Acadia (ACAD) is expected to submit the NDA for Pimavanserin
in Parkinson’s Disease Psychosis (PDP) soon. Hopefully! (I know the slow NDA
submission is raising some questions). Obviously, the regulatory path for Pimavanserin
will make 2015 a rather eventful year for Acadia. But there’s another catalyst
that will keep all the eyes pointed to
ACAD in the mid term … the much anticipated Pima Phase 2 (P2) trial readout in
Alzheimer’s Disease Psychosis (ADP). This is the subject of this post.
Is Pimavanserin going to work in ADP? The first instinct
might be to think that psychosis is psychosis and whether it is observed in PD
or AD shouldn’t matter much. So if Pima works for PDP, why shouldn’t it also
work for ADP (or for any other case of psychosis from schizophrenia to Loewy
body dementia)? Well, it is not known whether PDP and ADP share similar
pathophysiological mechanisms and hence offer similar therapeutic targets.
The successful P3 Pimavanserin trial in PDP, demonstrated that
selectively (and almost exclusively) targeting the Serotonin 5HT2a receptor is
a valid therapeutic approach. Could the same apply to ADP?
What do we know about the relationship between ADP and
5HT2a? Here’s a list of links involving 5HT2a in ADP, (some of them featured in
papers on Pimavanserin):
- EVIDENCE: visual hallucinations, a hallmark of in ADP (and
PDP), can also be induced by some 5HT2a agonist [1-2]. CAVEAT: Of course, the
fact that some 5HT2a agonists can induce visual hallucination does not imply
that there is only a single mechanism for inducing them [2]. In other words,
the presence of ADP visual hallucination does not necessarily imply a 5HT2a
dysregulation.
- EVIDENCE: there is a positive association between
polymorphisms for the 5HT2a gene and psychotic symptoms in AD [3]. CAVEAT: This
results has been confirmed by a meta-analysis of literature, but some studies
failed to find a significant association, suggesting that even if it exists it might
not be super strong. In addition, the functional significance of this
association is not entirely clear.
- EVIDENCE: preclinical work shows that Pimavanserin can be
effective in reducing psychotic-like symptoms in a rat model of AD [4]. As a
matter of fact, the effects in the AD model are equal or better than those in
the rat model of PD [5]. CAVEAT: the
predictive value of this rat model of ADP is not entirely clear at the moment
(obviously the PDP model did point to a solid effect in PDP).
- atypical antipsychotics have a high affinity not only for dopamine receptors
but also 5HT2 receptors [6]. Risperidone, olanzapine and clozapine share this
feature. Risperidone, and olanzapine can show some efficacy in reducing
psychotic symptoms in AD, however their adverse effects (AEs) offset the
potential efficacy and reduces their clinical relevance [7-8]. Some of the AEs
of risperidone, and olanzapine in ADP result from D2 antagonism, suggesting
that the doses clinically used target both 5HT2a and D2. Hence, it is difficult
to attribute the possible efficacy of risperidone, and olanzapine in ADP to
5HT2a antagonism. Clozapine, an antipsychotic widely used for PDP for his lack
of motor AEs [9], has not been used much for ADP due to its AEs. Interestingly,
risperidone has showed some efficacy also in PDP [9], suggesting that some
drugs can work in both conditions.
In summary, at this stage it is difficult to determine if selective
targeting of 5HT2a receptors could be beneficial in ADP. I do not see any
strong evidence either in favor, or against this hypothesis.
So how to behave in the face of this uncertainty? Given the
uncertainty, I assume speculations will keep fueling the stock price in
anticipation of P2 ADP results, particularly if the regulatory course of Pimavanserin
will be smooth. As a matter of fact, approval of Pimavanserin for PDP could be
an extremely important step for further understanding its prospects in ADP. Indeed,
AEs and safety issues of current antipsychotic therapies will open the door to
potential off-label use of Pimavanserin in ADP. If that will happen, the
chatter around Pimavanserin will increase, further fueling interest in the
results and providing hints (albeit anecdotal) to Pima’s prospects for ADP.
Until then, yours truly will continue to look into this
issue and try to find a way to guess the outcome of P2.
REFS
[1] Sinforiani E
et al - Neurol Sci.
2007 Apr;28(2):96-9.
[2] Rolland B et al - Biomed Res Int.
2014;2014:307106
[3] Ramanathan S, Glatt SJ. - Am J Geriatr Psychiatry. 2009
Oct;17(10):839-46
[4] Price DL et al - Behav Pharmacol.
2012 Aug;23(4):426-33
[5] Price DL et al - Behav Pharmacol.
2011 Oct;22(7):681-92
[6] Meltzer HY et al - J Pharmacol Exp Ther.
1989 Oct;251(1):238-46
[7] Schneider LS et al - N Engl J Med.
2006 Oct 12;355(15):1525-38
[8] Sultzer DL et al - Am J Psychiatry. 2008
Jul;165(7):844-54
[8] Eng ML, Welty TE. - Am J Geriatr
Pharmacother. 2010 Aug;8(4):316-30
[9] Ellis T et al - J Neuropsychiatry Clin
Neurosci. 2000 Summer;12(3):364-9
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