By Michael J. Kramer
What would the stock market be if there weren't always two sides to a story? After all that is what makes a market, for every buyer, there is a seller.
By now, you are aware on December 20th, Acadia Pharmaceuticals (NASDAQ:ACAD) released its exploratory Phase II data from its Alzheimers Disease Pyschosis (NASDAQ:ADP) trial. There has been some confusion regarding these results, which I will try to lay to rest today. It seems odd to me to even have to have this discussion, but it seems there were questions around this this trial result. These discussion and comments seem unfair and not accurate. So I feel I should present my side of the story.
Let's start from the beginning.
On November 14th, 2013 ACAD announced they would be running a Phase II trial in ADP. This is the part of the release that describes the trial and the part we are most concerned with at this point:
"The Phase II feasibility trial, referred to as the -019 Study, is a randomized, double-blind, placebo-controlled study designed to examine the efficacy and safety of pimavanserin in about 200 patients with ADP. The study is being conducted through a large network of research care homes established as part of the National Institute for Health Research (NIHR) Maudsley Biomedical Research Unit. Following a screening period that includes brief psycho-social therapy, patients will be randomized on a one-to-one basis to receive either 40 mg of pimavanserin or placebo once-daily for 12 weeks. The -019 Study will assess several key efficacy endpoints, including use of the Neuropsychiatric Inventory - Nursing Home (NPI-NH) scale to measure psychosis (hallucinations and delusions), agitation/aggression, and sleep/nighttime behavior, as well as use of the Cohen-Mansfield Agitation Inventory - Short Form (CMAI-SF) scale and the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) scale. Key efficacy endpoints will be based on the change at week six from baseline. The study will also assess additional exploratory endpoints, including the cognitive status of patients using the Mini-Mental State Examination (MMSE) scale, and the durability of response to pimavanserin through twelve weeks of therapy."
I have underlined the points that I think are the key. However, the most important point in this whole paragraph: "Key efficacy endpoints will be based on the change at week six from baseline."
I don't think that it could be any more clear, six week was the time frame.
Tuesday morning, ACAD reports top line that showed:
"Pimavanserin demonstrated efficacy on the primary endpoint of the -019 Study with a 3.76 point improvement in psychosis at week 6 compared to a 1.93 point improvement for placebo, representing a statistically significant treatment improvement in the NPI-NH Psychosis score (p=0.0451). Baseline mean scores for the pimavanserin and placebo treated groups were 9.52 and 10.00, respectively."
The important sentence: "Pimavanserin demonstrated efficacy on the primary endpoint of the -019 Study with a 3.76 point improvement in psychosis at week 6 compared to a 1.93 point improvement for placebo, representing a statistically significant treatment improvement in the NPI-NH Psychosis score (p=0.0451).
I read on other site, that this study had shifting endpoint, I thought it was important to not only review the clinicaltrial.gov website, but the clincaltrial.gov/archive website. That is the website that actual shows original trial information, along with all the changes made to trial. So Let's see what I came up.
This is the orginial link to the file for the NCT02035553 study, I made it easy, providing a screenshot:
Original text filed on 1/13/14:
Changes made on 1/21/14:
Key change: Primary efficacy will be assessed using the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH).
Changes made on 1/19/16:
Key Change:Placebo, taken as two tablets, once daily by mouth for 12 weeks.
Pimavanserin tartrate, 40 mg (taken as two 20 mg tablets), once daily by mouth for 12 weeks.
Finally, changes made upon completion of recruitment.
Active, not recruiting
So the trial hasn't changed since 1/21/14. The primary endpoint has been the same since 1/21/14.
Additionally, in terms of the six weeks question. We have of course have the original press release. Then of course we have Roger Mills, the chief medical officer at the time, on the 4Q'13 Confernce Call stating:
In this -019 Study, patients are randomized on a one-to-one basis to receive either 40 mg of pimavanserin or placebo, once daily for 12 weeks, following an initial three-week screening period that includes brief psychosocial therapy.
