Novartis Phase III study shows ACZ885 helped substantially reduce steroid use in 45% of patients with serious form of childhood arthritis

Novartis announced today new pivotal Phase III data showing 45% of children with active systemic juvenile idiopathic arthritis (SJIA) were able to substantially reduce their use of oral corticosteroids (often described as steroids) within 28 weeks of commencing treatment with ACZ885 (canakinumab) (p<0.0001)[3].

The results of the study, which met both primary endpoints, will be presented on November 9 at the American College of Rheumatology’s (ACR) Annual Scientific Meeting in Chicago, US[3].

“These data are very welcome because nearly half of ACZ885-treated patients were able to reduce their steroid use during the study, potentially helping decrease the impact that these drugs can have on this young population,” said Dr Nico Wulffraat, one of the study investigators and pediatric immunologist at Wilhelmina Children’s Hospital, University Medical Center in Utrecht, The Netherlands. “One of our main goals as physicians, and this applies to all therapies, is to provide patients with treatment options that combine effective control of their disease with a favorable safety profile, making long-term safety data monitoring important.”

In addition, patients with SJIA on ACZ885 were nearly three times (0.37 hazard ratio) less likely to suffer a new flare. Therefore, only 27% of ACZ885-treated patients experienced a new flare, vs. 75% of patients on placebo during the study (p=0.0043)[3].

Data from this trial support the safety and efficacy profile of ACZ885 in the study population. These results, along with data from a second pivotal study, are planned to form the basis for worldwide regulatory submissions in 2012. Side effects observed in this study were similar to those already seen for ACZ885’s approved indication, including infections and neutropenia[3,5]. In addition, cases of macrophage activation syndrome (MAS) were reported in this study[3].

“These data demonstrate the significant benefits that ACZ885 may provide this young population, both in steroid reduction and in extending the period these children can live free from SJIA flares,” said David Epstein, Head of the Pharmaceuticals Division of Novartis. “Novartis is committed to helping improve the health of patients with SJIA and other inflammatory diseases, which is why we are delighted to be sharing these results.”

ACZ885 is an investigational fully human monoclonal antibody which neutralizes the key inflammatory mediator, interleukin-1 beta (IL-1 beta), which plays an important role in a number of diseases including SJIA[5,6].

SJIA is the most serious form of childhood arthritis and affects less than one child per 100,000[7]. It is called ‘systemic’ because the inflammation affects the whole body, as well as most of the joints. The condition is characterized by potentially life-long, recurrent and painful flares, which can involve skin rash, daily spiking fevers, joint pain and limited motion[1,4]. These children can face joint destruction and growth retardation, with serious developmental and psychological consequences[1].

Therapies traditionally used to treat SJIA can only partially mitigate symptoms and do not normally prevent the long-term damage caused by the disease[7]. Long-term steroid use designed to treat SJIA symptoms can also contribute to slowed growth, delayed puberty and reduced bone density[1,2].

Novartis is also presenting a number of other studies at ACR, including a second pivotal Phase III trial of ACZ885 in SJIA, which was previously presented at the 2011 European Pediatric Rheumatology Congress in Bruges, Belgium, in September.

About the Study

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[3]. A total of 177 patients between the ages of 1 and 19 years with active SJIA were enrolled in the study[3]. In Part I, patients received a subcutaneous (s.c.) dose of ACZ885 (4 mg/kg, up to 300 mg) every 4 weeks. After 8 weeks, patients who met the adapted ACR Pediatric 30 criteria began tapering (reducing) their steroid use until either: a) the dose had been decreased to <= 0.5 mg/kg[8] 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)[3]. In Part II of the study, patients 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[3].

The primary endpoints were to: a) assess if ACZ885 allows tapering of steroids in at least 25% of SJIA patients (Part I); and b) demonstrate that time to flare is extended with ACZ885 vs. placebo (Part II) [3].

In Part I of the study (representing 58 patient years), 138 of 177 patients (78%) reported an adverse event (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[3]. Five SAEs led to discontinuation and one patient died of MAS[3]. During Part II, 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) [3]; and six patients in each arm experienced one or more SAE, which mainly included infections, MAS and flare-associated events[3].Six patients, all in the placebo arm, discontinued the study due to AEs or SAEs during Part II[3]. One patient died from MAS after study discontinuation in the placebo group.

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[4]. Approximately 10% of SJIA patients are diagnosed with MAS, some of whom suffer repeated episodes[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[5]. Excessive production of IL-1 beta plays a prominent role in certain inflammatory diseases, including SJIA[6]. ACZ885 works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation[5].

Under the brand name Ilaris®, ACZ885 is approved in more than 50 countries, including the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, inflammatory disorder with debilitating symptoms[5]. ACZ885 is also being studied in other diseases in which IL-1 beta plays a key role in causing inflammation, such as gouty arthritis, cardiovascular disease and diabetes. Not all potential patients with these diseases would be eligible for treatment with ACZ885, if approved.

References

1. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
2. Bailey KM, McDonagh JE, Prieur AM. Systemic juvenile idiopathic arthritis presenting in a young child with long term disability as an adolescent. Ann Rheum Dis 2004; 63(12):1544-8.
3. ACZ885 G2305 SJIA presentation (both G2305 and G2301) Ruperto N, Brunner H, Horneff G, et al. Efficacy and safety of canakinumab, a long acting fully human anti-interleukin-1 beta antibody, in systemic juvenile idiopathic arthritis with active systemic features: results from a phase III study. Presented on 9 November: The 2011 ACR Annual Scientific Meeting; November 5-9, 2011, Chicago, US. 2011.
4. Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol 2011; 7(7):416-26.
5. Ilaris [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2009.
6. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008; 4(1):34-42.
7. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005; 44(11):1350-3.
8. Novartis data on file. Abrams K, Dimitrov-Kuhl M, Doerr T et al. Clinical Study Protocol (CACZ885G2301): 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.