Other Strategies for Different Mutations Stuart Peltz, PhD, CEO PTC Therapeutics

Treatment development focuses across all DMD Intervention points Ataluren Utrophin upregulation DMD Dystrophin restoration & replacement Inflammation & fibrosis Muscle growth & regeneration Cardiac & calcium regulation Exon skipping Gene therapy Serca2a Anti-fibrotics Ryanodine receptor Steroids Traditional cardiac drugs We were asked to talk about different treatment approaches to genetic mutation. This is how PTC views it. Dystrophin is not such a complicated entity and the disease is mainly about loss of this protein, so to design therapies for Duchenne is important to fix the dystrophin and this is what we are trying to do There are many approaches to it exon skipping, read through, gene therapy, etc. Lack of dystrophin also bring other problems like injured muscles that lead to inflammation so there are drugs to help this problem It is also important to increase the muscle mass and reduce fibrosis and treatment needs to be developed to help And finally the cardiac problems need to be address All these together will help our boys mIGF1 myostatin Stem cells

PTC Therapeutics’ integrated approach to treat DMD Muscle Growth & Regeneration SERCA2a mIGF1 DMD Membrane Integrity Readthrough Therapy Utrophin This is a snapshot of PTC’s drug discovery effort in DMD. This slide makes a couple of points: 1) we’re committed to finding a treatment for DMD; 2)and to do this we have taken several approaches hitting all the different aspects of the problem: muscle growth, read through, small molecule ataluren preclinical Small molecule Exon skipping

Development history of Ataluren in nmDMD 98–2003 2008 2009 2011 2012 2013 2010 2007 2005 Phase 2a (004) 38 nmDMD patients 2006 2004 Phase 1 62 healthy males 2014 Phase 2b (007) 174 nmDMD patients EMA DMD draft guidelines Initial natural history publications ataluren discovery EMA approval of ataluren 2015 Phase 3 (020) 220 nmDMD patients 17 years of research & development 750+ healthy volunteers/patients exposed/treated and ~900 patient-years of treatment Safety profile: Generally well tolerated Phase 2a: Dystrophin expression demonstrated Phase 2b: Clinically meaningful benefit in 6MWT/Natural History data Phase 3: ACT DMD fully enrolled with data expected Q4 2015 EMA granted marketing authorisation approval for ambulatory nmDMD patients aged 5 years and older – July 2014 History of ataluren: First drug ever approved for DMD Over 17 years of journey, of which first 5 in pre-clinical, but that was the easy part (1 Mil compound screened) We set the path with your help for other drug development - all together we were pioneers

As Proof of concept, ataluren treatment results in full-length functional dystrophin production mdx mouse A five year process to arrive to a molecule in the animal model ataluren partially restored dystrophin protein in different muscle groups, including diaphragm and heart, and improved muscle function1,2 ataluren has also been found to enhance dystrophin expression in other preclinical models of nmDMD3,4

During Phase 2a study, we demonstrated an increase in dystrophin expression in patients with nmDMD Pretreatment End of treatment (day 28) Immunohistochemistry of muscle cross-sections to visualize dystrophin expression in extensor digitorum brevis at baseline and after 28 days of treatment with ataluren 40 mg/kg/day Improvements in dystrophin were seen in ~60% of patients after 28 days of ataluren 16 mg/kg/day, 40 mg/kg/day or 80 mg/kg/day* A mean change in dystrophin expression of 11% was observed after 28 days of treatment with ataluren (p = 0.008, paired t test) No dose–response relationship was observed We demonstrated Ataluren is active in dystrophin replacement but regulators also want to see the clinical benefit, so we (all together) had to find the best end point 61% of patients showed an increase in dystrophin staining in 28 days of ataluren treatment

Phase IIb (Study 007): Patients receiving ataluren 40 mg/kg/day showed a smaller decline in walking ability over 48 weeks than those given placebo1 Ataluren In Ph2b we were able to demonstrate the efficacy of ataluren to modify the course of the disease, with the primary end point of 6MWT *Adjusted p value from analysis of all data across three treatment arms with 80 mg/kg/day not different from placebo; 70% of placebo and ataluren patients respectively were receiving corticosteroids through study, as part of best standard of care. 6MWD, 6-minute walk distance; CI, confidence interval. 1. Haas et al. Neuromuscul Disord 2015 (25):5–13. Graph taken from Bushby K et al. Muscle Nerve 2014;50:477–87, with data from Haas et al. 2015. For 31.7 m, 95% confidence interval: 5.1, 58.3.

