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R&D Meeting
March 21, 2013
Disclaimer
This material contains forward-looking statements regarding the financial conditions, results of operations and business activities of Otsuka and its subsidiaries (collectively the “Otsuka Group"). All forward-looking statements, due to their inherent nature, will be influenced by future events and developments for which the occurrence is uncertain, and therefore involve risks and uncertainties. Otsuka cautions you in advance that actual financial conditions, results of operations and business activities could differ materially from those discussed in the forward-looking statements.
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1
Source:Byerly.M.: the 41st annual meeting of the American College of Neuropsychopharmacology, Dec. 10, 2002
Adherence Issue with Antipsychotics
3
61.9%
5.3% 0%
10%
20%
30%
40%
50%
60%
70%
チップによる集計で飲んでいないと 判定された患者さん
医師が飲んでいないと 判断した患者さん
Patients assessed as non-adherence by doctor
Assessment of the antipsychotic adherence by an electronic monitoring device (called the MEMS(R) cap), which recorded how often the container of medicine, was opened and at what time of day.
Definition of non-adherence: Taking of <70% of prescribed antipsychotics
Valenstein, M., et al.: Med. Care,40,630-639,2002
31.7 29.5 28.1
25.9 23.4
18.5 17.0 13.4
11.2 8.3
05
10152025303540
10 20 30 40 50 60 70 80 90 100
MPR(Medication Possession Ratio)=Prescribed days/treatment days
• Relapse rate of schizophrenia gets higher with poor adherence
• When medication discontinued, 60% of the patients relapsed within 1 year
(Johnson, D.A.W.: J. Clin. Psychiatry, 45(5), 13-21, 1984)
Poor Adherence Good
Relationship between re-hospitalization rate and adherence (N=48,148)
Cohort study by Veterans Health Administration
Def
ined
as
non-
adhe
renc
e (%
)
Patients assessed as non-adherence by MEMS
Re-
hosp
italiz
atio
n ra
tio fo
r 1 y
ear (
%)
MPR (%)
Current estimate of
patients treated: 70,000
Among them, 10% need treatment due to symptom deterioration:
Approx. 200,000 patients
Launch of ABILIFY MAINTENA
4
アリピプラゾール持効性注射剤(IMデポ製剤)
65% of them stop medication due to poor adherence:
1.95 million patients
Treated with oral schizophrenia drugs: 3 million patients (US)
Room for market
expansion up to 200,000
4
Treatment with depot formulation
1,425 1,500 1,588
21 134
579 180
224
4 54
238
474
849
1,128 1,309
1,446
1,814
2,391
0
500
1,000
1,500
2,000
2,500
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
ZYPREXA RELPREVV
INVEGA SUSTENNA
RISPERDAL CONST
$ Mil
Atypical antipsychotics depot market (global)
• Global depot market :$ 2,391Mil - CAGR(2007-2011) : 20.7% - RISPERDAL CONSTA : 8.9%
Source:Annual report of each company
A
Launch of ABILIFY MAINTENA
アリピプラゾール持効性注射剤(IMデポ製剤) ABILIFY MAINTENA(IM depot)
Indication: Maintenance phase of schizophrenia in adults Dosage and administration: Administered into gluteus
muscle once in 4 weeks. At the initial injection, oral aripiprazole or other oral antipsychotics is concomitantly used for 2 weeks. Thereafter, depot monotherapy starts.
Reconstitute before use:Reconstitute the lyophilized powder with sterile water(2ml)
Most commonly observed adverse event: akathisia Differentiation from existing drugs
– High tolerability suggested by its safety profile – Administration frequency: once monthly (IM) – Room-temperature storage – 21G injection needle, limited discomfort to patients – Formulation patents: October, 2024 (Japan, US, EU)
Aripiprazole: Highly evaluated safety profile
self-developed formulation technology (administered
once monthly)
Depot formulation with excellent adherance and
long-term safety = +
5
kit includes: Syringe with pre-attached needle,
vial of Abilify Maintena, etc.
Kit Package (400mg、300mg)
ABILIFY MAINTENA
Development History (US) - October 2010: Independent Data-Monitoring Committee’s interim analysis results for
Phase 3 study (placebo-controlled for schizophrenia) met efficacy and safety criteria for termination. The early study termination was recommended.
- September 2011: NDA submission - February 28, 2013: Approval - March 18, 2013: Launch Development History (EU) - Phase 3 study (non-Inferiority to oral Abilify for schizophrenia): completed - December 2012: EMA submission Development History (Japan) - Phase 3 study (non-Inferiority to oral Abilify for schizophrenia): ongoing Other indications - Bipolar disorder: Phase 3 (US & EU)
6
Formulation Technology
100
200
300
400
plasma concentration
(ng/ml)
Week 1 Week 2 Week 3 Week 4
No. of PK samples: 14 1)Abilify 30mg oral
tablet :Cmax 424ng/ml, trough 286ng/ml,
2) Abilify 10mg oral tablet: Cmax: 147ng/ml, trough 94ng/ml
Abilify 30mg oral tablet 1)
Abilify 10mg oral tablet2)
Pharmacokinetics parameter
ARI-ERIS- 400
(N=12)
ARI-ERIS- 300
(N=8)
ARI-ERIS- 200
(N=4)
Css,max ng/mL(SD) 316(160) 269(128) 100(68.4)
tmax day(median) 7.1(3.0-11.2) 6.5(0.5-21.2) 5.0(4.0-27.9)
AUC, mg-h/mL(SD) 163(88.8) 140(58.4) 54.5(39.4)
t1/2,Z day(SD) 46.5(10.8) 29.9(8.0) ND
Css,min ng/ml(SD) 212(113) 156(67.7) 95.0(86.2)
Pharmacokinetic Study
Source:Pharmacokinetic Study of Once-Monthly Aripiprazole Extended-Release Injectable Suspension in Adult Patients with Schizophrenia (164th Annual Meeting of the American Psychiatric Association, 14–18 May 2011, Honolulu, Hawaii) 7
ABILIFY MAINTENA P-3 Study Design
8
1)PANSS:Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 2)CGI-S: General assessment method. Assessment of general improvement level
Double-blind maintenance(52w)
Phase-4
ABILIFY MAINTENA 400mg or 300mg
N=269
Placebo N=134
Screening N1,025
(-42~-2Days)
Phase-0
Conversion N=843
(4~6w)
Phase-1
Oral stabilization
N=710 (4~12w)
Phase-2
ABILIFY MAINTENA stabilization
N=576 (12~36w)
Phase-3
R
Subject: Patients diagnosed with schizophrenia for at least 3 years (excluding newly diagnosed patients)
Assessments - Primary endpoint
• Time-to-impending relapse - Secondary endpoints
1) Proportion of subjects meeting impending-relapse 2) Mean changes in PANSS1) from baseline 3) Mean change in CGI-S2) from baseline
ABILIFY MAINTENA P-3 Study Results
9
20%
40%
60%
80%
100%
0 28 56 84 112 140 168 196 224 252 280 308 336 364
Hazard ratio 5.03 Long-rank test: p<0.0001
Placebo
Days from randomization
Pro
porti
on o
f sub
ject
s fre
e of
im
pend
ing
rela
pse
Aripiprazole IM depot
Time from randomization to impending relapse during double-
blind treatment
3.0%
5.6%
5.9%
5.9%
5.9%
9.7%
10.0%
3.7%
6.0%
1.5%
5.2%
7.5%
9.7%
9.0%
0% 2% 4% 6% 8% 10% 12%
注射部位痛
アカシジア
振戦
頭痛
不安
体重増加
不眠
プラセボ
アリピプラゾールIMデポ Aripiprazole IM depot
Adverse Events: >5% 1)
1) Depot formulation has less adverse events by temporal elevation of plasma concentration when administered oral tablet.
Primary endpoint: Time-to-impending relapse - ABILIFY MAINTENA significantly delayed time to
impending relapse - Relapse rate at 80 events of relapse (termination
criteria) Placebo: ABILIFY MAINTENA = 10.0%: 39.6%
Insomnia
Weight gain
Anxiety
Headache
Tremor
Akathisia
Injection-site pain
Placebo
Source: W. Wolfgang Fleischhacker et al., 165th Annual Meeting of the American Psychiatric Association, May 5–9, 2012, Philadelphia, PA
Comparison with competitive products Brand Name ABILIFY
MAINTENA® RISPERDAL CONSTA®
ZYPREXA RELPREVV®
INVEGA SUSTENNA®
Generic Name Aripiprazole Risperidone Olanzapine Paliperidone
Sales (2012)
• US:$484M • EU-5:€352M • JP:¥ 12B
• US:$11M • EU-5:€11M
• US:$557M • EU-5:$137M
Indications
Maintenance therapy for schizophrenia in adults
Schizophrenia, monotherapy or adjunctive therapy for maintenance of bipolar disorder
Acute and maintenance therapy for schizophrenia in adults
Acute and maintenance therapy for schizophrenia in adults
Concurrent use of oral tablet
Aripiprazole or other antipsychotic for 2 weeks
Risperdal or other antipsychotic for 3 weeks
Oranzapine for 2 – 4 weeks
Paliperidone or risperidone
Admn. interval 4 weeks 2 weeks 2 or 4 weeks 4 weeks
Injection site Gluteus Deltoid, gluteus Gluteus Deltoid, gluteus
Preparation Reconstitute before use (2ml)
Reconstitute before use(2ml)
Reconstitute before use (1~2.7ml)
Pre-filled syringe (0.5~1.5ml)
Storage Room temperature (< 30c)
Cold dark place (2~8 c)
Room temperature (< 30c)
Room temperature (15-30c)
Needle • 21G • 21G (deltoid) • 20G (gluteus)
• 19G(gluteus) • 22G(deltoid, gluteus) • 23G(deltoid)
10 Source: FDA
Three therapeutic options for patients with severe CNS disorders
Dis
ease
insi
ght
(Lev
el o
f und
erst
andi
ng o
f adh
eren
ce)
Relapse risk when not taking medicine (number of past hospitalizations)
+ _
Tablet
Understands the importance of adherence
Little experience of relapse
Smart Tablet
Understands the importance of adherence, but relapse occurs
frequently due to poor adherence
Abilify Maintena
Does NOT understand the importance of adherence and poor adherence
+
_
11
Brexpiprazole
Abilify
Partial Agonist
Second generation antipsychotics Dopamine-Serotonin Antagonist
First generation antipsychotics Dopamine Antagonist
Evolution of Otsuka’s CNS Research (partial agonist)
13
Product Concept • World first D2 dopamine partial agonist
• Distinct efficacy and safety profile
Patients Concept
• Long-term administration for social reintegration
Brexpiprazole Product Concept
• Better safety profile • Creation of new
market category with its wider affinity
Patients Concept
•Usefulness in quite different diseases
Schizophrenia
Bipolar disorder
MDD
Pediatrics
New indications
Brexpiprazole – New Partial Agonist Binding affinity to each receptor
Increased binding activity at 5-HT2A
receptor
Reduced intrinsic activity at D2
receptor
Decreased Irritation, nausea, vomiting
Therapeutic efficacy in negative
symptoms of schizophrenia
D2 D3 5-HT2A 5-HT1A α1A 5-HT2A/D2 α1A/D2
Brexpiprazole 0.29 1 0.47 0.12 3.8 1.6 13
Aripiprazole 0.87 1.1 4.7 1.3 52 5.4 60
Risperidone 1.9 - 0.22 - 0.60 0.043 0.31
Olanzapine 11 - 0.49 - 9.4 0.11 0.82
14
Partial agonist activity to D2 receptor
Source:Kikuchi T et al., Society of Biological Psychiatry 66th Annual Meeting (2011)
Brexpiprazole P-2 Study Result for Major Depressive Disorder
8 weeks Prospective treatment
6 weeks randomized
Screening (7-28 days)
N=850 NCT00797966
Placebo+ADT (N=126)
Primary endpoint
•MADRS2)
Secondary endpoint
•CGI-S3) •IDS4) •SDS5)
Placebo +
ADT1)
Single-blind • Select patients with
an inadequate response to ADT
P=0.006 P=0.016
15
0.15mg Brexpiprazole + ADT (N=62)
0.5mg±0.25mg Brexpiprazole+ ADT (N=119)
1.5mg±0.5mg Brexpiprazole + ADT (N=119)
Weeks after Randomization
Mea
n ch
ange
in M
AD
RS
Tot
al S
core
Placebo 0.15 mg 0.5±0.25 mg 1.5±0.5 mg
*
* * * * *
Secondary endpoints Mean change from baseline to CGI-S, IDS,
SDS
P=0.002
1) Antidepressant therapy; Desvenlafaxine, Escitalopram , Fluoxetine , Paroxetine CR , Sertraline , Venlafaxin, 2) MADRS:Montgomery-Asberg Depression Rating Scale, 3) CGI-S:Clinical Global Impression – Improvement scale, 4) IDS: Inventory of Depressive Symptoms, 5) SDS: Sheehan Disability Score
Primary endpoint Mean change from baseline to MADRS
Source: Michael E. Thase et al., ACNP 50th Annual Meeting
Source: Michael E. Thase et al., ACNP 50th Annual Meeting
Brexpiprazole P-2 Study Result for Schizophrenia
6 weeks treatment
Screening and washout
(14 days)
1 mg (N=88)Brexpiprazole
2.5 mg (N=90)Brexpiprazole
5 mg (N=92)Brexpiprazole
Primary endpoint: PANSS1)
Placebo (N=93)
15 mg±5mg (N=50)Aripiprazole
0.25 mg (N=41)Brexpiprazole
1)PANSS:Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 16
Enrollment N=454
NCT00905307
P-2 study for schizophrenia [dosage] - non-effective dose: 0.25 mg/day - effective dose range:1.0 – 5.0 mg/day [efficacy] -The placebo group exhibited higher than expected improvement making the results of this study difficult to interpret. -Improvements were similar to those observed with aripiprazole -Improvements in negative symptoms and cognition were greater than aripiprazole
-20
-15
-10
-5
0
0 1 2 3 4 5 6
Inpr
ovem
ents
from
bas
elin
e on
the
PAN
SS to
tal s
core
Week of treatment
Placebo
0.25mg OPC1mg OPC
2.5mg OPC
5mg OPC
Aripiprazole 15mg
Source:R. McQuade et al., 24th Annual US Psychiatric and Mental Health Congress
17
5.7%
6.1%
7.0%
8.3%
8.9%
10.8%
10.8%
2.0%
10.0%
6.0%
4.0%
10.0%
10.0%
8.0%
2.1%
4.2%
3.2%
4.2%
10.5%
10.5%
16.8%
0% 5% 10% 15% 20%
悪心
焦燥
体重増加
アカシジア
不安
頭痛
不眠
プラセボ
エビリファイ
Brexpiprazole
Incidence of adverse events in ≥5% of patients receiving brexpiprazole (schizophrenia)
Insomnia
Headache
Anxiety
Akathisia
Weight increased
Agitation
Nausea
Placebo
Placebo
Abilify
Brexpiprazole P-2 Study Result for Schizophrenia
Under Development:Brexpiprazole P-3 Study for Schizophrenia
6 weeks treatment
Enrollment N=660
NCT01393613
Lower dose (once daily)
Middle dose (once daily)
Higher dose (once daily)
Primary endpoint
• PANSS
Secondary endpoint
• CGI-S Placebo
Enrollment N=630
NCT01396421
1)PANSS:Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 2) CGI-S: Clinical Global Impression – Improvement scale 18
Screening
Washout (14 days)
Enrollment N=1,000
NCT01397786
4 weeks treatment
1~2mg/ day
52 weeks treatment (open label) 1~4mg/ day
Long-term safety study
8~12 weeks treatment
52 weeks treatment (open label)
0.5~3mg Brexpiprazole + ADT
8 weeks treatment
Under Development:Brexpiprazole P-3 Study for MDD
6 weeks treatment
Enrollment N=826
NCT01360645 Placebo + ADT
2 mg Brexpiprazole + ADT
Placebo + ADT
3mg Brexpiprazole + ADT
1 mg Brexpiprazole + ADT
Primary endpoint
・MADRS
Secondary endpoint
・SDS
Enrollment N=1,650
NCT01360632 Placebo + ADT
19
Placebo + ADT
1~3mg Brexpiprazole + ADT Enrollment
N=1,340 NCT01727726
Placebo + ADT
Placebo + ADT
Seroquel XR + ADT
Enrollment N=3,000
NCT01360866
Further Development of Dopamine Partial Agonist
20
behavioral disorder
Mental disorder, Mood disorder
anxiety disorder Depression
Bipolar Schizophrenia
Abilify
Brexpiprazole
Brexpiprazole creates new category which Abilify doesn’t have.
