Overview of the Newer Rheumatoid Arthritis Therapies

1
Overview of the Newer Rheumatoid Arthritis
Therapies

• NSAIDs DMARDs Devices
• Celecoxib Leflunomide Prosorba
• Rofecoxib Etanercept
• Meloxicam Infliximab

2
NSAIDs Mechanism of Action

• Cyclooxygenase inhibition

COX-1 (chromosome 9) Constituent pathway
(platelet/GI homeostasis)
COX-2 (chromosome 1) Inducible
pathway (inflammation, pain, fever)
3
COX-2Specific Inhibitor Celecoxib

• 12-week, double-blind, randomized trial 1103
  patients with RA in a flare state
• Celecoxib (100, 200, or 400 mg bid) vs naproxen
  (500 mg bid) vs placebo
• Efficacy of celecoxib generally comparable to
  naproxen
• Efficacy of all doses of celecoxib similar and
  superior to placebo on ACR 20, HAQ Disability
  Index
• Safety of celecoxib comparable to placebo
• COX-2specific at therapeutic doses

Geis et al. EULAR. 1999 Abstract 854.
4
Incidence of Endoscopic Gastroduodenal Ulcers
After Celecoxib Treatment
30
26
25
20
Incidence of ulcers ()
15
10
6
6
4
4
5
0
Placebo
Naproxen
Celecoxib
Celecoxib
Celecoxib
500 mg bid
100 mg bid
200 mg bid
400 mg bid
Correlation between findings of endoscopic
studies and relative incidence of clinically
serious upper GI events not fully established.
Plt0.001 vs naproxen. Simon et al. JAMA.
19992821921-1928.
5
COX-2Specific Inhibitor Rofecoxib

• 52-week double-blind, randomized trial vs
  diclofenac 693 patients with osteoarthritis (OA)
  of knee or hip
• 6-week double-blind, randomized trial vs
  ibuprofen 809 patients with clinical and
  radiographic knee or hip OA
• Efficacy of rofecoxib once daily comparable to
  that of diclofenac or ibuprofen three times daily
• Safety of rofecoxib comparable to that of placebo
• COX-2specific at therapeutic doses

Acevedo et al. EULAR. 1999 Abstract 858. Day et
al. EULAR. 1999 Abstract 860.
6
Rofecoxib vs Ibuprofen and Placebo Endoscopy
Studies
Cumulative Incidence of Gastroduodenal Ulcer
Placebo (n371)
Rofecoxib 25 mg qd (n390)
50
46.4
Rofecoxib 50 mg qd (n379)
Ibuprofen 800 mg tid (n376)
40
28.5
30
Patients with ulcers ()
20
13.5
9.7
8.1
7.3

10
4.7
ND
0
Week 12
Week 24
NDnot done. Plt0.001 vs ibuprofen. No
statistically significant differences vs
rofecoxib. Hawkey et al. EULAR. 1999 Abstract
861.
7
COX-2Selective Inhibitor Meloxicam

• 6-month, double-blind, randomized trial 379
  patients with active RA
• Meloxicam (7.5 mg/d) vs naproxen (750 mg/d) vs
  placebo
• Efficacy of meloxicam comparable to naproxen on
  most measures
• In other studies, efficacy of meloxicam greater
  for some parameters at a higher dose (15 mg/d)
• GI effects less common with meloxicam at 7.5-mg/d
  dose

Wojtulewski et al. Br J Rheumatol. 199635 (suppl
1)22-28. Lemmel et al. J Rheumatol.
199724282-290. Reginster. Br J Rheumatol.
199635(suppl 1)17-21. Meloxicam A safer
NSAID? Drug Ther Bull. 19983662-64.
8
Advantages of DMARDs

• Reduce signs and symptoms of RA
• Reduce functional disability
• Retard radiographic progression

9
Indications for the Newer DMARDs in the
Treatment of RA

• Leflunomide
• Active RA in adults
• To reduce signs and symptoms
• To retard structural damage evidenced by x-ray
  erosions and joint space narrowing
• Etanercept
• Moderate/severe RA in adults
• Moderate/severe polyarticular-course juvenile RA
• To reduce signs and symptoms after inadequate
  response to other DMARD(s)
• Infliximab
• For use with methotrexate after inadequate
  response to methotrexate alone

10
Efficacy of Leflunomide vs Placebo and
Sulfasalazine at 24 Months in a Multinational
Trial
Physician assessment
Patient assessment
HAQ
SJC
0
-2

