INDUSTRY PERSPECTIVE ON DRUG DEVELOPMENT FOR TYPE 1 SMA

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1 INDUSTRY PERSPECTIVE ON DRUG DEVELOPMENT FOR TYPE 1 SMA Kathie M. Bishop, PhD Disclosures: Currently, CSO of Tioga Pharmaceuticals, no activities in SMA; , full-time employee of Ionis Pharmaceuticals, led development of SMA program.

2 Outline Patient population for inclusion in trials Control group Outcome measures Biomarkers/PROs Challenges Future?

3 Drug Development in Type 1 SMA Responsibility to provide CLEAR evidence of efficacy and safety Heterogeneity of disease Small patient population Severe, very rapidly progressing Standard of care Ethical issues

4 Patient population Severe, rapidly progressing disease with permanent ventilation or death the eventual outcome Rare disease (estimated 300 SMA Type 1 births/year in EU; 200 in US) Heterogeneous disease: SMN2 Copy number 2 versus 3 Even within Copy number, is unexplained variability, not yet explained by other factors Variations in standard of care (country to country, but also site to site and parental preference) compound this variability Treatment as early as possible likely to provide the best potential for benefit Even at symptom onset, neuronal loss and degeneration Depending of mechanism, may require some time for effect Limit criteria to early = limits ability to enroll study

5 Control group May depend on: Size of drug effect expected Disease-targeted therapy versus symptomatic treatment Endpoints used Placebo- or sham-controlled (imbalance in randomization) Historical control (standard of care; contemporaneous history; pre-specified; lack of robust, multi-center studies in Europe?) In some cases, ethical issues with conducting a placebo/sham randomized trial balance with need to provide conclusive evidence of efficacy Severe, rapid progression not conducive to to cross-over or delayed entry; rescue option may create bias Open-label extension studies/creative use of interim analyses

6 Outcome measures (1) Time to death or surrogate of permanent ventilation (defined by >16 hours day for at least 2 or 3 weeks in the absence of an acute reversible illness or tracheostomy) Not an easy endpoint to implement, need for daily diary and adjudication of when endpoint has been met Affected by standard of care differences in respiratory use SMA infants can acquire a respiratory infection at any time - randomness May require larger sample size and longer trial Motor milestones: Sitting by definition is not acheived in Type 1 SMA Incremental improvements on a range of milestones can be detected by the HINE-2 scale May require shorter duration studies and fewer subjects Co-primary will require greater power

7 Outcome measures (2) Other Motor Function scales: CHOP-INTEND, developed specifically for SMA infants More general infant scales (i.e. AIMS, Bayley III for which can calculate z-score and normalized info, also includes fine motor and language) Other measures of impact on disaese: Disease-related AEs and SAEs (pre-specified) Hospitalizations G-tube use, feeding Time to requiring BiPap Some may be biased by care differences

8 Biomarkers/PROs Electrophysiology CMAP of ulnar nerve and peroneal nerve MUNE not generally feasible in infants CSF and/or plasma For some mechanisms, direct pharmacodynamic evidence and PK/PD analysis But leucocytes/rbcs/fibroblasts don t reflect target CNS No other clear biomarkers established PROs In this case, parent-reported and/or physician reported outcomes No SMA-specific PROs for infants, thus adopt more general scales Inclusion of autopsy in clinical trials of therapeutics

9 Challenges Severe nature of disease Variability Small patient population Standard of care: Reduce variability Also make sure that patients are receiving minimum care standards (i.e. nutrition, hydration) Is it ethical to standardize care in SMA Type 1 clinical trials? (Finkel et al, Child Neurology, 2016) Visit schedule, assessment burden Travel to study center - most will travel Extrapolation of results to broader patient populations, not just those meeting I/E criteria?

10 Future questions? What will the impact be of potentially changing phenotypes of Type 1 patients who may be treated with therapies that may be approved in the future? Need to conduct comparative studies? Issues of changing standard of care? Greater awareness of SMA and hope may alone impact standard of care? With an approved therapy, newborn screening may eventually be implemented?

11 Thank you!