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Evaluation of the efficacy and safety of pamapimod a p38 MAP kinase inhibitor in a double-blind methotrexate-controlled study of patients with active rheumatoid arthritis.

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Vol. 60, No. 2, February 2009, pp 335–344
DOI 10.1002/art.24266
© 2009, American College of Rheumatology
Evaluation of the Efficacy and Safety of Pamapimod,
a p38 MAP Kinase Inhibitor, in a Double-Blind,
Methotrexate-Controlled Study of Patients With
Active Rheumatoid Arthritis
Stanley B. Cohen,1 Tien-Tsai Cheng,2 Vishala Chindalore,3 Nemanja Damjanov,4
Ruben Burgos-Vargas,5 Patricia DeLora,6 Kathleen Zimany,6 Helen Travers,7
and John P. Caulfield8
Objective. To determine the efficacy and safety of
pamapimod (a selective inhibitor of the ␣-isoform of
p38 MAP kinase) as monotherapy in comparison with
methotrexate (MTX) treatment in adult patients with
active rheumatoid arthritis (RA).
Methods. Patients were randomly assigned to 1 of
4 treatment groups and received 12 weeks of doubleblind treatment. One group received MTX (7.5 mg/week
with planned escalation to 20 mg/week), and 3 groups
received pamapimod (50, 150, or 300 mg) once daily.
The primary efficacy end point was the proportion of
patients meeting the American College of Rheumatology
20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included
ACR50 and ACR70 responses, change from baseline in
the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against
Rheumatism response, and change from baseline in
each parameter of the ACR core set of measures. Safety
monitoring included recording of adverse events (AEs),
laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital
Results. Patients assigned to receive MTX and
pamapimod had similar demographics and baseline
characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in
the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary
efficacy end points showed a similar pattern. AEs were
typically characterized as mild and included infections,
skin disorders, and dizziness. Pamapimod was generally
well tolerated, but the 300-mg dose appeared to be more
toxic than either the 2 lower doses or MTX.
Conclusion. The present results showed that pamapimod was not as effective as MTX in the treatment of
active RA. identifier: NCT00303563.
Supported by Hoffman-La Roche, Nutley, New Jersey.
Stanley B. Cohen, MD: Metroplex Clinical Research, Dallas,
Texas; Tien-Tsai Cheng, MD: Chang Gung Memorial Hospital–
Kaohsiung Medical Center, and Chang Gung University College of
Medicine, Kaohsiung, Taiwan; 3Vishala Chindalore, MD: Pinnacle
Research Group, Anniston, Alabama; 4Nemanja Damjanov, MD,
PhD: Institut za Reumatologiju, Belgrade University School of Medicine, Belgrade, Serbia and Montenegro; 5Ruben Burgos-Vargas, MD:
Clı́nica para el Diagnostico y Tratamiento de las Enfermedades
Reumáticas and Hospital General de México, Mexico City, Mexico;
Patricia DeLora, BA, Kathleen Zimany, MS: Hoffman-La Roche,
Nutley, New Jersey; 7Helen Travers, PhD: Roche Products Ltd.,
Welwyn Garden City, UK; 8John P. Caulfield, MD: Roche Palo Alto,
LLC, Palo Alto, California.
Dr. Cohen has served as a clinical investigator and research
consultant for Genentech, Biogen Idec, Roche, Procter & Gamble,
Pfizer, Centocor, Amgen, Scios, and Wyeth-Ayerst, and has received
consulting and/or speaking fees from these companies (less than
$10,000 each). Dr. Chindalore has received speaking fees from Roche,
Pfizer, and GlaxoSmithKline (less than $10,000 each). Dr. BurgosVargas has received consulting fees, speaking fees, and/or honoraria
from Roche, Schering-Plough, Wyeth, and Abbott (less than $10,000
each). Ms DeLora owns stock or stock options in Hoffman-La Roche.
Dr. Caulfield owns stock or stock options in Roche.
Address correspondence and reprint requests to Stanley B.
Cohen, MD, Metroplex Clinical Research Center, 5939 Harry Hines
Boulevard, Suite 441, Dallas, TX 75235. E-mail:
Submitted for publication June 6, 2008; accepted in revised
form October 22, 2008.
Parenteral biologic therapies that selectively neutralize proinflammatory cytokines such as tumor necrosis factor ␣ (TNF␣) and interleukin-1␤ (IL-1␤) or their
receptors, such as the IL-6 receptor, substantially improve signs and symptoms of rheumatoid arthritis (RA),
reduce the number of swollen and tender joints, and
slow radiographic progression of erosive disease. However, there are no marketed orally active, safe, and
effective agents that act primarily to inhibit TNF␣ or
IL-1␤, despite attempts to develop such compounds
The p38␣ MAP kinase (MAPK) has been a major
molecular target for the development of an anti–
proinflammatory cytokine small-molecule oral therapy
for RA. The ␣-isoform is an enzyme important to the
intracellular signaling pathway for the generation of
TNF␣ or IL-1␤. Multiple extracellular stimuli, including
stress signals (lipopolysaccharide), osmotic or heat
shock, and proinflammatory cytokines (TNF␣ or IL-1␤),
stimulate the p38 pathway (4). The p38␣ MAPK also
regulates the expression of cyclooxygenase 2, the enzyme that regulates prostanoids (e.g., prostaglandin E2)
in inflammation (5). Activation of the p38␣ pathway
causes both transcriptional and translational modulation
of gene expression of TNF␣ and IL-1␤ that is both cell
type and signal specific. Inhibitors of p38␣ block the
production of TNF␣ and IL-1␤ in monocytes and in
animal models of arthritis (6). The evidence for a role of
the other 3 isoforms, ␤, ␥, and ␦, in TNF generation is
not as strong as that for the ␣-isoform, although the ␣
and ␥ isoforms have been localized to the rheumatoid
synovium (7–9).
