The original intent of this study was to assess efficacy of PTX to diminish loss of strength in DMD and to indicate the feasibility of a larger, randomized, controlled efficacy trial. While the immediate release, oral, liquid formulation of PTX provided a method for accurate dosing based on participant weight, it was not well tolerated.
The occurrence of leukopenia in 2 pediatric DMD participants (12% of study participants) contrasted with the reported incidence in adults of less than 1%.4
There are no published reports of PTX-related leukopenia in children. In our participants, leukopenia resolved upon PTX withdrawal. One participant was re-challenged and leukopenia rapidly recurred.
The 65% incidence of vomiting in pediatric DMD participants treated with PTX was also markedly higher than expected compared to a 4.5% reported incidence in adults.4
The striking difference in the incidence of vomiting associated with immediate release PTX administration between adults in reported studies and children in this study underscores the importance of performing pediatric safety trials. Differences in adverse events due to PTX between the participants in this study and those in previously published studies include the age of participants (adults vs. children), disease (non-DMD vs. DMD) and formulation of the immediate release PTX (capsule vs. liquid). These differences add to the complexity of identifying the relative contribution of each of these factors to toxicity.
Similar to multiple other studies, the unexpectedly high level of toxicity experienced by participants in this pilot study was not anticipated from the preclinical studies in the mouse model. The most prevalent toxicity in the human participants was vomiting, which would not be detected in a non-vomiting species such as mice,7
highlighting a limitation of the murine model for preclinical studies.
Approximately half of the participants finished the full 12-month treatment course. There was no significant difference in baseline characteristics between those participants who finished the 12 months of PTX treatment and those who did not finish. To the extent that participants who did not finish the trial were followed, we did not observe substantive changes in strength and motor function, other than the one participant who discontinued the study because of rapid deterioration. Because of the high study discontinuation rate among participants, a possible beneficial effect of a well-tolerated formulation of PTX on DMD cannot be excluded.
It is interesting to consider whether dystrophin deficiency may have contributed to the high frequency of gastrointestinal side effects found in this study. Children with dystrophin-deficient muscular dystrophy have been shown to have a derangement of gastric motility.8
In ex vivo
preparations of the gut comparing mdx
to normal mice, nitric oxide production was less in mdx
, and nNOS expression was reduced in mdx
stomach smooth muscle cells.9
The amplitude of spontaneous muscular contractions of the mdx
mouse ileum ex vivo
was increased, and it decreased to normal by application of relaxin, a hormone that upregulates NO biosynthesis.10,11
It is possible that PTX could compound the gut hypercontractility associated with dystrophin deficiency, and this may explain why the intensity and frequency of gastrointestinal side effects due to PTX were not anticipated based on prior non-DMD human studies done in adults and children.
In summary, the liquid formulation of immediate release PTX was poorly tolerated in boys with DMD largely because of gastrointestinal side effects and leukopenia. It remains possible that a different formulation of PTX would be better tolerated and could be more adequately tested for its ability to slow DMD disease progression.