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.

Alopecia Areata Clinical Trial Comparison

Concert Pharmaceuticals, just released CTP-543 Phase 2 Results for patients with moderate to severe Alopecia Areata. The phase 2 results included the 12 mg cohort of the clinical trial, in addition to the already completed 8 mg results. Below are comparison's made with Pfizer's drug PFE-06651600 Phase 2 Alopecia Areata. As seen by the data below, Concert's CTP-543's 12 mg results are shown to be the most efficacious versus their own 8 mg arm, and against Pfizer's PFE-06651600 at 24 weeks. The SALT % Increase (mean) drop from baseline (CTP-543 SALT dropped- 50%), is on a percentage basis the largest SALT improvement of the three results below. Results below are relative improvement from baseline, not placebo adjusted.

• SALT Score of 100 = zero hair growth
• SALT Score of 0 = full hair growth 

The percentage drop of SALT score (hair growth improvement) is one of the tools used to evaluate the efficacy of different Alopecia clinical trial drugs. Next CTP-543 will be tested in two large phase 3 clinical trials, but that won't occur until around mid 2020. 
                                                                  

PFE-06651600
	Total (n=45) at 24 weeks
		Baseline	End of Treatment
SALT (mean)		88.1	54.5
SALT Increase (mean)		-33.6
SALT % Increase (mean)		0	38.1%
% 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	42.0%
% SALT Reduction		% of 38 Patients Achieving Better SALT Scores
30%			not measured
50%			47.0%
75%			29.0%
90%			16.0%
CTP-543 12mg
	Total (n=36) 24 weeks
		Baseline	End of Treatment
SALT (mean)		87.3	43.6
SALT Increase (mean)		-43.6
SALT % Increase (mean)		0	50.0%
% SALT Reduction		% of 36 Patients Achieving Better SALT Scores
30%			not measured
50%			58.0%
75%			42.0%
90%			36.0%

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.

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 - $22.93

Using technical analysis as a tool to track where your stock has been trading, and potentially heading is interesting. A weekly chart of Concert Pharmaceuticals, CNCE is below.

The all-time high for the stock is right at the $25.00 dollar mark, which occurred in 2015. The company has since evolved with a patent victory, and the broadening of the pipeline, which will be announced in early 2018. INCY is a stock we currently do not hold, but are tracking. The company is the owner of the drug Ruxolitinib, commercially known as Jakafi, a Janus Kinase Inhibitor (JAK). A weekly chart is below.

INCY is down around 33% from it's recent high of around $149.00, creating a lower risk entry point in the near future. The relative strength index (RSI) is near the two year low, as confirmation. Lastly, the S&P 500 has been on a tare higher throughout 2017 without any kind of meaningful pullback at all. The S&P 500 is higher around 18% on the year. Notice the RSI on the weekly chart below, is in very overbought territory, the highest reading that it's seen during the last three years.



Bottom Line: Charting stocks and indices can be interesting, and help to create better, lower risk entry points for the stocks that we are interested in. CNCE is approaching the all-time high and a breakthrough of the prior resistance of $25.00 would lead to fresh highs. INCY has been sold off creating a lower risk entry point sometime in the future. The S&P 500 on the weekly chart is as overbought more than anytime during the last three years.  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.

Vertex Cystic Fibrosis Program

Vertex Pharmaceuticals (VRTX) has been, and will continue to be the leader in therapy for people with Cystic Fibrosis. Below is an update of all the different drugs in clinical trials that the company is currently running, including deuterated ivacaftor (VX-561), formerly known as CTP-656 that was purchased for $160 million from Concert Pharmaceuticals in July. Concert is eligible for up to $90 million more, dependent upon how far VX-561 progresses.

