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