TRIAD 1 & 2 Recruiting

Avanir Pharmaceuticals, a subsidiary of Otsuka, has initiated both arms of the phase 3 clinical trial for Alzheimer's Agitation termed TRIAD, and the Long Term Extension Study for patients who have completed 12 weeks of  either TRIAD 1 or 2.  Patients will be enrolled into the long term extension NCT02446132 study based on the following criteria:

• Patient has successfully completed Studies 15-AVP-786-301, 15-AVP-786-302, or 12-AVR-131.
• Patients will be enrolled in the study for approximately 52 weeks.
• Approximately 550 patients will be enrolled at approximately 110 centers in the US.
• All patients enrolled will receive AVP-786, the treatment dose assigned will be masked to the patient, investigator, study staff, and the sponsor.

The long term extension study is scheduled to complete in July of 2019, approximately 52 weeks after TRIAD 1 and 2 have completed dosing with AVP-786.  This long term extension study may be important for the drug label the FDA assigns during the approval process, for agitation in patients with dementia of the Alzheimer's type.  

AVP-786 (AVP-923) has exhibited a consistent and mild safety profile, making the drug a unique candidate for elderly patients with behavioral problems due to Alzheimer's or other dementia related diseases.  A mild safety profile, compared to current anti-psychotics could also promote off-label prescribing potential, for the drug.  The safety profile of AVP-923 was written about in a post here Rexulti & AVP-923 Safety Profile Comparison. Thank you for reading. 
 

Assessing the Success of AVP-786 for Patients with Treatment Resistant Major Depressive Disorder

Assessing the success of a clinical trial depends on many factors.  Trial design, primary endpoint, prior drug trials, safety and tolerability, competitor success with similar drug, and what is deemed successful by FDA standards, are just a few factors to consider.  Avanir Pharmaceuticals is nearing the end of a phase 2 clinical trial for AVP-786 as Adjunctive Therapy in Patients with Major Depressive Disorder With Inadequate Response to Anti-Depressant Treatment in clinical trial NCT02153502.

The first important factor to consider is that AVP-786 is the deutered version of AVP-923.  Both drugs were tested in a Phase 1, Single-center, Randomized, Double-blind, Double-dummy, 2-way Crossover Study Comparing AVP-786 with AVP-923 here NCT02336347.  The two drugs exhibited a similar PK and safety profile.  This is important because we will be using data from two AVP-923 clinical studies that had a subset of patients tested for depression, with either the BDI-2 (Beck Depression Inventory-II) or the Cornell Depression Scale.

Avanir ran a phase 3 clinical trial with AVP-923 evaluating the safety and efficacy of AVP-923 in PBA (Pseudobulbar Affect) patients with ALS or MS, trial named (STAR) here NCT00573443. The mean change from baseline at day 84 in the Beck Depression Inventory (BDI-II) Total Score was used as a secondary endpoint.  Patients with moderate depression on the BDI-II scale, greater than 18, scored a significant p=0.03 while taking AVP-923, 30mg dextromethorphan / 10mg quinidine.  Below is the Avanir, JP Morgan Healthcare Conference presentation in January 2014.

2014 JP Morgan Healthcare Conference
Treatment-Resistant MDD Clinical Rationale
The Beck Depression Inventory-II (BDI-II) was included as a secondary efficacy endpoint in the pivotal phase 3 trial in PBA patients
Major Depression Excluded
Among patients with baseline BDI-II scores >10, AVP-923 treatment was associated with a reduction in depression symptoms
STAR Trial; Avanir data on file

Endpoint BDI-II
(n=50)  -3.36  AVP-923 30/10
(n=55)    -2.3   AVP-923 20/10
(n=52)    -1.1    Placebo

P Value
0.065   AVP-923 30/10
0.378   AVP-923 20/10

"Among a subset of patients with baseline BDI-II scores > 18, AVP-923 30/10 was
associated with statistically significant improvement (p=0.03)".

Using the description below for the (p=0.03) subset, the trial had patients classified primarily in the moderate depression range, as the presentation listed major depression as excluded. The following is a breakdown of the BDI-II, which is a 21-item self-report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3.

BDI-II Depression Scale
0-13 is considered minimal range 
14 to 19 mild depression
20 to 28 moderate depression
29 to 63 severe depression
  

In a phase 2 clinical trial for Alzheimer's patients experiencing agitation. Trial NCT01584440 utilized a secondary endpoint called the Cornell Scale for Depression in Dementia (CSDD): which a statistical p=0.02 was observed. 

