Detailed analytical report on clinical development of TC-5619, product candidate selective for the a7 NNR.

1. Year: 2015
TC-5619
Cli ical Devel pment
www.clinInsight.com
Overview

2. Page 2 www.clinInsight.com
SEC Filli gs Status
Amount
Amount
Targacept entered into collaborative research and license agreement with AstraZeneca AB.
Notice served by Targacept under agreement offering AstraZeneca the right to license its
product candidate TC-5619 for specified conditions characterized by cognitive impairment.
DECEMBER 2005
Targacept started focusing on Cognitive disorders.JANUARY 2006
OCTOBER 2007
ASTRAZENECA AB
Amount $ 2,000,000 As Revenue
TARGACEPT Inc.
In accordance with a mutually acceptable development plan, Targacept agreed to develop
TC-5619 independently through the completion of Phase I and Phase II proof of concept
clinical trial.
Amendment to cognitive disorders agreement with AstraZeneca ABAPRIL 2010
ASTRAZENECA AB
$ 11,000,000 Deferred Revenue
TARGACEPT Inc.
ASTRAZENECA AB
Amount $ 2,000,000 Deferred Revenue
TARGACEPT Inc.
Targacept recognized all payment amounting $11,000,000 from AstraZeneca as Revenue.JUNE 2011
ASTRAZENECA AB
$ 11,000,000 Deferred Revenue
TARGACEPT Inc.
ASTRAZENECA AB
Amount $ 2,000,000 Deferred Revenue
TARGACEPT Inc.
Under the agreement, AstraZeneca had an option for an exclusive license to TC-5619 for various cog-
nitive disorders. In late April 2011, the Company received notice from AstraZeneca that it had deter-
mined not to exercise its license option.
Precli ical i for aio
urement and Treatment Research
to Improve Cognition in Schizo-
phrenia, or MATRICS initiative of
46 cognitive neuroscientists and
neuro pharmacologists have indi-
cated alpha7 NNR and cognitive
functions are closely associated
and compounds that selectively
target the alpha7 NNR may have
application in the treatment of
conditions such as schizophrenia,
cognitive impairment and in-
flammation.
TC-5619 is a compound that
selectively act on the alpha7
NNR, being developed for the
treatment of conditions charac-
terized by cognitive impairment
such as Schizophrenia, Alzhei-
mer's disease etc. A number of
published studies and a survey
conducted in connection with
National Institute of Mental
Health initiative known as Meas-
CLINICAL
DEVELOPMENT

3. Page 3 www.clinInsight.com
Mechanism of Action  Modulation of activity of the alpha7 NNR
Selective Target  alpha7 NNR
Therapeutic Area of
Focus
 Schizophrenia, cognitive impairment or
inflammation
Target Indication (s)  Conditions characterized by cognitive im-
pairment such as Schizophrenia, Alzhei-
mer's disease etc.
Route of Administra-
tion
 Oral
TC- 19 JOURNEY SO FAR...
JULY 2007
APRIL 2011
SINGLE RISING DOSE STUDY
SEQUENTIAL MULTIPLE ASCENDING DOSE STUDY
MULTIPLE RISING DOSE STUDY
SCHIZOPHRENIA
ATTENTION DEFICIT HYPERACTIVE DISORDER
SCHIZOPHRENIA
ALZHEIMER’S DISEASE
ATTENTION DEFICIT HYPERACTIVE DISORDER
PHASE I
PHASE II
TC-5619

4. Page 4
August 8, 2008
Targacept, Inc
FORM 10-Q, For the quarterly period ended June 30, 2007
(Pg 14)
…TC-5619. TC-5619 is a preclinical product candidate that modulates the a7 NNR for which we are currently
conducting a Phase I single rising dose clinical trial. We believe compounds that selectively target the a7 NNR may
have application in the treatment of conditions such as schizophrenia, cognitive impairment and inflammation…
(Pg 15)
…We also announced in July 2007 our initiation of a Phase I clinical trial of TC-5619. The trial is a double blind,
placebo controlled study with single escalating doses administered orally to healthy volunteers. The trial, which is
being conducted in France, is designed to evaluate the safety and tolerability of TC-5619 and to assess its
pharmacokinetic profile…
ASSIGNED TREATMENT: In a single rising dose trial, each subject in a dose group receives a single
dose of the agent being evaluated, with subjects in each subsequent dose group receiving a pre-determined
higher dosage than subjects in the preceding dose group .
