What is the current unmet medical need in the non-ambulant population with Type 2 or Type 3 spinal muscular atrophy (SMA), and how do you assess the clinical potential of myostatin inhibitors like those studied in the SAPPHIRE trial?

What is your perspective on the different clinical trial endpoints used by Scholar Rock, Roche, and Biohaven in their SMA studies, and how do you evaluate the clinical meaningfulness of improvements reported?

Do you expect any differences in add-on effects when combining myostatin inhibitors with risdiplam versus nusinersen, given their mechanisms of action in SMA treatment?

Based on the TOPAZ trial results, what is your level of confidence in the reported improvements from myostatin inhibitors, and how do you interpret the dose-dependent results in an unblinded study?

How would you rate your excitement or confidence in the myostatin inhibition drug class for SMA, and do you see it as a promising area for further resource investment?

General overview of SMA and the treatment landscape with the particular accent on unmetmedical need in non-ambulant population with Type II and Type III SMA (the patientpopulation in SAPPHIRE trial)

There are three companies thinking of add-on Therapy to current SoC by modulating myostatinpathway (Roche, BHVN and SRRK) – are you familiar with the three pivotal studies and can youtell us your point of view on differences in clinical trials endpoints across the different trialsand their significance?a. BHVN: MFM32 (motor Function Measure -32)b. Roche: RHS (revised Hammersmith Scale)c. SRRK: HFMSE (Hammersmith Functional Motor Scale Expandaded)

Can you tell us more about the natural history of nusinersen and risdiplam treatment– what doyou expect to see from the SoC after 2 years of treatment (at year 3 of treatment)?

Focus on TOPAZ, PhII study: it recruited patients after median of 25.9months on Tx (Nusinersen)– and reported in PhIII study population (N=26) improvement of 4.6points (1.8-7.4) in HFMSEa. the mean scores at 12 months of treatment were 5.3 (−1.5 to 12.2) for the 2-mg/kg (n =8) and 7.1 (1.8 to 12.5) for the 20-mg/kg (n = 9) arm

Duration of treatment – 12 months – is it enough to show the add-on effect?

Risdiplam not checked in PhII study  do you expect any differences in add-on effect of a-Myostatin when combined with Nusinersen vs Risdiplam?

What would be for your clinically meaningful benefit of add-on therapy in this settings(measured as improvement in HFMSE from the baseline)? What do you expect to see in order toinclude this add-on Tx as a standard of care for your patients?

Are you concerned about MoA failure in Duchenne's’ Muscular Dystrophy?