LAO Aripiprazole OW
Long Acting Oral aripiprazole Once Weekly
An alternative option to Long Acting Injectables
(LAI) in the rapidly expanding market for
prevention of psychotic relapse
Preventing Relapse in Schizophrenia and Bipolar Disorders
with oral once-weekly, fully medically-supervised therapy
Opportunity Summary
•
The total antipsychotic market in 2013 is US$ 24 billion; Zysis forecasts a 34.2% market share by value with peak year sales of ~1.4 billion USD.
•
Our Long Acting Oral aripiprazole Once Weekly product with medically
supervised dosing is intended to reduce relapse rate in the mild to moderate
maintenance population of schizophrenia patients who require approaches
to increase adherence but who are not ready yet for the highly invasive and
extremely expensive option of the long acting injectable (LAI).
•
An FDA New Drug Application submission is anticipated within 4 years, with
a total investment of approximately US$23 million for clinical trial work
required to reach this point. An open-label extension study (US$10 million)
will be undertaken as part of the phase III program for pricing justification to
demonstrate similar relapse rate improvements to LAIs.
•
This is a low-risk project with a high probability of technical success given
the now established pharmacokinetic (brain & plasma), safety and efficacy
profile of aripiprazole in schizophrenia.
2
Aripiprazole is the market leader in $24 Billion world wide
Atypical Antipsychotic Market
INVEGA/
SUSTENNA
3%
INVEGA/
paliperidone
3%
RISPERDAL/
risperidone
5%
RISPERDAL
CONSTA
7%
ABILIFY/
Aripiprazole
30%
$7.2
Billion
$7.2
billion
GEODON/
Ziprasidone
5%
SEROQUEL/
quetiapine
26%
ZPREXA/
olanzapine
18%
Other 5%
3
Targeting unmet needs in schizophrenia – non-adherence
Zysis is developing a true aripiprazole OW oral formulation
• Non-adherence rates are extremely high with schizophrenia therapy
– ~75% of patients with schizophrenia are non-adherent within 2
years of being discharged from hospital1
• The consequences of non-adherence are medically (and
economically) severe
– 69% of patients with poor adherence suffer a relapse2
– (Only 18% of patients with good adherence suffer a relapse2)
• Poor adherence is a predictor of poorer outcomes
– Poorly adherent patients are hospitalised more often, and for
longer periods of time3,4
References
1. Weiden PJ et al. Psychiatr Serv, 1995; 46: 1049–1054 3. Valenstein M et al. Med Care, 2002; 40: 630–639
2. Morken G et al. BMC Psychiatry, 2008; 8: 32–38
4. Gilmer TP et al. Am J Psych, 2004; 161: 692–699
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LAOs – An Alternative to LAIs for Psychotic Relapse
Prevention
LAO Aripiprazole – With Medically Supervised Dosing once weekly targets and prevents relapse before resorting to LAI therapy
• First-in-class antipsychotic therapy for orally dosed
relapse prevention
• Better outcomes for doctors & patients – fewer relapses
• Direct cost savings for payers - reducing relapse &
medical staff costs
• An earlier and more cost effective alternative to LAIs
5
How can we scientifically achieve aripiprazole oral OW?
Three key characteristics define the strategy : -
Gastrointestinal compartment
Slow release from formulation &
absorption over 24 to 48hours
Plasma compartment
Long plasma aripiprazole half-life
(3 days)
Brain compartment
Very slow aripiprazole dissociation
from the D2/D3 receptors in the
striatum
6
Clinical testing of aripiprazole oral OW
Mean pharmacokinetic performance demonstrates ideal SR profile
Healthy volunteers for SR-A and SR-B vs immediate release (IR) reference
7
Steady-state pharmacokinetic comparisons
Various IR and SR dosing regimens
30 mg IR OD
15 mg IR OD
10 mg IR OD
60 mg SR-A OW
100 mg SR-A OW
140 mg SR-A OW
100 mg IR OW
(for illustrative purposes)
8
Zysis Phase II study design
Comparing the receptor occupancy of aripiprazole OW with OD
Dose-ranging PET study in schizophrenia patients
•
This study is a randomised, single-centre, multiple group study in 30 schizophrenia patients
(as defined by the DSM-IV-TR criteria)
•
The primary objective of the study is to determine which dose
of aripiprazole OW matches D2 and D3 receptor occupancy in the striatum region of the
brain at trough (7 days post-dose), compared to aripiprazole OD.
•
All 30 patients will be treated with 15 mg aripiprazole OD for three weeks (steady state)
followed by PET imaging of receptor occupancy. After the run-in period, the patients will be
randomized to one of the following three groups:–
Group 1: 60 mg aripiprazole OW (n=10)
–
Group 2: 100 mg aripiprazole OW (n=10)
–
Group 3: 140 mg aripiprazole OW (n=10)
•
After six weeks treatment with the OW regimen, PET imaging will be repeated at day 42
and compared to the IR OD findings.
