Compare and contrast

From the most recent International Cannabinoid Research Society Meeting Abstract Book:

First the preclinical findings:

PRE-CLINICAL PHARMACOLOGICAL PROPERTIES OF NOVEL
PERIPHERALLY-ACTING CB1-CB2 AGONISTS

Thierry Groblewski1, Xiao Hong Yu1, Etienne Lessard1, Stéphane St-Onge1, Hua Yang1,
Rosemarie Panetta1, Chang Qing Cao1, Michael Swedberg2, Gvido Cebers2, Svante Nyberg2,
Magnus Schou2, Christer Halldin3, Balazs Gulyas3, Katarina Varnäs3, Chistopher Walpole1,
Kemal Payza1, Martin Perkins1 and Julie Ducharme1

1 AstraZeneca R&D Montréal, 7171 Fredrick Banting, H4S1Z9 Montréal, Qc, Canada
2 AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden
3 Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, S-171 76 Stockholm,
Sweden

There is a large body of pre-clinical evidence supporting a peripherally-mediated analgesic action of cannabinoids. We hypothesized that their therapeutic window could be improved, notably vs. their central side-effects, by limiting their access to the central compartment. To test the hypothesized peripheral analgesic mechanism and to assess the optimal level of peripheral restriction to combine efficacy with acceptable tolerability profile, we initiated pre-clinical studies with two novel orally active mixed CB1/CB2 agonists (AZD1940 & AZD1704) characterized by different extent of brain uptake (rat Cbr/Cpl ratio of ~0.1 & 0.01 for AZD1940 & AZD1704 respectively) and different CNS psychoactivity in a rat Δ9-THC drug discrimination test. Both compounds were orally active in various rat models of nociceptive and neuropathic pain and displayed improved safety margins vs. central side effects typically observed with various cannabinoids (e.g. Δ9-THC, WIN55212-2). Mechanistic studies involving local injection or recording of peripheral nerve activity in rat nociceptive and neuropathic pain models provided evidence for a peripheral site of action. Despite their mixed agonist activity at both CB1 and CB2 receptors, analgesic efficacy of this class of cannabinoids was found to be mainly driven by CB1 receptor. Indeed, the reported CB1 selective antagonist SR141716A completely reversed their analgesic efficacy in rat pain models. Additionally, activity of AZ11713908 (a mixed CB1/CB2 agonist tool compound) in the mouse FCA tail inflammation model was abolished in CB1 KO mice and remained unchanged in CB2 KO mice. Imaging PET study conducted with [11C]-AZD1940 in cynomolgous monkey confirmed low brain uptake previously evidenced in rodents. No pre-clinical safety issues preventing initiation of clinical studies with AZD1940 and AZD1704 were identified. Outcome of clinical studies are summarized in the next presentation. This oral presentation will provide the chemical structure of these novel compounds and a summary of their pre-clinical in-vitro and in-vivo pharmacological properties.

That’s great, novel, peripherally restricted CB agonists alleviate measures of pain in preclinical models.

Now the clinical findings:

PERIPHERALLY-ACTING CB1-CB2 AGONISTS FOR PAIN:
DO THEY STILL HOLD PROMISE?

Thierry Groblewski1, Rolf Karlsten2, Märta Segerdhal2, Jarkko Kalliomäki2, Bror Jonzon2,
Margareta Bielenstein2, Gvido Cebers2, Michael Swedberg2, Anita Annas2, Greg Christoph3,
Pernilla Tellefors2, Lars Ståhle2, René Bouw2, Urban Fagerholm2, Agneta Berg2,
Stephen Butler2, Michael O’Malley2 and Gudrun Anstrén2

1 AstraZeneca R&D Montréal, 7171 Fredrick Banting, H4S1Z9 Montréal, Qc, Canada
2 AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden
3 AstraZeneca R&D Wilmington, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USA

To test the hypothesized peripheral analgesic mechanism and to assess the optimal level of peripheral restriction to combine efficacy with acceptable tolerability profile, we initiated clinical studies with the two novel orally active mixed CB1/CB2 agonists (AZD1940 & AZD1704) characterized by different extent of brain uptake (rat Cbr/Cpl ratio of ~0.1 & 0.01 for AZD1940 & AZD1704 respectively). In clinical phase I single ascending dose (SAD) study, AZD1940 maximum tolerated dose (MTD) was 0.8 mg with plasma exposure of 1.7 nM free. The clinical efficacy of AZD1940 as a pain relief agent was explored in two single dose phase II studies (human capsaicin and 3rd molar extraction models) and in the multiple ascending dose (MAD) study performed with volunteers affected by chronic low back pain. The 2 single dose phase II studies conducted with the MTD showed no effects on primary endpoints (pain intensity and heat pain threshold for capsaicin study). In the multiple ascending dose (MAD) study where AZD1940 was administered for 12 days, repeated dosing led to slow compound accumulation (t1/2 ~ 80h). A daily 1mg dose led to a plasma exposure at steady state of 7 nM free. Significant weight gain and some hepatic enzymes increase were noticed. During the SAD study, AZD1704 exhibited hypotensive effects (up to 20 mm Hg supine systolic blood pressure drop with 2.4mg oral dose corresponding to a plasma exposure of ~2.0 nM free). No CNS adverse-events were noticed. The measured t1/2 (6-8h) was too short to consider repeated dosing to investigate potential tolerance development to the blood pressure lowering effects. To conclude, CB1 agonists with limited CNS access have been observed to display a different tolerability profile in human compared to more brain-permeable CB1 agonists. After our limited studies, optimal clinical efficacy of peripherally restricted CB1 agonists remains to be proven. In addition, it is unclear how the hemodynamic and metabolic effects observed in these clinical studies could be completely managed for this class of cannabinoids.

no pain relief + cardiovascular effects + liver tox + munchies. Bet that wasn’t what they were looking for.
So based on that, if you were a pharma company would you pursue this?

2 responses to “Compare and contrast

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