TIDMGSK
RNS Number : 4838F
GlaxoSmithKline PLC
17 May 2017
Issued: 17(th) May 2017, London, UK - LSE Announcement
GSK announces NEJM publication of positive phase III study
investigating mepolizumab in patients with Eosinophilic
Granulomatosis with Polyangiitis (EGPA)
Double-blind, placebo-controlled study of mepolizumab in
patients with EGPA demonstrates increased likelihood of remission
and reduced need for corticosteroids when mepolizumab is added to
existing standard of care (SOC)
GSK today announced publication in the New England Journal of
Medicine, of a randomised, double-blind, placebo controlled study
investigating the efficacy and safety of mepolizumab, an IL-5
antagonist, vs placebo as an add-on therapy in patients with
relapsing and/or refractory Eosinophilic Granulomatosis with
Polyangiitis (EGPA). EGPA is a rare disease characterised by
widespread inflammation in the walls of small blood vessels
(vasculitis) which may affect multiple organ systems and be
associated with fatigue, fever and weight loss.
The study was a collaboration between GSK and the National
Institute of Allergy and Infectious Diseases (NIAID), part of the
U.S. National Institutes of Health (NIH). Headline data from the
study were previously announced in November 2016.
Efficacy results
In the 52-week pivotal phase III study, mepolizumab treatment
demonstrated efficacy based on both co-primary efficacy endpoints
and all secondary endpoints. Treatment with mepolizumab was in
addition to standard of care (glucocorticoids with or without
immunosuppressants).
Patients treated with mepolizumab had a significantly greater
accrued time in remission (defined as a prednisolone/prednisone
dose of <=4mg/day and a Birmingham Vascular Activity Score = 0)
over the 52-week treatment period compared to placebo, with 28% of
patients on mepolizumab achieving remission for at least 24 weeks
versus 3% on placebo (p<0.001). In addition, a higher proportion
of patients in the mepolizumab group were in remission at both
Weeks 36 and 48 compared to the placebo group (32% versus 3%;
p<0.001).
More patients treated with mepolizumab achieved remission within
the first 24 weeks of the study and remained in remission until
Week 52 compared to those receiving placebo (19% versus 1%;
p=0.007). Over 52 weeks, time to first relapse was significantly
longer for patients on mepolizumab (p<0.001); time to first
major relapse was also longer for patients treated with mepolizumab
compared to placebo (p=0.042). Patients treated with mepolizumab
were also able to achieve significantly lower average doses of
prednisolone/prednisone during Weeks 48 to 52 compared to placebo,
with 44% able to taper their dose to <=4mg/day versus 7% on
placebo (p<0.001).
A total of 47% of mepolizumab-treated patients versus 81% of
placebo-treated patients did not achieve protocol-defined
remission. Approximately half the participants in the mepolizumab
group had a relapse, nonetheless a 50% lower rate of relapse with
mepolizumab treatment was seen than was observed with placebo in
this trial (1.14 per year for the mepolizumab group versus 2.27 per
year for the placebo group), which highlights the high morbidity
and challenge of managing patients with this progressive
disease.
Safety results
There was no difference between the two treatment groups in the
proportion of patients experiencing on-treatment adverse events
(97% versus 94%) and overall the adverse event profile for
mepolizumab was similar to that seen in previous studies with no
new safety signals observed. Fewer patients in the mepolizumab
group reported serious adverse events versus those in the placebo
group (18% versus 26%), with the most frequently reported being
asthma worsening/exacerbation (3% versus 6%). Systemic reactions
were infrequent and reported with higher incidence in the
mepolizumab group compared to placebo. One death was reported in a
patient receiving mepolizumab which was not considered by the
investigator to be related to study treatment.
Dr. Michael E Wechsler, Professor of Medicine at National Jewish
Health in Denver, Colorado, US, Principal Investigator and lead
author of the study said: "EGPA patients suffer from recurrent
relapses that place these patients at greater risk of permanent
tissue and organ damage. There are currently no therapies
specifically approved for EGPA. While systemic corticosteroids form
the cornerstone of EGPA treatment, they can be associated with
significant side effects. In this study, mepolizumab met several
important clinical goals in the treatment of EGPA: it increased
accrued time in remission, reduced frequency of relapse and
exacerbation, and enabled patients to reduce corticosteroid dose.
These data confirm the potential of mepolizumab as a future
treatment option for patients with this rare disease."
Steve Yancey, Vice-President and Medicines Development Lead for
mepolizumab, GSK, commented: "Uncontrolled eosinophilic
inflammation leads to an unpredictable condition for patients who
often fear the relapses that are a common feature of the disease.