Bottom Line:
Although the number of patients were relatively small in the two above trials showing benefits of AVP-923 for depression, it does give us some guidelines to the probabilities for potential success in the current clinical trial coming to completion.  Thank you for reading.

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.  
 

CTP-656 & GLPG1837 Drug Comparison

The North American Cystic Fibrosis Conference began yesterday.  Concert presented some new data for CTP-656, and Galapagos 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) 
http://www.glpg.com/rd-cystic-fibrosis

 

CTP-656

The half life of CTP-656 is 15 hours with a 150 mg dose.  

plasma concentration 150 mg 12 hours fed 1306 (ng/mL)

Kalydeco

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)

SAFETY PROFILE

-Concert said CTP-656 was similar to Kalydeco at all dose levels, and well tolerated up to 300 mg.

-Galapagos 500 mg dosed twice daily with six participants, all experienced tiredness, and five experienced headache, in healthy subjects.  Galapagos 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 Galapagos 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.  Galapagos plans to initiate a phase 2 clinical trial for CF patients by the end of 2015. Thank you for reading.  No positions in Galapagos.  
 

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.  
Adherence_to_Ivacaftor_is_suboptimal
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. 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.

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 could potentially 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.

2015 UK & NACFC 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 Galapagos (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, Galapagos chose not to use Kalydeco as a placebo comparison.  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 Galapagos 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.
 

ITI-007 Phase 3 Results

Today Intra-Cellular released results from the second phase 3 clinical trial for Schizophrenia called ITI-301. The press release is here Phase 3 ITI-301. The results below show that there is some effect that drug ITI-007 has for Schizophrenia patients using the PANSS clinical endpoint to measure efficacy versus placebo. The results are as follows.

• 60mg -14.5    p = .022
• 40mg -12.9    p = .164
• Placebo -10.3

An active comparator such as Risperidone was not used in this clinical trial.
Regarding negative symptoms of Schizophrenia the following quote from the CEO in the press release. "Furthermore, 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. These and additional data will be presented at upcoming scientific meetings".
The second phase 3 is currently running with an active comparator Risperidone called study ITI-302. Those results should give a better indication of the efficacy of ITI-007 for Schizophrenia. Thank you for reading.

2015 UK & NACFC 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 Galapagos (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, Galapagos chose not to use Kalydeco as a placebo comparison.  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 Galapagos 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.
 

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 on an expedited pathway, either 505(b)2 or other. Below is a weekly chart of CNCE.  

Source: Shaw Investments, StockCharts.com

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.
 

Patent Expiration Dates

A drug's patent is of extreme importance to the company that has developed the drug, and competitors looking for acquisition.  This is a running patent list, as new drugs become of interest.  The typical drug patent extends for 20 years from the priority date, once the patent is approved.  After 20 years, and any additional patent extensions, 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
AXS-05  US 2040
AXS-07 US 2036
D-Baricitinib US (August 2032)
D-Baricitinib EU xxxx
Baricitinib US 2028
CTP-543 US 2037
CTP-543 EU xxxx
Ruxolitinib US (Dec 2027)
CTP- 656 US (May 2031)
CTP- 656 EU xxxx
Kalydeco US 2027
Kalydeco EU 2025
CTP-692 2038
CTP- 730 US 2030
CTP- 730 EU 2030
Otezla US 2024 (pending through 2028)
Otezla EU 2028
GLPG0634  US (June 2029)
GLPG 1837  US 2034
ITI- 007 US 2028
JZP-386 US, EU, JP (2030-2032)
Xyrem  2019-2024
MIN-101 GR US 2035
D-Momelotinib US (Jan 2033)
D-Momelotinib EU  xxxx
Momelotinib US (March 2027)
Nuplazid US 2028
Nuplazid EU 2025
Rexulti US (February 2027)

Rexulti EU (December 2026)
SAGE-217 US  April 2034
SAGE-217 EU April 2034
SAGE-547 US  to 2033 - 2037
SAGE-718 US  Sep 2032 or Oct 2037
                                  
 

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.
 

AVP-786 for Treatment of Disinhibition

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 Trials.gov that pertains to Disinhibition Syndrome here Treatment of Disinhibition. There is not a drug specifically approved for this indication, 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.