Twice Daily  
Ivacaftor 
Ivacaftor + Lumacaftor
Ivacaftor + Tezacaftor

Twice Daily Triple Combo Phase 2
Ivacaftor + Tezacaftor + VX-440 
Ivacaftor + Tezacaftor + VX-152
Ivacaftor + Tezacaftor + VX-659
Ivacaftor + Tezacaftor + VX-445

Once Daily Triple Combo Phase 2
VX-561 + Tezacaftor + VX-659 readout March 2018
VX-561 + Tezacaftor + VX-445 readout April 2018

The Ivacaftor patent runs to 2027, the Deuterated Ivacaftor (VX-561) patent runs into 2031. The goal for the program is to create a triple combo (1 potentiator, 2 correctors) once daily dosing for the majority of CF people with the F508del mutation. The company plans to run phase 3 triple combo trials in 2018.  Thank you for reading.

Concert Pharmaceuticals Raises $30 Million in Venture Debt Financing

Announced today, Concert Pharmaceuticals has raised $30 million in a debt financing agreement with Hercules Capital. This deal looks good in that it is not dilutive, and carries a prime-based variable interest rate of 8.55%. There were minimal warrants tied into the deal in the amount of 61,273 at an exercise price of $12.24. With this capital raise, the company should have at the end of the second quarter (June 30th), around $100 million in cash. This sum excludes the potential for another $160 million when CTP-656 is officially sold to Vertex. The loan matures June 2021, about the time when AVP-786 could potentially be on the market, FDA approved for agitation of the Alzheimer's type. 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.

GLPG2451 for Cystic Fibrosis

Galapagos is aggressively pursuing drugs for people living with cystic fibrosis.  We previously wrote about Galapagos extensively here Galapagos.  Their previous top candidate, potentiator GLPG1837, has now been put on hold for a much more convenient once daily dosed potentiator GLPG2451.  The drug has completed the safety phase 1 clinical trial in healthy subjects, and by Galapagos standards was viewed as ready for a phase 1 combo trial with their lead corrector GLPG2222.  The ultimate goal for the company is to develop a triple combination for people with the F508del mutation, which represents around 90% of the total CF population.  The phase 1 and 2 clinical trials are being funded almost 100% by their partner AbbVie.  If this phase 1 combo clinical trial passes the safety test, then a third component corrector GLPG2737, which is currently in the safety phase of testing, will then be added to the combo 2451 and 2222 to form the triple.  The big picture goal is to produce a better therapy than currently approved Vertex's two drug combo Orkambi.  A once daily triple combo would be advantageous for CF patients that may take up to 20-40 pills per day for this disease. 

Interim Analysis of 2451 and 2222
According to Galapagos, an interim analysis will be conducted on the combo mid-year.  If the combo passes the safety test, then corrector #2 GLPG2737 will then be added to the mix, and the three drugs will be tested for CF patients with F508del around third quarter of 2017.  So, by the end of 2017, the first triple combination (one potentiator, and two correctors) will be tested.  However, if the current phase 1 clinical trial with 2451 and 2222, does not produce an acceptable drug/drug interaction safety profile in healthy participants, then the entire project would be delayed.   

CTP-656  in Phase 2
Concert Pharmaceuticals CTP-656 is currently in a phase 2 clinical trial as mono-therapy for CF patients harboring the G551D mutation.  The drug is dosed once daily, and has shown head to head comparison's with Kalydeco in several early clinical trials with PK advantage.  The drug could fit nicely into the mix for a combo also, with two correctors, dosed as one simplified daily pill for F508del CF patients. 

Bottom Line: 
We'll monitor progress of the Galapagos combo clinical trial (2451 + 2222), and CTP656's phase 2 clinical trial that is scheduled to complete by the end of 2017.  Thank you for reading. 

CTP-656 Receives Orphan Drug Designation

Concert Pharmaceuticals received Orphan Drug Designation from the FDA in press release here, Orphan Drug Designation for CTP-656 for the Treatment of Cystic Fibrosis.  The significance of this, is that CTP-656 could receive up to seven years of marketing exclusivity, and even more importantly, gets FDA assistance in clinical trial design.  Orphan Drug Designation is given to a disease or condition that affects less than 200,000 people in the U.S.  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.

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.

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.