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MEDICAL FRONTIERS - 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

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

The biologic agents first introduced for the treatment of rheumatoid arthritis (RA) more than a decade ago have provided unprecedented control in patients inadequately responsive to disease-modifying antirheumatic drugs (DMARDs). However, biologics require injection or infusion and some patients are non-responders. While biologics target cytokines and extracellular signalling, small-molecule inhibitors block intracellular signalling. They build on the same concept of targeting very specific steps in the inflammatory process, but they can be taken orally and they have the potential to circumvent unwanted inhibition of the immune response.

“We have been seeing very promising efficacy with these agents as the clinical trials have moved forward. These appear to be the first oral agents that act like a biologic,” reported Dr. Joel Kremer, Center for Rheumatology, Albany Medical College, New York, here at EULAR. While acknowledging that “patients generally prefer to take a pill than to receive an infusion,” he cautioned that these agents might not be interchangeable with biologics even if they share the concept of a targeted molecular effect.

Due to activity at very different points in the inflammatory pathway, their spectrum of activity and safety may differ not only from biologics but also from each other. Even within the same molecular targets, such as Janus kinase (JAK) and spleen kinase (Syk) pathways or mitogen-activated protein kinase-activated protein (MAPKAP), there are tyrosine kinase subtypes that might be affected differentially by specific inhibitors. This is potentially important because of cross-signalling and redundant pathways of inflammatory activation which may lead to different degrees of efficacy or risk when one or another subtype is inhibited. Some of these relative benefits and risks can now be evaluated clinically on the basis of clinical trials.

Study Findings

Here at EULAR, phase III data were presented on the JAK inhibitor tofacitinib (CP-690,550). In the late-breaker presentation of the ORAL Sync trial, 692 patients were randomized to 1 of the 2 active treatment arms in a 4:1 ratio relative to 2 placebo arms. In the active-treatment arms, patients received either 5 or 10 mg b.i.d. and were treated for a total of 12 months. Those in the 2 placebo arms did not receive active therapy during the initial 3 months. At month 3, non-responder placebo patients were blindly switched to either 5 mg or 10 mg b.i.d. At month 6, all remaining placebo patients were blindly advanced to either 5 mg or 10 mg b.i.d. for the active extension period of 6 months.

All patients, which included individuals enrolled in North America, South America, Europe and Asia, were required to have had an inadequate response to at least 1 DMARD prior to entry. Previous experience with a tumour necrosis factor inhibitor (TNF-I) was permitted but not required. During the study, all patients remained on at least 1 DMARD as background therapy. The primary efficacy end points were change in Health Assessment Questionnaire-Disease Index (HAQ-DI) at 3 months and the proportion of patients achieving an ACR20 response and a Disease Activity Score (DAS)28 <2.6 at 6 months. ACR50 and ACR70 were measured as secondary end points over the full 12 months of the study. Safety and tolerability were also assessed continuously throughout the 12-month study.

At month 3, reduction in HAQ-DI scores were -0.56 for the higher dose of tofacitinib, -0.46 for the lower dose and -0.21 for the placebo groups combined. The advantage of either dose of the active agent over placebo was highly statistically significant (P<0.0001). At month 6, the ACR20 rates of 58.3% for the higher dose and 52.7% for the lower dose were statistically significant vs. 31.2% in the combined placebo groups (P<0.0001) (Figure 1). Statistical significance in the proportion of patients achieving a DAS28 score <2.6 at month 6 was also observed in 14.8% (P<0.0001) and 11% (P<0.001), respectively, vs. 2.7%.

At 12 months, the proportion of patients completing the trial ranged from 79.2% in the group randomized initially to 10 mg b.i.d. to 89.9% in the group randomized to placebo and switched to 5 mg b.i.d. at 6 months. The discontinuation rates for adverse events were 9.1% in the high-dose group, 6.4% in the low-dose group, 3.8% in the placebo group switched to 10 mg b.i.d. at 6 months and 2.5% in the placebo group switched to 5 mg b.i.d. at 6 months. The rate of serious adverse events remained below 3% in all groups for each 3-month assessment period except in the placebo group (3.8%) during the first 3-month assessment period.

