Protection Against Radiologic Progression in Rheumatoid Arthritis with JAK Inhibition Appears Similar to IV Biologics

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PRIORITY PRESS - 76th Annual Meeting of the American College of Rheumatology (ACR)

Washington, DC / November 10-14, 2012

Washington, DC - Oral agents that target intracellular pathways of inflammation are showing remarkable similarities to injectable monoclonal antibodies in the control of rheumatoid arthritis (RA). Along with phase III data supporting the recent approval of a first oral Janus kinase inhibitor for RA in the US, new data were presented at the 2012 ACR on other investigational oral agents. The safety issues concerning the potential for downregulation of inflammatory pathways to alter immune function have so far not provided any signal in clinical testing that serious risks differ substantially between oral agents and the injectable therapies that act on cell surface receptors. The evidence that inhibition of intracellular signalling with oral agents appears to offer a degree of RA control that is at least commensurate with inhibition of extracellular signalling with injectable agents advances the effort to expand molecular targets in the treatment of inflammatory diseases.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Attention to oral intracellular inflammatory inhibitors at the 2012 ACR was intensified when the U.S. Food and Drug Administration (FDA) approved the first such agent just one week before the meeting convened. The phase III data that led to approval of tofacitinib were presented along with results from studies with other oral agents at various points in the development process, including baricitinib, ASP015K and GLPG0634. The oral therapies that have reached advanced stages of testing are the Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors, but data presented at the 2012 ACR was concentrated on the JAK pathway.

“The activity of the JAK inhibitors validates the experimental evidence that this target is important in the pathobiology of rheumatoid arthritis (RA),” reported Prof. Josef S. Smolen, Medical University of Vienna, Austria, and lead investigator for studies with several oral JAK agents, including tofacitinib and baricitinib. Prof. Smolen predicted that progress in blocking this signalling pathway will reveal more about the inflammatory cascade leading to RA at the same time that it is yielding new treatment alternatives.

The 4 known JAKs, JAK1, JAK2, JAK3 and Tyk2, activate the transcription of STAT which are responsible for inducing a variety of cell functions, including cytokine expression. Even though the oral JAK inhibitors in development differ in their relative activity on these 4 kinases, which may be meaningful for efficacy, safety or both, the consistency of anti-inflammatory effect from JAK inhibition has validated this pathway as a target in RA and potentially other inflammatory diseases.

Inhibition of Progression

Five phase III trials in RA were launched prior to the recent FDA approval of the JAK inhibitor tofacitinib. The ORAL Start trial was a head-to-head comparison of this agent to methotrexate (MTX) in biologic- and MTX-naive patients, of which 12-month data was presented at 2012 ACR. The 952 patients were randomized to tofacitinib 5 mg or 10 mg administered twice daily or a standard MTX regimen. The co-primary end points were van der Heijde modified Total Sharp Score (mTSS) of change in radiographs (radiographic progression) and the ACR70.

Efficacy was significantly greater for the JAK inhibitor on either end point. The rates of ACR70 on tofacitinib were 37.7% on the 10 mg dose, 25.5% on the 5 mg dose vs. 12% on MTX (P<0.001 both doses vs. MTX). Based on mTSS, no radiographic progression was observed in 89.7% of those on the higher dose, 83.5% of those on the lower dose and 70.5% of those on MTX (P<0.0001 for the higher dose and P<0.05 for the lower dose vs. MTX). According to the investigator who presented these results, Dr. Roy M. Fleischmann, University of Texas Southwestern Medical School, Dallas, this latter finding was noteworthy.

“To my knowledge, there has been no previous randomized, double-blind, placebo-controlled trial that has shown superior X-ray inhibition of progression for any medication vs. MTX,” Dr. Fleischmann noted. In addition to ACR70, he reported that all of the secondary efficacy indices, including ACR50, ACR20, DAS28-4(ESR) and Health Assessment Questionnaire (HAQ), supported significantly greater control for either dose of the JAK inhibitor relative to MTX.

