PTC Therapeutics, Inc....2010/07/28  · PTC Therapeutics, Inc. January 2015 Forward-Looking Statements This presentation includes ‘‘forward- looking statements’,’ within the

PTC Therapeutics, Inc.January 2015

Forward-Looking StatementsThis presentation includes ‘‘forward-looking statements’,’ within the meaning of the Private Securities Litigation Reform Act of 1995, that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘might,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘potential,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’ ‘‘continue,’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements in this presentation include, among other things, statements about: (i) the timing and conduct of our clinical trials of Translarna (ataluren) for the treatment of nmDMD, nmCF and nmMPS I, as well as our trials in spinal muscular atrophy and BMI1, including statements regarding the timing of initiation, enrollment and completion of the trials and the period during which the results of the trials will become available; (ii) our plans to pursue development of Translarna for additional indications other than nmDMD, nmCF and nmMPS I; (iii) our ability to advance our earlier stage programs, including our antibacterial program; (iv) our plans to pursue research and development of other product candidates; (v) the potential advantages of Translarna; (vi) the rate and degree of market acceptance and clinical utility of Translarna; (vii) our ability to maintain the conditional marketing authorization of Translarna for the treatment of nmDMD in the European Economic Area; (viii) the timing of and our ability to obtain additional marketing approvals of Translarna and our other product candidates, and the ability of Translarna and our other product candidates to meet existing or future regulatory standards; (ix) our estimates regarding the potential market opportunity for Translarna, including the size of eligible patient populations and our ability to identify such patients; (x) our ability to expand the approved product label of Translarna for the treatment of nmDMD; (xi) our ability to commercialize Translarna, including our ability to successfully negotiate favorable pricing andreimbursement processes in the countries in which we may obtain regulatory approval; (xii) the timing and scope of our commercial infrastructure expansion, including the growth of our international presence in Europe and in other territories; (xiii) the potential receipt of revenues from future sales of our product candidates, including our ability to earn a profit from sales or licenses of Translarna for the treatment of nmDMD; (xiv) our sales, marketing and distribution capabilities and strategy; (xv) our ability to establish and maintain arrangements for the manufacture of Translarna and our other product candidates that are sufficient to meet clinical trial and commercial launch requirements; (xvi) our estimates regarding expenses, future revenues, capital requirements and needs for additional financing; (xvii) our intellectual property position; (xviii) the impact of government laws and regulations; (xix) our competitive position; and (xx) our expectations with respect to the development and regulatory status of our program directed against spinalmuscular atrophy in collaboration with Roche and the Spinal Muscular Atrophy Foundation. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Our actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements we make as a result of a variety of risks and uncertainties, including those described in the ‘‘Risk factors’’ section of our most recent Form 10-Q. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

JAN 2015 1

Our mission

JAN 2015 2

To leverage our knowledge of RNA biology to bring

novel therapeutics to patients affected by rare and neglected disorders

Executing on PTC’s strategy

JAN 2015 3

Focus on the development and commercialization of TranslarnaTM (ataluren) in nmDMD, nmCF, nmMPS I and additional indications

Expand PTC’s clinical stage pipeline using our scientific expertise to develop novel compounds for unmet medical needs

Foster relationships with strong strategic partners to further leverage PTC's discovery and development capabilities

PTC’s RNA-focused small molecule technology platform

JAN 2015 4

DNA

intronexon

pre-mRNA

poly(A) tail

5’ cap

mRNA

tRNAGLU

VALLYS

ribosome

Protein

PTC’s Platform Technologies

Nonsense Readthrough

AlternativeSplicing

NucleotideRepeat

Protein Modification

Transcript Regulators

RNA degradation control

RNA translation control

RNA transport control

RNA processing control

PTC’s innovative discovery platform has produced multiple drug candidates

JAN 2015 5

Translarna™ (ataluren)Enables ribosomal read-through of

premature termination codons

PTC672 Inhibits resistant N.

gonorrhoeae

PTC725Inhibits g1 HCV

PTC299Selectively inhibits stress-induced

protein synthesis (VEGF)

PTC596Inhibits cancer stem cells

through BMI1

RG7800Alters SMN2 splicing to produce

functional protein

Biology

Chemistry

Pharmacology

Pipeline summary

JAN 2015 6

Product /Platform

Discovery Preclinical Phase 1 Phase 2 Phase 3 Status/Plans

EU launch underway P3 enrollment complete

Orphan genetic disorders

Oncology

Antibacterial

Gonorrhea

nmDMD

nmCF

MPS I

BMI1

SMA

DMD

P3 initiated

Initiating P2

P1b/2 initiated Nov

Lead discovery

P1 to start H1:15

DC candidate selected

TranslarnaTM

(ataluren)nonsense

readthrough

RG7800alternative splicing

PTC596tumor stem cell

targeting

PTC672DNA synthesis

DMD Exon 51alternative splicing

PTC value drivers

JAN 2015 7

2014 2015 2016

TranslarnaTM

P3 ACT CF Fully-Enrolled

Initiate P1 BMI1 with PTC596

First CommercialSales of

TranslarnaTM

Initiated SMA P1b/2

Study Moonfish

TranslarnaTM

P3ACT DMDTop-Line Data

Last PatientEnrolled in

P3 ACT DMD

TranslarnaTM

Approved in EU for nmDMD

TranslarnaTM

US Approval in DMD

Initiated P3ACT CF

File MAA for Translarna™ in

nmCF

Initiate TranslarnaTM

Proof-of-Concept Study

in MPS I

First TranslarnaTM

Sales via EAP

Initiate P2TranslarnaTM

in New Indications

Initiated SMA P1 Study

Translarna ™Nonsense mutation readthrough

JAN 2015 8

Translarna binds to the ribosome and enables readthroughof nonsense mutation to produce functional protein

JAN 2015 9

Potentially treats any nonsense mutation across multiple orphan disorders High specificity for nonsense readthrough without affecting normal termination codons Nonsense mutations are routinely identified by genetic testing

