Alzheimer's Disease Agitation

Alzheimer's Disease Agitation, is an unmet medical need. Three companies have addressed potential therapy for these patients.  Otsuka and partner Lundbeck with Brexpiprazole, has already achieved FDA approval as the first and only approved drug, but carries a Black Boxed Warning. Another candidate from Otsuka again, is AVP-786. AVP-786 has yet to achieve two meaningful positive clinical trial readouts, and has two clinical trials scheduled to complete in 2026. Axsome's AXS-05 has completed one successful clinical trial known as ADVANCE-1. AVANCE-2 is scheduled to read out in the first half of 2024. If successful, the company will pursue an sNDA filing with the FDA for approval.  Click on chart below for a larger version. Thank you for reading.

Thank you for reading: 586-431-8000

 

Agitation in Alzheimer's Disease - An Unmet Need Pt 2

We previously wrote about this unmet medical need back in 2016 here Agitation in Alzheimer's Disease - An Unmet Need. Since then, the field has narrowed with some of those companies no longer pursuing this indication for different reasons, but most likely their drug was not successful for this indication in clinical trials. With a safe and effective therapy for these patients experiencing agitation, the likelihood for them remaining in their homes becomes more favorable, as it would be easier on their caregivers, thus reducing the necessity for nursing home care. The companies still pursuing this important indication are as follows.

Axsome Therapeutics - AXS-05 completed first pivotal phase 2/3 

John Hopkins - Escitalopram first phase 3 ongoing

Otsuka - AVP-786 has not successfully completed a pivotal phase 3

Otsuka / Lundbeck - Brexpiprazole completed two phase 3's, with one showing efficacy

The path to FDA approval is especially important, due to becoming a first mover in that space and establishing your product within the medical community. The projected clinical readouts of the current clinical trials are listed in order, as follows. Brexpiprazole 4/2022, AVP-786 6/2022, , Escitalopram 8/2022, AXS-05 9/2022.

AVP-786 has completed one phase 3 clinical trial using the (SPCD) Sequential Parallel Comparison Design. The SPCD is designed to reduce the placebo effect. Avanir disclosed that one of the two doses showed significant efficacy, but the company did not go into detail whether the higher or lower dose achieved the significant efficacy. In the second clinical trial using a Parallel Group Placebo Controlled design, patients did not experience a significant improvement in agitation compared to patients treated with placebo, per Avanir press release. Thus, putting the entire Agitation in Alzheimer's Disease program in question.

Just a bit of history. The non-deuterated version of AVP-786 is known as AVP-923, which is a combination of dextromethorphan and quinidine. In a phase 2 clinical trial run by Avanir for patients with Alzheimer's disease experiencing agitation in 2014, AVP-923 was highly successful utilizing the (SPCD) clinical trial design. That clinical trial success, led to a $3.5 billion buyout of Avanir from giant Otsuka.

Understanding how AVP-786 ended up in Otsuka's hands, you have to go back several years when Concert Pharmaceuticals obtained a patent for the deuterated version of AVP-923, and licensed that version known as AVP-786 to Avanir, who later was acquired by Otsuka. The successful AVP-923 combo of 20mg dextromethorphan, and 10mg quinidine had a potential safety drawback known as QTc prolongation which may have become worrisome to the FDA for this elderly patient population. One of the goals of the deuterated version was to lower the quinidine inhibitor dose down from 10 mg to 4.9 mg as shown in a comparison of exclusion's between AVP-923, and AVP-786 clinical trial design here AVP-923 and AVP-786. 

There is one other issue to consider regarding AVP-786. When Concert Pharmaceutical's provided deuteration to AVP-923 and achieved patent, did the composition of AVP-786 get modified from the original in any way? We could only find one research article that may answer that question, here Deuterated (d6) - dextromethorphan elicits antidepressant effects in mice. This research suggests that AMPA, and Sigma 1, receptor targets of deuterated DM may differ from DM in their small animal study as quoted The data suggests d6-DM has anti-depressant like effects, though it may be recruiting different molecular targets and/or acting through a different mix or ratio of metabolites from regular DM. Perhaps that could be the performance difference between AVP-923 performing so well in the phase 2 clinical trial, and later AVP-786 not highly successful so far in clinical trials with a similar patient population. With limited research, we take that as speculation.

