Philip Conaghan MBBS PhD FRACP FRCP Director, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds Deputy Director, NIHR Leeds Biomedical Research Centre

1. 2020 OA Vision:
Emerging Therapeutics
on the OA landscape
Philip Conaghan MBBS PhD FRACP FRCP
Director, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
Deputy Director, NIHR Leeds Biomedical Research Centre
Leeds Institute of Rheumatic
& Musculoskeletal Medicine

2. Consultancies or speakers bureaus for:
AbbVie, AstraZeneca, Bristol Myers Squibb, EMD Serono,
Flexion Therapeutics, Galapagos, GlaxoSmithKline,
Medivir, Novartis, Pfizer, Samumed
Disclosure Information

3. Consensus on:
• Holistic assessment
• Symptomatic treatment
• Combination of
– non-pharmacological
– pharmacological approach
Current OA Therapy Guidelines

4. OA Therapies: Effect Size (by dose)
Da Costa et al.
Lancet 2016

5. SLR: Opioids in MSK Pain (over 60s)
Megele et al.
J Pain 2018

6. This Presentation
• Focus on recent pharmacological therapies
• Minimum PhII trials
• Symptoms and structure modification
• Not focussed on adverse events
• Use tissue-targeted classification

7. Cartilage as a target

8. Recombinant human Fibroblast Growth
Factor 18 (Sprifermin)
• Human version of naturally-
occurring FGF-18
• Binds to FGF receptor 3
(FGFR3) on chondrocytes,
leading to activation of
intracellular signalling
pathways and:
- stimulation of
chondrocyte proliferation
- induction of anabolic
phenotype
- ECM production
- reduction of type I
collagen expression
Gigout et al.
Osteoarthritis Cartilage 2017
Control Sprifermin
Porcine chondrocytes in monolayer culture, 7 days with 100 ng/mL of sprifermin
or in absence of compound (control)
The cell cytoskeleton (actin) was stained in green

9. Sprifermin 5 yr PhII trial: FORWARD
Hochberg et al. EULAR 2018

10. Sprifermin 5 yr PhII trial: FORWARD
Hochberg M et al. EULAR 2018
Primary endpoint met: dose-dependent increase in TFTJ cartilage thickness (qMRI),
with significant differences for sprifermin 100 µg q6mo and 100 µg q12mo vs placebo

11. Inflammation as a target

12. Microsphere Technology for Sustained
Delivery of IA Corticosteroid
• IA corticosteroids are effective, but provide short term
pain relief
• Injection of FX006 provides sustained release of
triamcinolone acetonide (TA-ER) from microspheres
• Reduces systemic exposure relative to IA corticosteroids
1
Conaghan et al.
J Bone Joint
Surg Am 2018

13. Full Analysis SetTA-ER Ph3 Single Dose Trial
Conaghan et al.
J Bone Joint Surg Am 2018
ADP
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
LSM(±SE)ChangeFrom
Baseline,ADP
BL 2 4 6 8 10 12 14 16 18 20 22 24
Weeks Post Treatment
Primary Endpoint
Week 12 TA-ER vs Saline-placebo
P < 0.0001
WOMAC-A
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
LSM(±SE)ChangeFrom
Baseline,WOMAC-A
BL 4 8 12 16 20 24
Weeks Post
Treatment
0.0Primary Endpoint
Week 12 TA-ER vs Saline-
placebo
P < 0.0001

14. Full Analysis SetTA-ER Ph2 RCT in Knee OA & Diabetes
Russell S et al.
Rheumatology 2018
Target glycemic range
<180 mg/dL