E Keppra
Levetiracetam
Mechanism of Levetiracetam Levetiracetam
Shows antiepileptic action by regulating the release of excitatory and inhibitory neurotransmitters (glutamine, GABA, etc.) from the presynaptic region by binding to synaptic vesicle protein SV2A
The synaptic vesicle cycle Synaptic vesicles: Cycle of vesicles containing
neurotransmitters existing inside presynaptic nerve terminals
Role of synaptic vesicles (1) Load neurotransmitters into synaptic vesicles via
transporters
(2) Transport synaptic vesicles inside the cell via trafficking proteins
SV2: One of the synaptic vesicle proteins SV2: a glycoprotein that penetrate the synaptic
vesicle membrane 12 times; has three subtypes (2A, 2B, and 2C)
Its physiological role has not been elucidated in detail, but it is thought to be involved in the release of neurotransmitters.
Characteristics of Levetiracetam Characteristics: (1) binds to synaptic vesicle protein
2A (SV2A); (2) inhibits N-type calcium (Ca2+) channels; (3) inhibits intracellular release of Ca2+; (4) opposes allosteric inhibition of GABA- and glycine-gated currents; and (5) inhibits neuronal hyper-synchronization
High affinity for SV2A (not seen in any other existing antiepileptic drugs) 22
The synaptic vesicle cycle
priming (3) docking (4) calcium
sensing
(5) fusion (exocytosis)
(6) reuptake (endocytosis)
storage
(1) loading
(2) mobilization
translocation
(7) coat protein removal (8) recycling
Synaptic vesicle
Source: Richmond J et al., WormBook : the online review of C. elegans biology 2005
Epilepsy Epilepsy: a disease whose cardinal symptom is recurrent seizures with excessive excitement
(electrical discharge) in brain cell networks due to various causes and associated with diverse symptoms besides seizures such as a decline in consciousness and motor function.
- Seizures recur as a result of increased seizure readiness - May develop due to encephalitis, meningitis, or brain trauma due to traffic accident or other causes.
Characteristics: Recurrent seizures that occur repeatedly at regular intervals and that will continue to recur without appropriate treatment
- Opportunistic convulsions: convulsive seizures such as convulsions in an infant with a fever (febrile convulsions) or that occur from heavy drinking or during childbirth. Opportunistic convulsions are different from epilepsy, since seizures do not recur after recovery from the medical condition.
Idiopathic epilepsy: unknown etiology - Symptomatic epilepsy: caused by encephalitis, brain tumor, or brain trauma (with clear cause)
Site of onset: seizure symptoms can be extremely varied, and the method of treatment differs depending on the seizure symptoms
- Partial seizures: excessive excitement of the brain occurs and spreads out from one part of the brain - Generalized seizures: excessive excitement deep within the brain spreads throughout the entire brain
Four major classifications of epilepsy Type of seizure
Partial seizures Generalized seizures
Cause Unknown etiology • Idiopathic localization-
related epilepsy • Idiopathic generalized
epilepsy Caused by organic disorder of the brain resulting
from a tumor or traffic accident, etc. • Symptomatic localization-
related epilepsy • Symptomatic
generalized epilepsy 23
Diagnosis
Symptoms and Diagnosis of Epilepsy Pathogenic mechanisms of epilepsy
24
(1) Seizure at the cellular level due to increased electrical activity
(2) Synchronization with surrounding neurons
• Decline in GABA inhibition • Increase in extracellular
potassium concentration • Open NMDA channels
(3) Propagation to adjacent regions of the brain
Normal condition • Surround inhibition
caused by the refractory period of ion channels and GABAergic neurons
Primary symptoms - Convulsions: tonic, clonic, and other forms of
involuntary movement - Disturbance of consciousness: transient (several
minutes to more than 10 minutes) followed by recovery
Detailed history taking
Classification Localization-
related, generalized
EEG
Seizures and syndrome
Pathological diagnosis
Video-EEG Neuroimaging
Definitive diagnosis
Source: Societas Neurologica Japonica, Treatment Guidelines for Epilepsy 2010
Antiepileptic Drug Market
Antiepileptic market (Japan) - No new drug has been approved in the epilepsy
market after clobazam was launched in 2000. - Since 2006, new drugs, including gabapentin, have
been launched, indicated as add-on therapy to existing drugs for non-responders. Sales of such products are added onto those of existing products.
- ¥48 billion market in 2012, with add-on portion of new drugs pushing up the market
25
Patients diagnosed with epilepsy:
930,000 (0.7% of population)
Patients treated with drugs: 830,000
(89% of diagnosed patients)
Generalized seizures
(40% of patients treated with drugs)
Partial seizures (60% of patients
treated with drugs)
Refractory (22% of patients
treated with drugsto )
Source: Decision Resource 2013
127 127 131 135 138 137 140 136
32 32 33 33 33 31 31 29
90 87 86 88 88 87 87 88
1 6 13 18 22 19 166 14 19 23 25 7
24 49
94 2
32
87
249 246 256275
298323
381
476
0
50
100
150
200
250
300
350
400
450
500
2005 2006 2007 2008 2009 2010 2011 2012
LEVETIRACETAM
LAMOTRIGINE
TOPIRAMATE
GABAPENTIN
Others
ZONISAMIDE
VALPROIC ACID
LaunchedGABAPENTIN
LaunchedTOPIRAMATE
LaunchedLAMORTIGINE
LaunchedLEVETIRACETAM
Antiepileptic Drug Market (Japan)100 mil Yen
Source:IMS 2013
Epilepsy Therapeutic Algorithm (NHS) Epilepsy treatment
(first stage)
Reconsider diagnosis
Consider alternative monotherapy
Consider surgical treatment
Consider combined treatment
Seizures not controlled
Seizures not controlled
Seizures not controlled
Consider surgical treatment
Reconsider diagnosis
Reconsider diagnosis
Refer to a third-party epilepsy specialist
Seizures controlled (follow-up)
•Consider discontinuing treatment if no seizures for two years
Partial: 82% monotherapy Generalized: 85% monotherapy
Partial: 54.1% combined regimen Generalized: 44.3% combined regimen
Partial: 74% combined regimen Generalized: 65% combined regimen
26
Mechanism of Antiepileptic Drugs
27
Excitatory neurotransmission
(glutamic acid neurons)
Na+ channels Glutamate receptors
Inhibitory neurotransmission
(GABA neurons)
SV2A
L-type Ca2+ channels
GABA receptors
SV2A
Ca2+ channels
AMPA/KA receptors
Phenytoin
Carbamazepine
Benzodiazepine
Topiramate
Topiramate Levetiracetam
Benzodiazepine
T-type Ca2+ channels
Valproic acid
Phenobarbital
Topiramate
Levetiracetam Gabapentin
Phenobarbital
Topiramate
Valproic acid
Rufinamide
Lamotrigine
Comparison of Mechanism among Antiepileptic Drugs
Substance Na2+
channels K+
channels Ca2+ channels GABA
nervous system
Glutamic acid nervous system
SV2A N L P/Q T
Phenytoin (PHT) ++ (+) + - Carbamazepine (CBZ) ++ (+) -
Zonisamide (ZNS) ++ + - Lamotrigine (LTG) ++ + + Valproic acid (VPA) ++ (+) + - Gabapentin (GBP) + ++ + (+) -
Ethosuximide (ESM) - ++ Diazepam (DZP) (+) (+) ++ -
Phenobarbital (PB) + (+) ++ (+) - Topiramate (TPM) + + + + ++
Levetiracetam (LEV) - + - - - ++ 28
++: strong effects, +: moderate effects, (+): slight effects, -: no effect (Source: Quoted from Sasa., J. jpn. J. Psychopharmacol. 13, 1671-1683 (2010))
6.11
19.6
27.7
0
10
20
30
40
Pracebo (n=65) LEV1000mg(n=64)
LEV3000mg(n=63)
(%)
* patients failed 1-3 existing antiepilepitic drugs (half of them have been receiving 3 drugs) and were not well responded to those drug(s.)
Analysis of N165 Study in Japan
Precentage reduction in seizure frequency in partial epilepsy case
(Wilcoxon rank sum test)
p=0.007
p=0.005
Prec
enta
ge re
duct
ion
in s
eizu
re fr
eque
ncy
(Med
ian)
Observation period (12 weeks)
Partial Epilepsy P-2/3 Short-term Trials in Japan
29
Titration period (4 weeks)
Assessment period (12 weeks)
1,000mg/day 2,000mg/
day
3,000mg/day
500mg/day 1,000mg/day
1-3 existing antiepileptic drugs
1-3 existing antiepileptic drugs
1-3 existing antiepileptic drugs
Levetiracetam 3,000mg group
(n=71)
Levetiracetam 1,000mg group
(n=72)
Placebo group (n=70)
Number of Concomitant AEDs
Primary endpoints Partial seizure frequency
Secondary endpoints Percentage reduction in partial
seizure frequency 50% responder rate Percentage of seizure-free
subjects Percentage reduction in seizure
frequency by partial seizure type
Characteristics of Levetiracetam 1. Inhibits seizures by binding to SV2A
The higher the binding affinity for SV2A of levetiracetam derivatives, the stronger the anticonvulsant action
2. Opposes inhibition by allosteric inhibitors of GABA-gated currents Activation of GABAergic nerves
3. Inhibits intracellular release of Ca2+ Different action from other drugs
Shows no affinity for receptors such as GABAA/B benzodiazepine receptors or glutamate receptors nor for transporters or second messengers
Has no effect on the main action-targets (Na+ channels and T-type Ca2+ channels) of existing antiepileptic drugs
Does not affect hepatic metabolic enzymes No need for titration (effective dose can be used
right from the initial administration) AE incidence: comparable to placebo Partial seizure frequency: reduction seen vs.
placebo - Enhanced effects is be expected from
concomitant use with other drugs.