What's important to keep in mind, is that Axsome's AXS-05 is the only drug which the FDA has granted, Breakthrough Therapy Designation (BTD) for this indication. We'll continue to monitor these clinical trials to see if the companies projected completion dates remain the same or change. Axsome Therapeutics AXS-05 is well positioned to become the first safe and effective therapy for this patient population as we await the phase 3 results with their second pivotal clinical trial. Next we will write about Brexpiprazole's path forward. Thank you for reading. 

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.   

Nuplazid: FDA Safety Label

Acadia Pharmaceutical's completed their advisory committee meeting (ADCOM) on March 29th.  After receiving a positive review from the committee, the next issue to be determined will be the box safety labeling.  Below is wording from the FDA Briefing Documents.

This sample of patients compared to their appropriate control group demonstrates more than double the risk of serious adverse events (SAE) in the PDP6 trial population (Observed Risk of death or SAE is 2.38 times greater [95% CI 1.00 to 5.73, p=0.05]) for 34 mg Pimavanserin vs. placebo.

Let's have a look at a mortality black box label that many of the anti-psychotics currently carry, including the newly approved Rexulti (brexpiprazole) for Acute Schizophrenia and as adjunct for Major Depression Disorder. 

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.

I think the above is a likely label scenario for Nuplazid.  In addition, the FDA may advise Acadia to run a phase 4 confirmatory clinical trial as part of approval.  

Bottom Line:  Acadia has completed some nice pre-marketing research for Nuplazid, and found that a black box warning label was not high on the list of doctors when deciding whether or not to prescribe this drug.  In other words, they would still prescribe the drug, as the best alternative for an unmet need regardless of the safety label, as Nuplazid has shown in clinical trials to not contribute to motor impairment.   May 1st, is the scheduled day that the FDA should approve the drug.  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.
 

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.
 

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.

Lundbeck

When considering major players in the CNS (central nervous system) market, Lundbeck is a name that comes to mind.  The company's corporate office is located in Copenhagen, Denmark with locations worldwide.  This post will take a look at it's current top CNS products and pipeline of potential drugs in trials.

Alzheimer's
Ebixa (memantine) for moderate to advanced AD.  For memory and cognition.

Parkinson's Disease
Azilect  (rasagiline) to treat signs and symptoms of PD,

Schizophrenia
Abilify Maintena  Atypical anti-psychotic for the treatment of Schizophrenia.  Extensively used off-label for MDD (major depressive disorder), and Bi-Polar.

Current Trials:
Lu AE58054  as an adjunct to Donpezil.  For mild to moderate AD.
NCT01955161 ADAS
Ph 3 Results - 2015
Ph 2 results - 90 mg achieved .004 at 24 weeks.

Brexpiprazole  Agitation associated dementia of the Alzheimer's type.
NCT01862640 CMAI
NCT01922258
Ph 3 Results - 2017

Brexpiprazole  Many trials for (MDD) Major Depressive Disorder and Schizophrenia as adjunct or mono-therapy.

From the Lunbeck website, there is not an approved drug for either Parkinson's or Alzheimer's disease psychosis that is safe for the elderly unlike Nuplazid is deemed to be. Abilify is black boxed for use in the elderly population experiencing psychosis related to dementia.

Brexpiprazole is currently in a phase 3 trial for agitation associated with dementia of the Alzheimer's type.  Within that trial, listed under other measures, is the NPI-NH, and Psychosis Subscale Score. So there will be a readout for hallucinations and delusions along with the primary outcome measure of agitation.  Thank you for reading.