Alopecia - Clinical Trial Results

Three companies have released phase 3 clinical results with their respective drugs for Alopecia, and plan to file for FDA approval for this unmet need. Graph below of the clinical results, showing what each companies highest dose achieved in their phase 3.                                                                                        

The above chart shows, the effectiveness that each drug to the SALT 20 scoring criteria. A lower SALT from baseline signifies that there was more hair growth while on therapy. The highest percentage of test participants that achieved under or equal to the SALT 20 score, was Concert's CTP-543 12mg, with 38% and 41% of patients scoring under, in two phase 3 clinical trials. The hope is that those suffering from Alopecia will have a selection of at least two effective drugs for their disease. Thank you for reading.

CTP-543 - Phase 3 THRIVE AA1 Results

Today Concert Pharmaceuticals released the first of two phase 3 clinical trials for the unmet medical need Alopecia Areata.  The results were impressive and mirrored their phase 2 clinical trial. The phase 3 had 41.5% of patients in the 12 mg group achieving the SALT 20 or lower score after 24 weeks of treatment. Note that the lower the SALT score the more head of hair that has grown back.  The percentage of the 8 mg group of patients achieving a SALT score of 20 or less was 29%. Adverse events were reported inline with their phase 2 clinical trial. Below are results from three companies targeting Alopecia with their respective drugs. 

Concert's CTP-543 (green bars in graph) is the most effective in the high dose of 12mg and their lower dose of 8mg versus the others, high and low dose. The second phase 3 THRIVE AA2 will read out in the third quarter. Thank you for reading.

 

CTP-543 - Patent Trial and Appeal Board Decision

Yesterday the PTAB (Patent Trial and Appeal Board) ruled on a PGR (Post Grant Review) in favor of Concert Pharmaceuticals. The petitioner Incyte Corporation, has not demonstrated beyond a preponderance of the evidence that each challenged claims is unpatentable. Incyte Corporation could appeal to the Federal Court system, but that can take several years to play out, and may come to the same conclusion that the PTAB just did.

CTP-543's patent runs to 2037, so plenty years ahead, even considering that Concert does not plan to submit a New Drug Application to the FDA until the first half of 2023, with expected approval, either end of 2023, early 2024. 

CTP-543 would be addressing the unmet need of Alopecia Areata, an autoimmune disorder that causes your hair to come out, and which there is not an FDA approved oral treatment available at this time. Phase 3 clinical trial Alopecia data from Concert is expected in the coming weeks. Concert's stock had a positive reaction to this news, chart below. Thank you for reading. 

Alopecia Areata - Long Term Efficacy

There's not an FDA approved drug, for unmet medical need Alopecia available for patients at this time. Both Lilly (Baricitinib) and Concert (CTP-543) have now released long-term (52 week) Alopecia efficacy data, using the SALT score of equal to, or less than a score of 20. Note, that a SALT score 0f zero is considered a full head of hair. So the lower the score the more hair growth has been achieved while on therapy. Below is a chart of the percentage of patients achieving the SALT score of equal to or below 20, in each Lilly and Concert's long-term clinical trials.

From the chart data above, Concerts CTP-543 has 57% of patients achieving SALT 20 or lower in their open label 52 week study. The Lilly press release of their results, can be found here Lilly. Concert’s information is located at their website under Scientific Presentations. There's a strong possibility that one, or both of these oral drugs will get approved, over the next two years. Thank you for reading. 

Alopecia Areata - CTP-543, Baricitinib, Ritlecitinib

Of the three companies addressing the unmet medical need that exits for Alopecia Areata, both Concert Pharmaceuticals, and Lilly, have officially released SALT 20 scores. With both companies completing either phase 2 or phase 3 clinical trials, we can make comparison's from the information the companies have released to the public. Lilly has completed two phase 3's Brave-AA1, Brave-AA2 with drug Baricitinib, and Concert has completed a phase 2 with CTP-543. Both have initiated two dosing arms in their trials.

Without considering safety issues for either CTP-543, Baricitinib or Retlecitinb at this time, CTP-543's 12 mg dose appears to have the strongest effect for patients with 42% achieving SALT equal or below a score of  20.

Pfizer has released Ritlecitinib phase 2/3 clinical data Abstract 41, but did not break out the SALT 20 scores, but has issued long-term 48 week results. Below is a comparison of Ritlecitinib 48 week and CTP-543 52 week (Mean SALT Score) results that the companies have released to the public. 