Time function test results Ataluren ….but also with other secondary end points important for functions and activities of daily living A clinically meaningful difference of 1.5 seconds1 was reached in three of the four TFT tests2, 3 No difference was seen for the stand from supine test, due to baseline demographics2, 3 1. Escolar DM et al. 2011 – the threshold for a clinically meaningful difference in timed function tests was defined as 0.4 log seconds, which was back-transformed to ~1.5 seconds; 2. ataluren EPAR EMA website; 3. Bushby K et al. Muscle Nerve 2014;50:477–87. TFT, timed function test. S, seconds. 70% of placebo and ataluren patients respectively were receiving corticosteroids through study, as part of best standard of care 8

Six minute walk test (6MWT) and time function tests are commonly used clinical endpoints utilized in ambulatory DMD trials 2008 ataluren ‘007 2010 drisapersen 2013 tadalafil 2013 ACT DMD 2015 eteplirsen Anti-myostatin Primary Endpoint 6MWD Stair Climb Secondary Endpoints Time to 10% 6MWD Worsening 10-meter walk/run Stair climb Pioneering the history of getting the first drug for DMD approved, we learnt about the different endpoint. 6MWT is the vaidated one that regulators prefer but many other secondary one are important like TFT and NSAA Stair descend North Star Ambulatory Assessment PedsQL PODCI Myometry Note: ataluren study conducted by PTC Therapeutics; drisapersen study conducted by GSK / Prosensa (Biomarin); tadalafil study conducted by Lilly; eteplirsen study conducted by Sarepta; anti-myostatin mAb study conducted by Pfizer.

Progressive loss of function highlights the complexities associated with conducting clinical studies in DMD 450m 400m 300m 150m Optimal window for 1 year clinical trials Ambulatory Function (6MWT) 6MWD Timed Function Tests (10m walk, stair climb, stair descend) Kids in the early stage of the disease are very stable which is fortunate for them but makes difficult to do clinical trials in one year as the clinical effect cannot be demonstrated when boys do not progress In the middle stage of the disease, when boys are progressing in one year but still are able to perform the 6MWT, this becomes the perfect tool for measuring drug When boys are below 300m their decline in one year is so fast that using 6MWT is not the right tool. These considerations are only for demonstrating efficacy in clinical trial setting, it does not mean that patients in the first and third group aren’t suitable for treatment. Loss of rise From floor Loss of Stair climb Loss of ambulation

This is repetitive of precious one, I would delete Data from Study 007 and ACT DMD of high performing DMD placebo patients (≥400m) show stable 6MWD over 48 weeks This is repetitive of precious one, I would delete In peer reviewed literature Pane et al 2014 demonstrated slower decline in subjects with baseline 6MWD of >350m

Emerging MRI data reinforce the view that patients with baseline 6MWD <300m are at higher risk of losing ambulation Imaging data illustrate infiltration of muscle by fat and fibrous tissue 6MWD 300 There is a correlation between the ability of kids to walk and the deterioration is happening in their muscles and the replacement of muscle fibres with fat and fibrotic tissue. When the 6MWT is around 300m, it was seen that the muscle have been replaces with too much fat and fibrotic tissue that the capability to walk decreases dramatically, which does not allow to perform the 6MWT anymore Data courtesy of H. Lee Sweeney, Ph.D. Myology Institute, University of Florida

