Translating Science. Transforming Lives ACT DMD Clinical Trial Results
FORWARD LOOKING STATEMENTS This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements, other than those of historical fact, contained in this presentation are forward-looking statements, including statements regarding the future expectations, plans and prospects for PTC; the timing of PTC s planned regulatory filings, including with the FDA, the EMA and other regulatory bodies outside of the United States and European Economic Area, or EEA; PTC s ability to maintain the marketing authorization of Translarna (ataluren) for the treatment of nonsense mutation DMD in the EEA, which is conditioned upon, among other things, completion of ACT DMD and submission of the final report, including additional efficacy and safety data from ACT DMD, during 2015 and which is subject to annual review and renewal by the EMA following its reassessment of the risk benefit balance of the authorization; the clinical utility and potential advantages of Translarna; the rate and degree of market acceptance of Translarna; PTC s estimates regarding the potential market opportunity for Translarna, including the size of eligible patient populations and PTC s ability to identify such patients; the timing and scope of PTC s commercial and early access program launches; PTC s strategy, future operations, future financial position, future revenues or projected costs; and the objectives of management. 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. PTC s actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of final analyses of the data from ACT DMD, which may vary from PTC s initial analysis, lead to different (including more or less favorable) interpretations of the results than the analyses conducted to date, and identify further important information that is not available at the time of this presentation; whether the FDA or the EMA or other regulators agree with PTC s interpretation of the results of ACT DMD; expectations for regulatory approvals, including PTC s ability to make regulatory submissions in a timely manner (or at all), adverse decisions by regulatory authorities, other delay or deceleration of the regulatory process, and PTC s ability to meet existing or future regulatory standards with respect to Translarna; the scope of regulatory approvals or authorizations for Translarna (if any), including labeling and other matters that could affect the availability or commercial potential of Translarna; PTC s ability to commercialize and commercially manufacture Translarna in general and specifically as a treatment for nonsense mutation DMD, including its ability to successfully negotiate favorable pricing and reimbursement processes on a timely basis in the countries in which it may obtain regulatory approval, including the United States, EEA and other territories; the initiation, conduct and availability of data from clinical trials and studies; PTC s scientific approach and general development progress; the eligible patient base and commercial potential of Translarna and PTC s other product candidates; and the factors discussed in the Risk Factors section of PTC s most recent Quarterly Report on Form 10-Q as well as any updates to these risk factors filed from time to time in PTC s other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that Translarna will receive full regulatory approval in any territory or maintain its current marketing authorization in the EEA, or prove to be commercially successful in general, or specifically with respect to the treatment of nonsense mutation Duchenne muscular dystrophy. The forward-looking statements contained herein represent PTC s views only as of the date of this presentation and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this presentation except as required by law. 2
Agenda ACT DMD clinical trial top-line data - Dr. Stuart Peltz Understanding clinical endpoints in Duchenne Muscular Dystrophy - Dr. Craig McDonald Review of ACT DMD & Study 007 clinical trial results - Dr. Stuart Peltz Translarna: A clinician s perspective - Dr. Craig Campbell Next steps for Translarna - Dr. Stuart Peltz 3
ACT DMD clinical trial top-line data 1. CEO Introduction Dr. Stuart Peltz 4
Phase 3 ACT DMD clinical trial confirms Translarna s benefit for nonsense mutation DMD patients In the overall Intent-to-Treat (ITT) population, Translarna demonstrated a 15m benefit in the six minute walk test (6MWT) which was not statistically significant (p=0.213, n=228) Translarna demonstrated a highly significant 47m benefit observed in 6MWT for the pre-specified 300m 400m baseline six minute walk distance (6MWD) patients (p=0.007, n=99) Pre-specified meta-analysis of combined ACT DMD and Study 007 show statistically significant 6MWT benefit of 22m (p=0.015, n=291) Key secondary endpoints favored Translarna including Time Function Tests (TFTs) across ACT DMD as well as the pre-specified meta-analysis North Star Ambulatory Assessment demonstrated benefit for Translarna No Translarna treated patients lost ambulation in the 300-400m baseline 6MWD group (0 / 47) vs four placebo patients in the same group (4 / 52) Translarna demonstrated a strong safety profile, consistent with previous studies Totality of data supports clinical benefit of Translarna 5 5
