497. Follistatin Gene Therapy Improves Six Minute Walk Distance in Sporadic Inclusion Body Myositis (sIBM)
Authors: Jerry R. Mendell, Zarife Sahenk, Mark Hogan, Samiah Al-Zaidy, Kevin Flanigan, Louise R. Rodino-Klapac, Markus McColly, Kathleen Church, Sarah Lewis, Linda Lowes, Lindsay Alfano, Katherine Berry, Natalie Miller, Igor Dvorchik, Melissa Moore-Clingenpeel, Brian K. Kaspar
Journal: Molecular Therapy (2016)

Treatment of sIBM poses many challenges. The cause of this disease is enigmatic, and although considered to be an inflammatory myopathy, there is resistance to anti-inflammatory and immunosuppressive agents. sIBM muscle biopsies show vacuolated muscle fibers, widespread inflammation, and intracellular amyloid deposits. Follistatin is a potent inhibitor of the myostatin pathway and its potential as a therapeutic vehicle is enhanced by a pathway independent of the activin IIB receptor. We have demonstrated both safety and efficacy following direct intramuscular injection of follistatin in the quadriceps muscle in a previously reported gene therapy trial in Becker muscular dystrophy (Mendell JR, et al Mol Ther 2015). No off target effects were encountered attributed to the use of an alternatively spliced follistatin isoform, FS344, also used in the current sIBM gene therapy trial. Enrollment in the current gene therapy trial included 6 subjects with either definite or possible sIBM (Griggs RC, et al. Ann Neurol 1995). Pretreatment MRI's were obtained to determine areas of relative muscle sparing/lack of fibrosis. The intramuscular injections of AAV1.CMV.FS344 to 12 to 14 sites in the quadriceps muscle delivered 1.2X1012 vg/kg. Injections were performed with direct ultrasound guidance to target the most normal appearing muscle bundles, and intramuscular position was confirmed with simultaneous EMG. A three-patient, single limb, safety trial preceded the Phase I/IIA trial reported here. During the ongoing gene therapy trial, a control sIBM group (n=20) was prospectively studied by performance of the 6MWT with follow up from 9-28 months. The 6MWT was the primary functional outcome (See table below). sIBM patients treated with AAV1.CMV.FS344 increased the 6MWT distance by 46.5m (457 to 503.5, p =0.001). Untreated sIBM controls lost 38.5m over a similar time period resulting in net difference of 85.0m between groups (p=0.0007). To validate findings and confirm the lack of selection bias we compared a subgroup of untreated sIBM controls (n=8), matched for age, gender, and 6MWD at baseline. Matched controls lost 39m (p=0.0036) in the 6MWD, a virtually identical loss to the larger control group. The results of this study demonstrate that sIBM can benefit from follistatin gene therapy based on improvement in distance walked in the 6MWT. We did find a hierarchy of response based on muscle preservation and avoiding gene delivery to areas of fibrosis. In this study, gene delivery was limited to the quadriceps muscle, but in future trials more widespread delivery could potentially be more effective. Tabled 1Six Minute Walk Distance Pre- and Post-Treatment* [median values (interquartile ranges provided)]GroupBaseline (m)Final Compared to Baseline (m)Change from Baseline (m)Change per Month (m)sIBM Gene Therapy Pts (n =6)457 (431,475)Improved to 503.5 (443, 573)+46.5 (2,117)+3.09 (0.39, 8.9)Untreated sIBM Controls (n =20)393 (356.5,.451.5)Declined to 354.5 (303.5,410.5)−38.5 (−73,−22) p =0.0007−2.3 (−4,−1. 1) P =0.0032Matched sIBM Controls for age, gender, and 6MWD (n = 8)459 (439.5,469)Declined to 420 (388.5,447.5)−39.0 (−77,−8) p = 0.0036−2.2 (−4.8. −0.7) P=0.0118 Open table in a new tab Data analysis used SAS 9.3 (SAS Institute, Cary NC) with two-sided p-values.