Pamapimod is a novel small molecule of the
pyridopyrimidine class that selectively inhibits the
␣-isoform of p38 MAPK (10). Its mean ⫾ SD 50%
inhibition concentration against recombinant p38␣ is
0.014 ⫾ 0.002 ␮M, while that against TNF␣ release from
cultured monocytic leukemia-derived THP-1 cells is
0.025 ⫾ 0.001 ␮M, and that against IL-1␤ production
from human whole blood is 0.10 ⫾ 0.03 ␮M. In a variety
of in vitro and in vivo preclinical models, pamapimod
inhibited TNF␣, IL-1␤, and IL-6 production; it also
reduced inflammation and provided joint protection in
collagen-induced arthritis in mice. In studies in healthy
volunteers, pamapimod was well tolerated and was
associated with mild dizziness, mild infections (such as
folliculitis, bronchitis, and urinary tract infections), and
mild, reversible elevations of creatinine phosphokinase
(CPK) (Zhang X, Huang Y, Caulfield JP: unpublished
data). Therefore, phase II development of pamapimod
as an oral agent to treat RA was initiated. In the study
reported here (PA18604), patients not currently receiving methotrexate (MTX) were given either pamapimod
once daily at 1 of 3 dosage levels or MTX weekly with
appropriate increase of the MTX dosage. In a companion study (PA18439), patients with an incomplete response to MTX were given once-daily or twice-daily
dosing regimens of pamapimod or were given placebo
(Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F,
Emery P, et al: unpublished observations).
Patients. Eligible patients were age ⱖ18 years, had
active RA according to the 1987 revised criteria of the American College of Rheumatology (ACR; formerly, the American
Rheumatism Association) (11), received antiinflammatory
therapy for RA on an outpatient basis, had ⱖ6 swollen joints
(of 66 joints assessed) and ⱖ8 tender joints (of 68 joints
assessed), and had a high-sensitivity C-reactive protein
(hsCRP) level ⱖ0.6 mg/dl or an erythrocyte sedimentation rate
(ESR) ⱖ28 mm/hour or morning stiffness ⱖ45 minutes. Patients were excluded if they were unable to get out of bed
without assistance or required use of a wheelchair, had a
history of or current inflammatory joint disease other than RA,
or had a rheumatic autoimmune disease other than RA or
significant systemic involvement secondary to RA; Sjögren’s
syndrome with RA was allowed. Other exclusion criteria
included discontinuation of previous MTX therapy due to
clinically important toxicity or insufficient efficacy, previous
treatment with alkylating agents, evidence of serious uncontrolled disease, history or evidence of tuberculosis, active
infections, history of recurrent bacterial infections, history of
hereditary or acquired immune deficiency disorder, pregnancy
or breast-feeding, or neuropathies or other painful conditions
that had the potential to interfere with pain evaluations.
Treatment with disease-modifying antirheumatic drugs
(DMARDs) and biologic agents had to be stopped prior to
baseline as follows: infliximab and adalimumab, 8 weeks;
leflunomide, 8 weeks, or after cholestyramine, 4 weeks; intraarticular or parenteral corticosteroids, 4 weeks; sulfasalazine,
azathioprine, cyclosporine, D-penicillamine, hydroxychloroquine, chloroquine, and gold, 3 weeks; etanercept and anakinra, 2 weeks.
Study protocol. This 12-week, double-blind, doubledummy, parallel-group, active-controlled study was conducted
at 61 centers in the US, Canada, Mexico, Europe, South
Africa, and Taiwan. All participating sites received approval
from their governing institutional review board (or equivalent),
all patients provided informed written consent, and the study
was performed in accordance with the Declaration of Helsinki.
A list of investigators who recruited patients for this study is
shown in Appendix A.
At screening, medical history was recorded, and information was collected regarding swollen and tender joints and
duration of morning stiffness. Vital signs and physical measurements were obtained, and a complete physical examination, electrocardiography (EKG), chest radiography, tuberculin skin test, clinical laboratory tests (hematology, serum
chemistry, nonfasting lipid panel, and urinalysis), and a serum
pregnancy test (as required) were performed. Blood samples
were obtained to test for hepatitis B surface antigen and
hepatitis C virus and to determine the hsCRP level and ESR.
Patients were randomly assigned (1:1:1:1) to 1 of 4
treatment regimens in a blinded manner and stratified by
geographic region and previous MTX exposure. The first
group received 50 mg pamapimod once daily (two 25-mg
tablets) plus MTX placebo weekly. The second group received
150 mg pamapimod once daily (two 75-mg tablets) plus MTX
placebo weekly. The third group received 300 mg pamapimod
once daily (two 150-mg tablets) plus MTX placebo weekly. The
fourth group received placebo pamapimod once daily (two
placebo tablets) plus MTX weekly in increasing doses. Patients
randomly assigned to the MTX group received MTX orally
once a week, commencing at 7.5 mg (three 2.5-mg tablets) on
day 1, which was increased to 15 mg weekly by week 4; a
further increase to 20 mg weekly was an option at week 8,
depending on whether the patient had painful and swollen
joints and did not have signs of significant MTX-related
toxicity. Of those in the MTX group who completed 12 weeks
of dosing, 71% were taking 15 mg/week and 29% were taking
20 mg/week at the end of the study. The mean cumulative dose
of MTX was 156.5 mg. In the 3 pamapimod groups, MTX
placebo was escalated to achieve similar nominal mean cumulative doses as in the MTX group, namely, 155.1 mg for the
50-mg group, 152.4 mg for the 150-mg group, and 142.4 mg for
the 300-mg group. MTX dosage reductions were permitted for
patients who experienced possible MTX-related side effects,
and dosage adjustments were performed in the same manner
for both active and placebo forms of MTX, due to the blinded
nature of the study.
