In the presentation, I discussed new concepts in OA pathogenesis and identified possible targets of treatment. This was followed by a review of new treatment options for osteoarthritis. Presented during the Joint RA OA SIG Symposium at the F1 Hotel last 28 November 2014.

1. Novel Treatment Targets
in OSTEOARTHRITIS
Sidney Erwin T. Manahan MD FPCP FPRA
28 November 2014

2. Osteoarthritis
• Most common arthritis
• No approved treatment known to
modify disease progression
• Many patients still need knee
and hip joint replacement
Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease
involving only cartilage or other articular tissues. Eklem
Hastalik Cerrahisl 2010; 21 (1): 2-14

3. RISK FACTORS
• Genetics
• Age
• Gender
• Race
• Hormonal status
• Joint trauma
• Misalignment
• Overuse
• Immobilization
• Obesity
OUTCOMES
• Joint destruction
• Severe pain
• Loss of function
• Disability
• Social Isolation
• Depression
• Reduced Quality of
Life
• Major Economic
Burder
Pharmacologic
Treatment
Joint Replacement
Rehabilitation
Weight Loss
Orthoses / Insoles
Wieland HA, Michaelis M, et al. Osteoarthritis – an untreatable disease? Nat Rev Drug Discov April 2005; 4
(4): 331-44.

4. Imbalance of
Cytokines, growth
factors, PGE2,
cartilage matrix,
neuropeptides,
O2 radical,
proteases
Wieland HA, Michaelis M, et al. Osteoarthritis – an untreatable disease? Nat Rev Drug Discov
April 2005; 4 (4): 331-44.
Pathophysiologic Processes
Altered mechanical
loading of cartilage,
bone and ligaments
Phasic synovial
inflammation &
angiogenesis
Reduced exercise,
muscle weakness,
impaired
proprioception,
joint laxity
Peripheral and
central Sensitization,
nociceptor activation
Destruction of matrix
and chondrocyte
death
Osteophytosis,
subchondral
sclerosis
Synovial fluid
abnormalities

5. Objectives
• Briefly review pathophysiologic
processes
• Identify possible targets of
therapy
• Discuss the status of “novel”
therapies

6. MILD
PainSeverity
Disease Severity / Radiographic Changes
Cartilage degradation, osteophytes, SYNOVITIS, osteochondral
cysts, BONE MARROW LESIONS, damage to peri-articular
structures, psycho-social factors, and comorbidities
MODERATE SEVERE
Sofat N, Kuttapitiya A. Future directions for the management of pain in osteoarthritis. Int J Clin
Rheumatol 2014; 9(2): 197-216

7. Cartilage – Synovium Connection

8. Chrondrocyte Phenotypes
ANABOLIC
Increased
Aggrecan and
T II Collagen
CATABOLIC
Overproduces
MMPs
HYPERTROPHIC
ECM mineralization
CC thickening
FIBROBLASTIC
Elaborates Type I
and III Collage
Hassanali SG, et al. Osteoarthritis: A Look at Pathophysiology and Approach to New Treatment. East African Ortho
J 2011; 5: 51-57.
Anabolic Inhibitory Catablolic
IGF1, TGFß
FGFs, BMPs
IL-4, IL-10, IL-11
IL-13, IFN
IL-1ß, TNF-alpha, IL-6
IL-17, IL-18

9. Events in the Synovium
Sofat N, Kuttapitiya A. Future directions for the management of pain in osteoarthritis. Int J Clin Rheumatol 2014;
9(2): 197-216

10. Auw Yang, et al. 2008 Chevalier, et al. 2009
P
167 Patients >18y with knee
symptoms + XR consistent with
OA (KL Grade I-III) and Pain
>40/100
160 Patients >18y with Knee OA
(ACR Criteria + XR) and Pain
VAS>30/100
I
Autologous IL-1Ra on Day 0, 3, 7,
10, 14 and 21 Vs Saline
Anakinra 50mg IA VS Anakinra
150mg IA Vs Placebo
M Randomized Double Blind Trial Randomized Double Blind Trial
O
No difference in WOMAC, Pain
VAS up to 12 mo post treatment
between IL-1Ra and saline
No difference in WOMAC scores,
pain VAS, analgesic use during
the 12 weeks post injection
Targeting IL-1 in Osteoarthritis
Auw Yang KG, et al. Autologous IL-1Ra improves function and symptoms in OA when compared to placebo in a
prospective randomized controlled trial. Osteoarth & Cart 2008; 16: 498-505. Chevalier X, et al. Intra-articular
injection of Anakinra in Osteoarthritis of the Knee: A Multicenter Randomized Double Blind Placebo Controlled
Study. Arth & Rheum 2009; 61 (3): 344-52

