Monday, November 16, 2015

Avanir Initiates (TRIAD) for Alzheimer's Agitation

Today it was announced that Avanir Pharmaceuticals (Otsuka) has initiated what they call their TRIAD clinical programs.  The clinical trials will utilize AVP-786 for the treatment of agitation in patients with Alzheimer's disease.  There will be two parts to the initial TRIAD program, Triad-1 which has been initiated, and Triad-2, which will be initiated in 2015 also. The clinicial trial should last around two years.  
TRIAD-1  NCT02442765
Dosing will be (DM/Q)  18/4.9 mg, or 28/4.9 mg over 12 weeks, and enroll 380 patients.
TRIAD-2   NCT02442778
Dosing will be (DM/Q)  28/4.9 mg, over 12 weeks, and enroll 325 patients.

Avanir also announced that the company has received "Fast Track" for this indication, and that AVP-786 used for their phase 2 clinical trial as adjunct for major depression disorder, will complete enrollment by the end of 2015.  

Bottom Line:  
The TRIAD program that has been announced today, is a big commitment to drug AVP-786, not only for agitation in Alzheimer's, but also adjunct for major depression disorder, residual schizophrenia, and disinhibition syndrome.  Thank you for reading.  


Saturday, November 7, 2015

Agitation in Alzheimer's Disease - An Unmet Need

Finding an effective and safe drug to treat agitation associated with Alzheimer's disease has been a challenge.  Currently there are no drugs approved for this indication.  Three drugs hold potential to treat this growing population.  


Avanir (owned by Otsuka) is planning two phase three pivotal clinical trials for treatment of agitation in patients with dementia of the Alzheimer's type.  In a phase 2 clinical trial with the primary endpoint being the NPI Agitation/Aggression Domain, a statistically significant p=.001 was achieved from publication released here Avanir JAMA Publication.  The drug was generally well tolerated. The two planned phase three trials will last around two years to complete, then another year to potential FDA approval.  In three years from the beginning of 2016, AVP-786 could be the first FDA approved drug for this indication, and reach commercialization in 2019.  The patent extends until 2030 in the U.S., and 2028 in the EU.

Owned by Otsuka, with a revenue sharing agreement with Lundbeck, there are two phase 3 clinical trials below for patients with agitation associated with dementia of the Alzheimer's type with a completion date around mid 2017.  This drug could prove effective for this indication, but the drug like it's predecessor Abilify, has a black box label.  Also, Otsuka chose to buy drug AVP-786 (via Avanir acquisition) for the same indication after starting the above two clinical trials a year into progress!

Intra-Cellular Therapies is planning on a phase two clinical trial in the first half of 2016 with ITI-007.  The company does not have any significant findings with the drug for this indication in prior clinical trials.  ITCI ran a phase 1/2 clinical trial primarily for cognition, as there were no patients that exhibited agitation at baseline.  The press release is here Intra-Cellular.   


Owned by Acadia, is currently in a phase 2 clinical trial for Alzheimer's patients experiencing psychosis, with other secondary endpoints such as agitation included.  The company has stated that they have received anecdotal evidence of the drug having an effect for agitation in the current phase 2 trial.  The company is planning a phase 2 clinical trial in 2016 for agitation associated with Alzheimer's disease. 

Bottom Line:  Atypical drug therapy for elderly patients with dementia has been deemed unsafe by the FDA, with black boxed warnings for certain indications.  AVP-786 is the only drug of the three that has been proven in a clinical trial for Alzheimer's Agitation.  The drug was generally well tolerated.  The drug is conservatively 1 to 2 years ahead of  ITI-007, and Pimavanserin to potential market, if the latter two drugs are even as effective in their phase 2 clinical trials, as AVP-786 was.  At present AVP-786 holds the most promise from proven clinical data, and is much further along in the FDA approval process. Thank you for reading.    


Friday, November 6, 2015

CNCE Third Quarter Conference Call

Concert completed their conference call yesterday.  A couple important highlights below.

There will be a small 40 patient phase 2 clinical trial in the second half of 2016, that will evaluate single dosing of CTP-656 in CF patients, that are already taking Kalydeco for the G551D mutation. There will be a washout period of a few days, and after that, the patients will be given CTP-656 for around a month.  So the company will have a FEV1 and sweat chloride baseline for the patients that are currently prescribed Kalydeco.  A comparison after the washout period over a month's time frame on CTP-656, could be the endpoint.  This will be a short efficient study, with an important comparison to the already approved standard of care Kalydeco, for CF patients with the G551D mutation.  

"We are encouraged by the favorable pharmacokinetic profile of 730 observed in our phase 1 clinical trial compared to historical data for Apremilast.  Going forward, Celgene will be responsible for any post phase 1 development for the program."
"The next development milestone that we could see would be either, the dosing in the phase three trial, or an acceptance of an NDA filing, and that would be a $15 million dollar milestone."

The company ended the quarter with $142 million in cash, which is expected to last into 2018.  Thank you for reading.


Monday, October 26, 2015

Drug Comparison In Clinical Trials

Drug comparisons made in clinical trials need to be highly scrutinized.  Such is the case with Galagapos.  On October 15th, 2015 the company made public that their triple combination drug (potentiator GLPG1837 with correctors GLPG2665 and GLPG2222) for Cystic Fibrosis patients, was reported, "The combination resulted in chloride transport up to six-fold greater than Orkambi in HBE cells with the homozygous F508del mutation".  The comparison made was against the current standard FDA approved Vertex drug Orkambi.  Is the comparison based on apples to oranges? First off, the important thing to remember is that Orkambi is a two drug combination of Kalydeco and Lumacaftor approved for the homozygous F508del mutation 12 years and older. Galagapos was comparing their triple combination in vitro to Orkambi. They were in essence comparing three drugs working together, compared against two drugs together in human bronchial epithelial (HBE) cells.
Since then Vertex has added a second corrector into the picture creating their triple combination drug, which is a three fold improvement over their own drug combo Orkambi in hetrozygous F508del (HBE).  What can we take from this comparison that Galagapos made?

1)  The up to six fold increase comparison is not on equal ground, due to Galagapos three drug combo versus Vertex two drug combo.
2)  The comparison that GLPG made is not known if they were comparing their three drug combo for homozygous F508del (HBE), versus Vertex homozygous or hetrozygous HBE cells.  The latter hetrozygous minimal function, has no approved treatment available yet, and is a harder to treat in the CF population.  
3)  To create a truly comparable study, the company should have done a double blinded study, with both drugs for the same mutations, under the same conditions.

Bottom Line:   When companies make drug comparisons, it is always wise to dig into the details to see if the comparison was on equal ground, or whether the company was comparing apples to oranges.  Can the Galagapos three drug combo become a significant improvement over current standard of care for Cystic Fibrosis patients?  Possibly, but there is no evidence based on the "six fold increase" statement that was made per company press release. Thank you for reading.  

Friday, October 9, 2015

CTP-656 & GLPG1837 Drug 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 an early 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 150 mg 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.


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, $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 and Galagapos will share responsibility and funding for phase 3 clinical development, from their agreement.

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.  

No positions in ITCI.


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 (2-23-2027)
Rexulti EU 2026 (12-31-26)


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.