PTC Therapeutics, Inc. June 2014

Transcription

1 PTC Therapeutics, Inc. June 2014

2 Forward-looking statements This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of All statements, other than those of historical fact, contained in this presentation, including statements regarding the future expectations, plans and prospects for PTC, our Phase 3 clinical trials for Translarna in nmdmd and nmcf, including the timing of enrollment for such trials, our collaboration in SMA with Roche and the SMA Foundation, the timing of regulatory approvals, including any determination (whether positive or negative) by the European Commission with respect to conditional marketing authorization for Translarna in nmdmd, the development of and potential market for Translarna, including our estimates regarding the size of the nmdmd patient population, our ability to satisfy the obligations necessary to obtain full approval for Translarna in nmdmd, and the objectives of management, are forward-looking statements. Other forward-looking statements may be identified by the words plan, guidance, anticipate, believe, estimate, expect, intend, may, predict, project, target, potential, will, would, could, should, continue, and similar expressions. 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 among others, those related to the initiation and conduct of clinical trials, availability of data from clinical trials, expectations for regulatory approvals, our scientific approach and general development progress, the availability or commercial potential of our product candidates and the other factors discussed in the Risk Factors section of our most recent Quarterly Report on Form 10-Q, which is on file with the Securities and Exchange Commission. You are urged to carefully consider all such factors. The forward-looking statements contained herein represent PTC s views only as of the date of this presentation, and we do not undertake or plan to update or revise any such forward-looking statements. June

3 Our mission To leverage our knowledge of RNA biology to bring novel therapeutics to patients affected by rare and neglected disorders June

4 Executing on PTC s strategy Focus on the late-stage development and commercialization of Translarna TM (ataluren) in nmdmd, nmcf 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 June

5 PTC s RNA-focused small molecule technology platform DNA pre-mrna mrna Protein exon intron 5 cap ribosome poly(a) tail GLU VAL LYS trna PTC s Platform Technologies Nonsense Readthrough Alternative Splicing Nucleotide Repeat Protein Modification Transcript Regulators June

6 Pipeline summary Product / Platform Discovery Preclinical Phase 1 Phase 2 Phase 3 Status/Plans Translarna TM (ataluren) nonsense readthrough Orphan genetic disorders nmdmd nmcf Other indications P3 enrollment ongoing Positive CHMP opinion Initiating P3 H Announce in 2014 SMA ( ) alternative splicing SMA program Entered P1 Jan 2014 DMD Exon 51 alternative splicing DMD Lead discovery PTC596 stem cell targeting PTC compound DNA synthesis Oncology BMI1 Antibacterial Gonorrhea IND-enabling studies Lead optimization June

7 European MAA for Conditional Approval How we worked with regulators to obtain a positive opinion June

8 Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder due to the loss of dystrophin protein Extracellular Matrix Muscles lacking dystrophin are more susceptible to muscle damage Dystrophin replacement is expected to prevent muscle damage Dystroglycans Sarcolemma Membrane Laminin-ɑ2 Sarcoglycan Complex Sarcospan ~34,000 boys in US/EU ~13% caused by nonsense mutations Dystrophin C-Term Syntrophins ɑ-dystrobrevin N-Term F-Actin Dystrophin stabilizes, but does not increase muscle strength June

9 DMD is a progressive and fatal genetic disorder Developmental delay Impaired standing Progressive ambulatory decline Transition to wheel chair skeletal deformity Very limited use of arms loss of self feeding Ventilation at night Ventilation 24 hours Death Ambulatory changes predict loss of function Age at loss of ambulation predicts loss of self feeding and need for ventilation June

10 PTC: Pioneer in DMD trial development Translarna TM discovery Phase 2b (007) 174 patients Phase 3 (020) 220 patients Phase 1 62 healthy males Phase 2a (004) 38 patients Initial Natural History Publications EMA DMD Draft Guidelines years of research & development 650+ healthy volunteers/patients exposed/treated Safety profile: Generally well tolerated Phase 2a: Dystrophin expression demonstrated Phase 2b: Clinical efficacy demonstrated/natural history established Phase 3: ACT DMD meeting enrollment projections June

11 Translarna CHMP positive opinion based on number of factors 1 Understanding the Natural History of DMD using the six minute walk test (6MWT) Efficacy in the Primary Endpoint 6MWT Efficacy across multiple secondary endpoints Good safety profile Confirmatory trial well underway June

