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Cristiano AF Zerbini*
andAndrea Barranjard
Vannucci Lomonte
Centro Paulista de Investigao Clinica
& Department of Rheumatology,
Hospital Helipolis, So Paulo, Brazil
*Author for correspondence:
Tel.: +55 11 35146022
Fax: +55 11 35146024
criszerb@uol.com.br
Rheumatoid arthritis
10.1586/ECI.12.19
ISSN 1744-666X
319
Drug Profile
320
Drug Profile
Properties
Abatacept (Orencia )
Fusion protein of the extracellular domain of human CTLA4 linked to a fragment of the FC segment
of human IgG1 specific for CD80/86
Adalimumab (Humira)
Anakinra (Kineret)
Etanercept (Enbrel )
Fusion protein of extracellular domain of the human p75 TNF-a receptor linked to the FC portion of
human IgG1
Golimumab (Simponi)
Infliximab (Remicade )
Tocilizumab (RoActemra /Actemra ) Humanized mAb specific for the IL-6 receptor
Drug Profile
JAK3SCID
JAK1
JAK3
= 34.0 nM for Tyk2, with approximately
membrane
1000-fold selectivity for JAK3 compared
with 82 other kinases for which IC50 has
been determined [25] . In a cellular setting,
a series of assays were performed with
P
combinations of JAK enzymes to evaluate
STAT
the potency of tofacitinib. The inhibitory
effect of tofacitinib was much more
potent against JAK1/3-dependent activity
than with other JAKs. In the two assays
mediated by JAK3 and JAK1, the IL-2Nuclear
membrane
dependent T-cell proliferation showed an
IC50 of ~11 nM and the mixed lymphocyte
showed IC50=87nM. A granulocyte
macrophage-colony stimulating factor
Transcription
(GM-CSF)-proliferation assay driven by
JAK2 resulted in an IC50 of ~324nM in a
Hu03 cell based assay, which suggests that
inhibition of JAK2 could only be seen at
higher concentrations invivo. The activity
Figure2. Cytokine signaling through the JAK1/JAK3/STAT pathway.
X-SCID
Target(s)
INCB-28050
JAK1/2
Tofacitinib/CP-690550
JAK1/3
VX-509
JAK3
VX-702
p38 MAPK
BMS-582949
p38 MAPK
Fostamatinib disodioum/R-788
SYK
322
Drug Profile
CN
O
N
N
N
H
Figure3. Tofacitinib.
Drug Profile
Drug Profile
to be seen in the 5-, 10- and 15-mg groups for ACR20 response
rates and secondary end points of the study, including ACR50,
ACR70 and DAS28-4(erytrocyte sedimentation rate [ESR]). The
highest ACR50 and ACR70 response rates at week 24 were seen
for tofacitinib 10mg b.i.d. and 15mg b.i.d.
PhaseIIb dose-ranging combination study in Japan
ClinicalTrials.gov
identifier
Doses (mg)
PhaseIIa monotherapy
NCT00147498
264
NCT00413660
[40]
24
[42]
24
[43]
12
[44]
NCT00603512
140
www.expert-reviews.com
325
Drug Profile
ClinicalTrials.gov RA population
identifier
Tofacitinib
regimen
ORAL
Solo
NCT00814307
Traditional or
Monotherapy
biologic DMARD-IR
Placebo control 6
[45]
ORAL
Scan
NCT00847613
MTX-IR
Placebo control 24
[46]
ORAL
Sync
NCT00856544
Traditional or
Combined therapy Placebo control 12
biologic DMARD-IR (background
traditional DMARD)
[103]
ORAL
NCT00853385
Standard
MTX-IR
Combined therapy
(MTX)
Placebo control 12
Adalimumab
[103]
ORAL
Step
NCT00960440
Anti-TNF-IR
Combined therapy
(MTX)
Placebo control 6
[47]
ORAL
Start
NCT01039688
MTX-naive
Monotherapy
MTX control
[103]
Combined therapy
(MTX)
Comparator
Duration
(months)
24
End points
Ref.
DMARD: Disease-modifying antirheumatic drug; IR: Inadequate responder; MTX: Methotrexate; RA: Rheumatoid arthritis.
Data taken from [103].
326
Drug Profile
Drug Profile
Drug Profile
CAF Zerbini has received grants for Reseach from Merck, Pfizer, Amgen,
Lilly, Novartis, Sanofi-Aventis, Servier, GSK and Roche, has presented at
medical conferences for Pfizer, Merck, Sanofi-Aventis and Servier and is on
the board committees for Sanofi-Aventis, Pfizer and Merck. The authors
have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
JAKs are a family of tyrosine kinases composed of four membrane-associated intracellular nonreceptor enzymes (JAK1, JAK2, JAK3
andTyk2).
JAK3 is predominantly expressed at high levels in hematopoietic tissues, being found in myeloid cells, thymocytes, natural killer cells and
activated B and T lymphocytes. JAK3 binds to only one cytokine receptor, the common g chain or gc. This chain is shared by many
inflammatory cytokine receptors, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
Tofacitinib is an oral selective and potent inhibitor of JAK1 and 3 capable of interfering with signaling through cytokine receptors of all the
cytokines listed above.
Tofacitinib is rapidly absorbed and eliminated with a time to peak concentration of approximately 0.5h and a half-life of approximately 3h.
The protein binding of tofacitinib is approximately 40%, raising the possibility of a low drug interaction due to drug displacement.
There is no need for dosage adjustment with coadministration of tofacitinib and methotrexate. Tofacitinib dosage adjustments or food
restrictions are not warranted during chronic treatment.
Tofacitinib administration showed significant anti-inflammatory effects in two rodent models of arthritis and animal models of
transplantation.
In a proof-of-concept monotherapy study, improvements in disease activity were observed as early as 1 week after treatment for all
tofacitinib groups (5, 15 and 30mg two-times a day) in comparison to placebo. Increased American College of Rheumatology (ACR)50 and
ACR70 response rates relative to placebo were seen at all time points by week 4.
Three Phase IIb dose-ranging trials lasting from 6 to 24 weeks in RA patients showed significant ACR20 improvements as early as week2
and sustained at week 24 in two studies. These studies led to the identification of the two-times a day doses now used in the PhaseIII trials.
A PhaseIII 6month monotherapy study evaluated two doses of tofacitinib in 610 RA patients. The month 3 ACR20 response rates for
tofacitinib 5 and 10mg two-times a day were significantly better than the placebo group responses.
PhaseIII studies in RA are included in a large clinical program called ORAL Trials. Additional results will be available soon.
Dose-related increases in the number of adverse events were observed in the clinical trials. Common adverse events included headache,
nausea, upper respiratory infections, urinary tract infections, anemia, leukopenia, neutropenia and hypercholesterolemia.
Results from the RA studies show that there is potential for trials in other illnesses like psoriasis, inflammatory bowel diseases and organ
transplantation.
rheumatoid arthritis. Arthritis Rheum. 31,
315324 (1988).
References
Papers of special note have been highlighted as:
of interest
of considerable interest
1
www.expert-reviews.com
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Drug Profile
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12
13
14
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26
16
27
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Burmester G, Blanco R, CharlesSchoemann C etal. Tofacitinib (CP690,550), an oral janus kinase inhibitor, in
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inadequate response to tumor necrosis
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(Abstract).
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49
Drug Profile
50
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Websites
101
102
103
ClinicalTrials.gov.
http://clinicaltrials.gov/ct2/results?term=C
P+690+550+rheumatoid+arthritis
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