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It seems almost everyone knows about Amgen's (AMGN) Denosumab. However, while the drug has been probably over-reported, one aspect of Denosumab has been under-reported. That is its profile in Rheumatoid Arthritis.

Patients with RA have severe and early osteoporosis, with incidence approximately twice that of age matched controls. This is due to the inflammatory process of RA (including IL-1 and TNF), drugs (such as steroids), inactivity, etc. In fact, 40% of patients have erosive disease within 6 months (Effects of RA on Bone: Current Opinion in RA. Haugeberg, G et al).

Older drugs used to treat RA have little effect on osteoporosis. Leflunomide decreases only peri-articular osteoporosis (Pfeil A et al. Rheumatol Int. 2009 Jan;29(3):287-95). Methotrexate in low doses (< 10 mg/week) has little effect, whereas doses higher than that leads to increased osteoporosis (Minaur et al. Rheumatology 2002; 41: 741-749). Data for Sulphasalazine or Hydroxychloroquine is very scant. In contrast, most anti-TNFs show activity against osteoporosis (Wijbrandts CA et al. Ann Rheum Dis. 2009 Mar;68(3):373-6, Seriolo B et al. Ann N Y Acad Sci. 2006 Jun;1069:420-7). Thus, a practicing rheumatologist has a choice – give cheaper older drugs for RA and add anti-osteoporotics such as Zoledronic acid or Alendronate, or give anti-TNFs (which are injections, and very expensive). Anti-TNFs do not have the same efficacy in managing osteoporosis when compared to anti-osteoporotics such as bisphosphonates. Wouldn’t it be nice if an anti-osteoporotic drug was marketed that had efficacy in RA, or a drug meant for RA was also a strong anti-osteoporotic?

Unfortunately, that has not happened yet. Of all marketed anti-osteoporotics, only Zoledronic Acid has shown some efficacy in RA. Zoledronic Acid is not only the most efficacious bisphophonate, but it also has an effect on the immune system by interacting with a type of T cell called the gamma delta T cell. Marketed by Novartis (NVS) as Aclasta or Reclast, it was evaluated in an exploratory phase II 26-week study where it showed very good efficacy in decreasing erosions, markers of bone turnover, and increasing bone mineral density (Jarrett SJ et al. Arthritis and Rheumatism 2006 Vol 54 No 5 Pages 1410 – 1414). Despite the small sample size of only 39 patients, Zoledronic Acid also showed some efficacy in treatment of signs and symptoms of RA by decreasing Patient Global Assessment, with p value <0.05 when compared to placebo. This may have been due to its effect on T cells. Unfortunately, other standard measurements such as ACR 20, 50, 70, Disease Activity Score, and Health Assessment Questionnaire were not undertaken. There is no public data on whether Novartis plans to develop Zoledronic Acid further in this indication or not.

This presents an opportunity for Amgen. Given its mechanism of action on the RANK pathway, which affects not only osteoclasts but also antigen presenting cells, would Denosumab be worth considering in RA, where the safety hurdle is less than that in osteoporosis? In fact, Amgen did undertake a one-year phase II study in RA (Cohen SB et al. Arthritis and Rheumatism 2008. Vol 58 No 5 1299 - 1309). As with Zoledronic Acid, there was a dramatic effect on erosions, markers of bone turnover, and bone mineral density. However, there was no effect on Joint Space Narrowing, another critical measure of effect on structural modification. In addition there was no effect on signs and symptoms of RA (as measured by ACR 20, 50, 70, DAS 28, and HAQ), and the higher dose (180 mg) was better than the recently approved dose (60 mg). So, where does that leave Amgen with RA?

Looking at Clinicaltrials.gov, there is no mention of Amgen conducting phase III studies in RA. And neither does Amgen’s website give any information of any phase III study being conducted with Denosumab in RA. Is Amgen missing an opportunity? Given the phase II data, if Amgen were to proceed in RA, it probably would have to use the higher dose. What would be the competitive profile of Denosumab in RA?

Strengths: Very strong efficacy in reducing erosions, dosing less frequent than biologics (except Anakinra), most likely to be less expensive than anti-TNFs.

Weakness: No efficacy on signs and symptoms, no efficacy on joint space narrowing, requires injections.

Opportunities: Amgen’s excellent rapport with rheumatologists, use in combination with DMARDS such as methotrexate in those patients reluctant to using biologics (due to cost or side effects of biologics).

Threat: Development of other drugs that have potential to treat RA and osteoporosis

All things considered, Amgen would be missing an opportunity if it were to neglect RA. Its best bet would be in combination with methotrexate rather than as a monotherapy.

Disclosure: Author has no positions in AMGN or NVS, but does have a relationship with a firm developing a novel, patented, improved version of Zoledronic Acid

Source: Another Positive Indication for Amgen's Denosumab