•
Study will be undertaken with Professor Gerhard Gründer and Dr Wolfgang Greb at
PharmaImage
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Zysis Phase III study design
Demonstrating maintenance of efficacy and improved relapse
prevention for OW vs OD
Several possible options for Phase III/clinical trials to launch
Cost
[USD]
Time to regulatory
submission
[years]
0
0
1.5
Single Phase III study of 6 weeks’
drug treatment
625
12.5 million
3
Single Phase III study of 12
weeks’ drug treatment
625
18 million
3
1,250
36 million
4
Phase III options
No Phase III study
Two Phase III studies of 12 weeks’
drug treatment
Patient numbers
Likely Phase III strategy
An Open-Label Extension phase will be required for any phase III program to gather
relapse rate improvement data for pricing purposes
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Zysis Phase III study design
Demonstrating maintenance of efficacy for OW vs OD
Topics under consideration ahead of EOP2 meeting with FDA
•
The primary efficacy endpoint of the study is the change in PANSS total
score from baseline. All participants will be eligible to continue in an openlabel phase and receive aripiprazole OW for an additional 12 months.
•
The objective of the extension phase of the study is to assess the safety
and long-term durability of effect for aripiprazole OW.
•
Three week run-in period for aripiprazole IR once daily before switch to
aripiprazole OW to match phase II study design.
•
The effect of improved adherence strategies will be investigated as part of
the extension study.
Zysis regulatory strategy was validated by the phase III study design announced
by Alkermes in December 2011 for ALKS 9070, a prodrug designed to provide
patients with once-monthly dosing of aripiprazole
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Zysis IP position
Aripiprazole oral OW has a strong intellectual property position
•
Zysis filed a UK patent application on the SR aripiprazole formulation, which
includes the OW positioning, with a priority date of 26 September 2006. A
Patent Cooperation Treaty (PCT) application was filed 12 months later.
•
The patent application entered the national phase of prosecution in key
markets (US, Europe, Japan, Israel, Australia, Canada and South Korea)
with amended claims in March 2009
•
Granted patent with broad claims in :– US (September 2013)
– Europe (January 2012)
– Israel (August 2012)
– Australia (August 2013)
•
Ongoing prosecution in Canada, South Korea and Japan
12
LAO Aripiprazole OW – Targeting Psychotic Relapse
Molecule
Sustained
Release
Formulation
Fully Medically
Supervised
Dosing
The antipsychotic Aripiprazole has the best efficacy/side
effect profile of all the atypicals
Our patent protected sustained release formulation allows
for oral once weekly dosing to become a reality by
increasing drug residence time at the site of action.
Fully Medically Supervised dosing ensures patients take
every dose without forgetting and still demonstrates cost
effective, health economic superiority to all other
therapies.
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Fully Medically Supervised Dosing eradicates all potential issues
that may arise with a OW Oral product
Issue
• Once Weekly dosing can be more difficult to remember than once daily dosing
Solution
• Medically supervised dosing takes away the responsibility of remembering from patients
ensuring continuous therapy provision (in common with LAIs)
Issue
• Many psychotic patients are on several once daily medications.
Solution
• Medically supervised dosing ensures that at least the most important therapy (the anti-psychotic)
is taken and reduces the number of drugs the patient has to remember to take once daily.
Issue
• A OW product is simply a convenience product with no real therapeutic benefit so price has to be
at generic level
Solution
• Medically Supervised Dosing ensures Relapse Rate Improvement which on a pharmacoeconomic basis justifies a higher price than generics albeit much more cost effective than LAIs
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Launch Product Profile for LAO Aripiprazole OW
Feature
Benefit
Long acting oral – otherwise as effective/safe etc as the
once daily oral
Patients only have to take their medicine orally, once
weekly
Structures are in place to support medically supervised
patient dosing in the clinic & by medical staff in the
community
The responsibility of remembering to take the treatment
is taken out of the patients hands using existing care
platforms
Observing the patient take the therapy can be done in
the clinic by a minimally-trained person
Requirements to monitor dosing in the clinic is not
onerous – no litigation requirement for two in surgery
cost, shorter paper trail, no needle disposal cost, no
secure storage cost, no refrigeration cost, no waiting in
surgery after dosing…all easier than a LAI
One year study shows relapse rate reduction
eg. from 45% to 20% for medically observed once
