modulating therapies: Prosensas DMD programme Aktion Benni - - PowerPoint PPT Presentation

The development of RNA- modulating therapies: Prosensa’s DMD programme

Aktion Benni Mitgliederversammlung 3 May 2014; Hamburg Claire Leyten

Manager Patient Group Relations - Prosensa

Forward-looking statements

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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.

What will we discuss?

Prosensa’s pipeline in Duchenne muscular dystrophy (DMD) Recap of recent events Further analyses of drisapersen data Prosensa’s re-dosing intentions The natural history study R&D programmes for other mutations Q&A

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Recent & upcoming events

Jan 12, 2014: Prosensa regains rights to drisapersen from GSK Jan 16, 2014: Prosensa reports initial findings of further analyses Jan 21, 2014: Prosensa webinar for the patient community Feb 18, 2014: Communication to patient groups announcing next steps towards potential re-dosing Mar 18, 2014: Announcement of intent to re-dose an initial group

• f boys in Q3 2014

Mar 25, 2014: UPPMD Webinar for the patient community Apr 29, 2014: Communication to patient groups with about re-dosing and regulatory path

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

Duchenne Muscular Dystrophy

Myotonic Dystrophy Huntington’s Disease

R&D Pipeline

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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Study Phase Study design n Status

CLIN-02 DMD114673 Phase I/II 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 53 Complete DEMAND III

DMD114044

Phase III Randomized, placebo-controlled, confirmatory study 186 Complete DEMAND IV

DMD114349

Ph II/III Extension Open label, extension study for DEMAND II & DEMAND III; 2 years 234 Closed DEMAND V

DMD114876

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

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

Drisapersen Clinical Program

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Efficacy results 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

Drisapersen DMD114673

8 weeks on – 4 weeks off

Efficacy results appear to show delay of disease progression Distance walked (m) Weeks

Age at week 177 Mean age 12.9

Drisapersen DMD114673

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

Mean change from baseline: -24.5 m Median change from baseline: +7.5 m

6MWT Efficacy Results: DEMAND II, V

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(11) 20

DEMAND II (25 week endpoint)

+32m (n=18)

DEMAND V (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 (post-hoc analysis 24/25 weeks)

• 4m (n=18)

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

• 11m (n=34)

Study Phase; study design n Trial duration (weeks) Clinically meaningful Statistically significant

DEMAND II

DMD114117

Exploratory (Phase II); placebo-controlled, dose regimen comparison, patients in early disease stage

53 48

✓

(35 m)

✓

(p=0.014)

DEMAND V

DMD114876

Exploratory (Phase II); placebo-controlled, dose comparison, patients in early disease stage

51 24

✓

(27 m)

✗

(p=0.069)

DEMAND III

DMD114044

Confirmatory (Phase III); placebo- controlled, patients in early and later disease stage

186 48

✗

(10 m)

✗

(p=0.415)

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Two out of three placebo-controlled studies show clinically meaningful improvement in 6MWT (primary endpoint) for drisapersen with respect to placebo

Summary of 6MWT Efficacy Data

Study Treatment Age (yrs), mean (sd), range

DEMAND II

DMD114117

Placebo 6.9 (1.2) 5-9 Drisapersen 7.2 (1.7) 5-11

DEMAND V

DMD114876

Placebo 8.0 (1.8) 5-11 Drisapersen 7.6 (2.7) 5-13

DEMAND III

DMD114044

Placebo 8.0 (2.4) 5-16 Drisapersen 8.3 (2.4) 5-16

DEMAND III included older patients…

10 Drisapersen arm = 6 mg/kg/week

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+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 3.3 3.1

• 18%

Muscle strength [lbs] 102 129 124

Baseline characteristics for Drisapersen 6 mg/kg/week groups

The drisapersen arm boys in DEMAND III were generally more advanced in their disease

…with more advanced disease…

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+22% Time since diagnosis [months] 54 46 44 DEMAND III DEMAND V DEMAND II

• 14%

6MWD [meter] 348 416 403 +30% 4 stairs climb- ascent time [sec] 4.6 3.5 3.5 99 128 122 Muscle strength [lbs]

• 19%

Baseline characteristics for placebo groups

+187% Rise from floor time [sec] 13.4 4.5 4.7 The placebo arm boys in DEMAND III were generally more advanced in their disease

…in both treatment arms

More than 50 trial sites in 25 countries on 5 continents

DEMAND III was Part of a Global Program

Study Design n pb/dr* Week Treatment difference P-value

DEMAND II db pb controlled 16/16 25 +35m 0.014 DEMAND V db pb controlled 16/18 24 +27m 0.069 DEMAND II+V integrated analysis 34/36 24 +31m 0.003 DEMAND III db pb controlled 59/117 48 +10m 0.415 DEMAND III, ≤7 pre-specified analysis 29/51 48 +21m 0.131 DEMAND III+II, ≤7 integrated analysis 42/62 48 +24m 0.048 DEMAND III, >7,300-450 subset analysis 14/34 48 +25m 0.292 DEMAND IV long-term open label 44/69 96 +46m NA DMD114673 long-term open label 12 177 NA NA