May 8, 2008
Targacept, Inc
FORM 10-Q, For the quarterly period ended March 31, 2008
(pg17)
… We have completed a Phase 1 single rising dose clinical trial of TC-5619 and plan to initiate a Phase 1 multiple
rising dose clinical trial of TC-5619 in the third quarter of 2008…
STUDY TITLE: Phase 1 multiple rising dose clinical trial of TC-5619 in healthy volunteers
STUDY ID: TC-238-CLP-002
PHASE: I
INITIATION:
JULY 2008
COMPLETION:
MAY 2008 ACCRUAL: NA
INDICATION: Schizophre ia, Cog iive I pair e t or
I la aioPATIENT SEGMENT: Healthy
STATUS: COMPLETED
OBJECTIVES: To evaluate the safety and tolerability of TC-5619. To assess the
pharmacokinetic profile of TC-5619.
ASSIGNED TREATMENT: In a multiple rising dose clinical trial, each subject in a dose
group receives a dosage of the agent being evaluated multiple times, with subjects in each
subsequent dose group receiving a pre-determined higher dosage than subjects in the preceding dose
group.
STUDY TITLE: Double blind, placebo controlled, Phase I study of TC-5619 with single escalating doses
administered orally to healthy volunteers
STUDY ID: NA
PHASE: I
INITIATION:
JULY 2007
COMPLETION:
MAY 2008 ACCRUAL: NA
INDICATION: Schizophrenia, Cognitive Impairment or
InflammationPATIENT SEGMENT: Healthy
STATUS: COMPLETED
OBJECTIVES: To evaluate the safety and tolerability of TC-5619. To assess the pharmacokinetic profile of
TC-5619.
SINGLE
RISING DOSE
STUDY
MULTIPLE
RISING
DOSE STUDY
November 6, 2008
Targacept, Inc
Form 8-K
…Completed dosing in a Phase 1 multiple
rising dose clinical trial of TC-5619, a
highly-selective alpha7 NNR-targeted
product candidate planned for develop-
ment for cognitive dysfunction in schizo-
phrenia and potentially one or more oth-
er conditions characterized by cognitive
impairment…
LOCATION: FRANCE
LOCATION:
UNITED STATES
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5. RESULTS: In the trial, the results on the Groton Maze Learning task met the pre-defined success criteria (adjusted p-value = 0.054), as well as at two of the trial’s
three measurement dates (at 4 weeks, unadjusted p-value = 0.018; and at 12 weeks, unadjusted p-value = 0.041), and were favorable for tobacco users as compared to
non-tobacco users and for subjects at study sites in the United States as compared to subjects at study sites in India. There was no activity in non-tobacco users. Estimates
of the prevalence of smoking amongst schizophrenia patients vary, with one study indicating as high as 80%. Each of the p-values noted above was derived after data log
transformation, a commonly utilized technique where the data does not follow a normal distribution. In addition, positive signals were observed in the trial on several sec-
ondary efficacy outcome measures, including Scale for Assessment of Negative Symptoms, an investigator assessment of improvement on the negative symptoms of schizo-
phrenia, Clinical Global Impression – Global Improvement, an investigator assessment of overall response, and Subject Global Impression – Cognition scale, a patient self-
assessment of cognitive change. Other secondary outcome measures of the trial, including a composite measure of the CogState Schizophrenia Battery, did not demon-
strate a drug effect in the dataset that included all subjects.
TC-5619 exhibited a favorable tolerability profile in the trial. There were two serious adverse events in the trial, one in
the placebo dose group and one in the TC-5619 dose group. Both were considered by the applicable investigator as not drug related.
