Friday, October 9, 2015

CTP-656 & GLPG1837 Comparison

The North American Cystic Fibrosis Conference began yesterday.  Concert presented some new data for CTP-656, and Galagapos released phase 1 data for drug GLPG1837 today.  Below is new data for drug GLPG1837, and some comparison of CTP-656 and GLPG1837.

GLPG 1837
The half life (t 1/2) of 1837 runs between 6 and 15 hours depending on the dosage.  I selected a middle of the range dosage of 500 mg used in the phase 1, for comparison to CTP-656 regarding plasma concentration, and their distinct profiles.  

plasma concentration 500 mg 12 hours fed around 200 (ng/mL) 

The half life of CTP-656 is 15 hours with a 150 mg dose.  
plasma concentration 150 mg 12 hours fed 1306 (ng/mL)

The half life (t 1/2) of Kalydeco is around 11 hours for a 150 mg dose.
plasma concentration 12 hours fed 412 (ng/mL)

-Concert said CTP-656 was similar to Kalydeco at all dose levels, and well tolerated up to 300 mg.
-Galagapos 500 mg dosed twice daily with six participants, all experienced tiredness, and five experienced headache, in healthy subjects.  Galagapos says final safety data is pending.

Bottom Line:
From the data above, it looks like GLPG1837 will have to be dosed twice daily judging by the half life range of 6-15 hours, and Galagapos did not breakout each individual dose with half life. Two distinct drugs, as plasma levels with CTP-656 150 mg at 12 hours is substantially higher than GLPG1837 500 mg.  Concert believes that QD dosage (once daily) is possible with CTP-656.  The company still has to run a multiple ascending dose phase 1 trial, evaluating CTP-656 against Kalydeco.  Galagapos plans to initiate a phase 2 clinical trial for CF patients by the end of 2015. Thank you for reading.  No positions in Galagapos.


Monday, October 5, 2015

Is Adherence to Ivacaftor Suboptimal

From a recent issue of the Journal of Cystic Fibrosis, the authors make a strong case that twice daily Ivacaftor adherence is suboptimal.  Although used interchangeably, let's attempt to differentiate between compliance and adherence. If a doctor prescribes Ivacaftor 150 mg twice daily, and you accept and fill the prescription, you are in compliance with your doctor.  Taking Ivacaftor twice daily is adherence to the prescription requirements.  The link to the article is below.  
In the small sample study, the authors found that adherence was 61% among patients prescribed Ivacaftor.  Keep in mind they studied patients taking Ivacftor for the G551D mutation, which showed an improvement of over 10% percentage points in clinical trials, in the percent predicted FEV1.  The latest  FDA approved combo Orkambi (Ivacaftor and Lumacaftor) scored much lower on FEV1 for patients with F508del, than what Ivacaftor alone did for G551D patients. Potentially, adherence could be much lower, as these patients simply may not see the small benefit of the twice daily combo that Orkambi offers.  There are a few companies currently working on a once daily for CF patients, which could increase adherence rates to a higher level. Thank you for reading.


Friday, September 25, 2015

What is a Confidential Treatment Order (CTO)

A company can file a CT Order or Confidential Treatment Order when seeking confidential treatment for certain documents and information that a company would otherwise have to file.  A CTO is issued by the SEC and may only be in effect for a certain period of time.  Concert Pharmaceuticals filed a CTO on August 27th, 2015, below.  

So, they must have had reason for discussing certain documents, or information with another company that they would otherwise have to file with the SEC.  The CTO's can be seen on the Nasdaq website where companies file their documents for public disclosure.  Another example of a company filing a CTO comes from Gilead Sciences on August 28th.

What a coincidence, the two companies filed CT Orders almost on the same day!  Thank you for reading. 


Tuesday, September 22, 2015

CTP-656 Phase 1 Single Dose Comparison

Just released today at the UK Cystic Fibrosis Trust Conference.  Data looks good, as the half life +34% compared to Kalydeco, and other PK measures by far outperformed.  Data below is a single dose of CTP-656 150 mg, compared to a single dose of Kalydeco 150mg.

C 12hr        +320%
C 24hr        +420%
AUC 24hr   +280%
C max         +100%
T 1/2             +34%

Of note, at steady state, Kalydeco exposure is predominately to less active metabolites compared to CTP-656.  This could potentially have CTP-656 being more efficacious than Kalydeco.

