Novartis Phase III study showed 62% of patients with most severe form of childhood arthritis were symptom-free with ACZ885 treatment
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Novartis International AG /
Novartis Phase III study showed 62% of patients with most severe form of
childhood arthritis were symptom-free with ACZ885 treatment
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* Data also showed one third of patients became steroid-free within five
months with ACZ885[1], a fully human monoclonal antibody that inhibits IL-1
beta[2]
* ACZ885 regulatory submissions on track for 2012 in systemic juvenile
idiopathic arthritis (SJIA), a rare, disabling and potentially fatal
autoinflammatory disease[3]
* A Phase II study of ACZ885 in TNF-receptor associated periodic syndrome
(TRAPS) showed substantial symptom relief in this rare, periodic
feversyndrome[4]
Basel, 6 June 2012 - Novartis announced today new data from two trials with
ACZ885 (canakinumab); a pivotal Phase III study in patients with systemic
juvenile idiopathic arthritis (SJIA), and a Phase II study in patients with
tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). SJIA
and TRAPS are both rare and serious autoinflammatory diseases that usually start
in childhood[4-6].
Both studies met their primary endpoints, and the results will be presented on
7 June at the annual congress of the European League Against Rheumatism (EULAR
2012), in Berlin, Germany[1,4].
In the Phase III study, 62% of SJIA patients treated with ACZ885 had inactive
disease status at the end of the placebo-controlled period. In contrast,
patients who had received ACZ885 treatment and were then randomized to receive
placebo had a 32% rate of inactive disease at this time point. Disease
inactivity is a rigorous definition of improvement, comprising absence of
symptoms including: no active arthritis, no fever, no rheumatoid rash, as well
as normalized blood markers normally associated with inflammation, such as ESR
(erythrocyte sedimentation rate) and CRP (C-reactive protein). In addition, one
third (33%) of SJIA patients treated with ACZ885 were able to completely
discontinue corticosteroids[1].
The aim of SJIA therapy is to suppress systemic inflammation and induce disease
inactivity[7]. Long-term corticosteroid use in children is associated with
potentially serious adverse effects, including Cushing syndrome, growth
suppression, and osteoporosis[7].
Data from this Phase III study support the safety and efficacy profile of ACZ885
in the study population. Side effects observed in this study were similar to
those already seen for ACZ885's approved indication in CAPS (Cryopyrin-
Associated Periodic Syndromes), including infections and neutropenia[1].
Infections were the most common category of adverse event (AE) in both parts of
the study. Cases of macrophage activation syndrome (MAS) were also reported[1].
"In clinical practice, our aim is to help children with SJIA lead a normal life.
It is encouraging to see many patients become free of SJIA symptoms in this
trial," said Prof Alberto Martini, Professor of Pediatrics at the University of
Genoa and Head of Pediatric Rheumatology at the G. Gaslini Research Institute,
Italy. "It is also positive that a third of patients achieved sufficient symptom
control with ACZ885 to allow them to completely discontinue corticosteroid
therapy."
In the Phase II study, 90% of TRAPS patients treated with ACZ885 experienced
clinical remission after only one week of treatment. Clinical remission included
a clinically significant improvement of disease symptoms, as assessed by the
treating physician. After two weeks of treatment, 95% of patients with TRAPS
treated with ACZ885 had achieved a complete or almost complete response
(clinical remission as well as reduced levels of CRP and/or serum amyloid A
[SAA], a protein associated with acute inflammation), which was maintained until
the end of treatment with monthly dosing[4].
Side effects observed in this study were similar to those already seen for
ACZ885's approved indication in CAPS. Infections, mostly upper respiratory tract
infections (URIs), were the most commonly reported category of AE[4].
"It is encouraging to witness that targeting interleukin-1 beta with ACZ885 can
result in such marked improvement of symptoms in patients with these rare and
debilitating conditions, such as SJIA and TRAPS", said John Hohneker, Head of
Development for Integrated Hospital Care for the Pharmaceuticals Division of
Novartis. "We are committed to investigating new treatments that can address the
existing unmet medical need in immune-mediated diseases, no matter how rare some
of these conditions may be."
SJIA is a rare systemic interleukin-1 beta (IL-1 beta)-mediated autoinflammatory
disease characterized by daily spiking fevers, rash, chronic pain, and arthritis
that may result in joint destruction, functional disability and impaired
growth[3,8]. Patients can also suffer enlargement of their liver and spleen, as
well as inflammation of the lining of their organs[3]. SJIA affects less than
one child per 100,000[9].
MAS is a known, potentially fatal condition associated with SJIA that is
characterized by liver abnormalities, bleeding disorders, central nervous system
dysfunction and multiple organ failure[10,11]. Approximately 10% of SJIA
patients are diagnosed with MAS, some of whom suffer repeated episodes[8].
TRAPS is a rare auto-inflammatory disease that can affect both children and
adults[12-14]. This genetically inherited disease is characterized by long and
intermittent attacks that can involve fever, rash, abdominal pain,
conjunctivitis, severe skin infection, inflammation around the eyes and severe
joint pain[12-14].
