Clinical Trials and Studies January-February 2007

Article Highlights:

Updates on research, clinical trials and studies as of  December 2006:

by Quest Staff on January 1, 2007 - 3:57pm

QUEST Vol. 14, No. 1

PTC124 trial shows promise in boys with Duchenne MD

Biotechnology company PTC Therapeutics of South Plainfield, N.J., which has received some $1.5 million from MDA for drug development, announced encouraging results in October from the phase 2 trial of its experimental compound PTC124 in 26 boys with Duchenne muscular dystrophy (DMD).

PTC124 is designed to coax cells to ignore, or "read through," a molecular stop signal known as a premature stop codon. These signals tell cells to stop processing a gene too soon, before they've read all the genetic instructions for synthesis of a protein.

The cause of DMD in about 15 percent of boys with the disease is a premature stop codon that cuts short the synthesis of the muscle protein dystrophin, before a functional dystrophin molecule is formed.

In this study, six boys took low-dose PTC124, and 20 took it at a higher dose, for 28 days. The average age in the low-dose group was 10, and in the high-dose group, it was 9.

When muscle biopsy samples were examined, dystrophin production was found in three of the six boys who took the lower dose and eight of the 20 who took the higher dose. In the high-dose group, there were significant decreases in blood levels of creatine kinase, an enzyme that leaks from damaged muscle cells into the bloodstream. The drug was well tolerated and appears safe.

PTC Therapeutics now wants to evaluate higher dose levels of PTC124 to see whether dystrophin production can be increased.

As of late November, the company was seeking regulatory approval to enroll patients at Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center.

After the trial criteria are finalized, information will be provided to families on PTC's mailing list, which can be joined by filling out the form under "Contact Us" at Information will also be posted on the MDA Web site at and at It can also be obtained from Kerri Donnelly at PTC Therapeutics at (908) 222-7000, ext. 112, or

Anyone seeking entry into a PTC124 trial must have a documented premature stop codon mutation. Testing can be obtained through the University of Utah in Salt Lake City. Contact Kim Hart at (801) 585-1299 or; or see


'Exon skipping' trial for DMD opens in Netherlands

The first trial to test a treatment strategy known as exon skipping in boys with Duchenne muscular dystrophy (DMD) is now under way at Leiden University Medical Center in the Netherlands, says Gerard Platenburg, CEO of the Dutch biopharmaceutical company Prosensa (, the trial's sponsor.

Exon skipping, which has shown promise in rodent models of DMD, is a technique that encourages cells to skip over faulty genetic information and construct a nearly normal protein from the remaining, correct information. (The parts of genes that supply codes for a protein's structure are called exons.) It differs from the stop codon read-through strategy described in "PTC124 Trial" because it could potentially be used to counteract a wider variety of DMD-causing genetic mutations.

The strategy is accomplished through antisense oligonucleotides (AONs), compounds that stick to specifically targeted genetic sequences and prevent cells from using those exons when manufacturing proteins.

In boys with DMD, the gene for the muscle protein dystrophin can have a variety of abnormalities, at least some of which can probably be circumvented by exon skipping.

The trial, which is fully enrolled, will include four to six boys with DMD who are between 8 and 16 years old. Each participant will receive a single intramuscular injection of an experimental AON.

The test AON was developed by Prosensa and builds on scientific contributions from many sources, including Judith van Deutekom at Leiden University's Department of Genetics, a former MDA grantee who developed this type of therapy in mice.

Platenburg notes that the trial is an "exploratory study on the efficacy, safety and tolerability of a single intramuscular dose" of an AON construct in DMD. If such treatment can restore production of dystrophin, the trial would provide "proof of principle" evidence that would encourage researchers to deliver the AON to the whole body.

"We have all reasons to expect that this trial will prove the therapeutic potential of our technology and thus form the basis for a viable cure for this terrible disease," Platenburg says.


Myodur kept on hold

CepTor, a Hunt Valley, Md., biopharmaceutical company, announced Oct. 6 that its application to test its experimental compound Myodur in boys with Duchenne muscular dystrophy (DMD) remains on hold. Myodur is designed to interfere with the actions of calpain, an enzyme that breaks down proteins.

The company says the Food and Drug Administration asked it to address two remaining issues. These issues are "straightforward and addressable," says an Oct. 6 press release from CepTor.


Congenital myopathies study seeks participants

MDA grantee Alan Beggs at Children's Hospital in Boston is conducting an ongoing study of the congenital myopathies (muscle diseases present from birth), including centronuclear/myotubular myopathy, congenital fiber-type disproportion, multiminicore disease, nemaline myopathy, and undefined congenital myopathies.

The primary goal of the research is to better understand the genes and proteins (gene products) involved in these diseases, through family history information and lab tests. Travel to Boston isn't required. For details, see or contact Elizabeth Taylor at (617) 919-2169 or

A team led by Beggs, in collaboration with researchers in the United Kingdom, Australia and Finland, recently identified a new gene that can cause nemaline myopathy when flawed.

Pankaj Agrawal and colleagues, who published their findings online in October in the American Journal of Human Genetics, identified a mutation in the gene for the protein cofilin 2 in two siblings from a Middle Eastern family whose previous diagnosis was a nonspecific congenital muscle disease. Like the other five genes associated with this disease, the cofilin 2 gene carries instructions for a protein associated with the inside of the muscle fiber, in the part where muscle filaments slide over each other to cause muscle contraction.


Idebenone shows safety, potential in Friedreich's

The antioxidant idebenone "has the potential to provide a possible treatment" for Friedreich's ataxia (FA), according to the U.S. National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health in Bethesda, Md. A trial of idebenone in FA conducted by NINDS, in collaboration with Santhera Pharmaceuticals of Liestal, Switzerland, also showed the drug is safe and well tolerated.

