Janus Kinase Inhibitors for AA

The race is on for an effective and safe drug to treat Alopecia Areata. The two companies at the foremost of drug discovery are Pfizer with drug PF-06651600 and Concert Pharmaceuticals with CTP-543.  So how do the two JAK Inhibitor drugs stack up in limited clinical trials to date.
Columbia University 20 mg bid Ruxolitinib
n=12
% SALT Score Improvement (mean)
66.9%

Liu, King Study 10 mg bid Ruxolitinib
n=8
% SALT Score Improvement (mean)
61.2%

Pfizer PF-06651600
n=45
% SALT Score Improvement (mean)
38.1%                                                               
Next we will add the results of Concert's phase 2 clinical trial of CTP-543 with the 4mg and 8mg doses once press released expected fourth quarter. Thank you for reading.

Pfizer's PF-06651600

Pfizer and Concert Pharmaceuticals are the two companies with the most advanced drugs for the indication of Alopecia Areata. Pfizer has press released results for their lead candidate PF-06651600 here Phase 2 Data in Alopecia Areata. The drug achieved a -33.6 reduction in SALT score at 24 weeks from a baseline of 88.1. Below are the percentages of reduction of SALT score points for both Pfizer drugs. PF-06651600 is the drug that the company will be taking forward into phase 3 clinical trials.
  
Table. Percentage of Patients with Better SALT Scores at Week 24 Weeks
Improvement in SALT ScorePF-06651600 Group %, PF-06700841 Group, %

30%                                                 47.9                                  59.6   

50%                                                 37.5                                  48.9

75%                                                 27.0                                  38.3

90%                                                 25.0                                  31.9

100%                                               12.5                                   12.0

In the Columbia University phase 2 clinical trial Ruxolitinib for Alopecia Areata, 20mg bid dosing achieved good results based on the percentage of SALT improvement from baseline. At this time we do not know what the maximum dose that the FDA will allow Concert to run in clinical trials, as it is currently testing 8mg. CTP-543 is the deuterated version of Ruxolitinib currently in phase 2 clinical trials for Alopecia Areata. Thank you for reading.

Concert Pharmaceuticals 3rd Quarter Results - $17.53

The company announced third quarter results on Thursday 11-9-17. The company benefited from the sale of CTP-656 to Vertex as a one-time revenue that produced results of $5.61 in earnings per share for the quarter. More notable were some other developments.

• Cash runway of $207 million expected to last into 2021
• Expanded pipeline with a new neurological indication forthcoming
• A second indication for CTP-543 will be announced in 1st quarter of 2018
• Phase 2A for Alopecia Areata 4mg dose completed enrollment
• Data Monitoring Committee to give safety opinion around February 2018 4mg dose
• PGR  (Post Grant Review) of Incyte's deuterated Ruxolitinib to be decided in January 2018

Bottom Line:
The next important catalyst to watch for is the PGR decision to be made in January of 2018, the DMC decision for 4mg of CTP-543 around February, and two new indications will be announced early 2018. Thank you for reading.
 

CTP-543 Patent Challenge Response

We wrote about the challenge to the patent here CTP-543 Patent Challenge by Incyte. In the lengthy preliminary response from Concert Pharma, and on page 67 was this. "Ruxolitinib has 18 hydrogens, which can create 218 – 1 = 262,143 different deuterated ruxolitinib analogs". That statement may hold importance on the challenge of obviousness.  Thank you for reading.                                            

CNCE: Three Hurdles to Clear

Prior to Concert Pharmaceuticals advancing as a drug development company addressing unmet medical needs, a few hurdles first need to be cleared.

Sale of CTP-656 to Vertex
1. Sale of CTP-656 to Vertex for 160 million upfront and potentially 90 million in future milestones. Closing the transaction will happen after it's determined that the Hart-Scott-Rodino Anti Trust Improvements Act (FTC) clears the way. If the transaction gets blocked due to anti-competitive monopoly concerns, then the company will have to consider a capital raise sometime in 2017, for the advancement of CTP-543 in clinical trials. Should the sale go through, the company will have around $10.00 per share in cash on hand, and runway into 2021.

Suspension of Phase 2 for Alopecia Areata
2. The FDA has put a temporary suspension on CTP-543's phase 2 clinical trial for moderate to severe Alopecia Areata. The company will be forwarding non-clinical toxicology studies, required by the FDA before proceeding. Once the company forward's the studies, the FDA will then have thirty days to respond. The company is expecting to resume the clinical trial around August 1st. The FDA has exhibited zero safety concerns with CTP-543 at this time. This is a low hurdle event, that will just take time to clear prior to resumption of the phase 2 trial.

Ruxolitinib Patent Infringement Claim By Incyte Corporation
3. We first wrote here CTP-543 Patent Challenge By Incyte. Concert has stated on prior conference calls, that they have sought out a third party patent specialist, and believe that they have freedom to operate drug CTP-543 for Alopecia Areata. There will be a response period addressing Incyte's claim of obviousness in the next few months. The height of this hurdle is still undetermined at this time, but more clarity should occur in the next few months.

