The Rare Disease Clinical Research Network, funded by the National Institutes of Health, has launched the Inherited Neuropathies Consortium to study various aspects of Charcot-Marie-Tooth disease (CMT). Three studies of CMT and a disease registry are open. (For more, see In Focus: CMT.)
The studies will analyze the natural history of different types of CMT; identify genetic factors that modify the course of type 1A CMT and genetic mutations that cause type 2 CMT; and develop and test a method of measuring CMT-related impairment in children.
The registry invites people with CMT or parents of children with the disease to volunteer information so that they can be notified about clinical trials in which they may want to participate. An online form asks for name, address, birth date, place of birth, email address and items relevant to the disease. No identifying information will be given to anyone without the registrant’s approval.
Favorable results were reported at the annual American Academy of Neurology meeting in April 2011 for a pilot study of etanercept (Enbrel) in dermatomyositis (DM), an autoimmune disease that affects the muscles and skin. Results indicated etanercept was safe and well-tolerated, and enabled trial participants who received it to take less of the corticosteroid drug prednisone to control disease symptoms.
Eleven participants began the trial on prednisone plus etanercept, and five started on prednisone plus a placebo. After week 24, the median prednisone dose needed to control the disease in the placebo group was 29.2 milligrams per day, while in the etanercept group it was 1.2 milligrams per day. Five participants who received entanercept developed a worsening skin rash during the study, compared to one participant who was taking the placebo.
Like prednisone, etanercept is an immunosuppressant and anti-inflammatory medication, but its mechanism of action is different. Marketed as Enbrel, the drug is approved for treatment of certain types of arthritis, the joint disease ankylosing spondylitis and the skin disease plaque psoriasis.
Because chronic treatment with corticosteroids can result in significant side effects such as weight gain, bone loss and psychological distress, finding a drug that lowers the need for corticosteroids can be beneficial.
However, etanercept also has a down side, including increasing the risk of developing serious infections and certain malignancies, as well as other autoimmune disorders.
Cautiously favorable results have been reported for PRO051/GSK2402968, an experimental exon-skipping drug being developed to treat boys with Duchenne muscular dystrophy (DMD) who have certain mutations in the gene for the muscle protein dystrophin. A caveat is that several trial participants excreted protein in their urine, a possible sign of kidney damage.
|Exon skipping is a strategy in which an antisense oligo-nucleotide is used to coax cells into skipping an exon (region of genetic instructions), splice together remaining exons and produce a functional protein.|
The latest available results were reported at the annual meeting of the American Academy of Neurology in April 2011.
Twelve boys with DMD participated in this phase 1-2a trial of PRO051/GSK2402968 conducted in Belgium and Sweden. All had specific dystrophin gene mutations that potentially allowed them to benefit from having their cells “skip” (not include) a region of the gene known as exon 51 when synthesizing dystrophin protein molecules.
After 48 weeks of weekly subcutaneous (under the skin) injections of PRO051/GSK2402968 at a dosage of 6 milligrams per kilogram of body weight, the trial participants showed an average increase of about 94 feet in the distance they could walk in six minutes compared to baseline measurements.
All trial participants produced dystrophin, apparently in response to the treatment, at variable levels.
An early-stage study of PRO051/GSK2402968 is now under way at Nationwide Children’s Hospital in Columbus, Ohio. This study, which is not expected to have any benefit to participants but only to assess what happens to the drug in the body, will include boys with DMD who are no longer walking and have specific dystrophin mutations. Eligible participants must have mutations involving exons 13-50 (inclusive); 29-50; 43-50; 45-50; 47-50; 48-50; 49-50; 50; or 52.
Broadly favorable results have been reported from a 26-week study of eteplirsen (formerly known as AVI-4658), another experimental exon-skipping drug for people with Duchenne muscular dystrophy (DMD) who have specific genetic mutations.
The results were reported at the April 2011 American Academy of Neurology meeting. AVI BioPharma is the developer of this drug. (For a detailed description of this trial, see the Oct. 15, 2010, news release on the AVI website.
Eteplirsen is designed to cause skipping of exon 51 of the dystrophin gene, as is PRO051/GSK2402968 (described in the previous item), although the two drugs have different structures.