Amyloidosis is a serious complication of TRAPS and is estimated to occur in 25%
of patients[15]. This long-term complication involves the production of SAA
during inflammation, and can lead to liver and/or kidney failure. In some
instances, amyloidosis can be fatal[16].
There are currently no approved treatments for TRAPS. While nonsteroidal anti-
inflammatory drugs, steroids and colchicine have been shown to relieve some
symptoms, there can be problems with limited and intermittent efficacy, in
addition to the side-effects of long-term steroid use, particularly in
children[12,17].
About the studies
ACZ885 in SJIA
The pivotal Phase III study in patients with SJIA comprised of an open-label,
single-arm active treatment period (Part 1) followed by a randomized, double-
blind, placebo-controlled, event-driven withdrawal design period (Part 2)[1]. A
total of 177 patients between the ages of >=2 and <20 years with active SJIA
were enrolled in the study[1]. In Part 1, patients received a subcutaneous
(s.c.) dose of ACZ885 (4 mg/kg, up to 300 mg) every 4 weeks. After 8 weeks,
patients who entered the trial using a corticosteroid and who had a minimum
adapted American College of Rheumatology (ACR) Pediatric 50 criteria began
tapering (reducing) their steroid use until either: a) the dose had been tapered
by a pre-specified amount depending on the baseline corticosteroid dose[18]while
maintaining the adapted ACR Pediatric 30 criteria (successful tapering of
steroids); or b) a maximum of 20 weeks passed without reaching this goal
(unsuccessful tapering of steroids)[1]. In Part 2 of the study, patients who had
a minimum adapted ACR Pediatric 30 criteria at the end of Part 1 were randomized
to either continue receiving ACZ885, or to receive placebo every 4 weeks, until
a pre-specified number (37) of flare-events ("flares") had occurred[1].
The primary endpoints were to: a) assess if ACZ885 allows tapering of steroids
in at least 25% of SJIA patients (Part 1); and b) demonstrate that time to flare
is extended with ACZ885 vs. placebo (Part 2)[1].
Both primary endpoints were met, with 45% of patients successfully reducing
their use of steroids within 28 weeks of commencing treatment with ACZ885
(p<0.0001)[1]. At this time point (end of Part 1), 31% of patients had inactive
disease. Patients using ACZ885 were nearly three times (0.37 hazard ratio) less
likely to suffer a new flare in Part 2. Only 22% of ACZ885-treated patients
experienced a new flare, vs. 52% of patients on placebo during the study
(p=0.0043)[1]. In Part 1 of the study (representing 58 patient years), 138 of
177 patients (78%) reported an AE, with the most common being nasopharyngitis,
headache and cough. Serious adverse events (SAEs) were reported in 15 patients,
with the most common being infections, MAS (four cases) or flare-associated
events[1]. Five SAEs led to discontinuation and one patient died of MAS[1].
During Part 2, AEs (the most common being arthralgia, cough, nasopharyngitis and
pyrexia) were reported by 40 of 50 (80%) ACZ885-treated patients (vs. 35 of 50
[70%] placebo-after-ACZ885-treated patients)[1]; and six patients in each arm
experienced one or more SAE, which mainly included infections, MAS and flare-
associated events[1]. Six patients, all in the placebo arm, discontinued the
study due to AEs or SAEs during Part 2[1]. One patient died from MAS after study
discontinuation in the placebo group.
ACZ885 in TRAPS
The ongoing Phase II, open-label, multicenter study investigating the efficacy
and safety of ACZ885 in patients with active TRAPS involves 20 patients with a
median age of 39 years (range, 7-78 years), who receive ACZ885 150 mg (or 300
mg) every four weeks. The primary endpoint of the study, is complete or almost
complete response at Day 15.
Complete response was defined as clinical remission and normal CRP and/or SAA
levels. Almost complete response was defined as clinical remission and elevated
but >=70% reduction of baseline CRP and/or SAA[4]. Clinical remission was
maintained for all patients from Day 15 onwards in the four month treatment
period, except for one patient with a relapse at Day 85 who subsequently
responded to the scheduled ACZ885 dose[4].
At least one AE was reported for 95% of patients, and most AEs were mild in
severity. One SAE, a URI that lasted two days, was reported[4].
About ACZ885
ACZ885 is a fully human monoclonal antibody that inhibits IL-1 beta, which is an
important part of the body's immune system defenses[2]. Excessive production of
IL-1 beta plays a major role in certain inflammatory diseases, including
SJIA[19] and TRAPS[4]. ACZ885 works by neutralizing IL-1 beta for a sustained
period of time, thereby inhibiting inflammation[2].
