Prosensa Corporate Overview Jefferies Healthcare Conference London, - - PowerPoint PPT Presentation

Hans Schikan, CEO

Prosensa Corporate Overview Jefferies Healthcare Conference London, UK November 19, 2014

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

• 1934. 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

• f 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.

Forward-Looking Statements

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

Our Mission

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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

Corporate Highlights

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4

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

Indication Compound Discovery Pre-Clinical Phase I/II Phase III Drisapersen PRO044 PRO045 PRO053 PRO052 PRO055 PROSPECT PRO289 PRO135

Duchenne Muscular Dystrophy

Huntington’s Disease Myotonic Dystrophy

R&D - Largest Pipeline in DMD

13% of DMD patients 6% of DMD patients 8% of DMD patients 8% of DMD patients 4% of DMD patients 2% of DMD patients

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Evolution of clinical symptoms of DMD

0 5 10 15 20 25 30

death ventilation 24h ventilation at night very limited use of arms wheelchair - skeletal deformity walking problems Age

X-linked, rare genetic disease Rapid progression of muscle degeneration 75,000 patients in addressable populations Severely debilitating and invariably fatal progressive neuromuscular disease

Duchenne Muscular Dystrophy (DMD)

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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 20-30 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 2013

DMD Natural History and Endpoints

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6-Minute Walk Distance, m

700 100 200 600 500 400 300

5 10

Functional Outcome - 6MWT

Conceptual Representation

Late intervention Early intervention

• Approx. age years

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7 Based on natural history, DMD boys lose approximately 40-60 meters in 6MWT per year

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 2021

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Study Phase Study design N Status

CLIN-02

DMD114673

Phase I/II + Extension Open label, repeat dose escalation (extension phase 6 mg/kg/wk intermittent); 12 Complete; extension ongoing DEMAND I

DMD114118

Phase I Placebo-controlled, pharmacokinetics/safety; single dose 20 Complete DEMAND II

DMD114117

Phase II Exploratory placebo-controlled, dose regimen comparison; ex-US, 24/48 wks 53 Complete DEMAND III

DMD114044

Phase III Randomized, placebo-controlled, confirmatory study; global, 48 wks 186 Complete DEMAND IV

DMD114349

Phase II/III Extension Open label, extension study for DEMAND II) & DEMAND III ; 96 wks 234 Closed DEMAND V

DMD114876

Phase II Exploratory placebo-controlled, dose-comparison; US only, 24 wks 51 Complete

DMD115501

Phase II/III Extension Open-label, extension study for US & Canadian subjects from DEMAND III, IV, V 72 Recruiting

Drisapersen Clinical Program

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More than 300 patients and over 450 patient treatment years in global clinical program

Overview of Supportive Studies + Analyses

*pb = placebo (DEMAND IV: pb/delayed treatment); dr = drisapersen 6 mg/kg; Tx difference on 6MWD; not all analyses shown

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Clinically meaningful treatment difference across program; DEMAND III outlier

Efficacy results up to 3.4 years (177 weeks) appear to show delay of disease progression

100 200 300 400 500 600 700 800 12 24 36 48 60 72 80 93 105 117 129 141 153 165 177

Distance walked (m) Weeks

Age at week 177

13.7 14.3 11.4 10.9 12.6 9.3 13.3 15.4 13.0 14.8

Long Term Study DMD114673

8 weeks on – 4 weeks off

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N=10

Mean age is 12.9 years at 177 wks

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Distance walked (m) Weeks

Mean change from baseline: +33 m [Median change from baseline: +64 m] Mean change from baseline: -25 m [Median change from baseline: +8 m]

Long-term data suggest stabilization on 6MWT Ambulant boys: N=8 All boys: N=10

Long Term Study DMD114673

Study Design Δ 6MWT (m) SD (m) Study (years) N McDonald 2010¹ Natural History

• 57

104 1 18 Ataluren 2010¹ Placebo arm

• 42

90 1 57 Mazzone 2011² Natural History

• 42

74 1 71 Goemans 2012¹ Natural History

• 38

96 1 19 McDonald 2013² Natural History

• 59

82 1 33 Mazzone 2013² Natural History

• 122

78-97 2 113⁴ Goemans 2013² Natural History

• 125

139 2 14 Pane, 2014³ Natural History

• 146

146 3 68 DMD patients lose approximately 40-60 m in 6MWD in 1 year, 150 m in 3 years

¹All ages; ²Age >7, ³Age ≥7, ⁴ All patients in study

Functional Outcome - 6 Minute Walk Test

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(11) 20

DEMAND II (DMD114117) (25 week endpoint)

+32m (n=18)

DEMAND V (DMD114876) (24 week endpoint)

+16m (n=18)

• 11m (n=16)

Δ6MWD = +31m p=0.003 Δ6MWD = +27m p=0.069 Δ6MWD = +35m p=0.014

DEMAND II + DEMAND V (DMD114117 + DMD114876) (post-hoc analysis 24/25 weeks)

• 4m (n=18)