Improvement (mean change at 2 years )
-4
-6
-8

-10

Leflunomide (n60)
-12
Sulfasalazine (n57)
Placebo-sulfasalazine (n25)
SJCswollen joint count HAQHealth Assessment
Questionnaire. Global assessment on Likert
scale. P0.01 vs sulfasalazine. Placebo group
was switched to sulfasalazine after6 months.
Kalden et al. Arthritis Rheum. 199942(suppl)
Abstract 1202.
11
Radiographic Disease Progression at 24 Months
With Leflunomide and Sulfasalazine
Larsen score
EJC
CRP
2
1
Improvement (mean change at 2 years )
0
-1
Leflunomide (n28)
-2
Sulfasalazine (n27)
Placebo-sulfasalazine (n10)
-3
EJC eroded joint count CRPC-reactive protein.
Placebo group was switched to sulfasalazine
after 6 months. Smolen et al. Arthritis Rheum.
199942(suppl) Abstract 68.
12
Efficacy of Leflunomide vs Methotrexate at 24
Months Year-2 Cohort of North American Trial
90
79
Leflunomide (n98)
80
Methotrexate (n101)
67
70
56
60
50
43
Patients classified as
ACR responders ()
40
26
30
21
20
10
0
ACR 20
ACR 50
ACR 70
There was a placebo arm, but because of its small
size in second year of trial (n36), no
statistical comparisons were made. Plt0.05 vs
methotrexate. Cohen et al. Arthritis Rheum.
199942(suppl) Abstract 1201.
13
Change From Baseline in MHAQYear-2 Cohort of
North American Trial
Methotrexate (n101, baseline1.2)
Leflunomide (n98, baseline1.2)
12 Months
12 Months
24 Months
24 Months
0.0
-0.1
Improvement
-0.2
-0.25
-0.3
-0.28
-0.4
-0.43
-0.45
-0.5
-0.6
MHAQModified Health Assessment Questionnaire.
Plt0.05 vs methotrexate. Cohen et al. Arthritis
Rheum. 199942(suppl) Abstract 1201.
14
Response to Leflunomide or Methotrexate After
Inadequate Response to the Other Agent

• 
  Patients Responding ()
• MTX? LEF LEF? MTX PL? LEF
• (n34) (n24) (n56)
• ACR 20 36 50 53
• ACR 50 21 17 28
• ACR 70 6 4 15

MTX ? LEF methotrexate to leflunomide LEF ?
MTX leflunomide to methotrexate PL ? LEF
placebo to leflunomide. Olsen et al. Arthritis
Rheum. 199942(suppl) Abstract 1021.
15
Efficacy of Leflunomide vs Methotrexate Results
of a 2-Year Multinational Trial
Year 1
Year 2
LEF
MTX
LEF
MTX
(n495)
(n489)
(n273)
(n298)
ACR 20 response () ACR 50 response () ? TJC ?
SJC ? HAQ
51 22 -8.37.9 -6.87.3 -0.37
65 34 -9.77.9 -9.07.3 -0.44
64 34 -10.58.1 -9.17.7 -0.45
72 38 -10.98.2 -10.37.3 -0.50
All values are mean SD. LEFleflunomide
MTXmethotrexate TJCtender joint count
SJCswollen joint count HAQHealth Assessment
Questionnaire. Plt0.05 vs LEF No significant
difference observed. Emery et al. Arthritis
Rheum. 199942(suppl) Abstract 1203.
16
Radiographic Disease Progression Results of
Three Trials
5.88
6
5
4
Leflunomide

