Products in development Review

There are a diverse range of emerging biologic and other treatments for the management of RA. These emerging treatments represent both advances in drug technology and strides our understanding of immune system targets (the cells and chemicals that take part in the immune response) that play a role in RA.

Development of new treatments for RA is driven by the desire to improve outcomes for patients, to decrease safety concerns, and to make treatments more convenient.

Major RA drug development efforts are focused in the following areas1-5:

  • New formulations of existing agents
  • New monoclonal antibodies
  • New molecularly targeted agents

 

Emerging treatments for RA

Agent
Sponsor
Target
Phase

New formulations of existing agents

Subcutaneous Actemra (tocilizumab)
Hoffmann-La Roche
IL-6
Phase III

New monoclonal antibodies

Sarilumab (REGN88/SAR153191)
Sanofi / Regeneron
IL-6 receptor
Phase III
Sirukumab (CNTO 136)
Janssen
IL-6
Phase III
BMS-945429 (formerly ALD518)
Bristol-Myers Squibb
IL-6
Phase II
Secukinumab (AIN457)
Novartis
IL-17A
Phase III
Ixekizumab (LY2439821)
Eli Lilly and Co
IL-17A
Phase II
Ustekinumab (Stelara)
Centocor
IL-12/23
Phase II
Guselkumab (CNTO 1959)
Janssen
IL23p19
Phase II
Ofatumumab (Arzerra)
GSK
CD20
Phase III
Tabalumab (LY2127399)
Eli Lilly and Co
BAFF
Phase III
Belimumab (Benlysta)
GSK
BLyS
Phase II
Mavrilimumab (CAM-3001)
MedImmune
GM-CSF receptor-α
Phase II

New molecularly targeted agents

Apremilast
Celgene
PDE
Phase II
Fostamatinib
AstraZeneca / Rigel
Syk
Phase III
VX-509
Vertex
JAK3
Phase II/III
LX3305
Lexicon
S1P lyase
Phase II
CCX354-C
ChemoCentryx
CCR1
Phase II

BAFF=B-cell-activating factor; BLyS=B lymphocyte stimulator; CM-CSF=granulocyte macrophage colony-stimulating factor; CCR1=C-C chemokine receptor type 1; IL=interleukin; JAK3=janus kinase 3; PDE=phosphodiesterase; Syk=spleen tyrosine kinase; S1P=sphingosine-1-phosphate.

 

New formulations of existing agents

One disease-modifying anti-rheumatic drug (DMARD) biologic Actemra (tocilizumab), a monoclonal antibody against the interleukin-6 receptor (IL-6R), which is already approved for administration as an intravenous (IV) infusion in RA patients who have failed to respond to conventional DMARD treatment, is currently being evaluated for subcutaneous (SC) administration. Phase 3 studies of SC Actemra have been completed and approval is projected for later in 2013. Results from the two Phase 3 randomized, controlled trials comparing SC Actemra, IV Actemra, and placebo (SUMMACTA and BREVACTA) showed that the SC formulation had efficacy (rates of ACR20 responses) equivalent to the IV infusion and significantly better than placebo.6

 

New monoclonal antibodies currently under development

A wide range of new monoclonal antibodies are currently under development for the treatment of RA. If approved for RA, these biologics will join established monoclonal antibodies designed to target immune system cells and chemicals including tumor necrosis factor (TNF)-α, B-cells, and interleukin-6 (IL-6).

The use of monoclonal antibodies as treatments for RA and other diseases is based on the same principle by which our bodies naturally produce antibodies against bacteria, viruses, and other foreign organisms that invade and pose a threat to our health. Following the example of our bodies, drug makers have engineered different antibodies to target the mechanisms that cause RA. For instance, the anti-TNF-α monoclonal antibody Humira binds to TNF-α receptors on immune system cells and inhibits TNF-α (an important immune system chemical) from carrying out its function in the immune process. It also causes the cells that have TNF-α receptors on their surface to rupture and die.

New monoclonal antibodies currently in advanced stages of development include agents that target different interleukins (these are immune system proteins that are involved in communications and signaling for immune system cells), including IL-6 or the IL-6 receptor (sarilumab, sirukumab, and BMS-945429), IL-17 or the IL-17 receptor (secukinumab and ixekizumab), and IL-12/23 (ustekinumab and guselkumab).1-3

Other new emerging monoclonal antibodies exploit a range of targets involved in immune system function, including CD20, a protein that appears on the surface of B-cells and helps them to function in the immune response, the cytokines B-cell-activating factor (BAFF) (also known as B lymphocyte stimulator [BLyS]), which is involved in supporting B-cell functions, and the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor (GM-CSF is a immune system protein that stimulates the production of a range white blood cells. However, it requires its receptor to function.). Ofatumumab (Arzerra) is a new CD20-targeted monoclonal antibody, tabalumab is a BAFF-targeted agent, belimumab is a BLyS-targeted agent, and mavrilimumab is a GM-CSF receptor-targeted agent.1-3

 

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. They are smaller, as measured by molecular weight, so they are water soluble and can pass through cell membranes. This allows them to target structures within cells. Their small size also allows them to be taken orally, which makes them more convenient as treatments. Because of their size and the way they are metabolized by the body, monoclonal antibodies must be administered either intravenously or by injection.

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).3-5

TKIs currently under development include another JAK inhibitor VX-509, the spleen tyrosine kinase (Syk) fostamatinib, and the sphingosine-1-phosphate (S1P) LX3305.3-5

Other molecularly-targeted agents under development for the treatment of RA target cellular proteins other than tyrosine kinases. One called 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.3-5

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