Correlation between affinity of similar compounds for human SV2A (hSV2A) and inhibitory effects on audiogenic seizures (pED50)
pKi o
f bin
ding
to h
SV2A
pED50 for inhibitory effects on audiogenic seizures
30
Kaminski R. M. et al., Neuropharmacology 2008
Rotigotine
for Parkinson’s Disease
Parkinson’s Disease Causes - Attributable to a decline in dopamine content in the striatum resulting from degeneration of dopamine-
secreting cells in the substantia nigra pars compacta of the midbrain - Abnormalities in dopaminergic neurotransmission in the basal ganglia cause malfunction of the loop
circuit running through the motor area in the cerebral cortex of the frontal lobe and the basal ganglia, leading to development of serious motor disorders such as akinesia, rigidity, and tremors
Signs and symptoms - Four cardinal characteristics: akinesia/hypokinesia, tremor at rest, muscular rigidity, and disturbance of
posture and gait - Other symptoms
• Non-motor symptoms: constipation, drooling, orthostatic hypotension (autonomic nervous symptom), postprandial hypotension, hyperhidrosis, and dysphagia resulting from muscle stiffening in the face and throat, etc.
• Psychiatric symptoms: apathy, anhedonia, anxiety, depression (complication in 60% of cases), visual hallucinations, and cognitive impairment
Diagnostic criteria (2011 Treatment Guidelines for Parkinson’s Disease)
32
Neurologic findings
1. Tremor at rest 2. Akinesia/hypokinesia: mask-like face; low, monotone
voice; slow movement; inability to change posture readily 3. Muscular rigidity with the cogwheel phenomenon 4. Disturbance of posture and gait: forward-flexed posture;
no hand shaking while walking; difficulty stopping once starts walking (pulsion); short-stepped gait; impaired righting reflex
Clinical laboratory findings
1. No abnormalities on general tests 2. No abnormalities on brain imaging tests (CT, MRI)
Differential diagnosis
1. not a drug-induced illness 2. Symptoms improve with L-DOPA administration 3. Neurodegenerative disease showing characteristic
findings and parkinsonism due to cerebrovascular disease ruled out
Stage Hoehn & Yahr Scale (medical subsidy for stage 3 and above)
1 • Unilateral parkinsonism
2 • Bilateral parkinsonism without impairment of balance
3 • Mild to moderate bilateral parkinsonism; impairment of balance; assistance not needed
4 • Severe parkinsonism; impairment of balance; still able to walk or stand unassisted
5 • Wheelchair bound or bedridden unless aided; difficulty walking even with assistance
Gowers: A manual of diseases of the nervous system, 1893
Basal ganglia Striatum (GABA)
Parkinson’s disease • Decline in dopamine content in the striatum resulting
from degeneration and loss of dopaminergic cells in the substantia nigra
• D1 receptors: GABAergic neurons have a weak inhibitory effect, since there is no excitatory effect, due to little binding of dopamine
• D2 receptors: GABAergic neurons have a strong inhibitory effect, since there is no inhibition due to little binding of dopamine
Direct pathway • Loss of excitatory input attenuation of cell activity
neural activity increases in globus pallidus internal segment
Indirect pathway • Loss of inhibitory input cellular activity increases
attenuation of neural activity in globus pallidus external segment subthalamic nuclei neural activity increases neural activity accelerates in globus pallidus internal segment
Depletion of dopamine in the striatum in Parkinson’s disease works to increase neural activity in the globus pallidus internal segment, as motor information passes through either direct or indirect pathway, ultimately inhibiting activity in the thalamus and motor area.
Basal Ganglia Loop (Parkinson’s disease)
33
Cerebral cortex (glutamate)
Thalamus (glutamate) Motor thalamic nuclei
D1 receptors
D2 receptors
Globus pallidus internal segment/ substantia nigra pars reticulata (GABA)
Globus pallidus external segment
(GABA)
Midbrain substantia nigra pars compacta
Subthalamic nucleus
(glutamate)
Direct pathway
Indirect pathway
Brain stem/ spinal cord
Parkinson’s Disease Normal
• Dopamine has inhibitory and Acetylcholine has excitatory effect for GABAergic neuron, both controlling GABAergic neuron.
Dopaminergic neuron
Cholinergic neuron
GABAergic neuron
• Dopamine has inhibitory effect for cholinergic and GABAergic neuron.
• Acetylcholine has excitatory effect for GABAergic neuron.
Dopaminergic neuron
Cholinergic neuron
GABAergic neuron
Parkinson’s Disease
• The lack of dopamine causes increase of acetylcholine effect by decrease inhibitory effect of dopamine. Inhibitory effect of dopamine for GABAergic neuron also decrease, resulting the increase of the excitatory effect.
Excitatory effect
Dopamine receptor
Acetylcholine receptor
corpus striatum
corpus striatum
34
Dyskinesia (-) Dyskinesia (+)
Dyskinesia (-)
Dyskinesia (+)
Parkinson’s Disease Therapy
35
Initial Parkinson’s disease therapy/diagnosis
No interference with daily life
Interference with daily life
Diagnosis every 3-6 months
Under age 70 with no dementia
Above age 70 or has dementia
Non-ergot-derived dopamine agonists
Inadequate improvement Ergot-derived
dopamine agonists
L-DOPA combination (L-DOPA + DCI)
Advanced stage Wearing-off phenomenon
Anticholinergic agent
Dopamine releasing agent
MAO-B inhibitor
Zonisamide
L-DOPA combination (L-DOPA + DCI)
Dopamine agonist L-DOPA combination +
Dopamine agonist L-DOPA combination
+
Anticholinergic agent
Dopamine releasing agent MAO-B inhibitor
Zonisamide
L-DOPA combination (L-DOPA + DCI)
+
L-DOPA combination (L-DOPA + DCI)
+
Advanced stage Wearing-off phenomenon
Dopamine agonist
DCI: decarboxylase inhibitor
Midbrain substantia
nigra
Pharmacological Effects of Antiparkinson Drugs
36
Norepinephrine
Dopamine
Norepinephrine precursor
L-DOPA
L-tyrosine
DOPA decarboxylase
inhibitor Levodopa
Dopamine 3-O-methyldopa (3-OMD)
Peripheral COMT inhibitor
Tyrosine hydroxylase
DOPA decarboxylase
Dopamine-β- hydroxylase
DOPA decarboxylase
+
Catechol-O-methyltransferase
(COMT)
3,4-dihydroxyphenylacetic
acid (DOPAC)
Homovanillic acid (HVA)
GA
BA
ergi
c ne
uron
Monoamine oxidase (MAO)
3-MT
Acetylcholine nervous system
MAO-B inhibitor
Monoamine oxidase (MAO)
Anticholinergic agent
Dopamine releasing agent
Dopamine agonist
Catechol-O-methyltransferase
(COMT)
Catechol-O-methyltransferase
(COMT)
MAO-B inhibitor
T-Type Ca channel blockade
Existing Products
Drug Generic name Brand name Dopamine precursor (L-DOPA formulation) Levodopa Menesit
Levodopa + DCI Levodopa/Benserazide (combination) Madopar Levodopa/Carbidopa (combination) Menesit
Dopamine releasing agent Amantadine Symmetrel
Norepinephrine precursor Droxidopa Dops
Dopamine receptor agonists (Dopamine agonists)
Ergot-derived agonists
Bromocriptine Parlodel Cabergoline Cabaser
Pergolide Permax
Non-ergot-derived agonists
Ropinirole Requip Talipexole Domin
Pramipexole BI Sifrol
Anticholinergic agents Trihexyphenidyl Artane
Biperiden Akineton Profenamine Parkin
COMT inhibitor Entacapone Comtan
MAO-B inhibitor Selegiline FP
37
Number of Potential Patients and Market
Size of antiparkinson drug market (2012): 60 billion yen
• Dopamine agonists are mainstream: 41% share of sales • L-DOPA + DCI (combination): 15% share of sales Market’s average annual growth rate (2007-
2012): +4.4% • COMT inhibitors: +56.5% (launched in 2007) • L-DOPA + DCI (combination): +2.6%
38
Potential patients: 250,000
(0.2% of population)
Diagnosed patients: 180,000
(72% of potential patients)
Drug treatment patients: 170,000
(93% of diagnosed patients)
Population (Japan): 126.7 million
Number of potential Parkinson’s patients
• Main Parkinson’s patients: above age 40
• Population in 40s: will increase by 0.7% per year for the next 10 years
• 30% have cognitive impairment
Hoehn-Yahr Scale
• Stage-1: 21% • Stage-2: 44% • Stage-3: 16% • Stage-4: 15.7% • Stage-5: 3.3%
Source: Decision Resource
Source: IMS 2013
25,530 24,634 24,221 23,775 24,357 25,112
8,017 8,360 8,645 8,725 9,082 9,093
3,904 3,604 3,426 3,173 3,150 3,058
3,575 3,445 3,251 3,039 2,903 2,800735 2,767 4,320 5,453 6,172 6,906
6,398 6,777 7,088 7,210 7,351
7,440 505 2,345
4,382 5,868
48,877 50,224 52,049
54,251
57,907 60,750
-
10,000
20,000
30,000
40,000
50,000
60,000
70,000
2007 2008 2009 2010 2011 2012
Other
MAO-B inhibitor
COMT inhibitor
Anticholinergic agents
Norepinephrine precursor
Dopamine releasing agent
Levodopa + DCI
Dopamine precursor
Dopamine agonist
(JPY mil) Antiparkinson drug market (Japan)
Rotigotine
Neupro Patch® (Rotigotine) - Non-ergot-derived dopamine receptor agonist
(D2/D3 receptor selectivity) - Formulation (transdermal patch, Terminal Heating formulation)
2.25mg, 4.5mg, 9mg, and 13.5mg formulations World’s first antiparkinson sustained-release transdermal patch Shows effects with little diurnal variation by maintaining a stable plasma concentration over
24 hours Reduction of burden on patients with dysphagia or many con-meds
- Formulation characteristics August 2007: Crystallization issue with the patch in the U.S. April 2008: recall from European and U.S. markets Phase III trials conducted by Otsuka with improved formulation (TH formulation) April 2012: FDA approval of new formulation (with room temperature storage)
as well as two additional indications of advanced Parkinson’s disease and restless leg syndrome July 16, 2012 : launch
- Patent exclusivity: December 2020 - Indications: Parkinson’s disease, restless leg syndrome
39
DA receptor selectivity
Lipid solubility
Dose titration / Maintenance period
Parkinson’s Disease Phase 3 Trial
40
Subjects: patients with advanced Parkinson’s disease on L-DOPA Study objectives: Superiority of rotigotine to placebo and non-inferiority to ropinirole Efficacy measurements Primary endpoints: Change in UPDRS Part III (ON state) score from the baseline Secondary endpoints:
• Changes in UPDRS II (average ON and OFF, ON, and OFF) score from the baseline • Changes in “time spent OFF” from the baseline and responder rate • Hoehn & Yahr scale
• UPDRS (Unified Parkinson's Disease Rating Scale): Consists of four parts—Part I: mentation, behavior, and mood; Part II: activities of daily life; Part III: test of motor ability; and Part IV: complications of treatment. Overall, 42 items are rate, generally in five levels, to quantify the severity of Parkinson’s disease.
Screening period
2 weeks N=546
16 weeks L-DOPA + rotigotine (N=168) 4.5 mg up to 36 mg/day
16 weeks L-DOPA + Ropinirole (N=167) 0.75 mg up to 15.0 mg/day
16 weeks L-DOPA + placebo (N=85)
Down- titration 4 weeks
Follow-up
1 week
Parkinson’s Disease Phase 3 Trial Results Primary endpoint
• Change in UPDRS Part III (motor ability, ON state) score from the baseline
Secondary endpoints (1) Change in UPDRS Part II (activities of daily life, ON)
score from the baseline
41
(2) Change in UPDRS Part II (activities of daily life, OFF) score from the baseline
Conclusions Efficacy • Superiority of rotigotine to placebo and non-
inferiority to ropinirole have been confirmed with statistical significance during a 16-week administration period.
Safety • Most common adverse event: application site
reaction (54.2%)
Y. Mizuno et al., 15th International Congress of Parkinson’s disease and Movement disorders
Rotigotine
for Restless Legs Syndrome
Restless Legs Syndrome (RLS) Epidemiology - Prevalence (Japan): 2.1 million (1.7% of population)
- No. of diagnosed patients: 43,000 (2% of potential patients)
- No. of treated patients: 43,000 (100% of diagnosed patients)
- Because of low recognition of the disease, it is often overlooked, misdiagnosed as insomnia or other disease, and not sufficiently treated.
Pathogenesis (exact cause unknown) - Metabolic abnormality resulting from decline in dopamine function
and insufficient iron in the central nervous system, abnormality of spinal cord and peripheral nerves, and genetic factors, etc.
Signs and symptoms - Subjective symptoms: Abnormal sensations such as creeping, an
urge to move, itching, or a feeling like bugs crawling, primarily in the legs, but potentially throughout the body, when in a still posture or lying down. Since it is difficult to suppress the symptoms, patients cannot stop moving legs and/or arms, trying to eliminate the sensations.