Bottom Line:  This was a good 15 minute presentation that displayed CTP-656 from a comparison, to Vertex drug Kalydeco.  The company reported that "CTP-656 was well-tolerated across all dose groups (75, 150, and 300 mg).  There were no serious adverse events reported in subjects who received CTP-656."  Vertex at present, holds a monopoly drug for CF patients, charging $300,000 per year therapy.  I think in two to three years, there will be a competing therapy of drugs, lower priced, with a better drug to drug interaction profile, with potential for single daily dosing.  Thank you for reading. 


Saturday, September 19, 2015

Upcoming Cystic Fibrosis Conferences

There are two cystic fibrosis conferences approaching.  The first is the UK Cystic Fibrosis Trust, that will start next week.  The second conference is the NACFC North American Cystic Fibrosis Conference which will start October 7th.  This is what we could potentially learn from both conferences regarding what is relevant to our investment.  

UK Conference

CTP-656 single dose comparison with Kalydeco as placebo.
This will be the first in human clinical trial, to assess the PK, and compare against the current standard of care (Kalydeco) for CF patients. CEO Tung has already alluded to the comparison as being "significant" from a metabolic point of view.  Concert will be presenting a late breaking abstract at this conference.  What this means for CF patients, is that CTP-656 could potentially be dosed as a once daily, and improve on the drug to drug interaction profile over Kalydeco.   We will be looking for the t1/2 life percentage improvement over Kalydeco, in addition to the AUC.  The US patent extends out five years further to 2032 over Kalydeco 2027. 

NACFC Conference

CTP-656 single ascending dose comparison with Kalydeco as placebo. Kalydeco is dosed 150 mg twice daily.  This part of the phase 1, could tell us what an equivalent dose to 150 mg Kalydeco, could be attained with the deutered CTP-656 as single daily dosing.  Following this will be a the multiple ascending dose part of the phase 1 trial, that should conclude early 2016. 

GLPG1837 Galagapos (GLPG) is in a phase 1 clinical trial to assess the safety, tolerability, and the PK of potentiator GLPG1837, against placebo in healthy volunteers.  From the NACFC abstract. 

This randomized, double-blind, placebo-controlled study was designed to assess the safety, tolerability and pharmacokinetics of GLPG1837 in healthy volunteers over a range of single and multiple doses. In the single ascending dose (SAD) part of the study, 2 alternating cohorts of subjects are exposed to single oral doses of 30 to 2000 mg in fasted conditions (with 500 mg further evaluated after a high-fat high-calorie breakfast). The multiple ascending dose (MAD) part of the study is designed to administer GLPG1837 orally at doses of 125 to 500 mg b.i.d. for a period of 14 days. At the time of submission of this abstract the study was still ongoing. GLPG1837 has been safe and well tolerated up to the 1500 mg single dose (latest dose tested), with no dose-related abnormalities on any of the safety parameters. Full safety/PK data will be presented at the conference.  Unlike Concert's CTP-656 phase 1 clinical trial, Galagapos chose not to use Kalydeco as a placebo comparison, because they really do not have to at this time. The company plans to start a phase II, clinical trial for CF patients with the G155D gene mutation by the end of 2015. AbbVie is responsible for clinical trials after the phase II, from their agreement with Galagapos.

Bottom Line:

We will have to wait until the October NACFC to get a good comparison between what CTP-656, and GLPG1837 look like, as far as a PK, safety and dosing comparison is involved.  Initially it looks like both drugs are safe in healthy humans, but how they interact with other drugs, and whether single or multiple dosing (b.i.d.)  is required may be the differentiating factor.  CTP-656 could potentially get through clinical trials quicker, if granted the expedited pathway by the FDA, and move directly to a phase 3 clinical trial after completing a phase 1.  Thank you for reading:)


Thursday, September 17, 2015

ITI-007 Phase 3 Results

Intra-Cellular Therapies (ITCI), released top line, phase 3 results with drug ITI-007, for patients with schizophrenia having an acute exacerbation of psychosis.  The primary outcome was the PAANS (positive and negative syndrome scale total score).  The secondary outcome measure was the Positive and Negative Syndrome Scale Subscales for the clinical trial NCT02282761.  The results are as follows.  I am including recent FDA approved Rexulti data as comparison, using the PAANS assessment tool for similar patients. 
ITI-007  60 mg  p=0.022
              40 mg  p=0.164
Rexulti    4 mg  p=0.0006  (recent approval, and phase 3 results using PAANS)
                2 mg  p=0.0001 
ITI-007  60 mg  p=0.003
              40 mg  p=0.025
Rexulti    4 mg  p=0.0012
                2 mg  p=0.0056
Somnolence     60mg 17.3%
                         40mg 10.7%
Mild Sedation  60 mg 12.0%
                         40 mg  9.3%