For higher and lower doses of tofacitinib and MTX, the rates of serious infections were similar (<1.0%, 1.1%, <1.0%, respectively), but the rates of serious adverse events (6.1%, 6.5% and 7.0%) and discontinuations due to adverse events (7.8%, 6.5% and 9.1%) were lower on the JAK inhibitor.

In another phase III trial, called ORAL Scan, 797 patients on a stable dose of MTX were randomized to the higher or lower dose of tofacitinib or placebo. The primary results, presented previously, associated either dose of the JAK inhibitor plus MTX with a highly significant advantage over placebo plus MTX for standard outcomes, such as ACR20, ACR50. However, a newly conducted post hoc analysis presented at the 2012 ACR demonstrated that relative benefits increased in patients with unfavourable prognostic characteristics. In this subgroup, the JAK inhibitor presented statistically significant protection against structural damage as early as 6 months that persisted through follow-up.

“These data support the notion that tofacitinib is indeed inhibiting structural progression as was also shown with the ORAL Start data,” reported Prof. Désirée van der Heijde, Leiden University Medical Center, The Netherlands.

A safety comparison of tofacitinib and approved injectable biologics drawn from collating data from independent and non-comparative trials suggests that the rates of malignancies, serious infections and serious adverse events are generally comparable. In these analyses, however, herpes zoster (HZ) has been more common on the JAK inhibitor. According to a detailed analysis of HZ rates, Dr. Kevin L. Winthrop, Oregon Health and Science University, Portland, noted that the increase in the incidence of HZ, a common problem in all aging individuals, is concentrated during the first 6 months of treatment. Although rates are higher on tofacitinib relative to IV biologics, all immunomodulatory agents appear to increase HZ over baseline. As a result,
Dr. Winthrop proposed preemptive HZ vaccination in any patient receiving immunomodulatory agents.

In Development

The promise of other oral JAK inhibitors remains strong. In results of a 301-patient phase IIb trial with baricitinib presented at the 2012 ACR by Prof. Smolen, improvements in patient-reported outcomes, such as HAQ, Short-Form 36 and visual analog scales for pain and global assessment, were observed as early as 2 weeks. Consistent with separately reported ACR70 data, in which 37% of those randomized to baricitinib 4 mg once-daily vs. 4% of those randomized to placebo (P<0.05) achieved this end point at 12 weeks, the improvements reported by patients were persistent at 12 weeks and were maintained or improved up to 24 weeks.

Data from a phase I study of ASP015K was reported to have provided the basis for moving to dose-ranging studies. In the phase I study, the goal was to confirm that there was no adverse drug interaction from co-administration of ASP015K and MTX. Pharmacokinetics (PK) parameters were evaluated with each drug separately and then when the drugs were combined in 15 participating RA patients. According to the co-author of the study, Dr. Vishala Chindalore, Pinnacle Research Group, Anniston Medical Clinic, Alabama, there were no significant adverse events or changes in PK on the combination relative to either drug taken alone. The next phase of study has already been initiated.

The study of GLPG0634, which shows a high selectivity for JAK1 relative to other clinically tested JAK inhibitors, was a single-centre, phase I, dose-ranging trial conducted in healthy volunteers. According to study lead investigator, Mrs. Florence Namour, MSc, Galapagos SASU, Romainville, France, GLPG0634 has the potential for a “cleaner safety profile” due to its JAK selectivity. In the trial, drug doses remained safe and well tolerated even when taken above the predicted therapeutic dose. The study also confirmed that GLPG0634 has a half-life that should support once-daily dosing.

Based on these results, “we are now moving forward with 2 sets of studies. One group will be to determine whether doses as low as 30 mg provide clinically significant activity in RA, while the other group will evaluate whether doses as high as 300 mg remain well tolerated and safe over longer study periods,” Mrs. Namour reported.


Oral intracellular inflammatory inhibitors, sometimes mislabeled as oral biologics because of their similarity of action to injectable monoclonal antibodies, appear capable of providing efficacy on the same level as injectable biologics with comparable levels of safety. Although the JAK and SYK pathways are the current focus of intracellular inhibition of inflammation, the ability to control RA through intracellular targets is likely to encourage identification of other pathways.


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