12 1 The placebo arm of the study defined the Natural History of DMD as measured by the 6MWT Results indicate that generally: 5-6 year old DMD boys can increase in walking 7 year old and greater then stabilize, slowly losing walking ability Once the baseline 6MWD is <350 meters DMD patients rapidly decline in ambulatory ability No Natural History Prior to This Study June

13 Phase 2b placebo-control data defined natural history of 6MWD 6 -M in u te W a lk D is ta n c e, m Maturational improvements Stabilization Decline P la c e b o (N = 5 7 ) A g e (y ) June

14 Natural history from Phase 2b trial are similar to Goemans et al. Placebo Data: Translarna TM Study sites (N=57) Baseline to Week 48 Natural History Data: Goemans et al [2013] N=25 Baseline to Week 52 Δ -44 meters (SD 88) Δ -43 meters (SD 90) Similar Δ -7.3% natural Predicted history results were also observed in the Prosensa/GSK Δ -8.1% Predicted phase 3 trial June

15 6 -M in u te W a lk D is ta n c e (m ) Baseline 6MWD is a key factor in determining whether DMD patients will decline substantially in a year C h a n g e in 6 M W D, m e a n (m ) B a s e lin e 6 M W D m (n = 3 4 ) m m P la c e b o (n = 5 7 ) Placebo (n=34) m A g e (y ) B a s e lin e T im e (w e e k s ) June

16 6 - M i n u t e W a l k D i s t a n c e, m Results from placebo arm show that baseline 6MWD is a key factor in determining whether DMD patients decline C h a n g e i n 6 M W D, m e a n ( m ) B a s e l i n e 6 M W D ( N = 3 5 ) m B a s e l i n e 6 M W D < m ( N = 2 2 ) <350 m m P l a c e b o Placebo ( N = 5 7 ) A g e ( y ) B a s e l i n e T i m e ( w e e k s ) Lessons learned 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 June

17 2 Translarna demonstrated efficacy in the Primary Endpoint 6MWT 31.3 meter difference in the 6MWT in the original, pre-specified analyses of the overall study population 49.9 meter difference in the ambulatory decline phase subgroup 68.2 meter difference in the pre-specified <350 subgroup A separation from placebo early in the pre-specified time-to-worsening analysis that increased over the 48 week period Improvements in 6MWD in DMD patients in all disease stages June

18 Translarna TM slowed disease progression in nmdmd patients C h a n g e 6 M W D (m ), m e a n (S E M ) 2 0 Based on Phase 2b post-hoc citt* analysis m (7 2 ) m p = m g /k g /d a y T ra n s la rn a (n = 5 7 ) P la c e b o (n = 5 7 ) m (8 8 ) -6 0 B a s e lin e T im e (w e e k s ) *citt= Corrected intent to treat analysis June 2014 conducted on a post-hoc basis 17

19 C h a n g e in 6 M W D (m ), m e a n (S E M ) Translarna TM demonstrated the greatest benefit over 48 weeks with patients in the ambulatory decline phase 2 0 Based on Phase 2b post-hoc subgroup 1 analysis and citt m (6 9 ) m n o m in a l p = m g /k g /d a y T ra n s la rn a (n = 3 2 ) P la c e b o (n = 3 1 ) m (8 5 ) -7 0 B a s e lin e T im e (w e e k s ) June In patients on corticosteroids, between 7 and 16 years of age, with baseline 6MWD 150m and 80% of predicted 18

20 C h a n g e in 6 M W D (m e a n, m ) Translarna TM treatment effect increases in the decline subgroup and in the pre-specified baseline 6MWD <350 m subgroup* W e e k = m 6 0 = m 4 0 = m 2 0 p = n o m in a l p = n o m in a l p = c IT T D e c lin e < m p h a s e (b a s e lin e ) June 2014 *Post-hoc analysis 19

21 Translarna TM treatment effect seen in all disease stages studied Improving C h a n g e in 6 M W D (m ), m e a n Severity m + 9 m n = 1 8 n = 2 2 n = 2 0 n = 2 3 n = 1 2 n = m m m m g /k g /d a y T ra n s la rn a P la c e b o m > 7 0 % % < 5 0 % B a s e lin e % -p r e d ic te d 6 M W D June