PRIMARY OUTCOME:
Measure of the trial is change from baseline on the Groton Maze Learning item of
the Cog State Schizophrenia Test Battery, a computerized battery of neuropsychi-
atric tests that assess specific cognitive domains, on each of three measurement
dates as compared to placebo.
Page 5
STUDY TITLE: Two-Part, Sequential Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and
Pharmacokinetics of TC-5619-238 in Elderly Subjects With and Without Alzheimer's Disease.
STUDY ID: TC-5619-238-CLP-003, NCT01254448
PHASE: I
INITIATION:
SEP-2010
COMPLETION:
MAR-2011 ACCRUAL: 38
INDICATION: Alzheimer’s Disease
PATIENT
SEGMENT:
Elderly Subjects
With and Without
Alzheimer's Disease
STATUS: COMPLETED
OBJECTIVE: To examine the safety, tolerability and pharmacokinetics of TC-5619 in elderly
subjects with and without Alzheimer's disease
November 6, 2009
Targacept, Inc
FORM 10-Q, For the quarterly period ended September 30, 2009
(pg17)
... We have completed a Phase 1 single rising dose clinical trial and a Phase 1
multiple rising dose clinical trial of TC-5619 in healthy volunteers. We expect to
initiate a Phase 2 clinical proof of concept trial of TC-5619 in cognitive dysfunction
in schizophrenia in the fourth quarter of 2009. Following completion of the
planned Phase 2 trial, AstraZeneca has the right to license TC-5619 on terms
specified in our agreement.
May 10, 2010
Targacept, Inc
FORM 10-Q, For the quarterly period ended March 31,
2010
(pg17-18)
…As part of the expanded TC-5619 development program, the
Company has agreed to conduct a Phase 2 clinical proof of con-
cept trial in adults with ADHD in addition to its ongoing Phase 2
clinical proof of concept trial in cognitive dysfunction in schizo-
phrenia, or CDS.
(pg20)
TC-5619. TC-5619 is a novel small molecule that modulates the
activity of the a7 NNR. We initiated a Phase 2 clinical trial of
TC-5619 in cognitive dysfunction in schizophrenia, or CDS,
in the fourth quarter of 2009 pursuant to a development
plan that we agreed upon with AstraZeneca.
(pg21)
Under our 2005 agreement with AstraZeneca:
...we are responsible for conducting and funding the ongoing
Phase 2 clinical trial of TC-5619 in CDS, the planned Phase 2 clini-
cal trial of TC-5619 in adults with ADHD and planned specified
clinical and non-clinical studies to support the potential advance-
ment of TC-5619 into Phase 2 clinical development for Alzheimer’s
disease, and AstraZeneca is responsible for conducting and fund-
ing other specified non-clinical studies to support the potential
advancement of TC-5619 into Phase 2 clinical development for
Alzheimer’s disease...
STUDY ID: TC-5619-238-CRD-001, PRO-05619-CRD-001 ,
NCT01003379
STATUS: COMPLETED
INDICATION: Schizophrenia
COMPLETION:
JAN-2011
INITIATION:
MAY-2010
PHASE: II
LOCATION:
UNITED STATES(7),
INDIA (12)
ACCRUAL:
200 (Planned)
184 (Actual)
STUDY TITLE:
A Double-Blind, Randomized, Placebo-
Controlled, Multicenter, Fixed Dose Study to Assess Efficacy, Safety, and
Tolerability of TC-5619 as Augmentation Therapy to Improve Cognition
in Outpatients With Cognitive Dysfunction in Schizophrenia.
PATIENT SEGMENT:
Outpatients With Cognitive Dys-
function
TRIAL DESIGN & TREATMENT ASSIGNMENT :
Double Blind, Placebo Controlled, Randomized, Parallel Group
Study
Subjects are were randomly assigned to receive either TC-5619 or
placebo, together with continued treatment with the atypical anti-
psychotic, for 12 weeks. As planned, approximately half of the
subjects were users of tobacco products. Subjects who received
TC-5619 received a 1mg daily dose for the first four weeks, a 5mg
daily dose for the next four weeks and a 25mg daily dose for the
last four weeks.