15. Full Analysis SetTA-ER Ph3b Repeat Dose Trial
Spitzer A et al. Rheumatol Ther 2019
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 4 8 12 16
MeanWOMAC-A
Score,0-4scale
Weeks Postinjection
2nd Injection at Week 16 (n=60)
1ˢᵗ injection
2ⁿᵈ injection
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 4 8 12 16 20
MeanWOMAC-A
Score,0-4scale
Weeks Postinjection
2nd Injection at Week 20 (n=37)
1ˢᵗ injection
2ⁿᵈ injection
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 4 8 12 16 20 24
MeanWOMAC-A
Score,0-4scale
Weeks Postinjection
2nd Injection at Week 24 (n=36)
1ˢᵗ injection
2ⁿᵈ injection
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 4 8 12
MeanWOMAC-A
Score,0-4scale
Weeks Postinjection
2nd Injection at Week 12 (n=45)
1ˢᵗ injection
2ⁿᵈ injection

16. Colchicine in knee OA (COLKOA) RCT
• Some data between SF uric acid and OA in non
clinical gout
• Crystal-induced inflammasome
• Hypothesis: colchicine blocks inflammasome-
mediated inflammation
• Double-blind, placebo-controlled RCT
• 0.5mg bd vs placebo for 16weeks
• Primary outcome >30% improvement in
totalWOMAC
Leung et al.
Osteoarthritis Cartil 2018

17. Colchicine in knee OA (COLKOA) RCT
Leung et al.
Osteoarthritis Cartil 2018
• Did reduce hsCRP and some pro-infl cytokines

18. Targeting Cytokines:
Anti-TNF in erosive hand OA
• 60 people erosive hand OA
• 40mg adalimumab or
placebo subcutaneously
every 2 weeks for 12
months
• Lower incidence of erosive
evolution in adalimumab
group (3.7%) than placebo
(14.5%, p=0.009)
• No significant changes in
clinical variables
Verbruggen et al,
Ann Rheum Dis 2012

19. Anti-IL-1α & β with Lutikizumab:
ILLUSTRATE-K trial
• IL-1α and IL-1β are expressed in the cartilage and
synovial membrane of OA
• ABT-981 is a novel human dual variable domain
immunoglobulin that binds and inhibits the actions
of IL-1α & β
• Acceptable preclinical and early clinical profile
• The aims of this PhIIa RCT were to determine
benefits on symptoms and structure in knee OA,
and assess safety
Fleischmann et al.
Arthritis Rheumatol 2019 [epub]

20. Anti-IL-1α & β with Lutikizumab:
ILLUSTRATE-K trial design
Fleischmann et al.
Arthritis Rheumatol 2019 [epub]

21. Anti-IL-1α & β with Lutikizumab:
ILLUSTRATE-K trial Results Pain
Fleischmann et al.
Arthritis Rheumatol 2019 [epub]

22. Anti-IL-1α & β with Lutikizumab:
ILLUSTRATE-K trial Results Structure
Fleischmann et al.
Arthritis Rheumatol 2019 [epub]

23. Humira in hand OA: HUMOR trial
• ACR hand OA
• Hand pain ≥5/10
• ≥1 Xray erosive joint, synovitis on MRI
• Randomised to PBO (25pts) or Adalimumab
40mg (18pts) s/c 2wkly for 12 wks, 8 wk washout
crossover design, follow for 12 wks
• Primary outcome = change in VAS hand pain over
12 wks
• Structural outcomes: HOAMRIS synovitis, BMLs
Aitken et al.
Osteoarthritis Cartil 2018

24. Humira in hand OA: HUMOR trial
• No change in AUSCAN, HOAMRIS features
Aitken et al.
Osteoarthritis Cartil 2018

25. Usual hand OA
medication
+
Hydroxychloroquine
Usual hand OA
medication
+
Placebo
People
with painful (VAS≥4/10)
radiographic hand OA
6 months
Primary outcome
Reduced pain?
Hydroxychloroquine Effectiveness at Reducing the
symptoms of hand Osteoarthritis (HERO)
6 months
Sustained
reduction in
pain?
Reduced
structural
progression?
HERO: A placebo-controlled RCT
Baseline
Ultrasound
Sub-study
Kingsbury et al.
Annals Intern Med 2018

