NEJM published study shows Novartis compound ACZ885 significantly relieves symptoms in patients with serious form of childhood

  NEJM published study shows Novartis compound ACZ885 significantly relieves
        symptoms in patients with serious form of childhood arthritis

- Endpoints met in two Phase III trials, including substantial symptom relief
in 84% of systemic juvenile idiopathic arthritis (SJIA) patients treated with
ACZ885 in trial-11

- SJIA patients treated with ACZ885 in trial-2 were nearly three times less
likely to suffer a new flare vs. placebo1

- In trial-2, corticosteroid use substantially reduced in 45% of
ACZ885-treated SJIA patients and discontinued completely in one third1

- ACZ885, a fully human monoclonal antibody, neutralizes interleukin-1 beta
(IL-1 beta),1 a key mediator in autoinflammatory diseases such as SJIA1

PR Newswire

EAST HANOVER, N.J., Dec. 19, 2012

EAST HANOVER, N.J., Dec.19, 2012 /PRNewswire/ -- The New England Journal of
Medicine (NEJM) published today the results of two Phase III trials, and both
show ACZ885 (canakinumab) provided substantial symptom relief in young
patients with systemic juvenile idiopathic arthritis (SJIA).^1 In addition,
ACZ885 delayed disease flare recurrence and allowed patients to substantially
reduce or discontinue use of corticosteroids.^1 ACZ885 is a Novartis compound
being studied for use in SJIA, a rare, disabling and potentially fatal
autoinflammatory disease, characterized by spiking fever, rash, and arthritis
that may result in joint destruction, functional disability and impaired
growth.^1,2

"Treatment options for SJIA are limited even though it is the most severe
subtype of juvenile idiopathic arthritis. By necessity, steroids are commonly
used to manage SJIA symptoms despite their known side effects. Long-term use
of steroids can negatively impact children's bones and growth," said Daniel
Lovell, MD, MPH, study investigator and Joseph E. Levinson Professor of
Pediatrics at the Cincinnati Children's Hospital Medical Center. "These data
show the potential for ACZ885 to manage SJIA symptoms and reduce the need for
high doses of corticosteroids, and that is exciting news."

In beta-SPECIFIC 1 (trial-1), 84% of SJIA patients treated with ACZ885
experienced at least a 30% improvement in symptoms compared to 10% for placebo
after 15 days of treatment, which was sustained after 29 days (p<0.001).^1 In
beta-SPECIFIC 2 (trial-2), 45% of ACZ885-treated patients who were prescribed
corticosteroids at study entry were able to substantially reduce their use of
steroids, and one third of patients completely discontinued steroids.^1
Additionally, ACZ885-treated patients were nearly three times less likely to
experience a new flare, with 74% of ACZ885-treated patients remaining
flare-free compared to 25% with placebo (p=0.003) (Kaplan-Meier estimate).^1

"The publication of these data in NEJM highlights the vital need to address
the severe burden of disease in children with SJIA," said Tim Wright, MD,
Global Head of Development, Novartis Pharmaceuticals. "Novartis is committed
to addressing the unmet medical needs of patients living with rare diseases,
and these results underscore the potential of ACZ885 to provide an important
new treatment option for children with SJIA."

Data from the Phase III program of ACZ885 in SJIA form the basis for worldwide
regulatory submissions. In the EU, regulatory submission was completed in
November 2012. US regulatory submission is also on track.

Both studies explored multiple secondary endpoints.^1 During the double-blind,
single-dose beta-SPECIFIC 1 study, a third of ACZ885 patients (33%)
experienced inactive disease – which includes a complete absence of disease
signs and symptoms – vs. 0% for placebo at Day 15.^1 This was sustained until
the end of the study (Day 29, 30% of patients for ACZ885 vs. 0% for
placebo).^1 At the end of 32 weeks of open-label ACZ885 treatment in
beta-SPECIFIC 2, 31% of patients attained inactive disease status, and 62% of
patients who continued to receive ACZ885 had inactive disease at the end of
the study.^1 In contrast, patients who had received ACZ885 treatment and were
then randomized to receive placebo had a 34% rate of inactive disease at this
time point.^1 At the end of beta-SPECIFIC 2, 82% of patients met the adapted
JIA American College of Rheumatology Pediatric (JIA ACR) 70 response criteria
with ACZ885, vs. 62% for placebo-after-ACZ885-treated patients.^1

