PTC Therapeutics, Inc.
(PTC), a biopharmaceutical company focused on the discovery and development
of small-molecule drugs targeting post-transcriptional control processes,
today announced encouraging data from a Phase 2 clinical trial of PTC124 in
patients with Duchenne muscular dystrophy (DMD) due to a nonsense mutation.
The results imply pharmacological activity based on preliminary data that
suggest increases in dystrophin in muscle biopsies in a number of patients
and statistically significant improvements in muscle enzymes in serum. The
preliminary data were presented today at the PPUK 4th International DMD
Conference in London, England.
“These results are the first example of an oral therapy addressing the
underlying cause of DMD by restoring dystrophin production,” said Dr.
Richard Finkel, Director of the Neuromuscular Program, Children’s Hospital
of Philadelphia, PA, one of the trial’s lead investigators. “There are
limited therapeutic options for patients living with DMD, and these data
strongly indicate PTC124 warrants further clinical investigation in this
patient population, which has a great unmet medical need.”
Langdon Miller, M.D., Chief Medical Officer, PTC, stated, “These
preliminary results in patients with DMD provide confirmation of proof of
concept that PTC124 can induce ribosomal readthrough of nonsense mutations
as an approach to treating genetic disorders. Given that PTC124 was very
well- tolerated and activity was observed at lower-than-expected plasma
concentrations, we are amending this trial to evaluate higher dose levels
and the potential to further increase dystrophin expression.”
“In the first half of 2007, we expect to present the final data set
from this Phase 2 clinical trial and meet with regulatory authorities to
determine the next steps for further clinical development of PTC124.
Following these discussions, we hope to initiate longer-term clinical
trials for PTC124 in 2007,” said Dr. Miller.
Patients with DMD lack dystrophin, a protein that is critical to the
structural stability of muscle fibers. This Phase 2 multi-site, open-label,
dose-ranging clinical trial is evaluating muscle dystrophin expression in
patients with nonsense-mutation-mediated DMD. Blood levels of
muscle-derived creatine kinase are being measured as assessments of muscle
integrity. PTC124 safety, compliance, and pharmacokinetics are also being
evaluated.
Patients included in the interim analysis were enrolled at three
clinical sites in the United States: Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania; Cincinnati Children’s Hospital Medical Center,
Cincinnati, Ohio; and the University of Utah, Salt Lake City, Utah. In the
study, patients received 28 days of PTC124 treatment at one of two dose
levels. All patients were boys with a nonsense mutation in the dystrophin
gene, substantially elevated serum creatine kinase, and symptoms associated
with DMD.
Assessment of the in vitro effects of PTC124 on dystrophin expression
showed dose-dependent production of full-length dystrophin in myocytes
obtained from multiple study subjects; these data suggest the potential for
response across a range of early to late nonsense mutations within the
dystrophin gene. Evaluation of the in vivo effects of PTC124 over the
28-day treatment course suggest an increase in dystrophin expression in
muscle biopsies in a number of the boys participating in the trial,
although quantitative analysis is not yet complete. Statistically
significant reductions in the concentrations of muscle-derived creatine
kinase levels in the blood were observed during PTC124 treatment. Although
no formal questionnaire was used to collect data on changes in DMD-related
symptoms, several parents and teachers reported that boys participating in
the study had improvements in terms of greater activity level and increased
endurance during treatment.
PTC124 was well tolerated among the 26 patients included in the study.
Potentially drug-related adverse events were infrequent, mild to moderate
in severity, did not result in therapy interruptions or discontinuations,
and were reversible. There were no safety concerns based on physical
examinations, vital sign measurements, electrocardiograms, or laboratory
parameters. Compliance was excellent at both dose levels.
“These preliminary results are very encouraging and add to the growing
body of clinical evidence supporting the potential of PTC124 as a treatment
for genetic disorders due to a nonsense mutation,” said Stuart W. Peltz,
Ph.D., President and Chief Executive Officer of PTC Therapeutics. “The
findings in the DMD trials are consistent with the results observed in
Phase 2 clinical trials of PTC124 in patients with cystic fibrosis. We
intend to extend this concept into other nonsense-mediated genetic
disorders.”
About Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a progressive muscle disorder that
causes the loss of both muscle function and independence. DMD is perhaps
the most prevalent of the muscular dystrophies and is the most common
lethal genetic disorder diagnosed during childhood today. Each year,
approximately 20,000 children worldwide are born with DMD (one of every
3,500 male children). More information regarding DMD is available through
the Muscular Dystrophy Association (mdausa) and the Parent
Project Muscular Dystrophy (parentprojectmd).
About PTC124
PTC124 is an orally delivered product candidate in Phase 2 clinical
development for the treatment of genetic disorders due to nonsense
mutations. Nonsense mutations are single-point alterations in the genetic
code that prematurely halt the translation process, producing a shortened,
non- functional protein. PTC124 has demonstrated activity in preclinical
genetic disease models harboring nonsense mutations allowing the
restoration of the production of full-length, functional proteins. In Phase
1 clinical trials, PTC124 was generally well tolerated, achieved target
plasma concentrations that have been associated with activity in
preclinical models, and did not induce ribosomal readthrough of normal stop
codons. PTC is currently conducting Phase 2 clinical trials of PTC124 in
nonsense-mutation-mediated cystic fibrosis (CF) and Duchenne muscular
dystrophy (DMD).
It is estimated that 10% of the cases of CF and 13% of the cases of DMD
are due to nonsense mutations. PTC believes that PTC124 is potentially
applicable to a broad range of other genetic disorders in which a nonsense
mutation is the cause of the disease. The FDA has granted PTC124 Fast-Track
designations and Orphan Drug designations for the treatment of CF and DMD
due to nonsense mutations. PTC124 has also been granted orphan drug status
for the treatment of CF and DMD by the Committee for Orphan Medicinal
Products (COMP) of the European Medicines Agency (EMEA). PTC124′s
development is supported by grants from the Muscular Dystrophy Association
(MDA), Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT), Parent Project
Muscular Dystrophy (PPMD), FDA’s Office of Orphan Products Development
(OOPD), and by General Clinical Research Center grants from the National
Center for Research Resources (NCRR).
About PTC Therapeutics, Inc.
PTC is a biopharmaceutical company focused on the discovery and
development of orally administered, proprietary small-molecule drugs that
target post-transcriptional control processes. Post-transcriptional control
processes regulate the rate and timing of protein production and are of
central importance to proper cellular function. PTC has assembled
proprietary technologies and extensive knowledge of post-transcriptional
control processes that it applies in its drug discovery and development
activities. PTC’s current pipeline of clinical and preclinical product
candidates addresses multiple indications, including genetic disorders,
oncology, and infectious diseases.
PTC Therapeutics, Inc
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