26. HERO: Baseline Characteristics
HCQ
N=124
Placebo
N=124
Age Mean 62.8 years 62.5 years
Gender Female 78% 85%
Grip Strength Mean 33.9 lbs 29.8 lbs
Structural Damage
(Kallman Score)
Mean (0-220) 42.7 47.2
Concomitant
Therapy
Paracetamol 62% 60%
Oral NSAIDs 40% 43%
Other 16% 21%
Baseline Pain Mean (0-10) 6.75 6.78Kingsbury et al.
Annals Intern Med 2018

27. 0
1
2
3
4
5
6
7
8
9
10
Overallhandpain(0-10max)
M0 M3 M6 M12
Months Follow-up
HCQ
Placebo
HERO Primary Outcome: Hand Pain
Diff: 0.24
95% CI (-0.30, 0.79)
p=.381
Diff: -0.16
95% CI (-0.72, 0.41)
p=.584
Diff: 0.14
95% CI (-0.44, 0.72)
p=.639
Kingsbury et al.
Annals Intern Med 2018

28. 0
10
20
30
40
50
60
70
80
KallmanRadiographScore(0-220max)
M0 M12
Months Follow-up
HCQ
Placebo
HERO Radiographic Outcome
Diff: 0.12
95% CI (-0.72, 0.97)
p=.776
Kingsbury et al.
Annals Intern Med 2018

29. HERO: Response by US synovitis
Positive Greyscale Synovitis
(n=134)
Positive Power Doppler
(n=84)
0
1
2
3
4
5
6
7
8
9
10
Overallhandpain(0-10max)
M0 M3 M6 M12
Months Follow-up
HCQ
Placebo
0
1
2
3
4
5
6
7
8
9
10
Overallhandpain(0-10max)
M0 M3 M6 M12
Months Follow-up
HCQ
Placebo
Kingsbury et al. Annals Intern Med 2018

30. Separate HCQ RCT in Hand OA
• 196 patients were included (placebo n=98, HCQ
n=98)
• HCQ 400mg once daily vs placebo, 24 wks
• Baseline mean pain VAS was 44.9 (SD 22.9) mm
placebo, and 43.2 (22.3) mm in the HCQ group
• At 24 wks, change in pain VAS was not
significantly different between groups
• Changes in AUSCAN total score and AIMS2-SF
total score in both groups were similar between
groups
Lee et al.
Arthritis Care Res 2017

31. Bone as a target

32. OA MRI: BMLs in RCTs
Laslett et al.
Ann Rheum Dis 2012
• 59 patients with clinical knee OA and MRI BMLS
• Randomised trial of zoledronic acid and placebo
• Significant reduction in knee pain and total BML area at 12 months in ZA
group compared to placebo

33. New Cathepsin K inhibitor
• Cathepsin K is a cysteine protease involved in
bone resorption, degrades type I collagen as well
as collagen type II and aggrecan
• MIV-711 is a potent, selective and reversible
inhibitor of cathepsin K, with an acceptable
preclinical and early clinical profile
• The aim of this early-phase trial was to determine
benefits on symptoms and structure in knee OA,
and assess safety
Conaghan et al.
ACR 2017

34. • Knee pain ≥4, <10 on NRS, K-L grade 2 or 3
• All patients remained on current stable analgesia
Study design
MRI MRI

35. Demographics
Statistic Placebo 100 mg 200 mg Overall
n 77 82 81 240
Age (years) Mean 62.3 61.2 62.0 61.8
BMI (kg/m^2) Mean 32.49 31.98 32.02 32.16
Female 62
(80.5%)
64
(78.0%)
58
(71.6%)
184
(76.7%)
Male 15
(19.5%)
18
(22.0%)
23
(28.4%)
56
(23.3%)
Discontinuations 11 8 10 29

36. Results: Symptoms
NRS overall pain (primary endpoint) WOMAC pain
No statistically significant changes demonstrated

37. Results: MRI measures
Area of bone in MF Average cartilage thickness in CMF
Reduction in bone area
increase for both doses
Trend for reduced cartilage
thickness loss for both doses
Unadjusted one-sided p values= 0.002 (100 mg), 0.004 (200 mg) Unadjusted one-sided p-values = 0.023 (100 mg) and 0.125 (200 mg)