Note that a SALT score of zero is a full head of hair. So the lower the SALT score from baseline, the more hair growth that has occurred. The baseline score (SALT 88.1) was derived from Pfizer's phase 2 part of the phase 2/3 clinical trial. Concert has used the 12 mg dose from two clinical trials to derive a baseline average score of SALT 86.5. Thank you for reading.

CTP-543 Phase 3 Design

Concert Pharmaceuticals is planning on running two phase 3 clinical trials for the indication of Alopecia Areata, to begin in the fourth quarter of 2020. Detail's of the phase 3 trial are below.

• Patients with moderate to severe Alopecia Areata
• Approximately 700 patients age 18-65 years with ≥ 50% hair loss
• Primary endpoint will be percentage of patients with SALT score ≤ 20
• 3:3:1 randomization to CTP-543 (8 mg BID or 12 mg BID) or placebo for 24 weeks

I like the simple design of this clinical trial, and believe based on the phase 2 CTP-543 results and comparison Clinical Trial Comparison, they can score high efficacy in the range of SALT score ≤ 20. Below is a three year chart of CNCE. Thank you for reading.

CTP-543 Patent Hearing Transcripts

Concert Pharmaceuticals is in patent battle with Incyte Corporation over CTP-543, which is deuterated Ruxolitinib. Ruxolitinib is owned by Incyte Corporation and is FDA approved for certain cancer indications such as myelofibrosis. The transcripts of the patent hearing that took place in January is here hearing - transcript.  The verdict will be announced in April. After reading the transcripts, I believe the counsel for Concert did well enough in the patent dispute to win, which will allow the company to advance CTP-543 forward for auto-immune indications such as Alopecia Areata. If by chance the ruling falls against Concert Pharmaceuticals, then the company has already stated that it will advance the patent dispute to circuit court. Thank you for reading.

CTP-543 and PFE-06651600

Now that Concert Pharmaceuticals has press released their top line results for CTP-543 8mg twice daily, CTP-543 Results from Interim Analysis of Phase 2a Trial in Patients with Alopecia Areata, a comparison can be made with Pfizer's  phase 2 results for drug PFE-06651600 for moderate to severe Alopecia Areata. In the comparison below, I am focusing on SALT % Increase (mean) End of Treatment. In this category CTP-543 had a 42.00% mean increase of SALT score after 24 weeks, versus a 38.13% increase for Pfizer's drug PFE-06651600. Concerts phase 2 study testing up to 8mg, may not be the highest dose available, as the company is currently testing a 12mg arm in the same phase 2 study.

PFE-06651600
	Total (n=45)	24 weeks
	Baseline	End of Treatment
SALT (mean)	88.1	54.5
SALT Increase (mean)	-33.6
SALT % Increase (mean)	0	38.13%
% SALT Reduction		% of 45 Patients Achieving Better SALT Scores
30%		47.9%
50%		37.5%
75%		27.0%
90%		25.0%
100%		12.5%
CTP-543 8mg
	Total (n=38)	24 weeks
	Baseline	End of Treatment
SALT (mean)	89.1	51.7
SALT Increase (mean)	-37.4
SALT % Increase (mean)	0	42.00%
% SALT Reduction		% of 38 Patients Achieving Better SALT Scores
30%		not measured
50%		47.0%
75%		29.0%
90%		16.0%
100%		0.0%

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.

Patent Board Does Not Institute PGR Proceeding

The press release is here Concert Pharmaceuticals Announces Patent Trial and Appeal Board Did Not Institute PGR Proceeding.  What this means to Concert Pharma is that, Incyte Corporation may be able at some point in time, challenge the patent of CTP-543. The second setback was that Concert has announced that they will not at this time initiate further clinical trials for other auto-immune indications that CTP-543 may have been useful for. The company continues to proceed with CTP-543 in their phase 2 clinical trial for patients with Alopecia Areata.  In addition the phase 3 clinical trial for AVP-786, which was scheduled to read out in July of 2018, has been pushed back to April of 2019, eliminating a potential catalyst for the company in 2018. The second half of 2019, which should reveal AVP-786's trial success, and phase 2 CTP-543 12mg arm effectiveness for Alopecia Areata patients, should be an important time for the company. 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 Clears Patent Challenge - $16.09

The press release is here PTAB Denies Incyte Petition Challenging CTP-543 Patent. More importantly drug deuteration is as strong as ever with the following five victories under it's belt.