- From evening through the nighttime the symptoms exacerbate, causing sleep-onset insomnia, deep sleep disorder, or middle-of-the-night insomnia, which have a profound impact on everyday life.
- Secondary symptoms: Disturbed sleep causes fatigue during daytime. Worsening of symptoms may lead to depression and chronic pain.
43
Potential patients (2011)
2.1 million (1.7% of population)
Diagnosed patients 43,000
(2% of potential patients)
Drug treatment patients 43,000
(100% of diagnosed patients)
Mild 46.1%
Moderate 33.8% Severe 16.2%
Very Severe 3.9%
20-29% of renal failure patients
20% of pregnant women
12% of Parkinson’s disease patients
Source: 1. Decision Resource 2013 2. Epidemiology and Clinical characteristics of restless legs syndrome, Dr. Kenji Kuroda, 15:
461-468, 2012, Japanese Journal of Clinical Psychopharmacology
Differential diagnosis • Tests: Blood tests, serum ferritin test • Ancillary tests - Overnight polysomnography (PSG) - Suggested Immobilization Test (SIT)2
• Diseases from which differentiation is needed - Polyneuritis, akathisia, peripheral circulatory
disorders of the lower extremities, Parkinson’s disease, etc.
Diagnostic Criteria
44
History taking • Family history, symptoms, time of symptom onset
Diagnostic criteria 1. Strong desire to move the legs due to abnormal
sensations in the legs. 2. The abnormal sensations exacerbate when at
rest or lying still. 3. The abnormal sensations improve with
movement. 4. The abnormal sensations increase in the evening
and at night.
Characteristics (diagnostic aids)
• Positive family history • Responds to dopamine agonists • Periodic limb movement disorder (PLMD1)
Severity rating International RLS Rating Scale
Severity Score Content of 10 questions
Mild Up to 10
• The system consists of 10 questions about the patient’s subjective symptoms that are answered by patients and scored in five levels from 0 to 4 based on the symptoms.
(1) leg discomfort, (2) tiredness or sleepiness, (3)
need to move, (4) frequency of symptoms, (5) relief of discomfort from moving, (6) affect on daily affairs, (7) sleep disturbance, (8) level of mood disturbance, (9) RLS as a whole, (10) severity of symptoms
Moderate 11-20
Severe 21-30
Very severe
31 and above
1) PLMD: Rapid leg movement caused by involuntary contraction of the tibialis anterior muscle in one or both legs. The rapid leg movement lasts for 0.5-5 seconds and occurs at intervals from 20-40 seconds apart. 2) SIT: An objective test, lasting 60 minutes and conducted 90 minutes before bedtime, that has been tried to evaluate periodic limb movement while waking (PLMW). The subject lies down in an easy chair at a 45-degree angle with the eyes open and the legs outstretched while EMG recording of activity in the tibialis anterior muscle is performed on the still state. A visual analog scale is filled out for leg discomfort every five minutes during the test. In a case of restless leg syndrome, PLMW increases in the second half of the SIT.
Refractory
RLS Therapy
45
Idiopathic RLS (60-80%) • Dopaminergic neuropathy • Iron disorder • Genetic factors
Ferritin level < 50 μg/L
Iron preparation
Benzodiazepine or add-on
Intermittent RLS
Continuous RLS
Clonazepam
Non-pharmacological therapy
• Abstain from caffeine, nicotine, and alcohol in the evening
• Taking a short walk, bath, cold shower, or messaging the limbs before bedtime
• Sleep hygiene instruction: regular bedtime, relax before bedtime
Suspension or dose reduction of drugs that could cause RLS (antihistamines, dopamine inhibitors, antidepressants)
Secondary RLS (20-40%) •Caused by other disease or drug
• Iron-deficiency anemia • Chronic renal failure • Congestive heart failure • Parkinson’s disease • Spinal cord disease • Folic acid deficiency, caffeine,
tricyclic antidepressants
GABA derivative Dopamine agonist
Low-strength opioid
Strong opioid
Pharmacotherapy
Switch to another drug
RLS Drugs
46 Otsuka Holdings September 13 2011
Mechanism Generic name Brand name Characteristics
Dopamine precursor L-DOPA Doparl • Tendency toward augmentation1 and rebound
Non-ergot-derived dopamine agonist
Pramipexole BI Sifrol • Contraindicated for renal failure • Indicated for RLS
Ropinirole Requip • Hepatic excretion
Rotigotine Neupro patch
• No drug interactions, transdermal patch • Indicated for RLS
Ergot-derived dopamine agonist Pergolide Permax • High risk of valvular heart disease and fibrosis
GABA derivative
Gabapentin Gabapen • Antiepileptic drug • Short plasma half-life, non-linear drug concentration
Gabapentin enacarbil Regnite
• A prodrug of gabapentin, little difference in blood levels • No tendency toward augmentation • Indicated for RLS
Opioid Oxycodone Oxycontin • Drug dependence, constipation
1) Augmentation: The increase in severity of RLS symptoms with the benefits of medication seen initially no longer being maintained. The time of symptom onset could become earlier than before medication began, symptoms could cause trouble both day and night, there may be pain, and symptoms could extend throughout the body. Diagnosed based on criteria released by the Max Planck Institute (MPI) in 2007.
Source: Interview survey of physicians, 2011, drug combination rate 8%
RLS Phase 3 Trial
Changes in IRLS sum score
47
Maintenance (8 weeks) Titration (5 weeks)
2 mg/24hr (N=95)
3 mg/24hr (N=94)
Placebo (N=95)
Screening (N=480) •IRLS score ≥ 15 •Responder to L-DOPA •Patients with sleep disorders, etc excluded
Initial dose 1 mg/24hr
Initial dose 1 mg/24hr
Phase 3 study design
Time course changes in IRLS sum score (FAS, LOCF)
Main adverse events
2 mg/ 24hr
3 mg/ 24hr Placebo
Application site reaction 42.1% 50.0% 7.4%
Nausea 33.7% 43.6% 9.5%
Somnolence 10.5% 14.9% 2.1%
Inoue Y et al., The 36th Annual Meeting of Japanese Society of Sleep Research
Taiho Oncology
Oncology Vision
“We contribute to cancer therapy worldwide through providing innovative drugs which lead to life extension, QOL improvement and potential cure, and trusted cancer care information.”
March 21,2013 Taiho Pharmaceutical Co., Ltd
Taiho Oncology pipeline
Copyright©Taiho Pharmaceutical Co., Ltd. 49
metastatic colorectal cancer JP :NDA (Feb. 26, 2013)
JP/US/EU :Phase 3
TAS-102 trifluorothymidine、pyrimidinedione hydrochloride compounding agent
“novel oral fluorothymidine antitumor drug”
Copyright©Taiho Pharmaceutical Co., Ltd. 50
We filed a J-NDA with the JMHLW for the approval of TAS-102 for the indication of colorectal cancer on Feb. 26, 2013.
51
TAS-102:NDA in Japan
Copyright©Taiho Pharmaceutical Co., Ltd.
News release
52
TAS-102:Mechanism of Action
FTD:trifluorothymidine TPI:thymidine phosphorylase inhibitor
molar ratio 1:0·5
Copyright©Taiho Pharmaceutical Co., Ltd.
•TAS-102 is a novel combination anti-tumor agent, consisting of FTD and TPI.
•FTD induces DNA dysfunction through efficient incorpora-tion into DNA, which leads to the inhibition of tumor growth.
•TPI prevents degradation of FTD.
TAS-102:Profile
53 Copyright©Taiho Pharmaceutical Co., Ltd.
• A novel oral fluorothymidine antitumor drug under development
• Extends overall survival in colorectal cancer patients with 3rd or later-line chemotherapy
• Significantly improve overall survival in KRAS mutation group
• Main Adverse Event: Myelosuppression Non-hematological AE was uncommon.
Japan US 5EU
Incidence※1 102,000 154,000 229,000
Mortality※1 43,000 51,000 95,000
≧3rd line Standard
Chemotherapy※2 KRAS Wild Type
CPT-11+C-mab Cape
FOLFIRI
P-mab FOLFOX+P-mab
FOLFIRI+ P-mab
Cape P-mab
CPT-11+C-mab
≧3rd line Standard
Chemotherapy ※2 KRAS Mutation
type
Cape FOLFIRI
Cape FOLFIRI +B-mab XELOX
Cape CPT-11 5FU+LV
C-mab:Cetuximab、P-mab: Panitumumab、B-mab:Bevacizumab、Cape:Capecitabine、FOLFIRI:5FU+leucovorin+CPT-11、 FOLFOX:5FU+leucovorin+oxaliplatin、XELOX:Capecitabine+ oxaliplatin ※1 GLOBOCAN2008 ※2 Kantar Health CancerMpactⓇ
54
TAS-102:Standard Chemotherapy of CRC
Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-102:clinical trial
55 Copyright©Taiho Pharmaceutical Co., Ltd.
N=112
N=57
Primary Endpoint:Overall Survival(OS) ※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO
TAS-102:Overall Survival(OS)
56 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-102 significantly improved overall survival compared with the placebo group.
TAS-102
Placebo
※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO
57
TAS-102:Subgroup analysis
Copyright©Taiho Pharmaceutical Co., Ltd.
※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO
KRAS KRAS
TAS-102 significantly improved overall survival in KRAS mutation group.
58
TAS-102:Safety
Myelosuppression was the main adverse events. Non-hematological adverse event was uncommon in TAS-102 treatment.
Copyright©Taiho Pharmaceutical Co., Ltd.
※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO
We are conducting global Phase 3 study of this Japan-origin compound, TAS-102 to meet patients’ needs worldwide.
59
TAS-102:Ongoing Study
Placebo + BSC
TAS-102 + BSC Radomized Primary Endpoint: Overall Survival(OS)
Secondary Endpoint: Progression Free Survival (PFS) N=800(TAS-102:Placebo = 2 : 1) Study period : Jun. 2012~ Dec. 2014
Main Clinical Sites: US:Dana-Farber Cancer Institute, Boston, MT EU:University Hospital Gasthuisberg, Leuven, Belgium JP:National Cancer Center Hospital East, Kashiwa, Chiba
Subjects: metastatic colorectal Cancer patients treated with Standard Chemotherapy
35 mg/㎡, b.i.d. d1-5, 8-12 q4wks until Progression
BSC:best supportive care
RECOURSE Study (Global Phase 3)
Copyright©Taiho Pharmaceutical Co., Ltd.
Gastric Cancer・Head & Neck Cancer Colorectal Cancer・Non-small cell lung cancer
Metastatic Breast Cancer Pancreatic Cancer・Bile Duct Cancer
TS-1 (S-1)
Copyright©Taiho Pharmaceutical Co., Ltd.
Japan :Taiho Europe :out-licensed to Nordic
60
61
TS-1:Proven efficacy
Copyright©Taiho Pharmaceutical Co., Ltd.
study name indication study design result
SPIRITS n=305
Gastric Cancer 1st line
TS-1 vs TS-1+cisplatin Lancet Oncol 2009
ACTS-GC n=1059
Gastric Cancer Adjuvant
Surgery alone vs TS-1 N Engl J Med 2007
FIRIS n=426
Colorectal Cancer 2nd line
FOLFIRI (5FU+LV+CPT-11) vs IRIS (TS-1+CPT-11)
Lancet Oncol 2010
ACTS-CC n=1504
Colorectal Cancer Adjuvant
UFT+LV vs TS-1 Ongoing
LETS n=564
NSCLC 1st line
Carboplatin+Paclitaxel vs Carboplatin+TS-1
J Clin Oncol 2010
CATS n=608
NSCLC 1st line
Cisplatin+Docetaxel vs Cisplatin+TS-1 ASCO 2012
SELECT BC n=618
Breast Cancer 1st line
Taxanes (Paclitaxel or Docetaxel) vs TS-1 Ongoing
GEST n=834
Pancreatic Cancer 1st line
Gemcitabine vs TS-1 vs Gemcitabine+TS-1 ASCO 2012
JASPAC-01 n=385
Pancreatic Cancer Adjuvant
Gemcitabine vs TS-1 ASCO-GI 2013
※ 2013 Gstrointestinal Cancer Symposium LBA#145 Presenter: Katsuhiko Uesaka (Shizuoka Cancer Center)
62
TS-1:Adjuvant therapy of Pancreatic Cancer
Copyright©Taiho Pharmaceutical Co., Ltd.
N=191 N=187
JASPAC-01 (Phase 3): Study Design
63 Copyright©Taiho Pharmaceutical Co., Ltd.
TS-1:Adjuvant therapy of Pancreatic Cancer
※ 2013 Gstrointestinal Cancer Symposium LBA#145 Presenter: Katsuhiko Uesaka (Shizuoka Cancer Center)
TS-1 demonstrated superiority in OS over GEM
News release
64
TS-1:Adjuvant therapy of Pancreatic Cancer
Copyright©Taiho Pharmaceutical Co., Ltd.
