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LAO Aripiprazole OW Long Acting Oral aripiprazole Once Weekly An alternative option to Long Acting Injectables (LAI) in the rapidly expanding market for.

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Presentation on theme: "LAO Aripiprazole OW Long Acting Oral aripiprazole Once Weekly An alternative option to Long Acting Injectables (LAI) in the rapidly expanding market for."— Presentation transcript:

1 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

2 Preventing Relapse in Schizophrenia and Bipolar Disorders with oral once-weekly, fully medically-supervised therapy The total antipsychotic market in 2013 is US$ 24 billion; Zysis forecasts a 3- 4.2% 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 Opportunity Summary

3 Aripiprazole is the market leader in $24 Billion world wide Atypical Antipsychotic Market ZPREXA/ olanzapine 18% INVEGA/ paliperidone 3% INVEGA/ SUSTENNA 3% RISPERDAL/ risperidone 5% RISPERDAL CONSTA 7% GEODON/ Ziprasidone 5% Other 5% SEROQUEL/ quetiapine 26% ABILIFY/ Aripiprazole 30% $7.2 Billion $7.2 billion 3

4 Targeting unmet needs in schizophrenia – non-adherence Non-adherence rates are extremely high with schizophrenia therapy –~75% of patients with schizophrenia are non-adherent within 2 years of being discharged from hospital 1 The consequences of non-adherence are medically (and economically) severe –69% of patients with poor adherence suffer a relapse 2 –(Only 18% of patients with good adherence suffer a relapse 2 ) Poor adherence is a predictor of poorer outcomes –Poorly adherent patients are hospitalised more often, and for longer periods of time 3,4 Zysis is developing a true aripiprazole OW oral formulation 4 References 1. Weiden PJ et al. Psychiatr Serv, 1995; 46: 1049–1054 2. Morken G et al. BMC Psychiatry, 2008; 8: 32–38 3. Valenstein M et al. Med Care, 2002; 40: 630–639 4. Gilmer TP et al. Am J Psych, 2004; 161: 692–699

5 LAOs – An Alternative to LAIs for Psychotic Relapse Prevention 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 LAO Aripiprazole – With Medically Supervised Dosing once weekly - targets and prevents relapse before resorting to LAI therapy 5

6 How can we scientifically achieve aripiprazole oral OW? Three key characteristics define the strategy : - 6 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

7 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

8 Steady-state pharmacokinetic comparisons Various IR and SR dosing regimens 8 100 mg IR OW (for illustrative purposes) 140 mg SR-A OW 30 mg IR OD15 mg IR OD10 mg IR OD 60 mg SR-A OW100 mg SR-A OW

9 Zysis Phase II study design 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 Comparing the receptor occupancy of aripiprazole OW with OD Dose-ranging PET study in schizophrenia patients 9

10 Zysis Phase III study design Phase III optionsPatient numbers Cost [USD] Time to regulatory submission [years] No Phase III study001.5 Single Phase III study of 6 weeks’ drug treatment 62512.5 million3 Single Phase III study of 12 weeks’ drug treatment 62518 million3 Two Phase III studies of 12 weeks’ drug treatment 1,25036 million4 Demonstrating maintenance of efficacy and improved relapse prevention for OW vs OD Several possible options for Phase III/clinical trials to launch 10 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

11 Zysis Phase III study design 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 open- label 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. Demonstrating maintenance of efficacy for OW vs OD Topics under consideration ahead of EOP2 meeting with FDA 11 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

12 Zysis IP 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 Aripiprazole oral OW has a strong intellectual property position 12

13 Fully Medically Supervised Dosing Fully Medically Supervised dosing ensures patients take every dose without forgetting and still demonstrates cost effective, health economic superiority to all other therapies. LAO Aripiprazole OW – Targeting Psychotic Relapse 13 Sustained Release Formulation 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. Molecule The antipsychotic Aripiprazole has the best efficacy/side effect profile of all the atypicals

14 Fully Medically Supervised Dosing eradicates all potential issues that may arise with a OW Oral product 14 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 pharmaco- economic basis justifies a higher price than generics albeit much more cost effective than LAIs 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.

15 Launch Product Profile for LAO Aripiprazole OW FeatureBenefit 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 USD 9 is justified by modelling and data generated through relapse rate improvement pricing study 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 15

16 Pricing and cost-effectiveness 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 Key concepts to build a strong cost-effectiveness argument The argument justifying the price of LAO Aripiprazole OW: 16

17 Modelling Medically Supervised Dosing for Aripiprazole OW Cost benefits are achievable with medically supervised dosing over all other therapies 17

18 LAO Aripiprazole OW – Market Share Analysis Maintenance Market Segment* 18 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) Disease severity Moderate ~65% Mild ~25% Severe ~10% Adherent ~25% Disease severity and prevalence Few Relapses ~10% Repeat Relapses ~55% Frequent Relapses ~10% Oral Once-Daily Long Acting Oral Long Acting Injection *Maintenance Market Segment represents 70% of total schizophrenia market

19 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 : 19 * 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.

20 Market Penetration Upside Sales Analysis 20 Once the Supervised Dosing strategy has achieved market acceptance… Why wait for multiple relapses? ‘To be used just before LAIs’ Becomes ‘To be used after first relapse, as non-adherence is clearly now an issue’ First Relapse Second Relapse Third Relapse Fourth Relapse (or more) Re-stabilised 2-3 months in hospital Non-adherence re-emerges Non-adherence re-emerges Non-adherence re-emerges Last Resort The LAI

21 Zysis 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 Management Team 21


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