Double-blind placebo-controlled study ACT DMD was designed to evaluate effect of ataluren on trial endpoints over 48 weeks in patients with nmDMD Double-blind placebo-controlled study Primary endpoint Change in 6MWD Secondary endpoints 10% worsening in 6MWD Change in 10-m walk/run Change in 4-stair climb Change in 4-stair descend Exploratory endpoints Change in NSAA Change in PODCI Ataluren 10, 10, 20 mg/kg N=110 R 1:1 Placebo N=110 Open-label extension 48 weeks ACT DMD Design 13 13 13

ACT DMD results demonstrate consistent benefit for Duchenne patients 49m (p=0.026) ** (n=114) (n=44) (n=228) (n=99) Study 007 ACT DMD ** pre-specified cITT: corrected ITT ACT DMD study confirmed benefit for DMD patients previously observed in Study 007

Pre-specified analysis of 300m-400m baseline 6MWD patients showed benefit across primary and secondary endpoints  -4.3s (p<0.001) 6MWT 10m Run/Walk 4-Stair Climb 4-Stair Descend ACT DMD 300m – 400m Baseline 6MWD (n=99) Primary and secondary results consistent with Study 007 subgroup results

A meta-analysis demonstrated a statistically significant benefit in favor of ataluren across primary and all TFT key secondary endpoints 2.0s (p=0.004*) 6MWT 10m Walk Stair Climb Stair Descend Meta Analysis: ACT DMD and Study 007 (n=291) * Statistically significant

Loss of ambulation occurred more frequently in placebo patients with 300-400m baseline 6MWD across both ACT DMD and Study 007 It is important to point out that while 8-9% of the boys in the pre-specified subgroup lost ambulation in the placebo arm, in the ataluren one none lost it. Study 007 300m-400m Baseline 6MWD ACT DMD 300m-400m Baseline 6MWD Six placebo patients with 300m-400m baseline 6MWD lost ambulation vs. no ataluren patients across both ACT DMD and Study 007

17 different items with increasing level of difficulty The NSAA is a comprehensive DMD specific instrument developed in Europe to measure global ambulatory status Stand Walk Sit to stand Single leg stand (right) Single leg stand (left) Climb step (right) Climb step (left) Descend step (right) Descend step (left) Lying to sitting Rise from floor Lift head Stand on heels Jump Hop (right) Hop (left) Run 17 different items with increasing level of difficulty Level of difficulty NSAA is a tooldeveloped in the UK that checks different activities that boys can or cannot anymore do in an increasing level of diffiulties 3 point scale from 0-2

North Star Ambulatory Assessment The NSAA demonstrated positive trend favoring ataluren in the ITT population and larger, statistically significant benefit (p=0.04) in the 300-400m baseline population North Star Ambulatory Assessment Decline Improvement The NSAA complements the 6MWT by assessing a wide spectrum of functions important in everyday life [Mazzone 2013]

ACT DMD confirms favorable safety profile for ataluren 101 (87.8%) subjects had a treatment-emergent adverse event (TEAE) in placebo group compared to 103 (89.6%) in the ataluren-treated group The majority of adverse events were mild or moderate No life threatening AE were reported in ataluren treated patients Only 8 patients (4 in each arm) experienced at least 1 serious adverse event SAEs in ataluren-treated patients were pneumonia, bronchiolitis, post-traumatic pain, tendon disorder, adenoidal hypertrophy and nasal turbinate hypertrophy 2 patients (1 in each arm) discontinued due to adverse events 1 ataluren-treated patient D/C due to constipation considered possibly related to study drug Two Phase II studies, one positive (p=0.014), one trending (p=0.069), and positive when pooled (p=0.003) 6MWD treatment difference =27-35m Long-term extension data showing durability of effect Long-term follow-up data exhibiting sustained effect and superiority over natural history controls Supportive evidence from secondary endpoints Phase III primary outcome p-value=0.415 (=10m) It is very important to highlight, and we probably do not talk enough, about the very good safety profile of ataluren that was tested in more than 950 people.

These advances and successes have only been possible with the support of boys, young men, families, doctors and patient associations 4/25/2017 We are very happy on hoe the scientific community welcomed our data We have been pioneer with your help We have advanced the science of DMD together We are proud to have now a proven drug for nm-DMD THANK YOU!