Our goal is to provide patients and healthcare professionals with a
new treatment option to help control this disease. The success of
this study is a testament to the hard work of the GSK team, the
NIAID, and the investigators, and we thank all the patients whose
participation enabled the study to proceed."
Results of this study in patients with relapsing and refractory
EGPA will support GSK's plans to submit regulatory applications,
expected later in 2017.
Mepolizumab is not approved for use anywhere in the world for
EGPA.
Results of the study are available at:
http://www.nejm.org/doi/full/10.1056/NEJMoa1702079?query=featured_home
In addition, full results of the study are being presented
during the American Thoracic Society meeting:
- 9.15-11.15am 21(st) May - NEJM-JAMA session: Discussion on the
Edge: Reports of Recently Published Pulmonary Research
- 9.15-11.15am 22(nd) May - Oral presentation: Mepolizumab for
the Treatment of Patients with Eosinophilic Granulomatosis with
Polyangiitis: A Phase III Randomized, Placebo-Controlled Trial.
About the study
The pivotal phase III study was a randomised, double-blind
placebo controlled study designed to investigate the efficacy and
safety of mepolizumab 300mg (administered subcutaneously every 4
weeks) compared to placebo, in patients already receiving standard
of care, over a 52-week study treatment period. The study was
conducted in 31 academic centres and hospitals across nine
countries and enrolled 136 patients (mepolizumab n = 68; placebo =
68) with relapsing or refractory EGPA receiving standard of care
therapy (i.e. treatment for more than four weeks on stable dose
prednisolone/prednisone >=7.5mg - <=50mg day) with or without
immunosuppressive therapy. The study population was representative
of patients with EGPA treated with glucocorticoids with or without
additional immunosuppressant therapy.
Study endpoints
The co-primary endpoints were the total accrued weeks of
remission over the full trial period, and the proportion of
patients in remission at both Weeks 36 and 48. Remission was
defined by a Birmingham Vasculitis Activity Score (BVAS), a scoring
system to assess disease activity, of zero, and a
prednisolone/prednisone dose <=4mg/day.
The study included six secondary endpoints investigating
relapse, remission and corticosteroid use, all considered
clinically relevant for patients with EGPA.
About EGPA (previously known as Churg-Strauss Syndrome)
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare
disease that causes inflammation of the small blood vessels (or
vasculitis). The global incidence is generally reported to be in
the range 1-4 per million, with an estimated prevalence of
approximately 14-45 per million. The mean age of diagnosis is 48
years and the disease can be life-threatening for some
patients.
In EGPA, patients usually develop asthma initially, before the
vasculitis extends to inflammation of the small blood vessels that
supply tissues in the lungs, sinuses, skin, nerves and other
organs. EGPA can result in damage to almost every organ in the body
and the symptoms common to most include extreme fatigue, weight
loss, muscle and joint pain, sinonasal symptoms and breathlessness,
all of which affect patients' ability to carry out everyday
activities without difficulty.
The current approach to disease management is primarily based on
reduction of active inflammation and suppression of the immune
response through the use of corticosteroid therapy and concomitant
immunosuppressive therapy (e.g., methotrexate, azathioprine,
mycophenolate mofetil) and/or cytotoxic agents (e.g.,
cyclophosphamide). Although the use of these treatments can be
effective for establishing remission, patients remain vulnerable to
either the complications of the long-term use of these therapies,
or to the risk of relapse, particularly if the dose of
corticosteroid is reduced.
About mepolizumab
Mepolizumab is a humanised IgG monoclonal antibody specific for
interleukin 5 (IL-5). IL-5 is a cytokine which regulates the
growth, activation and survival of eosinophils (white blood cells)
and provides an essential signal for the movement of eosinophils
from the bone marrow into the lung and other organs. Mepolizumab
binds to human IL-5, stopping it from binding to its receptor on
the surface of eosinophils. Inhibiting IL-5 binding in this manner
reduces blood, tissue and sputum eosinophil levels, which in turn
reduces eosinophil-mediated inflammation.
Mepolizumab is not approved anywhere in the world for EGPA.
Mepolizumab is approved for use in the E.U., under the brand name
Nucala, for use as an add-on treatment for severe refractory
eosinophilic asthma in adult patients. Nucala is approved for use
in the U.S. as an add-on maintenance treatment of patients with
severe asthma aged 12 years and older, and with an eosinophilic
phenotype. It is not approved for the treatment of other
eosinophilic conditions or relief of acute bronchospasm or status
asthmaticus.
Nucala has also been approved in Canada, Australia, Japan,
Switzerland, Chile, South Korea and Taiwan. Trade marks are owned
by or licensed to the GSK group of companies.