Bottom Line:
Drug development is never easy, and not for CNCE as noted above. I think #1, should be cleared late summer, and #2 should be cleared around August 1st. #3, is a longer process to determine the outcome. Thank you for reading.

CTP-543 Patent Challenge by Incyte Corporation

On April 7th, Concert Pharmaceuticals CTP-543 (deuterated Ruxolitinb) patent was challenged for Inter Partes Review (IPR). The filing details are listed below.

Trial Number - IPR2017-01256
Filing Date - 4/7/2017
Patent # - 9,249,149
Title - DEUTERATED DERIVATIVES OF RUXOLITINIB
Patent Owner - CONCERT PHARMACEUTICALS INC.
Petitioner - INCYTE CORPORATION
Tech Center - 1600

We have written about what is considered obvious and referred to this well written article Deuterated Drugs: Unexpectedly Non Obvious?  Inevitably this was going to happen sooner or later, and perhaps sooner is overall better for the company. Below is a list of Pro's and Con's that I came up with.
Pro's

• The patent office issued a deuterated Ruxolitinib patent to Concert Pharmaceuticals.
• Concert's patent for deuterated ruxolitinib has Alopecia Areata listed as a potential indication that CTP-543 will be tested for. 
• Incyte Corporation's patent for Ruxolitinib, does not list Alopecia Areata as a target indication.
• Original Ruxolitinib patent has zero mention of deuteration in the patent. 
• The drug, per company press release exhibits a 20% reduction in dosing. A 16mg tablet of CTP-543 has similar dosing characteristics as a 20mg dosage of Ruxolitinib.   

Con's

• Outside of a 20% dosing advantage that CTP-543 has shown, the two drugs are dosed twice daily, as the half-life, and the metabolite profiles, are similar from Concert press releases. Challenge based on obvious.
•  The only other deuterated drug patent challenge, Auspex Pharma's Venlafaxline, stated in their litigation that the "deuterated venlafaxine claimed in the '317 patent however, has superior pharmacokinetic properties compared to venlafaxine, including increased half-life, reduced Cmax, and reduced inter-patient variability."

Bottom Line: 
We don't know which factor is seen as the most important in drug patent litigation. If it is specific for the drug indication intended use, then Concert should have a very strong case as Alopecia Areata is listed in their deuterated Ruxolitinib patent, and Incyte Corporation's patent does not list Alopecia Areata within their patent as an intended indication. On the other hand, if drug pharmacokinetic, metabolites, and dosing frequency differentiation is an important factor in determining the outcome, then Incyte may get the nod, as Concert has even stated the two drugs are similar, except for the 20% dosing reduction that CTP-543 has shown in phase 1 clinical trials. Thank you for reading.
 

What is CTP-543

CTP-543 is the deuterated version of FDA approved drug Ruxolitinib, approved for myelofibrosis, and polycythemia vera.  Concert Pharmaceuticals plans to address unmet need Alopecia Areata with CTP-543.  Proof of concept was confirmed with this academic clinical trial, by Columbia University here JCI.  The company will be in a phase 2 clinical trial with around 90 participants beginning in the first quarter of 2017, with readout by the end of 2018. Thank you for reading.

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.
 

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.  

Ruxolitinib Five Year Safety and Efficacy

Below is a press release from Incyte Corporation with data that was presented at ASCO early June. 

- COMFORT-I data demonstrate that treatment with Jakafi resulted in a 31 percent reduction in the risk of death and sustained durable spleen volume reduction in patients with MF
- These five-year data support previously published findings for Jakafi

CTP-543 Phase 1 Initiated

Concert Pharmaceuticals has begun dosing in a phase 1 clinical trial with 80 healthy volunteers to assess safety and pharmacokinetics (PK).  From the company press release below.
“Alopecia Areata is a disease that can have devastating effects on patients but which currently lacks approved and effective therapies. We are pleased to broaden Concert’s pipeline of clinical drug candidates with the advancement of CTP-543 into clinical testing. CTP-543 is another example of how we have applied our novel deuterium platform to create medicines that represent new treatment options,” said Roger Tung, Ph.D., President and Chief Executive Officer of Concert Pharmaceuticals. “Recent advances in our understanding of alopecia areata biology, combined with patient data from several investigator-initiated studies, give us confidence that CTP-543 has potential to be an effective treatment. We hope to move this program quickly through Phase 1 evaluation in order to initiate efficacy studies in patients with alopecia areata next year.”

Aclaris Therapeutics acquired the rights, Aclaris Pipeline of a JAK inhibitor, and this is the patent, WO2013149194A that Columbia University through Vixen Pharmaceuticals, sold the rights to Aclaris Therapeutics.

CTP-543 Patent: 2032
Ruxolitinib Patent: 2028

Thank you for reading.