22 Treatment 6MWT outcomes in approved drugs that treat neuromuscular disorders vs Translarna TM Translarna TM in the < 350 meters Baseline 6MWD subgroup (nmdmd) Δ 68.2 m Translarna TM in the Decline Phase Subgroup (nmdmd) Δ 49.9 m Aldurazyme (MPS I) Δ 38 m Elaprase (MPS II) Δ 35 m Translarna TM in the Overall Population (nmdmd) Δ 31.3 m Translarna TM Lumizyme, Myozyme (Pompe Disease) Δ 28 m Approved Drug Vimizim, Biomarin (MPS IVa) Δ 23 m Mean Change in 6WMD Treatment vs Placebo June 2014 *Measured in separate trials 21

23 Translarna TM slowed disease progression in nmdmd patients P e r c e n t N o t 1 0 % W o r s e n e d % p ro g re s s in g m g /k g /d a y T ra n s la rn a (N = 5 7 ) P la c e b o (N = 5 7 ) 4 4 % p ro g re s s in g Pre-specified analysis (citt) 40 mg/kg/day Translarna TM vs. placebo - nominal p= W e e k s Translarna TM was effective, with separation between treated and placebo patients occurring early June

24 3 Translarna demonstrated positive trends in multiple secondary endpoints Improvements in the Timed Function Tests (TFTs) in the original, pre-specified analyses of the overall study population 10-meter Run/Walk 4 Stair Climb 4 Stair Descend Trends more prominent in the TFTs in the ambulatory decline phase subgroups (decline phase and <350 meter subgroups) Other indications of improvement also considered by CHMP: Strength as measured by myometry in the 5-6 year olds QoL physical functioning Accidental falls Time in wheelchair Step activity monitoring June

25 Timed function tests (TFTs) are key secondary endpoints Well-established clinical outcome measures Predict loss of ability to climb stairs and loss of ambulation [CINRG Natural History Study - Neuromuscular Disorders 2013] Associated with measures of activities of daily living [Mazzone 2011] 10-meter walk/run: Measure of burst activity (instead of endurance) 4-stair climb (ascend/descend) requires both upper and lower limbs Changes in TFTs are strongly associated with changes in patient perception of activities of daily living and QOL [Henricson 2013] TFTs Predict time to loss of stair climb and ambulation 1.5 second threshold is a clinically meaningful difference in DMD 1 June Escolar

26 Phase 2b demonstrated activity in timed function tests: Overall population and decline subgroups Worsening C h a n g e fro m B a s e lin e, m e a n (s e ),s e c o n d s D e c lin e P h a s e < m e te r s P h a s e 2 b (a ll p a tie n ts ) s u b g ro u p s u b g ro u p 1 0 m W R C lim b D e s c e n d m W R C lim b D e s c e n d 1 0 m W R C lim b D e s c e n d s -2.4 s -1.6 s -2.8 s -2.9 s -2.9 s s s -5.0 s T ra n s la rn a 4 0 m g /k g /d a y P la c e b o No other dystrophin restoration treatments have shown positive trends on timed function tests at 48 weeks June

27 Additional secondary endpoints trended in favor of Translarna TM Frequency of accidental falls Patient-reported physical function: QOL Time in wheelchair Step-activity monitoring Myometry (Rapporteur-requested analysis) Translarna TM -treated patients demonstrated benefit in multiple measures of physical functioning June

28 Myomety is only sensitive in young patients: Strength vs. Function Function: 6MWT Strength: Knee Extension [McDonald 2013] [Abresch 2011 American Academy of Neurology presentation] Largest improvements in 6MWT up to age 7 Largest decline in strength up to age 7 followed by floor effect June

29 Mean change from baseline in muscle strength evaluated by myometry (patients 5-6 years old) Worsening M e a n C h a n g e (lb ) Most reliable tests in 5 and 6 year olds P la c e b o (N = 1 4 ) T ra n s la rn a 4 0 m g /k g /d a y (N = 9 ) Knee Extension No other dystrophin restoration treatments have shown positive trends in strength Elbow Flexion Knee Flexion Elbow Extension Shoulder Abduction* * For shoulder abduction, the mean change in the placebo arm was 0.0 lbs June

30 4 Translarna demonstrated a good safety profile.the CHMP also considered the safety profile of Translarna which was not of concern CHMP Summary Opinion June

31 5 Confirmatory trial is well underway The ACT DMD confirmatory trial is well underway which addressed CHMP previous concerns about study completion June

