| Reference | 1. Arthritis Rheumatol. 2017 Apr;69(4):709-719. doi: 10.1002/art.39955.
<br>
Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid
Arthritis in Patients With an Inadequate Response to Methotrexate.
<br>
Kivitz AJ(1), Gutierrez-Ureña SR(2), Poiley J(3), Genovese MC(4), Kristy R(5),
Shay K(5), Wang X(5), Garg JP(5), Zubrzycka-Sienkiewicz A(6).
<br>
Author information: <br>
(1)Altoona Center for Clinical Research, Duncansville, Pennsylvania.
(2)Hospital Civil de Guadalajara, Guadalajara, Mexico.
(3)Arthritis Associates, Orlando, Florida.
(4)Stanford University, Palo Alto, California.
(5)Astellas Pharma Global Development, Northbrook, Illinois.
(6)ARS Rheumatica, Warsaw, Poland.
<br>
OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily
peficitinib in combination with methotrexate (MTX) in patients with
moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to
MTX.<br>
METHODS: In this multinational, phase IIb, randomized, double-blind,
placebo-controlled, dose-ranging trial, patients with RA (n = 378) were treated
with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg plus MTX, or matching placebo
plus MTX once daily for 12 weeks. The primary end point was the percentage of
patients who met the American College of Rheumatology 20% improvement criteria
(achieved an ACR20 response) at week 12.<br>
RESULTS: ACR20 response rates at week 12 were 43.9%, 61.5% (P < 0.05 versus
placebo), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150
mg, and placebo groups, respectively. Significant decreases from baseline in the
Disease Activity Score in 28 joints using the C-reactive protein level were seen
in the peficitinib 50 mg (P < 0.05) and 150 mg (P < 0.01) groups compared with
placebo at week 12. Overall, the incidence of adverse events (AEs) was similar
between peficitinib and placebo. The most common AEs were urinary tract infection
(n = 22 [6%]), upper respiratory tract infection (n = 16 [4%]), and diarrhea
(n = 16 [4%]). There were 3 cases of herpes zoster infection (2 in the
peficitinib 100 mg group and 1 in the 150 mg group) and 2 cases of serious
infection (viral infection in the peficitinib 100 mg group and erysipelas in the
150 mg group).
CONCLUSION: The ACR20 response rate in the group receiving peficitinib 50 mg plus
MTX was significantly different compared with the rate in patients receiving
placebo, but there were no apparent dose-dependent responses, and the placebo
response rate was high. Peficitinib plus MTX in patients with moderate-to-severe
RA was well tolerated, with limited safety signals emerging.
<br>
2. J Pharmacol Sci. 2017 Jan;133(1):25-33. doi: 10.1016/j.jphs.2016.12.001. Epub
2016 Dec 23.
<br>
A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat
adjuvant-induced arthritis model.
<br>
Ito M(1), Yamazaki S(2), Yamagami K(2), Kuno M(2), Morita Y(2), Okuma K(2),
Nakamura K(2), Chida N(2), Inami M(2), Inoue T(2), Shirakami S(2), Higashi Y(2).
<br>
Author information: <br>
(1)Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba,
Ibaraki 305-8585, Japan. Electronic address: [email protected].
(2)Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba,
Ibaraki 305-8585, Japan.
<br>
The Janus kinase (JAK) family of tyrosine kinases is associated with various
cytokine receptors. JAK1 and JAK3 play particularly important roles in the immune
response, and their inhibition is expected to provide targeted immune modulation.
Several oral JAK inhibitors have recently been developed for treating autoimmune
diseases, including rheumatoid arthritis (RA). Here, we investigated the
pharmacological effects of peficitinib (formerly known as ASP015K), a novel,
chemically synthesized JAK inhibitor. We found that peficitinib inhibited JAK1
and JAK3 with 50% inhibitory concentrations of 3.9 and 0.7 nM, respectively.
Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5
phosphorylation in vitro and ex vivo. Furthermore, peficitinib dose-dependently
suppressed bone destruction and paw swelling in an adjuvant-induced arthritis
model in rats via prophylactic or therapeutic oral dosing regimens. Peficitinib
also showed efficacy in the model by continuous intraperitoneal infusion. Area
under the concentration versus time curve (AUC) at 50% inhibition of paw swelling
via intraperitoneal infusion was similar to exposure levels of AUC at 50%
inhibition via oral administration, implying that AUC might be important for
determining the therapeutic efficacy of peficitinib. These data suggest that
peficitinib has therapeutic potential for the oral treatment of RA.
|