JASPAC-01 (Phase 3): Compliance
全生存期間
TS-1 was well tolerated as adjuvant therapy of pancreatic cancer
S-1群
GEM群
※ 2013 Gstrointestinal Cancer Symposium LBA#145 Presenter: Katsuhiko Uesaka (Shizuoka Cancer Center)
< Indication & Approval Date > Breast Cancer : Sep. 23, 2010 Non-Small Cell Lung Cancer : Feb. 21, 2013 Gastric Cancer : Feb. 21, 2013 Pancreatic Cancer : Ongoing (Phase 1/2)
Abraxane
Copyright©Taiho Pharmaceutical Co., Ltd.
in-licensed from Celgene(Area:Japan)
nab-paclitaxel
65
Abraxane:Profile
66 Copyright©Taiho Pharmaceutical Co., Ltd.
• nab-Paclitaxel (Abraxane), an albumin-bound form of paclitaxel, was developed to avoid toxicities associated with the Cremophor in solvent-based paclitaxel, with shorter infusion schedules (30 minutes) and no premedication.
• Approved in 41 countries (Sep. 2010) • NCCN guideline 【Breast Cancer, Non-Small Cell Lung Cancer】 recommends
abraxane as “Preferred Regimens”.
nab-paclitaxel
Particle of abraxane
Paclitaxel
albumin abraxane
erythrocyte
Abraxane:Clinical Trial Status
67 Copyright©Taiho Pharmaceutical Co., Ltd.
Trial Name/ CancerType Area Study Design P1 P2 P3 NDA
CA-012 Breast Cancer
US/EU q3w sb paclitaxel vs q3w Abraxane
Nov. 2005 Published
July. 2010 Approved
CA-024 Breast Cancer
US/EU q3w Docetaxel vs q3w/qw Abraxane
Aug. 2009 Published
J-0201 Breast Cancer
JP q3w Docetaxel vs qw Abraxane Ongoing
CA-031 NSCLC
JP/US/EU Carboplatin+Paclitaxel vs Carboplatin+Abraxane
June. 2012 Published
Feb. 2013 Approved
J-0200 Gastric Cacner
JP q3w Abraxane (2nd line) June. 2011 Presented
Feb. 2013 Approved
MPACT/CA046 Pancreatic Cacner
US/EU Gemcitabine vs Gemcitabine+Abraxane
Jan. 2013 Presented
J-0107 Pancreatic Cancer
JP Gemcitabine+Abraxane (feasibility) Ongoing
※ 2013 Gstrointestinal Cancer Symposium LBA#148 Presenter: Daniel D. Von Hoff (Virginia G. Piper Cancer Center, US )
68
Abraxane:1st L treatment of Pancreatic Cancer
Copyright©Taiho Pharmaceutical Co., Ltd.
MPACT/CA046(Phase 3): Study Design
Primary endpoint:Overall Survival(OS)
GEM+Abraxane demonstrated superiority in OS over GEM alone.
69
Abraxane:1st L treatment of Pancreatic Cancer
Copyright©Taiho Pharmaceutical Co., Ltd.
MPACT/CA046(Phase 3):Overall Survival
※ 2013 Gstrointestinal Cancer Symposium LBA#148 Presenter: Daniel D. Von Hoff (Virginia G. Piper Cancer Center, US )
Abraxane:1st L treatment of Pancreatic Cancer
No increase in serious life threatening toxicity was observed. AEs associated with GEM+Abraxane treatment were acceptable and manageble.
Adverse Events (≧G3) GEM+Abraxane GEM
Neutropenia 38% 27% Feblire Neutropenia 3% 1% Thrombocytopenia 13% 9% Amenia 13% 12% Fatigue 17% 7% Sensory Neuropathy 17% <1% Diarrhea 6% 1%
70 Copyright©Taiho Pharmaceutical Co., Ltd.
MPACT/CA046(Phase 3):Safety Profile
※ 2013 Gstrointestinal Cancer Symposium LBA#148 Presenter: Daniel D. Von Hoff (Virginia G. Piper Cancer Center, US )
MPACT/CA046(Phase 3): Summary
71
• GEM+Abraxane is superior to GEM alone (Median OS: 8.5 vs 6.7 months [HR 0.72, P=0.000015] , 1-yr: 35% vs 22%)
• No increase in serious life threatening toxicity • AEs associated with GEM+Abraxane were acceptable
and manageable.
Abraxane combination shows the benefit of 1st line treatment in patients with advanced pancreatic cancer. We are conducting a bridging study in Japan.
Copyright©Taiho Pharmaceutical Co., Ltd.
Abraxane:1st L treatment of Pancreatic Cancer
Positioning of TAIHO’s pipeline in pancreatic cancer treatment in Japan
Copyright©Taiho Pharmaceutical Co., Ltd.
1st line
2nd line
2013
GEM, S-1 GEM+S-1
GEM+Erlotinib
GEM, S-1 GEM+S-1
GEM+Erlotinib
GEM+ABI FOLFIRINOX GEM, S-1
S-1, GEM, GEM+S-1 S-1 GEM+S-1,GEM
Adjuvant S-1 GEM, S-1 GEM+S-1
72
73
Next Generation : Oncology Pipeline
At EORTC-NCI-AACR 2012, we presented exciting preclinical in vitro and in vivo data for 8 New Compounds, developed exclusively at Taiho Oncology. Copyright©Taiho Pharmaceutical Co., Ltd.
★Anti-Metabolites Drug discovery targeting “clear molecular target”
→ World first’s dUTPase inhibitor Drugs to “improve overall survival” and to “reduce
adverse events”
★Molecular-targeted drugs Targeting cancer driver gene Strongly inhibiting important cancer signaling pathways Overcoming drug-resistance
Discover unique molecules based on original chemistry
technology
Selective ATP competitive inhibitors Allosteric inhibitors Target molecule specific covalent binders
Copyright©Taiho Pharmaceutical Co., Ltd.
Strategy of Drug Discovery in Oncology
74
Direction of the Development of Novel Anti-Metabolites
Novel deoxy-uridine type antimetabolite
TAS-114 (dUTPase inhibitor) + S-1 or Cape
Launched in 1999
Launched in 1984
Launched in 1974
FT
UFT
TAS-102 FTD+TPI
Global PIII on going
PI on going
TS-1
“Maximizing TS inhibition by 5FU and reducing side effects”
“Maximizing TS inhibition by 5FU + additional antitumor effect of
5FU which incorporated into DNA due to the inhibition of dUTPase”
“Maximizing the antitumor effect of the compound which incorporated into DNA. ”
75
76
Target of antimetabolites and signaling transduction inhibitors
Copyright©Taiho Pharmaceutical Co., Ltd. DNA
PI3K
AKT
dUTPase
AuroraA
NR NR
TAS-115
TAS-116
TAS-114
TAS-2104
Nucleus
Blood vessel
Cell
Cell growth
TAS-2985
Tumor growth Metastasis
TAS-2913
AKT TAS-117
TAS-102
77 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-114 dUTPase inhibitor (First in class)
Mechanism of Action Key Data <Preclinical Study>
Concept: TAS-114 is a novel potent inhibitor of dUTPase with modest DPD inhibition. TAS-114 demonstrates the potential to improve the therapeutic efficacy of 5-FU-based chemotherapy. Clinical benefits : Potentiating anti-tumor activity of 5-FU based drug with dUTPase inhibition. DPD inhibition enables the dose reduction of Capecibatine and it would improve AE profiles caused by 5-FU higher dosing. (e.g. HFS). Status: Phase I Solid tumors JP/US/EU
TS inhibition
FBAL
DNA incorporation
of 5-FU
dUTPase DPD
Antitumor Activity
Survival
Adverse Events
Reduced
5-FU
Enhanced
TAS-114
0 10 20 30 40 50 60 70 80 90
100
0 50 100 150
Sur
viva
l rat
e (%
)
Time (days)
Capecitabine/TAS-114 (160/600)
Capecitabine(539) Control
78
TAS-115 VEGFR/MET dual inhibitor
Copyright©Taiho Pharmaceutical Co., Ltd.
Improved survival by TAS-115 in sunitinib*-resistant MET amplified
cancer dissemination models
Tumor vessels
Tumor
VEGFR signal * Sunitinib: approved VEGFR-targeted multi-kinase inhibitor
Concept : To aim at more potent curative effect via inhibiting both angiogenesis and tumor growth/metastasis with improved safety properties. Clinical benefits : A highly potent c-MET + VEGFRs dual inhibitor with preeminent safer profile. Potential therapeutic value in mono- or combination therapy. Status: Phase I Solid tumors JP
Mechanism of Action Key Data <Preclinical Study>
79
TAS-116
Copyright©Taiho Pharmaceutical Co., Ltd.
Highly potent, oral HSP90 inhibitor with unique tissue distribution properties
Mechanisms of Action Key Data <Preclinical>
Concept : Induction of multiple cancer-related HSP90 clients degradation provides an opportunity to treat several types of cancer. Compound profile : Novel structural class oral HSP90 inhibitor. Potential to maximize antitumor activity while minimizing adverse events such as ocular toxicity observed with other compounds of this class by unique tissue distribution. Clinical benefits : Effective in chemotherapy or molecular-targeted drug refractory/resistant tumors.
TAS-116 is highly distributed in sc tumor over retina in rat model
TAS-116 induces tumor regression in human AML xenograft model
80 Copyright©Taiho Pharmaceutical Co., Ltd.
Annals of Oncology(2010) 21; 683-691
p110 PTEN loss AKT
Protein synthesis Cell growth
Cell survival Proliferation Cell cycle
Metabolism
Control
Lapatinib 100 mg/kg Oral, BID, Day1-14
TAS-117 24 mg/kg Oral, QD, Day1-14
KPL4 xenograft mouse model Human breast cancer (Her2 gene amplification, PI3K mutation)
Mechanisms of Action Key Data <Preclinical Study>
TAS-117 Highly potent and selective AKT inhibitor
TAS-117
Concept : AKT regulates multiple cellular functions, including proliferation, survival and glucose metabolism. AKT activation involved in resistance to chemotherapies and targeted therapies by inhibiting apoptosis. Inhibition of AKT sensitizes tumor cells to above therapies Compound profile : Potent and highly selective oral allosteric AKT inhibitor. Good physicochemical and pharmacokinetic properties. Clinical benefits : Enhance antitumor effects of chemotherapies and targeted therapies
81 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-2104 Selective Aurora A inhibitor
Concept : Enhance anti-tumor efficacy of taxanes through activation of spindle assembly checkpoint, unique concept Compound Profile : Potent and selective Aurora A inhibitor. Unique prolife compared with competitor’s Aurora inhibitors (selective over Aurora B & C) Clinical benefits : Aurora A overexpression in various types of cancer with high frequency; breast, gastric, lung, prostate, ovarian, pancreatic etc. TAS-2104 has combination effect with paclitaxel, docetaxel, abraxane, cabazitaxel
Aurora A Inhibition causes activation of spindle checkpoint
Cells in mitotic phase
Paclitaxel Cell cycle arrest,
cell death Aurora A
overexpression Abnormal spindle
formation
Activation of spindle assembly checkpoint
82 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-2104 Key Data <Preclinical Study>
Enzyme IC50 (nM), human Aurora A 0.41
Aurora B 135 Aurora C 37
Paclitaxel
TAS(4days)
500
1000
1500
2000
0 5 10 15 20 Days
Tum
or V
olum
e (m
m3)
Control
Combo (2day)
Paclitaxel alone
Combo (4days)
TAS(2day)
500
1000
1500
2000
0 5 10 15 20 Days
Tum
or V
olum
e (m
m3)
Docetaxel alone
Control
Combo (2day)
Combo (4days)
Docetaxel
TAS(4days) TAS(2day)
Potent and selective Aurora A inhibition
Enhancement of anti-tumor efficacy in vivo
Paclitaxel Docetaxel
263 kinase panel
83
TAS-2913 Mutant Selective EGFR Inhibitor
Copyright©Taiho Pharmaceutical Co., Ltd.
6-12month
Molecular target drug≑Key
EGFR-TKIs potently inhibit muEGFR
Drug Resistant mutation
NSCLC 1st line
No response
Concept : The 1st generation EGFRi; Gefitinib and Erlotinib, have been found effective in treatment of a subset of NSCLC patients harboring activating mutations. Over time (median of 6-12 months), most tumors develop resistance to EGFR inhibitors by the development of drug-resistant mutations including gatekeeper T790M mutations. Compound profile : Potent and oral mutant EGFR (T790M) selective inhibitor. Clinical benefits: Effective in acquired resistance to EGFRi (Gefitinib and Erlotinib) in NSCLC.
84 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-2913 showed tumor growth inhibition on NCI-H1975 xenograft model and a significant prolongation of lifespan in treated mice.