Mean change in Sharp score at end point
Methotrexate
3
Sulfasalazine
2.48

2.32
2.16
Placebo
2
1.62
0.89
1
0.53

0.23
0
ULTRA
MN301
MN302
Sharp scoresum of erosion and joint space
narrowing scores. ULTRA Utilization of
Leflunomide for Treatment of Rheumatoid
Arthritis. Plt0.0007 active treatment vs placebo
Plt0.0004 active treatment vs placebo. Schiff et
al. Arthritis Rheum. 199942(suppl) Abstract 63.
17
HRQOL Changes With Leflunomide and Methotrexate
Year-2 Cohort in North American Trial
Mean Change From Baseline Score HAQ Disability
Index
Leflunomide (n97, baseline1.2)
Methotrexate (n101, baseline1.2)
12 Months
12 Months
24 Months
24 Months
0.0
-0.1
Improvement
-0.2
-0.3
-0.4
-0.37
-0.38
-0.5
-0.6
-0.60
-0.61
-0.7
HRQOLhealth-related quality of life HAQHealth
Assessment Questionnaire. P0.0117 vs
methotrexate. Tugwell et al. Arthritis Rheum.
199942(suppl) Abstract 70. Tugwell et al. ACR
1999. Poster.
18
HRQOL Changes With Leflunomide and Methotrexate
Year-2 Cohort in North American Trial (contd)
Mean Change From Baseline Score PET Weighted Top
5
Leflunomide (n97, baseline19.9)
Methotrexate (n101, baseline18.4)
12 Months
12 Months
24 Months
24 Months
0
-2
Improvement
-4
-4.3
-4.5
-6
-8
-9.1
-10
-9.5
PETProblem Elicitation Technique. P0.0098 vs
methotrexate. Tugwell et al. Arthritis Rheum.
199942(suppl) Abstract 70. Tugwell et al. ACR
1999. Poster.
19
HRQOL Changes With Leflunomide and Methotrexate
Year-2 Cohort in North American Trial (contd)
Mean Change From Baseline Score SF-36 Physical
Component
11.9
12
10.8
10
8.4
8.0
8
6
4
Improvement
2
0
12 Months
12 Months
24 Months
24 Months
Methotrexate (n97, baseline30.2)
Leflunomide (n93, baseline30.9)
SF-36Medical Outcomes Survey Sheet Form
36. Tugwell et al. Arthritis Rheum.
199942(suppl) Abstract 70. Tugwell et al. ACR
1999. Poster.
20
Pharmacokinetics of Leflunomide in Combination
With Methotrexate

• 30 RA patients with disease activity despite at
  least 6 months of methotrexate therapy
• No significant changes in the pharmacokinetics of
  methotrexate or the active metabolite of
  leflunomide over the course of the study
• With different modes of action (inhibition of
  pyrimidine production vs inhibition of polyamine
  synthesis and promotion of adenosine release),
  leflunomide and methotrexate appear to be
  synergistic in limiting RA inflammation

Weinblatt et al. Arthritis Rheum.
1999421322-1328.
21
Efficacy of Leflunomide Plus Methotrexate ACR
Responder Status by Month
60
50
40
Responders ()
ACR 20
30
ACR 50
Remission
20
10
0
0
2
4
6
8
10
12
14
Months on Combination Therapy
Reprinted with permission from Weinblatt et al.
Arthritis Rheum. 1999421322-1328.
22
Safety of Leflunomide Plus Methotrexate

• Increased efficacy of combination therapy was
  achieved with little or no increase in number or
  severity of AEs
• Most common laboratory abnormality during 52
  weeks of therapy asymptomatic, reversible
  elevations of plasma liver enzymes (gt1.2 x ULN)
• In 70 of cases, levels reverted to normal range
  without reduction in leflunomide dose
• Three patients were withdrawn from study for
  persistent elevations of liver enzymes

Weinblatt et al. Arthritis Rheum.
1999421322-1328.
23
Safety of Leflunomide and Methotrexate Results
of Two Trials

• NA Trial MN Trial
• LEF MTX PL LEF MTX
• Withdrawals due to AEs () 27 17 9 25 21
• Tx-related deaths (no.) 2
• Reversible abnormal LFTs () 13 11 4 3
  6

NANorth American MNmultinational AEsadverse
events Txtreatment LFTsliver function tests.
Defined as gt2 x upper limit of normal.
Pneumonitis/pneumonia after pancytopenia. Study
year 2. Cohen et al. Arthritis Rheum.
199942(suppl) Abstract 1201. Emery et al.
Arthritis Rheum. 199942(suppl) Abstract 1203.
24
Effect of LEF, MTX, and SSZ on Renal Function
1-Year Results From Three Trials

• Placebo Control Active Control
• LEF MTX SSZ PL LEF MTX
• ? Cr (µM/L) 0.36 1.90 0.25 0.28 0.2
  3.34
• ? BUN (mM/L) -0.35 -0.27 -0.4 0 -0.41 -0.14
• ? UA (µM/L) -61.4 1.8
  -15.6 1.4 -62.2 11.9