In a careful analysis of 4 deaths in the study, 1 was considered possibly treatment-related by the participating investigators who did not identify any clear pattern. The investigators attributed the death to respiratory failure, but a safety end point adjudication committee concluded that the death was due to infection in an individual with multiple medical conditions, including congestive heart failure, anemia and renal insufficiency. Dr. Kremer, who presented these results, told delegates that the overall safety is consistent with earlier studies and reassuring. He concluded, “The evidence for a rapid onset of efficacy and a sustained response at 12 months suggests that this may be an important option for patients who are not adequately controlled on DMARDs.”

Another phase III tofacitinib trial (ORAL Solo) presented here at EULAR generated the same types of results. This study was of similar design but advanced all placebo patients to the 5 mg b.i.d. and 10 mg b.i.d. regimens at 3 months for the remainder of the study up to 6 months. There were similar entry criteria and the same efficacy end points as those employed in ORAL Sync. The primary efficacy end points, ACR20 response, change in HAQ-DI and rate of patients achieving DAS28 <2.6 were assessed at 3 months. Of the 610 patients randomized, 91% completed the study. In this study, efficacy was analyzed by a number of stratifications, including those for age, weight, sex and rheumatoid factor status. Quality-of-life (QoL) data were also presented.

Figure 1.

“The relative advantage of this agent over placebo for the outcome of ACR20 was reflected in significant improvements in all domains of the SF-36 QoL tool as well as in tools for evaluating fatigue and sleep,” reported Dr. Vibeke Strand, Adjunct Clinical Professor, Division of Immunology and Rheumatology, Stanford University School of Medicine, California. Noting that results are consistent with the phase II trials performed previously, Dr. Strand characterized the dose-related improvements in outcome as “clinically meaningful” based on the patient-reported measures that accompanied the objective measures.

Syk Inhibition

There were no comparable phase III data with a Syk inhibitor, but there was a QoL update from a phase II trial of fostamatinib (formerly R788) published last year (Weinblatt et al. N Engl J Med 2010;363:1303-12). In the published data, which compared fostamatinib 100 mg b.i.d., 150 mg q.d. and placebo, ACR20 rates at 6 months were 67%, 57% and 35%, respectively. Both doses were significantly superior to placebo (P<0.001). The most common adverse events were diarrhea (19% in the 100-mg group vs. 3% among those on placebo), upper respiratory tract infection (14% vs. 7%) and neutropenia (6% vs. 1%). Dropout rates were modest in all 3 groups, and the new QoL data support a favourable benefit:risk ratio.

“Compared with placebo, fostamatinib 100 mg b.i.d. was associated with significant improvements from baseline to month 6 in physical health status and in fatigue as measured by the SF-36 Physical Component Summary (PCS) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, respectively,” reported Dr. Michael E. Weinblatt, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. He informed delegates that the improvements in physical functioning on the HAQ-DI were particularly pronounced, with scores of 0.22 and 0.24 in the active treatment groups vs. 0.6 in the placebo group (P=0.001).

Emerging Science

Other small-molecule inhibitors at a much earlier point in development are being explored. New safety and pharmacokinetic data with GLPG0259, a MAPKAP-5 inhibitor, in healthy volunteers was sufficient to launch a phase IIa trial, according to a team that included investigators from the Clinical Pharmacology Unit, SGS, Antwerp, Belgium. Targeting another intracellular pathway of inflammation, the agent was tested with methotrexate in this initial phase I study to rule out interactions. Based on data presented here at EULAR, the 180-patient, placebo-controlled phase IIa trial has already been initiated and will include efficacy end points.

