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. 

AXS-05 Path to Approval for MDD

• Axsome Therapeutics met with the FDA and was given an expedited pathway of AXS-05 for Major Depressive Disorder or MDD. Under this new agreement, the company's phase 2 clinical trial known as Ascend for MDD was given pivotal status, and will only need one other pivotal phase 3 with efficacy, to file a New Drug Application (NDA).
• The company plans to enroll for a new phase 3 placebo clinical trial in the 2nd quarter of 2019, with an expected completion date by the end of 2019. The company plans on initiating this phase 3 with an increased number of clinical sites recruiting participants, which will allow for completion faster over the successfully completed phase 2 Ascend clinical trial for MDD.
• The timeline for filing an NDA would then be in the first half of 2020. If this timeline holds up, AXS-05 could potentially get to commercialization around the same time as Sage Therapeutics drug SAGE-217, which is also pursuing the same MDD indication.

AXS-05 was given Breakthrough Therapy Designation (BTD) from the FDA for Major Depressive Disorder, and the patent extends out to 2034. Thank you for reading.

ACAD: Filled the Gap

A frequent term used in technical analysis is "filling the gap".  When a stock opens the day much higher than the previous day's close, it creates a gap of no trading volume between the previous day's close and the current day's open.  I mentioned this gap last week after ACAD received the "breakthrough therapy designation" from the FDA, which was a very positive news release, but also noted that it created a gap in the chart that was pointed out below, last week.

Fast forward to today and the present chart that ACAD has, and you will notice that the gap was indeed filled today, and a small bounce higher once that occurred from the chart below.  

Bottom Line:  The gap that needed to be filled, was in black and white, and that is what technical analysis is all about.  Eliminating the emotion, and seeing the chart for what it really is created a low risk buy point.  We are long term shareholders of Acadia Pharmaceuticals.  Thank you for reading.

Technical Look at ACAD

In between press releases, ACAD becomes highly correlated to the XBI Biotechnology Index, with extra beta above and beyond.  Below is a three day chart with the XBI and ACAD that shows a close correlation.

A daily chart below, has the stock still consolidating the recent months gains.  But there is a gap around the $24.00 area, that technically could get filled if the overall market puts in more than just the current pullback, as of today.  

Bottom Line:  ACAD has had a strong months worth of catalyst or positive press releases that has included the following.  

1)  EU strategy discussed during the second quarter conference call.

2)  Roche buyout of ITMN, had a positive effect on biotechnology in general.

3)  Breakthrough Therapy Designation granted from FDA.

4)  Positive comments made from CNBC.
 

Acadia: "Breakthrough Therapy" Designation

Acadia Pharma announced today that the FDA has granted the company "Breakthrough Therapy" designation for it's lead drug Nuplazid (pimavanserin) for Parkinson's Disease Psychosis. Breakthrough therapy designation was created by the FDA to expedite the development and review of drugs that are meant to treat serious or life threatening conditions.

The weekly chart above has the stock breaking out to a new six month high. The stock gained (+11%) today.

Bottom Line:  What this means for investors of Acadia, is that the drug approval process for Nuplazid (pimavanserin), to treat Parkinson's Disease Psychosis, will get an expedited process from the FDA.