In addition to the study drug, patients were to receive
folic acid (5 mg weekly) during the study. Oral corticosteroids
(ⱕ10 mg/day prednisone or equivalent) and nonsteroidal
antiinflammatory drugs were permitted if the dosage was
stable for ⱖ4 weeks and ⱖ2 weeks, respectively, prior to
baseline and maintained during the study. The following
treatments were prohibited during the study: DMARDs, MTX
(except as part of protocol-defined study therapy), prednisone
or equivalent at a dosage of ⬎10 mg/day, intraarticular or
parenteral corticosteroids, biologic agents, cell-depleting therapies, alkylating agents (including cyclophosphamide), any
investigational agent other than pamapimod, immunizations,
and immunoabsorption columns.
Efficacy parameters were assessed at baseline and then
routinely throughout the 12 weeks of treatment according to
the following schedule. The swollen and tender joint counts
and the Stanford Health Assessment Questionnaire disability
index (HAQ DI) score (12) were obtained at weeks 2, 4, 8, and
12. An assessment of fatigue using the fatigue subscale of the
Functional Assessment of Chronic Illness Therapy questionnaire (FACIT-F) (13) was performed at weeks 4 and 12. All
other efficacy assessments (patient’s and physician’s global
assessment of disease activity, patient’s assessment of pain,
hsCRP level, ESR, and morning stiffness) were performed at
weeks 1, 2, 4, 8, and 12.
Safety assessments, including EKGs and vital signs,
were monitored routinely. Safety laboratory testing (hematology, blood chemistry including CPK level, lipid panel, and
urinalysis) was performed at screening and baseline and at
weeks 1, 2, 4, 8, and 12. In addition, immunology laboratory
testing for rheumatoid factor (RF), anti–cyclic citrullinated
peptide (anti-CCP), lymphocyte subtype analysis (CD4⫹,
CD3⫹, CD8⫹, and CD19⫹ cells were sorted), anti–doublestranded DNA (anti-dsDNA), antitetanus titer, IgG, IgA, and
IgM was performed at baseline and at week 12.
All adverse events (AEs) encountered during the study
and through 4 weeks following discontinuation of study treat-
ment were recorded. AEs were monitored until they stabilized
or returned to baseline status. For each AE, the investigator
assessed and recorded the intensity (as mild, moderate, or
severe), relationship to the study drug (unrelated or remotely,
possibly, or probably related), action taken (i.e., whether a
treatment was given or a procedure performed and whether
the study drug was discontinued or the dose adjusted), and
outcome. A serious AE was defined as any experience that
resulted in death, was life-threatening, required hospitalization
or prolonged an existing hospitalization, resulted in a persistent or significant disability, resulted in a congenital anomaly/
birth defect, or required intervention to prevent one or more
of the outcomes listed above.
Clinical assessments. The primary efficacy end point
was the proportion of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) at week 12 (14),
defined as a 20% improvement from baseline in swollen joint
count and tender joint count and in at least 3 of the following
5 variables: HAQ DI score, patient’s global assessment of
disease activity, patient’s global assessment of pain, physician’s
global assessment of disease activity, and level of an acutephase reactant (primarily CRP; ESR was used only if CRP was
missing). Secondary end points included ACR50 and ACR70
responses (50% and 70% improvement, respectively, from
baseline in the parameters used to define an ACR20 response), change from baseline in the Disease Activity Score in
28 joints (DAS28) (15), categorical analyses of DAS28/
European League Against Rheumatism response (16), and
change from baseline in each parameter of the ACR core set
of measures (17) (swollen joint count, tender joint count,
patient’s and physician’s global assessment of disease activity,
patient’s assessment of pain, HAQ DI score, hsCRP level,
and ESR). Additional secondary end points included assessments of the FACIT-F score and the severity and duration of
morning stiffness.
Statistical analysis. Pamapimod and MTX were expected to have similar efficacy levels, with an assumed ACR20
response rate of 50–70% based on historical data. For a
response rate of 70%, a sample size of 50 patients for a given
treatment group would provide a 90% confidence interval
(90% CI) with a margin of error of ⬃10%. For a response rate
of 50%, the same sample size would provide a 90% CI with a
margin of error of ⬃12%.
Efficacy analyses were based on the intent-to-treat
(ITT) population, defined as all patients who received at least
1 dose of double-blind study medication. Patients who prematurely withdrew from the study for any reason, or for whom an
assessment was not performed for any reason, were included in
the ITT population. Analysis of safety data included all
randomized patients who received at least 1 dose of study
medication and had at least 1 safety assessment.
