https://asa1cadmoremedia.blob.core.windows.net/asset-07d26763-27ea-41ef-b71a-ead5e403ce30/Study 019 author video.mp4
MÁR TULINIUS: Hello my name is Már Tulinius and I'm a professor in the Department of Pediatrics at Gothenburg University in Sweden.
CRAIG MCDONALD: And I'm Craig McDonald, professor at the University of California Davis School of Medicine in the United States.
MÁR TULINIUS: Today, we are going to provide a summary of our paper, "Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients", recently published in the Journal of Comparative Effectiveness Research. Ataluren is an orally administered drug that promotes ribosomal read through of premature stop codons in the messenger RNA and has previously been shown to delay loss of ambulation in patients with nonsense mutation Duchenne muscular dystrophy, also called DMD
MÁR TULINIUS: compared with DMD patients receiving only standards of care. The findings from this long term open label phase III study revealed a significant delay in the time to loss of ambulation and the time to respiratory decline in nonsense mutation DMD patients treated with ataluren compared with a matched cohort of DMD patients receiving standard of care in an external natural history study.
CRAIG MCDONALD: DMD is a debilitating and ultimately fatal disease that results from mutations in the DMD gene. It is characterized by progressive muscle weakness and patients typically experience loss of ambulation in their early teens, leading to wheelchair dependency. Weakness eventually develops in the upper limbs, respiratory, and cardiac muscles, resulting in death in the second to fourth decades of life.
CRAIG MCDONALD: Approximately 10% to 15% of patients with DMD have a nonsense mutation in the DMD gene, resulting in the incorporation of a premature stop codon and the production of a truncated dystrophin protein.
MÁR TULINIUS: Ataluren, an oral drug that promotes ribosomal read-through of in-frame premature stop codons, is a therapy for ambulatory patients with nonsense mutation DMD. Ataluren has previously been studied in two randomized placebo controlled trials. Although these two studies did not meet their primary endpoints., meta-analyses of the trials indicate that ataluren can delay decline in ambulatory function compared with placebo.
MÁR TULINIUS: Ataluren was also generally well-tolerated in this patient population. Consistent results have also been reported in STRIDE a multicenter registry providing real world data on the use of ataluren in patients with nonsense mutation DMD. The objective of the current analysis was to determine the effect of ataluren on clinically meaningful milestones of disease progression by evaluating age of loss of ambulation, and age of respiratory decline for patients with nonsense mutation DMD treated with ataluren and a long term safety study compared with a cohort of patients with DMD receiving standard of care treatment in an external natural history study.
MÁR TULINIUS: A Study 019 was a phase III long-term multicenter international open-label study designed to assess the safety and tolerability of ataluren in patients with nonsense mutation DMD. Secondary objectives explored the long term efficacy of ataluren and included measuring the ages at loss of ambulation and decline in respiratory function. Eligible patients were males who had received ataluren and prior PTC Therapeutics-sponsored studies at investigational sites outside the United States.
MÁR TULINIUS: Patients enrolled in study 019 received ataluren at a dose of 40 milligram per kilo per day, including 10 milligrams per kilo in the morning and at midday and 20 milligrams per kilo in the evening.
CRAIG MCDONALD: As Study 019 did not include a placebo control arm, the comparator group was comprised of patients enrolled in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study known as the CINRG DNHS. This study enrolled patients with DMD aged two to 28 years at 20 centers in nine countries between 2006 and 2016.
CRAIG MCDONALD: Patients in the CINRG comparator group received standard of care treatment defined as corticosteroids and palliative therapies. Patients who had received an investigational drug in previous clinical trials were excluded from these analyses. To allow for robust comparison between the two cohorts, propensity score matching was used to identify patients in study 019 who were similar to those in the CINRG comparator group, according to established predictors of disease progression.
CRAIG MCDONALD: The propensity score was created using a logistic regression model with the following four covariates: age at first clinical symptoms, age at initiation of corticosteroids, duration of deflazacort use, and duration of other corticosteroid use. Age at first symptoms was not recorded in study 019, as it was unavailable for use as a covariate for propensity score matching.