11. Guler Yuksel, et al . 2010 Verbuggen, et al . 2012
P
416 Patients with active RA
(participating in BeST); Hand OA
was present in 37% DIP 13% PIP
60 Patients >18 years with
Erosive Hand OA (ACR +
Radiographs)
I
Infliximab 3-10 mg/kg + MTX vs
MTX for 6 months
Adalimumab 40 mg SC q 2w Vs
Placebo for 12 months
M Observational Study x 3years Randomized Double Blind Trial
O
No significant difference
between treatment groups in
incident and progressive OA rate
No significant difference in new
active jt involvement or XR
progression by Week 52
Targeting TNF-a in Osteoarthritis
Guler Yuksel M, et al. Treatment with TNF-a inhibitor infliximab might reduce hand OA in patients with RA.
Osteoarth and Cart 2010; 18: 1256-62. Verbuggen G, et al. Tumor necrosis factor blockade for the treatment of
erosive hand OA of the IP finger joints: A double blind randomized trial on structure modification. Ann Rheum Dis
2012; 71: 891-8.

12. Stimulating Cartilage via FGF-18
Study Descriptors
P
168 Patients >40 years with symptomatic Knee OA
Quantitative MRI done at 6, 12 months.
I Sprifermin (rh FGF-18) 10ug, 30ug and 100 ug IA Vs Placebo
M Randomized Double Bind Proof of Concept Trial
O
No statistical difference in Medial TF Cartilage thickness.
Reduced loss of Lateral TF cartilage thickness and volume and
less Lateral TF JSN
No difference in WOMAC Scores
Lohmander LS, et al. Intra-articular sprifermin in knee OA: a randomized double blind placebo controlled trial.
Arthr Rheumatol 2014; 66(7): 1820-31.

13. NSAIDs: Beyond COX Inhibition
• Severe Knee OA for Joint
Replacement
– 10 on Celecoxib 200mg/d
– 10 on Aceclofenac 200 mg/d
– 10 on Placebo
• 3 months of treatment
CONCLUSIONS
• CBX & ACF improved pain and
function and reduced PGE2,
COX expression
• CBX & ACF have different
anti-inflammatory profiles
Alvarez-Soria MA, et al. Arth & Rheum 2006; 65:998-1005.

14. “Novel” Targets of Inflammation
Pre-Clinical Studies In vitro MOA
Cat’s Claw Reduced OA Pain
Inhibits LPS-induced PGE2
production and activation of
TNF-a
Devil’s Claw Alleviates OA Pain
Inhibited release of TNF-a, IL-
1B, IL-6 and PGE2
Edible Bird’s
nest extract
Not reported
Reduced expression of MMP-1,
MMP-3, IL-1, IL-6, IL-8, COX-2,
PGE2 and increased type II
collagen and aggrecan
Collagen
hydrosylates
Alleviates OA related pain
Stimulates regeneration of Type
II collagen and PG biosynthesis
Green Tea Not reported
Reduced TNF-a, COX-2, IL-17
and increased IL-10
Leong DJ, et al. Nutraceuticals: Potential for chondroprotection and molecular targeting in OA. Int J
Molecular Science 2013; 14: 23063-23085

15. • Ligamental strain
• Muscle spasm
• Bursitis
• Elaboration of cytokines
• Low grade chronic inflammation
• Bone Marrow Like Oedema
Lesions
• Micro-channels in sunchondral
• Subchondral bone cysts
• Inadequate flow to osteocytes
• Evacuation of non-viable bone
• Subchondral bone collapse
Changing Concepts in Pathogenesis
BMLOL
MECHANICAL
BONE
ISCHEMIA
SYNOVITIS
Punzi L, et al. New Horizons in OA. Swiss Med Weekly 2010.