From the Intra-Cellular press release "both doses of ITI-007 improved the PANSS Negative Symptom Subscale score more than placebo in the ITT population, but the improvement did not reach statistical significance in this 4 week study.  
My thoughts.  ITI-007 has a strong safety profile and may not get a black box label similar to other anti-psychotics, but is less efficacious than newly approved Rexulti for the same patients.  The CGI-S (clinical global impression scale for severity of illness) was not listed in the clinical trial website as either a primary or secondary endpoint.  Perhaps the company added that secondary measure as needed.  Add it if the data fits, but make no mention, if not statistically significant.  In this case the CGI-S was significant over placebo. Avanir/Otsuka just started a phase 2 clinical trial with drug AVP-786, for Residual Schizophrenia patients with the primary endpoint being the NSA 16 (16 item negative symptom assessment). Several other secondary endpoints will also be measured. 

Bottom Line:  The results were deemed a win by Intra-Cellular as the primary endpoint of the PAANS was met.  The negative symptom subscale, the PANSS did not reach statistical significance. The CGI-S, which was not listed as a primary or secondary endpoint, was added as a secondary endpoint for the significance it achieved.  We'll know more when they test the same drug against Risperidone in another phase 3 clinical trial for the same patient population over a six week period. AVP-786 will be tested for patients with Residual Schizophrenia in a phase 2 trial, with the primary endpoint being the NSA 16 negative symptom assessment.  ITI-007 did not prove to be statistically significant on the PANSS Negative Symptom Subscale.  Thank you for reading.


Friday, September 11, 2015

Concert Pharmaceuticals ($19.27)

Busy week for the company as they presented at two investor conferences, and the company had coverage initiated by Aegis Capital with a buy rating and a $26.00 price target.  The only new, or somewhat unexpected from the two conferences, was from the question answer session when asked about partnering their lead drug for Cystic Fibrosis CTP-656, and CEO Tung's response was that they have not fully committed to partnering the drug, but will proceed to continue to test the drug in clinical trials.  The company believes that the drug may improve over Kalydeco with once daily dosage, and a better drug/drug interaction profile.  A once daily oral potentiator (CTP-656), with a once daily corrector, could be the ideal patient therapy from a convenience and economical point of view.  The company may be able to take CTP-656 from a phase 1 clinical trial, directly to a phase 3 clinical trial, on an expedited pathway the CEO has mentioned, either 505(b)2 or other. The company should have enough cash if the expedited pathway is granted from the FDA, to complete a phase 3 clinical trial on their own. Below is a weekly chart of CNCE.  
Source: Shaw Investments,
Bottom Line:  A good week for company presentations, and stock movement to the upside. September 22nd will be the day that an abstract will be presented at the UK Cystic Fibrosis Conference.  The abstract will illustrate single dosage CTP-656, against placebo Kalydeco, from a safety, tolerability, and PK profile.  The stock has reached an all-time closing high on good volume this week.  Thank you for reading.


Monday, September 7, 2015

Drug Patent Dates of Interest

A drug's patent is of extreme importance to the company that has developed the drug, and competitors looking for acquisition.  This post will develop a running patent list, as new drugs become of interest to our investment thesis.  The typical drug patent extends for 20 years once the patent is approved, from the priority date.  After that, generic companies are able to replicate, and sell the drug at a very high discount to the expired patented drug.

AVP-923 US 2026                                                          
AVP-923 EU 2023
AVP-786 US 2030
AVP-786 EU 2028
CTP- 499 US 2029
CTP- 499 EU 2029
CTP- 656 US 2032
CTP- 656 EU xxxx
CTP- 730 US 2030
CTP- 730 EU 2030
GLPG 1837 2034
ITI- 007 US 2025
Kalydeco US 2027
Kalydeco EU 2025
Lumacaftor US 2026
Lumacaftor EU 2026
MAT 9001 US 2033
MAT 8800 US 2033
MAT 2203 US 2027
MAT 2501 US 2027
Nuplazid US 2028
Nuplazid EU 2025
Otezla US 2024
Otezla EU 2024
Rexulti US 2027
Rexulti EU 2025


Friday, September 4, 2015

The Economist: Deuterated Drugs

The September 5th edition of The Economist discusses some interesting facts about deutered drugs, and mentions Auspex and Concert Pharmaceuticals, of which both are the leaders in this area.  The potential for legal battles ensuing between the company applying deuteration, and the original owner of the drug may be overstated.  In Concert's case, they seek to partner with large pharma companies, creating a potential win/win situation, as the original drug owner gets an improved metabolic profile drug, the potential for less dosing and improved efficacy, with a longer patent life. 
In May we linked an article about what is obvious, or non-obvious as it relates to patent infringement here Patent Infrigement: Obvious or Nonobvious.  The placing of deuterium must be a skill or art in itself.  Some drugs could potentially have thousands of options to choose from, and that alone becomes a skill in itself that sets deuterium drugs apart from others.  Thank you for reading.