The study is designed to assess several key efficacy endpoints, including the use of the Neuropsychiatric Inventory Nursing Home, or NPI-NH scale, to measure psychosis, agitation aggression and sleep nighttime behavior, as well as additional exploratory endpoints.
The key efficacy endpoints were based on the change of week 6 from baseline, which is a standard duration for psychosis studies. A full 12-week treatment period will allow us to explore additional endpoints, including the cognitive status of patients.
We were looking to show that we do not worsen cognition relative to placebo-treated patients. In contrast, currently marketed antipsychotics have been linked to cognitive decline in elderly patients with dementia related psychosis.
You can see reason why they change the language now on January 13th, 2013 to January 21, 2013. From reading these comments it would seem psychosis, agitation aggression and sleep nighttime behavior, as well as additional exploratory endpoints are part of NPI-NH scale.
Then we have Serge Stankovic the now CMO, on the 2Q'16 Conference Call stating this:
"Thank you, Terry and good afternoon everybody. We have had a very productive first half of 2016 with the FDA approval and launch of NUPLAZID. In parallel, we have also made significant progress in building our R&D capabilities to enable us to execute on the broad development plans for pimavanserin. Let me start with our efforts in Alzheimer's disease and the two programs we are pursuing there. Similar to Parkinson's disease, Alzheimer's patients experienced a number of serious neuropsychiatric complications including psychosis and agitation. Today there is no FDA approved treatment available for patients with Alzheimer's disease psychosis or Alzheimer's disease agitation. As Steve mentioned, we have completed enrollment in our exploratory Phase 2 study with the pimavanserin in Alzheimer's disease psychosis or AD psychosis.
Just some background on this study, this study, our first in AD psychosis, is being conducted through a single site with a large network of nursing homes in the London, England area. As you are aware, the study has taken longer to enroll than we originally anticipated due in part to the logistics of having the study conducted at just one site. Let me remind you of the key parameters of this study. This is an exploratory Phase 2, 12-week randomized, double-blind, placebo controlled study designed to examine the efficacy and safety of 34 milligram pimavanserin compared to placebo in patients with AD psychosis. We enrolled 181 patients in this study.
The primary endpoint is psychosis as measured by the Neuropsychiatric Inventory - Nursing Home version, subscales for hallucinations and delusions or domains A and B at study week six. We are also assessing secondary measures, including behavioral symptoms and sleep. Additionally, we are assessing Mini-Mental Status Exam over 12 weeks of treatment in order to demonstrate that pimavanserin does not have a negative impact on the cognitive status of these patients as compared to placebo. We look forward to announcing top line data from this study by the end of this year."
So, I ask you, has anything changed in this study since 1/21/14? Have end points shifted? Originally management changed the primary endpoint it looks by shorting the description exactly one week after the initial filing.
The actual results of the trial were impressive and showed the company may be headed in the right direction. There was a clear statically significant improvement from baseline seen at week 6, which has been the endpoint for nearly three years now. Was the P-value great? I personally would have liked seen a lower number. Why did the benefit of pimavanserin vanished at week 12? We do not know. In fact, for all we know it can have been a placebo improvement of only a half point. However, until we get more information, we will be left to wonder. In my humble opinion, there seemed to be a placebo effect, it would seem. More trials will need to be run.
Whatever the case may be regarding the results of the trial, you always need to do your own homework and not rely on others to form your opinion.
These results to me are exciting and hold promise that pimavanserin can be a utility to treating patients with ADP. Although a 2 point improvement may not seem like much on the surface, for those who suffer it is better than the alternative of nothing, because there are no approved drugs. Let's hope for those that suffer pimavanserin lives up to its promise.
I am and the Clients of Mott Capital Management, LLC are Long Shares of ACAD.
Disclosure: I am/we are long ACAD.
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