Please login to the form below

Not currently logged in
Email:
Password:

Latest treatments for rheumatoid arthritis

Oral kinase inhibitors are starting to rival the long-held supremacy of TNF inhibitors, as they are pills and do not require injecting, but questions remain over cardiovascular risk

Arthritis x-rayRheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation of the joints and surrounding tissues. The immune system attacks the body's own tissues, primarily the synovium. Accumulation of synovial fluid in the joints causes pain and systemic inflammation. RA is symmetrical, affecting joints on both sides of the body equally, particularly the fingers, wrists, knees, ankles and feet. Joint inflammation is accompanied by thickening of articular soft tissue, with extension of synovial tissue over articular cartilages, which become eroded.

The course is variable but is often chronic and progressive, leading to deformities and disability. The disease course is more prevalent in women and, although it can occur at any age, onset is most frequent between the ages of 40 and 50 years.

Treatment of RA is divided into two main areas: symptomatic therapies and biologic modifiers (biologics). Symptomatic therapies are used to reduce pain and inflammation. These include nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclo-oxygenase (COX)-1 and COX-2, and selective COX-2 inhibitors.

Although NSAIDs are effective, long-term use can cause bleeding and ulcers. Over the past decade, significant advances have been made in the treatment of RA, the most important being the development of biologics. At least 30 biologics are currently in clinical trials for RA.

Expanding biologics market
Biologics are genetically engineered proteins derived from human genes that reduce disease progression by altering pathogenic disease mechanisms. Unlike traditional RA therapies, biologics target specific components of the immune system. Nine biologics are currently approved for the treatment of patients who are refractory to methotrexate and other disease-modifying antirheumatic drugs (DMARDs), including five tumour necrosis factor (TNF) inhibitors – etanercept (Enbrel; Amgen), adalimumab (Humira; Abbott), infliximab (Remicade; Johnson & Johnson), golimumab (Simponi; Johnson & Johnson) and certolizumab (Cimzia; UCB).

The majority of patients who fail to respond to methotrexate or other oral DMARDs receive first-line therapy with one of these TNF inhibitors. Patients with an inadequate response to TNF inhibitors can choose between abatacept (Orencia; Bristol-Myers Squibb), tocilizumab (Actemra; Roche) and rituximab (Rituxan; Roche). All have efficacy similar to TNF inhibitors.

Abatacept is a first-in-class CTLA4-IgG fusion protein that prevents T-cell proliferation by binding with high affinity to CD80, a receptor that co-stimulates T-cell activation by binding to CD28. Intravenous (IV) abatacept has been launched in the US, Canada and the EU for the treatment of RA, and as second-line therapy for the same indication in Japan. IV abatacept is most often used to treat RA patients who have had an inadequate response to one or more TNF inhibitors.

Tocilizumab, an anti-interleukin (IL)-6 monoclonal antibody, is perhaps the superior drug of the three, but has only been available in the US since 2010. Rituximab, a blockbuster anti-CD20 monoclonal antibody used primarily for non-Hodgkin's lymphoma, has had relatively limited use for treatment of RA.

Abatacept is arguably the safest of the biologics, although TNF inhibitors also have a stellar safety profile. Based on clinical evidence, its efficacy is similar to the other biologics, although head-to-head comparisons are lacking. According to rheumatologists, the primary concern with abatacept is its slow onset of action. Fast onset of action is a key advantage to tocilizumab and all the TNF inhibitors.

Another factor holding abatacept back has been the need for IV infusion. Four of the five TNF inhibitors are available in subcutaneous (SC) formulations, while abatacept, tocilizumab and rituximab are IV. In order to address this issue and offer improved convenience and dosing flexibility over the IV formulation, Bristol-Myers Squibb has developed a new SC formulation of abatacept, which has been approved in the US for the treatment of RA.

It is expected that most patients will transition to the SC formulation over the next few years. The SC formulation of abatacept will give it a significant edge over tocilizumab and rituximab. However, according to inThought analysts, this advantage is likely to be abruptly lost with the expected approval of Pfizer's oral kinase inhibitor, tofacitinib – previously known as tasocitinib.

Kinase inhibitors
Oral kinase inhibitors are the most promising class of new RA drugs. They hold the hope for efficacy and tolerability similar to biologics, with the added convenience of a once- or twice-daily pill. Several inhibitors of Janus activated kinase (JAK) and spleen tyrosine kinase (SYK) are now in phase II and III development and, of these, tofacitinib is the closest to approval. Its robust phase III programme has generated promising results. Behind tofacitinib are several other oral kinase inhibitors, including the SYK inhibitor fostamatinib (Rigel/AstraZeneca] and two phase II JAK inhibitors, one from Vertex and one from Lilly/Incyte.

