Clinical Trials and Studies March-April 2008

Article Highlights:

Updates on clinical trials and studies as of February 2008

by Quest Staff on March 1, 2008 - 10:21am

QUEST Vol. 15, No. 2

This article includes items about: Duchenne muscular dystrophy, myasthenia gravis, spinal muscular atrophy and acid maltase deficiency (Pompe disease)

Results of phase 1 trial of exon skipping in DMD heralded as ‘proof of concept’

The Dec. 27 issue of the prestigious New England Journal of Medicine featured the fully analyzed and encouraging results of a phase 1 clinical trial of an exon-skipping compound in four boys with Duchenne muscular dystrophy (DMD). Preliminary findings from this trial, conducted in the Netherlands, were announced in May.

Judith van Deutekom, formerly at Leiden University in the Netherlands and now at Prosensa in Leiden, received MDA funding to work on preclinical development of exon skipping for DMD (see “European team”) and is the first author on this study. The clinical trial was funded by several European agencies and Prosensa, which produced the therapeutic compound.

The exon skipping was achieved by blocking the mutation-containing part of the gene with an antisense oligonucleotide, or AON.

The hoped-for result, which occurred in this trial in all four participants, is the production of smaller-than-normal, but potentially functional, dystrophin protein, which is missing in DMD.

Two of the participants were 10 and 11 years old, and two were 13. None had any detectable dystrophin in muscle biopsy samples prior to treatment, and all had mutations that were potentially correctable by skipping over a part of the dystrophin gene known as exon 51, which Prosensa’s PRO051 AON was designed to block.

Each boy received four injections of PRO051 in a muscle at the front of the lower leg. A biopsy a month later showed dystrophin production that was between 3 percent and 12 percent of a normal level of the protein. No functional changes were observed, but none were expected from this low dose and restricted area of injection. The results are considered “proof of concept,” however, for exon skipping via antisense as a strategy to treat DMD.

The investigators did not observe any problems related to safety of PRO051, although one participant reported pain at the injection site, two reported a few days of flulike symptoms after the injections, and one experienced mild diarrhea for a day.

Importantly, there were no apparent inflammatory or toxic responses to the compound.

In an accompanying editorial, long-time DMD researcher Eric Hoffman, now at Children’s National Medical Center in Washington, describes the promise of the Dutch study, as well as the hurdles yet to be cleared.

Hoffman, who has been awarded several MDA grants, notes that an exon-skipping compound, to be truly useful, would have to be delivered systemically to all muscles, without toxicity, and that several compounds (perhaps dozens) would have to be designed for the hundreds of different dystrophin mutations in boys with DMD.

If each AON compound has to be put through the full gamut of U.S. Food and Drug Administration approval tests, he says, the regulatory hurdles for this treatment strategy will be formidable. Instead, he suggests, perhaps the FDA will consider approving such compounds as a class of drugs, rather than as individual therapeutic agents.

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PTC Therapeutics to start longer studies of PTC124

PTC Therapeutics of South Plainfield, N.J., has announced its intention to conduct longer and larger studies of its drug PTC124, which targets a specific type of mutation in the dystrophin gene in boys with Duchenne muscular dystrophy (DMD).

This oral drug, developed by PTC with support from MDA, is designed to coax muscle cells to ignore, or “read through,” a molecular stop signal, known as a premature stop codon or nonsense mutation, that stops dystrophin protein synthesis too early in some 15 percent of people with DMD.

Because PTC124 and exon-skipping compounds require knowledge of the specific DMD-causing mutation, MDA will launch a program this year to assist all interested DMD-affected families in obtaining dystrophin DNA testing.  For more news as it becomes available, see or

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Gene transfer appears safe in six boys with DMD

A phase 1, MDA-supported trial in Duchenne muscular dystrophy (DMD) to test the effects of intramuscular injections of genes for the muscle protein dystrophin inside adeno-associated viruses has shown the procedure is safe, the investigators say.

So far, six participants at Nationwide Children’s Hospital and Research Institute (Columbus, Ohio) have received dystrophin injections into an arm muscle.

“The patients have been carefully followed for side effects of the treatment, and none has been encountered,” says neurologist Jerry Mendell, director of the Gene Therapy Center and co-director of the MDA clinics at Nationwide Children’s and Ohio State University Hospitals in Columbus, and the clinician on this study. “This is primarily a safety trial, and we can confidently report that safety has been achieved.”

Mendell adds that an additional goal of this study is to lay the groundwork for future gene therapy trials by establishing the ideal dose for treatment. “In this trial, two doses have been tested, and another will be required before completion of the study,” he says, noting that “by all indications,” a higher dose will be safe to administer.

Results are expected when all participants have completed the study.

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Amarin will continue testing EN101 in MG

Development of EN101, an experimental drug for myasthenia gravis (MG) that blocks the synthesis of the enzyme acetylcholi-nesterase, will continue, but under the auspices of a new company. In December, the London-based biotechnology firm Amarin acquired Ester Neurosciences, the Israeli company that first developed the drug. (See "Clinical Trials and Studies," Quest, November-December 2007).