32 First Positive CHMP Opinion for Conditional Approval for the Underlying Cause of DMD Primary Secondary Tertiary Positive 6MWT results Improvement seen in TFTs Better outcomes observed 31.3 m in overall population 49.9 m in ambulatory decline group 68.2 m in <350 m group 10 m walk- run Stair climb Stair descend All ambulatory phases of disease Myometry in 5&6 year olds Quality of life Fewer falls Step activity Less time in wheelchair Positive Opinion Natural History independently confirmed and consistent Safety: Generally well tolerated Confirmatory Trial: Well underway June

33 Ongoing confirmatory Phase 3 ACT DMD clinical trial targeting patients in the ambulatory decline phase Double-blind placebo-controlled study Length of Trial Translarna TM (n) Placebo (n) 48 weeks Primary outcome measure: 6MWD (change from baseline) Secondary outcome measure: Timed-function tests North Star PODCI QoL Eligibility Criteria 7 years & 16 years Steroid use 6MWD 150 m 80% of predicted for age and height Stratification 350 m vs <350 m 9 years vs <9 On-track to complete enrollment in mid-2014 June

34 Key commercialization capabilities underway in Global HQ, European HUB and targeted early access countries GLOBAL HQ PTC EU HUB UK EC ratification expected within 3 months Pursuing Early Access Programs Well-defined supply chain 33

35 Financial snapshot March 31, 2014 cash balance: ~$247 million Market capitalization: ~$713 million (as of May 30, 2014) Approximately 30.1 million shares outstanding June

36 PTC value drivers Additional SMA Data Expected Translarna TM CF P3 Study Fully-Enrolled Submit for Translarna TM Full Approval in DMD in 2016 Translarna TM DMD P3 Study Fully Enrolled Initiate P3 Translarna TM DMD Study Declare SMA Development Candidate Highlighted Pipeline at 1st R&D Day Initiate SMA P1 Study Initiate P3 Translarna TM CF Study Translarna TM Proof-of-Concept Study in Other Indications Translarna TM DMD P3 Top-Line Data Translarna TM CF P3 Top-Line Data EMA CHMP Opinion June

37 Questions & Answers Appendix slides June

38 Ataluren treats a distinct patient population within DMD Company Product candidate Target % DMD Population Phase Largest Trial Translarna Nonsense mutation 13% Ph drisapersen Exon 51 skip 13% Ph eteplirsen Exon 51 skip 13% Ph. 2b 12 PRO-044 Exon 44 skip 6% Ph. 1/2a 18 June

39 Translarna Nonsense mutation readthrough June

40 Translarna binds to the ribosome and enables readthrough of nonsense mutation to produce functional protein 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 June

41 Translarna: Late-stage asset with disease-modifying potential in multiple orphan disorders Characteristics Market Potential Status Orally bioavailable Reliable manufacturing Pediatric-friendly formulation Generally well tolerated ~600 individuals dosed to date ~11% of patients across all monogenic disorders have a nonsense mutation Potential disease modifying therapy Orphan designation EU & US PTC retains worldwide commercial rights Confirmatory Phase 3 trial in nmdmd ongoing Phase 3 nmcf trial initiation in H Additional indications in 2014 Patents until (composition & method of use) N O F N CO 2 H June

42 Translarna is active in numerous indications Muscle disorders Duchenne muscular dystrophy (Welch et al. 2007, Kayali 2012, Arner 2013) Miyoshi Myopathy (Wang 2010) Ion channel disorders Cystic fibrosis (CF) (Du 2008, Kerem 2008, Sermet-Gaudelus 2010, Wilschanski 2011, Gonzalez-Hilarion 2012) Long QT syndrome (Yu 2014) Neurological disorders Infantile neuronal ceroid lipofuscinoses (INCL) (Sarkar 2011, Miller 2013) Late infantile ceroid lipofuscinoses (LINCL) (Miller 2013) Ataxia telangiectasia (Du 2013) Usher syndrome (USCH1C) (Goldmann 2011, Goldmann 2012) Skin disorders Pseudoxanthoma elasticum (Zhou 2013) Eye disorders Choroideremia (Moosajee unpublished) Aniridia (Gregory-Evans 2014) Pulmonary disorders Heritable pulmonary arterial hypertension (HPAH) (Drake 2013) Metabolic disorders Carnitine palmitoyltransferase 1A deficiency (Tan 2011) Methylmalonic aciduria (MMA) (Buck 2012) Propionic acidemia (PA) (Sanchez-Alcudia 2012) Maroteaux-Lamy syndrome (MPS VI) (Bartolomeo 2013) Hurler s syndrome (MPS I) (Keeling et al. unpublished) Reporters GFP and Luciferase (Welch et al. 2007, Lentini 2014) Xeroderma pigmentosum (Kuschal 2013) (independent investigators) June

