DESCRIPTION
Proprietary Name:  Recombinant Human Necrosis Factor-αReceptorII:IgG Fc (rhTNFR:Fc) Fusion Protein for Injection
Brand Name:   Yisaipu
Composition:   Yisaipu is formulated in single-use vials containing 12.5mg or 25 mg rhTNFR:Fc, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection.

CLINICAL PHARMACOLOGY
TNF plays an important role in the clinical pharmacology processes of rheumatoid arthritis (RA). Yisaipu, the human necrosis factor-αreceptorⅡpart, binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses and plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), and ankylosing spondylitis. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.

Yisaipu is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. It inhibits binding of both TNFα and TNFβ to cell surface TNFRs, rendering TNF biologically inactive. Cells expressing trans-membrane TNF that bind Yisaipu are not lysed in vitro in the presence or absence of complement. Yisaipu can also modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (i.e., E-selectin and to a lesser extent intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g., IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin).

PHARMACOKINECICS
According to publicly available information, PK study was done on 25 RA patients with a protocol of 6 months period of twice a week injection, each injection was 25 mg. A mean half-life of 102 ± 30 (SD) hours was observed with a clearance rate of 160 ± 80 mL/hr. A maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours were observed in these patients following a single 25 mg dose. (N =23). Patients exhibited a two to seven-fold increase in peak serum concentrations and approximately four-fold increase in AUC0-72 hr (range 1 to 17 fold) with repeated dosing. Pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients.

Yisaipu is also administrated by a single subcutaneous (SC) injection of 25 mg dosage. The PK study of Yisaipu was conducted on 11 RA patients, with a similar protocol but only for 6 weeks period. A mean half-life of 74± 4 (SD) hours was observed with a clearance rate of 102.8 ±10.4mL/hr. A maximum serum concentration (Cmax) of 3.0 ± 0.2 mcg/mL and time to Cmax of 408 ± 20 hours were observed in these patients (N =11).

APPLICATION                                                            
Yisaipu is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Yisaipu can be initiated in combination with methotrexate (MTX) or used alone.

Yisaipu is indicated for reducing signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more DMARDs.

Yisaipu is indicated for reducing signs and symptoms and inhibiting the progression of structural damage of active arthritis in patients with psoriatic arthritis. Yisaipu can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Yisaipu is indicated for reducing signs and symptoms in patients with active ankylosing
spondylitis.

Yisaipu is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.