38. Results: Biomarkers
CTX-I CTX-II
MIV-711 demonstrates target engagement with rapid and sustained reduction of both CTX-I and CTX-II,
with no significant differences between doses

39. Multiple targets

40. STAT3: signal transducer and activator of transcription 3, SIRT1: sirtuin 1, TCF7: transcription factor 7,
NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, FOXO1: forkhead Box O1
Osteoarthritis
Wnt/Mechanical stress/Metabolic/Trauma
Osteoarthritis
Wnt/Mechanical stress/Metabolic/Trauma
Inflammatory gene
expression
Inflammatory gene
expression
Wnt gene expressionWnt gene expression
Chondrocyte
differentiation/function
Chondrocyte
differentiation/function
Structural Damage
DYRK1ADYRK1A
CLK2CLK2
LorecivivintLorecivivint
Symptoms
Cytokines
FOXO
1
TCF7
Alt. splicing
hMSCs
Chondrocytes
Altered
protein
levels
Synovial
fibroblasts
NF-κB
Alt. splicing
Wnt pathway inhibition: Lorecivivint

41. ≡
◙
390 13 26 52/EOSStudy Week
≡ ≡
4
≡
≡
◙
Follow Up
Follow Up
Follow Up
Follow Up
0.07 mg SM04690 (n=117)
Vehicle (PBO) (n=114)
0.03 mg SM04690 (n=112)
0.23 mg SM04690 (n=109)
2mL Injection at Day 1
≡
◙
Lorecivivint: Ph2a study design
Primary objective: Change from baseline in WOMAC Pain at Week 13
≡ Clinical assessments: WOMAC Function, Pain; Patient and MD Global
Assessment; SF-36
◙ Imaging: Fixed flexion knee X-ray with QuAP™ positioner
Safety assessments: Adverse events (AEs), vital signs, physical exam,
lab panels Yazici Y et al,
EULAR 2017

42. Lorecivivint Ph2a: WOMAC Pain
Yazici Y et al,
EULAR 2017
ITT
Unilateral symptomatic without
widespread pain

43. Lorecivivint Ph2a:
SRMs based on radiographic inclusion
Conaghan et al,
ESCEO 2018
*Ladder plots from baseline-adjusted ANCOVA comparing treatment to placebo at Week 52 with Standardized Response Means
(SRMs) reported as favoring lorecivivint. ‡0.13mm is radiographic Minimal Detectable Difference. (Dupuis, et al. (2003) OAC.) δ:SRM

44. Lorecivivint Ph2b
Yazici Y et al. ACR 2018
Pain NRS (FAS) Patient Global (FAS)

45. Lorecivivint Ph2b: mJSW (mm)
Yazici Y et al. ACR 2018

46. Nerves as a target

47. Peripheral pain mediators
Ji RR et al.
Nat Rev Drug Discov 2014
IL-1β
IL-6
PGE2
TNFα
Pain signalling
TRPA
Cytokine
receptors
ASICs
Intracellular
kinases
PKA
PKC
P13K
MAPKs
ERK
P38
JNK
NGF
TRKA
TRPV1
Nav 1.7
Nav 1.8
Mast cells
Neutrophils
Macrophages
CB1

48. Monoclonal Ab to NGF: Tanezumab
Lane N et al.
New Eng J Med 2010
• Phase II Study
• Multiple doses of tanezumab
• OA knee patients
• 450 patients randomised

49. Tanezumab: Ph3 1056 Study
Schnitzer T et al.
ACR 2018
tanezumab 2.5 mg (n=231)placebo (n=232) tanezumab 2.5/5 mg (n=233)
WOMAC Pain WOMAC Physical Function
-2.6 -2.6
-3.2 -3.2-3.4 -3.5-4.0
-3.0
-2.0
-1.0
0.0
Baseline = 7.3 7.1 7.3 7.4 7.2 7.4
Meanchangefrom
baseline(SE)
PGA of OA
3.5 3.4 3.5
* ** **
***
*
**
-0.65
-0.87 -0.90
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
*p≤0.05; **p≤0.01; ***p≤0.001 vs placebo
Intent to treat, multiple imputation
Co-primary endpoints