0
2
4
6
8
10
12
0 5 10 15
Rel
ativ
e Tu
mor
Vol
ume
Day
Control
TAS-2913 25mg/kg/day
TAS-2913 100mg/kg/day
TAS-2913 200mg/kg/day
TAS-2913 Key Data <Preclinical Study>
Tumor growth inhibition Prolongation of lifespan
85 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-2985 Potent and irreversible FGFR inhibitor
Concept :FGFR is considered as a cancer driver gene as its gene abnormalities are reported in various types of cancers Compound Profile : First irreversible FGFR inhibitor which will be tested in clinic. Highly potent and selective. Selectively inhibits tumor growth of cancer cells with FGFR abnormalities. Clinical benefits : Tumors with FGFR gene abnormalities; gastric (undifferentiated, type IV), breast, lung (SCLC), bladder, endometrial, multiple myeloma
FGFR gene abnormalities in cancers Microenvironment
Translocation
Amplification Active
mutation
86 Copyright©Taiho Pharmaceutical Co., Ltd.
TAS-2985 Key Data <Preclinical Study>
Enzyme IC50 (nM)
FGFR1 5.2
FGFR2 1.7
FGFR3 2.0
FGFR4 13.0
Potent and selective inhibition of FGFR FGFR2
TAS-06-02985
-40
-20
0
20
40
60
80
100
120
140
0 0.3 1 3 10 30 100 300 1000 3000 10000
AZ-521 MKN-45 Kato III NCI-N87 AGS MKN-74 SNU-1 OCUM-2M OCUM-2MD3 SNU-16
Selective growth inhibition in vitro
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0 2 4 6 8 10 12 14 16Days
RTV
ControlTAS-06-02985 3mg/kg/day
Potent anti-tumor efficacy; tumor regression in gastric cancer model
87
Taiho Oncology http://www.taiho-oncology.com/
Copyright©Taiho Pharmaceutical Co., Ltd.
Tolvaptan
Development History of Tolvaptan
1991 Discovery
of non-peptidie
V1 receptor(2)
2009 US:Hyponatremia
EU:SIADH
2010 Japan: Cardiac
edema
2003 V2
antagonist inhibits PKD in vivo4)
2013 1980 1990 2000 2010
1979 Discovery of
V1/V2 receptor 1)
ADPKD
1983 Needs from clinicians
1984 Focus on vasopressin
1989 Lead compound
discovered
1991 synthesis of
tolvaptan 1992
Discovery of non-peptidid
V2 receptor3)
SALT (Hyponatremia)
1)Biochem.Soc.Trans. 7, 861 1979 2) Science 252 (5005) 572, 1991 3) Br.J Pharmacol 105; 787, 1992 4) Nature Medicine 9 (10), 2003
EVEREST (heart failure)
Quest (Cardiac edema )
TEMPO (PKD)
89
Mode of Action of Tolvaptan
90
2 actions of V2-Receptor
Tolvaptan(SAMSCA®) V2-Receptor Antagonist
1) Diuretic function that excretes water
only
Changes electrolyte concentration
• Hyponatremia • Hyponatremia by
SIADH
Decreases body fluid
• Cardiac edema • Hepatic edema
2) Inhibits kidney cyst formation by V2-
Receptor
ADPKD Autosomal Dominant
Polycystic Kidney Disease
Mode of Action of Tolvaptan
2 actions of V2-Receptor
Tolvaptan(SAMSCA®) V2-Receptor Antagonist
1) Diuretic function that excretes water
only
Changes electrolyte concentration
• Hyponatremia • Hyponatremia by
SIADH
Decreases body fluid
• Cardiac edema • Hepatic edema
2) Inhibits kidney cyst formulation by
V2-Receptor
ADPKD Autosomal Dominant
Polycystic Kidney Disease
91
Hyponatremia
92
Water Metabolism Control: urinary concentrating mechanism and drinking behavior
- Urinary concentrating mechanism (maintain body fluid): renal function and pituitary hormone AVP are involved.
- Renal function: Filtering blood approx. 150L/day at the glomerulus. 90% of filtered primitive urine is passively reabsorbed at Proximal convoluted tubule and 10% are actively reabsorbed at collecting duct by AVP. Urine volume is controlled 1-2L/day.
- AVP secretion: Controlled through hypothalamic osmoreceptor and baroceptor in carotid sinus, aortic arch and left atrium.
- Osmoreceptor: Promotes AVP secretion by plasma osmolarity increases. - Baroceptor: Promotes AVP secretion by low body fluid, low
blood pressure and low left atrial pressure.
- Secreted AVP binds to AVP2 receptor at collecting duct cells, increases inner-cell cAMP and promotes water reabsorption by activating aquaporin-2. This results in water reabsorption promotion, increase of body fluid, decrease of plasma osmolarity, inhibits AVP secreting activity.
carotid sinus・ aortic arch ・left
atrium
Hypothalamus osmoreceptor(perceives changes in
plasma osmolality)
AVP synthesis and secretion
collecting duct cells
AVP V2 receptor
Increase cAMP
aquaporin-2 expression
water reabsorption
plasma osmolality/
circulatory blood volume
baroceptor (reacts to decrease in
body fluid volume, blood pressure and left artial
pressure)
Hyponatremia - Condition that sodium level in the blood is under136mEq and excess of total body water for total sodium volume in the body.
- Symptoms:Functional disorder in CNS such as altered personality, lethargy and confusion. Stupor state, enhancement of neuromuscular excitability, twitch, lethargy and sometimes death occur due to the decrease in blood sodium level to under 115mEq. Sequela: Hypothalamic infarction, posterior pituitary infarction,brain-stem hernia.
Activates PKA
Characteristic of Tolvaptan
93
Most of the existing diuretics also work at other sites than distal tubule, excreting both sodium and water
Category Mode of Action Major drugs
Thiazide diuretics
• Act on Na+/Cl-cotransporter of distal convoluted tubule
• Excretion of Na+, K+, Cl-
• Trichlormethiazid • hydrochlorothiazide • Indapamide • Chlorthalidone, etc
Loop diuretics
• Act on Henle's loop Na+/K+/2Cl-cotransporter
• Excretion of Na+, K+, Ca2+, Cl-
• Furosemide • Torasemide • Azosemide • Bumetanide, etc
Aldosterone antagonist (K-sparing diuretic)
• Act on distal convoluted tubule and aldosterone receptor at collecting duct
• Promote Na+ excretion
• Spironolactone • Eplerenone
• Tubule Na+ channel inhibitor • Triamterene • Amiloride
Tolvaptan (V2-receptor antagonist) Tolvaptan shows water diuretic action without directly affecting the excretion of electrolytes by inhibiting of water re-absorption at renal collecting tubule.
The more use, the more imbalance of blood electrolytes
hemofiltration 150L/day
Thiazide diuretics
Aldosterone antagonist
Loop diuretics Aquaretics
(V2-receptor antagonist)
K-sparing diuretic
dist
al c
onvo
lute
d tu
bule
Glomus
Henle’s loop
Collecting duct
10% reabsorption 90%
reabsorption
Prox
imal
co
nvol
uted
tubu
le
Types of Hyponatremia
94
Na+ Na+ Na+Na+
Normal Condition A Condition B Condition C
Decrease of Na Decrease of body
fluid volume
•disease:vomiting, diarrhea, salt losing nephropathy, primary hypoadrenalism
Decrease of Na Body fluid
volume±10% •disease:SIADH, MRHE, Hypothyroidism, Glucocorticoid deficiency, hypopituitarism
Decrease of Na Increase of body
fluid volume
•disease: Renal failure, Heart failure, Cirrhosis, Nephrosis syndrome
extr
acel
lula
r flu
id v
olum
e
Na reabsorption disorder
Decrease of extracellular fluid
AVP supersecretion
AVP supersecretion
Increase of Na and water reabsorption
Collecting duct Blood
Tolvaptan Mode and Site of Action
95
H2O
GS ↑cAMP PKA
DNA
AQP2 H2O
V 2
AVP
AQP2
AQP-3&4 Na+
K+ H2O
Collecting duct Blood
H2O
Na+
K+
GS
DNA H2O
V 2
SAM
SCA
Vasopressin binds to
V2-receptor
Tolvaptan inhibits
binding to V2-receptor
Enhance water permeability and
reabsorption
Inhibits expression of aquaporin 2
Enhance water excretion
Nor
mal
Tr
eatm
ent b
y To
lvap
tan
AVP:arginine vasopressin、PKA:protein kinase A、AQP:aquaporin
Number of Patients
96
Hyponatremia(%HN<125)0.33 mil3)
Insufficient with existing drug
0.23 mil2)
Japan:Indication (cardiac edema) • Indication: Treatment of volume overload in
heart failure when adequate response is not obtained with other diuretics (e.g., loop diuretics).
• Dosage and administration:orally-administered 15mg/day, once daily
Hyponatremia(US)
chronic cardiac failure 1.04 mil1)
CHF Cirrhosis SIADH other
Data source: Otsuka Fact Book
SIADH (no. of patients in Europe)
Germany4) Spain5) UK5) Italy5) Nordic5)
3,591 2,472 974 682 528
Source 1)Decision Resource Patients Base, 2)OECD data 2008, 3)Verispan Database, 4)Netigate Research, Germany, May 2012, 4) Market Survey data, 5)Sales Provision
Sales of SAMSCA ¥100 mil
EU Launch
US Launch
Japan launch
5)
Mode of Action of Tolvaptan
97
2 actions of V2-Receptor
Tolvaptan(SAMSCA®) V2-Receptor Antagonist
1) Diuretic function that excretes water
only
Change electrolyte concentration
• Hyponatremia • Hyponatremia by
SIADH
Decrease body fluid
• Cardiac edema • Hepatic edema
2) Inhibits kidney cyst formation by V2-
Receptor
ADPKD Autosomal Dominant
Polycystic Kidney Disease
PKD (Polycystic Kidney Disease)
98
PKD :Polycystic Kidney Disease - Prevalence (There are 2 kinds of genetic conditions in PKD)
• ADPKD- Autosomal Dominant Polycystic Kidney Disease: Frequency of genetic mutation in one in 400 to 1000 people. 85% caused by genetic mutation of PKD1, 15% by PKD2 which is less severe.
- Estimated diagnosed patients: Japan: 31,0001), US: 116,0002), EU (G5): 143,0003) • ARPKD- Autosomal Recessive Polycystic Kidney Disease: This is a rare disease observed in infants
and pediatrics, causing death within 1 year from birth in most cases.
1) source: abstracted from application document approved as orphan drug in 2006 (reference: article by Prof. Higashihara) 2) source: Applied for orphan drug based on prevalence report by Prof. Willy of University of Rhode Island and approved on April 6. 3) EU G5 population 319 mil (source: World Bank 2011), number of patients are worked out 4.5 per 10,000. 4) source: research team of progressive renal impairment, Ministry of Health, Labour and Welfare
Characteristic of ADPKD - Genetic disorder - No symptoms until 30s to 40s in most of cases - Subjective symptoms: hematuria, abdominal pains, lumbar
backache, abdominal bloating, high blood pressure. - Formation and growths of a number of cysts in both kidneys.
Cysts growth causes decline in kidney function with aging. Half of the patients develop ESRD, an end-stage renal disease, and receive dialysis.
- Faster progression of disease is shown in patients with PKD1 genetic mutation than PKD2.
- Average age requiring dialysis: PKD1: 54.3, PKD2: 74.0 - Approx. 5-10 % of ESRD patients have ADPKD4) - Treatment: No available therapeutic drugs
father mother
Inheritance probability: 50%
ADPKD genetic form
Chromosome No.4 or No. 16.
Genetic mutation A a A a
a A A a a a A A
Genetic test ・ Genetic test is not conducted in Japan as a reliable method has not been established
Diagnosis of ADPKD
99 Source: Japanese Society of Nephrology Magazine (2011) Medical treatment policy of PKD, August 2010
Initial symptoms hematuria, abdominal pains, lumbar backache,
abdominal bloating, high blood pressure.
Family history No family history
Ultrasonography CT, MRI
More than 3 cysts in both
kidney
Under 15 Over 16
More than 3 cysts in both
kidney
More than 5 cysts in both
kidney
More than 5 cysts in both
kidney
imaging test
Diagnosed as ADPKD
exclusive diagnosis
Criteria of severity severity serum creatinine
1 Less than 2mg/dl
2 Less than 2~5mg/dl
3 Less than 5~8mg/dl
4 Over 8mg/dl without dialysis
5 Initiation of dialysis or renal transplant
• Judgment of severity is based on renal function and the volume of intracranial aneurysm, intracranial bleeding and abdominal bloating
Judgment of severity is based on renal function using serum creatinine level as a substitute, and adds the volume of intracranial aneurysm, intracranial bleeding and abdominal bloating.