16. Events at the
OSTEO-
CHONDRAL
JUNCTION
Sofat N, Kuttaptiya A. Future
directions in the
management of pain in
osteoarthritis. Int J Clin
Rheumatol. 2014; 9(2): 197-
216

17. Bisphosphonates in OA
Drug (Trials) OA Site Results
RISENDRONATE
(KOSTAR, BRISK)
Knee
(N=2767)
• RIS 5mg/d, 15 mg/wk, 35 mg/wk,
50 mg/wk VS Placebo
• No differences in WOMAC Pain,
Function Subscales and WOMAC Total
• No difference in radiographic
progression
• Dose-dependent reduction in
cartilage breakdown biomarker
ALENDRONATE
(Jokar et al 2010)
Hip
(N=37)
• ALE 70 mg/wk VS Placebo
• No difference in WOMAC, use of
NSAIDs at 6 months
(Nishi et al 2012) Knee
(N=51)
• ALE 35 mg/wk VS Placebo
• Less pain after 2 years of use
• No difference in JSN
Sofat N, Kuttaptiya A. Future directions in the management of pain in osteoarthritis. Int J Clin Rheumatol.
2014; 9(2): 197-216. Davis AJ, et al. Are Bisphosphonates Effective in the Treatment of OA Pain: A Meta-
analysis and SR. PLoS 2013; 8(9): 372714

18. Bisphosphonates in OA
Drug (Trials) OA Site Results
ZOLENDRONATE
(Laslett et al 2012)
Knee
(N=59)
• ZOL 5 mg INFUSION VS Placebo
• -14.5mm Pain VAS at 6 months (but
no significant diff at 3 and 12 mo)
• Reduction in BML area at 6 months
(but not significant at 12 mo)
CLODRONATE
(Saviola et al 2012)
Hand
(N=37)
• CLO 300 mg IV x 7 days + 100mg IM
x 14 days q 3 months vs HCQ 400mg
OD x 1 mo then 200 mg OD x 11 mo
• Significantly reduced pain, better Pt –
MD Global Assessment at 24 months
Sofat N, Kuttaptiya A. Future directions in the management of pain in osteoarthritis. Int J Clin Rheumatol.
2014; 9(2): 197-216. Davis AJ, et al. Are Bisphosphonates Effective in the Treatment of OA Pain: A Meta-
analysis and SR. PLoS 2013; 8(9): 372714

19. Strontium Ranelate in OA (SEKOIA)
Study Descriptors
P
Caucasians >50years with Knee OA (ACR + XR), Pain VAS
>4/10, and KL grade 2-3 XR
I
445 Strotium Ranelate 1g/d Vs 454 Strontium Ranelate 2g/d
VS 472 Placebo over 3 years
M Randomized Double Blind Controlled Trial
O
Joint space narrowing was significantly less in RAN-treated pts
-0.23+0.56mm in RAN 1g/d
-0.27+0.63mm in RAN 2g/d
-0.37+0.59mm in Placebe
Reginster JY, et al. Efficacy and safety of strontium ranelate in the treatment of knee OA: results of a
double-blind, randomized placebo-controlled trial. Ann Rheum Dis 2013; 72:179-86

20. % of Patients with OA Progression
22
8
26
7
33
12
Radiographic Progression Radioclinical Progression
RAN 1g/day RAN 2g/d Placebo
(JSN >0.5mm in 3 yrs) (JSN >0.5mm or lack of >20%
WOMAC Pain improvement in 3 yrs)

21. WOMAC Scores in SEKOIA Trial
-14.6 -15.6
-12.2
-41.8
-22.9
-19.1 -18.3
-15
-51.9
-28.5
-14.7 -14
-11.7
-40.7
-24.2
Pain Stiffness Function Total Pain VAS
RAN 1g/d RAN 2g/d Placebo
* p-value <0.05 compared to placebo
*
*

22. The Role of NGF in OA Pathogenesis
Sofat N, Kuttaptiya A. Future directions in the management of pain in osteoarthritis. Int J Clin Rheumatol.
2014; 9(2): 197-216

23. Studies on Tanezumab
Lane, et al,2010 Schnitzer, et al 2011
P
450 Patients Age 40-75y w/ OA
based on ACR Criteria + XR
inadequate response to non-opioid
analgesics Pain VAS >5/10
281 Patients age 40-75 w/ OA
based on ACR Criteria + XR &
inadequate response to non-opioid
analgesics Pain VAS >5/10
I
Tanezumab 10-200ug/kg at Week
0 and 8 vs Placebo
Tanezumab 50ug/kg q 8 weeks for
8 infusions
M POC Study of 16 weeks duration Open-label extension trial
R
• Reduced walking pain (45-62%
vs 22%)
• Pt Global Ass (29-47% vs 19%)
• OARSI Response Criteria (74-
93% vs 44%)
• Improvements in knee pain
were sustained over 1 year (-
12.8+1.78 mm further
reduction) up to 70 days after
the last dose
Lane NE, et al. Tanezumab for the treatment of Pain from OA of the knee. NEJM 2010; 363: 1521-31.
Schnitzer TJ, et al. Long term open label study of tanezumab for moderate to severe OA Knee Pain.
Osteoarth and Cart 1011; 19: 639-46.