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.  
 

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, StockCharts.com

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, StockCharts.com

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.

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, StockCharts.com

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, StockCharts.com

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.  

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.
 

Allergan Buys NMDA drug for $560 Million

Allergan says yes to CNS (central nervous system) and NMDA (N-methyl-D-aspartate) modulating drugs for depression, with the purchase of private company Naurex for $560 million.  We previously wrote about NMDA drugs and Naurex here, NMDA Receptor Modulators.  NMDA drugs are rapidly gaining press as mono and adjunct therapy for depression patients.  Avanir is currently in a phase 2 clinical trial with their NMDA modulator AVP-786, as an adjunctive therapy in patients with Major Depressive Disorder, with an inadequate response to anti depressant treatment. Avanir will complete their phase 2 clinical trial in the first half of 2016.  Naurex has already tested NRX-1074 as an IV as adjunctive in a phase 2 study for patients with Major Depressive Disorder.  Next, the company will test an oral NRX-1074 in a planned phase 2 clinical trial as mono-therapy for Major Depressive Disorder (MDD).

Bottom Line:  At this point we have no idea how NRX-1074 oral will perform, compared to their completed intravenous phase 2 clinical trial for patients with Major Depressive Disorder (MDD). Avanir with drug AVP-786, is most likely two years ahead of NRX-1074 in the clinical trial process. Thank you for reading.      

CTP-730: Potential Milestone and Royalty Winner

We originally wrote about CTP-730 here, What is CTP-730.  Today Celgene held it's second quarter conference call this morning.  This is what Scott Smith head of Global Inflammation and Immunology had to say regarding the launch of Otezla, and the future pipeline of indications that Otezla could potentially get approved for.  
Scott Smith President, Global Inflammation and Immunology
"Thank you, Jackie.  Q2 was a great quarter for Celgene I and I.  During the quarter, we saw significant acceleration of prescriptions and revenues for OTEZLA in the U.S. and strong initial uptake in the early launch countries internationally. We also made progress on indication expansion for OTEZLA advancing a global Phase III program in Behcet's Disease and Phase II studies in atopic dermatitis and ulcerative colitis.
Now turning to OTEZLA, were seeing a substantive uptick in revenues and demand in the U.S. Total prescriptions far outpace the recent launch analogs in the I & I space and currently measure over 4,500 TRx' per week based on the latest data. Revenues for the quarter grew to $90 million worldwide and we're tracking well in line with internal plans. We're very encouraged at the progress we're seeing outside of the U.S., both in Canada and in early launch countries in the EU.  After only five months, we're outpacing all recent launches in Germany.  Still very early in the launch, but this initial success helps reinforce the global value proposition of OTEZLA and the need for novel approaches to the treatment of I & I disease.
The trends in the U.S. are supported by positive launch metrics.  While the PSA launch continues to make strong and steady progress, the launch of psoriasis indication has fueled much of the recent acceleration.
Access to new therapies is a critical component of success in the market.  And it's important to note that over 70% of OTEZLA prescriptions in pre-biologic patients are being approved on first pass. Total U.S. patient share for OTEZLA in psoriasis surpassed ALLERA some months ago and passed ENBREL's overall patient share in June.  The source of business in psoriasis continues to be heavily weghted towards the pre-biologic sector with 75% of patients coming to OTEZLA from topical therapy or no therapy at all over the past 12 months".

Bottom Line:  CTP-730 is Concert Pharmaceutical's deutered enhanced Otezla, that just finished a phase 1 clinical trial.  CTP-730 has been licensed to Celgene, with future milestone, and royalty payment potential for Concert.  Otezla has had a very strong launch, and could expand into Behcet's Disease, atopic dermatitis, and ulcerative colitis. Thank you for reading.
 

Rexulti & AVP-923 Safety Profile Comparison

There is not an FDA approved drug for the treatment of agitation in patients with dementia of the Alzheimer's type.  Otsuka Pharmaceuticals has a total of five phase 3 clinical trials that have been in progress, or about to start.  The two drugs that are addressing this indication are Rexulti (Brexpiprazole), and AVP-923 (AVP-786). Rexulti is a joint 50% ownership between Lundbeck and Otsuka.  AVP-923 (AVP-786) is 100% owned by Otsuka, with a milestone and royalty licensing agreement with Concert Pharmaceuticals.  The side effect comparison between Rexulti and AVP-923 is below.

