disorders. Monitor for signs of bleeding
- Acthar may be associated with central nervous system effects
ranging from euphoria, insomnia, irritability, mood swings,
personality changes, and severe depression to psychosis. Existing
conditions may be aggravated
- Patients with comorbid disease may have that disease worsened.
Caution should be used when prescribing Acthar in patients with
diabetes and myasthenia gravis
- Prolonged use of Acthar may produce cataracts, glaucoma, and
secondary ocular infections. Monitor for signs and symptoms
- Acthar is immunogenic and prolonged administration of Acthar
may increase the risk of hypersensitivity reactions. Neutralizing
antibodies with chronic administration may lead to loss of
endogenous ACTH activity
- There is an enhanced effect in patients with hypothyroidism and
in those with cirrhosis of the liver
- Long-term use may have negative effects on growth and physical
development in children. Monitor pediatric patients
- Decrease in bone density may occur. Bone density should be
monitored for patients on long-term therapy
- Pregnancy Class C: Acthar has been shown to have an embryocidal
effect and should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus
Adverse Reactions
- Common adverse reactions for Acthar are similar to those of
corticosteroids and include fluid retention, alteration in glucose
tolerance, elevation in blood pressure, behavioral and mood
changes, increased appetite, and weight gain
- Specific adverse reactions reported in IS clinical trials in
infants and children under 2 years of age included: infection,
hypertension, irritability, Cushingoid symptoms, constipation,
diarrhea, vomiting, pyrexia, weight gain, increased appetite,
decreased appetite, nasal congestion, acne, rash, and cardiac
hypertrophy. Convulsions were also reported, but these may actually
be occurring because some IS patients progress to other forms of
seizures and IS sometimes masks other seizures, which become
visible once the clinical spasms from IS resolve
Other adverse events reported are included in the full
Prescribing Information.
Please see full Prescribing Information for
additional Important Safety Information.
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
concerning Acthar Gel including its potential impact on patients
and anticipated 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
For Trade Media
Inquiries
Caren Begun
Green Room Communications
201-396-8551
caren@greenroompr.com
For Financial/Dailies Media Inquiries
Ron Bartlett
H+K Strategies
Senior Vice President
M: +1 813 545 2399
ron.bartlett@hkstrategies.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. ©2020 Mallinckrodt. US-2000523 04/20
References
i AEs reported in ≥1.5% of patients in part 1 or in
either group in part 2.
ii ACR20=American College of Rheumatology 20%
improvement; ACR50=American College of Rheumatology 50%
improvement; ACR70=American College of Rheumatology 70%
improvement
1 Acthar® Gel (repository corticotropin injection)
[prescribing information]. Mallinckrodt ARD LLC.
2 Disease Activity Score 28-joint count Erythrocyte
Sedimentation Rate.
3 Fleischmann R, Furst DE, Connolly-Strong E, Liu
J, Zhu J, Brasington R. Rheumatol Ther (2020).
https://doi.org/10.1007/s40744-020-00199-3.
4 Mayo Clinic website. Rheumatoid Arthritis.
Overview. Available at:
https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648.
Accessed April 1, 2020.
5 Arthritis Foundation. What is Rheumatoid
Arthritis? Available at:
http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/what-is-rheumatoid-arthritis.php.
Accessed April 1, 2020.
6 Arthritis Foundation. Rheumatoid Arthritis
Treatment. Available at:
http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php.
Accessed April 1, 2020.
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