TranslarnaTM: Potential across multiple rare disorders

Muscle disorders DMD (Welch 2007; Kayali 2012; Finkel 2013; Li 2014;

Bushby 2014) Miyoshi myopathy/ Dysferlin (Wang 2010)

Neurological disorders Infantile Neuronal Ceroid Lipofuscinoses (INCL) (Sarkar

2011; Miller 2013) Late Infantile Ceroid Lipofuscinoses (LINCL) (Miller

2013, Yu 2013) Ataxia telangiectasia (Du 2013) Usher syndrome (USCH1C) (Goldmann 2011; Goldmann

2012)

Ion channel disease Cystic fibrosis (CF) (Du 2008; Kerem 2008; Sermet-

Gaudelus 2010; Wilshanski 2011; Gonzalez-Hilarion2012; Johansonn 2014; Kerem 2014; Pibiri 2014)

Long QT syndrome (Yu 2014)

Skin disease Pseudoxanthoma elasticum (Zhou 2013) Xeroderma pigmentosum (Kuschal 2013)

Eye disorders Choroideremia (Moosajee 2014) Aniridia (Gregory-Evans 2014)

Pulmonary disease Heritable pulmonary arterial hypertension (HPAH)

(Drake 2013)

Metabolic disorders Carnitine palmitoyltransferase 1A Deficiency (Tan

2011) Methylmalonic aciduria (MMA) (Buck 2010) Propionic acidemia (PA) (Sanchez-Alcudia 2012) Maroteaux-Lamy syndrome (MPS VI) (Bartolomeo

2013) Hurler’s syndrome (MPS I) (Keeling, unpublished)

Genetically defined epilepsy CDLK5 Rett Syndrome Dravet Syndrome

JAN 2015 10

(independent investigators)

Translarna™:First approved therapy for Duchenne muscular dystrophy

JAN 2015 11

ON

N

CO2H

F

Characteristics

Orally bioavailable

Reliable manufacturing

Pediatric-friendly formulation

Generally well tolerated >750 individuals dosed to date

Market Potential

~11% of patients across all monogenic disorders have a nonsense mutation

Potential disease modifying therapy

Orphan designation EU & US

PTC retains worldwide commercial rights

Patents until 2024-2027 (composition & method of use)

Status

EU approval for nmDMDambulatory patients 5 yrsand older

Confirmatory Phase 3 nmDMD trial - enrollment complete

Phase 3 nmCF trial initiated

Phase 2 in MPS I initiating

Translarna™Nonsense mutation Duchenne Muscular Dystrophy

12JAN 2015

Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder due to the loss of dystrophin protein Muscles lacking dystrophin

are more susceptible to muscle damage

Dystrophin replacement is expected to prevent muscle damage

~34,000 boys & young men in US/EU ~13% caused by nonsense

mutations

JAN 2015 13

Extracellular Matrix

Laminin-ɑ2

Dystroglycans

F-Actin

Syntrophins

ɑ-Dystrobrevin

Dystrophin

SarcoglycanComplex

Sarcospan

Sarcolemma Membrane

Dystrophin stabilizes, but does not increase muscle strength

C-Term

N-Term

DMD is a progressive and fatal genetic disorder

JAN 2015 14

Developmental delay

Transition to wheel chair – skeletal deformity

Very limited use of arms –loss of self feeding

Ventilation at night

Ventilation 24 hours

Death

0 5 10 15 20 25

Impaired standing

Progressive ambulatory decline

Ambulatory changes predict loss of functionAge at loss of ambulation predicts loss of self feeding and need for ventilation

First drug approved for the underlying cause of DMD

JAN 2015 15

EUApproval

Positive 6MWT results 31.3 m in overall

population 49.9 m in ambulatory

decline group 68.2 m in <350 m

group

Primary

Natural History independently confirmed and

consistent

Improvement seen in TFTs 10 m walk- run Stair climb Stair descend All phases of disease

Secondary

Safety:Generally well tolerated

Better outcomes observed Myometry – in 5&6

year olds Quality of life Fewer falls Step activity Less time in

wheelchair

Tertiary

Confirmatory Trial:Well underway

Ongoing confirmatory Phase 3 ACT DMD clinical trial targeting patients in the ambulatory decline phase

JAN 2015 16

Primary outcome measure: 6MWD (change from baseline)

Secondary outcome measure: Timed-function tests North Star PODCI QoL

Double-blind placebo-controlled study

Enrollment complete - Top-line data Q4 2015

Length of Trial TranslarnaTM (n) Placebo (n)

48 weeks 110 110

Eligibility Criteria Stratification

≥7 years & ≤16 years Steroid use 6MWD ≥150 m ≤80% of predicted for age and

height

≥350 m vs <350 m ≥9 years vs <9 years

Commercial launch activities are well underway

JAN 2015 1

Senior commercial leadership team in place and international organization established

Supply chain and distribution processes in place

Early Access Programs authorized in France, Italy, Spain, Turkey and Israel

Market Access Dossiers in key launch countries submitted

First commercial sales began in Germany

Translarna access expanding rapidly: Focusing first on fastest access geographic areas

Early Access Programs

Full Commercial Launches

Translarna access expanding rapidly: Focusing first on fastest access geographic areas

nmDMD prevalencein the EU

~ 2,500 patients

Early Access Programs

Full Commercial Launches

~ 40-50% under currentlabel

~ 1,000 – 1,250 patientsBased on internal assumptions

Maximizing access to patients in markets with successful orphan drug history

Est. nmDMDPrevalence

JPN : ~ 600 pts.

Global concurrent expansion processEarly Access Programs

Full Commercial Launches

N. America: ~2,100 pts.

EUR: ~ 2,500 pts.

BRA: ~ 1,000 pts.

AUS: ~ 100 pts.

ARG: ~ 200 pts.

COL: ~ 200 pts.

TUR: ~ 400 pts.