50. • CNTX-4975 is a highly purified, synthetic trans-capsaicin
• Specific activity for TRPV1-containing pain nociceptors
(Aδ and C)
- Does not impact other sensory fibers such as touch or pressure
• Only desensitizes pain nociceptors within the joint
- Nerve body and axon remain intact and fibers regrow over time
CNTX-4975 Selectively and Rapidly
Inactivates Pain Fibers
© 2015 The Joints Clinic.
All Rights Reserved
joint
capsule
capsaicin
bone
Stevens et al.
Ann Rheum Dis (suppl) 2017

51. CNTX-4975 PhII Trial (TRIUMPH)
© 2015 The Joints Clinic.
All Rights Reserved
Stevens et al.
Arthritis Rheumatol 2019 [epub]
Demographics and Baseline Disease Characteristics of Study
Subjects, Safety Population
Placebo
(n=70)
CNTX-4975
0.5 mg
(n=34)
1.0 mg
(n=71)
Age, mean (SD), years 60.6 (8.9) 59.6 (6.4) 59.1 (7.7)
Female, n (%) 45 (64.3) 20 (58.8) 45 (63.4)
Race, n (%)
White 51 (72.9) 24 (70.6) 52 (73.2)
Black or African American 19 (27.1) 10 (29.4) 18 (25.4)
Multiple 0 0 1 (1.4)
Ethnicity, n (%)
Not Hispanic/Latino 44 (62.9) 22 (64.7) 46 (64.8)
BMI category, n (%)
≥30 kg/m2 47 (67.1) 21 (61.8) 50 (70.4)
K-L grade 2–4 (index knee), n (%) 70 (100) 34 (100) 71 (100)
Baseline WOMAC A1 severity, mean (SD) 7.4 (1.0) 7.2 (1.1) 7.2 (1.2)
Baseline WOMAC A1 severity, n (%)
Moderate (scores >4–6) 24 (34.3) 13 (38.2) 33 (46.5)
Severe (scores >7–10) 44 (62.9) 20 (58.8) 38 (53.5)
Missing 2 (2.9) 1 (2.9) 0

52. CNTX-4975 PhII: AUC in Change From
Baseline in WOMAC A1 (Pain With Walking)
• In the K-L 2–3 subgroup, treatment with CNTX-4975 1.0 mg resulted in significant
improvements in AUC WOMAC A1 score vs placebo (P<0.0001)
– Similar results for the limited number of subjects in the K-L 4 subgroupc
aSubjects rated pain when walking using a numerical rating scale from 0 (pain absent) to 10 (severe pain). bPrimary endpoint. cK-L 2–3 subgroup: placebo,
n=62; CNTX-4975 0.5 mg, n=30; CNTX-4975 1.0 mg, n=65; K-L 4 subgroup: placebo, n=7; CNTX-4975 0.5 mg, n=3; CNTX-4975 1.0 mg, n=5; p=0.07
*P<0.10, †P=0.0002, ‡P<0.0001, CNTX-4975 vs placebo. Baseline scores: placebo, 7.42; CNTX-4975 0.5 mg, 7.24; CNTX-4975 1.0 mg, 7.20.
†
†
*
Stevens et al.
Arthritis Rheumatol 2019 [epub]

53. Final Thoughts

54. OA Therapies: Effect Size (by dose)
Smith TO et al.
J Rheumatol 2019 [epub]

55. 2020 OA Vision
• Existing pharmacotherapies even more limited
• Some promising DMOADs, but….
• Structure- pain relationship complex and underpins
regulatory acceptance
• Hip vs knee vs hand
• Many lessons learnt about trial inclusions,
outcomes (symptoms and structure)
• Keep everyone strong!!!!!!

56. p.conaghan@leeds.ac.uk
Contact Details