Data from ULTRA (LEF, MTX vs PL) and MN301 (LEF,
SSZ vs PL). LEFleflunomide MTXmethotrexate
SSZsulfasalazine PLplacebo Crcreatinine
BUNblood urea nitrogen UAuric acid. Schiff
et al. Arthritis Rheum. 199942(suppl) Abstract
1679.
25
Etanercept A Recombinant Human TNF Receptor
Fusion Protein

• TNF? induces proinflammatory activity of
  cytokines that cause synovitis and joint
  destruction
• Etanercept (recombinant soluble p75 TNF receptor
  molecules fused to Fc fragments of IgG1) inhibits
  TNF? by preventing its binding to cell-surface
  receptors
• Indicated for moderately to severely active RA in
  patients with inadequate response to one or more
  DMARDs

Goldenberg. Clin Ther. 19992175-87. Moreland
et al. Ann Intern Med. 1999130478-486. Maini et
al. Arthritis Rheum. 1998411552-1563.
26
Efficacy and Safety of EtanerceptResults of a
3-Month Trial
57
60
53
50
43
10 mg 1x/wk 25 mg 2x/wk
37
40
Mean improvement ()
30
20
10
0
Painful joints
Swollen joints
European Etanercept Investigators Group.
Arthritis Rheum. 199942(suppl) Abstract 69.
27
Long-Term Safety of Etanercept Results at 33
Months

• 782 patients previously enrolled in etanercept
  trials followed for 12 to 33 months
• Sustained response seen for duration of therapy
• 16 with no active joints at 2 years (n73)
• No significant adverse events with long-term
  therapy
• 43 had injection-site reactions, resulting in
  withdrawal in lt0.5
• Other adverse events comparable to normal adult
  population

Moreland et al. Arthritis Rheum. 199942(suppl)
Abstract 1981.
28
Efficacy of Etanercept vs Methotrexate Results
of a 12-Month Study
Methotrexate
40

Etanercept 25 mg
34.9
Etanercept 10 mg
28.7
28.5
30
Mean weeks of
ACR response (AUC)
20
14.7
10.9
10
0
After 6 months
After 12 months
Plt0.001 vs methotrexate Plt0.009 vs
methotrexate and Plt0.03 vs 10 mg
etanercept. Finck et al. Arthritis Rheum.
199942(suppl) Abstract 280.
29
Efficacy of Etanercept Plus MethotrexateResults
of a 24-Week Trial
80

Etanercept-methotrexate (n59) Placebo-methotrexat
e (n30)
70
60
50

Patients responding ()
40
30

20
10
0
ACR 20
ACR 50
ACR 70
Plt0.001 P0.03. Weinblatt et al. N Engl J Med.
1999340253-259.
30
Efficacy of Etanercept Plus Methotrexate
Measures of Disease Activity
Etanercept-methotrexate (n59)
100
Placebo-methotrexate (n30)




80



60
Mean improvement
from baseline ()


40
20
0
TJC
SJC
ESR
CRP
Pain
Morning
stiffness
Disability
index
Physician
assessment
Patient
assessment
TJCtender joint count SJCswollen joint count
ESRerythrocyte sedimentation rate
CRPC-reactive protein. P lt0.001 P0.003
P0.008 P0.001 P0.004. Weinblatt et al. N
Engl J Med. 1999340253-259.
31
Safety of Etanercept Plus Methotrexate

• Combination of etanercept and methotrexate
  generally well tolerated
• Upper respiratory infections most frequent AE in
  etanercept-methotrexate and placebo-methotrexate
  groups
• Injection-site reactions more frequent in
  etanercept-methotrexate group
• No significant laboratory abnormalities noted

Weinblatt et al. N Engl J Med. 1999340253-259.
32
Long-Term Efficacy and Safety of Etanercept Plus
Methotrexate

• 6 12 18 Baseline months months months
• ACR 20 () N/A 72 81 71
• ACR 50 () N/A 37 58 52
• ACR 70 () N/A 16 26 26
• Pts. with 0 active joints () 0 0 9 16
• TJC (median) 26.1 7 5.1 2.1
• SJC (median) 18.8 5.3 3.7 2.1

N/A not applicable SJCswollen joint count
TJCtender joint count. Weinblatt et al.
Arthritis Rheum. 199942(suppl) Abstract 1982.
33
Infliximab An Anti-TNF Monoclonal Antibody