Drisapersen 6 mg/kg/week Placebo Two placebo-controlled studies show treatment benefit on 6MWD +20m (n=36)

• 11m (n=34)

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Placebo Controlled Studies - 6MWD

Visit Treatment N n Unadjusted mean baseline value (sd) Adjusted mean (se) Treatment difference (m) 95% CI P-value

All Subjects Week 48 Placebo 61 59 348 (92)

• 53 (10)

Drisapersen 125 117 337 (96)

• 42 (7)

+10 (-15,35) 0.415 ≤ 7 years at baseline Week 48 Placebo 29 29 383 (67)

• 25 (11)

Drisapersen 51 50 368 (65)

• 4 (9)

+21 (-7,50) 0.131 > 7 years at baseline† Week 48 Placebo 32 30 316 (101)

• 83 (16)

Drisapersen 74 67 316 (107)

• 76 (11)

+7 (-29,43) 0.703 > 7 years at baseline, and baseline 6MWD ≥300m and ≤450m Week 48 Placebo 15 14 351 (34)

• 67 (20)

Drisapersen 34 33 375 (42)

• 42 (13)

+25 (22,72) 0.292

Model includes terms for Treatment, Visit, Treatment by Visit, Study, Baseline 6MWD and Baseline 6MWD by Visit

DEMAND III by Age and Baseline 6MWD

†Includes subjects >11 years of age: drisapersen, n=11; placebo, n=1

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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

• lder, 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

+29% Time since diagnosis [months] 58 47 45 DEMAND III DEMAND V DEMAND II

• 21%

6MWD [meter] 337 396 428 +167% Rise from floor time [sec] 12.3 5.0 4.6 +48% 4 stairs climb- ascent time [sec] 4.7 4.6 3.1

• 18%

Muscle strength [lbs] 102 125 124 Baseline characteristics in DEMAND III; boys were generally more advanced in disease

DEMAND III - More Advanced Disease

Drisapersen arm = 6 mg/kg/week; figure shows differences for drisapersen arm; similar baseline characteristics for placebo arm

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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 –67 m (69) –113 m (44) +46 m (113) DEMAND IV feeder study DEMAND II –5 m (17) –57 m (13) +52 m (30) DEMAND IV feeder study DEMAND III –87 m (52) –136 m (31) +49 m (83) DEMAND IV ≤ 7 years of age +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

• nce the subject had lost ambulation; zero minus baseline value).

Long Term (96 weeks) - DEMAND IV

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Time (weeks) Placebo Drisapersen Drisapersen tissue level (mg/g)

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

qRT-PCR Tissue PK IFA CK

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Confirmed Mechanism of Action

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10 20 30 40 50 10,000 12,000 8,000 6,000 14,000

∆ in CK level between Drisapersen (6mg/kg/wk) and placebo

• 4,045

(p<0.001) DEMAND III (at week 48) DEMAND V (at week 24) DEMAND II (at week 25)

• 3,327

(p=0.064)

• 1,305

(p=0.439)

CK levels [IU/L]¹

DEMAND III DEMAND V² DEMAND II

Placebo Drisapersen 6mg

Week

¹Preliminary analysis; ²Treatment duration 24 weeks

Muscle Pathology: Decrease in CK

Consistent decrease in Creatine Kinase (CK) across 3 placebo controlled studies

5 10 15 Semi- tendinosus Bicep femoris Vastus medialis Vastus intermedius Vastus lateralis Rectus femoris

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Preliminary MRI data suggest reduced fat infiltration. Data are supportive for drisapersen-induced improved muscle pathology Drisapersen 6mg/kg/week (n=5) Placebo (n=5) DEMAND V: Change in apparent fat fraction from baseline [%] at 48 weeks in 6 muscle groups

Muscle Pathology: Reduced Fat Infiltration

Key Safety Data

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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

• wing 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

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

• n 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

Drisapersen Regulatory Update

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• 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.

Confirmatory Studies - FDA Guidance

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0% 20% 40% 60% 80% 100% 200 400 600 800 1000

% fibres

Fibre dystrophin intensity (a.u.)

Distribution dystrophin per fibre cumulative %

Dystrophin Assessment Methodology

32 40 38 36 42 2 1 10 16 6 4 9 11 7 5 3 12 15 13 8 14 23 18 17 21 20 22 30 19 24 29 28 27 26 25 35 33 31 34 44 43 41 39 37 47 46 45 49 48

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

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

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 Q1 2015 Placebo-controlled study anticipated to start 1H 2015

PRO045

Dose finding study ongoing; preliminary results expected in Q4 2014

PRO053

Dose finding study ongoing; preliminary results expected in Q1 2015

PRO052/PRO055/PROSPECT

Preclinical studies ongoing

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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

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Q3-2014 Re-dose initial group of boys (US & EU) Q4-2014 NDA rolling submission commenced with FDA Q1-2015 Anticipated completion of NDA submission with FDA Q1-2015 Expected MAA application for drisapersen with EMA 1H-2015 Initiation of two confirmatory studies to support potential accelerated approval for drisapersen

Key Milestones Drisapersen

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

Corporate Highlights

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