Identifying and mapping patients: Germany example

JAN 2015 21

Estimated nmDMD prevalence in Germany ~400

pts.

~ 40-50% under currentlabel

~ 160-200 patients

Known identified patients on label (50%)~ 90 patients

Patient #s based on internal assumptions

H2H1Positioned to maximize the commercial launch in 2015

JAN 2015 22

GERMANY

DENMARK

SWEDEN

AUSTRIA

UK

FRANCE

ITALY

SPAIN

EU launches on track pending pricing negotiations

Translarna™Nonsense mutation Cystic Fibrosis

23JAN 2015

Cystic fibrosis is a progressive and fatal genetic disease

Life-threatening disease with average age of death in the mid-twenties

Death typically due to respiratory failure

Caused by defects in the CFTR gene

~70,000 patients in US/EU

~10% caused by nonsense mutations

Nonsense mutations are the most severe form

For patients with a nonsense mutation only palliative treatments are available

JAN 2015 24

CFTR

Nonsense mutations cause the most severe form of CF

JAN 2015 25

VReducedSynthesis

2%

CFTR

CFTR channelthrough

cell membrane

CFTR protein

cftr gene incell nucleus

Class

CFTR

CFTR

CFTR

Normal

% CF Patients

CFTR

CFTR

CFTR

IVConductance

2%

Compounds

INo Synthesis

10%

Translarna™

CFTR

CFTR

CFTR

IIIGating

3-5%

Kalydeco™

1. VX809 and VX661 are only for homozygote, 45-55%

IIProcessing

Block

70%

VX809VX661

1

CFTR

CFTR

CFTR

Translarna is only compound in development for the most severe form (Class 1)

Translarna had a clinically meaningful benefit (ΔFEV1 +5.7%) in the ~65% of nmCF patients not on inhaled TOBI®

JAN 2015 26

8 1 6 2 4 3 2 4 0 4 8-8

-6

-4

-2

0

2

4 0 m g /k g /d a y a ta lu re n (n = 7 2 )

P la c e b o (n = 7 4 )

B a s e lin e

T im e (w e e k s )

Re

lati

ve

Ch

an

ge

in

%-P

red

icte

d F

EV

1,

Me

an

-0 .7 %

-6 .4 %

8 1 6 2 4 3 2 4 0 4 8-8

-6

-4

-2

0

2

4 0 m g /k g /d a y a ta lu re n (n = 4 4 )

P la c e b o (n = 4 2 )

B a s e lin e

T im e (w e e k s )

Re

lati

ve

Ch

an

ge

in

%-P

red

icte

d F

EV

1,

Me

an

-4 .1 %

-5 .5 %

1. No antibiotics or use of non-aminoglycoside antibiotics

2. Alone or with other antibiotics3. Overall population decreased 23%

(n=226, p=0.0992)

Without Inhaled TOBI®1 With Inhaled TOBI®2

Week 48 Δ= +5.7% (nominal p=0.008)

Week 48 Δ= -1.4% (nominal p=0.43)

Translarna decreased pulmonary exacerbation rates in Non-TOBI® patients by 41% vs. placebo nominal p=0.0053

Based on Phase 3 post-hoc analysis

2

4

6

8

10

0

Significant FEV1 changes seen in recent CF trials vs. TranslarnaTM

JAN 2015 27

12

Class III

*Measured in separate trials

Class I

Class II

Translarna, non TOBI® subgroup

ENVISION (Kalydeco™)

abs. Δ12.5%

KONNECTION (Kalydeco™)

abs. Δ10.7%

KONDUCT(Kalydeco™)

abs. Δ 2.1%

TRAFFIC AND TRANSPORT

(Kalydeco/ VX-809)

abs. Δ 2.8-3.3%

relative Δ 5.7%

abs. Δ 3.5%

ACT CF (Ataluren Confirmatory Trial) study design

JAN 2015 28

Primary outcome measure: % predicted FEV1

Secondary outcome measure: Pulmonary exacerbation rate CFQ-R BMI and LFTs

On-track to complete enrollment in H2 2015

Length of Trial TranslarnaTM (n) Placebo (n)

48 weeks 104 104

Eligibility Criteria Stratification

Nonsense mutation CF ≥6 years FEV1 ≥40% and ≤90% predicted No chronic inhaled TOBI

Age: ˂18 vs ≥18 years Inhaled antibiotic use (yes vs no) Baseline FEV1: ≥65% vs <65% of

predicted

MPS 1: Next Proof-of-Concept Study for TranslarnaTM

Muscle disorders DMD (Welch 2007; Kayali 2012; Finkel 2013; Li 2014;

Bushby 2014) Miyoshi myopathy/ Dysferlin (Wang 2010)

Neurological disorders Infantile Neuronal Ceroid Lipofuscinoses (INCL) (Sarkar

2011; Miller 2013) Late Infantile Ceroid Lipofuscinoses (LINCL) (Miller

2013, Yu 2013) Ataxia telangiectasia (Du 2013) Usher syndrome (USCH1C) (Goldmann 2011; Goldmann

2012)

Ion channel disease Cystic fibrosis (CF) (Du 2008; Kerem 2008; Sermet-

Gaudelus 2010; Wilshanski 2011; Gonzalez-Hilarion2012; Johansonn 2014; Kerem 2014; Pibiri 2014)

Long QT syndrome (Yu 2014)

Skin disease Pseudoxanthoma elasticum (Zhou 2013) Xeroderma pigmentosum (Kuschal 2013)

Eye disorders Choroideremia (Moosajee 2014) Aniridia (Gregory-Evans 2014)

Pulmonary disease Heritable pulmonary arterial hypertension (HPAH)

(Drake 2013)

Metabolic disorders Carnitine palmitoyltransferase 1A Deficiency (Tan

2011) Methylmalonic aciduria (MMA) (Buck 2010) Propionic acidemia (PA) (Sanchez-Alcudia 2012) Maroteaux-Lamy syndrome (MPS VI) (Bartolomeo

2013) Hurler’s syndrome (MPS I) (Keeling, unpublished)

Genetically defined epilepsy CDLK5 Rett Syndrome Dravet Syndrome

JAN 2015 29

(independent investigators)

MPS 1 CNS effects are not addressed by existing therapy

Enzyme replacement therapy has limited efficacy in addressing the CNS

pathology of MPS I 1

CNS involvement in MPS I can result in a wide range of developmental delay

Most severe cases result in severe retardation

Brain compression seen as a secondary CNS effect

Cardiac and bone/joint-related abnormalities may not be corrected by

either Bone marrow transplant/HSCT or ERT

30

1. Kakkis E, McEntee M, Vogler C, Le S, Levy B, Belichenko P, et al. Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. Mol Genet Metab. 2004;83:163–174.