Gene Responsible for ADPKD
100 Source: Naohiko Yokoyama, Cell Technology 2009, Nature Cell Biology (2010)
Primary cilium of kidney sensory organelle projected from ureter
Ca2+
PC1 Urine cilium
Ca2+
Gene Coding protein notes
PKD1 Polycystin-1 (PC1) 85 % abnormity in ADPKD patients
PKD2 Polycystin-2 (PC2) 15 % abnormity in ADPKD patients
<responsibility> 1) Ciliary action by urinary flow in renal tubule 2) Proteins in PC1 and PC2 respond and
controls inner-cell calcium 3) Controls the size of renal tubular cell
PC2
Inside of a cell
ureter renal papilla
renal medulla
renal cortex
kidney
glomus Bowman's capsule
Proximal convoluted
tubule
distal convoluted
tubule
Henle’s loop
Collecting duct
cut
To renal papilla scanning electron microscopical
image in urine cytology
Function of Renal Tubular Epithelial Cells
101
cilium
Urine
endoplasmic
reticulum
Normal
Urine PC1
PC2
↑cAMP PKA
Ca2+
Ca2+ 5’AMP
Ca2+ ERK
V2
AVP
adenylate cyclase
ATP
※ ERK:Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is expressed broadly in whole body cells. Called as MAP kinase.
enhance inhibit
nuclear transcription
factor DNA
Function of Renal Tubular Epithelial Cells
102
cilium Urine
endoplasmic
reticulum
PKD
Urine PC1
PC2
↑cAMP PKA
Ca2+
5’AMP
Ca2+ ERK
V2
AVP
adenylate cyclase
ATP
transcription factor
DNA
Growth of abnormal cells
Wallace DP et al., Biochim Biophys Acta (2011)
initiation development
※ ERK:Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is expressed broadly in whole body cells. Called as MAP kinase.
enhance inhibit
Function of Renal Tubular Epithelial Cells
103
cilium Urine
endoplasmic
reticulum
PKD
Urine PC1
PC2
↓cAMP PKA
Ca2+
5’AMP
Ca2+ ERK
adenylate cyclase
ATP
transcription factor
DNA
Inhibits growth of abnormal cells
V2
Tolvaptan
Source: Torres VE et al., N Engl J Med. 2012 ※ ERK:Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is
expressed broadly in whole body cells. Called as MAP kinase.
enhance inhibit
Source:Torres VE et al., N Engl J Med. 2012
Tolvaptan P-3 Study Result (TEMPO3:4)
Secondary Endpoint Annual rate of kidney-function decline
Primary Endpoint Annual rate change in the total kidney volume
Methods - Patients:Total kidney volume>750 mL, creatinine clearance>60 mL/min - Duration:36 months - Tolvaptan(N=961) ( Oral administration, daily morning and afternoon doses of 45 mg/15 mg, 60 mg/30
mg, 90 mg/30 mg), Placebo(N=484)
Slowed the increase in total kidney volume by approx. 50% Slowed decline in kidney function
104
Tolvaptan P-3 Study Result (TEMPO3:4)
105
Tolvaptan decreases the risks of multiple events with progression of disease
36% Decrease of Risk of Kidney Pain
61% Decrease of Risk of Worsening Kidney Function
Event Tolvaptan (N=961)
Placebo (N=483)
Thirst 55.3% 20.5% Polyuria 38.3% 17.2% Nocturia 29.1% 13.0%
Headache 25.0% 24.8% Pollakiuria 23.2% 5.4% Dry Mouth 16.0% 12.2%
Hypertension 32.2% 36.0% Renal Pain 27.0% 35.0%
Nasopharyngitis 21.9% 23.0% Back Pain 13.7% 18.2%
Increased creatinine level 14.0% 14.7% Hematuria 7.8% 14.1%
Urinary tract infection 8.3% 12.6% ALT elevation 0.9% 0.4% AST elevation 0.9% 0.4%
• white:over 15% AE in Tolvaptan group • yellow:over 10% AE in placebo group • gray:Serious AE more common in Tolvaptan group
Ophthalmology Business
Dry Eye
•Improves subjective symptoms such as foreign body sensation and pain in the eyes •Makes Innovation of dry eye treatment
Mucosta ophthalmic suspension
Glaucoma
•Prevents blindness of glaucoma patients with new mode of action
Dry AMD
•Provides a new drug for disease for which there is no treatment available
No. of patients; Dry eye (Japan 8 Mil, US 20 Mil), Dry AMD (US 10.5 Mil), Glaucoma (Japan 4.14 Mil, US 7.6 Mil)
Strategy of Ophthalmology Business In collaboration with Acucela (ophthalmology specialized R&D company),
Otsuka provides valuable novel products to clinical setting. Focus on total eye care
Anterior eye Posterior eye
Optic nerve
Macula
Retina
Sclera Conjunctiva
Iris
Pupil
Cornea
Lens
AC
PCIOL
OPA-6566 ACU-4429
107
Mucosta ophthalmic suspension (Generic name: rebamipide)
Active site
Pharmacol-ogical action
(1) Increases mucus (2) Repairs mucosa (3) Anti-inflammatory 1) Increases amount of gastric mucus 2) Repairs damaged gastric mucosa 3) Suppresses increase of inflammatory cytokines in gastric mucosal epithelial cells
1) Promotes production of corneal and conjunctival mucin 2) Ameliorates corneal and conjunctival epithelium injury 3) Suppresses production of IL-6 and IL-8 through TNF-α stimulation in corneal epithelial cells
Target diseases Gastric ulcer and gastritis Dry eye
Marketing status
• Best selling antiulcer drug in Japan (Rx no.)
• Marketed in 10 countries1
• Japan: Introduced in January 2012
• U.S.: Started P-3
Expanded Indications for Mucosta’s Action of Normalizing Mucosa
Gastric mucosa Ocular surface mucosa
1) 10 countries: Japan, South Korea, China, Indonesia, Malaysia, the Philippines, Thailand, Vietnam, Cambodia, and Egypt 109
Function and Structure of Tears Tears
• Secreted in a certain amount from the lacrimal glands at every blinking of the eyes (about 20-30 times per minute)
90% drains from the lacrimal canaliculi through nasolacrimal duct to the pharynx; 10% evaporates
Amount of tears covering the cornea and conjunctiva is 5-10 μl; protects the eyes by constantly coating the surface of the eyes through blinking
• Primary functions Prevents eye dryness; disinfects the eyes; cleans the eyes (dust, antigens,
allergens, etc.) - Supplies cornea and other tissues with oxygen and nutrition
22
Structure of tears • Tear film consists of three layers: lipid, aqueous, and mucin 1) Lipid layer: prevents evaporation of water; content is lipid film secreted from meibomian glands 2) Aqueous layer: primary component of tears; 95% water; moisturizes the
eyes; immune proteins such as IgA in this layer protect the eyes from bacteria
3) Mucin layer: stabilizes lacrimal fluid; allows even distribution of the tear as the cornea sheds water with a sticky substance; primary component is mucin secreted from conjunctival goblet cells
0.6μm
0.3μm
6μm
Main lacrimal glands Tear film layers
Mucin layer Aqueous layer Lipid layer
Meibomian glands
Structure of tears
Mucin Epithelial cells Microvilli
Flow of lacrimal fluid Lacrimal
gland Eyelid
Drains from lacrimal canaliculi
Lacrimal punctum
Lacrimal sac
Nasolacrymal canal
Evaporation 10%
110
Dry Eye
Definition of dry eye (corneal xerosis, keratoconjunctivitis sicca): A chronic disease of lacrimal fluid and corneal and conjunctival epithelium resulting from various causes and associated with eye discomfort and abnormal visual function 1.Dry spots appear when the amount of tears decreases. 2.Volume and quality of tears decrease 3.Dry spots remain and the cornea becomes exposed 4.The eyes stay dry
111
Dry eye
Destabilization of tear film
Damage of cornea and conjunctiva (decrease
in mucin)
Suppression of mucin secretion
Worsening of subjective symptoms
Chronic inflammation
Stress on cells by high osmolality, eyelids, and
external stimuli
Inflammation damages lacrimal glands, reducing tears
Mucin: high molecular weight glycoproteins - Secretory mucin: produced by epithelial cells, etc. - Membrane mucin: has a hydrophobic
transmembrane part and binds to cellular membrane
Conceptual diagram of lacrimal fluid layers Lipid layer
Aqueous/mucin layer
Secretory mucin and membrane mucin detached
from membrane surface
Membrane mucin
Epithelial cells
Conceptual diagram of dry eye
Membrane mucin
Epithelial cells
Aqueous layer caused by surface tension
Dry spot
Diagnostic Criteria of Dry Eye Diagnosis of dry eye Defini
tive Suspected
Suspected
Suspected
1) Subjective symptoms ✔ ✔ ✔
2) Lacrimal fluid abnormality1 ✔ ✔ ✔
a) Schirmer's test I (≤ 5 mm)
b) Tear film breakup time (B.U.T.) ( ≤ 5 seconds)
3) Corneal and conjunctival epithelium disorder2 ✔ ✔ ✔
a) Fluorescein staining score (≥ 3 < 9)
b) Rose bengal staining score (≥ 3 < 9)
c) Lissamine green staining score (≥ 3 < 9)
(2) Lacrimal fluid abnormality A) Schirmer's test I (tear quantity) Normal: ≥ 10 mm
Abnormal: ≤ 5 mm
B) Tear film breakup time (B.U.T.) (tear quality) - Determines the ability of tears to stay
together by measuring the time until the breakup of tear film on the corneal surface
Normal: ≥ 10 seconds
Abnormal: ≤ 5 seconds
112
Source: Shimazaki, Jun (Dry Eye Society). Journal of the Eye 24(2) 18) 2007
0-3 points
0-3 points
0-3 points
(1) Ocular subjective symptom severity - Determined using a subjective symptom
assessment scale - Eye pain, sensitivity to bright light, blurring of
eyes, foreign body sensation, feeling of dryness, photophobia, itching, eye discharge, feeling of dull pressure, eyestrain, eye discomfort, watery eye
1) Positive if either a) or b) fulfilled 2) Positive if any of a) to c) fulfilled
(3) Corneal and conjunctival epithelium disorder
- Cornea: mainly fluorescein - Conjuntiva: rose bengal, lissamine
green
Temporal conjunctiva
Nasal conjunctiva
Cornea
Mild dry eye
Severe dry eye
Major Causes of Dry Eye
Dry Eye Tear evaporation
Meibomian gland dysfunction
Decreased tear production
Sjögren syndrome
LASEK, PRK1)
Aging, other
Others
Lack of blinks
Allergic conjunctivitis
Contact Lenses
Abnormality of tear drainage process
Population
Prevalence(201)~302) mil) 16.7~25.0%
Diagnosed (1.33)~2 4) mil) 6.5%~10%
Treated (1.13)~1.44) mil) 86%~56%
1) Japan Ophthalmologists Association “IT eye syndrome and environmental factor” Research Group (leader: Shigeru Kinoshita, Professor, Ophthalmology, Kyoto Prefectural University of Medicine
2) Miki Uchino, Debra A, Schaymberg et al, Ophthalmology 2008; 115, 1982-1988
3) EPOCA Marketing survey 4) IMS 2009
Causes of Dry Eye Dry Eye Prevalence
Sales of Dry Eye Drugs (Japan)
DIQUAS Launch
1)PRK:Photorefractive keratectomy is one of a laser eye surgeries. PRK does not formulate flap, different from LASEK, it changes the shape of the anterior central cornea using an excimer laser.
MUCOSTA Launch
Source:IMS 2013 Dataview
100 mil yen
113
Well improved
7%
Improved50%
Neither34%
Not improved8%
Not improved at all1%
Source: Total Planning Center OSAKA corp “Survey of Dry Eye Patients” Feb, 2010 N: 500 (dry eye patients aged 20-60)
Improvement rate by eye drop treatment
No subjective feeling of
improvement 43.4%
Issues of Existing Therapy and Efficacy of Mucosta Ophthalmic Suspension No improvement in symptoms confirmed by eye drops which
works on tears
114
Efficacy of Mucosta Ophthalmic Suspension
115
Efficacy of Mucosta Ophthalmic Suspension
Decrease in mucin secretion causes imbalance of tears
• Improves hydration by tear stabilization • repairs scars on conjunctiva and cornea
by its anti-inflammatory effect • Improves ocular symptom severity
Conjunctiva
•Increases mucin on conjunctiva •Increases goblet cells
Cornea
•Increases mucin on cornea • Promotes corneal epithelial cells growth
Epithelium disorder
• Protection • Repair
Mucosta Ophthalmic Suspension
fluid fluid
mucin
corneal and conjunctival epithelial cell
fluid
mucin
Rebamipide P-3 Study (Japan)
116
4-week treatment (data collected after 2 weeks)
Screening 2 weeks (use of
artificial tears)
Hyalein Mini Ophthalmic solution 0.1% (6 times/day)
(N=95)
Primary endpoints •Corneal Damage: Fluorescein corneal staining score ( non-inferiority) •Conjunctival damage: Lisamingreen conjunctive staining score (superiority)
Secondary endpoints • Tear film break-up time • Schirmer's test dry eye related symptoms • Major symptoms:foreign body
sensation, dryness sensation, photophobia, eye pain, blurred vision
• Secondary symptoms: eye itching, eye discharge, dullness of the eye, asthenopia, eye discomfort, lachrymation
• Patients’ impression
Rebamipide Ophthalmic suspension 2.0% (4 times/day)
(N=93)
Follow- up
2 weeks
Mucosta Ophthalmic Suspension (rebamipide) P-3 Study
117
4 weeks treatment
Japan
Enrollment N=200
NCT01660256
Placebo Primary endpoint
(2, 4weeks) ・change in fluorescein
Rebamipide (4 times/day) 2% ophthalmic solution
Rebamipide (4 times/day) 2% ophthalmic suspension
4 weeks treatment US
Enrollment N=560
NCT01632137
Placebo
Primary endpoints (4weeks)
・change in fluorescein ・ocular symptom severity
Secondary endpoint (2weeks)
・change in fluorescein ・ocular symptom severity
Rebamipide (4 times/day) 2% ophthalmic suspension
ACU-4429
119
Age-related Macular Degeneration: AMD Age-related Macular Degeneration: AMD - AMD is a disease that macular in retina degenerates with aging. - Dry AMD: results from atrophy of the retinal pigment epithelial layer below the retina, which causes vision loss
through loss of photoreceptors in the central part of the eye. Progression is slow. - Wet AMD: causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the
choriocapillaris, through Bruch's membrane, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated. Progression is fast.