1. Auspex deuterated form of venlafaxine challenge was denied.

2. Auspex purchased by TEVA Pharmaceuticals for  3.5 billion.

3. Austedo first deuterated drug approved by FDA for  Huntington's chorea.

4. Vertex purchasing CTP-656 for up to 250 million.

5. CTP-543 patent holds validity versus Incyte Corporation.

This completes the CNCE Three Hurdles To Clear, and now the company can solely focus on developing CTP-543 for Alopecia Areata, and a second soon to be announced indication. Thank you for reading.

CTP-656 Cleared for Sale to Vertex Pharmaceuticals - $15.11

The FTC (Federal Trade Commission) has terminated the waiting period for the sale of CTP-656 to Vertex Pharmaceuticals. CTP-656 is the deuterated version of Kalydeco which is approved for people with Cystic Fibrosis. This is another hurdle cleared which we wrote about CNCE: Three Hurdles to Clear. The company will now hold $260 million in cash or around $11.55 per share in cash. The third and last hurdle to clear will be the patent challenge for drug CTP-543 by Incyte Corporation. This one will take longer to circumvent. 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.                                            

Phase 2 CTP-543 Clinical Hold Lifted

Today Concert Pharmaceuticals announced that the phase 2 clinical trial of CTP-543 for Alopecia Areata will resume by the end of this month after a two month suspension. We initially wrote about this being one of three hurdles to be cleared CNCE: Three Hurdles to Clear.  The small downside is that the company will start the 24 week trial with the doses of only 4mg and 8mg, but with the potential to amend the protocol to explore higher doses. Prior to the suspension of the trial by the FDA, they were planning on using 4,8,12, and 16mg twice daily from the start. The FDA wants to take a measured approach for the development of using JAK inhibitors for various indications is what the company indicated. That coupled with the phase 1 clinical trials of CTP-543 that only lasted for 7 days of testing, makes sense.
The next hurdle to clear will be the pending sale of CTP-656 to Vertex, which is being considered by the FTC, whether it would be anti-competitive. I expect that second hurdle to clear in the next couple of months. 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 Clinical Trial Initiated

This phase 2 for Alopecia Areata will have a primary endpoint with the number of responders achieving at least 50% improvement in SALT score at 24 weeks.

Estimated Enrollment: 100
Anticipated Study Start Date:	May 2017
Estimated Study Completion Date:	July 2018
Estimated Primary Completion Date:	March 2018 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: CTP-543, 4 mg Oral tablet, dosed twice-daily	Drug: CTP-543 tablets
Experimental: CTP-543, 8 mg Oral tablet, dosed twice-daily	Drug: CTP-543 tablets
Experimental: CTP-543, 12 mg Oral tablet, dosed twice-daily	Drug: CTP-543 tablets
Experimental: CTP-543, 16 mg Oral tablet, dosed twice-daily	Drug: CTP-543 tablets
Experimental: Placebo Oral tablet, dosed twice-daily	Drug: Placebo tablets

Detailed Description:

This is a double-blind, randomized, placebo-controlled, parallel dose-comparison, multi-center study of CTP-543. Subjects will be randomized to either an active dose of CTP-543 or placebo for an initial 24-week efficacy period. A 28-week dose-adjustment period will follow where patients tolerating treatment may adjust dose at Week 24 as needed, and placebo patients will be switched to active treatment.

 

Below is a daily chart of Concert Pharmaceuticals. The stock has been basing since the big move higher on March 6, when the company announced the sale of CTP-656 to Vertex. 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.
 

CTP-656 Sold to Vertex Pharmaceuticals for $250 Million

Very nice news from Concert Pharmaceuticals on Monday March 6th.  CTP-656 for cystic fibrosis nets $160 million upfront, and another $90 million in milestones for the sale to Vertex Pharmaceuticals, closing by October 31st.  This deal gives Concert around $250 million (in present terms) cash on hand, with a cash runway into 2021.   The focus will be CTP-543 for Alopecia Areata, and to broaden their future pipeline.  With the upfront $160 million, the company will have around $11.50 per share in cash, zero debt.  Below is a 60 minute chart of CNCE.  The stock has gained 76% this week through Thursday. 



Bottom Line:

A well timed move by management to get the cash without diluting shares at extremely undervalued prices.  The future now is with CTP-543 for the initial indication of unmet need Alopecia Areata, and potentially others to follow. Thank you for reading.