INCLUSION CRITERIA:
Subjects meeting DSM-IV criteria for schizophrenia, with stable psychotic symptoms and taking a stable dose of an approved medication from the drug
class known as atypical anti-psychotics (either quetiapine, marketed as Seroquel, or risperidone, marketed as Risperdal)
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6. May 10, 2010
Targacept, Inc
FORM 10-Q, For the quarterly period ended March 31,
2010
(pg17-18)
…As part of the expanded TC-5619 development program, the
Company has agreed to conduct a Phase 2 clinical proof of concept
trial in adults with ADHD in addition to its ongoing Phase 2 clinical
proof of concept trial in cognitive dysfunction in schizophrenia, or
CDS…
(pg20)
... As part of an April 2010 amendment to our 2005 agreement with
AstraZeneca, we have also agreed to conduct a Phase 2 clinical
proof of concept trial of TC-5619 in adults with ADHD and we and
AstraZeneca have each agreed to conduct specified studies to
support the potential advancement of TC-5619 into Phase 2 clinical
development for Alzheimer’s disease…
(pg21)
Under our 2005 agreement with AstraZeneca:
...we are responsible for conducting and funding the ongoing Phase
2 clinical trial of TC-5619 in CDS, the planned Phase 2 clinical trial of
TC-5619 in adults with ADHD...
STUDY DESIGN & TREATMENT:
Double blind, placebo controlled, forced titration, multi-center,
12-week study
Adult subjects are randomly assigned to one of two cohorts, TC-
5619 or placebo, and dosed over a 12-week period. Subjects in the
TC-5619 cohort receive 1mg doses of TC-5619 for the first four
weeks, 5mg doses of TC-5619 for the next four weeks and 25mg
doses of TC-5619 for the last four weeks.
RESULTS: TC-5619 did not meet the primary outcome
measure of the trial, but showed encouraging signals on
some of the trial’s efficacy measures in the subpopulation of
subjects with ADHDi.
August 9, 2011
Targacept, Inc.
FORM 10-Q, For the quarterly period ended June 30, 2011
...Preparations for a planned Phase 2b clinical trial of TC-5619 as a
treatment for negative symptoms and cognitive dysfunction in schizo-
phrenia, as well as potential additional development in either or both
of Alzheimer’s disease and ADHD, are ongoing...
PRIMARY OUTCOME MEASURE: Change from
baseline on the inattention subscale of the Conners’ Adult
ADHD Rating Scale—Investigator-Rated, or CAARS-INV, after
four weeks of treatment with TC-5619 as compared to
placebo.
May 9, 2011
Targacept, Inc
FORM 10-Q, For the quarterly period ended March 31,
2011
(pg16)
...The Company has completed two Phase 2 clinical proof of concept
trials, one in cognitive dysfunction in schizophrenia and one in adults
with ADHD...
STUDY TITLE: A Double-blind, Randomized, Placebo-controlled, Multicenter, Fixed Dose Titration Study to Assess Efficacy, Safety,
and Tolerability of TC-5619 in Adults With Attention Deficit/Hyperactivity Disorder (ADHD)
STUDY ID: TC-5619-238-CRD-002, PRO-05619-CRD-002, NCT01124708
ACCRUAL: 135
INDICATION: Attention Deficit Hyperactivity Disorder (ADHD) PATIENT SEGMENT: Non-tobacco-using adults with ADHD
PHASE: II
INITIATION:
MAY 2010
COMPLETION:
FEBRUARY 2011
STATUS: COMPLETED
LOCATION: UNITED STATES
STUDY ID: TC-5619-238-CRD-003, NCT01488929
LOCATION: UNITED STATES, HUNGARY, ROMANIA, RUSSIAN
FEDERATION, SERBIA, UKRAINE
PRIMARY OUTCOME MEASURE: Change from baseline on the Scale for the Assessment of Negative Symptoms, or SANS, at the end of
the treatment period with TC-5619 as compared to placebo.