Understanding clinical endpoints in Duchenne muscular dystrophy Dr. Craig McDonald, U.C. Davis 1. CEO Introduction 6
Six minute walk test has been the most validated clinical endpoint utilized in ambulatory DMD trials Primary Endpoint 2008 ataluren 007 6MWD 2010 drisapersen 2013 tadalafil 2013 ACT DMD 2015 eteplirsen 2015 Antimyostatin Stair Climb Secondary Endpoints Time to 10% 6MWD Worsening 10-meter walk/run Stair climb Stair descend PedsQL Myometry North Star Ambulatory Assessment PODCI 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. 7
6MWD inclusion criteria continue to evolve to select the population that can best demonstrate a treatment effect Study Inclusion Criteria for 6MWD 0 m 100 m 200 m 300 m 400 m 500 m 2008 ataluren 007: 75m 2010 drisapersen: 75m 2013 tadalafil: 200m 400m 2013 ataluren ACT DMD: >150m 80% Predicted* 300 400m Inclusion criteria Pre-specified Subgroup 2015 eteplirsen: 300m 300 450m 2015 anti-myostatin mab: Stair Climb: 2.5 12 secs 8
Natural history data implies high performing DMD patients are stable / lower performing DMD patients decline rapidly 20 007 Baseline 6M W D 350 (N = 34) Change in 6M W D, m ean (m ) 0-2 0-4 0-6 0-8 0-100 -120 G SK Ph 3 Placebo Baseline 6M W D <350 and >7 yr old (N = 23) -5 m -2 0 m ACT-DMD Placebo Baseline 6M W D 350 and 7 yr old (N = 70) 007 Baseline 6M W D <350 (N = 21) ACT-DMD Placebo -106 m Baseline 6M W D <350-107 m and 7 yr old (N = 39) -125 m -140 B a s e lin e 6 12 18 24 30 36 42 48 Tim e (w eeks) 350m baseline 6MWT marks an inflection from moderate decline to more rapid declines over the following 48 weeks 9 9
Emerging MRI data reinforce the view that patients with baseline 6MWD <300m are at higher risk of losing ambulation 6MWD 300 Imaging data illustrate infiltration of muscle by fat and fibrous tissue Data courtesy of H. Lee Sweeney, Ph.D. Myology Institute, University of Florida 10
300m 400m baseline 6MWD may be the optimal window for conducting clinical trials in ambulatory DMD patients Six-minute walk test is the most validated clinical endpoint for ambulatory studies in Duchenne muscular dystrophy today Well validated across multiple natural history publications Decline in 6MWT is predictive of time to loss of ambulation; time to loss of upper arm movement and self feeding; time to required ventilation and ultimately mortality Significant patient to patient variability across disease state limits appropriate utilization window for clinical trials of 48 week duration 350m 6MWD predicts a transition from slow decline to a more rapid decline Higher performing boys in untreated arms tend to remain relatively stable (>70% predicted) Lower performing boys are at risk of losing ambulation regardless of treatment (<50% predicted) Important secondary outcome measures including Time Function Tests and North Star Ambulatory Assessment are becoming increasingly recognized as important endpoints to support 6MWT results 11
Detailed review of ACT DMD and Study 007 clinical trial results Dr. Stuart Peltz 12
ACT DMD study design and SAP developed in the context of Study 007 and evolving DMD understanding Phase 2b Study 007 enrolled a broad population 5 years and older; Minimum 6MWD of 75 meters Evolving DMD understanding indicate that high performing DMD boys are stable over 48 week while lower performing boys are at higher risk of losing ambulation ACT DMD study was designed to enrich for patients in the decline phase of the disease Inclusion / exclusion criteria designed to enrich a population with greatest opportunity to detect a clinical benefit over a 48 week study while being inclusive enough to enroll over a feasible time period (orphan disease) 7 years and older; Minimum 6MWD of 150 meters; maximum 6MWD of 80% predicted Statistical Analysis Plan focused on patients with highest potential to show clinical benefit Pre specified population with 300m 400m baseline 6MWD Meta analysis of ACT DMD and Study 007 providing greater statistical power to show Translarna s benefit 13
ACT DMD enrollment criteria were designed to enrich for the decline phase of Duchenne Age (years) Study 007 N=114 ACT DMD N=228 Mean (Range) 8.5 (5-20) 8.9 (7-14) 5-6 year olds (% / n) 20% / 23 N/A 7 9 year olds (% / n) 55% / 63 68% / 155 10 years and older (% / n) 25% / 28 32% / 73 Baseline 6MWD (m) Mean 356m 364m < 300 m (% / n) 25% / 28 20% / 45 300 m 400 m (% / n) 39% / 44 43% / 99 > 400 m (% / n) 37% / 42 37% / 84 Large subgroup of 99 patients in 300-400 meter baseline 6MWD 14