For the primary efficacy analysis, no formal hypothesis
testing was performed. Descriptive statistics, including CI
estimates, were used to evaluate differences among treatment
groups. Patients with missing ACR20 response values at week
12 (including patients who had withdrawn from the study prior
to week 12) were classified as nonresponders for the purpose
of the analysis. The primary efficacy variable (ACR20 response
at week 12) was analyzed using the Cochran-Mantel-Haenszel
test, with region and previous MTX exposure as stratification
Table 1. Baseline characteristics of the patients*
Age, years
Female, no. (%)
Swollen joint count (of 66 joints)
Tender joint count (of 68 joints)
RF positive, no. (%)
RF, IU/ml
Anti-CCP positive, no. (%)
CRP level, mg/dl
ESR, mm/hour
Morning stiffness ⱖ45 minutes, no. (%)
DAS28 using ESR
HAQ DI score
FACIT-F score
Patient’s global assessment of disease activity,
0–100-mm VAS
Physician’s global assessment of disease activity,
0–100-mm VAS
Patient’s assessment of pain, 0–100-mm VAS
Use of corticosteroids, no. (%)
Previous exposure to MTX, no. (%)
Previous use of DMARDs, no. (%)
Number of previous DMARDs
Previous use of anti-TNF agents, no. (%)
(n ⫽ 53)
50 mg
once daily
(n ⫽ 52)
150 mg
once daily
(n ⫽ 51)
300 mg
once daily
(n ⫽ 48)
47.3 ⫾ 12.4
44 (83)
15.5 ⫾ 8.4
28.5 ⫾ 14.6
34 (64)
154.4 ⫾ 282.4
32 (60)
1.62 ⫾ 1.91
39.7 ⫾ 22.4
47 (89)
6.40 ⫾ 0.90
1.36 ⫾ 0.65
28.1 ⫾ 11.1
62.4 ⫾ 26.7
51.4 ⫾ 11.5
45 (87)
17.5 ⫾ 9.2
27.0 ⫾ 12.6
37 (71)
308.4 ⫾ 650.3
36 (69)
2.04 ⫾ 2.41
47.8 ⫾ 33.7
46 (88)
6.42 ⫾ 0.97
1.33 ⫾ 0.74
29.9 ⫾ 11.0
55.6 ⫾ 24.2
50.7 ⫾ 12.4
43 (84)
15.7 ⫾ 9.5
27.0 ⫾ 15.2
33 (67)
235.0 ⫾ 411.3
38 (75)
1.95 ⫾ 2.10
44.3 ⫾ 25.1
45 (90)
6.30 ⫾ 1.03
1.37 ⫾ 0.75
30.4 ⫾ 11.3
58.6 ⫾ 24.8
50.2 ⫾ 12.8
40 (83)
19.2 ⫾ 10.9
28.2 ⫾ 14.7
27 (57)
142.6 ⫾ 248.0
33 (69)
2.58 ⫾ 2.95
42.0 ⫾ 22.8
42 (88)
6.61 ⫾ 1.00
1.58 ⫾ 0.74
26.6 ⫾ 11.2
63.6 ⫾ 23.9
58.1 ⫾ 20.8
56.8 ⫾ 19.5
54.4 ⫾ 20.4
59.9 ⫾ 21.2
53.6 ⫾ 25.0
25 (47)
21 (40)
29 (55)
2.4 ⫾ 1.2
4 (8)
49.8 ⫾ 19.5
28 (54)
22 (42)
32 (62)
1.8 ⫾ 0.9
3 (6)
52.2 ⫾ 19.8
21 (41)
16 (31)
28 (55)
2.0 ⫾ 1.2
1 (2)
55.7 ⫾ 24.3
25 (52)
16 (33)
25 (52)
2.2 ⫾ 1.1
3 (6)
* Except where indicated otherwise, values are the mean ⫾ SD. MTX ⫽ methotrexate; RF ⫽ rheumatoid factor; anti-CCP ⫽ anti–cyclic citrullinated
peptide; CRP ⫽ C-reactive protein; ESR ⫽ erythrocyte sedimentation rate; DAS28 ⫽ Disease Activity Score in 28 joints; HAQ DI ⫽ Health
Assessment Questionnaire disability index; FACIT-F ⫽ Functional Assessment of Chronic Illness Therapy–Fatigue; VAS ⫽ visual analog scale;
DMARDs ⫽ disease-modifying antirheumatic drugs; anti-TNF ⫽ anti–tumor necrosis factor.
For the secondary efficacy analyses, results for categorical parameters were analyzed as described for the primary
efficacy analysis. Patients with missing ACR50 and ACR70
response values were considered nonresponders for the week-12
analyses. For all other categorical variables, the observed data
were used. Results for continuous parameters were summarized using descriptive statistics.
Patient characteristics. Study data were collected
between February 9, 2006 and June 21, 2007. Of the 271
patients screened, 204 were enrolled; 53 were randomized to receive MTX and 151 to receive pamapimod (52,
51, and 48 patients to the 50-, 150-, and 300-mg groups,
respectively). Table 1 summarizes the demographics and
baseline characteristics of the 4 treatment groups. The
majority of patients were women, and the mean age of
the patients ranged from 47.3 years to 51.4 years across
the treatment groups. At baseline, the majority of
patients tested positive for RF and anti-CCP, 88% of
patients reported having morning stiffness of ⱖ45 minutes, and 47% had CRP values that were ⱖ1.0 mg/dl.
Data on duration of disease were not captured. Fifty-six
percent of patients had reported prior use of DMARDs
(mean of 2) for treatment of RA, 37% of patients had
prior exposure to MTX, and 2–8% of patients had used
an anti-TNF medication. At baseline, approximately half
of the patients were using corticosteroids at a dosage
equivalent to ⱕ10 mg prednisone once daily. The 4
treatment groups were generally similar at baseline with
regard to the ACR core set (17) characteristics of
swollen and tender joint counts, HAQ DI score, patientassessed pain, and patient and physician globally assessed disease activity (Table 1).