Translarna crosses BBB & penetrates other key tissues

JAN 2015

Translarna treatment reduces GAG levels in multiple tissues in an MPS I (Hurler) nonsense-mutation mouse model

31

WT Idua-W392X**p<0.01

(t-test, compared to Idua-W392X vehicle)

0

1

2

3

4

5

6Brain

**

Tiss

ue G

AG

(ug

GA

G /

mg

tissu

e)

0

5

10

15

Spleen

WT Idua-W392X

**

Tiss

ue G

AG

(ug

GA

G /

mg

tissu

e) untreated

treated

Neufeld and Muenzer, The Mucopolysaccharidoses, in The Metabolic and Molecular Bases of Inherited Disease,2001

Keeling et al unpublished data

JAN 2015

TranslarnaTM: Potential across multiple rare disorders

Muscle disorders DMD (Welch 2007; Kayali 2012; Finkel 2013; Li 2014;

Bushby 2014) Miyoshi myopathy/ Dysferlin (Wang 2010)

Neurological disorders Infantile Neuronal Ceroid Lipofuscinoses (INCL) (Sarkar

2011; Miller 2013) Late Infantile Ceroid Lipofuscinoses (LINCL) (Miller

2013, Yu 2013) Ataxia telangiectasia (Du 2013) Usher syndrome (USCH1C) (Goldmann 2011; Goldmann

2012)

Ion channel disease Cystic fibrosis (CF) (Du 2008; Kerem 2008; Sermet-

Gaudelus 2010; Wilshanski 2011; Gonzalez-Hilarion2012; Johansonn 2014; Kerem 2014; Pibiri 2014)

Long QT syndrome (Yu 2014)

Skin disease Pseudoxanthoma elasticum (Zhou 2013) Xeroderma pigmentosum (Kuschal 2013)

Eye disorders Choroideremia (Moosajee 2014) Aniridia (Gregory-Evans 2014)

Pulmonary disease Heritable pulmonary arterial hypertension (HPAH)

(Drake 2013)

Metabolic disorders Carnitine palmitoyltransferase 1A Deficiency (Tan

2011) Methylmalonic aciduria (MMA) (Buck 2010) Propionic acidemia (PA) (Sanchez-Alcudia 2012) Maroteaux-Lamy syndrome (MPS VI) (Bartolomeo

2013) Hurler’s syndrome (MPS I) (Keeling, unpublished)

Genetically defined epilepsy CDLK5 Rett Syndrome Dravet Syndrome

JAN 2015 32

(independent investigators)

Spinal Muscular AtrophyDiscovery of a small molecule therapeutic

JAN 2015 33

Spinal Muscular Atrophy:The leading genetic cause of mortality in infants

Spinal muscular atrophy (SMA) is caused by the loss of a SMN-1 gene

Low expression of SMN protein leads to the loss of motor neurons in the spinal cord

Low levels of SMN lead to the death of motor neurons in the spinal cord and muscle atrophy

One in every 10,000 children born is affected with the disorder

No marketed therapies for SMA, only palliative treatments

SMA program partnered with Roche and the SMA Foundation

JAN 2015 34

Dorsal RootVentral Root

Targeting alternative splicing in SMA

JAN 2015 35

SMA patients rely on a related SMN2 gene which produces only low levels of SMN protein due to a splicing defect

Small molecule selectively targets SMN splicing to include exon 7 and produce functional SMN

FunctionalSMN protein

7DNA

7mRNA

SMN1

Unstable SMN protein,

rapidly degraded

77 7

mRNA, missing exon 7

SMN2

FunctionalSMN protein

7

DNA

7

mRNA

The Spinal Muscular Atrophy program validates PTC’s splicing platform Highly active, orally bioavailable

compounds

SMN splicing correction and protein induction in cells from SMA patients

SMN splicing correction and protein induction in mouse models of SMA

Significant improvement in survival, body weight gain and motor behavior in mouse model of severe SMA

Currently in clinical development

PTC’s splicing platform may be broadly applicable to many biological targets

JAN 2015 36

P1a showed no S.A.Es Demonstrated proof of mechanism

MOONFISH enrolling- completion expected Jan 2016

JAN 2015 37

Primary outcome measure: Safety and tolerability

Secondary outcome measure: Plasma concentration & AUC SMN protein and SMN2 mRNA

levels in blood Nerve and muscle function

Double-blind placebo-controlled study

Dosing (n)

12 week cyclesMultiple doses

48

Enrollment Criteria

≥2 years & ≤55 years Primarily SMA types 2 & 3

Pipeline summary

JAN 2015 38

Product /Platform

Discovery Preclinical Phase 1 Phase 2 Phase 3 Status/Plans

EU launch underway P3 enrollment complete

Orphan genetic disorders

Oncology

Antibacterial

Gonorrhea

nmDMD

nmCF

MPS I

BMI1

SMA

DMD

P3 initiated

Initiating P2

P1b/2 initiated Nov

Lead discovery

P1 to start H1:15

DC candidate selected

TranslarnaTM

(ataluren)nonsense

readthrough

RG7800alternative splicing

PTC596tumor stem cell

targeting

PTC672DNA synthesis

DMD Exon 51alternative splicing

www.ptcbio.com

JAN 2015 39

PTC596BMI1 Tumor target

JAN 2015 40

BMI1 imparts both immortality and resistance to tumor cells

JAN 2015 41

Epigenetic silencing of tumorsuppressor expression

(e.g. Ink4A, PTEN)