• Chimeric, mouse/human IgG1 monoclonal antibody
  that binds to TNF? with high affinity and
  specificity
• Efficacy, safety, and immunogenicity in RA
  evaluated in combination with methotrexate
• Development of human antichimeric antibodies
  (HACA) potentially induces allergic reactions to
  infliximab and reduces long-term efficacy
• Methotrexate could potentiate the antirheumatoid
  activity of infliximab while reducing its
  immunogenicity

Maini et al. Arthritis Rheum. 1998411552-1563.
34
Infliximab Plus Methotrexate Study Design and
Dosage Schedule for a 26-Week Trial

• Monotherapy Combination Control
• Infliximab 1 mg/kg per dose 1 mg/kg per dose
• Methotrexate 7.5 mg/wk 7.5 mg/wk
• Infliximab 3 mg/kg per dose 3 mg/kg per dose
• Methotrexate 7.5 mg/wk 7.5 mg/wk
• Infliximab 10 mg/kg per dose 10 mg/kg per dose
  
• Methotrexate 7.5 mg/wk 7.5 mg/wk

Maini et al. Arthritis Rheum. 1998411552-1563.
35
Efficacy of Infliximab Plus MethotrexateResults
at 26 Weeks
50

1 mg/kg infliximab or matching placebo


3 mg/kg infliximab or matching placebo

40

10 mg/kg infliximab or matching placebo
30
Paulus responders at end point ()
20
10
0
Infliximab
Infliximab
Placebo
Infliximab
Infliximab
Placebo
MTX
MTX
MTX
MTX
Paulus 20 criteria
Paulus 50 criteria
MTXmethotrexate dose, 7.5 mg/wk in all groups.
P0.01 P0.005 P0.004 P0.002 all P
values vs placebo MTX group. Maini et al.
Arthritis Rheum. 1998411552-1563.
36
Safety of Infliximab Plus MethotrexateResults
at 26 Weeks

• Infusion reactions seen infrequently
• Dose of infliximab and incidence of adverse
  events appear unrelated
• 32.2 of infliximab patients and 21.4 of
  methotrexate patients had infections that
  required antibiotic treatment (PNS)
• Causal relation to anti-TNF? therapy unclear, but
  infections may be anticipated because of role of
  TNF? in host defense
• Asymptomatic development of anti-dsDNA IgM
  antibodies was induced by treatment but
  disappeared during or after therapy in most cases

Maini et al. Arthritis Rheum. 1998411552-1563.
37
Efficacy and Safety of Infliximab Results of the
ATTRACT Trial at 30 Weeks
70

60



50
40
ACR 20 response ()
30
20
10
0
Placebo
3 mg/kg
3 mg/kg
10 mg/kg
10 mg/kg
q8wk
q4wk
q8wk
q4wk
Patients in the q8wk groups received treatment at
intervals of 4 weeks, alternating infliximab and
placebo. P0.001 vs placebo. Maini et al.
EULAR. 1999 Abstract 0P 9.
38
Efficacy and Safety of Infliximab Results of the
ATTRACT Trial at 54 Weeks

• 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg
• Placebo q8wk q8wk q4wk q4wk
• n 88 86 87 86 81
• ACR 20 () 17 42 59 48 59
• ACR 50 () 9 21 40 35 38
• ACR 70 () 3 11 26 18 19
• SJC ( D) -18 -51 -70 -63 -71
• TJC ( D) -28 -62 -75 -70 -69

SJCswollen joint count TJCtotal joint count.
Plt0.001 Plt0.05 all P values vs placebo.
Lipsky et al. Arthritis Rheum. 199942(suppl)
Abstract 1980.
39
Prosorba A Selective Extracorporeal
Immunoadsorption Column

• Purified protein A bound to inert silica matrix
• Binds to IgG-containing circulating immune
  complexes in plasma
• Two pilot trials in RA patients unresponsive to
  DMARD therapy
• 24-week trial 9/11 patients met Paulus 50
  criteria at 13 weeks
• 12-week trial 10/15 patients met Paulus 50
  criteria 8 weeks after final treatment

Wiesenhutter et al. J Rheumatol. 199421804-812.
Caldwell et al. J Rheumatol. 1999261657-1662.
40
Prosorba Results of a 12-Week Sham-Controlled
Trial
31.9
35
30
25
20
ACR response rate ()
11.4
15
10
5
0
Prosorba treatment
Sham treatment
P0.019. Felson et al. Arthritis Rheum.
1999422153-2159.