New molecularly targeted agents

The most recent development in drug therapy for RA has involved molecularly-targeted agents. These small molecule drugs target cellular structures and immune system proteins. Small molecule drugs are different from monoclonal antibodies in several important ways. Their smaller size, as measured by molecular weight, makes them water soluble so that they can pass through cell membranes. This allows them to target structures within cells. Their size also allows them to be taken orally, which makes them more convenient as treatments.

Many molecularly-targeted agents fall within the drug class called tyrosine kinase inhibitors (TKIs). A tyrosine kinase is an enzyme (a type of protein) that plays an important role in signaling and communication within cells. By inhibiting the function of different tyrosine kinases within cells, you can switch off cellular functions. This can be especially useful with out-of-control immune system cells, such as those involved in the RA. One small molecule TKI already approved for the treatment of RA is the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz).1-3

TKIs currently under development include another JAK inhibitor VX-509, the spleen tyrosine kinase (Syk) fostamatinib, and the sphingosine-1-phosphate (S1P) inhibitor LX3305.1-3

Other molecularly-targeted agents under development for the treatment of RA target cellular proteins other than tyrosine kinases. Apremilast targets the enzyme phosphodiesterase (PDE), which plays a key role in signaling within cells. Another, CCX354-C, targets the C-C chemokine receptor type 1 (CCR1), which is the cellular receptor for various specialized immune system proteins (chemokines). Without the ability to bind to this receptor, chemokines are unable to play their role in immune cell functions, resulting in a dampening of immune response.1-3


Emerging molecularly targeted agents

Phase II
AstraZeneca / Rigel
Phase III
Phase II/III
S1P lyase
Phase II
Phase II

CCR1=C-C chemokine receptor type 1; JAK3=janus kinase 3; PDE=phosphodiesterase; Syk=spleen tyrosine kinase; S1P=sphingosine-1-phosphate.



Apremilast is an inhibitor of PDE4 being developed by Celgene. The PDE4 enzyme is present in immune system cells including T-cells, neutrophils, and macrophages. Inhibition of PDE4 affects the synthesis of a number of cytokines that play key roles in the immune system, including tumor necrosis factor-alpha (TNF-α). Apremilast works in RA by suppressing production of TNF-α through PDE4 inhibition. Preclinical studies of apremilast showed that it inhibited production of TNF-α in synovial membrane tissues.4

Despite promising preclinical results, a Phase 2 pilot study in which apremilast was given in combination with methotrexate failed to show any significant improvement in rates of ACR20 responses. A Phase 2 randomized, controlled trial is currently underway to evaluate apremilast as monotherapy in RA. However, one of the sponsors of fostamatinib, AstraZeneca, recently announced their decision not to pursue further development of the drug.4-6



Fostamatinib is a Syk inhibitor being developed in a cooperative effort by AstraZeneca and Rigel. The function of the Syk tyrosine kinase is transmission of signals in B- and T-cells. Syk plays an especially important role in B-cell function and antibody production. Inhibition of Syk in RA can result in decreased autoantibody production by B-cells and interruption of other B-cell immune system functions.7

There have been three Phase 2 studies of fostamatinib in RA to date, TASKi1, TASKi2, and TASKi3. TASKi1 evaluated a range of doses of fostamatinib in patients with active RA despite treatment with methotrexate. The highest fostamatinib dosing groups (100 and 150 mg twice daily) taken with methotrexate achieved rates of ACR20 responses of 65% and 72%, respectively versus 38% for placebo + methotrexate (P<0.01). TASKi2 was conducted in patients who had active RA despite long-term disease-modifying anti-rheumatic drug (DMARD) treatment (including methotrexate and/or biologics). The 100-mg twice daily and 150-mg once daily fostamatinib dosing groups (given with methotrexate) achieved rates of ACR20 responses of 67% and 57%, respectively versus 35% for placebo + methotrexate (P<0.001). In TASKi3, fostamatinib was evaluated in patients who had had an inadequate response to one or more DMARD biologic treatments. Rates of ACR20 responses in TASKi3 were similar between the fostamatinib treatment and placebo groups.7

A series of Phase 2 and 3 studies evaluating fostamatinib in various RA patient groups (eg, anti-TNF-α failures, methotrexate failures) and in comparison with other biologic DMARDs are in various stages of completion. Results from these studies should clarify the future role that fostamatinib will play in the treatment of RA.5



VX-509 is a JAK3 inhibitor being developed by Vertex. VX-509 has been evaluated as monotherapy (used alone) in a Phase 2 study in patients who had an inadequate response to DMARD treatments. VX-509 given at range of doses resulted in rates of ACR20 responses ranging from 39% to 66% compared with 29% for placebo. Other Phase 2 and 2/3 studies are currently ongoing.3,5



LX3305 is a S1P lyase inhibitor being developed by Lexicon. The S1P lyase plays a role in intracellular lymphocyte signaling. Therefore, inhibition of the S1P lyase may result in a dampening of the immune response in RA. LX3305 (in combination with methotrexate) was evaluated in a Phase 2 proof-of-concept study conducted in patients who had an inadequate response to DMARD treatment. LX3305 was shown to have potential clinical benefit, resulting in a rate of ACR20 response of 60%, with a favorable safety profile. No further studies of LX3305 are currently underway.2,5,8



CCX354-C is a CCR1 inhibitor being developed by ChemoCentryx. CCR1 is the cellular receptor for various specialized immune system proteins (chemokines). Without the ability to bind to this receptor, chemokines are unable to play their role in immune cell functions, resulting in a dampening of immune response. CCX354 was evaluated in a randomized, controlled Phase 2 study (CARAT-2), which was completed in 2012. CARAT-2 tested a range of CCX354 doses given with methotrexate in RA patients who had had an inadequate response to methotrexate. CCX354 200 mg once daily resulted in a rate of ACR20 response of 56% versus 30% in placebo + methotrexate (P=0.014) and also resulted in a significant decrease in C-reactive protein (CRP) versus placebo.9

Written by: Jonathan Simmons | Last reviewed: September 2013.
View References