Thank you for the opportunity to provide the information, facts and ACADIA's
perspective on this matter. This document provides a comprehensive account and
in-depth look at the facts. For ease of reference, a few key takeaways include:

- ACADIA maintains strict protocols with its approach to scientific studies and
the marketing of its product.

- Parkinson's disease (PDP) is more typically seen in elderly patients
with numerous medical comorbidities, and with an overall high risk of
morbidity and mortality.

- As part of our standard pharmacovigilance efforts, ACADIA continues to
regularly monitor and evaluate mortality risks for NUPLAZID, and we report
this quarterly to the FDA in the Periodic Adverse Drug Experience Report
(PADER). Since launch. NUPLAZID overall mortalig rate is 12.4 per
100 patient years. It's important to note that thIs '5 lower than the

overall mortality rate for PDP patients in the Medicare Claims
Dt 212-21 f2.2 r1 tint .

- ACADIA distributes its drug through specialty distribution, which puts us in
frequent contact with patients and caregivers. This increased interaction
naturally results in more frequent adverse event reporting. In contrast,
traditional are distributed through the retail channel, which
means adverse events are only reported spontaneously. Therefore, it would
not be appropriate to compare the number of reports from ACADIA's regular
interactions with patients, caregivers and physicians gathered through
spontaneous reports mthrough our specialty distribution channels to
spontaneous reporting occurring with other 

- Since NUPLAZID's approval in 2016, ACADIA has conducted two controlled
clinical studies in an aggregate of more than 300 patients with Alzheimer's
disease (AD). In these controlled studies in elderly patients with dementia,
there was no difference in the number of deaths reported between
pimavanserin and placebo.

- ACADIA is committed to patient safety. We carefully monitor and continuously
analyze safety reports from clinical studies and post-marketing reporting to
ensure the ongoing safety of NUPLAZID.

ACADIA's mission is to offer safe and effective solutions to address serious medical
conditions and we care deeply about the wellbeing of those individuals who use our
medication. Over 50% of people living with Parkinson's disease (PD) will experience
hallucinations and delusions overthe course of the disease. PDP is more typically
seen in the advanced stages of PD, in elderly patients with numerous medical
comorbidities. Consequently, these patients are at a high overall risk of morbidity
and mortality.

As an illustration, an epidemiology study recently submitted to the International
Congress of Parkinson's Disease and Movement Disorders (2018) examined
comorbidities and mortality associated with PD and PDP in the Medicare patient
population from 2012 to 2015. This analysis found that patients with PD 
were older, had more medical, neurological and comorbidities, and had
higher mortality rates than the overall PD population age-standardized

mortality in the PD patients with psychosis was significantly higher than in the PD
patients without psychosis, 28.2 vs 7.3 deaths per 100 patient-years, p<0.0001)
(Appendix A). The results highlight the various burdens and complexities associated
with treating PDP and the need for prompt diagnosis and management. As the only
drug currently approved by the US FDA for the treatment of hallucinations and
delusions associated with PDP, NUPLAZID is filling an important and previously
unmet need.
ACADIA maintains strict protocols with its approach to scientific studies
and the marketing of its product.
 It is important to note that before going to market, NUPLAZID (pimavanserin)
underwent rigorous testing, including numerous clinical studies. These
studies formed the basis of a NUPLAZID New Drug Application (NDA) for
which FDA granted a priority review.
 The FDA designated NUPLAZID as a Breakthrough Therapy for PDP on the
basis of data showing a substantial and clinically meaningful effect.
 To be clear, the clinical development program involved 25 clinical studies in
greater than 1,200 patients, comprising over 600 PDP patients (with
approximately 170 patients treated for at least two years) thus presenting
the largest clinical safety database in PDP patients to date.
 In response to the citation of Dr. Paul Andreason in the Quarter Watch report
that you reference, we refer you to the April 29, 2016 Memorandum written
by Dr. Robert Temple, Acting Deputy Director, Office of Drug Evaluation. In
this memo, Dr. Temple outlines his conclusion that NUPLAZID
demonstrated a clinically meaningful effect in PD Psychosis (with no
negative impact on PD motor symptoms) without any additional
concerns of serious adverse events than that seen historically with
antipsychotic drugs in fragile patients, and should be approved. These
findings are similar to the conclusion of the Director of Psychiatry Drug
Products Division, Dr. Mitchell Mathis, which can be found in this report.
 The FDA’s approval of NUPLAZID was subsequent to an FDA expert
Psychopharmacological Drug Advisory Committee convened on March 29,
2016 which voted overwhelmingly that NUPLAZID’s safety profile had been
adequately characterized (11-3 in favor) and that NUPLAZID had a positive
benefit/risk balance for the proposed indicated use (12-2 in favor). We refer
you to the minutes of this meeting, which can be found here.
 In June 2017, Dr. Mathis, Dr. Temple and several members of Dr. Mathis’
review team published a paper in the Journal of Clinical Psychiatry providing
additional perspective supporting their view of the positive benefit/risk profile
NUPLAZID possessed, as labeled. A summary of the paper can be found here,
and a complete copy of the article is attached to the cover email.
Pimavanserin clinical studies in elderly patients conducted after NUPLAZID
approval.
 Since NUPLAZID’s approval in 2016, ACADIA has conducted two controlled
clinical studies in patients with Alzheimer’s disease (AD). In these studies,
including a total of more than 300 elderly patients with dementia (average
age between two studies was 82.5), there was no difference in the number of

 



deaths between patients on pimavanserin (4 deaths) and on placebo (4
deaths).
Pimavanserin is currently being evaluated in multiple, large clinical trials in
over 1,300 patients with schizophrenia, major depressive disorder, and
dementia-related psychosis. These studies are being monitored by ACADIA
and no new safety observations have been reported.
For studies in vulnerable patient populations (e.g., dementia and
schizophrenia), ACADIA utilizes independent safety data monitoring
committees to perform regular assessments of safety and provide
appropriate recommendations in respect to conduct of the trials. To date,
there have been no issues identified by the independent safety data
monitoring committees.