Tofacitinib is an orally active immunosuppressant that specifically inhibits JAK3, which has a pivotal role in cytokine signal transduction that governs lymphocyte survival, proliferation, differentiation and apoptosis. The product is awaiting approval in the EU, US and Japan for the treatment of RA and is on track to become the first oral kinase inhibitor approved for this disease. Phase III results suggest that the efficacy and tolerability of tofacitinib are on a par with biologics and the twice-daily dosing will be preferred by many patients over SC injections.

Although the long safety record and proven efficacy of TNF inhibitors will make them difficult to replace, it is thought that tofacitinib and other oral kinase inhibitors will quickly become the default choice for patients with an inadequate response to TNF inhibitors. If so, this will relegate abatacept to a third-line choice for patients who fail to respond to TNF inhibitors and oral kinase inhibitors.

Not all good news
While experts are excited about the potential of tocilizumab, they cite increases in low-density lipoprotein (LDL) cholesterol and other lipids as an issue that has held back prescription of the drug. Trials of tofacitinib and other JAK inhibitors have shown similar, although perhaps milder, increases in the same lipids. Because lipid levels are subclinical markers for heart disease, there are concerns about whether patients taking tocilizumab or tofacitinib are at greater risk for a cardiovascular event. However, there is insufficient evidence to date that either drug increases the risk of cardiovascular disease (CVD).

This cholesterol issue remains one of many factors that will make TNF inhibitors difficult to displace as the first-line option for patients

Analysis is complicated by the fact that RA itself increases the risk of CVD, and therefore drugs that control RA should lower CVD risk. Long-term cardiovascular outcome studies are needed, the first of which is currently under way. Roche has initiated a 5.5-year study to compare the rate of ischaemic cardiovascular events seen with etanercept versus tocilizumab.

However, experts are not optimistic that a clear answer will emerge from the trial. The net result of the evidence for and against increased CVD risk with tocilizumab and tofacitinib is uncertainty. Definitive answers will not be available for several years. This cholesterol issue remains one of many factors that will make TNF inhibitors difficult to displace as the first-line option for patients who have had an inadequate response to methotrexate, both for tocilizumab and other IL-6 inhibitors as well as for tofacitinib and other JAK inhibitors.

In addition to the uncertainty over its impact on cardiovascular health, tofacitinib faces other tolerability issues. Serious infections and deaths were observed in the phase III programme. These will make it difficult for rheumatologists to choose tofacitinib over a TNF inhibitor, because the latter are a known quantity with more than a decade of safety data. On the efficacy side, tofacitinib looks at least as good as TNF inhibitors.

Vertex Pharmaceuticals is developing VX 509, an orally administered JAK3 inhibitor, for the treatment of RA. At the American College of Rheumatology (ACR) meeting in November 2011, Vertex presented phase II data from 200 RA patients treated with VX 509 or placebo. Efficacy appeared to be as good as tofacitinib. Tolerability, while not perfect, was sufficient to move the programme forward to phase III. However, as with tofacitinib, serious infections and mortality will be an issue for VX 509. In the phase II trial, serious adverse events occurred in five per cent of VX 509 recipients versus two per cent with placebo, cholesterol and other lipids increased with VX 509 and two deaths occurred in the VX 509 100mg group.

Conclusion

Drug development for RA has been one of the most successful and lucrative areas of drug development over the last 15 years. According to inThought analysts, the nine biologics currently approved for the treatment of patients who are refractory to methotrexate or other DMARDs generate more than $16bn each year in worldwide sales for various autoimmune diseases. Approximately 75 per cent of those sales are in the area of RA.

Given the large revenue potential of RA drugs, it is not surprising that drug development is so active. With a disease incidence in the region of three cases per 10,000 population per annum, there continues to be a high demand for effective and well-tolerated therapies.

RA may be a chronic, incurable disease, but early treatment has been shown to reduce joint pain and damage significantly. With many pharmaceutical companies competing for their share of the RA marketplace, physicians, and their patients, already have a plethora of options available to them, with the promise of more to come.

Hannah Blair, Adis International
The Author

R&D Pipeline was written by Hannah Blair of Adis International (Springer Healthcare), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, contact Daniela Ranzani on +39 02 423 4562 or Email: Daniela.Ranzani@wolterskluwer.com

9th March 2012

Share

Featured jobs

Subscribe to our email news alerts

PMHub

Add my company
PRMA Consulting Ltd

PRMA Consulting is an independent consultancy solving some of the most challenging pricing, reimbursement and market access issues facing international...

Latest intelligence

Solaris Health looks at the gene therapy revolution
Gene therapies are bringing new hope for many people with diseases caused by genetic disorders...
PM Society Digital Awards – the power of together
Our chief executive, Emma Statham, writes about the value of awards and the power of together....
Seduction_feature_image_thumb.jpg
Seduce anyone in four simple steps
You know the health of the global economy is dependent on our ability to seduce one another – don’t you? And you know that we need to be able to...

Infographics