24. The First Phase III Trial on Tanezumab
P
621 Patients diagnosed with hip OA who are unable/ unwilling to take
non-opioids or candidates for IA injections or surgery
I Tanezumab 2.5, 5 and 10 mg IV at Week 0 and 8 vs Placebo
Brown MT, et al. Tanezumab reduces OA Hip Pain. Arth & Rheum 2013; 65 (7): 1795-1803

25. First Asian Trial on Tanezumab
P
83 Patients age 44-73 w/ knee OA based on ACR Criteria + XR who are
unable/ unwilling to take non-opioids or intervention candidates
I Tanezumab 10-200ug/kg IV at Week 0 vs Placebo
Nagashima H, et al. Preliminary assessment of the safety and efficacy of tanezumab in Japanese
patients with moderate-severe OA of the knee. Osteoarth & Cart 2011; 19: 1405-12.
Pain Physical Function

26. Trials on Tanezumab & Analgesics
NSAID
With Tanezumab With
Placebo5 mg 10 mg
Diclofenac -2.2 -2.3 -1.7
Naproxen -2.13 -2.36 -1.44
Celecoxib -2.22 -2.41 -1.43
Feist E, et al. Efficacy and safety of tanezumab added on to diclofenac in patients with knee and hip OA.
Arth Rheum 2011; 63 (S10): S427-8. Yazici Y, et al. Efficacy of tanezumab compared with NSAIDs in
patients with knee and hip OA. Arth Rheum 2011 (S10): S326
However, in all trials, authors observed an increased risk for rapidly
progressive OA in tanezumab treated patients.

27. Neuropathy in Anti-NGF Trials
Trials Tanezumab Placebo
Lane, et al. 2010 70 (14%) 6 (4%)
Schnitzer, et al 2011 18 (6.4%)
Brown, et al, 2013 20 (4.3%) 5 (3.2%)
Nagashima, et al. 2011 4 (33%) 0
* Abnormal peripheral nerve sensation – allodynia, burning sensation,
dysesthesias, hyperesthesias, hypoesthesias, neuralgia, neuritis,
paresthesias and sensory loss.
Lane NE, et al. Tanezumab for the treatment of Pain from OA of the knee. NEJM 2010; 363: 1521-31.
Schnitzer TJ, et al. Long term open label study of tanezumab for moderate to severe OA Knee Pain.
Osteoarth and Cart 1011; 19: 639-46. Brown MT, et al. Tanezumab reduces OA Hip Pain. Arth & Rheum
2013; 65 (7): 1795-1803. Nagashima H, et al. Preliminary assessment of the safety and efficacy of
tanezumab in Japanese patients with moderate-severe OA of the knee. Osteoarth & Cart 2011; 19:
1405-12.

28. Newer Anti-NGF Agents
Fulranumab Fasinumab
P
466 Patients with knee or hip OA
of moderate-severe intensity
217 Patients with knee OA of
moderate-severe intensity
I
1-10 mg IV q 4-8 weeks vs
Placebo
0.03-0.3mg/kg IV on Week 0
and 8 vs Placebo
M
Randomized Double-Blind Trial –
Exploratory
Randomized Double-Blind Trial –
Exploratory
O
Greater pain reduction than
placebo at doses of 3 mg q 4w,
6 mg q 8w and 10 mg q 8 w
Improved walking pain and
WOMAC Scores in treatment
groups
Sanga P, et al. Efficacy, safety and tolerability of fulranumab, an anti-nerve growth factor antibody, in the
treatment of patients with moderate-severe OA pain. Pain 2011; 12 (S4): 53. Tiseo PJ, et al. Fasinumab,
an antibody against nerve growth factor for the treatment of pain: results from a double blind, placebo
controlled exploratory study in OA of the knee. Pain 2014; 155 (7): 1245-52.