In beta-SPECIFIC 1, 56% of patients experienced adverse events (AEs) with
ACZ885 vs. 39% with placebo.^1 In Part I of beta-SPECIFIC 2, 78% of patients
had a reported AE and during Part II, AEs were reported for 80% of
ACZ885-treated patients (vs. 70% of placebo-after-ACZ885-treated patients).^1
Serious adverse events (SAEs) that were most frequently reported were flares
of SJIA, infections and macrophage activation syndrome (MAS).^1 MAS occurred
in seven patients across beta-SPECIFIC 1 and beta-SPECIFIC 2, and infections
were more frequent with ACZ885 than placebo.^1 

About the studies

Beta-SPECIFIC 1
The Phase III, 4-week, randomized, double-blind, placebo-controlled study
involved 84 patients between the ages of 2 and 19 years with active SJIA.^1
Patients were treated with either a single subcutaneous (s.c.) dose of ACZ885
(4 mg/kg, up to 300 mg) or placebo.^1

The primary endpoint was the proportion of patients achieving the JIA ACR 30
response criteria, defined as 30% improvement in at least three of the six
variables, worsening of more than 30% in no more than one of the criteria, and
resolution of fever, from baseline at Day 15.^1 The six variables included
physician's assessment of disease activity, parent's or patient's assessment
of overall well-being, functional ability (assessed by an adapted version of
the Childhood Health Assessment Questionnaire-Disability Index [CHAQ-DI]),
number of joints with active arthritis, number of joints with limitation of
motion and C-reactive protein, a laboratory measure of inflammation.^1

Other evaluations included an adapted JIA ACR 50, 70 and 100 response criteria
(representing a 50%, 70% and 100% improvement, respectively), and disease
inactivity.^1 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).

The most common AEs were abdominal pain and nasopharyngitis.^1 SAEs, including
infections, were reported for two patients for ACZ885 vs. two for placebo.^1
These did not lead to discontinuation.^1

Beta-SPECIFIC 2
The Phase III, two-part study had an open-label, single-arm active treatment
in Part I followed by a randomized, double-blind, placebo-controlled,
event-driven withdrawal design in Part II.^1 A total of 177 patients between
the ages of 2 and 19 years with active SJIA were enrolled in the study.^1 Some
of these patients had previously participated in the beta-SPECIFIC 1 trial. In
Part I, patients received a s.c. dose of ACZ885 (4 mg/kg, up to 300 mg) every
4 weeks. After 8 weeks, patients using corticosteroids who met the adapted JIA
ACR 50 response criteria began tapering (reducing) their corticosteroid use
until either: a) the corticosteroid dose had been decreased while maintaining
the JIA ACR 30 criteria; or b) a maximum of 20 weeks passed without reaching
the tapering goal.^1 In Part II of the study, patients were randomized to
either continue receiving ACZ885, or to receive placebo every 4 weeks
("placebo-after-ACZ885 group"), 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
corticosteroids in at least 25% of SJIA patients (Part I); and b) demonstrate
that time to flare is extended with ACZ885 vs. placebo (Part II).^1 The
adapted JIA ACR 30, 50, 70 and 100 were evaluated, in addition to disease
inactivity.^1

In Part I of the study, the most common AEs were nasopharyngitis, abdominal
pain and headache.^1 SAEs were reported in 15 patients, and included seven
patients with infections and four patients with MAS.^1 Five SAEs led to
discontinuation and one patient died of MAS.^1

In Part II, the most common AEs were abdominal pain, cough and
nasopharyngitis.^1 Six patients in each treatment group experienced one or
more SAE, which included two infections in each group, and one case of MAS in
the placebo-after-ACZ885 group.^1 Six patients, all in the
placebo-after-ACZ885 group, discontinued the study due to AEs or SAEs, and one
patient died from MAS.^1