Amarin is now overseeing an ongoing phase 2a trial of EN101, in which three different doses of the drug are being compared to Mestinon, a standard treatment for MG.

Acetylcholinesterase, the target of EN101, is an enzyme that degrades acetylcholine, a carrier of signals from nerve fibers to muscle fibers. Interfering with this enzyme’s action boosts acetylcholine levels, which is a logical way to increase strength and function in MG. Mestinon blocks the acetylcholinesterase enzyme after it’s been synthesized, and EN101 prevents its synthesis.

In December, Amarin said that “interim data suggest EN101 may have superior efficacy, longer duration of action, [and] a more favorable side effect profile and dosing regimen, as compared with Mestinon.”

The company said its focus will be on completing the phase 2a study and laboratory studies in preparation for beginning a phase 2b or phase 2-3 trial.

For more information, see

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Children with severe SMA are surviving longer

Survival time in type 1 spinal muscular atrophy (SMA), the most severe form of the disease, is significantly longer in children born between 1995 and 2006 than for those born between 1980 and 1994, say researchers at Columbia University in New York and Indiana University in Indianapolis.

Maryam Oskoui, now at the Montreal Neurological Institute, together with Petra Kaufmann and Darryl De Vivo, both co-directors of the MDA clinic at Columbia, with colleagues there and at IU, analyzed treatment and survival data for 143 children with type 1 SMA from the International SMA Patient Registry. They published their findings in the Nov. 13 issue of Neurology.

The researchers say the improved survival time is due to more widespread use of noninvasive assisted ventilation, cough assist devices, and gastrostomy tube feeding, as well as to a change in attitude about aggressive treatment of children with severe SMA because of increased optimism about future treatments.

The probability of survival to age 2 for children with an SMA1 diagnosis born between 1980 and 1994 was 30.8 percent. For children with this same diagnosis born between 1995 and 2006, the likelihood of surviving to age 2 was 73.9 percent. Surviving to age 4 for the group born between 1980 and 1994 had a probability of 26.2 percent, while for those born between 1995 and 2006, the probability was 65.1 percent.

The authors note that the new findings should affect the way doctors counsel parents of children with SMA1 and should affect the plans parents make for their children, many of whom eventually will start school.

They also note that it will be important to take into account the change in the “natural history” of SMA1 when planning clinical trials in this disease.

“Given the improvement of outcomes over time, it could be misleading to compare trial participants now to untreated patients in the past,” Kaufmann said, adding that the study underscores the need for controlled clinical trials, in which a group taking the test medication is compared to a current group taking a placebo.

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Myozyme improves endurance, pulmonary function in late-onset Pompe disease

The Cambridge, Mass., biotechnology company Genzyme has determined that treating patients with late-onset Pompe disease (also known as acid maltase deficiency) with the synthetic enzyme Myozyme for 18 months increased endurance and pulmonary function.

The company announced these results in a Dec. 13, 2007, press release.

The study involved 90 people with Pompe disease who were at least 8 years old, at eight sites in the United States and Europe. Participants received either Myozyme, an enzyme designed to compensate for a deficiency of acid maltase (also known as acid alpha-glucosidase), or a placebo (inactive substance) by intravenous infusion. MDA provided supplemental support for the trial.

After 18 months, participants treated with Myozyme increased the distance they could walk in six minutes by an average of about 30 meters (about 90 feet), while those in the placebo group showed no improvement from their baseline measurement.

A respiratory measurement known as forced vital capacity increased by 1 percent in the Myozyme-treated group, while it declined by approximately 3 percent in the placebo-treated patients.

The safety of Myozyme was found to be similar to that of an intravenously infused placebo.

Genzyme says it’s completing an analysis of this study and intends to present more detailed results at medical meetings and in a scientific journal.

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MDA and chest physicians release recommendations for anesthesia care in DMD

MDA, in collaboration with the American College of Chest Physicians, has issued a consensus statement on management of patients with Duchenne muscular dystrophy (DMD) undergoing anesthesia or sedation. The complete statement is published in the December issue of the journal Chest.

Valerie Cwik, MDA’s medical director and vice president of research, along with several MDA clinic directors, pulmonologists and respiratory therapists, participated in its development. They noted that longer survival because of better cardiac and respiratory care in DMD has made it more likely that patients will undergo surgical procedures and more important that guidelines for patient care during and after surgery be developed.

The physicians recommended considering using intravenous, rather than gas, anesthetics; not using depolarizing muscle relaxants, such as succinylcholine; having an intensive care unit for postoperative care; providing respiratory support during anesthesia or sedation; monitoring blood oxygen saturation using a pulse oximeter throughout the procedure; and when possible, monitoring blood or lung carbon dioxide levels.

They also advised consideration of moving the patient from intubation (tube in the trachea) during surgery to noninvasive positive pressure ventilation right after surgery; using extreme caution when administering supplemental oxygen; using manually assisted cough and insufflation-exsufflation assisted cough postoperatively to clear secretions; and obtaining a cardiology consultation and closely monitoring cardiac and fluid status postoperatively.

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