29. SENSITIZATION happens
in Osteoarthritis

30. Duloxetine for Knee OA Pain
Study Descriptors
P
• Patients >40 years with Knee OA (ACR Criteria – clinical,
radiographic) and Pain VAS >4/10
• 70% female, 91.6% Caucasian
• Mean BMI 30 kg/m2
• Comparable % of patient on NSAIDs
• MDD was an exclusion criteria
I 239 Duloxetine 60-120mg/d vs 248 Placebo for 13 weeks
O Average Daily Pain Severity (0-10 scale)
M 2 Randomized Double-Blind Controlled Trials
Micca JL, et al. Safety and efficacy of duloxetine treatment in older and younger patients with OA knee
pain: a post hoc, sub-group analysis of two randomized placebo controlled trials. BMC Musculo Dso 2013;
14:137.

31. Significant Pain Reduction among
Patients on Duloxetine
Micca JL, et al. Safety and efficacy of duloxetine treatment in older and younger patients with OA knee
pain: a post hoc, sub-group analysis of two randomized placebo controlled trials. BMC Musculo Dso 2013;
14:137.

32. Adverse Events in >5% of Patients
Patients >65y Patients <65y
Placebo
N 94 (%)
Duloxetine
N 103 (%)
Placebo
N 154 (%)
Duloxetine
N 136 (%)
At least 1 AE 40 (42.6) 55 (53.4) 51 (33.1) 65 (47.8)
Constipation 2 (2.1) 11 (10.7) 0 3 (2.2)
Diarrhea 2 (2.1) 4 (3.9) 4 (2.6) 7 (5.1)
Dizziness 3 (3.2) 1 (1.0) 1 (0.6) 9 (6.6)
Nausea 3 (3.2) 9 (8.7) 2 (1.3) 11 (8.1)
Somnolence 3 (3.2) 6 (5.8) 1 (0.6) 4 (2.9)
At least 1 SAE 2 (2.1) 3 (2.9) 2 (1.3) 1 (0.7)
Micca JL, et al. Safety and efficacy of duloxetine treatment in older and younger patients with OA knee
pain: a post hoc, sub-group analysis of two randomized placebo controlled trials. BMC Musculo Dso 2013;
14:137.

33. Pregabalin for Knee OA Pain
Study Descriptors
P
• Patients with knee pain >1 mo and OA based on
radiographs
• 70% female, Mean age 70+8 years
• PainDETECT Screen applied to all patients (25% had NP)
I
31 Meloxicam 10mg/d vs 28 Pregabalin 25mg/d vs 20
combination tx
O
• Pain VAS (0-10)
• WOMAC Scores
M Randomized Prospective Trial
Ohtori S, et al. Efficacy of combination meloxicam and pregabalin for pain in Knee OA. Yonsei Med J 2013;
54 (5): 1253-58.

34. Mean Pain Scores During the Study
5.6
4.6
3.6
2
5
4.4
3.5
2
5.4
3.4
2.2
1
Week 0 Week 1 Week 2 Week 4
MLX PGB MLX + PGB
Ohtori S, et al. Efficacy of combination meloxicam and pregabalin for pain in Knee OA. Yonsei Med J 2013;
54 (5): 1253-58.

35. Mean WOMAC Scores at Week 4
6.3 4.9
30
41.2
6.6
4.5
29.3
40.4
3.6 2.5
18.3
24.4
Pain Stiffness Function Total
MLX PGB MLX + PGB
Ohtori S, et al. Efficacy of combination meloxicam and pregabalin for pain in Knee OA. Yonsei Med J 2013;
54 (5): 1253-58.

36. Sofat N, Kuttapitiya A. Future directions for the management of pain in osteoarthritis. Int J Clin Rheumatol 2014;
9(2): 197-216
INFLAMMATION
BONE
NERVES
CENTRAL PAIN

37. What we’ve reviewed
WHAT WORKS WHAT DIDN’T
Symptoms Alendronate - Knee
Strontium Ranelate – knee
Zolendronate – Knee
Clodronate – Hand
Tanezumab – Knee, Hip
Duloxetine – Knee
Pregabalin – Knee
Anakinra- - Knee
Risendronate – Knee
Alendronate – Hip
DMOAD potential Strontium Ranelate – knee
Zolendronate – Knee
Sprifermin – Lateral Knee
Adalimuab – Hand
Infliximab – Hand
Sprifermin – Medial Knee

38. Summary
• Reviewed pathophysiology relevant
to possible treatment targets in
osteoarthritis
• Discussed novel treatments for
osteoarthritis
• Reviewed the evidence surrounding
the efficacy of novel treatment