Ring1

HPH2

PRC1

DMNT1

Ring2

BMI1

p53 stability

Mediates poly-ubiquitylationand degradation of p53

Ring2

BMI1

p53u u

u uu Recruited to DNA breaks to

aid in homologous recombination

ATR

ATM

Ring2

BMI1

DNA damage repairEpigenetic regulator

BMI1

Faccino et al. The Journal of Neuroscience, July 28, 2010 • 30(30):10096

Su et al. PNAS. 2013 Jan 29;110(5):1720-5

Agherbi et al. PLoS One. 2009 May 20;4(5):e5622

High BMI1 protein expression predicts poor overall survival in the clinic: Colorectal cancer

JAN 2015 42

BMI1 low

BMI1 high

Sur

viva

l (fra

ctio

n)

PTC compounds reduce the expression of BMI1 and deplete tumor stem cell populations within model systems

JAN 2015 43

From: “Targeting self-renewal, an Achilles' heel of cancer stem cells” MS Wicha, Nature Medicine 20, 14–15 (2014)

The combination of PTC596 and standard-of-care extends survival of mice with patient-explant GBM tumors

Nov 2014 44

0 5 0 1 0 0 1 5 00

5 0

1 0 0

D a y

Pe

rce

nt

surv

iva

l

V e h ic le P T C 5 9 6 (1 2 m g /k g P O b iw )

T M Z (2 5 m g /k g q d x 5 )

C o m b in a tio n

3 cures

*p<0.05, ANOVA, multiple pairwise comparisons (PTC596 vs. combination, and temozolomide vs combination)

S Keir, 2014 (unpublished)

PTC value drivers

JAN 2015 45

2014 2015 2016

TranslarnaTM

P3 ACT CF Fully-Enrolled

Initiate P1 BMI1 with PTC596

First CommercialSales of

TranslarnaTM

Initiated SMA P1b/2

Study Moonfish

TranslarnaTM

P3ACT DMDTop-Line Data

Last PatientEnrolled in

P3 ACT DMD

TranslarnaTM

Approved in EU for nmDMD

TranslarnaTM

US Approval in DMD

Initiated P3ACT CF

File MAA for Translarna™ in

nmCF

Initiate TranslarnaTM

Proof-of-Concept Study

in MPS I

First TranslarnaTM

Sales via EAP

Initiate P2TranslarnaTM

in New Indications

Initiated SMA P1 Study

Appendix slides

JAN 2015 46

Miyoshi myopathy: Translarna treatment of nmMyoshimyopathy patient myotubes increases dysferlin expression Muscle wasting disorder in early adults Caused by mutations of the DYSF/ANOS genes In Japan incidence is 1/440,000

JAN 2015 47

+Translarna

+Tra

nsla

rna

Muscle wasting disorder in early adults Caused by mutations of the DYSF/ANOS genes In Japan incidence is 1/440,000

Translarna restores morphology and sight in Aniridiamouse model

JAN 2015 48Gregory-Evans 2014 JCI

vehicle

Untreated

+ Translarna

P60

Aniridia caused by mutations in the paired box 6 gene (PAX6) Incidence is 1 in 60,000 births, 20% have nonsense mutations Treatment methods used today are mostly surgical and ineffective

Efficacy of Translarna in nonsense mutation choroideremia

JAN 2015 49

X-linked recessive chorioretinal disease resulting in blindness in patients Caused by mutations in the REP1 gene Nonsense mutations account for over 33% of patients

Moosajee et al. unpublished data

Wild type

Mutant + vehicle

Mutant + Translarna

Two potential points of intervention at a nonsense codon

JAN 2015 50

No full-length protein produced Reduced mRNA abundance due to accelerated decay

++ ++++

Combination

Translarna™Nonsense mutation Duchenne Muscular Dystrophy

51JAN 2015

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8- 1 3 0

- 1 1 0

- 9 0

- 7 0

- 5 0

- 3 0

- 1 0

1 0

- 5 m

- 1 0 7 m

B a s e l i n e

T i m e ( w e e k s )

Ch

an

ge

in

6M

WD

, m

ea

n (

m)

B a s e l i n e 6 M W D ≥ 3 5 0 ( N = 3 5 )

B a s e l i n e 6 M W D < 3 5 0 m ( N = 2 2 )

Phase 2b placebo-control data defined natural history of 6MWD

JAN 2015 52

4 5 6 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

7

P l a c e b o

( N = 5 7 )

A g e ( y )

6-M

inu

te W

alk

Dis

tan

ce

, m

<350 m

Lessons learned

Baseline 6MWD is a key factor in determining whether DMD patients decline The mean ∆6MWD in >350 meter population was relatively stable

Difficult to demonstrate a drug effect over a 48-week study The mean ∆6MWD in <350 meter population show a large decline

Best population to demonstrate an effect in ambulation in a 48-week study Confirmatory trial has inclusion criteria to enrich patients in the decline phase

Placebo

TranslarnaTM treatment effect increases in the decline subgroup and in the pre-specified baseline 6MWD <350 m subgroup

JAN 2015 53

c IT T D e c lin ep h a s e

< 3 5 0 m (b a s e lin e )