The six-month, phase 2 trial included 48 participants, with 12 in each of three dosage groups taking Santhera's SNT-MC17 idebenone compound and a placebo (inactive substance) group. There was a statistical trend toward dose-related improvement in neurological function, based on the International Cooperative Ataxia Rating Scale (ICARS), which consists of 19 measurements of sensory and motor skills

Principal investigator Nicholas Di Prospero at NINDS says in an Oct. 6 press release that his group is "encouraged to pursue further trials to establish [idebenone's] positive effect on neurological function in young [FA] patients."


Blood cell infusions helpful in MNGIE

Infusions of either mature blood cell fragments (platelets) or blood stem cells from healthy donors partially corrected biochemical abnormalities in three out of four patients with the mitochondrial disease MNGIE.

In this disease, mutations in the gene for the thymidine phosphorylase (TP) enzyme severely reduce its ability to metabolize thymidine and deoxyuridine, which accumulate to toxic levels and damage mitochondria, the energy-producing units of cells.

MDA grantee Michio Hirano at Columbia University in New York was involved in both studies, results of which were published online Sept. 13 in Neurology.

The researchers reasoned that supplying patients with TP-producing blood cells from donors might normalize the chemical environment and reduce damage to mitochondria. They infused (introduced through a blood vessel) mature, TP-producing platelets into a 23-year-old woman and a 16-year-old boy with MNGIE. In both cases, the infusions briefly increased TP levels and reduced levels of thymidine and deoxyuridine, although the patients' symptoms didn't improve.

The infused TP apparently doesn't have to enter muscle cells to be effective; it only has to be in the vicinity to lower the po-tentially damaging compounds.

They next tried infusing stem cells from donors, with the hope that these cells might permanently establish themselves in the circulation (engraft) and continuously produce TP.

When umbilical cord stem cells were infused into a 21-year-old man with severe MNGIE, they failed to engraft. But when a 30-year-old woman with MNGIE received blood stem cells from her healthy brother, some of them engrafted, and she experi-enced less abdominal pain, better swallowing, and decreased numbness in her hands and feet.

The researchers note that direct administration of stabilized TP protein or perhaps gene therapy with the TP gene might be more effective treatments than cell infusions. They added that treatment should begin as early after diagnosis as possible, before irreversible damage to the mitochondria occurs.


Sleep problems linked to impaired learning in Myotonic MD

A French research group has found that disordered sleep is common in young people with childhood-onset type 1 myotonic dystrophy (MMD1). They define the condition as showing symptoms between ages 1 and 10, with normal development during the first year of life and subsequent failure to thrive, abdominal problems, mental retardation and weakness.

Maria-Antonia Quera Salva at the Raymond Poincare Hospital in Garches, and colleagues, who published their findings in the October issue of Neuromuscular Disorders, speculated that disordered sleep might contribute to learning disabilities in MMD-affected children.

They conducted overnight sleep studies, questionnaire surveys and other tests in 21 children and young adults with MMD1 whose average age was 15.

Of the 21 patients, 19 (90 percent) had learning disabilities, and 17 (81 percent) reported fatigue and/or sleepiness. Six were found to have sleep apnea (periodic cessation of breathing during sleep); eight had abnormal periodic limb movements during the night; and one person had both.

The researchers say that fatigue and sleepiness are well documented in adult MMD1 and can severely impair performance. They recommend oral and upper airway examinations to look for obvious causes of sleep apnea that can be treated with surgery or orthodontic braces. They also advise testing children with periodic limb movements for blood iron level abnormalities, and considering modafinil, a drug that promotes wakefulness, for some patients.

"Whether effective treatment of these abnormalities improves the learning difficulties seen in these patients deserves to be investigated," they write.


Infantile-onset FSHD rare but severe

Facioscapulohumeral muscular dystrophy (FSHD) symptoms usually begin in the teen years, with weakness in the muscles of the face and shoulders and a slow progression to other muscle groups. But about 4 percent of the time, FSHD follows a rapidly progressive course beginning in infancy, even though the baby's parents may have few or no symptoms themselves.

Lars Klinge and colleagues at University of Newcastle Upon Tyne in the United Kingdom studied seven infantile-onset FSHD patients who were between 9 and 25 years old, finding that only one was still walking; all had impaired ability to show facial expression (none could smile); one had abnormal retinal blood vessels; and two had diminished hearing.

In some cases, a parent of an affected child is found to have an FSHD mutation in only some of his or her cells but to have conceived the child with a sperm or egg cell containing the mutation.

In these families, the parent's disease is masked by the presence of large numbers of normal muscle cells, but the child, whose conception begins with an FSHD-causing mutation that will be replicated in all of his or her cells, can be severely affected.

"Our data confirm that infantile FSHD represents less than 5 percent of the total FSHD population, but that it is a severe and progressive disease," the authors write in the October issue of Neuromuscular Disorders. They say that the risk to an adult with classical FSHD of having a child with this severe form of the disease is "probably low."


Wyeth analyzing MYO-029 results in MD

In November, Wyeth Pharmaceuticals announced that results of its trial of MYO-029 in adult muscular dystrophy were being analyzed.

MYO-029, a recombinant human antibody (laboratory-developed immune system protein), is designed to stick to and interfere with the activity of myostatin, a natural protein that prevents skeletal muscle formation. Studies conducted in mice with muscular dystrophy contributed to the development of this trial, which included about 100 adults with Becker, limb-girdle or facioscapulohumeral MD.


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