CRAIG MCDONALD: Age at diagnosis was thus used as the conservative proxy for this assessment. To be eligible for the analysis of age at loss of ambulation, patients must have had available data for age of loss of ambulation, as well as the four covariates used for the matching. To be eligible for the analysis of age of decline in respiratory function, patients must have been non-ambulatory and have available data for age of loss of ambulation, and for the defined respiratory events, as well as for the four covariates used for the propensity matching.
CRAIG MCDONALD: Kaplan-Meier analysis and Cox regression were used to estimate the distribution of age at loss of ambulation and age at which forced vital capacity declined to below 60% predicted, below 50% predicted, and below 30% predicted, as well as below a 1 liter absolute forced vital capacity, which are clinically meaningful thresholds influencing pulmonary management in DMD.
MÁR TULINIUS: In total, 94 patients were enrolled in study 019. These comprised 90 patients from the phase 2b study, study 007, and its open label extension, three patients from phase 2a study, study 004 and its open label extension, and one patient enrolled via special exemption. Of the 440 patients enrolled in the CINRG comparator group, 22 had participated in previous clinical trials of investigational drugs leaving 418 patients who were eligible for this analysis.
MÁR TULINIUS: Sixty patients from study 019 were eligible for the age of loss of ambulation analysis and were compared with 60 propensity score matched patients from the CINRG comparator group.
MÁR TULINIUS: In this cohort, ataluren treatment was associated with a significant delay of approximately 2.2 years in age of loss of ambulation compared with control patients in the CINRG comparator group. The median age of loss of ambulation was 15.5 years in this cohort of patients from study 019 compared with 13.3 years for the matched cohort from the CINRG comparator group.
CRAIG MCDONALD: For the respiratory function analysis, 45 patients were eligible from study 019 and were matched to 45 patients from the CINRG comparator group. Ataluren treatment resulted in a significant 3.0 year delay and decline to predicted FVC of below 60% compared with matched controls. Overall 51% of patients in this cohort from study 019 and 71% of matched controls experienced a decline to below the 60% predicted FVC threshold.
CRAIG MCDONALD: The median age for this milestone was 18.1 years in study 019 and 15.1 years in the CINRG comparator group.
CRAIG MCDONALD: Fewer patients in study 019 compared with matched control patients reached the milestones of percent predicted FVC below 50%, predicted FVC below 30%, and absolute FVC below one litre. FVC below one litre has been shown to be a strong predictor of mortality, and in this analysis only one patient out of 45 in study 019 experienced a decline in respiratory function below this critical threshold.
CRAIG MCDONALD: In contrast 9 out of 45 matched patients from the CINRG comparator group declined to this milestone, predictive of increased mortality.
CRAIG MCDONALD: Patients in study 019 received ataluren for up to 336 weeks. The safety profile of ataluren was consistent with previous studies and no new risks were identified. Most treatment emergent adverse events were mild or moderate in severity and no life threatening adverse events were reported. 33% of patients experienced a serious adverse event, but in only one of these patients were they considered to be related to ataluren.
CRAIG MCDONALD: Two serious adverse events led to death but these were considered to be unrelated to the study drug.
MÁR TULINIUS: Under the current standard of care, DMD remains a disease with devastating consequences and a poor prognosis. The development of targeted treatment options will be critical to improve outcomes for these patients. The findings presented here are consistent with ataluren delaying disease progression in both ambulatory and non-ambulatory patients. Ataluren was associated with a delay in the age of loss of ambulation of approximately 2.2 years and a delay in predicted FVC decreasing to below 60% of approximately three years.
MÁR TULINIUS: Two ataluren treated patients experienced predicted FVC declining to below 30% or absolute FVC declining to below one liter. Longer follow up will be required to investigate these advanced milestones.
CRAIG MCDONALD: These results are highly clinically meaningful. The delay in loss of ambulation in study 019 represents both prolongation of personal autonomy in daily life and also a delay in the onset of subsequent disease milestones. The potential preservation of respiratory function is important as respiratory failure is one of the most common causes of death in DMD. The results presented here, therefore, support the concept that ataluren can provide further benefit in terms of preserving ambulation and respiratory function, on top of that provided by corticosteroids.
CRAIG MCDONALD: The delay in loss of motor function associated with ataluren is also highly meaningful to patients and their families, since the loss of physical function in DMD is irreversible. The respiratory findings also extend prior results that were primarily studied in ambulatory patients. [MUSIC PLAYING]