New Mechanisms of Action for Disease Modification in RA

Rheumatoid arthritis (RA) is an autoimmune disease primarily affecting the musculoskeletal system with typical symptoms including swollen and painful joints, joint stiffness and loss of function, ultimately leading to disability if untreated. RA also produces significant systemic affects such as fatigue and depression that may appreciably impact quality of life for many patients. Prevalence varies between 0.3 – 1.0% and is more common in women and in developed countries.¹

Concept of symptomatic treatment versus disease-modifying drugs

Modern RA treatment paradigms such as ‘treat to target’ focus on achieving remission or low disease activity through the use of disease-modifying anti-rheumatic drugs (DMARDs) to minimize or prevent joint damage and subsequent disability. The foundation of ‘treat to target’ regimens is usually based on conventional synthetic DMARDs [csDMARDs], most often methotrexate (MTX) at doses in the range of 15-25mg per week with additional csDMARDs and/or the newer biologic DMARDs (bDMARDs) being add-on therapies when MTX is inadequate to control disease, or as monotherapies when MTX is poorly tolerated. In the last ten to fifteen years, these biologic agents which target key inflammatory mediators (TNF-alpha, IL-1, IL-6), or key immune cells and/or activation pathways of the adaptive immune system (B cells and T cell co-stimulation pathways) have revolutionized the treatment of RA and many other immune-mediated inflammatory diseases (IMIDs), and have rapidly been introduced into accepted treatment paradigms.^2,3 Additional biologics that target other mechanisms of action have entered clinical development, including, but not limited to:

IL-17 receptor modulator CNTO 6785 (Jansen R&D)
Bispecific monoclonal antibody (mAb) targeting inhibition of both IL-17 and TNF-alpha
- ABT-122 (Abbvie)
Infliximab biobetter (STI-002; Mabtech/Sorrento Therapeutics)
Interleukin 10 (Dekavil, Pfizer)
GM-CSF mAb (GSK)
CD40 ligand inhibitor (MedImmune)
MMP9 mAb inhibitor

Targeted synthetic DMARDs

Though great advances have been made with use of the first generation of biologics, and more recently a second generation focused on newer targets, in general 30–40% of patients with significant disease activity still do not respond to a given prescribed biologic.^3,4 In addition, these treatments are associated with possible serious adverse effects such as infections and toxicity risk.⁵ Therefore, there remains a significant unmet need for therapies that are more efficacious, more convenient, safer, less expensive, or all of the above. In response, companies are developing biosimilar versions of the popular brand name biologics, which will presumably be less expensive, yet comparably safe and efficacious when compared to the brand name agents. These are often referred to as biosimilar DMARDs (bsDMARDs).⁶ It is hoped that the availability of biosimilars will lead to broader access to biologics by RA patients who previously were unable to afford them.

In addition to the rise of less expensive biosimilars, a whole new class of oral agents that target novel intracellular pathways are in development, some showing strong efficacy and manageable safety profiles, quite similar to the biologics. These are called targeted synthetic DMARDs (tsDMARDs). The first new class of agents to reach the market is oral tyrosine kinase inhibitors that target the Janus Kinase pathway (JAKis). Pfizer’s tofacitinib (Xeljanz) was the first in this class, approved in the US (FDA) in 2012; though not initially in the EU. In February 2017, Eli Lilly/Incyte’s baricitinib (Olumiant) was approved for RA in the EU, followed very quickly by Xeljanz. Both of these JAKis carry labeling that is consistent with use in moderate-to-severely active disease in adults who have not responded to one or more DMARDs, as well as for use as monotherapy. Following these are a number of additional JAK pathway blockers with varying specificity for the four members of the JAK family (e.g. Gilead Sciences’ JAK1 inhibitor, Filgotinib).

The JAKis are becoming well recognized as evidenced by a preview of the updated RA treatment guidelines⁸ presented at the 2016 EULAR Congress discussing JAKis as early-line treatment options similar to the use of TNF and non-TNF biologics in methotrexate-refractory patients. The prior EULAR guidelines placed JAKis after biologics in the treatment algorithm.

JAKis appear to fill one aspect of unmet need for an effective, but more convenient DMARD in the EU,⁵ but price will be key factor for achieving broad uptake in the cost-constrained European healthcare systems. JAKis will also have competition from the availability of cost-effective biosimilars. Despite Xeljanz’s slow start, if Xeljanz and Incyte can gain use in early lines of therapy, they are anticipated to reach blockbuster status and be the primary drivers for the continued growth of the RA market.

In addition to inhibitors of the JAK pathway, agents targeting other promising pathways and mechanisms are in development and include, but are not limited to:

BTK inhibitors
Syk inhibitors
IP3 inhibitors
Integrin alpha1-beta1 antagonist(SAN-300); Valeant Pharmaceuticals

Advanced Therapies

Very early in development, is another completely new class of agents for treatment of autoimmune disease (including RA), referred to as advanced therapies. Some studies of these advanced therapies utilize allogeneic mesenchymal precursor cells (e.g. rexlemestrocel-L; (Mesoblast), but the data is too early and limited at this point to reach any firm conclusions with regard to efficacy.

http://www.who.int/chp/topics/rheumatic/en/
Rheumatology 2016;55:826839 DOI: https://doi.org/10.1093/rheumatology/kev42
Keystone EC Kavanaugh AF Sharp JT et al. . Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400–11.
Weinblatt ME Kremer JM Bankhurst AD et al. . A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253–9.
Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2010;39:327–46.
Smolen JS, van der Heijde D, Machold KP, Aletaha D, Landew R. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis. 2013 Sep 26. doi: 10.1136/annrheumdis-2013-204317.

New Mechanisms of Action for Disease Modification in RA

Concept of symptomatic treatment versus disease-modifying drugs

Targeted synthetic DMARDs

Advanced Therapies

Mark Fletcher and Martin Knight

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Concept of symptomatic treatment versus disease-modifying drugs

Targeted synthetic DMARDs

Advanced Therapies

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Mark Fletcher and Martin Knight

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