43 Tissue GAG (ug GAG / mg tissue) Tissue GAG (ug GAG / mg tissue) Translarna s activity in a Hurler nonsense mutation model 6 Brain Spleen 5 4 ** ** untreated 0 WT Idua-W392X 0 WT Idua-W392X treated **p<0.01 (t-test, compared to Idua-W392X vehicle) Ataluren treatment reduces GAG levels in multiple tissues in a Hurler nonsense mutation mouse model Neufeld and Muenzer, The Mucopolysaccharidoses, in The Metabolic and Molecular Bases of Inherited June 2014 Disease, 2001 Keeling et al unpublished data 42

44 Translarna s activity in an aniridia nonsense mutation model Pax6 protein (% of wildtype) Ataluren increases PAX6 in Pax6 Sey mice 120 * 100 * Wt Sey Sey Neu Neu Wt Sey Sey Neu Neu WT = wild type Neu = splice-site mutation Sey = nonsense mutation * p<0.001; n=6. Treated with ataluren Retina Corneal Epithelium Ataluren increases PAX6 protein in retina and cornea in the nonsense mutant (Sey), not in the splice-site mutant (Neu) June 2014 Gregory-Evans 2014 JCI 43

45 Translarna treatment restores morphology and sight Wild type untreated Mutant + vehicle Mutant + ataluren P60 WT Mt Mt + ataluren Gregory-Evans 2014 JCI June

46 Efficacy of Translarna in nonsense mutation choroideremia 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 Wild type Mutant + vehicle Mutant + ataluren June 2014 Moosajee et al. unpublished data 45

47 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 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 CFTR June

48 Nonsense mutations cause the most severe form of CF CFTR channel through cell membrane CFTR CFTR CFTR CFTR CFTR protein CFTR CFTR CFTR CFTR CFTR CFTR CFTR CFTR CFTR cftr gene in cell nucleus Class Normal I No Synthesis II Processing Block III Gating IV Conductance V Reduced Synthesis % CF Patients 10% 70% 3-5% 2% 2% Compounds ataluren 1 VX809 VX661 Kalydeco Translarna is only compound in development for the most severe form (Class 1) 1. VX809 and VX661 are only for homozygote, June % 47

49 R e la tiv e C h a n g e in % -P r e d ic te d F E V 1, M e a n R e la tiv e C h a n g e in % -P r e d ic te d F E V 1, M e a n Translarna had a clinically meaningful benefit (ΔFEV %) in the 65% of nmcf patients not on inhaled TOBI Without Inhaled TOBI 1 With Inhaled TOBI 2 2 Week 48 Δ= +5.7% (nominal p=0.008) 2 Week 48 Δ= -1.4% (nominal p=0.43) % % m g /k g /d a y a ta lu re n (n = 7 2 ) -6.4 % m g /k g /d a y a ta lu re n (n = 4 4 ) -5.5 % P la c e b o (n = 7 4 ) P la c e b o (n = 4 2 ) -8 B a s e lin e B a s e lin e T im e (w e e k s ) T im e (w e e k s ) Translarna decreased pulmonary exacerbation rates in Non-TOBI patients by 41% vs. placebo nominal p= No antibiotics or use of nonaminoglycoside antibiotics 2. Alone or with other antibiotics June Overall population decreased 23% (n=226, p=0.0992) 48

50 Our experience informed our Phase 3 trial design Initial Phase 3 Next Steps TOBI use interfered with Translarna s efficacy Non-TOBI patients had meaningful benefit Translarna decreased pulmonary exacerbations Generally well tolerated Start confirmatory Phase 3 in H Primary endpoint: FEV 1 Restricted TOBI use Targeting complete enrollment mid-2015 Translarna nmcf Phase 3 data expected mid-2016 June

51 Spinal Muscular Atrophy Discovery of a small molecule therapeutic

52 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 Dorsal Root Ventral Root June