All patients received at least 1 dose of the study
drug and were included in both the ITT and safety
analysis populations. Overall, 81% of patients completed
12 weeks of treatment; 15.1% of patients in the MTX
group and 19.9% of patients in the combined pamapimod groups discontinued study treatment prematurely
(Table 2). Reasons for discontinuation were attributed
to AEs, lack of efficacy, and refusal of continued treatment (which included noncompliance and withdrawal of
consent). The rates of and reasons for discontinuation
were similar between the MTX group and the 2 lower-
Table 2. Disposition of the patients*
50 mg
150 mg
300 mg
MTX once daily once daily once daily
(n ⫽ 53) (n ⫽ 52) (n ⫽ 51) (n ⫽ 48)
Adverse event
4 (7.5)
3 (5.8)
Insufficient therapeutic 3 (5.7)
4 (7.7)
Refused treatment†
1 (1.9)
2 (3.8)
45 (84.9) 43 (82.7)
4 (7.8)
3 (5.9)
10 (20.8)
2 (4.2)
2 (3.9)
42 (82.4)
36 (75.0)
* Values are the number (%) of patients. MTX ⫽ methotrexate.
† Includes patients who withdrew consent and those who were not
compliant with the protocol.
dose pamapimod groups. The incidence of discontinuation due to an AE was highest in the 300-mg pamapimod
group (with a rate of 21%, compared with 6–8% in the
other 3 groups).
Clinical efficacy. The percentage of patients with
an ACR20 response at week 12 was lower in each of the
3 pamapimod groups (23%, 18%, and 31% in the 50-,
150-, and 300-mg groups, respectively) than in the MTX
group (45%) (Figure 1A). The percentage with an
ACR20 response at week 12 was higher in the 300-mg
pamapimod group than in the 2 lower-dose pamapimod
groups. Similarly, a greater percentage of patients in the
MTX group had an ACR50 response at week 12 compared with the pamapimod groups (23% in the MTX
group, versus 12%, 6%, and 13% in the 50-, 150-, and
300-mg pamapimod groups, respectively) (Figure 1B).
Few patients (ⱕ8% in each treatment group) had an
ACR70 response, and rates were similar in all 4 dosage
groups (Figure 1C). A Cochran-Mantel-Haenszel analysis of the ACR20 response at week 12 was used to
calculate the weighted difference in proportions, adjusted for stratification factors, between each of the
pamapimod groups and the MTX group (pamapimod
minus MTX), with a 95% CI for the treatment difference. The results were as follows: ⫺0.22 (95% CI ⫺0.40,
⫺0.05) for the 50-mg group, ⫺0.28 (95% CI ⫺0.45,
⫺0.12) for the 150-mg group, and ⫺0.14 (95% CI ⫺0.32,
0.04) for the 300-mg group. Thus, MTX had superior
efficacy to pamapimod, although for the 300-mg dose
level, the CI encompassed zero. While the mean DAS28
decreased over time in all groups, by week 12, the MTX
group showed the greatest improvements (Figure 1D).
For each of the 8 ACR core component criteria,
the MTX group showed the greater improvement from
baseline compared with the 3 pamapimod groups (Table
3). In the 300-mg pamapimod group, the improvement
Figure 1. A–C, Percentages of patients meeting the American College of Rheumatology 20%, 50%, and
70% improvement criteria (achieving ACR20 [A], ACR50 [B], and ACR70 [C] responses, respectively)
over the 12-week study period in the intent-to-treat population. D, Changes in the Disease Activity Score
in 28 joints (DAS28) over the 12-week study period in the intent-to-treat population. MTX ⫽
methotrexate; QD ⫽ once daily.
Table 3. Analysis of variance of absolute change from baseline in the American College of Rheumatology core set parameters at week 12*
No. of patients
Adjusted mean
50 mg once daily
No. of patients
Adjusted mean
95% CI of difference
150 mg once daily
No. of patients
Adjusted mean
95% CI of difference
300 mg once daily
No. of patients
Adjusted mean
95% CI of difference
joint count
(of 66 joints)
joint count
(of 68 joints)
Patient’s global
assessment of
disease activity,
Physician’s global
assessment of
disease activity,
of pain,
CRP level,
DI score
⫺3.1, 3.5
⫺0.9, 9.2
5.5, 26.6
⫺0.7, 16.9
7.7, 28.8
0.4, 2.0
2.7, 17.2
0.0, 0.5
⫺1.1, 5.6
⫺1.6, 8.6
5.0, 26.4
0.3, 18.1
3.8, 25.0
0.2, 1.9
4.9, 19.6
⫺0.1, 0.4
⫺3.3, 3.6
⫺3.3, 7.2
0.1, 22.1
⫺3.3, 15.2
3.4, 25.5
⫺0.4, 1.3
⫺0.5, 14.6
0.1, 0.6
* 95% CI ⫽ 95% confidence interval (see Table 1 for other definitions).
in joint scores was almost as good as with MTX;
however, improvements in the patient’s disease activity
and pain assessment scores were less than with MTX.
CRP levels decreased from baseline for patients in the
MTX group and increased for patients in the 50- and
150-mg pamapimod groups; in the 300-mg pamapimod
group, there was a modest initial decrease in CRP levels
followed by small changes that remained near baseline
(Figure 2).
FACIT-F scores showed mean increases from
baseline over time, suggesting reduced fatigue; these
increases were similar across treatment groups (data not
shown). The duration of morning stiffness appeared to
decline in all groups over the course of the study; while
the majority of patients had morning stiffness for ⱖ45
minutes at baseline, by the end of the study the majority
of patients experienced morning stiffness for ⱕ45 minutes, with the greatest shift observed in the MTX group
(data not shown).
