Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Abstract

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years.

Methods: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups.

Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies.

Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

Conflict of interest statement

APM, JM, JD, TS, CS, SW, MH, LL, JVH, and PC report no conflict of interest. Professor Willis has served on advisory boards for PTC pharmaceuticals, Genzyme Sanofi, Sarepta and Biogen and has received honorariums for lectures and symposium from PTC pharmaceuticals, Genzyme Sanofi and Biogen. Yousry has received honoraria and travel expenses for advisory committee work from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by University College London) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG for analysis of data from MS trials. James performs consultancy work (training physiotherapists) for: Roche, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus and has participated in advisory boards for PTC Therapeutics. Mayhew performs consultancy work (training physiotherapists) for: Roche, Avexis, Biogen, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus, Tamoxifen noncommercial study for DMD and has participated in advisory boards for: PTC, AMO Pharma, Roche, Summit, Biogen, Modus, Novartis. Eagle performs consultancy work for: Biomarin, GSK, Prosensa, Italfarmaco, Amicus, Capricor, Catabasis, Eli Lilly, Fibrogen, MNK, PTC, Santhera, Solid, Summit, Sarepta, Theracon, Reveragen and Wave. Thornton has received research support from GlaxoSmithKline, Medtronic, and Siemens. Vissing has received research and travel support, and speaker honoraria from Sanofi Genzyme, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals and aTyr Pharma, and served as consultant on advisory boards for Sanofi/Genzyme, aTyr pharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals, Sarepta Therapeutics, Audentes Therapeutics and Stealth Biotherapeutics within the last 3 years. Hollingsworth reports grants from the United Kingdom Medical Research Council, Diabetes UK, the European Union (H2020, 667078) and the Newcastle Healthcare Charity, consultancy for Summit pharmaceuticals and trial support from ImagingDMD outside the submitted work. All reimbursements were received by Newcastle University, no personal benefits were received. Straub has or had been a chief/principal investigator for trials sponsored by Sanofi Genzyme, GSK, Prosensa/Biomarin, Ionis Pharmceuticals, and Sarepta and a subinvestigator for many other commercial studies. He received speaker honoraria from Sanofi Genzyme and is or has been on advisory boards for Audentes Therapeutics, Biogen, Biomarin, Bristol‐Myer Squibb, Exonics Therapeutics, Italfarmaco S.p.A., Nicox, Sanofi Genzyme, Santhera Pharmaceuticals, Sarepta Therapeutics, Summit Therapeutics, Tivorsan, TrophyNOD, and Wave Therapeutics. He received funding for research collaboration with Ultragenyx and Sanofi Genzyme.

Figures

Figure 1

Box plot showing the change in fat percentage from baseline to 6 years. The blue bars show the interquartile range and the median. The lines show the range of the data. Outliers one to three times the interquartile range are marked as circles. Outliers greater than three times the interquartile range from the median are shown as individual asterisks. The median change is shown for each muscle group on the left. Note that the median change will not be equal to the difference in the median baseline and 6 year medians given in Table 2. a Due to difficulties in ROI placement in the rectus femoris muscle, the fat fractions for two participants were excluded for this muscle group, and no composite results calculated where appropriate (n=21).

Figure 2

Images showing the change in fat replacement over 6 years. Fat fraction maps acquired from the left thigh and lower leg at baseline and 6‐year follow‐up (0–100% scale). Progression of fat replacement was visible in almost all muscles, with changes most noticeable in the muscles relatively spared at baseline, such as the Sartorius (white arrow A ‐ in this participant fat fraction increased from 21.3% to 34.2%) and the gracilis (white arrow B ‐ increased from 40.3% to 58.7%) muscles. As indicated by the white arrow (C), fat replacement began at the borders of the rectus femoris muscle at both baseline and 6 years, which caused difficulties in ROI placement. In this participant, the fat fraction was 78.9% at baseline increasing to 81.9% at 6 years. The shape and size of the biceps femoris short head muscle also caused difficulties in ROI placement as demonstrated by the white arrow (D).

Figure 3

Line graphs demonstrating individual participant progression in functional tests from baseline to 6 years. The functional assessments with the highest SRM values were selected to compare individual progression over time. On the 6‐min walk test, there was no clear cut‐off for predicting loss of ambulation, 6/9 participants who walked ≤300 m became nonambulant by 6 years. Two participants improved on both the 10‐m walk or run test and sitting forced vital capacity.

Figure 4

Line graphs demonstrating individual participant progression in fat fraction from baseline to 6 years. The composite muscle measures with the highest SRMs were selected to compare individual progression over time. Quadriceps and thigh measures were excluded as these were not available in all participants due to difficulties in ROI placement in the rectus femoris. The individual lines suggest there is only one participant who does not progress over the 6 years and six participants who have little infiltration at baseline and increase relatively slowly over the 6 years.