0

2 0

4 0

6 0

8 0

W e e k 4 8C

ha

ng

e i

n 6

MW

D (

me

an

, m

)

n o m in a lp = 0 .0 0 9 6

n o m in a lp = 0 .0 2 8

p = 0 .0 5 6 1 *

n o m in a lp = 0 .0 0 5 3

∆ = 31 .3 m

∆ = 49 .9 m

∆ = 68 .2 m

*MMRM analysis adjusted for multiplicityPost-hoc analysis on cITT population

TranslarnaTM treatment effect seen in all disease stages studied

JAN 2015 54B a s e l in e % -p re d ic te d 6 M W D

Ch

an

ge

in

6M

WD

(m

), m

ea

n

> 7 0 %M ild d is e a s e

5 0 -7 0 %M o d e ra te d is e a s e

< 5 0 %S e v e re d is e a s e

-1 2 5

-1 0 0

-7 5

-5 0

-2 5

0

2 5

P la c e b o

4 0 m g /k g /d a y T ra n s la rn a

n = 2 0

n = 1 8

n = 2 3

n = 2 2

n = 1 2 n = 1 5

-1 1 6 m

-7 5 m

-3 8 m

+ 9 m

-8 m

+ 1 2 m

Impr

ovin

g

Δ= 20m Δ= 47m

Δ= 41m

Phase 2b demonstrated activity in timed function tests:Overall population and decline subgroups

0

2

4

6

8

1 0

1 2

1 4

1 6

P la c e b o

T ra n s la rn a 4 0 m g /k g /d a y

Ch

an

ge

fro

m B

as

eli

ne

, m

ea

n (

se

),s

ec

on

ds

1 0 m W R C lim b D e s c e n d

P h a s e 2 b (a ll p a t ie n ts )D e c lin e P h a s e

s u b g ro u p

1 0 m W R C lim b D e s c e n d

-1 .4 s

-2 .4 s -1 .6 s -2 .8 s

-2 .9 s -2 .9 s

1 0 m W R C lim b D e s c e n d

< 3 5 0 m e te rss u b g ro u p

-3 .5 s

-6 .4 s

-5 .0 s

JAN 2015 55

Wor

seni

ng

No other dystrophin restoration treatments have shown positive trends on timed function tests at 48 weeks

Myometry is only sensitive in young patients: Strength vs. Function

JAN 2015 56

Function: 6MWT Strength: Knee Extension

[Abresch 2011 – American Academy of Neurology presentation][McDonald 2013]

Largest improvements in 6MWT up to age 7Largest decline in strength up to age 7 followed by floor effect

Mean change from baseline in muscle strength evaluated by myometry (patients 5-6 years old)

JAN 2015 57

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 .2 5

0 .5 0

0 .7 5

1 .0 0

1 .2 5

1 .5 0T ra n s la rn a 4 0 m g /k g /d a y (N = 9 )

Mea

n C

han

ge

(lb

)P la c e b o (N = 1 4 )

* For shoulder abduction, the mean change in the placebo arm was 0.0 lbs

KneeExtension

ElbowFlexion

KneeFlexion

ElbowExtension

ShoulderAbduction*

Wor

seni

ng

Most reliable tests in 5- and 6-year-olds

No other dystrophin restoration treatments have shown positive trends in strength

TranslarnaTM slowed disease progression in nmDMD patients

JAN 2015 58

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8-6 0

-5 0

-4 0

-3 0

-2 0

-1 0

0

1 0

2 0

P la c e b o (n = 5 7 )

4 0 m g /k g /d a y T ra n s la rn a (n = 5 7 )

B a s e lin e

-4 4 .1 m (8 8 )

-1 2 .9 m (7 2 )

T im e (w e e k s )

Ch

an

ge

6M

WD

(m

), m

ea

n (

SE

M)

∆ 3 1 .3 mn o m in a lp = 0 .0 2 8p = 0 .0 5 6 1 †

*cITT= Corrected intent to treat population† = MMRM analysis adjusted for multiplicity

Based on Phase 2b post-hoc subgroup1 analysis and cITT

TranslarnaTM demonstrated the greatest benefit over 48 weeks with patients in the ambulatory decline phase

JAN 2015 591. In patients on corticosteroids, between

7 and 16 years of age, with baseline 6MWD ≥150m and ≤80% of predicted

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8-7 0

-6 0

-5 0

-4 0

-3 0

-2 0

-1 0

0

1 0

2 0

P la c e b o (n = 3 1 )

4 0 m g /k g /d a y T ra n s la rn a (n = 3 2 )

-6 2 .2 m (8 5 )

-1 2 .3 m (6 9 )

T im e (w e e k s )

Ch

an

ge

in

6M

WD

(m

), m

ea

n (

SE

M)

B a s e lin e

∆ 4 9 .9 mn o m in a l p = 0 .0 0 9 6

Based on Phase 2b post-hoc subgroup1 analysis and cITT

TranslarnaTM slowed disease progression in nmDMDpatients

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0

P la c e b o (N = 5 7 )4 0 m g /k g /d a y T ra n s la rn a (N = 5 7 )

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

W e e k s

Pe

rce

nt

No

t 1

0%

Wo

rse

ne

d

2 6 % p ro g re s s in g

4 4 % p ro g re s s in g

JAN 2015 60

Pre-specified analysis (cITT) 40 mg/kg/day TranslarnaTM vs. placebo - nominal p=0.039

Separation between treated and placebo patients occurred early

Translarna treatment was associated with improvements in dystrophin expression in Phase 2a nmDMD clinical trial

JAN 2015 61

Over 28 days, improvements were seen in ~60% of patients

Phase 2a study; Bönnemann et al, Neuromusc. Disord. 2007

Pretreatment End of Treatment (Day 28)

Bell-Shaped Concentration-Responses to Translarna Are Observed in Cells, Fish, and Mice

JAN 2015 62

0

5

1 0

1 5

1 7 . 5 1 0 1 5 2 0 3 0

C o n c e n t r a t i o n ( µ g / m L )

Fo

ld I

nc

re

as

e±

SE

M

4 02 . 5 7 . 55

Human nmDMD Myotubes nmDMD Zebrafish

0 0 1 2 . 5 5 1 0 2 0 4 0

0

5 0

1 0 0

( - / - )( + / + )g e n o t y p e :

C o n c e n t r a t i o n ( u g / m l )

