The Therapeutic Potential of Secukinumab in Rheumatic Diseases

Secukinumab Rheumatic Diseases new
Secukinumab – rheumatic-diseases

A review by Marije Koenders in Drug Design, Development and Therapy outlines some major features and characteristics of the new biological Secukinumab, which blocks the actions of interleukin 17A (IL-17), and explores its development, therapeutic potential and use in several rheumatic diseases.

Arthritis is one of the clinical manifestations of rheumatic diseases, and is characterized by pain, swelling, and stiffness of the affected synovial joints. Rheumatoid arthritis (RA) is the most common inflammation-driven rheumatic disease, which mainly affects the joints in a symmetrical manner and finally results in the destruction of cartilage and bone.

In contrast to RA, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are considered seronegative rheumatic diseases; both PsA and AS are associated with genetic inheritance of the HLA-B27 gene.

Despite the differences in pathogenesis and clinical presentation of RA, PsA, and AS, the treatment of these inflammatory rheumatic disorders is very overlapping. Nonsteroidal anti-inflammatory drugs are used to reduce pain and inflammation in rheumatic diseases; also, additional disease-modifying antirheumatic drugs, such as methotrexate (MTX) and sulfasalazine, are prescribed to slow down disease progression, and are more frequently and effectively applied in RA than in AS.

Biologicals form a relatively new class of treatments that specifically target specific cytokines or cells in the immune system. The most frequently applied biological agents approved for RA, PsA, and AS are tumor necrosis factor alpha (TNFα) inhibitors (including infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol).

A new kid on the block is the interleukin-17 (IL-17) inhibitor secukinumab, which has been recently approved by the US Food and Drug Administration (FDA) for moderate-to-severe plaque psoriasis, PsA, and AS.

IL-17 provides protection against extracellular bacterial and fungal infections. However, IL-17 and Th17 cells are perhaps the central drivers of inflammation in several chronic autoimmune and inflammatory diseases. The Th17–IL-17–IL-17R system has been implicated in psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis and Takayasu arteritis. This also includes autism, Guillain-Barré Syndrome and the  meningeal remodeling and induction of tertiary lymphoid tissues (TLTs) formation during the early stages of EAE.

In the early 1990s, the remarkable therapeutic success of targeted inhibition of TNF-α in patients with rheumatoid arthritis have indicated that a selective targeting of cytokines may suppress inflammation and tissue destruction. Now, it appears that IL17 is a new therapeutic target in several common human maladies, and particularly rheumatic diseases.

Secukinumab (registered by Novartis with the brand name Cosentyx®) and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. These biologicals were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis.

In the Drug Design, Development and Therapy review Marije Koenders summarizes some milestones in the development of secukinumab. As per this review Phase III trials proved the clinical efficacy of this anti-IL-17 antibody in psoriasis, followed by a rapid FDA approval of secukinumab for moderate-to-severe plaque psoriasis.

In rheumatoid arthritis, however, Phase II/III randomized controlled trials failed to demonstrate convincing data that secukinumab is effective in this condition. In contrast, Phase III trials appear to indicate that secukinumab is an efficacious treatment for psoriatic arthritis patients.

Moreover, it seems that secukinumab is also effective in ankylosing spondylitis – secukinumab is the first selective IL-17A inhibitor to meet primary endpoint in Phase III studies in active ankylosing spondylitis patients’. Most of the studies demonstrate a rapid and significant improvement of signs and symptoms, and importantly, a reduction of spinal inflammation as assessed by magnetic resonance imaging.

Thus, according to Marije Koenders the international treatment guidelines for various rheumatic diseases may need to be updated. Also secukinumab appears to be a novel class of drugs currently available for the treatment for several rheumatic diseases.

Source: Drug Des Devel Ther 2016; 10: 2069–2080
Read more: Drug Design, Development and Therapy

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Cover Image Credit (Left Panel): The five interleukin-17 receptor (IL-17R) complexes and their corresponding ligands. IL-17B binds to the receptor complex composed of the IL-17RB subunit and an unknown subunit. IL-17A and IL-17F are stimulated by T-helper-17 (TH17) cells and bind to the IL-17RC and IL-17RA receptor complex (not shown: IL-17A/IL-17F heterodimers also bind to this receptor complex). IL-17E (IL-25) binds to the IL-17RB and IL-17RA receptor complex. IL-17C binds to the IL-17RE and IL-17RA receptor complex. The ligand for the IL-17RD and IL-17RA receptor complex is currently unknown. Secukinumab inhibits IL-17A and prevents it from binding to its receptor. From: Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis, Jillian Frieder et al. Ther Adv Chronic Dis 2018 Jan;9(1):5-21. (Right Panel): Osteoarthritis, the most common form of arthritis, involves the wearing away of the cartilage that caps the bones in your joints. With rheumatoid arthritis, the synovial membrane that protects and lubricates joints becomes inflamed, causing pain and swelling. Joint erosion may follow; From: Rheumatic Diseases,