SAGE-217 Patent Issued

SAGE-217 was issued patent number US 9,512,165 B2, which runs to April 2034.  The link to other patent applications can be found here SAGE Patent Applications.  SAGE-217 is the oral version of SAGE-547, and will be running four proof-of-concept, phase 2 clinical trials in 2017.  Thank you for reading.                

CTP-543 Phase 1 Top-Line Results

Concert Pharmaceuticals announced top-line results this week for CTP-543.  The single and multiple ascending dose study was well-tolerated across all dose groups.  The company is planning on testing four doses (4, 8, 12, and 16 mg BID) in the phase 2 clinical trial scheduled to begin early 2017.  The phase 2 clinical trial will enroll around 100 patients with moderate to severe alopecia areata, with six month readout by the end of 2017.  Thank you for reading.

SAGE-547 Expedited Pathway Revealed

We initially wrote about Sage here, SAGE-547.  This week SAGE revealed through this press release Sage Therapeutics, the expedited pathway for drug SAGE-547 for Postpartum Depression.  The important news was that the FDA in agreement with Sage, anticipates that no additional controlled studies will be necessary to file an NDA.  The company believes that they may be able to file for a new drug application for Postpartum Depression in 2018.  If approved by the end of 2019, the company will have patent until around 2034, or approximately 15 years of exclusivity.  Below are the important aspects of the expedited pathway for SAGE-547, agreed upon by the FDA.

• Current SAGE-547 clinical studies confirmed as appropriate to support registration, if successful
• No additional efficacy studies expected to be required beyond those currently underway
• Trial design of studies 202B and 202C are considered appropriate for registration, with increase in size and other minor modifications
• The primary clinical endpoint for these pivotal trials was unchanged and agree upon with FDA
• Additional patient safety data may be acquired through an open-label program

Below is a year-to-date chart of SAGE.  Despite the company having an extraordinary year with SAGE-547 the stock is down -4.49% this year.  The company currently has $431 million in cash, or about $13.00 per share in cash.  

Source: Shaw Investments, StockCharts.com

Thank you for reading.                

CTP-656 Clinical Trial Initiated

CTP-656 for cystic fibrosis patients with CFTR gating mutations is now loaded in the clinicaltrials.gov website here NCT02971839.  The phase 2 trial is expected to start enrollment in January of 2017 to avoid the busy holiday season approaching.  The readout completion date is by the end of 2017.  Sweat chloride will be the primary endpoint of the study with FEV1 secondary.  With only 6-8 patients in each arm, the trial is not specifically powered for efficacy, but more likely to compare the three different dosages, and decide which one will be taken further into a phase 3 clinical trial, where FEV1 will be the primary endpoint.

Estimated Enrollment:	40
Study Start Date:	January 2017
Estimated Primary Completion Date:	December 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: CTP-656, Dose 1, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 1 (QD)
Experimental: CTP-656, Dose 2, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 2 (QD)
Experimental: CTP-656, Dose 3, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 3 (QD)
Active Comparator: Kalydeco, 150 mg Tablet (open label) 150 mg, oral tablet dosed twice-daily for 28 days	Drug: Kalydeco, 150 mg Tablet (BID; open-label)
Placebo Comparator: Placebo, Oral Tablet, QD Oral tablet dosed once-daily for 28 days	Drug: Placebo (QD)

Detailed Description:

This is a randomized, parallel-group, double-blind, placebo controlled multicenter study to evaluate the safety and efficacy of CTP-656 in CF patients with CFTR gating mutations, compared to Kalydeco, for a total of 28 days. Subjects will be randomized to receive either double-blind CTP-656 or placebo, or open-label Kalydeco.

 

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

GLPG1837 for Cystic Fibrosis

Galapagos presented data at the 2016 NACFC conference in Orlando yesterday, with a focus on SAPHIRA (2) results with drug GLPG1837 for CF people with the S1251N mutation.

