Lee S. Simon, MD SDG LLC Cambridge, MA

1. Approval of Therapeutics for
Osteoarthritis in 2019
Lee S. Simon, MD
SDG LLC
Cambridge, MA

2. Consulting
• Affinergy
• Astrazeneca
• Abraxxis
• Alpha Rx
• NuvoResearch
• Roche
• Pfizer
• Novartis
• PLx Pharma
• Hisamatsu
• Dr Reddys
• Avanir
• Cerimon
• Leerink Swann
• Alimera
• Nomura
• Luxor
• Paraexel
• Antares
• Bayer
• Rigel
• JP Morgan
• Regeneron
• XTL
• Inmedix
• Eupraxia
• Fidelity
• Extera
• Wyeth
• Asahi
• Sammuded
• Metabolex
• Shire
• Anthera
• Antares
• Vical
• Daiichi Sankyo
• Flexion
• AcelRx
• Inotek
Gilead
• Sandoz
• Knopp
• Abbott
• Omeros
• Jazz
• Takeda
• Teva
• Zydus
• Proprius
• Alder
• Cephalon
• Purdue
• EMDSerono
• Altea
• Talagen
• Tigenix
• Agenus
• Forest
• Genzyme
• CaloSyn
• pSivida
• Horizon
• Pozen
• Eicos Sciences
• Analgesic Solutions
• Bayer
• Kowa
• Array
• JRX Biopharm
• Imprimis
• Dara
• Genco
• Neos
• Durect
• Sanofi
• Lilly
• Idera
• Medac
• Remedy
• Kiniksa

3. What is Needed For Approval: In General
• Non clinical data performed in terms of GLP
• Manufacturing practices performed in terms of GMP
• Clinical data performed in terms of GCP
– Two replicate adequate and well controlled trials
– One if the p < 0.001 (robust p value)

4. 5
Pain
Function
Bone
Cartilage
Tendon/Ligament
Total Joint Replacement
Clinical
Surrogate
Osteoarthritis: The “Joint Organ”
Synovium
Biomarkers

5. What Are Potential Measurable Outcomes?
CLINICAL OUTCOMES
Biomarkers Performance
Clinician-
Reported
Observational
Patient-
Reported
• Walking
time/distance
• Range of
motion
• Muscle strength
• Global
impression of
severity
• Joint
replacement
• Quantity of
rescue
medication
used for pain
• Pain
• Function
• Distress
• Biochemical
(urinary CTXII)
• Imaging (MRI
cartilage
thickness;
radiographic
joint space
narrowing)
SURVIVAL
Adapted from Patrick et al. 2014
Figure 3

6. Problems with OA Development
• Typical Development program
– Signs and symptoms
• Pain
• Function
• Patient global
• Structural Development Program
– Structural benefit must be linked in some manner with symptomatic
benefit
– Assess benefit to entire joint
• Halt progression of damage
• Reverse damage

7. Why is this so?
• OA is multifactorial in cause, with an unpredictable
progression and has a complex etiopathogenesis
– Is it a progressive disease of the whole joint: subchondral bone
followed by effects on cartilage, with consequent increase in low
grade inflammation
– Is it a progressive disease of cartilage subsequently having impact
on subchondral bone and consequent increase in low grade
inflammation
• Is it a progressive disease of abnormal cartilage sustaining normal load or
normal cartilage being subjected to abnormal loading
– All of the above?

8. 9
Time
JSN
Rapid
Slow
No change
a
a
b
c
OA: JSN progression

9. Why is This So?
• In assessing OA there is a recognized discordance between
structural changes and signs, symptoms and function
• There is a lack of standard definitions of disease progression by
xray or other imaging techniques
• There is an absence of measured endpoints to reliably assess the
ability of a product to alter OA disease progression

10. These Issues Then Lead to
• Because of the complex and variable pathologic changes through which OA impairs
function and leads to long-term disability and/or joint replacement,
– It is unclear what magnitude of change in structural endpoints would translate to a
clinically meaningful benefit to patients
• i.e., reliably predict both reduced pain and increased function or prolonged time to end-stage
disease
• To accept structural endpoints as valid outcome measures for accelerated approval,
there should be substantial confidence that an effect on the candidate structural
endpoint will reliably predict an effect on the clinical outcomes
– Based on empirical evidence from randomized, controlled comparisons from clinical trials
– Based on a comprehensive understanding of the disease process and product
mechanism of action,

11. Goals of a Structure Modifying
Development Program
• The ultimate goal of treatments related to alteration of structural
damage (targeting the underlying pathophysiology associated with
OA) is to avoid or significantly delay the complications of joint
failure and the need for joint replacement
• An equally important goal would be reduce the deterioration of
function and worsening of pain
• Either might be considered important clinically relevant outcomes

12. Structural Development
Program
• If there is an identified method of measuring change in the
joint structure, is that change correlated with how a patient
feels, functions or survives?
• Currently all of these measures must be concurrent
– What ever benefit is demonstrated, the powering of the clinical trial
must be able to provide measure of benefit both in terms of structure
and symptoms

13. An Example of a Structure Modifying Trial
• Risedronate in the treatment of OA
• 23,000 patients screened with 2300 recruited into trial for
2 years
• Signs and symptoms and flouroscopically positioned
specialized xray with central reading
• Post hoc small number of patients who were determined
to be rapid progressors evidenced structural modification
but not able to be identified at start of trial and not linked
to symptom benefit
Bingham CO III, 2006; Arthritis Rheum 54: 3494-3507

14. Biomarker and Surrogate Endpoints
Definitions
Biomarker: biological marker or imaging marker is a
characteristic that is measured and evaluated as an
indicator of normal biologic processes, pathogenic
processes, or pharmacologic responses to a
therapeutic intervention.
Clinical endpoint- A characteristic or variable that
measures how a patient feels, functions or survives
Surrogate endpoint- A marker intended to substitute
for a clinical endpoint

15. Surrogates as Drug Approval
Measures
A surrogate endpoint of a clinical trial is a laboratory measurement,
imaging measure, or a physical sign used as a substitute for a clinically
meaningful endpoint that measures directly how a patient feels,
functions, or survives.
Changes induced by a therapy on a surrogate endpoint are expected to
reasonably likely reflect changes in a clinically meaningful endpoint.

16. Achieving Evidence for Structural
Benefit Linked to Clinical Benefit

17. Achieving Evidence for Structural Benefit Linked to Clinical
Benefit

18. Conclusions
• OA has significant patient impact causing pain, loss of function, increased
disability and significant risk of increased mortality, in some patients
• OA affects a large population
• Developing drugs to alter the complex structures involved in the joint will be
difficult
– Target cartilage?
• Decrease loss?
• Stimulate new cartilage growth?
– Target subchondral bone? And show what?
– Both? And do changes link to how a patient feels, functions or survives

20. Questions? Contact
lssconsult@aol.com