Every so often a unique medicine comes along. Denosumab is a drug that’s going to be used for both osteoporosis as well as rheumatoid arthritis. Sort of like the old Doublemint gum commercial with the Doublement twins. Double your fun.
It’s given by subcutaneous injection every six months so the dosing interval is attractive. What the price tag attached to this invention is the big question.
This is an abstract that appeared in a recent journal…
Denosumab for joints and bones
Current Rheumatology Reports, 07/30/09
Lewiecki EM et al. – Denosumab suppresses bone turnover by inhibiting the action of RANKL on osteoclasts. [Editor’s note: osteoclasts are the cells that break down bone] Denosumab reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density, reduces fracture risk in women with postmenopausal osteoporosis, and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment. It is generally well tolerated, with a good safety profile. Adverse and serious adverse events, including infections and malignancy, are similar in patients treated with denosumab or placebo.
When this drug will be approved by the FDA is still uncertain.
[The first study looking at gene therapy for RA was done by Targeted Genetics in Seattle, Washington. Their results have been published in a number of journals and presented at a number of conferences. The Targeted Genetics product looked at a method for transferring a gene for anti-tumor necrosis factor via an adeno-associated virus. The preliminary data looked very promising. This study on an anti-IL-1 gene transfer model also looks promising. NW]
BIDMC Contact: Bonnie Prescott
Phone: (617) 667-7306
BOSTON — Researchers have reported the first clinical evidence that gene therapy reduces symptoms in patients with rheumatoid arthritis, an important milestone for this promising treatment which has endured a sometimes turbulent past. Described in the February issue of the journal Human Gene Therapy the findings stem from a study of two patients with severe rheumatoid arthritis conducted in Germany and led by an investigator at Beth Israel Deaconess Medical Center (BIDMC).
Originally conceived as a means of treating genetic diseases, such as cystic fibrosis and hemophilia, gene therapy involves implanting a normal gene to compensate for a defective gene in the patient. The first clinical trial to test gene therapy was launched in 1990 for the treatment of a rare, genetic immunodeficiency disease.
“This study helps extend gene therapy research to nongenetic, nonlethal diseases,” explains principal investigator Christopher Evans, PhD, Director of the Center for Advanced Orthopaedic Studies at BIDMC. “Rheumatoid arthritis [RA] is an extremely painful condition affecting multiple joints throughout the body. Arthritis is a good target for this treatment because the joint is a closed space into which we can inject genes,” adds Evans, who is also the Maurice Muller Professor of Orthopaedic Surgery at Harvard Medical School.
A classic autoimmune disease, RA develops when, for unknown reasons, the body’s immune system turns against itself, causing joints to become swollen and inflamed. If the disease is inadequately controlled, the tissues of the joint are eventually destroyed. Although anti-inflammatory agents and biologics can help to mitigate symptoms, there is no cure for the condition, estimated to affect more than 2 million individuals in the U.S. alone.
Evans has spent many years studying the molecules responsible for the breakdown of cartilage in patients with arthritis, identifying interleukin-1 as a good target. But, he adds, once he had this answer, another question was not far behind: How could he effectively reach the joints to block the actions of this protein?
Gene therapy provided the answer.
By implanting a gene in the affected joint, he was able to stimulate production of a human interleukin-1 receptor antagonist protein, which serves to block actions of the interleukin-1 protein.
“The idea is that by remaining in place, the new gene can continuously block the action of the interleukin-1 within the joints,” says Evans. “In essence, the gene becomes its own little factory, continuously working to alleviate pain and swelling.”
In 2005, in a study published in the Proceedings of the National Academy of Sciences (PNAS), Evans and colleagues demonstrated that the IL-1Ra gene could be safely transferred to human joints in patients with RA. In this new paper, the authors aimed to prove that the therapy was not only safe, but that it was of therapeutic benefit.
Two study subjects were recruited. (The number reduced from six study subjects following severe adverse events in an unrelated gene therapy trial taking place elsewhere, according to Evans.) Both subjects were postmenopausal females under the age of 75 with a diagnosis of advanced rheumatoid arthritis. After tissue was removed from the subjects’ knuckle joints, a harmless retrovirus was inserted into the tissue cells, in order to serve as a “vector” to transport the gene into the patients’ joints. After being placed in culture to grow and replicate, the cells were injected back into the afflicted joints
After four weeks, patients reported reduced pain and swelling, according to Evans. “In one of the two subjects, these effects were dramatic, and the gene-treated joints remained pain-free even though other joints experience flares.” Subsequent laboratory tests showed that tissues removed from the subject’s joint tissue synthesized lower amounts of disease-related proteins, confirming that the reduction in pain and swelling resulted from the actions of the implanted gene.
“Existing treatments for rheumatoid arthritis are costly and need to be administered regularly,” says Evans, adding that in addition to risk of side effects, not all patients respond well. “This paper provides us with the first real evidence that painful symptoms can indeed be lessened through gene therapy.”
Ongoing work will focus on the use of gene therapy for the treatment of osteoarthritis, as well as rheumatoid arthritis.
This study was funded, in part, by grants from the National Institutes of Health and Orthogen, a German biotechnology company.
Study coauthors include Peter Wehling, Julio Reinecke, Axel Baltzer, Marcus Granrath, Klaus Schulitz, Carl Schultz, and Rudiger Krauspe of the University of Dusseldorf School of Medicine, Germany; Theresa Whiteside, Elaine Elder and Paul Robbins of the University of Pittsburgh School of Medicine; and Steven Ghivizzani of the University of Florida College of Medicine.