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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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 For 31.7 m, 95% confidence interval: 5.1, 58.3.

8. 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 – 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

9. 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.

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. Loss of ambulation occurred more frequently in placebo patients with m 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

18. 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

19. 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 m 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]

20. 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.

21. 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!