Important Safety Information for Nucala in Severe Eosinophilic
Asthma
The following information is based on the US Prescribing
Information for Nucala. Please consult the full Prescribing
Information for all the labelled safety information for Nucala.
CONTRAINDICATIONS
Nucala should not be administered to patients with a history of
hypersensitivity to mepolizumab or excipients in the
formulation.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions (e.g. anaphylaxis, angioedema,
bronchospasm, hypotension, urticaria, rash) have occurred following
administration of Nucala. These reactions generally occur within
hours of administration but in some instances can have a delayed
onset (i.e. days). In the event of a hypersensitivity reaction,
Nucala should be discontinued.
Acute Asthma Symptoms or Deteriorating Disease
Nucala should not be used to treat acute asthma symptoms, acute
exacerbations, or acute bronchospasm.
Opportunistic Infections: Herpes Zoster
In controlled clinical trials, 2 serious adverse reactions of
herpes zoster occurred in subjects treated with Nucala compared to
none in placebo. Consider varicella vaccination if medically
appropriate prior to starting therapy with Nucala.
Reduction of Corticosteroid Dosage
Do not discontinue systemic or inhaled corticosteroids (ICS)
abruptly upon initiation of therapy with Nucala. Decreases in
corticosteroid doses, if appropriate, should be gradual and under
the direct supervision of a physician. Reduction in corticosteroid
dose may be associated with systemic withdrawal symptoms and/or
unmask conditions previously suppressed by systemic corticosteroid
therapy.
Parasitic (Helminth) Infection
It is unknown if Nucala will influence a patient's response
against parasites. Treat patients with pre-existing helminth
infections before initiating therapy with Nucala. If patients
become infected while receiving treatment with Nucala and do not
respond to anti-helminth treatment, discontinue treatment with
Nucala until infection resolves.
ADVERSE REACTIONS
The most common adverse reactions (>=3% and more common than
placebo) reported in the first 24 weeks of two clinical trials with
Nucala (and placebo) were: headache, 19% (18%); injection site
reaction, 8% (3%); back pain, 5% (4%); fatigue, 5% (4%); influenza,
3% (2%); urinary tract infection 3% (2%); abdominal pain upper, 3%
(2%); pruritus, 3% (2%); eczema, 3% (<1%); and muscle spasm, 3%
(<1%).
Systemic Reactions, including Hypersensitivity Reactions: In 3
clinical trials, 3% of subjects who received Nucala experienced
systemic (allergic and nonallergic) reactions compared to 5% in the
placebo group. Systemic allergic/hypersensitivity reactions were
reported by 1% of subjects who received Nucala compared to 2% of
subjects in the placebo group. Manifestations included rash,
pruritus, headache, and myalgia. Systemic nonallergic reactions
were reported by 2% of subjects who received Nucala and 3% of
subjects in the placebo group. Manifestations included rash,
flushing, and myalgia. A majority of the systemic reactions were
experienced on the day of dosing. Reports of anaphylaxis have been
received postmarketing.
Injection site reactions (e.g. pain, erythema, swelling,
itching, burning sensation) occurred at a rate of 8% in subjects
treated with Nucala compared with 3% in subjects treated with
placebo.
USE IN SPECIFIC POPULATIONS
The data on pregnancy exposures from the clinical trials are
insufficient to inform on drug-associated risk. Monoclonal
antibodies, such as mepolizumab, are progressively transported
across the placenta in a linear fashion as pregnancy progresses;
therefore, potential effects on a foetus are likely to be greater
during the second and third trimesters of pregnancy.
GSK - one of the world's leading research-based pharmaceutical
and healthcare companies - is committed to improving the quality of
human life by enabling people to do more, feel better and live
longer. For further information please visit www.gsk.com.
GSK enquiries:
Fiona McMillan +44 (0) 20 (London)
8047 5502
David Daley +44 (0) 20 (London)
8047 5502
US Media enquiries: Anna Padula +1 215 751 (Philadelphia)
4271
Sarah Spencer +1 215 751 (Philadelphia)
3335
Analyst/Investor Sarah Elton-Farr +44 (0) 20 (London)
enquiries: 8047 5194
Tom Curry + 1 215 751 (Philadelphia)
5419
Gary Davies +44 (0) 20 (London)
8047 5503
James Dodwell +44 (0) 20 (London)
8047 2406
Jeff McLaughlin +1 215 751 (Philadelphia)
7002
Cautionary statement regarding forward-looking
statements
GSK cautions investors that any forward-looking
statements or projections made by GSK, including
those made in this announcement, are subject
to risks and uncertainties that may cause actual
results to differ materially from those projected.
Such factors include, but are not limited to,
those described under Item 3.D 'Principal risks
and uncertainties' in the company's Annual Report
on Form 20-F for 2016.
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