In this 19-person trial, conducted in the United Kingdom, boys with DMD with specific dystrophin mutations received weekly intravenous infusions of eteplirsen at one of six dosage levels. The drug was well-tolerated, and three people showed substantial levels of dystrophin-positive muscle fibers, with no apparent immune response to the new dystrophin protein.
A phase 1 study of eteplirsen at Nationwide Children’s Hospital in Columbus, Ohio, is under way but is no longer recruiting participants. See Nationwide's Neuromuscular Clinical Studies page.
A phase 2, dose-escalation study of ACE-031 in boys with DMD was terminated, and the extension study for boys who had completed the original study was suspended, based on preliminary safety data. Both studies were being conducted in Canada, and the plan had been to open study sites in the United States at some time in the future.
The adverse events that the trial participants experienced — minor bleeding of the nose and gums, and dilation of blood vessels in the skin — were not, in and of themselves, considered dangerous. However, the companies and regulatory agencies involved said they would need to fully understand these events before continuing clinical studies of ACE-031.
ACE-031 is designed as a decoy to lure myostatin, and other naturally occurring proteins that limit muscle growth, away from muscle fibers.
Analysis of the human data and of animal studies is expected to shed light on the safety of ACE-031 and help determine whether new trials can be initiated.
A French and Tunisian research group has reported moderately encouraging results from a safety and tolerability trial of intramuscular gene therapy for the type 2C form of limb-girdle muscular dystrophy (LGMD). The findings were announced at the April 2011 annual American Academy of Neurology meeting.
Trial results found that participants who received mid-to-high dosages of gamma-sarcoglycan genes appeared to produce gamma-sarcoglycan protein. LGMD2C is caused by a deficiency of the gamma-sarcoglycan protein at the muscle-fiber membrane, as a result of mutated gamma-sarcoglycan genes.
In this study, nine participants ages 16 to 38 were divided into three dosage groups. The first two groups received a single injection into a forearm muscle of gamma-sarcoglycan genes encased in the shells of the type 1 adeno-associated viruses (AAV1s).
The second group received a higher dose than the first group, and the third group received three injections at the same site, for the highest total dose.
The therapy was well-tolerated, and those in the mid-to-high dosage ranges showed evidence of gamma-sarcoglycan protein production from the injected genes. One trial participant had an immune response either to the AAV1 shell or to the gamma-sarcoglycan protein.
The investigators interpreted their results as basically positive and as paving the way for future developments in gene therapy for muscle diseases.
Similarly encouraging results were reported in October 2010 in an MDA-supported trial in which genes for the alpha-sarcoglycan protein were injected into a foot muscle in people with the type 2D form of LGMD. A cautionary note is that one person in this trial showed an immune response to the viral vehicle used to deliver the new genes. (See Researchers encouraged by LGMD gene therapy trial results, Clinical Trials, January-March 2011 Quest.)
|Developers of AT2220 hope it will improve the efficacy of intravenous infusions of enzyme replacement therapy for Pompe disease.|
Amicus Therapeutics announced March 8, 2011, that the U.S. Food and Drug Administration had removed the hold it had previously placed on clinical testing of AT2220, an experimental treatment the company is developing for Pompe disease (acid maltase deficiency).
Its developers hope that AT2220 will prevent a loss of activity of enzyme replacement therapy in the bloodstream; increase tissue uptake of the replaced enzyme; and improve the ability of the replaced enzyme to do its job of reducing toxic buildup of glycogen.
In an upcoming trial, AT2220 will not be given alone, as was originally planned, but will be given only in combination with enzyme replacement therapy. An earlier trial, in which adults with Pompe disease were given high-dose AT2220 alone, resulted in two serious adverse events that may have been related to the drug.
The motor function of children and adolescents with spinal muscular atrophy (SMA) who were 3-17 years old and able to walk or stand did not benefit from treatment with valproic acid and carnitine. Excessive weight gain was a common adverse event.
The 28 participants were in part 2 of a two-part trial of this experimental SMA treatment, for which results were announced in April 2011 at the annual American Academy of Neurology meeting.
Part 1, for which similar results were announced in 2010, included 61 children with SMA who were 2 to 8 years old and were unable to walk or stand. Like the ambulatory children, the nonwalkers did not show motor function benefit from the treatment and gained an excessive amount of weight.