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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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

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

Creatine Kinase Decrease

Study Treatment drisapersen 6mg/kg/wk N Any event of special interest Injection-site reactions* Renal abnormalities† Inflammation Hepatic Thrombo- cytes

DEMAND V

(DMD114876)

Placebo 16 9 (56%) 5 (31%) 5 (31%) 1 (6%) 1 (6%) Drisapersen 18 16 (89%) 13 (72%) 5 (28%) 5 (28%) 1 (6%) DEMAND II

(DMD114117)

Placebo 18 13 (72%) 6 (33%) 7 (39%) 9 (50%) 1 (6%) Drisapersen 18 16 (89%) 14 (78%) 13 (72%) 10 (56%) 2 (11%) DEMAND III

(DMD114044)

Placebo 61 37 (61%) 10 (16%) 20 (33%) 16 (26%) Drisapersen 125 114 (91%) 97 (78%) 80 (64%) 33 (26%) 7 (6%)

*Includes discolouration, erythema, rash, induration; †Includes proteinuria, red blood cells in urine

Most commonly reported adverse events include injection-site reactions and renal adverse events (including subclinical proteinuria); cases of thrombocytopenia (moderate-to-severe) have been observed

Summary of key safety data

Two subjects in DEMAND III at 6 mg/kg/wk had serious adverse events (SAEs) reported by the investigator as drug-related (glomerulonephritis; intracranial venous sinus thrombosis and spinal pain); no SAEs were reported in the placebo group

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“In spite of being in the typical period of decline our son’s strength seems to be stable since starting on the study. His endurance (in particular) continues to astound us with its improvements. What I am asking is that Prosensa allows us to continue on with the study on compassionate grounds while this analysis is performed. We believe there is a strong benefit to our son, and that the time spent waiting for the data is critical."

Parents Support Re-dosing

Letters of support from parents with boys participating in clinical trials

“During the course of the trial he made many amazing achievements. My son had never been able to pull himself up onto a swing […] Just within the last 6 months, he is able to swing with no additional help. […] His quality of life has been improved dramatically. He has never felt better and he hasn’t complained of his legs hurting in about a year. While GSK and Prosensa look for the right way to measure improvements, we ask on compassionate grounds for our son to continue on Drisapersen while analysis takes place."

Re-initiation of Drisapersen Dosing

Re-dosing will begin in Q3 2014

First cohorts in North-America and Europe Re-dosing will take a staged approach, under new treatment protocol or via an expanded access program Drug supply being transferred from GSK Active outreach to existing sites ongoing

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120 day transition period

Complex and large dataset Crucial that all information and data are transferred correctly Joint Transfer Team of Prosensa and GSK Transfer of relevant data, know-how and drug product Involves many departments

Joint Transfer Team

Manu- facturing

Clinical

Statistics

Quality Other

Pharmaco vigilance

R & D Regula- tory

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Impact on Other DMD Programs

Ongoing studies continue As we learn more information from the drisapersen clinical program, we may adapt our findings to our follow on programs Currently too early to speculate about the exact impact on other compounds As soon as we have more clarity, we will provide additional information Prosensa is committed to finding a solution for as many DMD boys as possible

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PRO044, PRO045

PRO044 phase I/II study completed Dystrophin restoration confirmed 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 Start of extension study expected to start H2 2014 PRO045-CLIN01 dose-finding study ongoing Natural history controls Results of phase I/II study expected in H2 2014 Expanded treatment phase awaiting final drisapersen path forward

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PRO053, PRO052, PRO055

PRO053-CLIN01 dose-finding study ongoing Natural history controls Results of phase I/II study expected in H2 2014 Expanded treatment phase awaiting final drisapersen path forward PRO052/PRO055 In preclinical stage Next steps awaiting drisapersen path forward

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PROSPECT – Multiple Exon Skipping

• Initially exons 10–18 or 10–30
• Applicability between 5-13% of DMD patient population

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Natural History Study

Sites for natural history study aiming to enroll 250 patients for 3 years Currently >200 patients enrolled

Thank You!

We would like to thank all the boys that have participated or are participating in the Prosensa clinical programs We realize how much commitment and time it takes to participate in a clinical study and how difficult this period is We would also like to thank the community at large for their input, confidence and patience We will continue to work closely with clinical experts, regulators and patient groups on the next steps We remain committed to doing what is in the best interest of the Duchenne community, to drisapersen and to our other exon-skipping programmes

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Summary

Drisapersen Further analyses of results suggest treatment benefit in patients with less advanced disease; longer treatment may be required for those with more severe disease Re-dosing the first cohort of boys in Q3 2014 We expect to communicate on a potential regulatory path forward before the end of June Follow-on programmes Ongoing dose-ranging clinical trials with PRO045 and PRO053 continue Follow-up studies may be adapted dependent up on findings from drisapersen Discovery programme to address rare mutations a high priority

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Patient Group Support

03/05/2014 Confidential 27

And many others!

Q & A

If you would like to discuss the implications for your son, we recommend you to contact the treating physician Questions to Prosensa: patientinfo@prosensa.nl

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