GA

G r

ed

uc

tio

n (

% a

vg

)

0 0 0 . 1 0 . 3 1

0

5 0

1 0 0

( - / - )( + / + )g e n o t y p e :

C o n c e n t r a t i o n i n f o o d ( w / w )

GA

G r

ed

uc

tio

n (

% a

vg

)

nmHurler Fibroblasts nmHurler Mice

Concentration (µm/mL)

Fold

incr

ease

±SE

MFo

ld In

crea

se ±

SEM

GAG

Red

uctio

n (%

avg

)

Concentration (µm/mL) Concentration in food (w/w)

GAG

Red

uctio

n (%

avg

)

(-/-)(+/+)genotype:

0

50

100

0 0 1 2.5 5 10 20 40(-/-)(+/+)genotype:

0

50

100

0 0.10 0.3 1

Individual change in 6MWD for patients meeting confirmatory Phase 3 nmDMD clinical trial entry criteria

JAN 2015 63

-3 0 0

-2 0 0

-1 0 0

0

1 0 0

P a tie n ts

a ta lu re n m e a n

-1 2 .3 m

Patients from Phase 2b study: on steroids, age 7-16 y, baseline 6MWD ≥150 m, and baseline 6MWD <80%-predicted

-3 0 0

-2 0 0

-1 0 0

0

1 0 0

P a tie n ts

Ch

an

ge

in

6M

WD

(m

)

p la c e b o m e a n

-6 2 .2 m

Placebo (n=30) Translarna (n=30)

All low-dose Translarna subjects had mean ataluren concentrations <19.3 µg/mL 2 hours after the morning dose

JAN 2015 64

Range

4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0 4 20

5

1 0

1 5

2 0

2 5

4 0 m g /k g /d a y a ta lu re n (n = 5 7 )

8 0 m g /k g /d a y a ta lu re n (n = 6 0 )

< 1 9 .3 µ g /m L > 1 9 .3 µ g /m L

4

6

5

1 4 1 4

6

5

2

11

3

5

8

6

3

7

8

4

2

3

4

3

1 1 1

C o n c e n tra t io n (µ g /m L )

Pe

rce

nt

of

Pa

tie

nts

6MWT results were better in the low concentration groupof the 80 mg/kg/day group in the Phase 2b nmDMD trial

JAN 2015 65

-12.9 m

-22.6 m

-57.0 m

-42.6 m

-70

-60

-50

-40

-30

-20

-10

0M

ean

chan

ge in

6M

WD

(m)

40 mg/kg/day ataluren (n=57)

80 mg/kg/day, low conc. ataluren (n=26)

80 mg/kg/day, high conc. ataluren (n=33)

Placebo (n=57)

Mean and significance levels for change in 6MWD by 2-hour plasma concentrations ranges confirmed better outcomes at lower exposures

JAN 2015 66

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

(n= 4 0 ) 5

-18

(n= 4 0 ) 6

-19

(n= 3 9 ) 7

-20

(n= 4 0 ) 8

-21

(n= 3 9 ) 9

-22

(n= 3 9 ) 1

0 -23

(n= 3 6 ) 1

1 -24

(n= 2 6 ) 1

2 -25

(n= 2 3 ) 1

3 -36

(n= 2 1 ) 1

4 -37

(n= 2 2 ) 1

5 -28

(n= 1 9 ) 1

6 -29

(n= 1 8 ) 1

7 -30

(n= 1 7 ) 1

8 -31

(n= 1 6 ) 1

9 -32

(n= 1 7 ) 2

0 -33

0 .0 0 1

0 .0 5

0 .1 0

0 .5

0 .0 1

0 .2 5

(n= 1 5 ) 2

1 -34

(n= 1 4 ) 2

2 -35

(n= 1 1 ) 2

3 -36

(n= 1 1 ) 2

4 -37

(n= 1 3 1 ) 2

5 -38

1 .0

(n= 3 2 ) 1

-14

(n= 3 4 ) 2

-15

(n= 3 7 ) 3

-16

(n= 4 0 ) 4

-17

C o n c e n tra t io n R a n g e (µ g /m l)

Dif

fere

nc

e i

n C

ha

ng

e f

rom

Ba

se

lin

e M

ea

n a

nd

95

% C

I, m

p-v

alu

e fro

m M

MR

M (t-te

st)

0 .0 2 5

For patients on steroids, 7-16 y, ≥150 m 6MWD, <80% predicted

Low-Exposure Translarna Minus Placebo (n=31) at Week 48

PTC: The pioneer in DMD trial development

15 years of research & development 650+ healthy volunteers/patients exposed/treatedSafety profile: Generally well toleratedPhase 2a: Dystrophin expression demonstratedPhase 2b: Clinically meaningful benefit in 6MWT/Natural History data Phase 3: ACT DMD fully enrolled with data expected Q4 2015

JAN 2015 67

Phase 2a (004)38 patients

Phase 3 (020)220 patients

Phase 2b (007)174 patients

EMA DMDDraft Guidelines

Initial Natural History Publications

TranslarnaTM

discovery

Phase 162 healthy volunteers

98–2003 2008 2009 2011 2012 2013201020072005 20062004 2014

Translarna™Nonsense mutation Cystic Fibrosis

68JAN 2015

Increased CFTR expression in intestine

CFTR chloride channel activity

Increased CFTR production after ataluren treatment

Demonstrated CFTR chloride channel activity

Trends in improvement in pulmonary function

Reduction in cough

Sermet et al, Ped Pulm, 2008

Ataluren mechanism of action has been demonstrated in preclinical and clinical studies in nmCF

JAN 2015 69

Control

Time

Volta

ge

Ataluren

Time

Volta

ge

nmCF mouse model Phase 2a nmCF clinical trial

Du et al, PNAS, 2008

Class I cystic fibrosis patients have a more rapid decline in lung function than patients with Class II mutations

