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RA market to flourish

Doubts over COX-2 inhibitor safety may make the RA market more receptive to new drugs

Doubts over COX-2 inhibitor safety may make the RA market more receptive to new drugs

Merck pulled Vioxx (rofecoxib) from the market in September 2004 due to cardiovascular safety concerns. Pfizer's Bextra (valdecoxib) was withdrawn seven months later at the request of regulators.

The withdrawal of these two members of the COX-2 inhibitor, or coxib, class of analgesics and anti-inflammatories shook the rheumatoid arthritis (RA) field and cost the companies dearly in lost revenues: Vioxx had amassed nearly $1.5bn in 2004, while Bextra had netted $1.3bn.

Following the surge of attention sparked by these events, now is the right time to assess future treatment provision for RA, a complicated, chronic disease characterised by painful and destructive inflammation that affects an estimated 35 to 50 million patients worldwide.

Current RA treatments
Early-stage disease management focuses mostly on symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, and coxibs. The discovery of the coxib class was hailed as an advance over NSAIDs, which, while cheaper, can cause serious gastrointestinal side effects that the coxibs were designed to avoid.

Anti-inflammatory corticosteroids can also be used to treat RA, but are reserved for specific indications: eg, where other anti-inflammatory medicines have been unsuccessful. Opioids are good for treating extreme pain, but become tolerated, have side effects and are open to abuse.

Later-stage RA is treated with disease- modifying anti-rheumatic drugs, referred to as DMARDs which, while very expensive, are effective in slowing disease progression.

This group includes older drugs, such as gold salts, penicillamine and methotrexate, which are used in the first instance. Newer biological agents, such as antibody-based therapies that target specific components of the RA immunological cascade, are added in if, and when, the older DMARDs fail.

Biological agents use proteins rather than synthetic compounds in their fight against disease. Johnson & Johnson's Remicade (infliximab), Abbott's Humira (adalimumab) and Amgen's Enbrel (etanercept) are all biological DMARDs on the market.

They block inflammation by inhibiting the proinflammatory cytokine, tumour necrosis factor (TNF). Remicade and Humira are anti-TNF antibodies that bind the cytokine to prevent it from reaching its receptor. Enbrel has the same action, but is a soluble form of the TNF receptor, rather than an antibody.

Market gap
Opportunities exist for more effective and safer drugs, and for new ways of targeting the disease - cheaper biologicals mean they could be used at an earlier stage of disease progression.

The painkillers and anti-inflammatories will continue to play a key role in managing RA, but it is the DMARDs, with their ability to affect disease progression, that hold the most promise for future treatment.

Data from Thomson Pharma reveals a healthy pipeline in this respect. Recently launched in the US is Bristol-Myers Squibb's (BMS) immunoglobulin CTLA4-Ig (Orencia, abatacept), an intravenous biologic that is awaiting approval in Europe. It stops antigen-presenting cells delivering the necessary 'costimulatory' signals that activate T-cells, which are involved in inflammation.

Biogen Idec, Genentech and Roche's non-Hodgkin's lymphoma drug, Rituxan (rituximab), has been approved for RA in the US and is in phase III trials in Canada and Europe. It is an intravenous anti-CD20 antibody that kills B-cells, another form of lymphocyte involved in inflammation.

There are few drugs in late-stage trials for RA, and they are all injectable agents that block various proinflammatory cytokines involved in the disease.

Celltech and UCB's CDP-870 (Cimzia, (certolizumab pegol) is a PEGylated anti-TNF antibody fragment. This technology means cheaper production costs, and the drug has been shown to reduce signs and symptoms of RA in two phase III European combination and monotherapy studies.

Centocor and Schering-Plough's CNTO-148 (golimumab) is an anti-TNF antibody, like Remicade and Humira. It entered phase III trials in December 2005, and launch is expected in 2009/2010.

Chugai and Roche's Actemra (tocilizumab) is an antibody against proinflammatory interleukin-6 (IL-6) which reduced joint destruction in a phase III trial. It is expected to be filed for approval in Japan in 2006, and in the US and Europe in 2007.

Several alternative methods of blocking TNF are in the pipeline, including receptor antagonists, nanobodies and TNF converting enzyme (TACE) inhibitors.

Various other proinflammatory cytokines, including GM-CSF (granulocyte-macrophage colony stimulating factor) and IL-1, are being targeted using cytokine antagonising antibodies, and a small-molecule inhibitor of IL-12 is in phase II trials.

Other proteins involved in disease pathogenesis, such as VEGF (vascular endothelial growth factor) and chemokines, are also under investigation.

Gene therapy

An alternative way to target inflammatory mediators is via gene-based approaches. Targeted Genetics and Arthrogen are both using adeno-associated virus (AAV) vectors to deliver genes into arthritic joints to get localised protein expression.

Targeted Genetics' tgAAV-TNFR:Fc delivers the gene for the soluble TNF receptor, and is in a phase I trial in North America. Arthrogen's preclinical therapy delivers the gene for IFN-fl, an anti-inflammatory cytokine, which can act as a counterbalance to proinflammatory mediators.

RNAi technology (the mechanism of which sees double-stranded RNA specifically suppress the expression of a gene bearing its complementary sequence) is also being investigated for use in RA, although it has not yet reached the clinic.

Nastech Pharmaceutical has an RNAi therapy against the TNF gene in preclinical development in the US, and Cell Signals has one at the same stage in Japan that targets the gene for midkine, a growth factor implicated in proinflammatory cell survival and migration.

Oligonucleotide decoys are also putting in an appearance, such as those being developed by AnGes and Osaka University which both target NFB, a transcription factor for a number of genes involved in inflammation. Osaka's programme is in phase I trials, while AnGes is preparing to enter the clinic.

Yet, patient acceptance is likely to be greatest for oral drugs, which can be taken at home rather than in the hospital setting.

GlaxoSmithKline, Scios, Vertex and Takeda all have small molecules in phase II trials targeting the p38 MAP kinase, a cellular protein involved early on in the inflammatory cascade and production of inflammatory mediators, such as cytokines.

By inhibiting such a protein, one drug can block several inflammatory components.

The fate of the coxib class
The cardiovascular risks that prompted the withdrawal of Vioxx and Bextra from the market raised the spectre of a possible 'class effect' for coxibs - and potentially all NSAIDs - which could have had an even more dramatic effect on the market.

In some markets, boxed warnings were added to coxib labelling, and information regarding potential cardiovascular and gastrointestinal risks were added to the labels of all over-the-counter NSAIDs.

Meanwhile, approval of Merck's Arcoxia (etoricoxib) for RA has been delayed in the US pending further safety and efficacy data, although it is already launched in the UK and several other countries.

Novartis' new coxib, Prexige (lumiracoxib), was launched recently in the UK for the treatment of osteoarthritis and pain.

Regardless of the future for coxibs, the recent shake-up of the RA market will allow competition to flourish. Success will require more effective and safer (preferably oral) drugs that slow disease progression and can be used earlier in treatment.

The Author
Charlotte Jago is an editor in the Drug Information team at Thomson Scientific. The article uses data from the Thomson Pharma database (

2nd September 2008


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