Novartis announced today results of two pivotal Phase III trials in patients with severe gouty arthritis, showing that ACZ885 (canakinumab) provided superior pain relief and reduced the risk of suffering new attacks by up to 68% compared to an injectable steroid (triamcinolone acetonide, TA) used to treat gouty arthritis attacks(1,2). ACZ885 is an investigational fully human monoclonal antibody.
The studies involved more than 450 gouty arthritis patients for whom the standard anti-inflammatory therapies, non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, were inadequate or inappropriate(1,2). Results will be presented for the first time at the 2011 European League Against Rheumatism (EULAR) Congress in London.
"Patients describe gouty arthritis as agonizingly painful," said Naomi Schlesinger, MD, Associate Professor of Medicine, Chief, Division of Rheumatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson University Hospital. "This new research demonstrates that ACZ885, which inhibits interleukin-1 beta, effectively treated and extended the time to new gouty arthritis attacks, thus reducing new attacks in gouty arthritis patients for whom many standard therapies were inadequate or inappropriate."
Both trials used an internationally recognized pain scale to measure differences in pain 72 hours after treatment, and found ACZ885 reduced pain by an additional 11.4 millimeters (mm) (p=0.0005) in one study and 9.8 mm in the other (p=0.0018), compared to TA(1). ACZ885 also significantly reduced the risk of suffering a new gouty arthritis attack within three months compared to TA, by 55% in one study (p=0.0014) and 68% in the other (p<0.0001)(2).
Gouty arthritis, commonly referred to as gout, is a serious, chronic and progressive inflammatory disease that affects up to 8.3 million Americans(3,5). The most common form of inflammatory arthritis in adults, gouty arthritis is estimated to be five times more prevalent than rheumatoid arthritis in the US(5,6).
"We are very excited about these results, which indicate that ACZ885 may become a significant new alternative for gouty arthritis patients where many standard anti-inflammatory treatments are inadequate or inappropriate," said David Epstein, Head of the Pharmaceuticals Division of Novartis. "Novartis is committed to meeting this unmet medical need and to further investigating the potential of ACZ885 in a number of other conditions where interleukin-1 beta may play a role."
Gouty arthritis attacks occur when the body has a strong inflammatory response to uric acid crystals forming in the affected joint, typically of the toe, foot, ankle or knee(7-9). This intense inflammatory response causes the severe pain and other debilitating symptoms associated with gouty arthritis attacks, which can last for a week or more(3,9-11).
Treatments currently available to manage the pain and inflammation of gouty arthritis attacks, such as NSAIDs or colchicine, may be inadequate or inappropriate in patients who have coexisting medical problems(12-14). This poses a significant unmet treatment need in gouty arthritis. In the US alone, more than 95% of patients with gouty arthritis or high uric acid levels (hyperuricemia) have at least one coexisting disease(15), a portion of whom may be unable to take these standard therapies.
Regulatory filings for the use of ACZ885 in gouty arthritis patients with limited treatment options were submitted in the EU in 2010 and in the US, Canada and Switzerland in the first quarter of 2011. ACZ885 is currently approved in the US and other countries for a different disease state.
About the Studies
The two studies were Phase III, 12-week, randomized, multicenter, double-blind, double dummy, active-controlled studies involving 228 and 226 patients who met the American College of Rheumatology (ACR) criteria for acute gouty arthritis(1,2). Patients had suffered from three or more gouty arthritis attacks in the previous 12 months and were either unresponsive or intolerant to common therapies like NSAIDs or colchicine, or these treatments were contraindicated. Patients were randomized to receive a single dose of ACZ885 150 milligrams (mg) via subcutaneous (s.c.) injection or TA 40 mg via intramuscular (i.m.) injection(1,2). In the case of a new attack, patients received a new dose of the same treatment they were randomized to at baseline.
Both studies had the same two primary endpoints: pain intensity at 72 hours post-dose; and time to the first new gouty arthritis attack(1,2). Pain in the affected joint was measured according to an internationally recognized pain scale, the Visual Analog Scale (VAS).
In one study, patients treated with ACZ885 had significantly lower mean pain scores at 72 hrs, with pain intensity decreasing from 73.3 mm at baseline to 28.1 mm for ACZ885 vs. 74.8 mm at baseline to 39.5 mm for TA (p=0.0005)(1,16). Similarly, patients in the other study receiving ACZ885 had significantly lower mean pain scores at 72 hrs, with pain intensity decreasing from 74.9 mm at baseline to 22.1 mm for ACZ885 vs. 73.6 mm at baseline to 31.9 mm for TA (p=0.0018)(17).