Rexulti (Brexpiprazole)
In clinical trials here phase 3 Schizophrenia, the 2 mg group of Rexulti exhibited the following side effect profile.
Insomnia 13.4%
Headache 9.3%
Agitation 8.6%
In clinical trials here phase 3 Adjunctive Major Depression, the 2 mg group of Rexulti exhibited the following side effect profile.
Weight Increase 8.0%
Akathisia 7.4%

AVP-923 (AVP-786)
In a phase 2 clinical trial for patients with agitation of the Alzheimer's type, the following side effect profile was exhibited.
Falls 8.6%
Diarrhea 5.9%
Urinary Tract Infection 5.3%

Falls had a baseline skew, that had more patients in the treatment group (17.2% to 12.6%) and 25% more patient-day exposure to AVP-923 than placebo, noted here JAMA DM/Q Phase 2 Alz. Agitation.  In addition from that phase 2 clinical trial, there were no new cardiovascular safety signals and no clinically significant changes in QTc observed in the study.  These results above are consistent with several other clinical trials that Avanir has run with AVP-923, for traumatic brain injury, or stroke here Prism II, with diarrhea being the most commonly reported adverse event.

Bottom Line:  Otsuka has advanced the deutered version of AVP-923, (known as AVP-786) into three phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type, to begin soon.  The company also has two ongoing clinical trials in progress with Rexulti for the same patients, that started in 2013. The patent for Rexulti runs until 2027 US and until 2025 EU, the patent for AVP-786 runs until 2030 in the US, and 2028 in the EU. Thank you for reading.
              

FDA Approves Rexulti (Brexpiprazole)

Late Friday the FDA approved Otsuka and Lundbeck's atypical antipsychotic drug Rexulti (Brexpiprazole), as mono therapy for Acute Schizophrenia, and as adjunct therapy for Major Depressive Disorder. We previously wrote about Brexpiprazole here Lundbeck Clinical Trials Update .  Otsuka, the maker of Abilify has been under pressure to replace lost sales of the world's number one selling drug Abilify (Top Selling Drugs) in 2014, due to patent expiration in 2015. Rexulti (Brexpiprazole) has been the drug to replace Abilify for several similar CNS indications. Under the marketing agreement Lundbeck (co-developer and co-commercialization) will get 45% of Brexpiprazole U.S. net sales, and 50% net sales in Europe.  The patent for Rexulti runs until 2027 US, and 2025 in the EU. The label for Rexulti is below.

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI ^®(brexpiprazole)
INDICATIONS
REXULTI is indicated for:

• Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
• Treatment of schizophrenia in adults

IMPORTANT SAFETY INFORMATION

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Rexulti (Brexpiprazole) deemed the second generation Abilify, is getting a similar safety label as Abilify, even though the side effect profile between the two drugs varies, with Rexulti showing improvement in some areas such as akathisia.  It will be interesting to see what kind of label AVP-786 gets for the Treatment of Agitation in Patients with Dementia of the Alzheimer's Type.  AVP-786 is about to enter phase 3 clinical trials in September. Thank you for reading.
 

Orkambi Gets FDA Approval

Today the FDA approved the combination of Vertex's Lumacaftor and Kalydeco (Orkambi) for cystic fibrosis people, 12 years and older, with two copies (homozygous) of the F508del mutation. We originally wrote about Orkambi here Vertex Pharmaceutical Passes Advisory Committee, when they were front and center with the FDA advisory committee.

Orkambi has been appoved for CF patients despite the relatively small improvement in FEV1 in two F508del clinical studies.  How high is the bar set for other companies to get clinically significant improvement over Kalydeco as mono therapy for the G551D mutation, and Orkambi combination therapy, for patients 12 years and older, with two copies of the F508del mutation?

G551D Through 24 weeks Kalydeco 150 mg q12h

• 10.6% and 12.5% FEV1 improvement vs. placebo

G551D Through 48 weeks Kalydeco 150 mg q12h

• 10.5% and 10.0% FEV1 improvement vs. placebo
• 3,000 Worldwide Patients

F508del Through 24 weeks 2 tablets (ivacaftor 125 mg / lumacaftor 200 mg) q12h

• 2.6% and 3.0% FEV1 improvement vs. placebo
• 26,000 U.S. + EU Orkambi Patient Potential

These are the FEV1 (forced expired volume) numbers that other companies will be considering as significant, to improve current therapy for CF patients.  The side effect profile was mild, as a high percentage of patients completed the Vertex clinical trials.  The annual wholesale acquisition cost (WAC) will be priced at around $259,000 per patient for the Orkambi combination.  Thank you for reading.
 