ACADIA collects information and is in frequent contact with patients
and/or caregivers through our distribution channels. This differs from
many other antipsychotics (used off-label in PDP), which affects the total
number of adverse events reported.
 All adverse event reports, both from post-marketing surveillance and from the
ongoing clinical trials, are reported by ACADIA to FDA, as required. The most
recent Periodic Adverse Drug Experience Report (PADER) for NUPLAZID,
submitted to FDA in February 2018, concluded that, based on a thorough
review and analysis of reports of fatal events, there is nothing to suggest a
causal relationship to NUPLAZID.
 Our distribution channels (i.e. through central hub or specialty pharmacies)
are in frequent (in most cases monthly) contact with the patients and/or
caregivers and proactively collect information through this regular contact. If
you are actively and regularly engaging patients and/or caregivers, it is
inevitable that you will see a higher number of adverse events reported,
especially in an older, chronically ill patient population with numerous
medical comorbidities, and with an overall higher risk of morbidity and
mortality. Other antipsychotics are typically distributed through retail
channels that do not provide patient and/or caregiver support services and
therefore do not collect the extent of adverse events that are gathered in a
specialty pharmacy distribution system. Instead, retail channels rely primarily
on spontaneous reporting, making the reported adverse event rates
incomparable.
 Per ACADIA’s most recent PADER, since launch, a total of 727 fatal reports
were submitted for patients receiving NUPLAZID as part of their treatment
regimen. When conservatively the lowest estimate of exposure to NUPLAZID
is applied, totaling 5856 patient years, the overall estimated mortality
rate for NUPLAZID is 12.4 per 100 patient-years (95% Confidence
Interval 11.5-13.4). This rate is lower compared to the abovereferenced mortality rate of 28.2 per 100 patient-years for PDP
patients in the Medicare Claims Database.
 It is important to consider the data and any associated conclusions regarding
the relationship and association of a particular event with a particular
medication in the context of the limitations of the FDA Adverse Event
Reporting System (FAERS) database. As cautioned in an October 2017 press
release from Dr. Scott Gottlieb, FDA Commissioner, and as also outlined in a

 resultant FAERS website, FAERS contains reports on
adverse events associated with a particular drug or biologic this

does not mean that the drug or biologic caused the adverse event."
Importantly, one cannot calculate incidence of the event on that basis and

the FAERS data by themselves are not an indicator of the safety profile of the
drug or biologic.

In summary, continues to vigorously monitor all adverse events through
robust pharmacovigilance activities and evaluates the benefit/risk profile of
on an ongoing basis. To date, based on the totality of available post-
marketing and clinical trial information, our benefit/risk assessment of NUPLAZID
remains unchanged. is committed to the safe use of NUPLAZID as indicated
and in accordance With the FDA approved prescribing information.

In addition to the above, we are including supportive statements from industry

experts, including physicians monitoring patients on NUPLAZID, as well as other

information you may find helpful. Please let us know of any outstanding questions
ou ma have.

 

Appendix A
Brief Summary of the Medicare Claims Database Analysis:
Methods
A retrospective study evaluated the Medicare claims database during a 4-year
period from January 1, 2012 to December 31, 2015. Parkinson’s disease (PD)
patients were identified as patients having at least one claim for a diagnosis of PD
and another confirmatory claim for PD at some point during the study period. PDP
patients were identified as those with at least one psychosis diagnosis claim during
the study period and at least 2 PD diagnosis claims, with at least one of those
occurring before the first psychosis diagnosis.
Results
Overall, there were 106,893 PD patients identified in the analysis; 68,821 PD
patients without psychosis and 38,072 PD patients with psychosis. The cohort of PD
patients with psychosis was older (mean age=81.9 vs 78.7 years (p<0.0001). The
cohort of PD patients with psychosis had more medical comorbidities, with a mean
Charlson Comorbidity Index score = 4.14 vs 2.46 in the cohort of PD patients
without psychosis (p<0.0001). The most common comorbidities, defined as
prevalence >10% in the cohort of PD patients with psychosis and >2x the prevalent
in the cohort of PD patients without psychosis, include: UTI, dementia, congestive
heart failure, depressive symptoms, stroke, and pneumonia. Hospitalizations were
greater in the cohort of patients with psychosis vs. the cohort of patients without
psychosis (43.3% vs. 17.6%, p<0.001). Additionally, accident and emergency visits
were statistically greater in the cohort of PD patients with psychosis vs. the cohort
of PD patients without psychosis (63.1% vs. 32.6%, p<0.001). Age-standardized
mortality in the cohort of PD patients with psychosis was significantly higher than in
the cohort of PD patients without psychosis (28.2 vs 7.3 deaths per 100 patientyears; p<0.0001).