AVP-786 for Neurobehaviorial Disinhibition

A new clinical trial AVP-786 was recently posted on the clinicaltrials.gov website. Avanir Pharmaceuticals (the company Concert Pharmaceuticals licensed AVP-786 to) will be initiating AVP-786 for patients who experienced a traumatic brain injury (TBI), and suffer from neurobehavioral disinhibition, including aggression, agitation, and irritability. The phase 2 clinical trial is planning on enrolling 150 patients at 17 U.S. locations. The completion date is estimated to finish in December of 2019. More importantly, this is further validation that Otsuka is committed to furthering AVP-786 for neurological indications. Concert could achieve royalties in the mid single digits to low double digits based on AVP-786 future sales. Thank you for reading.

Otsuka's Commitment to AVP-786

Otsuka a focused CNS company, and the producer of Abilify, purchased drug AVP-786 for $3.5 billion through their acquisition with Avanir on November 13, 2014.  To get a sense of just how committed the company is to AVP-786, we have to look at the clinical trials that have started since the acquisition, and compare that to the number of clinical trials the company has started with another Otsuka drug Brexpiprazole, deemed the second generation drug of Abilify, that would compete in the indications similar to AVP-786.

Clinical Trials Started Since Acquisition
(3)  Alzheimer's Agitation - U.S.        phase 3
(1)  Residual Schizophrenia                phase 2
(1)  Disinhibition                                   phase 2
(1)  Alzheimer's Agitation - Japan     phase 3

Ongoing Trials With AVP-786
(1)  Treatment Resistant Major Depression Disorder  phase 2

New Otsuka Clinical Trials with Brexpiprazole
(0)
The company was previously in clinical trials prior to the acquisition of AVP-786, for Alzheimer's Agitation, MDD, and Schizophrenia as co- partner with Lundbeck.  But has not initiated anything new since agreeing to acquire AVP-786 from Avanir late 2014.  

Bottom Line:  Some significance into the timing of initiating clinical trials, may help us identify a companies priority in their clinical pipeline.  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.  
 

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.  
 

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.      

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.
              

Avanir Pharmaceuticals: Buy Out

A busy day as one of the stocks we hold received a buyout offer from Otsuka Pharmaceuticals (the maker of Abilify) for $3.54 billion or $17.00 per share, in a stock transaction. My initial impression is that Otsuka received a good deal, as they will get a nice pipeline including indications such as agitation / aggression in Alzheimer's patients (phase 3 2015), along with Major Depressive Disorder or (MDD), which is in the early stages of a phase 2 trial.  AVNR patents extend out to 2030.  

Avanir Pharmaceuticals

Avanir Pharmaceuticals (AVNR) is a biopharmaceutical company, focused on acquiring, developing, and commercializing novel therapeutic products for the treatment of central nervous system disorders (CNS).  The company just released top line results of their phase 2 trial for the treatment of agitation / aggression in Alzheimer's patients that were statistically significant.  The stock increased almost 100% after the top line results were released.

Quick Facts:
206 million shares outstanding
2.3 billion market cap
$317 million in cash

Intellectual Property:
AVP-923 US 2026
AVP-923 EU 2023
AVP-786 US 2030
AVP-786 EU 2028

AVP-923  (Nuedexta)
Approved in the U.S. for (PBA), Pseudobulbar Affect, and approved in the EU also for PBA. Commercialization in the U.S. in 2011, and EU currently underway.

Phase 2 trial for Agitation / Aggression in Alzheimer's patients:
JAMA Phase 2 Agitation Alzheimer's
Primary endpoint .001 on the agitation/aggression domain score of the NPI 
Stage 1 (baseline to week 5) .001
Stage 2 (week 5 to week 10 change) .02 
Cornell Scale for Depression in Dementia, 10 week  = .03

AVP-786 Adjunct Therapy Major Depressive Disorder
NCT02153502
Phase 2 - Results 2016

Bottom Line:  Avanir Pharmaceuticals has many moving parts in various stages of progress. The most important date for this company is the PDUFA date of November 26, 2014, which will be the FDA's decision on whether to approve AVP-825 for acute treatment of migraine. This is an inhaled treatment that has proven much more effective than oral capsule.  The recent top line results look very promising for AVP-923 in Alzheimer's patients who are experiencing agitation / aggression.  AVP-786 holds promise for CNS indications and it has patent out to 2030 U.S. Thank you for reading.