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.   

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.
 

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.
 

Lundbeck - New Holding ($19.19)

We recently purchased shares of Lundbeck under the symbol (HLUYY).  I previously mentioned this company before here Lundbeck and here Clinical Trial Update.  The company is located in Copenhagen Denmark, and their description from their website is as follows.
Lundbeck's R&D strategy is aimed at enabling the discovery and development of new pharmaceuticals targeting the underlying mechanisms of brain disorders. This approach allows us to treat the symptoms more effectively and also to potentially alter the course of the diseases.  The strategy requires comprehensive research into the brain and the biology and mechanisms of brain diseases, as well as improved understanding of research targets and clinical outcomes. 
The company falls into the catagory of a CNS, (central nervous system) research and development company. I best describe this as a value investment and a turnaround story. The company and its partner (Otsuka), have suffered from patent expiration from their main producer Abilify. But during the past two years the company has produced some successful clinical trials with extended patent dates for drugs that treat MDD, (major depressive disorder) and acute schizophrenia, both of which I am expecting FDA approval mid 2015.  The new products coming on line with extended patent dates, makes this a lower risk value proposition.  My initial price target on the stock is around $27.00 in the intermediate term.  Thank you for reading.

Top Selling Drugs in 2014

The top selling U.S. drugs by sales (as opposed to prescriptions) in 2014 are listed below. The sales were tracked on a 12 month rolling basis from mid 2013 to mid 2014 by research firm IMS Health.

1.  Abilify $7,240 billion
2.  Humira $6,310
3.  Nexium $6,303
4.  Crestor $5,672
5.  Enbrel $5,097
6.  Advair Diskus $5,064
7.  Sovaldi  $4,469
8.  Remicade $4,342
9.  Lantus Solostar $3,829
10. Neulasta $3,688

Abilify achieved the number one spot in 2014 despite receiving an FDA issued black box warning in 2006.

Elderly people with psychosis related-dementia treated with antipsychotic 

medicines including ABILIFY, are at an increased risk of death compared to placebo. ABILIFY is not approved for the treatment of patients with dementia-related psychosis.

I continue to believe that Acadia Pharmaceutical's drug Nuplazid will become palliative care for the elderly, and follow in the footsteps of Abilify, on a sales growth basis over time. The drug has shown an improved safety profile to that of other atypical antipsychotics already approved. The company has mentioned that a clean label is highly probable when Nuplazid gets approval for Parkinson's Disease Psychosis in 2015.  A clean label for Nuplazid could prompt Neurologist and Psychiatrists to switch at a high rate, and prescribe the drug more readily off-label for similar indications. Sales will likely start strong, as new patients will be prescribed Nuplazid for Parkinson's Disease Psychosis (PDP), existing patients under another therapy will switch at a high rate, and the drug could eventually become an add-on, to existing therapies in other areas, such as cognition. Thank you for reading.   

Lundbeck Clinical Trials - Update

Lundbeck and their marketing partner Otsuka (the manufacturer of the #1 selling drug Abilify) are major players in the central nervous system (CNS) space.  An update on new phase 3 trial data for depression and schizophrenia are listed below.  The links are below.

12-10-2014
Lundbeck 2014 Press Releases
Trial: (NCT01360645) Phase 3
Brexpiprazole as adjunct for Major Depressive Disorder (MDD)
Study 1 (2mg + ADT (N=175): -3.21, p=0.0002)  MADRS

12-11-2014
Lundbeck 2014 Press Releases
Trial: (NCT01396421) Phase 3
Brexpiprazole as mono-therapy for adults with Acute Schizophrenia.
Total Score (4mg: -19.65, p=0.0006) PANSS

Both studies achieved significant efficacy results, which may lead to approval from the FDA mid 2015.  Brexpiprazole has patent exclusivity through 2026.