Prosensa Corporate Overview Jefferies Healthcare Conference London, UK November 19, Hans Schikan, CEO

Transcription

1 Prosensa Corporate Overview Jefferies Healthcare Conference London, UK November 19, 2014 Hans Schikan, CEO

2 Forward-Looking Statements This presentation may contain statements that constitute forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of Forward-looking statements are statements other than historical fact and may include statements that address future operating, financial or business performance or Prosensa s strategies or expectations. In some cases, you can identify these statements by forward-looking words such as may, might, will, should, expects, plans, anticipates, believes, estimates, predicts, projects, potential, outlook or continue, and other comparable terminology. Forward-looking statements are based on management s current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include, but are not limited to, the timing and conduct of clinical trials of drisapersen and Prosensa s other product candidates, plans to pursue research and development of product candidates for DMD and other indications, the clinical utility of Prosensa s product candidates, the timing or likelihood of regulatory filings and approvals, Prosensa s intellectual property position, expectations regarding payments under Prosensa s collaborations and Prosensa s competitive position. These risks and uncertainties also include those described under the captions Risk Factors and Management s Discussion and Analysis of Financial Condition and Results of Operations in Prosensa s Annual Report on Form 20-F and other filings with the Securities and Exchange Commission. Forward-looking statements speak only as of the date they are made, and Prosensa does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. All forward-looking statements are qualified in their entirety by this cautionary statement.

3 Our Mission To develop innovative, RNA-modulating therapeutics to fill unmet medical needs for patients with rare genetic diseases 2

4 Corporate Highlights Rare disease company based in the Netherlands, listed on Nasdaq (RNA) Largest pipeline and clinical program in Duchenne muscular dystrophy (DMD) NDA submission under accelerated approval for drisapersen underway, followed by MAA in EU for conditional approval Orphan Drug status for 6 DMD compounds FDA Breakthrough Therapy Designation for drisapersen Solid intellectual property position Management with extensive experience in commercializing orphan drugs Cash position (Sept 30, 2014): EUR 62M; Cash burn (FY-2013): EUR 22M; (H1-2014): EUR 12.7M; YE 2014 cash balance guidance: EUR 52-54M 3

5 Our Science - RNA Modulation Technology platform enables us to design sequences of nucleotides that bind to specified regions of pre-mrna which may induce exon skipping or exon inclusion, reduce mutated toxic RNA or protein, remove specific protein domains or block protein expression 4

6 R&D - Largest Pipeline in DMD Indication Compound Discovery Pre-Clinical Phase I/II Phase III Duchenne Muscular Dystrophy Huntington s Disease Myotonic Dystrophy Drisapersen PRO044 PRO045 PRO053 PRO052 PRO055 PROSPECT PRO289 PRO135 13% of DMD patients 6% of DMD patients 8% of DMD patients 8% of DMD patients 4% of DMD patients 2% of DMD patients 5

7 Duchenne Muscular Dystrophy (DMD) Severely debilitating and invariably fatal progressive neuromuscular disease X-linked, rare genetic disease Rapid progression of muscle degeneration 75,000 patients in addressable populations Age Evolution of clinical symptoms of DMD walking problems wheelchair - skeletal deformity very limited use of arms ventilation at night ventilation 24h death 6

8 DMD Natural History and Endpoints 6MWT is a validated functional endpoint for DMD and other rare diseases Age & baseline walking ability are important variables that determine decline in the ability to walk as measured by 6MWT* Recent publication suggests clinically meaningful change in walking ability, as measured by 6MWT, to be in the range of meters* Creatine Kinase (CK) is a marker of muscle damage - DMD patients have elevated levels of CK in their blood serum Prosensa has completed enrollment with 269 patients in an observational study to characterize the natural history and progression of DMD in addition to capturing potential biomarkers * McDonald, Muscle & Nerve

