Rheumatoid arthritis (RA) is a chronic and systemic autoimmune syndrome affecting up to 1 per cent of the world’s population, mainly women and the elderly, and the syndrome entails several inflammatory cascades that primarily result in persistent synovial inflammation and associated articular damage.
The progression of RA can also involve other organ systems such as the skin, eyes, lungs and vascular system. One of the key inflammatory cascades is over-expression of tumour necrosis factor (TNF). This leads to the overproduction of many pro-inflammatory cytokines, such as interleukin-6 (IL-6), which promote persistent inflammation and invasion of cartilage by fibroblasts. Fifty per cent of the risk of developing RA is attributable to genetic factors and many of these have now been identified. Smoking is the predominant environmental risk factor and doubles the risk of developing RA. Uncontrolled RA causes joint damage, disability, reduced quality-of-life and cardiovascular and other co-morbidities.
Disease-modifying antirheumatic drugs (DMARDs) are the key therapeutic agents in reducing synovitis and systemic inflammation, and for improving function. The leading DMARD is methotrexate, which is often used in combination with other drugs of this type such as leflunomide and sulphsalazine. More recently, biological agents have been used in the treatment of RA, usually when DMARDs fail to control the disease or result in unacceptable toxicity. The ultimate goal in the treatment of RA is long-term remission induced by intensive, short-term treatment selected by patient-specific biomarker profiles.
A therapeutic revolution
Although significant improvements in disease outcomes preceded the introduction of biological drugs, these highly effective therapies have heralded a therapeutic revolution which has transformed the outlook for RA patients. TNF inhibitors were the first marketed biological agents, followed by abatacept, rituximab and tocilizumab. The effects can be especially striking in RA patients who are inadequately treated or non-responsive to traditional DMARD therapy. Biologicals are conventionally combined with a DMARD, and are typically administered subcutaneously or by infusion. Biologicals are expensive (often around $20,000 per patient/year) which is also why they are generally only approved or funded for patients with refractory disease. There are currently six different biological agents for RA on the global market plus four biosimilars.
Merck & Co’s Remicade (infliximab) is a chimeric IgG1K monoclonal antibody that specifically targets and irreversibly binds to TNF-alpha. Infliximab was first launched for RA in the UK in 2000 and is administered by IV infusion. In the multinational ATTRACT study, 428 patients who had active RA despite treatment with methotrexate, received either IV infliximab 3 or 10mg/kg, or placebo, every 4 or 8 weeks. At 54 weeks, significantly more infliximab, compared with placebo, recipients had achieved reductions in the signs and symptoms of RA, as assessed by the American College of Rheumatology (ACR) 20, 50 and 70 criteria. Celltrion also has an infliximab biosimilar on the market for the treatment of RA and other autoimmune conditions.
Abbvie’s Humira (adalimumab) was first launched for RA in the US in January 2003. Adalimumab is a fully human recombinant monoclonal IgG1 antibody specific for TNF-alpha. It is delivered once-fortnightly by subcutaneous injection and has a response rate similar to methotrexate in RA, and in combination nearly doubles the response rate of methotrexate alone. In the ReAlise observational study in patients who completed the ReAct phase III trial (n = 3433), the effectiveness of adalimumab was sustained for three years in patients with or without history of prior anti-tumour necrosis factor (anti-TNF) therapy. Adalimumab was effective irrespective of the reason for discontinuation or type of anti-TNF therapy received. The most common adverse events are injection site reactions and infections, with some of the latter being potentially serious.
Roche/Genentech/Biogen Idec MabThera/Rituxan (rituximab) is a mouse/human chimeric monoclonal antibody targeting the cell surface marker CD20. The drug is administered intravenously, although development is underway of a subcutaneous formulation, and results in rapid and dose-dependent depletion of B cells. Rituximab was first approved for the treatment of RA in Europe and the US in 2006. The phase III SERENE study met its primary endpoint by showing that significantly more patients with RA treated with rituximab, in combination with methotrexate, achieved an improvement in disease signs and symptoms compared to patients treated with methotrexate. There are also three rituximab biosimilars marketed worldwide.
Roche’s Actemra (tocilizumab) is a humanised anti-IL-6 receptor monoclonal antibody that was originally developed by Chugai Pharmaceutical, and has been co-developed with Roche. It was first launched for RA in Japan in 2008. Synovial fluid levels of IL-6 are elevated in patients with RA, and correlate with clinical and laboratory markers of disease activity. Tocilizumab therapy markedly improved the disease activity score-28 (DAS28) from a baseline level of 5.53 to 3.00 at week 28 in a study in 2,072 patients with moderate to severe RA. The disease remission rate was 45.0 per cent at week 28.
