Agitation in Alzheimer's Disease - An Unmet Need

There is not an FDA approved drug for Agitation in Alzheimer's disease.  This unmet need has seen an increase in clinical trials recently.  Below are a few companies that are either in, or entering into a clinical trial for agitation in Alzheimer's Disease with various drug candidates.

AVP-786                                      
Avanir (owned by Otsuka) is running two phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type NCT02442765, NCT02442778.
In a phase 2 clinical trial with the primary endpoint being the NPI Agitation / Aggression Domain, a stastistically significant (p=.001) was achieved with the non-deuterated version of called AVP-923. The results and publication of that trial is here Avanir JAMA Publication.  The drug was generally well tolerated. The current clinical trials will complete July 2018.  In four years from the beginning of 2016, AVP-786 could be the first FDA approved drug for this indication, and reach commercialization in 2020.  The patent extends until 2030 in the U.S., and 2028 in the EU.

AXS-05                                           
Owned by Axsome Therapeutics, is a combination of Dextromethorphan / Buproprion.
The company expects to enter a clinical phase 2/3 trial in 2016.  
7-21-17: Axsome has now entered into a Phase 2/3 Dementia via Agitation with potential readout first half of 2020.  

4-27-20: Results of phase 2/3, CMAI p=0.010

Brexpiprazole                           
Owned by Otsuka, with a revenue sharing agreement with Lundbeck.  There are two phase 3 clinical trials for patients with agitation associated with dementia of the Alzheimer's type currently running NCT01862640, NCT01922258, with a completion date of around June 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 this indication, while two clinical trials with Brexpiprazole were over a year into progress.       
1-9-2017:  Both clinical trials are now active, but not recruiting participants.  There will be 12 weeks plus a 30 day follow-up period.  Participants that have completed the 12 weeks double blind trial, are eligible to enroll in a 2 month observational study. 
6-7-2018: Otsuka is taking another try with Brexpiprazole with this US only clinical trial to complete in December of 2020 NCT03548584.

Lexapro (Escitalopram)                           
4-17-2017: This phase 3 clinical trial with 15mg Lexapro (escitalopram) is being sponsored by John Hopkins School of Public Health (JHSPH) for patients with agitation associated with Alzheimer's disease. The clinical trial is here NCT03108846, and has a completion date of August 2022. This is the first of potentially two phase 3 clinical trials that may be required by the FDA prior to filing an NDA if the drug is effective.

ITI-007                                     
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.  
6-28-16:  Intra-Cellular has now entered into a phase 3 clinical trial for Alzheimer's patients experiencing agitation here NCT02817906 with readout August 2018. Results: Terminated study.

Pimavanserin                        
12-12-2016:  Acadia has now entered into a phase 2 clinical trial for Alzheimer's patients experiencing agitation with their 5HT2A Pima here NCT02992132, with readout June 2019.
12-20-2016:  ACAD releases top-line phase 2 ADP data.  But does not break out the sub-category of the primary endpoint NPI-NH, such as agitation and aggression.  The company announced in their conference call, that agitation and aggression was no different than placebo group.

Bottom Line Update 12-21-2019:  AXS-05 and Escitalopram, are the two drugs that hold the most promise for their respective clinical trial for Alzheimer's Agitation. AXS-05 should have phase 2/3 readout in the first half of 2020, and Escitalopram in 2022. Thank you for reading.   

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.

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.
              

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.

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.

Concert Pharmaceuticals - ($14.73)

Concert Pharmaceuticals (CNCE), is an interesting company, with a well established and cohesive management team.  The company description below is directly from the most recent 10-K. "We are a clinical stage biopharmaceutical company applying our extensive knowledge of deuterium chemistry to discover and develop novel small molecule drugs. Our approach starts with approved drugs, advanced clinical candidates or previously studied compounds that we believe can be improved with deuterium substitution to provide better pharmacokinetic or metabolic properties, thereby enhancing clinical safety, tolerability or efficacy. We believe our approach may enable drug discovery and clinical development that is more efficient and less expensive than conventional small molecule drug research and development".

The company is taking existing drugs, and potentially improving them with selective deuterium.  They plan on developing drugs in-house and through partnership with other companies.  Some quick facts below.

Quick Facts:
22 million shares outstanding
330 million market cap
75 million in cash

Intellectual Property:
AVP-786 (Otsuka) (2030 US), (2028 EU) 
AVP-923 (Otsuka) (2026 US), (2023 EU)
Rexulti (Otsuka) (2027 US), (2025 EU)
CTP-499 (2029 - 2030) U.S. EU, Japan
CTP-730 (2029 - 2034) U.S. EU, Japan
JZP-386 (2030 - 2032) U.S. EU, Japan
CTP-656 (2032) U.S.
Kalydeco (Vertex) (2027 US), (2025 EU)

As you can see above, the company has done a fine job of protecting their intellectual property with extended patent dates, which gives them enough time to get through clinical trials to commercialization, either in house or through partnership. A $280 million market cap puts CNCE in microcap territory (less than $300 million). Hard to find a microcap stock with this much future potential, with an established and cohesive management team in place. We'll have more to say about Concert Pharmaceuticals. Thank you for reading.

 

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.