ACT DMD results demonstrate consistent benefit for Duchenne patients 60.0 6MWD Treatment Difference vs. Placebo (m) 50.0 40.0 30.0 20.0 10.0 0.0 49m (p=0.026) 47m (p=0.007) 32m (p=0.020) 15m (p=0.213) citt 300m - 400m ITT 300m - 400m (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 300m-400m baseline 6MWD patients showed benefit across primary and secondary endpoints 6MWD Treatment Difference vs. Placebo (m) 70.0 60.0 50.0 40.0 30.0 20.0 10.0 47m (p=0.007) Change in TFT Treatment vs. Placebo (s) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 1.8s (p=0.066) 3.5s (p=0.030) 4.4s (p<0.001) 0.0 0.0 6MWT 10m Run / Walk Stair Climb Stair Descend ACT DMD 300m 400m Baseline 6MWD (n=99) Primary and secondary results consistent with Study 007 subgroup results 16
Pre-specified Meta-analysis shows statistically significant benefit across primary and secondary endpoints 50.0 2.5 6MWD Treatment Difference vs. Placebo (m) 40.0 30.0 20.0 10.0 22m (p=0.015*) Change in TFT Treatment vs. Placebo (s) 2.0 1.5 1.0 0.5 1.4s (p=0.025*) 1.6s (p=0.018*) 2.0s (p=0.004*) 0.0 0.0 6MWT 10m Walk Stair Climb Stair Descend Meta-analysis: ACT DMD and Study 007 (n=291) * Statistically significant 17
Pre-specified Meta-analysis in 300-400m baseline 6MWD patients shows more robust benefit across 6MWT and TFTs 80.0 4.5 4.3s (p<0.001) 6MWD Treatment Difference vs. Placebo (m) 70.0 60.0 50.0 40.0 30.0 20.0 10.0 45m (p<0.001) Change in TFT Treatment vs. Placebo (s) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 2.2s (p=0.008) 3.4s (p<0.001) 0.0 0.0 6MWT 10m Walk Stair Climb Stair Descend Meta-analysis: ACT DMD and Study 007 (n=143) 18
Sensitivity analysis highlights Translarna s benefit in 6MWT demonstrated across multiple baseline 6MWD groups Baseline 6MWD, m 0 m 100 m 200 m 300 m 400 m 500 m P Pre-Specified 300 to <400 47.2 m 0.007 Sensitivity 250 to <400 29.5 0.035 Sensitivity 200 to <400 26.6 0.0501 Sensitivity 300 to <450 24.4 0.0504 19
Loss of ambulation occurred more frequently in placebo patients with 300-400m baseline 6MWD across both ACT DMD and Study 007 Percentage of Patients Losing Ambulation (%) -1% -3% -5% -7% -9% -11% -13% 9% (2 of 22) 0% (0 of 22) 8% (4 of 52) 0% (0 of 47) -15% Placebo Translarna Placebo Translarna Study 007 300m-400m Baseline 6MWD ACT DMD 300m-400m Baseline 6MWD Six placebo patients with 300m-400m baseline 6MWD lost ambulation vs. no Translarna patients across both ACT DMD and Study 007 20
North Star Ambulatory Assessment favored Translarna with benefit in 300-400m baseline 6MWD patients Linear North Star Ambulatory Assessment Score Linear NSAA Score ITT p = 0.268 ITT (N=228) 300m Subgroup 400m (N=99)* baseline p = 0.041 0.03-2 -1 0 1 2 3 4 5 6 7 8 9 Mean and 95% CI, (score) NSAA Score favored Translarna by 1.5 points in the ITT population and 4.3 points in the 300m 400m baseline population 21
Totality of data shows clinical benefit across primary and secondary endpoints Decline Improvement Meters, mean and 95% CI -100-75 -50-25 0 25 50 75 100 6MWD Meta-Analysis (N=291) ACT DMD (N=228) Phase 2 Subgroup (N=63)* 10-m walk/run 4-stair climb 4-stair descend 6 5 4 3 2 1 0-1 -2-3 -4-5 -6 * Including only patients in the ambulatory decline phase subgroup matching ACT DMD entry criteria Seconds, mean and 95% CI 22
Translarna: A clinician s perspective Dr. Craig Campbell, London Health Science Center 23
Translarna: A clinician s perspectives Benefit risk profile is critical in the decision to prescribe for DMD boys Current standard of care includes steroids which while beneficial, are associated with complications Translarna has an important clinical benefit without increasing the patient burden Encouraged to see a benefit demonstrated over a one year period in the prespecified endpoints Cumulative benefit will be seen over time but clinicians will recognize the benefit seen over a one year study Both the 47m benefit demonstrated in the pre-specified 300m-400m combined with 15m across the broader population is important and indicative of longer term benefit for patients Totality of the data as demonstrated in the meta-analysis provides compelling evidence of clinical benefit for DMD patients New data from the Phase 3 trial is a key piece of additional information supporting Translarna s effectiveness 24
Next Steps for Translarna Dr. Stuart Peltz 25
Next Steps for Translarna Plan to complete rolling NDA for Translarna in nmdmd and submit to the FDA before year-end 2015 Submit results of ACT DMD to EMA Complete enrollment of ACT CF Phase 3 clinical trial Prepare for EMA review and discussion of Translarna CF submission Continue to explore the potential for Translarna in additional nonsense mutation-based genetic disorders PTC plans to finalize rolling NDA for Translarna in nmdmd and complete submission to FDA by year-end 2015 26
Q&A Stuart Peltz, CEO Dr. Craig Campbell, London Health Science Center Dr. Craig McDonald, U.C. Davis 27