9 6-Minute Walk Distance, m Functional Outcome - 6MWT Conceptual Representation Based on natural history, DMD boys lose approximately meters in 6MWT per year Early intervention Late intervention Approx. age years 8

10 Lead Compound - Drisapersen 20-mer Antisense Oligonucleotide (AON) with specific binding to exon 51 of dystrophin gene pre-mrna Administered by once weekly subcutaneous injection (6mg/kg) May address up to 13% of all DMD patients Granted orphan drug status in US, EU, Japan, Australia Breakthrough Therapy designation granted by the FDA NDA submission initiated under rolling review and Fast Track status Issued patents include US patent expiring 2023; EU patent expiring

11 Drisapersen Clinical Program More than 300 patients and over 450 patient treatment years in global clinical program Study Phase Study design N Status CLIN-02 DMD Phase I/II + Extension Open label, repeat dose escalation (extension phase 6 mg/kg/wk intermittent); 12 Complete; extension ongoing DEMAND I DMD Phase I Placebo-controlled, pharmacokinetics/safety; single dose 20 Complete DEMAND II DMD Phase II Exploratory placebo-controlled, dose regimen comparison; ex-us, 24/48 wks 53 Complete DEMAND III DMD Phase III Randomized, placebo-controlled, confirmatory study; global, 48 wks 186 Complete DEMAND IV DMD Phase II/III Extension Open label, extension study for DEMAND II) & DEMAND III ; 96 wks 234 Closed DEMAND V DMD Phase II Exploratory placebo-controlled, dose-comparison; US only, 24 wks 51 Complete DMD Phase II/III Extension Open-label, extension study for US & Canadian subjects from DEMAND III, IV, V 72 Recruiting 10

12 Overview of Supportive Studies + Analyses Clinically meaningful treatment difference across program; DEMAND III outlier *pb = placebo (DEMAND IV: pb/delayed treatment); dr = drisapersen 6 mg/kg; Tx difference on 6MWD; not all analyses shown 11

13 Distance walked (m) Long Term Study DMD Efficacy results up to 3.4 years (177 weeks) appear to show delay of disease progression N=10 Age at week Weeks 8 weeks on 4 weeks off Mean age is 12.9 years at 177 wks

14 Distance walked (m) Long Term Study DMD Long-term data suggest stabilization on 6MWT Mean change from baseline: +33 m [Median change from baseline: +64 m] Ambulant boys: N=8 Mean change from baseline: -25 m [Median change from baseline: +8 m] All boys: N=10 Weeks 13

15 Functional Outcome - 6 Minute Walk Test DMD patients lose approximately m in 6MWD in 1 year, 150 m in 3 years Study Design Δ 6MWT (m) SD (m) Study (years) McDonald 2010¹ Natural History Ataluren 2010¹ Placebo arm Mazzone 2011² Natural History Goemans 2012¹ Natural History McDonald 2013² Natural History Mazzone 2013² Natural History ⁴ Goemans 2013² Natural History Pane, 2014³ Natural History ¹All ages; ²Age >7, ³Age 7, ⁴ All patients in study N 14

16 Placebo Controlled Studies - 6MWD Two placebo-controlled studies show treatment benefit on 6MWD Δ6MWD = +35m p= m (n=18) Placebo Δ6MWD = +27m p= m (n=18) Drisapersen 6 mg/kg/week Δ6MWD = +31m p= m (n=36) 20-4m (n=18) DEMAND II (DMD114117) (25 week endpoint) -11m (n=16) DEMAND V (DMD114876) (24 week endpoint) -11m (n=34) (11) DEMAND II + DEMAND V (DMD DMD114876) (post-hoc analysis 24/25 weeks) 15