NMDA Receptor Modulators for Depression

NMDA (N-mythel-D-asparate) roots track back to a drug known as Ketamine or street name Special K, with hallucination effects.  Ketamine is an NMDA receptor antagonist originally used as an anaesthetic.  The glutamate receptor subtype known as (NMDA) plays a central role of modulating brain activity in the central nervous system, such as synaptic transmission, synaptic plasticity, and excitotoxicity. Pharmaceutical firms have been developing NMDA type drugs for over two decades, and a few including Memantine, and Nuedexta are being marketed for other indications outside of depression.
There have been several studies modulating the NMDA receptor, that have shown efficacy in patients with treatment-resistant depression.  A trial performed by Avanir Pharmaceuticals for pseudobulbar affect with drug AVP-923 (Nuedexta), showed efficacy in a subset of patients for depression using the Beck Depression Inventory II or BDI-II. Data showed that the dextromethorphan (an NMDA receptor antagonist, sigma 1 agonist) / quinidine combination was effective in patients with BDI-II scores greater than 18 at inclusion with AVP-923 30/10, and was associated with a statistically significant improvement of (p=0.03). What's also significant is that major depression was an exclusion into the trial.  Avanir is now in a phase 2 clinical trial with AVP-786, for major depressive disorder patients as adjunct to current antidepressant here NCT02153502.  I think the chances of success are high, based on how the dextromethorphan/quinidine combination performed in the subset of patients in prior trials.
Private company Naurex, is also working on NMDA drugs for depression patients. The company has displayed good data in early clinical trials using IV, and soon to be launched an oral NMDA drug for depression.  Thank you for reading.

AVP-786 is Concert Pharmaceutical's deutered enhanced version of AVP-923.

Concert Pharmaceuticals: ($16.91)

Quick technical look at Concert Pharmaceuticals with a daily chart below. Everyday the stock closes higher, a new all-time closing high is achieved.

The out performance is evident when shown on a chart that has the XBI Small Cap Biotechnology Fund, and the S&P 500 below over a five day period.  

Bottom Line:  Funds are adding shares, as they see future value at these prices.
Thank you for reading.

AVP-923 and AVP-786

Avanir Pharmaceuticals with drug AVP-923 completed a very successful phase 2 trial for symptoms of agitation in Alzheimer's patients.  Avanir now under the Otsuka umbrella, is conducting two phase 3 trials with the deuterated version of AVP-923, known as AVP-786 for the same patients.  So what are the drug dose differences and exclusion criterias between the successful phase 2 AVP-923 clinical study, and the AVP-786 phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type?

AVP-923  NCT01584440
Phase 2 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 20 mg / Quinidine 10 mg
Dextromethorphan 30 mg / Quinidine 10 mg

Exclusion Criteria:

• Patient has other type of dementia (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia).
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g. malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, certain cardiac conduction abnormalities including QTc prolongation, or unstable valvular heart disease).
• Patients with myasthenia gravis.

AVP-786   NCT02442765, NCT02442778
Phase 3 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 28 mg / Quinidine 4.9 mg
Dextromethorphan 18 mg / Quinidine 4.9 mg

Exclusion Criteria:

• Patient has dementia predominantly of non-Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia)
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g., malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease)
• Patient with myasthenia gravis

The difference in the exclusions from the phase 2 AVP-923 trial and the deutered version using AVP-786 is that QTc prolongation, which was an exclusion in the phase 2 is not listed in the current phase 3 trials.  The reduction in the dose of quinidine to 4.9 mg from 10 mg could be the prime reason for the two new phase 3 trials not including QTc prolongation as an exclusion criteria.  I expect these two phase 3 trials to recruit at a much faster rate, than the AVP-923 trial achieved. I also expect that patients currently taking AVP-923 for other indications, will eventually switch to the deutered version AVP-786, which has a similar PK profile to AVP-923, favorable dosing, and has a longer patent that extends to 2030 US and 2028 EU. Thank you for reading.