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.