Saturday, August 29, 2015

CNCE Second Quarter Conference Call

This conference call was actually completed on August 5th, as I have been behind on posting relevant notes from that presentation.  The highlights primarily involved CTP-656, which is known as d-Ivacaftor, or Vertex Pharmaceuticals non-deutered commercial drug known as Kalydeco, for Cystic Fibrosis.  Some bullet points below for reference.
  • The first part of the phase 1 that led to the selected compound CTP-656, could be presented as interim data at any time, or the company may elect to wait until the second part of the phase 1 clinical trial is complete, which includes single and multiple ascending doses against placebo Kalydeco, to be completed around years end 2015.
  • The company intends to progress CTP-656 for CF patients that have the G551D mutation first as mono therapy, than later consider any combo therapy.
  • The company believes once daily dose for CF patients with CTP-656 is a potential.
  • Open discussions with companies working in the CF area have been an ongoing process, but only completed details will be released to the public.  
  • The cash balance of $151 million, is believed to be sufficient to fund operations into 2018. 
Bottom Line:  This was a good conference call, with meaningful analyst questions following the presentation. The company reserves the right to present interim data of CTP-656 as sees appropriate, or hold the data until the phase 1 clinical trial has been completed, which includes single and multiple ascending doses against Kalydeco, as placebo in the control arm.  The company is scheduled to appear at the UK Cystic Fibrosis Conference on September 22nd, with deuterated Ivacaftor as the subject of presentation.  Thank you for reading.  


Friday, August 28, 2015

AVP-786 for Disinhibition Syndrome

The number of clinical trials utilizing Avanir / Otsuka NMDA modulator drug AVP-786 is increasing with each quarter. The number now stands at six with the addition of the latest posting at Clinical that pertains to Disinhibition Syndrome here Treatment of Disinhibition. There is not a drug specifically approved for Disinhibition Syndrome, or Frontal Temporal Dementia (FTD) that I can find.  The main inclusion into the trial is as follows.
  • Documented diagnosis of a Neurodegenerative Disorder including frontotemporal dementia, Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DBL), vascular cognitive disorders, or Huntington's disease, at least 3 months prior to Baseline.
This is a very broad inclusion into this phase 2 clinical trial, with only 12 patients aged 50-90 being recruited.  In general the patient must have some sort of Neurodegenerative Disorder. The list of AVP-786 clinical trials that are in progress or set to start soon is below.  

Phase 2 Major Depressive Disorder (Adjunct)
Phase 2 Residual Schizophrenia
Phase 3 Agitation in patients with dementia of Alzheimer's
Phase 3 Agitation in patients with dementia of Alzheimer's
Phase 3 Long term, extension study agitation in patients with dementia of Alzheimer's
Phase 2 Treatment of Disinhibition

Bottom Line:  It's easy to see why Otsuka bought Avanir Pharmaceuticals for $3.5 billion in 2014. They see the potential for NMDA drug AVP-786, and it's use for many indications.  Thank you for reading.  


Tuesday, August 25, 2015

Still A Bull With Volatility

Weekly charts are a valuable tool to understanding a more distant look into market comparisons. Then we can decide whether we are still in an up trending market or we have turned downward, based on the technical pattern.  Below is a weekly chart of the S&P 500 Index.
Source:  Shaw Investments,
From the weekly chart above.  The current correction low that we achieved yesterday, is above the correction low that was achieved in 2014, still creating an upward trend line, based on the weekly chart.  
Source:  Shaw Investments,
The $VIX chart above has not seen high levels like this since 2011.  Expect volatility in the near term, until the $VIX reading declines to more normal historical levels, which could take a few weeks.  

Bottom Line:  The S&P 500 Index above put in a correction reading (greater than -10% from peak), but remains above the 2014 correction low, creating an upward trending market.  So we are in a long term bull market, and an intermediate term up trending market.  The $VIX remains very high historically, so expect a whip lashing type market in the near term or until the $VIX declines to more historical average levels.  Thank you for reading.


Sunday, August 23, 2015

Cystic Fibrosis Clinical Studies - Update

We previously wrote about CF clinical studies here Cystic Fibrosis Clinical Studies.  When analyst predict peak drug revenue in the $6 billion range, like they have done for Vertex Pharmaceutical's combo Orkambi, other companies take notice.  The other major players that are interested in developing Cystic Fibrosis drugs are Galapagos (AbbVie), and Novartis.