weekly dosing
Patients stay out of hospital and symptoms are under
control
HE modelling demonstrates substantial direct & indirect
HE benefit priced at USD9 per day
Patients on oral OW therapy cost less overall, long-term
to treat
USD 9 is justified by modelling and data generated through relapse rate
improvement pricing study
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Pricing and cost-effectiveness
Key concepts to build a strong cost-effectiveness argument
The argument justifying the price of LAO Aripiprazole OW:
• Open label extension study will be added onto the Phase III program to
investigate relapse rate improvement and generate the data for LAO
Aripiprazole OW pricing arguments
• Risperdal depot achieved 17% relapse rate in a similar open label
extension phase study
• LAO Aripiprazole OW should achieve at least an equal relapse rate to
Risperdal Depot
• Phase ii independent Health Economic Modelling justifies a price of
USD 9 per day at a relapse rate of 17% per year
Precedent is set with payers - LAIs use improvement in relapse rate to justify
premium pricing
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Modelling Medically Supervised Dosing for Aripiprazole OW
Cost benefits are achievable with medically supervised dosing over all other
therapies
Cost Savings Per Patient Per year
USD
LAO Aripiprazole OW with medically supervised dosing at 9 USD/day
Long-acting injectable Aripiprazole once monthly
Long-acting injectable Paliperidone once monthly
Long-acting injectable Risperidone twice monthly
Long-acting injectable Generic once monthly
Immediate release oral Branded daily therapy
Immediate release oral Generic daily therapy
$5,899
$4,804
$4,648
$889
$3,712
$427
The costs of Schizophrenia therapy are driven by the cost of relapse
A treatment that improves relapse rates can justify a higher price (cf LAI Aripiprazole OM)
17
LAO Aripiprazole OW – Market Share Analysis
Maintenance Market Segment*
Disease severity and prevalence
Disease severity
Mild ~25%
Adherent
~25%
Oral Once-Daily
Moderate ~65%
Few Relapses
~10%
Repeat Relapses
~55%
Long Acting Oral
Severe ~10%
Frequent Relapses
~10%
Long Acting Injection
LAO Aripiprazole OW Conservative Scenario Market Share
10% of Repeat Relapses, or 5.5% of *Maintenance Market Segment
Market Share of Total Schizophrenia Market = 3-4.2% (vol or pats)
*Maintenance Market Segment represents 70% of total schizophrenia market
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Forecast Sales
Assuming Relapse Rate Improvement Data justifies 9 USD per Day
Sales for a product priced at USD 9 Per Day, with a 3 - 4.2% market
share:
2019
2020
EU Schizophrenia patients (m)
US Schizophrenia patients (m)
EU BP1 patients (m)
US BP1 patients (m)
EU Penetration of Ari OW (%)
US Penetration of Ari OW (%)
EU patients treated with Ari
OW (k)
US patients treated with Ari
OW (k)
3.13
3.57
3.13
3.59
0.005
0.010
Total patients treated
Price per patient per year
Gross Sales ($m) *
2021
2022
2023
2024
2025
2026
0.010
0.020
3.14
3.61
3.14
3.61
0.015
0.025
3.14
3.63
3.14
3.63
0.020
0.030
3.14
3.65
3.14
3.65
0.025
0.035
3.14
3.68
3.14
3.68
0.030
0.040
3.15
3.70
3.15
3.70
0.030
0.042
3.15
3.72
3.15
3.72
0.030
0.042
15.66
31.35
94.11
125.56
157.06
188.61
188.74
188.87
35.68
71.79
180.54
217.95
255.80
294.10
310.66
312.52
51.34
2785
103.13
2785
274.65
2785
343.51
2785
412.87
2785
482.71
2785
499.40
2785
501.39
2785
142.97
287.19
764.79
956.55
1149.67
1344.15
1390.62
1396.18
* Sales in Major Depressive Disorder (MDD) are not included in this analysis however Aripiprazole Once Daily has an indication for this
condition and off-label MDD sales are anticipated for Aripiprazole OW.
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Upside Sales Analysis
Once the Supervised Dosing strategy has achieved market acceptance…
Why wait for multiple relapses?
Last Resort
The LAI
Non-adherence
re-emerges
Non-adherence
re-emerges
Non-adherence
re-emerges
Re-stabilised
2-3 months in
hospital
Fourth Relapse (or more)
Third Relapse
Second Relapse
First Relapse
‘To be used just before LAIs’ Becomes ‘To be used after first relapse, as non-adherence is clearly now an issue’
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Zysis
Management Team
•
Dr Peter Cozens, Non-Exec Chairman
– More than 30 years’ experience in licensing
– Chairman of the Intellectual Property Advisory Committee of the UK BIA
•
Dr Ian Wilding, VP – Development
– Founder of Pharmaceutical Profiles, a Phase 1 CRO
– Leading authority in drug delivery and formulation development, with 250 patents
and publications
– Advisor to US FDA
•
Mr Russ Pendleton, VP – Commercial
– 14 years in big pharma Sales & Marketing, including the global launch of three
psychiatric drugs – Global Brand Manager – Seroquel, AZ
– Founder of Cortex Congress Neuroscience Conference company; 12 years of
establishing and managing conferences in psychiatry and neurology
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