Novartis announced first ever results from the pivotal phase III FUTURE 1 and FUTURE 2 studies showing AIN457 (secukinumab) demonstrated rapid and significant clinical improvements versus placebo in improving the signs and symptoms of psoriatic arthritis (PsA). PsA is part of a family of long-term diseases impacting joints, known as spondyloarthritis (SpA), which also includes ankylosing spondylitis. There is a high unmet treatment need for patients with PsA. Many patients do not respond to, or tolerate, anti-TNF (tumour-necrosis-factor) medicines, the current standard of care and approximately 45per cent of people are dissatisfied with current treatments. Secukinumab stops the action of interleukin-17A (IL-17A), which is central to the development of inflammatory diseases. These results are being presented at the American College of Rheumatology (ACR) Congress in Boston, USA.
"We are thrilled to present these landmark phase III results of secukinmab in PsA, a painful and debilitating condition, with a significant unmet treatment need for patients," said Vasant Narasimhan, Global Head of Development, Novartis Pharmaceuticals. "We are committed to addressing unmet medical needs in rheumatology by bringing highly effective and long-lasting therapies to patients and these important data are expected to form the basis of our regulatory filing submission in PsA planned in 2015."
Clinically and statistically significant improvements in signs and symptoms of PsA were achieved versus placebo, as measured by a 20 per cent reduction in the American College of Rheumatology response criteria (ACR 20), a standard tool used to assess improvement at Week 24. Between 50per cent to 54 per cent of secukinumab patients achieved at least ACR 20 in both FUTURE 1 (150 mg; p<0.0001) and FUTURE 2 (150 and 300 mg; p<0.0001. This is in comparison to 17.3per cent and 15.3 per cent of placebo patients who achieved ACR 20 in FUTURE 1 and FUTURE 2, respectively.
Secukinumab patients in all dose groups experienced rapid onset of effect as early as Week 1 in FUTURE 1 (p<0.0001) and Week 3 in FUTURE 2 (150 mg p<0.0001 and 300 mg p<0.001) [1]-[4]. Long-term data from FUTURE 1 also confirmed these improvements were sustained through 52 weeks of treatment. Importantly, clinical benefits with secukinumab were observed in patients who had not been previously treated with anti-TNF therapies (anti-TNF naïve), the current standard of care for PsA, and also in patients who had an inadequate or no response to anti-TNFs. Those who had prior exposure to anti-TNFs included 29.5 per cent and 35per cent of study participants in FUTURE 1 and FUTURE 2, respectively.
In FUTURE 1, more than 80per cent of patients experienced no progression of joint structural damage, which is suffered by approximately two-thirds of patients with PsA, and is associated with loss of function and disability. Improvements in joint damage were shown in both anti-TNF naïve patients and in the patients with inadequate or no response to anti-TNFs. Additionally, secukinumab demonstrated rapid, significant and sustained improvements in skin psoriasis in both FUTURE 1 and FUTURE 2 which was consistent to results of the phase III psoriasis studies.
Secukinumab was well tolerated in both studies, with a safety profile that was consistent with that observed in the large psoriasis clinical trial programme involving nearly 4,000 patients. The most common adverse events (AEs) were the common cold, headache and upper respiratory tract infection.
FUTURE 1 and FUTURE 2 are the first multi-centre, randomised, placebo-controlled phase III studies to evaluate the efficacy of secukinumab in IL-17A inhibition in PsA. In the FUTURE 1 study patients received an intravenous loading dose every two weeks for the first four weeks of treatment followed by monthly subcutaneous doses of 75 mg or 150 mg compared to placebo, and FUTURE 2 compared subcutaneous loading dose secukinumab 75 mg, 150 mg and 300 mg to placebo. The intravenous loading period used in FUTURE 1 was designed to provide high systemic exposure for induction of response, in keeping with the initial proof of concept study in PsA with secukinumab. FUTURE 2 utilised an administration route (subcutaneous loading dose) and dose range (up to 300 mg) that is more consistent with the psoriasis programme. A combined total of more than 1,000 patients were enrolled in the studies.
Both studies met their primary endpoint, the American College of Rheumatology response criteria (ACR 20) at Week 24 a standard tool used to assess improvement (at least 20 per cent improvement) in PsA signs and symptoms and findings were consistent across the two studies:
FUTURE 1, 50.5 per cent and 50.0per cent for both secukinumab treatment arms, respectively, versus 17.3 per cent for placebo; p<0.0001.. FUTURE 2, 29.3 per cent for secukinumab 75 mg (p<0.05); 51.0per cent and 54.0 per cent for secukinumab 150 mg and 300 mg, respectively, versus 15.3per cent for placebo; p<0.0001.
Full results of secondary endpoints will be presented at ACR. Secondary endpoints at Week 24 in FUTURE 1 and FUTURE 2 included 75 per cent and 90 per cent improvement in Psoriasis Area-and-Severity Index score (PASI 75 and PASI 90), Change from baseline in 28-joint Disease Activity Score using C-reactive protein (DAS28 – CRP).
Physical function assessed using the Medical Outcome Short Form (36) Health Survey physical component summary scores (SF-36 PCS)
Physical function assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI), ACR 50 (American College of Rheumatology response criteria) response, proportion of subjects with dactylitis and enthesitis, Overall safety and tolerability of each secukinumab regimen compared with placebo, Additional secondary endpoint at Week 24 in FUTURE 1.
Radiographic progression assessed using the van der Heijde modified total Sharp score (mTSS), closely associated with psoriasis, psoriatic arthritis (PsA) is part of a family of long-term diseases impacting joints, known as spondyloarthritis (SpA); approximately 30 per cent of patients with psoriasis have psoriatic arthritis. Psoriatic arthritis (PsA) is a debilitating, long-lasting inflammatory disease linked with significant disability, poor quality of life and reduced life expectancy. PsA is associated with joint pain and stiffness, skin and nail psoriasis, swollen toes and fingers, persistent painful tendonitis, and irreversible joint damage. Between 0.3 per cent and 1per cent of the general population may be affected by PsA and as many as one in four people with psoriasis may have undiagnosed PsA.
Secukinumab (AIN457) is a human monoclonal antibody that selectively neutralises IL-17A. Secukinumab is the first IL-17A inhibitor with positive phase III results for the treatment of PsA and AS. Research shows that IL-17A plays an important role in driving the body's immune response in psoriasis and other inflammatory arthritic diseases, including PsA and AS.
In addition to PsA, secukinumab is also in clinical trials for the treatment of ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Global regulatory applications for secukinumab in AS and PsA are planned for 2015. This follows the secukinumab global regulatory applications for moderate-to-severe plaque psoriasis which were filed in October 2013 with approvals anticipated in late 2014 or early 2015.