JAN 2015 70Cystic Fibrosis Foundation Registry Data

6 -1 2 Y e a r O ld s 1 2 -1 8 Y e a r O ld s7 0

8 0

9 0

1 0 0

% -P re d ic te d F E V 1 M e a n

C la s s I

C la s s I I

%-P

red

icte

d

FE

V1

M

ea

n

Impact of antibiotics on Translarna activity:in vitro reporter system*

JAN 2015 71

5 0

7 5

1 0 0

T ra n s la rn a T ra n s la rn a +T o b ra m y c in

T ra n s la rn a +G e n ta m ic in

T ra n s la rn a +C o lis tin

T ra n s la rn a +A z tre o n a m

Pe

ak

rea

d t

hro

ug

h (

% o

f T

ran

sla

rna

)

*Results from 2 independent experiments

Aminoglycoside Non-aminoglycoside

Relative Change in %-Predicted FEV1 (ITT; Observed Data) in Study 009 and 009e

0 1 6 3 2 4 8 6 4 8 0 9 6-1 0

-8

-6

-4

-2

0

2

A ta lu re n /A ta lu re n (A /A )

P la c e b o /A ta lu re n (P /A )

T im e , w e e k s

Rel

ativ

e C

han

ge

in %

-Pre

dic

ted

FE

V1,

Mea

n

8 2 4 4 0 5 6 7 2 8 8

n = 1 1 6 1 1 3 1 0 3 1 0 2 1 0 0 9 8 1 0 0 9 1 9 1 8 3 7 8 7 8 7 5n = 1 1 6 1 1 0 1 0 9 1 0 5 1 0 2 1 0 0 1 0 3 8 9 8 8 8 2 7 2 6 9 6 6

Spinal Muscular AtrophyDiscovery of a small molecule therapeutic

JAN 2015 73

Severity of SMA determined by % functional SMN

JAN 2015 74

Type Disease Severity % Functional SMN1

IMost severe, infants have trouble breathing and don’t usually live past 2 years of age

25 – 40%

IIOnset at 6-18 months, patient may walk briefly, death likely in early adulthood

~60% (+/- 5%)

IIIPatients may walk into early adulthood ~70% (+/- 5%)

1. Protein levels measured in vitro fibroblast cells as a percent of heterozygous levels

Incremental increases in SMN protein levels create meaningful clinical improvements

PTC compounds increase SMN protein in multiple tissues to near or above heterozygous levels Oral dosing for 10 days in SMA Type 3 mouse model

JAN 2015 75

Brain Peripheral Blood Mononuclear Cells

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

V e h ic le

H e te ro z y g o u s (n od is e a s e p h e n o ty p e )

* * *

* * *

* * *

SM

N p

rote

in%

in

cre

as

e±

SE

M

2 6 1 0

D o s e (m g /k g )

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

V e h ic le

H e te ro z y g o u s (n od is e a s e p h e n o ty p e )

* *

* * *

* * *

SM

N p

rote

in%

in

cre

as

e±

SE

M

2 6 1 0

D o s e (m g /k g )

SMN protein levels in peripheral blood cells correlate to those in brain

Similar increases in SMN observed in spinal cord, muscle, heart, liver, skin

Crosses blood brain barrier for pan-tissue distribution

Naryshkin et al., 2014 Science, 345:688

Compound modifies SMN2 alternative splicing and increases SMN protein in vitro in SMA patient cells

-3 -2 -1 0 10 .0

0 .5

1 .0

1 .5

2 .0

2 .5

S M N 2 F L

S M N 2 ∆ 7

C o n ce n tra t io n (µ M )

SM

N2

mR

NA

Fo

ld r

ela

tive

to

DM

SO

± S

D

0 .0 0 1 0 .0 1 0 .1 1 1 00 .8

1 .0

1 .2

1 .4

1 .6

1 .8

2 .0

C o n ce n tra t io n (µ M )

SM

N p

rote

in

Fo

ld r

ela

tive

to

DM

SO

± S

DΔ7

FL

DM

SO

3 µM3 nM

GAPDH

SMN

DM

SO

3 µM3 nM

SMN2 alternative splicing correction(end-point RT-PCR)

SMN protein increase(Western blot)

SMN2 alternative splicing correction(RT-qPCR)

SMN protein increase(HTRF)

Naryshkin et al., 2014 Science, 345:688 76JAN 2015

PTC compounds confer long term survival and prevent body-weight loss in Type I SMA mice

JAN 2015 77

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 00

2 5

5 0

7 5

1 0 0

A g e o f m ic e (d a y s )

Pe

rce

nt

su

rviv

al

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 00

1 0

2 0

3 0

4 0

5 0

A g e o f m ic e (d a y s )M

ea

n b

od

y w

eig

ht

(g)

Heterozygous (n=10), Placebo (n=15), 6 mg/kg PO (n=15)

Naryshkin et al., 2014 Science, 345:688

Pre-clinical data demonstrated improved phenotype and survival

Prolonged Survival Body Weight Gain

Prevention of muscle atrophy in severe Type I SMA mice

JAN 2015 78

Wild type SMA mouse Treated SMA mouse

Mice were treated from 3-days old through 14-days old with Compound (3 mg/kg IP)

Courtesy of Dr. Ko (USC)

SMN protein can be monitored as a biomarker

0 1 0 2 0 3 00

5 0

1 0 0

1 5 0

T im e p o s t-d o s e (h )[s in g le o ra l d o s e (1 0 m g /k g ) in m ic e ]

SM

N p

rote

in o

r F

Lm

RN

A

% in

cre

as

e±

SD

B ra in S M N p ro te in

B lo o d S M N F L m R N A

P la s m a d ru g le v e l (n g /m L )

JAN 2015 79

Protection from neuromuscular junction denervation

JAN 2015 80

SMA treated

Blue = neuronal axonGreen = NMJ, neuronRed = NMJ, muscle

WT vehicle

SMA vehicle

Courtesy of Dr. Ko (USC)