- Symptoms 1) Metamorphopsia: a type of distorted vision in which a grid of straight lines
appears wavy and parts of the grid may appear by distortion of retina caused by swelling of retina or gathering of liquid under retina. Surrounding parts are clearly seen since other parts except macular is not damaged.
2) Decreased vision, central scotoma: Damaged retina of macula causes central scotoma and decreased vision. Wet AMD progression is fast and in most cases, leads to severe ingravescence of visual acuity
Healthy macular region
macular region
Corpus Vitreum
Retina Optic nerves
Macular Degeneration
Drusen
Neovascular
Blue light
Bruch’s membrane
Retinal pigmented epithelium (RPE)
Neovascular Rods and cones
120
all-trans-retinol dehydrogenase
11-cis-retinal dehydrogenase (alcohol dehydrogenase) Isomerase
Function of Retinol
11-cis-retinal
11-cis-retinol all-trans-retinal
all-trans-retinol (Vitamin A)
phosphatidylethanolamine
A2-PE
VISUAL CYCLE
Biological function
Opsin Protein
Rhodopsin
Protein
• Cone cell: A fundamental cell of color vision, that develops visual pigment with different wavelength characteristic. Cone cell has a low luminous sensitivity and needs abundant light volume.
• Rod cell: Develops only single visual pigment and no color vision. Rod cell functions in the darkness as it has a high luminous sensitivity,
while cone cell doesn’t. This results that the shape of object can be clearly identified but not the color in the darkness, • Rhodopsin:Pigment in rod cell responsible for formulation of light receptor cell in retina and early stage of light recognition. The object
can be seen red-purple color in the light and black-white in the darkness, as rhodopsin mostly absorb aeruginous light. Rhodopsin fades immediately by sudden exposure to the light and recovery takes approximately 30 minutes.
β carotene
Conformational change of isomerization from cis-retinol in protein to all-trans-retinol is transmitted into cells by light stimulation, which transmitted to visual cell as signal of “light”.
• There are abundant alcohol dehydrogenase in retina that oxidizes retinol to retinal.
• Production of formaldehyde in retina, when consumed methanol, results in death of visual cell and blindness by its toxicity.
• Rhodopsin consists of vitamin A. Lack of vitamin A causes shortage of rhodopsin necessary for rod cell. The rod cell cannot receive a small light stimulation, resulting in the vision loss at night.
• Lack of rod cell causes night blindness as cone cell cannot receive light stimulation under low-intensity light.
42)(CHNHRCH −=
422 )(CHNH −
121
all-trans-retinol dehydrogenase
11-cis-retinal dehydrogenase Isomerase (RPE65)
Mechanism of AMD
11-cis-retinal
11-cis-retinol all-trans-retinal
all-trans-retinol
phosphatidylethanolamine
A2E biosynthesis
A2-PE
VISUAL CYCLE
A2E
lipofuscin
Nucleus
RPE
Nucleus
Phagosome contains
A2E
Drusen
atrophy, vestigium
blood vessel
formation
reactive oxygen species
Drusen
Neovascular
Ischemia chronic inflammation
WET type
DRY type
A2E accumulation
122
all-trans-retinol dehydrogenase
11-cis-retinal dehydrogenase Isomerase
MOA of ACU-4429
11-cis-retinal
11-cis-retinol all-trans-retinal
all-trans-retinol
phosphatidylethanolamine
A2E biosynthesis
A2-PE
VISUAL CYCLE
A2E
lipofuscin
Nucleus
RPE
Nucleus
Phagosome contains
A2E
Drusen
atrophy, vestigium
blood vessel
formation
reactive oxygen species
Drusen
Neovascular
Ischemia chronic inflammation
WET type
DRY type
A2E accumulation
ACU-4429
ACU-4429 » Decrease of the all-trans-retinal
reduces the biosynthesis and accumulation of A2E.
» Retinal isomerase is a rate-limiting, retina-specific visual cycle enzyme.
» Inhibition of isomerization slows the rate of the visual cycle turnover and reduces the level of all-trans-retinal available for A2E biosynthesis.
AMD Prevalence
123
Prevalence rate over 40yrs 10.4 mil (10.7%)
Early Dry AMD over 40yrs 8.8 mil(7.2%)
Late AMD over 50yrs 2.6 mil(2.6%)
Dry AMD over 50yrs 1.16 mil(1.2%)
Wet AMD over 50yrs 1.44 mil (1.5%)
Prevalence rate over 50yrs 15.3 mil (13.1%)
Early Dry AMD over 55yrs 12 mil(8.6%)
Late AMD over 50yrs 3.3 mil(2.8%)
Dry AMD over 50yrs 1.1 mil(0.9%)
Wet AMD over 50yrs 2.2 mil(1.8%)
USA
Europe
Prevalence rate over 40yrs 3 mil (4.2%)
Early Dry AMD over 40yrs 2.6 mil(3.6%)
Late AMD over 55yrs 0.48 mil(1.0%)
Dry AMD over 55yrs 0.11 mil(0.2%)
Wet AMD over 55yrs 0.37 mil(0.8%)
Japan
Source:Epi-database
It is important to provide drugs for both types of AMD as primary care.
Early AMD • No visual parafunction nor
subjective symptom • 視機能異常なし、自覚症状なし
視機能異常なし自覚症状なし
Geographic atrophy
Intermediate AMD • Visual parafunction and subjective
symptom for some patients
Advanced Dry AMD • Loss of macula visual cells
Wet AMD •Bleeding from undeveloped new blood vessel under the retina and retinal detachment
choroidal neovascular
Prevalence rate
Development Status
Electroretinogram - Contact lenses-type electrodes are placed on the cornea and retina is exposed to standardized stimuli.
The resulting signal is displayed showing the changes of electrical potentials between retina and cornea, investigating if the retina is normal.
- Damages to rod photoreceptors lead to impaired adaptation to darkness. Adaptation to darkness is defined as a recovery of photoreceptors in retina in the darkness after exposure to brightness. Adaptation to darkness may be a bio-assay of conditions in RPE, Bruch's membrane and choroid layer. Impaired adaptation to darkness could be a clinical marker for the diagnosis of those diseases states.
124
Inhibits isomerase by drug
Rate-limiting of visual cycle
Inhibits A2E generation
Inhibits geographic atrophy
development
Electroretinogram(ERG)
• Confirmed POC as
a biomarker
Phase Population Objective Dose/duration Status
P1a Healthy volunteers:N=46 (ACU-4429: N=38、Placebo:N= 8)
Safety, tolerability, PK/PD (ERG)
• formulation and duration:tablet , once/day • dose:2, 7, 10, 20, 40, 60, and 75 mg (or
placebo)
completed (2008)
P1b Healthy volunteers:N=40 (ACU-4429:N= 30、Placebo: N=10)
Safety, tolerability, PK
• Route and duration:tablet, once/day for 14 days
• dose:5 , 10, or 20 mg (or placebo)
completed (2009)
P2a Patients with Dry AMD:N=56 (ACU-4429:N= 42、Placebo: N=14)
Safety, tolerability, PK/PD (ERG)
• Route and duration:tablet, once/day for 3 months
• dose:5 , 10, or 20 mg (or placebo)
completed (2012)
Standardized stimuli
ACU-4429 Study
125
24 month treatment
P2/3
Enrollment N=440
NCT01802886
Placebo
Primary Endpoint ・Geographic atrophy scale
Secondary Endpoint ・BCVA 1) score
ACU-4429 (2.5 mg/day)
ACU-4429 (5 mg/day)
ACU-4429 (10 mg/day)
1)BCVA: best corrected visual acuity
90 days treatment
P-2a
Enrollment N=72
NCT01002950
Placebo
Primary Endpoint ・Safety Secondary Endpoint ・PK
Safety assessed until 1-2 weeks after treatment ACU-4429
(titration)
2 mg 5 mg 7 mg 10mg
OPA-6566
126
Glaucoma Glaucoma
- Caused by elevation of intraocular pressure to abnormal level by imbalance of aqueous humor production and outflow.
- Aqueous humor is generated at ciliary body, flows to anterior chamber then outflows from angle. Intraocular pressure is stabilized by flows of aqueous humor .
- Visual loss from optic nerve compression is caused by elevation of intraocular pressure by slow outflow of aqueous humor in anterior chamber.
127
Classification - Open angle glaucoma: The drainage system gradually become clogged over several months to
years. Impediment to drainage of aqueous humor causes gradual elevation of intraocular pressure while it is produced normally.
- Closed angle glaucoma: Onset of this kind of glaucoma is less frequent. The drainage system suddenly becomes clogged and causes acute elevation of intraocular pressure. Angle:angle at joint of iris and cornea around anterior chamber. Over 96% of aqueous humor outflows
from angle through trabecular pathway, canal of Schlemm or surface of ciliary body and choroidal vessels.
Symptoms - Open angle glaucoma: At the initial stage there is no pain or apparent symptoms but expansion of
visual field defect gradually develops over the years. Many patients are unaware of the disease until the last stage as it develops slowly. Vision will be lost peripherally, causing concentric contraction of visual field. The disease results in blindness if not treated early.
- Closed angle glaucoma: Causes severe pain, headache, vomiting, red eye, blurred vision and sudden decrease of vision with acute elevation of intraocular pressure. Vision may be seriously damaged if prompt treatment was not given when the symptoms occur.
- In both open angle and closed angle glaucoma, once the disease develops in one eye, it tends to occur on the other eye.
pressure and damage on the optic nerve
Normal flow of aqueous humor Closed angle glaucoma
Angle
Iris Ciliary body
Lens
Aqueous humor
Narrow angle
Lens
Retina
Cornea
Macula
Optical nerve
pressure
Closed angle glaucoma Open angle glaucoma
Aqueous Humor
drainage
Aqueous Humor
drainage
Angle
lens lens
Aqueous humor
Iris Iris
Aqueous humor
Ciliary body
Aqueous humor
Ciliary body
Early phase Mid phase Late phase
MOA of Anti-glaucoma Agents
128
Collecting duct
Canal of Shlemm
Extraocular Vessels
Uvea sclera
trabecula
pupil
posterior chamber
anterior chamber
iris
ciliary body
aqueous vein
episcleral vein
aqueous humor flow
production • Sympathetic stimulant • Sympatholytic drug • Carbonic anhydrase
inhibitor
• Parasympathetic stimulant • Sympathetic stimulant
• PG related drug • α1 blocker • Parasympathetic stimulant • Sympathetic stimulant
Aqueous humor outflow through canal of Schlemm Uveoscleral outflow
inhibit
increase
Outflow(10%)
Outflow (90%)
canal of Schlemm
trabecular pathway
iris
the vitreous
lens
aqueous humor flow
uveoscleral outflow
ciliary body
increase
Issues of existing treatment • Prostaglandin, which is widely used, has side effects
such as decrease intraocular pressure. There is no drug with high safety profile for long-term use.
Problems of glaucoma patients • Hyperemia, ocular itchy sensation • Poor compliance Expectations of doctors · New drug that acts on trabecular pathway · Drugs that increase aqueous outflow, not decrease
aqueous humor formation (normal function)
OPA-6566
129
New MOA:adenosine A2a receptor agonist · Acting on adenosine A2a receptor as agonist,
OPA-6566 decreases intraocular pressure by increasing aqueous outflow from trabecular pathway.
inhibition of aqueous humor formation at ciliary body
• Beta blocker/ anticholinergic agen
increase uveoscleral outflow
• Prostaglandin/Alpha- agonist canal of
Schlemm
trabecular pathway
iris
the vitreous
lens
aqueous humor flow
increase trabecular flow
OPA-6566
Prevalence and Market
130
Prevalence rate over 50 yrs 3 mil (3.1%)
Secondary glaucoma 0.3 mil(0.3%)
Primary glaucoma 2.75 mil(2.8%)
Open angle glaucoma 2 mil(2.0%)
Closed angle glaucoma 0.75 mil(0.8%)
Prevalence rate over 50 yrs 4 mil (3.4%)
Secondary glaucoma 0.36 mil(0.3%)
Primary glaucoma 3.7 mil(3.1%)
Open angle glaucoma 2.8 mil(2.4%)
Closed angle glaucoma 0.9 mil(0.8%)
USA
Europe
Prevalence rate over 50 yrs 3.1 mil (5.6%)
Secondary glaucoma 0.2 mil(0.4%)
Primary glaucoma 3 mil(5.4%)
Open angle glaucoma 2.5 mil(4.5%)
Closed angle glaucoma 0.47 mil(0.8%)
Japan
source:Epi-database
視機能異常なし自覚症状なし
地図状萎縮 脈絡膜新生血管
Prevalence Rate
Market Growth in 7 Major Countries Market size:$5,200 Mil(2010)
$ Mil
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