Safety. The percentage of patients experiencing
at least 1 AE (including AEs experienced during the
4-week followup period) was 58% in the MTX group,
63% in the 50-mg pamapimod group, and 73% in the
150- and 300-mg pamapimod groups (Table 4). Events
considered related to study treatment occurred in 42%
of MTX-treated patients and in 35–56% of pamapimodtreated patients, showing an increased incidence with
dose level. Similarly, the incidence of serious AEs increased with pamapimod dose level, with incidences of
2%, 8%, and 10% in the 50-, 150-, and 300-mg pamapimod groups, respectively, compared with a 4% incidence
in the MTX group. Infections were the most frequently
Figure 2. Change from baseline in C-reactive protein levels over
the 12-week study period. Values are the mean. See Figure 1 for
Table 4.
Summary of adverse events*
Any adverse event
Serious adverse event†
Related serious adverse events‡
Adverse event leading to withdrawal
Adverse events with ⱖ5% incidence
Infections and infestations
(system organ class)
Skin and subcutaneous tissue
disorders (system organ class)
Hepatic enzyme increased
Upper respiratory tract infection
Rheumatoid arthritis
Urinary tract infection
(n ⫽ 53)
50 mg
once daily
(n ⫽ 52)
150 mg
once daily
(n ⫽ 51)
300 mg
once daily
(n ⫽ 48)
31 (58)
2 (4)
4 (8)
33 (63)
1 (2)
1 (2)
3 (6)
37 (73)
4 (8)
1 (2)
4 (8)
35 (73)
5 (10)
2 (4)
10 (21)
13 (25)
12 (23)
14 (27)
17 (35)
2 (4)
6 (12)
4 (8)
9 (19)
3 (6)
2 (4)
3 (6)
6 (11)
4 (8)
1 (2)
3 (6)
1 (2)
3 (6)
1 (2)
2 (4)
4 (8)
3 (6)
3 (6)
4 (8)
2 (4)
2 (4)
1 (2)
2 (4)
2 (4)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
2 (4)
5 (10)
2 (4)
1 (2)
5 (10)
1 (2)
2 (4)
1 (2)
3 (6)
2 (4)
1 (2)
3 (6)
1 (2)
1 (2)
7 (15)
6 (13)
4 (8)
3 (6)
4 (8)
3 (6)
1 (2)
3 (6)
2 (4)
1 (2)
3 (6)
* Values are the number (%) of patients. MTX ⫽ methotrexate.
† Defined in Patients and Methods.
‡ Considered by the investigator to be remotely, possibly, or probably related to the study drug.
reported serious AEs, occurring in 2%, 2%, and 6% of
patients in the 50-, 150-, and 300-mg pamapimod groups,
respectively, with 0% in the MTX group. Of these
infections, 3 were considered by the investigator to be
possibly or probably related to the study drug: sialadenitis (50-mg group), pneumonia (300-mg group), and
gastrointestinal (GI) infection (300-mg group). One
additional serious AE, GI hemorrhage in the 150-mg
pamapimod group, was considered related to the study
drug. There were no deaths reported during the 12-week
study or 4-week followup period.
Withdrawals from the study due to an AE were
similar between the MTX group and the 2 lower-dose
pamapimod groups (6–8%); in contrast, the rate was
substantially higher in the 300-mg pamapimod group
(21%). In the MTX group, AEs that led to treatment
withdrawal included elevated liver enzyme levels (3
patients) and dizziness (1 patient). In contrast, in the
300-mg pamapimod group, AEs that led to withdrawal
included infection (1 patient), skin disorders (2 patients), elevated liver enzyme levels (3 patients), GI
disorders (3 patients), and RA flare (1 patient).
AEs involving infections or skin disorders as well
as dizziness and increased hepatic enzymes occurred
with greater frequency in pamapimod-treated patients
than in MTX-treated patients (Table 4). Nausea occurred more frequently in the MTX group than in the
pamapimod groups (11% of MTX-treated patients,
compared with 3% of all pamapimod-treated patients).
The proportion of patients experiencing skin
disorders trended upward with increasing pamapimod
dosage, and while the type of skin disorders varied, the
most commonly reported were rash and acne. Skin
lesions were predominantly on the face and torso and
consisted of maculopapular lesions with or without
pustules. The majority of the skin disorders resolved
while patients continued pamapimod treatment, and
only 2 patients receiving pamapimod discontinued treatment because of the dermatitis.
Dizziness appeared to be associated with pamapimod, and the incidence increased with dosage level; only
1 patient (in the 150-mg pamapimod group) withdrew
from the study due to dizziness. In the pamapimod
groups, dizziness generally occurred soon after treat-
ment was started (ranging from 1 day to 12 days) and
generally persisted for ⬍2 weeks in the lower-dose
groups and for ⬎2 weeks through the duration of the
study for patients in the 300-mg group.
Several patients had normal values on laboratory
measures at baseline but had at least 1 value outside the
normal limits following the start of MTX or pamapimod
treatment. These laboratory abnormalities included
neutrophilia, defined as ⬎9.25 ⫻ 109 cells/liter and a
⬎20% increase from baseline at any postdose time point
(13% of patients in the MTX group, 20% in the 50-mg
pamapimod group, 12% in the 150-mg pamapimod
group, and 25% in the 300-mg pamapimod group),
hematuria (8% of patients in the MTX group, 18% in
the 50-mg pamapimod group, 10% in the 150-mg pamapimod group, and 15% in the 300-mg pamapimod
group), and leukocyturia (9% of patients in the MTX
group, 8% in the 50-mg pamapimod group, 6% in the
150-mg pamapimod group, and 13% in the 300-mg
pamapimod group). Hematuria and leukocyturia were
defined on a scale of 1–4⫹; values ⬎1⫹ and increased
by ⬎2⫹ over baseline were recorded as abnormal.
