Results of current gene modifying and molecular therapies
There is a number of recent studies of novel therapies for DMD (Ataluren, Indebadone and Etiplersin) which include either primary or secondary respiratory outcomes.
Ataluren is an oral treatment for patients with nonsense mutation DMD (nmDMD), designed to facilitate ribosomal readthrough of an in-frame premature stop codon, increasing production of full-length dystrophin protein 44. Propensity matching, using age at first symptoms, age at first use and duration of steroid use as well as time-to-event motor, pulmonary and cardiac features, was employed in order to match patients in the Strategic Targeting of Registries and International Database of Excellence (STRIDE) to individuals in an historical registry, the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS)41. Individuals were matched according to age at first symptoms, age at first use and duration of steroid use, as well as time-to-event motor, pulmonary and cardiac features. Mercuri et al. demonstrated significant impacts on measures of skeletal muscle function (standing, stair climbing, timed motor tasks) in nonsense mutation DMD (nmDMD) but for a number of reasons, including the insensitivity of the outcome measures used (VC%pred), the relative youth of the treated subjects compared to controls and the duration of follow up, no significant impact on respiratory outcomes was identified.
In a publication describing the results of three studies of Eteplirsin, Khan 45 found a significant difference in the rate of decline of VC%pred in 74 DMD patients; 2.19 to 3.79 % per year for Eteplirsin compared to 5.56 to 6% per year for the three CINRG DNHS control groups. However, the study group 201/202, randomized initially to placebo vs. 30 or 50 mg Eteplirsen, was only 1.5 years younger and had the greatest improvement in VC decline. However, there was a considerably higher baseline %pred VC of 96.9% for the Eteplirsin treated subjects vs. at best, 79.6% for the controls. Interestingly, no data were presented for the placebo-controlled portion of the study. The authors concluded that the results were “meaningful” and “will likely impact both the quality of life and the duration of life in patients with DMD.”
In a Phase II randomized placebo-controlled study in 21 DMD boys at age 8–16 years, Buyse 46 found that idebenone, a short-chain benzoquinone, antioxidant and inhibitor of lipid peroxidation, at a dose of 450 mg/d had a significant effect on their primary outcome, peak expired flow (PEF) but only in steroid naïve subjects. PEF, in the absence of air flow limitation, is not only a composite reflection of VC, MIP and MEP but also bears a marked clinical significance in terms of cough effectiveness and airway clearance in patients with NMD. In DMD, absolute PEF remains quite stable during the first and second decade but PEF%pred declines linearly from age 7 or 813. Not surprisingly, values of PEF%p correlated well with the percent predicted values for MIP and FVC. Idebenone was associated with an 8.0% improvement in PEF%pred, while those on placebo declined by 12.3% (p < 0.05) over 12 months. Indebenone did not significantly affect the rate of decline in steroid treated subjects.
A subsequent, one-year phase 3 placebo-controlled trial for DMD subjects age 10-18 yrs who were not using steroids, was also reported. Subjects were randomized to Idebenone 900 mg daily vs. placebo with the primary outcome, again being PEF%pred 47. In the intention to treat analysis, the one-year change in PEF%pred from baseline was –2·57 vs. – 8·84, p<0·0001. The Idebenone group was 1.5 yrs younger and although post hoc analysis did not indicate that age had an effect, younger patients did seem to benefit more, possibly because their VC (absolute) values were still rising. Observations were not influenced by past steroid use. No significant differences were found in the change from baseline for MIP, MEP or peak cough flow. The authors also noted fewer patients in the treated group reaching milestones of VC (1 L) and peak cough flow (160 L/min) suggesting that delaying these thresholds might result in less morbidity and mortality. Avoiding the need for ventilatory support and airway clearance for a period of time might indeed be a useful outcome but again, noninvasive ventilation when needed improves sleep quality and QoL and it is well established that DMD patients can survive for decades with vital capacities well below 1L, even zero (23, 28, 39).
Taken together, these studies do suggest a modest impact of emerging therapies on respiratory function decline in individuals with DMD. Whether or not an improvement in health-related quality of life can be demonstrated remains to be seen. As long as noninvasive ventilation and airway clearance strategies are properly employed, survival is unlikely to be impacted by additional treatments. Mortality continues to be defined by favorable or unfavorable cardiac function, not respiratory decline 48.
Respiratory Outcome Measures to Consider in Future Studies
Given the limitations of pulmonary function measures in a number of studies to date, more sensitive measures are needed which account for the natural evolution of respiratory function at different ages.
Maximum inspiratory pressure (MIP)
Based on the pressure/volume relationship of the respiratory system and the reserve present in respiratory muscles, it is accepted that MIP is a much more sensitive, earlier measure of respiratory muscle impairment than VC 49,50, although VC has been widely used in clinical management and study outcomes. Indeed, in younger patients, VC is still rising in to early teen years. In a review paper, Schoser found MIP included as a secondary outcome in one published46 and three ongoing trials in DMD. In the Idebenone trial 46 MIP improved, though not significantly compared to a decline in the placebo group. There is however contradiction in published results. Neve studied 33 steroid naïve DMD age 11 (5-16.7 yrs) and found no significant change in absolute MIP values 40 while Gayraud found a declining MIP in a similar age group (9.1 +/- 1 to 16 +/- 1.4 yrs) with %pred MIP being only 67% at first measurement 17. MIP might, then, be superior to some outcome measures for interventions directed at young patients with DMD in whom VC is relatively well preserved.
Sniff nasal inspiratory pressure (SNIP)
In the absence of much change in MIP, Neve concluded that sniff nasal inspiratory pressure (SNIP) was a more sensitive measure of weakness40. In a 3-year study of 33 steroid-naïve, 5–20-year-old DMD patients, SNIP measurements were found to be reliable. SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and then declined. SNIP identified respiratory muscle impairment earlier (at 10.5 years) than VC (at 12.5 years). Others have found measurements of SNIP to have less variability and to be performed consistently in children as young as 5 yrs 51. Standardized performance of SNIP measurements is not entirely agreed upon and a recent publication, including about 20% muscular dystrophy patients, noted that occluding the opposite nostril from that with the pressure monitor resulted in consistently higher values52.
Abdominal/Rib Cage contribution to tidal volume
In a retrospective but elegant, 7-year study of 115 individuals with DMD, 6-24 yrs old, with 574 visits, LoMauro 13employed nonlinear regression model analysis and presented the evolution of mean curves of spirometry, lung volumes, spontaneous breathing and thoraco-abdominal pattern, measured by optoelectronic plethysmography. Although more appropriate for older subjects, measures of respiratory pattern have the advantage of requiring no cooperation or effort. During spontaneous breathing it was determined that the abdominal contribution to tidal breathing was reduced at 14.8 yrs., the tidal volume was reduced at 17.3 yrs., the minute ventilation was reduced at 18.1 yrs. and minute ventilation at 22 yrs. Spontaneous respiratory patterns are not commonly studied but may have a role to play in assessing the effect of therapeutic interventions, particularly for those who are unable to cooperate with pulmonary functions measurements such as those under 6 yrs. or with severe weakness or cognitive delay