53 Targeting alternative splicing in SMA SMA patients rely on a related SMN-2 gene which produces only low levels of SMN protein due to a splicing defect Small molecule targets splicing to correct defective splicing of exon 7 SMN-1 SMN-2 SMN-2 with Treatment DNA DNA DNA RNA 7 RNA RNA 7 SMN protein Unstable SMN protein Functional SMN protein June

54 Severity of SMA determined by % functional SMN Type I II III Disease Severity Most severe, infants have trouble breathing and don t usually live past 2 years of age Onset at 6-18 months, patient may walk briefly, death likely in early adulthood Patients may walk into early adulthood % Functional SMN % ~60% (+/- 5%) ~70% (+/- 5%) Incremental increases in SMN protein levels create meaningful clinical improvements 1. Protein levels measured in vitro fibroblast 1. June 2014 cells as a percent of heterozygous levels 53

55 PTC compounds have demonstrated dose-dependent increases in SMN protein S M N p r o te in % in c r e a s e S E M S M N p r o te in % in c r e a s e S E M Oral dosing for 10 days in SMA Type 3 mouse model Brain Peripheral Blood Mononuclear Cells * * * H e te ro z y g o u s (n o d is e a s e p h e n o ty p e ) * * * * * * * * * H e te ro z y g o u s (n o d is e a s e p h e n o ty p e ) * * * * * 0 V e h ic le V e h ic le D o s e (m g /k g ) 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 June

56 Prolonged survival & body weight gain in Type I SMA mice 100 M e a n b o d y w e ig h t (g ) Prolonged Survival Body Weight Gain 3 0 Percent survival Age of mice (days) A g e o f m ic e (d a y s ) Heterozygous (n=10), Placebo (n=15), 1 mg/kg PO (n=16), 10 mg/kg PO (n=16) Pre-clinical data demonstrated improved phenotype and survival June

57 Prevention of muscle atrophy in severe Type I SMA mice Wild type SMA mouse Treated SMA mouse Mice were treated from 3-days old through 14-days old with Compound (3 mg/kg IP) June 2014 Courtesy of Dr. Ko (USC) 56

58 SMA Collaboration with Roche and SMAF SMAF/Roche Collaboration in SMA SMA Phase 1 Program (RG7800) Initial funding in part provided by SMA Foundation Partnered with Roche in late 2011 $30M upfront Up to $460M in milestones Healthy volunteer study n=48 Two arms: single ascending dose vs. placebo FPI Q Royalties Development Candidate declared in July 2013: $10M milestone Entered clinical development in Jan 2014: $7.5M milestone June

59 Observational studies in SMA program SMA Biomarker Study SMA Natural History Study Purpose: Single-center study with blood samples taken from SMA patients during a single visit for biomarker analysis Timeframe: Single visit Primary Outcome Measures: SMN1/SMN2 detection in blood by mrna assay Secondary Outcome measures: SMN protein level in blood / lymphocytes Purpose: Single-center study, 24-week longitudinal study in SMA patients matched to healthy volunteers by age and gender Timeframe: 24 weeks; testing at baseline, Week 12 and 24 Primary Outcome Measures: Quantitative muscle MRI and T2 values Disease progression, assessed through Motor Function Measure test Secondary Outcome measures: Disease progression using 6MWT Levels of SMN RNA Levels of SMN protein June

60 SMA program validates PTC s alternative splicing platform Focus on Alternative Splicing Include or exclude exons in mrna splicing to affect protein production DMD Exon51 Oncology Myostatin June

61 Evaluating PTC s genetic disorder pipeline Translarna and Nonsense readthrough program Additional potential indications Next generation readthrough Nonsense-mediated decay Leveraging PTC s RNA platform Nucleotide repeat sequences Exon skipping June

62 Translarna targets a different sub-population in DMD vs. exon skipping therapies in development Nonsense + Ataluren Nonsense Normal Deletion Normal Exon Skipping Nonsense Mutation Readthrough Exon Skipping VAL PHE TYR C A C A A A A U G G U G U U U U A C VAL PHE No natural trna Singlepoint alteration C A C A A A G U G U U U U A G Nonfunctional VAL PHE TYR C A C A A A G U G U U U U A G June 2014 Truncated and 61 functional