Changes in laboratory parameters were observed
in all 4 treatment groups. Notably, the MTX group and
the 300-mg pamapimod group showed changes from
baseline to the end of treatment in levels of alanine
aminotransferase (ALT), aspartate aminotransferase
(AST), and CPK. Substantially elevated ALT and/or
AST values (i.e., values both ⬎2 times the upper limit of
normal [ULN] and ⬎50% over baseline) occurred in 6
MTX-treated patients (11%) and in a total of 12
pamapimod-treated patients (8%) (3 patients in the
150-mg group [6%] and 9 patients in the 300-mg group
[19%]). In both MTX- and pamapimod-treated patients,
elevated values generally occurred within 2 months after
starting the study treatment.
Within the MTX group, 3 patients with normal
ALT and AST values at baseline discontinued study
treatment due to elevations of both ALT (4.2, 14.3, and
4.0 times the ULN) and AST (2.9, 3.3, and 3.8 times
the ULN). In all 3 patients, the elevated liver enzyme
levels resolved without sequelae within 1 month following discontinuation of MTX. Similarly, within the
pamapimod-treated groups, 3 patients, all in the 300-mg
group and with normal values at baseline, discontinued
the study drug due to elevated liver enzyme levels; all 3
patients had elevated levels of ALT (3.3, 3.5, and 16.4
times the ULN), and 2 of the patients had high levels
of AST (5.0 and 7.9 times the ULN). All events were
considered possibly or probably related to the study
drug. In 2 patients, these AEs resolved without sequelae
within 1 month following discontinuation of pamapimod; in the third patient, the event was considered
ongoing at the time of last contact (30 days after
discontinuation of pamapimod). Patients with elevated
ALT and AST values had concurrent total bilirubin
values that remained within the normal range (0–17
␮moles/liter); there were no values ⬎15.6 ␮moles/liter.
Elevations of CPK levels, ranging from 2.9-fold
to 9.4-fold the ULN, were observed in 3 MTX-treated
patients (6%) and in 4 pamapimod-treated patients
(3%); of the latter patients, 3 in the 150-mg group had
values ranging from 2.0-fold to 6.2-fold the ULN, and 1
in the 300-mg group had a value of 2.2-fold the ULN.
Two patients, 1 in the MTX group and 1 in the 150-mg
pamapimod group, each had 2 reports of elevated CPK
values measured ⬃30 days apart; all other patients had
only a single episode. There was no trend in time of first
onset of elevated CPK levels; the range was 10–58 days
following the start of treatment. No patients reported
symptoms of muscle pain or weakness, and there were
no treatment discontinuations due to elevated CPK
There were no changes in RF, anti-CCP, antidsDNA, or immunoglobulin concentrations, lymphocyte
subtypes, or antitetanus titer between baseline and 12
weeks in any treatment group. There were no clinically
significant changes in EKG findings or vital signs during
the study for any treatment group.
This 12-week study demonstrated that treatment
with 50-, 150-, and 300-mg once-daily doses of pamapimod, a novel p38 MAPK inhibitor, resulted in lower
frequencies of response according to the ACR improvement criteria and the DAS28, compared with MTX
started at 7.5 mg/week and increased to 15 mg/week. The
2 lower doses of pamapimod yielded similar frequencies
of ACR improvement response, and while the frequency
of this response with the 300-mg dose was higher than
that with the lower doses, it was well below the frequency of ACR improvement response with MTX.
Pamapimod was generally well tolerated, but the overall
side effect profile suggested that the 300-mg dose was
more toxic than the 2 lower doses or MTX.
The results of this study are important, since this
is the first large randomized clinical trial evaluating a
p38 MAPK inhibitor for which efficacy and safety results
have been reported. Several p38 inhibitors have been
investigated in the clinic. In terms of efficacy, VX-745
was shown to result in a significantly better ACR20
response than placebo in a phase II study, but development was stopped because of preclinical toxicity findings
(18). Doramapimod (BIRB796), showed no efficacy in
Crohn’s disease (19). Scio-469 was efficacious in the
relief of dental pain (20) and has been tested in phase
IIa and IIb trials, but the results are unreported.
Why did pamapimod fail to show efficacy? In
vitro, pamapimod selectively inhibits p38␣ MAPK and
inhibits the production of TNF, IL-1, and IL-6 in both
human and rodent cell cultures. Pamapimod also inhibits the in vitro release of constitutively expressed TNF
from primary synovial explant cultures, with potency
similar to that found in other in vitro assays (10). The
drop in CRP levels in the first 2 weeks with pamapimod
at the 300-mg dose suggests that at this dosage level,
pamapimod may have suppressed proinflammatory cytokine pathways in the patients studied. However, at the
lower dosage levels, pamapimod failed to suppress CRP,
and the dosage levels were probably too low for this
effect to occur. The weakening of CRP inhibition seen
after 2 weeks in the 300-mg pamapimod group suggests
that inflammatory pathways may have been up-regulated
in response to the p38␣ blockade. Candidates for p38␣
bypass might include other p38 isoforms or NF-␬B,
ERK, activator protein 1, and/or JNK pathways. A
substantial early decline in CRP levels with subsequent
elevation was also seen with BIRB796 in Crohn’s disease
(19). There was no decrease in plasma exposures of
pamapimod at any dosage level (data not shown), suggesting that metabolism did not account for the lack of
effect. The AE profile seen with the 300-mg pamapimod
dose (i.e., worse than that with MTX) mitigates against
testing higher once-daily dosing levels for long-term
treatment of RA.