MAS is a known, potentially fatal condition associated with SJIA that may
include liver abnormalities, bleeding disorders, central nervous system
dysfunction and multiple organ failure.^3 Approximately 7% of SJIA patients
are diagnosed with MAS.^3

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.^4 Excessive production
of IL-1 beta plays a major role in certain inflammatory diseases, including
SJIA.^5 ACZ885 works by attaching itself to IL-1 beta for a sustained period
of time, neutralizing its activity and inhibiting IL-1 beta-mediated
inflammation.^4

ACZ885 is currently approved in the US and other countries for a different
disease state. ACZ885 is also being studied in other diseases in which IL-1
beta plays a key role in causing inflammation, such as TNF-receptor associated
periodic syndrome, Familial Mediterranean Fever, gouty arthritis and
cardiovascular disease. ACZ885 is not approved for the treatment of SJIA. Not
all potential patients with these diseases would be eligible for treatment
with ACZ885, if approved for the applicable disease.

About SJIA
SJIA is a rare systemic interleukin-1 beta (IL-1 beta)-mediated
autoinflammatory disease characterized by spiking fever, rash, and arthritis
that may result in joint destruction, functional disability and impaired
growth.^1,2 Patients can also suffer enlargement of their liver and spleen, as
well as inflammation of the lining of their organs.^1,2 SJIA affects less than
one child per 100,000.^6

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.^1,8,9

Disclaimer
The foregoing release contains forward-looking statements that can be
identified by terminology such as "potential," "committed," "on track," or
similar expressions, or by express or implied discussions regarding potential
new indications or labeling for ACZ885 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. 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 regulatory actions
or delays or government regulation generally; unexpected clinical trial
results, including unexpected new clinical data and unexpected additional
analysis of existing clinical data; 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 Pharmaceuticals Corporation researches, develops, manufactures and
markets innovative prescription drugs used to treat a number of diseases and
conditions, including cardiovascular, dermatological, central nervous system,
bone disease, cancer, organ transplantation, psychiatry, infectious disease
and respiratory. The company's mission is to improve people's lives by
pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is
an affiliate of Novartis AG, which 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 achieved net sales of USD 58.6 billion, while
approximately USD 9.6 billion (USD 9.2 billion excluding impairment and
amortization charges) was invested in R&D throughout the Group. Novartis Group
companies employ approximately 127,000 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. Canakinumab in Systemic Juvenile
    Idiopathic Arthritis: 2 randomized trials. N Engl J Med 2012; e-pub ahead
    of print.
2.Pascual V, Allantaz F, Arce E. Role of Interleukin-1 (IL-1) In the
    Pathogenesis of Systemic Onset Juvenile Idiopathic Arthritis and Clinical
    Response to IL-1 Blockade. The Journal of Experimental Medicine 2005;
    201(9):1479-1486
3.Behrens EM, Beukelman T, et al. Occult Macrophage Activation Syndrome in
    Patients with Systemic Juvenile Idiopathic Arthritis. J Rheumatol
    2007;34;1133-1138
4.Ilaris [prescribing information]. East Hanover, NJ: Novartis
    Pharmaceuticals Corp; 2012
5.Martinon F, Petrilli V. Gout-associated uric acid crystals activate the
    NALP3 inflammasome. Nature 2006; 440(9): 237-241
6.Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis
    belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005;
    44(11):1350-3.
7.Wallace CA. Current Management Of Juvenile Idiopathic Arthritis. Best
    Practice & Research Clinical Rheumatology Vol. 20, No. 2, pp. 279–300,
    2006
8.U.S. National Library of Medicine (NLM), National Institutes of Health
    (NIH). Cushing Syndrome. Available at:
    http://www.nlm.nih.gov/medlineplus/ency/article/000389.htm. Last accessed:
    12/12/12
9.Teitelbaum SL, et al. Should Bisphosphonates be Used for Long-Term
    Treatment of Glucocorticoid-Induced Osteoporosis? Arthritis Rheum. 2011
    February 63(2): 325–328. doi:10.1002/art.30135

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