SMA Treatments and Clinical Trials

Kenneth Hobby, PresidentMary Schroth, MD, Chief Medical OfficerJill Jarecki, PhD, Chief Scientific Officer

Agenda• Introduction

– Kenneth Hobby, President• Spinraza Update

– Mary Schroth, MD, Chief Medical Officer• Zolgensma Update

– Kenneth Hobby, President• Clinical Trial Update

– Jill Jarecki, PhD, Chief Scientific Officer• Making Treatment Decisions

– Jill Jarecki, PhD, Chief Scientific Officer• Q & A

SMA Drug Pipeline

Current Treatment: Spinraza• 1st Approved Treatment

• Expectations:– Not a cure– Not for everyone– Impact

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Natural History

Spinraza Treated Patients– October 2018:

• ~2700 patients dosed in US– Including extension trials and support programs– ~50% of children < 2 yo with SMA receiving Spinraza– Increasing number of adults– ~30% of all in US– ~6,000 Globally

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US Patients Dosed

Treatment Sites and CapacityWebsite Directory of New Treatment Network:

• Spinraza: 159 sites in44 states and DC with at least one site/state

• ~100 more sites dosing

www.curesma.org/spinraza/sites Contact: treatments@curesma.org

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US Sites Public Listing

Coverage and Payors• 95-100% Coverage:

– Types I, II, III– 2, 3 copies SMN2– Pediatric

• 76-80% Coverage:– 4 copies SMN2– Adult– Non-invasive ventilation

• Restrictive:– Types 0, IV– 1 copy SMN2– Tracheostomy or

permanent ventilation

New Therapies and Care• Standard of Care - critically important to optimize

function– Breathing

• Close monitoring• Coughing support and clearing secretions• Breathing support during sleep as needed

– Nutrition• Growing and gaining weight is key to optimizing motor function and

strength• Monitoring swallow

– Physical and Occupational Therapy• Optimize function and impact of new treatments

http://www.curesma.org/support-care/for-healthcare-providers/educational-resources/

2 years of Spinraza

• Improved Access– More adults are receiving Spinraza,

• ~15% of all adults (>18 years old)– Increasing experience with techniques to safely deliver treatment

– ~ 50% of pediatric patients (birth to 17 years) are receiving therapy

• Impact:– Increased infant survival – Earlier treatment in infants results in the best

outcomes regardless of treatment– Changing care needs with careful monitoring

Gene Therapy - Zolgensma• Replacing missing SMN1 gene - One time treatment• Two Delivery Approaches:

– Same therapeutic, but different delivery approaches– Intravenous (IV) and Intrathecal (IT)– IV:

• Now with FDA• BLA

– IT• Ongoing clinical trials

• Results are very good in young Type I:– Don’t know yet in other types and older

• Don’t wait on approval:– Time more important– Unknowns and narrow label

IV Gene Therapy

• Timing:– FDA date of May 2019

• Expectations:– Approval for close to clinical trial criteria:

• Type I and under 8.5kg (maybe under 9 months)• Maybe also presymptomatic

– Insurance will strictly follow label• Switch or both unlikely:

– Costs and data and label

IT Gene Therapy

• Timing:– Possibly 2020

• Expectations:– Approval for older and other types– Will FDA go broader here than trial criteria:

• Type II to 5 years– Other trials needed

Why Different This Time

• Will not be same as Spinraza, with rapid approval and label for all– very unusual– Have a treatment approved– New technology– Limits to IV approach

• Normal is to match the trial criteria

Why Two Approaches

• IV: Throughout whole body• IT: Just to central nervous system

• Older and Bigger:– Need more virus and this may not be safe

when given IV everywhere– Greater chance of AAV antibodies

Recruiting Clinical Trials

A Study of RO7034067 (Risdiplam) in Adult and Pediatric Participants with SMA

– (Clinicaltrials.gov Identifier: NCT03032172)– Also Known By: JEWELFISH – General Criteria*: Children, teens and adults age 12-60

who have previously been exposed to an SMN2-targeting therapy.