17 DEMAND III by Age and Baseline 6MWD Visit Treatment N n All Subjects Week 48 7 years at baseline Week 48 Unadjusted mean baseline value (sd) Adjusted mean (se) Placebo (92) -53 (10) Treatment difference (m) 95% CI P-value Drisapersen (96) -42 (7) +10 (-15,35) Placebo (67) -25 (11) Drisapersen (65) -4 (9) +21 (-7,50) > 7 years at baseline Week 48 Placebo (101) -83 (16) Drisapersen (107) -76 (11) +7 (-29,43) > 7 years at baseline, and baseline 6MWD 300m and 450m Week 48 Placebo (34) -67 (20) Drisapersen (42) -42 (13) +25 (22,72) Model includes terms for Treatment, Visit, Treatment by Visit, Study, Baseline 6MWD and Baseline 6MWD by Visit Includes subjects >11 years of age: drisapersen, n=11; placebo, n=1

18 What Happened in DEMAND III? Variability 44 clinical trial sites, across 19 countries Many centers new to DMD clinical trials Difference in standards of care Heterogeneity Patient population was generally older, more heterogeneous & more advanced in their disease than in the previous placebo controlled studies, as evidenced by baseline characteristics 1 in 4 pts was >7 yrs & <300m baseline 6MWT 17

19 DEMAND III - More Advanced Disease Baseline characteristics in DEMAND III; boys were generally more advanced in disease DEMAND II DEMAND V DEMAND III +29% +167% +48% -21% -18% Time since diagnosis [months] Rise from floor time [sec] 4 stairs climbascent time [sec] 6MWD [meter] Muscle strength [lbs] Drisapersen arm = 6 mg/kg/week; figure shows differences for drisapersen arm; similar baseline characteristics for placebo arm 18

20 Long Term (96 weeks) - DEMAND IV Study Mean change in 6MWD for continuous treatment (n)* Mean change in 6MWD for placebo/delayed treatment (n)* Difference in change in 6MWD between treatment arms (n)* DEMAND IV all patients DEMAND IV feeder study DEMAND II DEMAND IV feeder study DEMAND III DEMAND IV 7 years of age 67 m (69) 113 m (44) +46 m (113) 5 m (17) 57 m (13) +52 m (30) 87 m (52) 136 m (31) +49 m (83) +8 m (31) 29 m (21) +37 m (52) DEMAND IV >7 years of age 128 m (38) 190 m (23) +62 m (61) *Includes all subjects (21 subjects lost ambulation during DEMAND III; 13 subjects lost ambulation during DEMAND IV. Zero values were imputed once the subject had lost ambulation; zero minus baseline value). 19

21 Drisapersen tissue level (mg/g) Confirmed Mechanism of Action Tissue PK qrt-pcr IFA CK Leaky muscle fibers in DMD promote AON uptake AONs enter nuclei, bind to exon 51 of DMD pre-mrna, and induce skipping Exon 51 skipping results in novel dystrophin production Improved muscle physiology and structure Placebo Drisapersen Time (weeks) 20

22 Muscle Pathology: Decrease in CK Consistent decrease in Creatine Kinase (CK) across 3 placebo controlled studies CK levels [IU/L]¹ 14,000 Drisapersen 6mg Placebo DEMAND II DEMAND V² DEMAND III in CK level between Drisapersen (6mg/kg/wk) and placebo 12,000 10,000 8,000 DEMAND II (at week 25) DEMAND V (at week 24) -1,305 (p=0.439) -3,327 (p=0.064) 6, ¹Preliminary analysis; ²Treatment duration 24 weeks Week DEMAND III (at week 48) -4,045 (p<0.001) 21

23 Muscle Pathology: Reduced Fat Infiltration Preliminary MRI data suggest reduced fat infiltration. Data are supportive for drisapersen-induced improved muscle pathology DEMAND V: Change in apparent fat fraction from baseline [%] at 48 weeks in 6 muscle groups 15 Placebo (n=5) Drisapersen 6mg/kg/week (n=5) Rectus femoris Vastus lateralis Vastus intermedius Vastus medialis Bicep femoris Semitendinosus 22