INDICATION: Schizophrenia PATIENT SEGMENT: Negative Symptoms and Cognition in Outpatients With Schizophrenia
ACCRUAL: 450 (Planned); 603 (Actual)
PHASE: II
INITIATION:
DECEMBER 2011
COMPLETION:
NOVEMBER 2013
STATUS: COMPLETED
STUDY TITLE: A Double-Blind, Placebo-Controlled, Multicenter, Parallel Group Study to Assess Efficacy, Safety, and Tolerability of
TC-5619 as Augmentation Therapy to Improve Negative Symptoms and Cognition in Outpatients With Schizophrenia
STUDY DESIGN & TREATMENT:
Double-Blind, Placebo-Controlled, Multicenter, Parallel Group Study
The trial design provided for a four-week screening period, followed by a 24-week treatment period during which subjects received either one of two
daily doses of TC-5619 (5mg or 50mg) or placebo together with continued treatment with an atypical antipsychotic.
Page 6 www.clinInsight.com

7. Page 7
INDICATION: Attention Deficit/Hyperactivity Disorder (ADHD)
STUDY ID: TC-5619-238-CRD-004, NCT01472991
STATUS: COMPLETED COMPLETION: JULY 2012INITIATION: NOVEMBER 2011 LOCATION: UNITED STATES
ACCRUAL: 152 (Planned), 250 (Actual)
STUDY TITLE:
A Double-Blind, Randomized, Placebo-Controlled, Multicenter, Fixed Dose Study
to Assess Efficacy, Safety, and Tolerability of TC-5619 in Adults with Inattentive
-Predominant Attention Deficit/Hyperactivity Disorder (ADHD)
PATIENT SEGMENT: Adults with Inattentive-Predominant ADHD
March 14, 2014
Targacept, Inc.
FORM 10-K, For the fiscal year ended December 31,
2013
(pg 3)
TC-5619 and TC-6987
TC-5619 and TC-6987 are novel small molecules highly
selective for the a7 NNR. The a7 NNR has been shown to
play a role in a variety of biological pathways associated
with various diseases and disorders. We previously con-
ducted clinical studies of TC-5619 as a potential treatment
for schizophrenia, Alzheimer’s disease and attention deficit
hyperactivity disorder and exploratory studies of TC-6987
as a treatment for inflammatory disorders. We do not have
plans to pursue additional development of these com-
pounds in these therapeutic areas.
PRIMARY OUTCOME MEASURE: Change from
baseline on the inattention subscale of the Conners’ Adult
ADHD Rating Scale—Investigator-Rated, or CAARS-INV,
after four weeks of treatment with TC-5619 as compared to
placebo.
STUDY DESIGN A 3-arm, fixed dose, double blind, placebo controlled, parallel
group, multi-center, 12-week study
STUDY TREATMENT: Subjects in the trial were randomly assigned to receive a daily
dose of 5mg TC-5619, 25mg TC-5619 or placebo.
RESULTS: TC-5619 did not meet the primary outcome measure of the trial, but showed encouraging signals on some of the trial’s
efficacy measures in the subpopulation of subjects with ADHDi.
March 15, 2013
Targacept, Inc.
FORM 10-K, For the fiscal year ended December 31,
2012
(pg 3)
TC-5619
TC-5619 is a novel small molecule that modulates the activity
of the a7 NNR. We are currently conducting a Phase 2b
clinical trial of TC-5619 as a treatment for negative
symptoms and cognitive dysfunction in schizophrenia. We are
also currently evaluating potential additional Phase 2 clinical
development of TC-5619 as a treatment for Alzheimer’s
disease.
PHASE II (ALZHEIMER’S DISEASE)
STATUS: COMPLETED
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PHASE: II
RESULTS :
TC-5619 did not meet the primary outcome measure and did not demonstrate improvement on the key secondary measures.

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