– Phase: Phase 2, with sites in NYC, Italy, Switzerland– Ongoing

Recruiting Clinical Trials

Pre-Symptomatic Study of Intravenous AVXS-101 in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2 (SPR1NT)

– ClinicalTrials.gov Identifier: NCT03505099– AVXS gene therapy with one-time IV infusion– International trial in pre-symptomatic patients with SMA

Types 1, 2, 3– 44 patients with 2, or 3 copies of SMN2, under six weeks

of age and pre-symptomatic– Ongoing

Recruiting Clinical Trials

• Spinraza in Adult Spinal Muscular Atrophy (SAS)– ClinicalTrials.gov Identifier: NCT03709784– Safety, tolerability, and effectiveness of SPINRAZA®

(nusinersen) in ambulatory and non-ambulatory adult patients with SMA,18 years to 60 years of age.

– 73 participants.– Study visits including standardized assessments of

strength and function will occur at baseline, day 15 after treatment initiation, day 30, day 60, and then 4-month intervals through month 30.

– Multi-center

Recruiting Clinical Trials• Study of Intrathecal Administration of AVXS-101 for

Spinal Muscular Atrophy (STRONG)– Clinicaltrials.gov Identifier: NCT03381729- Up to 60 months of age and three copies of SMN2 and

symptoms < 12 months of age- Sit independently and not standing or walking independently- Currently fully-enrolled at the low- and mid-dose cohorts. - Enrollment starting for higher dose cohort is to explore whether it

will provide the opportunity for additional efficacy. - Phase 1 Trial for 51 subjects at multiple sites in the US

Planned Clinical Trials• Scholar Rock

– SRK-015 (myostatin inhibitor) to improve muscle strength– Safety trial on health volunteers by Q2 2018– Proposed patient trials for SMA patients who are on therapies to up-regulating

SMN levels and as monotherapy in certain populations – Phase 2 proof-of-concept study in the first quarter of 2019

• REACH – AVXS gene therapy with one-time IT injection– Multi-national trial expected in early 2019 in SMA Types 1, 2, and 3– Likely 50 patients between six months and 18 years of age– Timeline TBD

• Phase III trial of Reldesemtiv (CK-2127107) in Patients with SMA– Muscle function drug acting as fast skeletal muscle troponin activator – TBD for enrollment criteria– Timeline TBD

• RO7034067 (Risdiplam) in pre-symptomatic infants with SMA– Also called Rainbowfish– Timeline TBD

Considerations to be Discussed with Neurologist on Approved Treatment vs. Trials

• Recommended not to wait for future trials to open, if other options available now– Delays in opening trials are common and can’t be predicated– Changes in inclusion and exclusion are common until

formally announced– Earliest possible administration of SMN enhancing drugs

yield best results

Timing is one of biggest factor in degree of response to SMN!

Considerations to be Discussed with Neurologist on Approved Treatment vs. Trials

• Evaluate available safety and efficacy data• Evaluate possibility of placebo

– Small molecule versus other drug modality

– Type I enrollment versus other SMA types

• Evaluate route and timing of administration• Understand inclusion and exclusion criteria• Determine whether previous drug exposure allowed and when

– Most trials today will prohibit co-utilization with Spinraza

– Particularly if another SMN enhancer

– Increased motor function must be detected for FDA approval

– Much harder when already another SMN enhancer to detect signal

Considerations for Combination Therapies: Combinations Must be Chosen Carefully

• General– Are they safe when used together?

– Is there additive clinical benefit?

– Does that benefit outweigh the risk of using together?

– Does one drug reduce efficacy or availability of the other?

– Can they readily be co-administered?

• Combining Two SMN Enhancers– Do they work by different biological mechanisms?

– Are SMN levels increased together over either drug alone?

– Do they target different cells?

– Do they provide longer duration of effect together?

– Readouts in trials with two combination therapies more challenging.

Resources• Cure SMA website:

– www.cureSMA.org/Spinraza– www.cureSMA.org/Spinraza/sites– www.cureSMA.org/Zolgensma– www.cureSMA.org/risdiplam– www.cureSMA.org/currenttrials– www.cureSMA.org/news/

• Email– treatments@curesma.org

• Social Media– www.facebook.com/cureSMA– www.twitter.com/cureSMA– www.Instagram.com/cureSMAorg– www.youtube.com/FamiliesofSMA1