63 Experience and natural history data informed our trial design What We Saw in Our Phase 2b trial Phase 3 Trial Ongoing 31 m delta in 6MWD for overall citt population 50 m delta in 6MWD in post hoc analysis of the decline subgroup Bell-shaped dose-response curve: demonstrated effective dose Generally well tolerated Inclusion criteria enriches for patients in decline 6MWD >150 m and <80% of predicted Boys 7-16 yrs 40 mg/kg/day dose Powered for 30 m delta in 6MWD Translarna nmdmd Phase 3 data expected mid-2015 June

64 Extension cross-over trial demonstrates that patients FEV 1 is maintained or improves R e la tiv e C h a n g e in % p r e d ic te d F E V 1, M e a n 6 4 S tu d y S tu d y e m g /k g /d a y a ta lu re n P la c e b o T im e, w e e k s Relative change in %-predicted FEV 1 through Week 96 June

65 Protection from neuromuscular junction denervation WT vehicle Blue = neuronal axon Green = NMJ, neuron Red = NMJ, muscle SMA vehicle SMA treated June 2014 Courtesy of Dr. Ko (USC) 64

66 Translarna treatment was associated with improvements in dystrophin expression in Phase 2a nmdmd clinical trial Pretreatment End of Treatment (Day 28) Over 28 days, improvements were seen in ~60% of patients Phase 2a study; Bönnemann et al, June 2014 Neuromusc. Disord

67 Human myotube* data demonstrates a bell-shaped ataluren dose-response curve for dystrophin expression D y s tr o p h in E x p r e s s io n F o ld In c r e a s e ± S E M Mean Increase in Full-Length Dystrophin Expression Relative to Control A ta lu r e n C o n c e n tr a tio n ( g /m L ) * Samples from Phase 2a June 2014 nmdmd clinical trial patients 66

68 Time to persistent 10% worsening indicated a slower disease progression in the Translarna group P e r c e n t N o t 1 0 % W o r s e n e d mg/kg/day Translarna vs placebo Nominal p= % p ro g re s s in g % p ro g re s s in g m g /k g /d a y a ta lu re n (n = 5 7 ) 4 0 P la c e b o (n = 5 7 ) W e e k s June

69 C h a n g e in 6 M W D (m ) Individual change in 6MWD for patients meeting confirmatory Phase 3 nmdmd clinical trial entry criteria Placebo (n=30) Translarna (n=30) a ta lu re n m e a n p la c e b o m e a n m m P a tie n ts P a tie n ts Patients from Phase 2b study: on steroids, June 2014 age 7-16 y, baseline 6MWD 150 m, and baseline 6MWD <80%-predicted 68

70 All low-dose Translarna subjects had mean ataluren concentrations <19.3 g/ml 2 hours after the morning dose P e r c e n t o f P a tie n ts 2 5 Range < g /m L > g /m L m g /k g /d a y a ta lu re n (n = 6 0 ) 4 0 m g /k g /d a y a ta lu re n (n = 5 7 ) C o n c e n tr a tio n ( g /m L ) June

71 6MWT results were better in the low concentration group of the 80 mg/kg/day group in the Phase 2b nmdmd trial 0-10 Mean change in 6MWD (m) m 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) m m June

72 D iffe r e n c e in C h a n g e fr o m B a s e lin e M e a n a n d 9 5 % C I, m p -v a lu e fr o m M M R M (t-te s t) Mean and significance levels for change in 6MWD by 2-hour plasma concentrations ranges confirmed better outcomes at lower exposures Low-Exposure Translarna Minus Placebo (n=31) at Week ( n = 3 2 ) ( n = 3 4 ) ( n = 3 7 ) ( n = 4 0 ) For patients on steroids, 7-16 y, 150 m 6MWD, <80% predicted ( n = 4 0 ) ( n = 4 0 ) ( n = 3 9 ) ( n = 4 0 ) ( n = 3 9 ) ( n = 3 9 ) ( n = 3 6 ) ( n = 2 6 ) ( n = 2 3 ) ( n = 2 1 ) ( n = 2 2 ) ( n = 1 9 ) ( n = 1 8 ) ( n = 1 7 ) ( n = 1 6 ) ( n = 1 7 ) C o n c e n tr a tio n R a n g e ( g /m l) ( n = 1 5 ) ( n = 1 4 ) ( n = 1 1 ) ( n = 1 1 ) ( n = ) June

73 Translarna s activity in a Hurler nonsense mutation model 100 GAG reduction (% avg) genotype: (+/+) (-/-) Concentration (ug/ml) Mouse embryonic fibroblasts June 2014 Keeling et al unpublished data 72