Five Small Steps Toward New Drug Options for OA
Five Small Steps Toward New Drug Options for OA
No speaker at the OARSI meeting turned up with the Holy Grail -- a new disease modifying osteoarthritis drug (DMOAD). Some promising alternatives discussed at the conference are not available to US patients; others are in very preliminary testing.
Submicron diclofenac: The pharmaceuticals firm Iroko Pharmaceuticals of Philadelphia is currently developing a submicron formula of diclofenac to allow effective delivery of the oral NSAID at a safer, lower dose for patients with moderate osteoarthritis (OA). In a 285-patient study carried out by rheumatologists Allan Gibofsky MD of the Hospital for Special Surgery in New York and Marc Hochberg of the University of Maryland Medical Center, patients with chronic Kellgren-Lawrence grade 2 or 3 OA of the hip or knee had significantly greater reductions on the WOMAC pain scale after taking 35 mg of the submicron diclofenac twice or three times daily for 12 weeks than those who took placebo. Serious adverse events were generally comparable at both dose levels to those of placebo, primarily colds and constipation, although nausea, diarrhea and headache appeared more common in the diclofenac group. The company is also testing the submicron particle techology with indomethacin for acute pain relief.
OralVisc: An oral preparation containing hyaluronic acid, OralVisc significantly reduced WOMAC pain and function scores after 3 months of treatment in a small randomized trial involving 40 patients. The drug also significantly reduced levels of serum bradykinin, a mediator of inflammation. The drug produced by Bioiberica of Barcelona, Spain, was tested at Henry Ford Hospital in Detroit, although . Oralvisc is not marketed in the US.
Strontium ranelate: European researchers gave updated results for knee OA from the large phase III SEKOIA study of strontium ranelate. In a sample of 1,371 patients, the calcium-like drug showed structure-modifying activity. Those who took either 1 g or 2 g doses were significantly less likely than those on placebo to show progression in radiological measures of joint space narrowing. A pilot study with hand OA showed encouraging but not definitive results. Strontium ranelate is used for osteoporosis in the United Kingdom but is not approved in the United States due to concerns about adverse events: memory loss and blood clots. (On the day after this article was posted, the European Medicines Agency issued an advisory calling for restrictions in use of strontium ranelate due to concerns about an increased risk of heart attack.)
Sprifermin: Merck KgGA of Germany last month announced a strategic partnership with Nordic Bioscience to continue phase II trials with its formulation of fibroblast growth factor 18 (FGF-18), despite disappointing results reported at last year's OARSI conference. At this year's conference, Yoshifumi Mori of Merck Serono Research in Germany described studies that led to the identification of FGF-18 as a useful candidate for an injectable DMOAD. Collaborating with a team at the University of Tokyo, Merck researchers found that injections of recombinant human FGF-18 reduced cartilage degeneration in a dose-dependent manner in a rat surgery model of OA. The substance induced increased expression of TIMP1, which inhibits cartilage catabolism.
The fibroblast growth factors are a very complex system, having both anabolic and catabolic effects, and the ratio between various subtypes may be important in inflammation, said Richard F. Loeser MD, head of molecular medicine at Wake Forest University Medical School. But Mori reported that FGF-18 was the "only soluble factor" that stimulates cell proliferation and migration and inhibits cartilage degradation. Animal studies have shown that FGF-18 is strongly expressed in articular cartilage, but scarcely in the femoral growth plate, theoretically validating its specificity as a treatment for knee OA.
Lubricin: It's still far too early for clinical trials, but this molecule from synovial fluid, whose biochemical name is proteoglycan 4 (PrG4), has been generating interest. A report last month in Science Translational Medicine laid out the rationale for its use in OA, based on mouse studies showing that injection of Prg4 protected against cartilage degeneration after cruciate ligament injury. A study described at OARSI focused on its effects in vitro. Investigators at the Center for Dental Medicine in Zurich have found that lubricin is upregulated in chondrocytes at times of increasing shear stress in the temporomandibular joint.
Why is it so challenging to find a new DMOAD? Several agents have produced some structural modifications, but most early trials have not met stated primary outcomes in premarketing clinical trials, said rheumatologist Roy Altman MD, professor of medicine at UCLA. He went on to count some of the reasons why it's difficult to prove efficacy in human beings with spontaneous osteoarthritis: "There's a tremendous placebo effect on symptoms. For disease modification, patient selection is difficult as only 10% of patients have rapid progression. It is also of interest that half of people with X-ray evidence of OA don't even have symptoms."