Janus Kinase (JAK) Inhibitors

Janus Kinase Inhibitors - JAK's have shown to be successful in a variety of different disease indications.  The science of these inhibitors is still in the early stages of understanding.   They operate by inhibiting one or more of the family of enzymes, (JAK1, JAK2, JAK3, TYK2), and interfering with the signaling pathway.  They have shown to be successful in cancer and inflammatory diseases to date.  Concert Pharmaceuticals currently owns patents for the following three deuterated JAK inhibitors, with indications that each has shown to be effective in, prior to the company adding deuterium to the entity.

D-Ruxolitinib
Selectivity: JAK1,2 
Indication:  Myelofibrosis, Polycythemia Vera, Alopecia Areata  
Patent: 2032 US

D-Baricitinib
Selectivity: JAK1,2, TYK2
Indication: Rheumatoid Arthritis, Psoriasis
Patent: 2032 US

D-Momelotinib
Selectivity:  JAK1,2
Indication:
Patent: 2033 US

The non-deuterated versions of these JAK's have already shown proof-of-concept (POC), essentially reducing the risk for Concert to bring the drugs to market, for other or same, previously tested indications.  It's rare to have a full runway of patent years ahead, with clinically tested drugs, at your disposal. We'll follow the Janus Kinase landscape with any new findings in the future.  Thank you for reading. 

CTP-543 Alopecia Areata Market Opportunity

Concert Pharmaceuticals will be entering a phase 2 clinical trial with CTP-543, for the indication of moderate to severe alopecia areata, in the first quarter of 2017.  Proof-of-concept (POC), has already been indicated in a small phase 2 academic study by Columbia University with results of the auto-immune disease here JCI.  We are estimating total revenue that CTP-543 could achieve if FDA approved for alopecia areata, based on some recent Dermatologic Drug Prices.

Up to 650,000 affected with alopecia areata U.S. any given time (Concert literature)
30% to 50% may have moderate to severe (195,000 to 325,000) US
Mid range population moderate to severe = 260,000 US
Market capture rate of 25% = 65,000 US moderate to severe
Price per tablet once daily = $23.33 or $700 per month

Peak revenue estimate $700 x 12 x 65,000 = $546 million

Risks to Assessment
Revenue split with another equally effective drug
The pool of potential patients is too high
Market capture rate of 25% too high 
$700 monthly, or $23.33 per tablet
Insurance does not cover the indication       

STAT3 Phosphorylation with CTP-543

Concert Pharmaceuticals is currently running a phase 1 pharmacodynamics (PD) clinical trial, before heading into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata.  The goal of the (PD) part of the phase 1 trial, will test CTP-543's ability to affect downstream gene regulation similar to ruxolitinib, with results in Q1 2017.  Ruxolitinib which is already an FDA approved drug for various cancer indications has been tested for it's ability to affect downstream gene regulation STAT3.  The results for ruxolitinib are below, and which can also be found in this link JAKAVI-ruxolitinib. 

Pharmacodynamics 
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF patients.  Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and myelofibrosis patients.

Metabolism
In vitro studies indicate that CYP3A4 is the major enzyme responsible for metabolism of ruxolitinib.  Parent compound is the predominate entity in humans representing 60% of the drug-related material in circulation.  The two major and active metabolites were identified in plasma of healthy subjects representing 25% and 11% of parent AUC.  These metabolites have one-half to one-fifth of the parent JAK-related pharmacological activity.  The sum of all active metabolites contribute to 18% of the overall pharmacodynamics of ruxolitinib.  

Bottom Line:  CTP-543 will be compared to the above ruxolitinib data, after completion of the current phase 1 clinical trial.  The drug will be advancing into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata, in the first quarter of 2017.  CTP-543 is the deuterated version of ruxolitinib.  Thank you for reading.
 

Axsome Therapeutics Progress Update

We originally wrote about Axsome Therapeutics (AXSM) and their drug AXS-05 here AXS-05 A Novel Mechanism Of Action.  Some new information for Axsome occurred this week.  

• First the company completed an agreement for a term loan of up to $20 million dollars from Silicon Valley Bank, with minimal dilution.  This bolsters their cash to around $40 to $50 million.  The company plans to move AXS-05 into a phase 2/3 clinical trial for Alzheimer's patients with agitation symptoms with this new capital.
• Other news that could have an impact on Axsome and their NMDA / bupropion drug combination AXS-05 for TRD (treatment resistant depression), is that competitor Otsuka, who was also pursuing the same indication with AVP-786 (NMDA, Sigma-1), has decided not to advance the drug past their recently completed phase 2 clinical trial.  So at present, AXS-05 is one of the most advanced oral NMDA (dextromethorphan) drug in clinical trials for treatment resistant depression. 

Bottom Line:  The increased cash raise was needed to advance AXS-05 into other clinical trials.  The company is extremely lean, as their quarterly burn rate was just $6.8 million in the second quarter, but is expected to increase with more clinical trials planned.  AXS-05, drug combination for treatment resistant depression, should have phase 3 results mid 2017, with patent into 2034.  Thank you for reading.  

Contact:  586-431-8000