INDUSTRY PERSPECTIVE ON DRUG DEVELOPMENT FOR TYPE 1 SMA Kathie M. - - PowerPoint PPT Presentation

INDUSTRY PERSPECTIVE ON DRUG DEVELOPMENT FOR TYPE 1 SMA

Kathie M. Bishop, PhD

Disclosures: Currently, CSO of Tioga Pharmaceuticals, no activities in SMA; 2009-2015, full-time employee of Ionis Pharmaceuticals, led development of SMA program.

Outline

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

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

Patient population

• Severe, rapidly progressing disease with permanent ventilation
• r 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

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

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
• f 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

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

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

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?

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?

Thank you!