1. University of Virginia Licensing & Ventures Group BIO 2016
Pain Program Overview
University of Virginia Licensing & Ventures Group
BIO 2016

2. Neuropathic Pain
Nerve injury or inflammation can produce neuropathic pain
Approximately 4 million people in US had neuropathic pain in 2006 (1)
Associated with neuronal central sensitization (2)
Role of microglial cell priming suggested to play role in pain intensity and duration (3)
Activated glial cells release (4):
pro-inflammatory cytokines, IL-1β, IL-6, TNFα
Chemokines
Prostaglandins, ROS and NO
Decreasing spinal pro-inflammatory cytokines or increasing anti-inflammatory cytokines reduces allodynia induced by neuropathy (4-6)
1. Taylor 2006, 2. Hanisch 2007, 3. Hains 2010, 4. Watkins 2007, 5. DeLeo 2001, 6. Milligan 2006

3. Adenosine Actions in Neuropathic Pain
Adenosine can reduce pain in some human pain conditions
Adenosine binds to four receptor subtypes, A1, A2A, A2B and A3
A1 receptors are expressed in neurones (1)
A1 agonists reduced pain in a number of pain models
A2A agonists have potent anti-inflammatory effects
via suppression of pro-inflammatory cytokines and increased anti-inflammatory cytokines
A2A receptor is expressed in neutrophils, macrophages, and T cells
but also in basal or activated glial cells from primates and rodents (2-4)
A2A agonists reduce pain in preclinical animal models
Last 2 bullets is rationale for why A2A agonists
1. Hasko 2007, 2. Boison 2010, 3. Gyoneva 2009, 4. van der Putten 2009

4. Glial Cells as Target for A2A Agonists
A2A receptor expression is increased in glial cells

5. Chronic Constriction (CCI) Model of Neuropathic Pain.
Fukuoka and Noguchi, 2002 .
Fukuoka and Noguchi, 2002 BL 1 2 4 8 9 12
Timecourse (wks)
sham
CCI
50% Withdrawal Threshold (g)
0.3
0.6
1.0
1.8
3.2
5.6
10.0 BL 1 2 4 8 9 12
Timecourse (wks)
sham
CCI
50% Withdrawal Threshold (g)
0.3
0.6
1.0
1.8
3.2
5.6
10.0
Therapeutic
benefit
CCI model of neuropathic pain, Filament (plastic) applied, gram threshhold for removal
Four ligatures loosely tied around sciatic nerve, induces neuropathic pain
Measurement is force in (g) applied to hind paw with a filament before the paw is withdrawn.
Filament test is used in podiatrist office to test for diabetic nephropathy in patients for example

6. ATL313 Reduces pain for 4-5 weeks After Single Injection (1) - no tolerance
Repeated injection, no tolerance
In week 6 , pain response is going back up, probably due to the turnover in macrophages
1. Loram et al 2009

7. ATL313 Reduces Pain for Duration of Study - multiple administration maintains anti-allodynia effect
Multiple administrations, pain tolerance is almost back to sham animals

8. Co-administered A2A Antagonist Blocks Effect of ATL313 Antagonist Does Not Reverse Anti-Allodynic action
Looking at MOA
Left side co administration with antagonist (ZM241385)
Right side, 313 administered, time delay, then either ZM2 or vehicle administered
Shows that once the switch is flipped you cant block the effect b/c its now a secondary message from or within the glial cells
Note these animals still have a normal pain response to heat

9. IL-10 Neutralization Reverses effects of ATL313 - ATL313 appears to upregulate IL-10
Continue to look at MOA, 313 upregulates IL10
IL10 Ab neutralizes 313 effects

10. Intrathecal ATL313 in Pain Management
Neuropathic pain is associated with glial cell activation
A2A receptor expression is increased in glial cells
A2A activation reduced pro-inflammatory cytokines and increases anti-inflammatory cytokines
ATL313 decreases TNF α and increases IL-10 in CSF cells from CCI rat model and changes expression of TNF α and IL-10 in microglial cells in culture
Intrathecal IL-10 reverses neuropathic pain (1)
ATL313 reduces pain in three rodent models of neuropathic pain
One injection reduces pain for 4 to 5 weeks
Injections every 4 weeks maintains efficacy
Increased IL-10 production appears to help mediate the ATL313 response
1. Soderquist 2010

11. Safety Pharmacology and Toxicology Studies
Previously licensed to Adenosine Therapeutics, LLC
Partnered with Santen in 2010 for glaucoma
Full package completed for compound to enter P2a clinical trials in glaucoma
Did not lower intraocular pressure
Returned to Adenosine Therapeutics, LLC in 2013
Subsequently returned to UVa LVG

12. Conclusions Strong rationale for ATL313 treatment of neuropathic pain
Effect appears to be mediated by increased IL-10 production
Toxicology plan can be based on prior studies in rats and dogs with intrathecal adenosine
Non-intrathecal toxicology and PK data available
Safety pharmacology, hERG, systemic toxicology, PK
Human experience with intrathecal adenosine suggests:
No major safety issues
Reduction in pain can occur if appropriate patient population chosen
Strong IP Portfolio
Composition of matter patents issued in US, Europe, and Asia (Expires 2028)

13. BACK UP

14. Intrathecal A2A Agonist Effects on Pain
ATL313 is a potent and selective A2A agonist
Chronic constriction injury [CCI] model
Four ligatures loosely tied around left sciatic nerve of rats
Neuropathic pain induced
ATL313 (1 μl) was injected intrathecally days post-CCI A1
A2A
(high affinity)
(low affinity)
A2B A3
Human
26.3
0.3
11.2
3561
122.3
Rat
13.1
*0.7
25.6
3970
65.8
*estimated based on human A2A high to low affinity Ki ratio

15. Clinical Development of ATL313 - based on discussion with five KOLs
Glial cell activation important in chronic neuropathic pains
Proof of Concept Study
Enroll patients with steady state pain (VAS = 6-10)
Unsuccessful pain alleviation with other pain medications, especially narcotics
ATL313 + opioid versus opioid alone
Endpoints: self administration of opioids (not FDA approved) and pain scores