Another JAK inhibitor, GLPG0634, has reached initial stages of clinical testing. Unlike tofacitinib, which primarily inhibits JAK1 and JAK3, GLPG0634 primarily inhibits JAK1, JAK2 and another member of the JAK family, TYK2. Relative to other members of the JAK family, JAK3 has been a favoured target because its expression is essentially limited to hematopoietic cells and it constitutively binds to the gc chain which is a common receptor subunit for IL-1, IL-4, IL-7, IL-9, IL-5 and IL-21 (Figure 2). However, cross signalling may be important, and the relative advantage of specificity for blocking JAK3 signalling has not been established.

Over a 10-day period at doses high enough to produce a clinical effect as predicted in experimental studies, the drug was acceptably well tolerated. In whole blood taken from patients at 10 days, the changes in JAK-STAT response, gene modulation and other biomarkers were of a magnitude predicted to be clinically meaningful. Results of this phase I study, conducted by many of the same investigators who presented data on the MAPKAP-5 inhibitor, were characterized as being sufficiently encouraging to warrant further clinical
ent.

Figure 2.

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Exploring Safety

In clinical studies to date, the rapid onset of clinical effect with tofacitinib and fostamatinib has been a shared feature and is likely to relate to fundamental changes in processes regulated by intracellular signalling. The studies in RA, where clinical application of many biologics were initiated, will likely lead to development in an array of other autoimmune inflammatory processes. Many of the biologics have broad indications outside of joint diseases, including control of psoriasis and inflammatory bowel diseases. A similar trajectory of development for JAK and Syk inhibitors will be pursued if their safety and efficacy in RA persists in further development.

“The biologics are an important addition to the treatment options for RA. So far, it appears that the small-molecule inhibitors have the same type of efficacy profile, but they may also have the same safety profile, including an increased risk of infection, which is probably related to their effect on immune function. We clearly need more data to conduct a useful discussion about how these compare to biologics,” Dr. Kremer told EULAR delegates.

He added that one unexpected adverse event associated with tofacitinib has been an increase in LDL-C. However, this side effect, which was noted early in development, may not be a meaningful obstacle to clinical application in patients with potential to benefit.

In a late-breaker placebo-controlled study presented here at EULAR, the feasibility of employing tofacitinib with a statin suggested that hypercholesterolemia can be fully circumvented, according to Dr. Iain McInnes, Professor of Experimental Medicine and Rheumatology, University of Glasgow, UK. While LDL-C levels did rise in those randomized to tofacitinib and placebo, the LDL-C levels were lower after 12 weeks of treatment in those randomized to the combination of tofacitinib and atorvastatin (Figure 3). There were no significant differences in safety with the addition of the statin.

Given the potential for important clinical differences in the safety and efficacy from targeting very specific inflammatory pathways, it is unclear whether biologics and small-molecule inhibitors will compete directly or be employed within an algorithm that favours one over the other when DMARDs are not sufficiently effective alone. While oral agents are more convenient and likely to be better accepted by patients, the ultimate goal is to employ agents that rapidly control disease to reduce the risk of irreversible joint damage with the lowest risk of serious adverse events. It is hoped but not yet proven that intracellular signalling provides a more speci
key mediators of RA or other inflammatory diseases.

Figure 3.

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Summary

There are numerous potential intracellular targets for inhibiting the pro-inflammatory pathways that characterize RA and other autoimmune diseases. While the signalling from cytokine stimulation of extracellular receptors proceeds down the same pathways, small-molecule inhibitors such as those developed to block JAK and Syk signalling can be provided in oral formulations. Whether intracellular inhibition provides more specific anti-inflammatory activity than the extracellular biologics currently in use is unclear. However, an expansion of treatment options is attractive because of the limitations of biologics. Favourable safety and efficacy with small-molecule inhibitors in phase III studies suggest these agents are coming forward for clinical application in RA and perhaps other conditions. The specific action of these agents is potentially important for better understanding the pathophysiology of autoimmune inflammatory processes and may provide insight into the optimal targets for control.