The number of patients with new attacks across both studies was also significantly reduced with ACZ885 compared to TA(2). In the first study, nearly twice as many patients experienced a new gouty arthritis attack in the TA group compared to ACZ885 (40 vs. 21 patients respectively [p=0.0061])(18). In addition, in the second study nearly three times as many patients in the TA group experienced a new attack compared to ACZ885 (42 vs. 15 patients respectively [p=0.0001])(18). In the previous year, patients in both studies suffered an average of at least six attacks (6.5 for ACZ885 and seven for TA in study one; and 6.5 and 5.9 respectively in study two)(16,17).
ACZ885 was generally well tolerated in the two studies. In one study, 55.8% of patients had adverse events (AEs) with ACZ885 vs. 38.3% with TA(16). In the other study, 54.5% of patients had AEs with ACZ885 vs. 50.9% with TA(17). Serious adverse events (SAEs), 10 for ACZ885 vs. five for TA in one study and three for ACZ885 vs. one for TA in the other study, were not considered to be related to study medication by the investigators(16,17).
ACZ885 is a fully human monoclonal antibody that inhibits interleukin-1 beta (IL-1 beta), which is part of the body's immune system defenses(19). Excessive production of IL-1 beta plays a major role in many inflammatory diseases, including gouty arthritis(19). ACZ885 works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation(10).
The foregoing release contains forward-looking statements that can be identified by terminology such as "may", "will", "committed", "potential" 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 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 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; 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.
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- So A, Alten R, Bardin T, et al. Canakinumab vs triamcinolone in the treatment of acute flares in gouty arthritis patients contraindicated, intolerant and unresponsive to NSAIDs and/or colchicine. Abstract (EULAR11-2483) at: The 2011 Annual European Congress of The European League Against Rheumatism; 2011 May 25-28; London, United Kingdom.
- Schlesinger N, Alten R, Bardin T, et al. Efficacy of canakinumab vs triamcinolone acetonide in preventing recurrent flares in acute gouty arthritis patients contraindicated, intolerant or unresponsive to NSAIDs and/or colchicine. Oral presentation (OP0107) at: The 2011 Annual European Congress of The European League Against Rheumatism; 2011 May 25-28; London, United Kingdom.
- Schumacher HR Jr. The pathogenesis of gout. Cleve Clin J Med. 2008; 75(5):S2-4.
- Annemans l, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005. Ann Rheum Dis. 2008; 67(7):960-6.
- Zhu Y, Pandya B, Choi H. Increasing gout prevalence in the US over the last two decades: The National Health and Nutrition Examination Survey (NHANES). Presented at: The American College of Rheumatology Annual Scientific Meeting; 2010 Oct; Atlanta, GA.
- Myasoedova E, Crowson CS, Kremers HM et al. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576-1582.
- Martinon F, Glimcher LH. Gout: new insights into an old disease. J Clin Invest. 2006; 116(8):2073-5.
- Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440(7081):237-41.
- Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008; 75(5):S5-8.
- Busso N, So A. Mechanisms of inflammation in gout. Arthritis Res Ther. 2010; 12:206-13.
- So A, De Meulemeester M, Pikhlak EA, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis. Arthritis Rheum. 2010 October; 62(10):3064-76.
- Terkeltaub R, Edwards NL. Gout: Diagnosis and Management of Gouty Arthritis and Hyperuricemia. 1st ed. West Islip, NY: Professional Communications, Inc; 2010.
- Schlesinger N, Dalbeth N, Perez-Ruiz F. Goutwhat are the treatment options? Expert Opin Pharmacother. 2009;10:1319-28.
- Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology. 2007;46:1372-4.
- Riedel AA, Nelson M, Wallace K, Joseph-Ridge N, Cleary M, Fam AG. Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting. J Clin Rheumatol. 2004 Dec; 10(6):308-14.
- So A, Alten R, Bardin T, et al. A controlled trial of canakinumab vs triamcinolone acetonide in acute gouty arthritis patients: results of the Beta-RELIEVED study (REsponse in acute fLare and In prEVEntion of episoDes of re-flare in gout). Oral presentation (OP0108) at: The 2011 Annual European Congress of The European League Against Rheumatism; 2011 May 25-28; London, United Kingdom.
- Schlesinger N, Alten R, Bardin T, et al. Efficacy of canakinumab versus triamcinolone acetonide in acute gouty arthritis patients: results of the Beta-RELIEVED II study (REsponse in acute fLare and In prEVEntion of episoDes of re-flare in gout). Poster (THU0019) presented at: The 2011 Annual European Congress of The European League Against Rheumatism; 2011 May 25-28; London, United Kingdom.
- Schlesinger N, Alten R, Bardin T, et al. Efficacy of canakinumab vs triamcinolone acetonide in preventing recurrent flares in acute gouty arthritis patients contraindicated, intolerated or unresponsive to NSAIDs and/or colchicine. Abstract (EULAR11-2018 for OP0107) at: The 2011 Annual European Congress of The European League Against Rheumatism; 2011 May 25-28; London, United Kingdom.
- ILARIS [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2009.
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