DONA™ USA NEWS

November 2, 2000
ROTTA'S GLUCOSAMINE PREVENTS DAMAGE IN OA

Osteoarthritis is the most prevalent form of arthritis, affecting approximately 10-12% of the world's population. As a pharmaceutical market, it is much larger than rheumatoid arthritis, which afflicts approximately 1% of the population. It is more common in the elderly, affecting about 85% of people aged over 70, and is one of the leading causes of disability in this group. In the US, OA is conservatively estimated to account for 46 million physician visits, 3.7 million hospital admissions, 185 million bed days and 68 million work days lost every year. Often described as "wear and tear", osteoarthritis involves a complex degeneration of the joints. The cartilage becomes thin and flaky, and begins to split, and the bone underneath thickens and starts to protrude from the edges of the joint, restricting movement. The joints become swollen, stiff and painful, and in severe cases, are permanently deformed.

Rotta's glucosamine sulphate has significantly reduced the progression of osteoarthritis (OA) in a three-year placebo-controlled study reported at the recent American College of Rheumatology meeting in Boston. The Italian firm markets glucosamine sulphate as a prescription product, but the substance is also widely sold over-the-counter by many different manufacturers as a "nutraceutical". "This is the first time that any product has shown a structure modification effect in osteoarthritis," commented lead investigator Jean-Yves Reginster, professor of epidemiology and public health at the University of Liege, Belgium (and also the Belgian representative at the EMEA). Noting that glucosamine also had effects on symptoms, he proposed calling it a disease-modifying agent for OA. There are no such drugs at present - all existing disease-modifying agents are for rheumatoid arthritis. Current treatment of osteoarthritis is aimed at pain and symptom relief, and involves analgesics (NSAIs), and intra-articular injections of steroids or hyaluronic acid, as well as advice on weight loss and exercise.

. . . significant X-ray differences
The three-year study involved 212 patients with osteoarthritis of the knee, and X-rays of the affected joint were taken on enrolment, after one year and after three years. Symptoms were scored every four months on the WOMAC index (a composite of pain, stiffness and physical function). The difference between treated and placebo groups for the three-year X-rays was significant and remained significant regardless of whether the data were analysed on an intention-to-treat analysis or on a per protocol basis (including only patients who completed the three-year study - 71 on placebo and 68 on glucosamine). Although no significant difference was seen between groups in the one year X-rays, there was a trend in favour of the treated group, Professor Reginster noted. Placebo-treated patients had an average joint space narrowing of 0.08-0.1mm/year, while the group taking glucosamine sulphate 1,500mg once daily saw no significant joint space narrowing, he said. In addition, there was an improvement in symptoms, with scores for pain and agility significantly better in the treated group compared with those on placebo. In the placebo group, a "slight worsening of the symptoms was evident at the end of treatment, compared with the improvement observed after glucosamine".

. . . Rotta markets as medicine
Rotta markets glucosamine sulphate as a prescription medicine under several different trade names - including Dona, Viartril and Arthryl - throughout Europe, South America and Southeast Asia. In many countries, it is the best-selling prescription product for osteoarthritis, the company says. It is number one in Germany, where it was launched in the 1980s, number two in Italy, and number four in Spain, where it was launched three years ago (as Xicil). It is the company's best-selling product, bringing in sales of $49 million last year. Rotta has further OA studies underway in Europe, including another three-year pivotal study. The company intends to apply for approval of glucosamine in other markets worldwide, including the US, and will license it out in countries where it has only a small presence. Rotta emphasises that its product is a "chemically well defined and pure substance", and should be clearly differentiated from other products which are undefined macromolecular derivatives or extracts from animal cartilage.

. . . many nutraceuticals
Glucosamine is also widely available as a "nutraceutical", sold over-the-counter in health shops and pharmacies, both alone and in combination with chondroitin. Many of the products available in the US contain glucosamine hydrochloride, which differs from the sulphate form in bioavailability and recommended doses. Glucosamine is an amino sugar precursor to glycosaminoglycans, which are large polysaccharides found in articular cartilage. Chondroitin sulphate is the most abundant glycosaminoglycan found in articular cartilage (the other is hyaluronic acid). Although their mechanisms of actions are not well understood, glucosamine is thought to increase the production of glycosaminoglycans and related substances that make up the collagen matrix in cartilage, while chondroitin is believed to inhibit enzymes that degrade cartilage. These products have become increasingly popular with patients in recent years. This has led both to criticism from medical circles over "hype" which suggests a "cure" for arthritis, and accusations from the other side that medics are ignoring a "rational and safe therapeutic strategy" because it is not a patentable drug. But the growing interest from patients, and those supplying them with the products, has forced the medical community to sit up and take note. In the US, so many OA patients are taking these supplements that recruitment to placebo groups in clinical trials is proving difficult, one investigator commented.
Last year in the US, the National Center for Complementary and Alternative Medicine (part of the NIH), convened a group of experts, including representatives from the FDA, who declared that "there is a real and urgent public health need to test these agents in a rigorous way". As a result, a large NIH-funded study is planned. The first US multicentre study of glucosamine and chondroitin sulphate in knee osteoarthritis will be a Phase III study which will last four years, involving more than 1,000 patients to test for efficacy, safety and side-effects. The $6.6 million research contract was awarded in September to the University of Utah School of Medicine.

Zosia Chustecka