The dominant side effects seen in this trial are
consistent with preclinical toxicities and side effects
reported with other compounds. Pamapimod caused
an increase in infections that were generally mild and
primarily of the upper respiratory tract and nasopharynx, skin lesions usually described as folliculitis or
acneiform rash, dizziness or vertigo, and GI AEs. Infections are often seen with immunomodulatory compounds.
The skin lesions may be infectious in origin, and p38 has
been implicated in maintenance of skin barrier function
(21). However, skin lesions have been reported with
other kinase inhibitors (22), so the precise mechanism is
not clear. Skin lesions (23) and dizziness (24) have also
been described with other p38 inhibitors. Since p38␣ is
found in the cerebellum (25), the maximum
concentration–related dizziness may be caused by inhibition of the molecular target. Finally, GI AEs have
been reported with other p38 inhibitors in smaller
studies and may be a target-related class toxicity perhaps
associated with infection or changes in gut flora. Elevation of transaminase levels has occurred with p38 inhibitors as well (19). Preclinical data suggest that p38 is also
found in myocardium, developing tissues, skeletal muscle, and hematopoietic cells as well as in the immune
system, liver, and central nervous system (26). However,
there is no clear correlation between AEs in humans and
the first 4 of these tissues. At this point the p38 class side
effect profile in RA patients appears to be dizziness, skin
lesions, infections, GI AEs, and transaminase elevations.
While the results of this study are disappointing,
over time the p38 inhibitors have become progressively
more potent and selective (27). In addition, studies are
ongoing in neuropathic pain, chronic obstructive pulmonary disease, atherosclerosis, and oncologic indications
as well as in RA (28). Different selectivity and pharmacokinetic profiles of other p38 inhibitors may offer
some advantage over pamapimod. Alternatively, RA
may be the wrong indication for p38 inhibitors, as sepsis
was for the anti-TNF biologic agents. Additional studies
will be needed to define the clinical utility of this new
class of immunomodulators.
Dr. Cohen had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Cohen, Caulfield.
Acquisition of data. Cheng, Chindalore, Damjanov, Burgos-Vargas,
DeLora, Zimany.
Analysis and interpretation of data. Cohen, Damjanov, DeLora,
Zimany, Travers, Caulfield.
Manuscript preparation. Cohen, Chindalore, Damjanov, BurgosVargas, DeLora, Zimany, Travers, Caulfield, D. M. Lidgate (nonauthor; Roche), S. Peng (nonauthor; Roche).
Statistical analysis. DeLora, Travers, M. Rabbia (nonauthor; Roche).
Medical monitoring. S. Wax (nonauthor; Roche).
Programming. J. Chen (nonauthor; Roche), X. Y. Lue (nonauthor;
The study was funded by Hoffman-La Roche (Nutley, NJ)
and managed by Roche personnel at several locations (Nutley, NJ;
Welwyn Garden City, UK; and Palo Alto, CA). The study was
designed by clinicians and scientists at Roche with input from the
investigators. Data were collected by the investigators and entered into
a database that was maintained by Roche. The data were analyzed by
Roche statisticians and programmers. Dr. Caulfield and Dr. Cohen
wrote a draft of the manuscript with assistance from a medical writer.
All authors reviewed, offered revisions, and approved the content of
the manuscript before submission. All authors agreed to submit the
final version of the manuscript.
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Clinical A service of the US National Institutes of
Health. URL:
Investigators who recruited patients for this study were as
follows: Canada: A. Bookman (Toronto), D. Sholter (Edmonton);
Croatia: D. Martinovic Kaliterna (Split), S. Novak (Rijeka); Czech
Republic: S. Augustinova (Ceske Budejovice), J. Vencovsky (Prague),
P. Vitek (Zlin), R. Zahora (Terezin); France: C. Jorgensen (Montpellier), M. Nguyen (Paris); Italy: C. M. Montecucco (Pavia), B. Seriolo
(Genoa), G. Valesini (Rome); Mexico: H. Avila-Armengol (Guadalajara), R. Burgos-Vargas (Mexico City), C. Ramos-Remus (Guadalajara); Romania: G. Mirea (Brascov), C. Tanasescu (Bucuresti); Serbia/
Montenegro: N. Damjanov (Belgrade); South Africa: F. Khatib
(Johannesburg), D. Nel (Pretoria), B. J. van Rensburg (Bloemfontein);
Spain: F. Blanco (La Corunda), S. Marsal (Barcelona), R. Queiro
(Oviedo); Taiwan: T.-T. Cheng (Kaohsiung), S. Luo (Taoyuan);
United States: J. Anderson (Wichita, KS), R. Capps (Knoxville, TN),
V. Chindalore (Anniston, AL), S. B. Cohen (Dallas, TX), K. Colburn
(Loma Linda, CA), G. M. Eisenberg (Morton Grove, IL), J. Habros
(Scottsdale, AZ), T. Harrington (Danville, PA), H. Holt (Memphis,
TN), S. Ishaq (Covington, LA), D. Kirby (Belmont, NC), M. J. Maricic
(Tucson, AZ), C. Matejicka (Lancaster, PA), D. Radin (Stamford,
CT), G. Roane (Charleston, SC), D. Sandoval (Bend, OR), N. Straniero (South Bend, IN), M. Thurmond Anderle (Amarillo, TX),
C. Young (Escondido, CA).
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