Galapagos Abstract 253
Phase 2 results from SAPHIRA (2) S1251N
The bottom line with this small clinical trial that included n=7 patients, was that the company monitored in line FEV1, but below expectations for sweat chloride (readings in naïve patients that have never received Kalydeco, did not show a reduction in sweat chloride when administered GLPG1837 for 7 days) both compared against what Kalydeco had previously achieved at two weeks, in clinical trials for similar CF patients.  Sweat chloride readings is a biomarker that the FDA will want to see in clinical trials, prior to any approval.
  
Phase 2 from SAPHIRA (1) for G551D 
The company will have top line results by the end of 2016.  The company mentioned that Kalydeco for similar patients in (G551D), the FEV1 was around 6% to 10% improvement at the two week timeframe.  So that may be seen as a close comparison for their top-line results.  Below is a new CF timeline schedule for the company.  

Timeline for Potentiators:
GLPG1837 Phase 2 SAPHIRA (1) G551D readout by end of 2016
GLPG2451 Phase 1 readout first half of 2017
GLPG3067 Phase 1 start in 2017  (NEW)

Timeline for Correctors:
GLPG2222 Phase 2 start Q4 2016
GLPG2737 Phase 1 start Q4 2016
GLPG2851 Phase 1 start 2017

Bottom Line:
GLPG1837 was the first potentiator to enter clinical trials as twice daily dosing for Cystic Fibrosis people.  The company should have a readout by the end of 2016 for n=27 phase 2 clinical trial SAPHIRA (1) participants of the G551D mutation.  This will be an important readout regarding the future of that drug.  Concert should be into a phase 2 clinical trial with drug CTP-656 for G551D participants in the next few months, with readout by the end of 2017.  Thank you for reading. 

Contact: 586-431-8000

SAGE-217

The future pipeline will be more dependent upon SAGE-217, which is built around the same premise as SAGE-547, but as a once daily oral delivery. 
The company describes SAGE-217 as "a novel neuroactive steroid that acts as a positive allosteric modulator of synaptic and extra-synaptic GABAa receptor subtypes.  Unlike many of the naturally occurring neuroactive steroids, SAGE-217 has a pharmacokinetic profile to potentially support once-daily oral dosing and a selectivity profile that minimizes potential off-target side effects." 

Patents: SAGE-217 to April 2034

Bottom Line:
Sage Therapeutics is an interesting company with plenty of cash and a very successful phase 2 clinical trial completed.  The future will be focused on their oral, once daily SAGE-217.  Thank you for reading. 

NACFC 2016 Conference October 27-29th

This years North American Cystic Fibrosis Conference (NACFC), will be held in Orlando from October 27th through the 29th.  Below are some abstracts to look for during that conference.  
Concert:  Abstract 224:  CTP-656  Multiple Dose Pharmacokinetic Profile Continues to Support a Once-Daily Potentiator for Cystic Fibrosis Patients with Gating Mutations.  The trial showed a superior PK profile compared to ivacaftor.  

Galapagos:  Abstract 252:  Safety, tolerability, and pharmacokinetics of a novel CFTR corrector molecule GLPG2222 in healthy volunteers.  Full safety and PK data will be presented at the conference.  
Galapagos: Abstract 253:  GLPG1837 in subjects with cystic fibrosis (CF) and the S1251N mutation:  Results from a phase IIA study (SAPHIRA2).  Pending results September.

Proteostasis Therapeutics: Abstract 187:  Phase 1 initial results evaluating safety, tolerability, PK and biomarker data using PTI-428, a novel CFTR modulator, in patients with cystic fibrosis.  PTI-428 is an amplifier designed for any mutation.  

 Vertex:  Abstract 188:  Discovery and biological profile of next-generation CFTR Correctors.  VX-152 and VX-440 are highlighted in this abstract.  Vertex has other abstracts listed, that have been previously presented.

The link to the NACFC abstracts can be found here, 2016 NACFC Abstracts.            
Thank you for reading.                       

Ruxolitinib For Alopecia Areata

This academic Alopecia Areata clinical study by Columbia University, has finally been released in full to the public.  I highlighted what I believe are the important points to consider regarding this study.  The complete study can be found here JCI.