This is a phase 1 study to read-out fall of this year.  The trial is first in human study of GLPG1837 in healthy human subjects to test the safety and tolerability of the drug.

This trial is a phase 2 study that has been running since mid 2014, and is scheduled to read-out by end of 2015.  This trial is testing QBW251 in healthy and CF patients.  Safety, PK, PD, and FEV1 will be measured.

Should receive European Union approval for Orkambi by the end of 2015, for patients 12 years and older with two copies of the F508del mutation.  The company received U.S. FDA approval in July for the same CF population.  The company is several years ahead of any competition mentioned above. 

Bottom Line:  The Galagapos and Novartis trials, are two clinical studies that many will be waiting for results.  The Galagapos trial is just phase 1, and in healthy subjects.  Adverse events will be the primary endpoint, with PK data as secondary endpoint.  The phase 2 (four part) clinical trial of Novartis drug QBW251, should provide more information about the effect of the drug as it is being tested on healthy, and CF patients, in single and multiple ascending oral doses.  There are a number of smaller companies that are working on related symptoms from having CF, and other companies that are developing drugs that could enhance the effectiveness, of already approved CF drugs like Orkambi.  Thanks for reading. 


Friday, August 21, 2015

Week In Review

Remaining objective during stock market corrections is the best possible solution.  We can remain objective by viewing charts, and by blocking out any emotional related news that seems to circulate, when there is a sell-off at hand.  Remember, market corrections are a healthy process that cleanses out all the excesses, to the point that value creation emerges.  In other words, these are good times to be putting cash to work, which we have this week.  So let's view a couple charts below to understand better, how far down this correction could go.  

Source:  Shaw Investments,
The above chart is of the S&P 500 index, which is one of the world's most watched index.  I tracked last year's market correction loss just to compare what we may be looking for at this precise moment. Last October's correction took the market down -9.89%.  We are currently lower from the recent high at -7.29%.  So we are closing in on last years percentage correction low.  In addition the market at this time is very oversold, and we should get a relief bounce higher at minimum, in the near future. 
Source:  Shaw Investments,
The above chart depicts what is known as the VIX.  The VIX is also known as a fear gauge, based on how much volume is exhibited in the options market with put buying.  The higher the VIX spikes the more fear is said to be in the market.  The important thing here is to observe the extremes of the VIX. Based on that theory, the huge spike in the VIX could signal a sell-off stock market bottom may be getting close at hand.  The move higher is getting very close to matching last years VIX correction high reading.  

Bottom Line:  Great time to be adding to existing positions over the course of this correction.  The sell-off so far, is getting close to last years correction low, so we may be getting close to a bottom, if using last years sell-off on a comparison basis.  Thank you for reading.  

Saturday, August 15, 2015

CTP-499: Special Protocol Assessment (SPA)

Two important FDA designations are Orphan Drug Status and Special Protocol Assessment. Today we'll discuss the SPA and how it relates to CTP-499.  An SPA is a designation from the Food and Drug Administration that an uncompleted phase 3 clinical trials design, clinical endpoints, and statistical analysis are acceptable for FDA approval. Basically means that if the company meets those pre-determined endpoints in the trial, FDA approval should be a very high probability.
We previously wrote about one of Concert's drug for Type 2 Diabetic Nephropathy named CTP-499 here, What is CTP-499. The company has been under negotiations with the FDA for an SPA for that drug for over a year.  The CEO has stated that they should have an SPA for CTP-499 by the end of this calendar year.  After that, a partnership will be selected, and the costs of the lengthy (three years) trial will be split in some equitable way. The selected partner should feel more comfortable about the trial's design being granted an SPA from the FDA, and there will be one pivotal phase 3 clinical trial, as opposed to two phase 3 trials. The trial's design in this case is a result of the completed phase 2 clinical trial's findings, from a subset of patients and their results vs. placebo.  If the phase 3 trial starts the beginning of 2016, lasts three years, and the company files a New Drug Application (NDA) after that, FDA approval could potentially take a year from there.  So, by the beginning of 2020, the drug could go to commercialization and have approximately ten years of patent exclusivity.  
The patent for CTP-499 runs until 2029 - 2030 in the US, EU, and Japan.  The market for Diabetic Nephropathy is estimated to reach $3 billion by 2020 from research here Global Market Study. CTP-499 will be used as co-therapy with ACEI and/or ARB for patients that have advanced to a specified point of disease.  Thank you for reading.