Janssen Biotech’s Simponi (golimumab) is a high affinity, fully humanised anti-TNF-alpha monoclonal antibody, first approved in 2009, with both subcutaneous and intravenous formulations available for the treatment of RA. It is one of the better-tolerated biological agents with generally mild adverse events and low rates of discontinuations. Simponi plus methotrexate significantly inhibited radiographic progression of disease in patients with active moderate to severe RA compared with methotrexate alone, according to data from the phase III GO-FURTHER trial. At week 24 patients receiving Simponi plus methotrexate showed a mean change in total van der Heijde-Sharp scores of 0.03 from baseline compared with 1.09 in the placebo + methotrexate group. Approximately 60 per cent of patients receiving golimumab achieved at least a 20 per cent improvement in the ACR 20 score at week 14, with nearly 66 per cent of patients achieving that response at week 52.
Astellas Pharma/UCB Cimzia (certolizumab pegol) is the Fab fragment of a humanised monoclonal antibody that binds with high affinity to TNF-alpha. It is administered by subcutaneous injection and was first approved in 2009. At week 12 of the phase IIIb REALISTIC trial, 51.1 per cent of patients who received certolizumab pegol achieved ACR20 response versus 25.9 per cent of patients in the control group. ACR 20/50 responses were significantly superior to control. Certolizumab pegol rapidly improved fatigue, sleep problems, and pain and was associated with rapid and consistent improvements in a broad population of RA patients irrespective of prior therapy with tumour necrosis factor inhibitors.
The biosimilar challenge
Almost the entire global RA phase III pipeline consists of biosimilars for the marketed drugs mentioned above. Initially, biosimilars are expected to compete as therapeutic alternatives, more like branded drugs rather than equivalent, inexpensive generics. Physicians and insurers are also expected to be cautious in switching patients until positive evidence with them accumulates in clinical settings. Given their nature, biosimilars need to undergo the full clinical trial process to show comparability with the reference products. To date only four biosimilars for the treatment of RA have made it to market, but this appears likely to change in the coming few years and certainly poses a threat to the multibillion dollar sales figures of the established biologicals market. There are some notable exceptions to this trend however.
Novartis’ secukinumab is a monoclonal antibody targeting IL-17A that is now in phase III for RA in a number of countries worldwide and European and US regulatory submissions were completed in 2013. Positive efficacy data has been reported from a trial of intravenously administered secukinumab in patients with active RA despite methotrexate therapy. Interim results showed that a significantly higher percentage of patients in the secukinumab group achieved an ACR 20 response at 6 weeks compared with the placebo group (46 per cent vs 27 per cent). A clinically relevant improvement was seen for ACR 50 (27 per cent vs 15 per cent), but not for ACR 70 (8 per cent vs 8 per cent).
There are currently 6 different biological agents for RA on the global market plus 4 biosimilars
GlaxoSmithKline/Centocor’s sirukumab is a human monoclonal IgG1 kappa antibody that targets IL-6. A subcutaneous formulation of sirukumab is in phase III development for RA in various countries worldwide. Sirukumab given subcutaneously at dosages of 100mg every 2 weeks or 50mg every 4 weeks, in addition to background methotrexate, was effective in patients with methotrexate-resistant active RA in a two-part, phase II trial.
Earlier phase development also features many more biosimilars but does show a wide spread of mechanisms, with many biologicals used in oncology or other autoimmune disease being investigated for RA. This includes Genmab’s CD20 inhibitor ofatumumab; Xencor’s CD 19 inhibitor XmAB 5871, Ablynx’s TNF-alpha inhibitor ozoralizumab; Biotie Therapies Corp’s AOC3 protein inhibitor BTT 1023 and Lilly’s IL-17 inhibitor ixekizumab. All of these compounds have shown initial promise in RA and will perhaps one day compete with the forthcoming flood of biosimilars.
Given current regulatory hurdles and the low prospects of emerging dynamic competition from next generation products, the level of cost savings from biosimilars during the rest of the decade is likely to be low. It is likely that medical practices and reimbursement procedures will evolve to be more receptive to the use of biosimilars over time however, but the focus in the short term will likely be on more personalised utilisation of the therapy combinations available today.