24 Key Safety Data Drisapersen is generally well tolerated, with an adverse event (AE) profile consistent with that described previously for this class of molecule 59 SAEs reported on drisapersen, most considered unrelated: 15/59 SAEs were considered related or possibly related to drisapersen In total 12 of >300 subjects have withdrawn permanently from treatment owing to AEs Most commonly reported AEs include injection-site reactions and renal abnormalities (including subclinical proteinuria); cases of (moderate to severe) thrombocytopenia have been reported 23

25 Drisapersen Regulatory Update FDA Guidance Letter received on June 2, following meeting on May 14. Regulatory pathway possible under accelerated approval on existing data Rolling NDA submission underway with first module (>15,000 pages) submitted on October 10; next module in preparation, anticipated submission December Regular interactions with FDA (meetings September and October); next meeting planned for January 2015, with submission of final module expected shortly thereafter Two confirmatory post-approval studies were discussed with FDA in meeting on October 22; studies planned to start prior to anticipated approval EMA - interactions ongoing, plan to file for conditional approval shortly after submission of file with FDA 24

26 Confirmatory Studies - FDA Guidance 1. Open-label study of drisapersen with historical control Prosensa s fully enrolled Natural History Study (269 patients) may serve as a control 2. Randomized, placebo-controlled trial of another exon-skipping drug with a similar mechanism of action, directed at a different exon PRO044 may serve this purpose Both study designs discussed with FDA Final protocols currently in preparation for submission to IRB s Anticipated start in Q1 and Q2 2015, resp. 25

27 % fibres cumulative % Dystrophin Assessment Methodology Sensitive, reproducible and objective methodology for dystrophin analysis developed by Prosensa and published in peer-reviewed online journal (PLOS ONE) Objective: measures dystrophin over the entire membrane of a fibre and is operator independent Reproducible: method verified across multiple samples and experiments Sensitive: assesses dystrophin levels by immunofluorescence in muscle biopsies from BMD & DMD patients Distribution dystrophin per fibre 100% 80% 60% 40% 20% 0% Fibre dystrophin intensity (a.u.)

28 Dystrophin Expression is Variable Demonstration of a pharmacodynamic effect requires comparison of 2 biopsies pre- and post-treatment, taken from the same muscle, & sampled from areas of similar disease state

29 Follow-on Exons Moving Forward PRO044 Positive dystrophin response detected in 12 of 21 evaluable biopsies Dose exposure modelling predicts effective dose range at 6-9 mg/kg i.v. Safety findings consistent with known class safety profile; no drug-related SAEs Dosing of first patients in extension study Q Placebo-controlled study anticipated to start 1H 2015 PRO045 Dose finding study ongoing; preliminary results expected in Q PRO053 Dose finding study ongoing; preliminary results expected in Q PRO052/PRO055/PROSPECT Preclinical studies ongoing 28

30 PROSPECT - Multiple Exon Skipping Addresses rare mutations, initially in exon 10 to 40 region Proof-of-concept obtained in multiple patient muscle cell cultures Initial applicability between 5% and 20% of DMD patient population 29

31 Key Milestones Drisapersen Q Re-dose initial group of boys (US & EU) Q NDA rolling submission commenced with FDA Q Anticipated completion of NDA submission with FDA Q Expected MAA application for drisapersen with EMA 1H-2015 Initiation of two confirmatory studies to support potential accelerated approval for drisapersen 30

32 Corporate Highlights Rare disease company based in the Netherlands, listed on Nasdaq (RNA) Largest pipeline and clinical program in Duchenne muscular dystrophy (DMD) NDA submission under accelerated approval for drisapersen underway, followed by MAA in EU for conditional approval Orphan Drug status for 6 DMD compounds FDA Breakthrough Therapy Designation for drisapersen Solid intellectual property position Management with extensive experience in commercializing orphan drugs Cash position (Sept 30, 2014): EUR 62M; Cash burn (FY-2013): EUR 22M; (H1-2014): EUR 12.7M; YE 2014 cash balance guidance: EUR 52-54M 31

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