Under the brand name Ilaris(®), ACZ885 is approved in more than 60 countries,
including the EU, US and Switzerland for the treatment of adults and children as
young as four years with CAPS, a rare, lifelong, inflammatory disorder with
debilitating symptoms[2]. ACZ885 is also being studied in other diseases in
which IL-1 beta plays a key role in causing inflammation, such as gouty
arthritis and cardiovascular disease. ACZ885 is not approved for the treatment
of SJIA or TRAPS. Not all potential patients with these diseases would be
eligible for treatment with ACZ885, if approved.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "on track," "potentially," "will," "encouraging,"
"committed," "being studied," "potential," or similar expressions, or by express
or implied discussions regarding potential submissions or approvals of new
indications or labeling for ACZ885 or the timing of any such submissions or
approvals, or regarding potential future revenues from ACZ885. You should not
place undue reliance on these statements. Such forward-looking statements
reflect the current views of management regarding future events, and involve
known and unknown risks, uncertainties and other factors that may cause actual
results with ACZ885 to be materially different from any future results,
performance or achievements expressed or implied by such statements. There can
be no guarantee that ACZ885 will be submitted or approved for any additional
indications or labeling in any market, or at any particular time. Nor can there
be any guarantee that ACZ885 will achieve any particular levels of revenue in
the future. In particular, management's expectations regarding ACZ885 could be
affected by, among other things, unexpected clinical trial results, including
unexpected new clinical data and unexpected additional analysis of existing
clinical data; unexpected regulatory actions or delays or government regulation
generally; competition in general; government, industry and general public
pricing pressures; unexpected manufacturing issues; the company's ability to
obtain or maintain patent or other proprietary intellectual property protection;
the impact that the foregoing factors could have on the values attributed to the
Novartis Group's assets and liabilities as recorded in the Group's consolidated
balance sheet, and other risks and factors referred to in Novartis AG's current
Form 20-F on file with the US Securities and Exchange Commission. Should one or
more of these risks or uncertainties materialize, or should underlying
assumptions prove incorrect, actual results may vary materially from those
anticipated, believed, estimated or expected. Novartis is providing the
information in this press release as of this date and does not undertake any
obligation to update any forward-looking statements contained in this press
release as a result of new information, future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the evolving
needs of patients and societies. Headquartered in Basel, Switzerland, Novartis
offers a diversified portfolio to best meet these needs: innovative medicines,
eye care, cost-saving generic pharmaceuticals, preventive vaccines and
diagnostic tools, over-the-counter and animal health products. Novartis is the
only global company with leading positions in these areas. In 2011, the Group's
continuing operations achieved net sales of USD 58.6 billion, while
approximately USD 9.6 billion (USD 9.2 billion excluding impairment and
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companies employ approximately 124,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visit http://www.novartis.com.
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References
1. Ruperto N, Brunner H, Quartier P, et al. Efficacy and safety of
canakinumab, fully human anti-interleukin-1 beta antibody, in systemic juvenile
idiopathic arthritis: Oral presentation at: The European League Against
Rheumatism (EULAR) congress: June 6-9, 2012, Berlin, Germany.
2. Ilaris [precribing information]. Surrey, UK: Novartis Pharmaceuticals
UK Ltd; 2011.
3. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management,
and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
4. Gattorno M, Obici L, Meini A, et al. Efficacy and safety of
canakinumab patients with TNF Receptor-Associated Syndrome (TRAPS): Poster
presentation at: The European League Against Rheumatism (EULAR) congress: June
6-9, 2012, Berlin, Germany.
5. Wallace CA, Levinson JE. Juvenile rheumatoid arthritis: outcome and
treatment for the 1990s. Rheum Dis Clin North Am 1991; 17(4):891-905.
6. Kimberley FC, Lobito AA, Siegel RM, Screaton GR. Falling into
TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever
syndrome. Arthritis Res Ther 2007; 9(4):217.
7. Prince FH, Otten MH, van Suijlekom-Smit LW. Diagnosis and management
of juvenile idiopathic arthritis. BMJ 2010; 341:c6434.
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idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol
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9. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic
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2007; 19(5):477-81.
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North Am 2005; 52(2):413-42, vi.
12. Fietta P. Autoinflammatory diseases: the hereditary periodic fever
syndromes. Acta Biomed 2004; 75(2):92-9.
13. Simon A, van der Meer JW. Pathogenesis of familial periodic fever
syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr
Comp Physiol 2007; 292(1):R86-98.
14. Borghini S, Fiore M, Di Duca M, et al. Candidate genes in patients
with autoinflammatory syndrome resembling tumor necrosis factor receptor-
associated periodic syndrome without mutations in the TNFRSF1A gene. J Rheumatol
2011; 38(7):1378-84.
15. Dode C, Cuisset L, Delpech M, Grateau G. TNFRSF1A-associated periodic
syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. J Nephrol
2003; 16(3):435-7.
16. Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor
receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral
origins, genotype-phenotype studies, and evidence for further genetic
heterogeneity of periodic fevers. Am J Hum Genet 2001; 69(2):301-14.
17. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive
effects of regular inhaled corticosteroids. Arch Dis Child 1998; 78(2):172-3.
18. Novartis data on file. Abrams K, Dimitrov-Kuhl M, Doerr T et al.
Clinical Study Protocol (CACZ885G2301): β-SPECIFIC 2: Study of Pediatric
EffiCacy wIth FIrst-line use of Canakinumab [A randomized, double-blind, placebo
controlled, withdrawal study of flare prevention of canakinumab (ACZ885) in
patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and active systemic
manifestations]. 23 May 2011.
19. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and
interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol
2008; 4(1):34-42.
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Datum: 06.06.2012 - 07:15 Uhr
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