Update on Novel and Emerging Therapies for RA: Report From the ACR 2007 Annual Meeting

[Guest guest]

Update on Novel and Emerging Therapies for RA: Report From the ACR 2007

Annual Meeting CME

I. Fox, MD, PhD

http://www.medscape.com/viewarticle/567521?src=mp

Introduction

The annual American College of Rheumatology (ACR) meeting in Boston,

Massachusetts, held November 6-11, 2007, was attended by over 15,000

participants with interests with regard to preclinical investigation,

clinical trials, and clinical practice. This article presents a summary of

the conference's highlights related to therapeutic advances for rheumatoid

arthritis (RA).

RA

In recent years, rheumatologists have been fortunate to have seen the

clinical response of " biologic agents, " such as tumor necrosis factor (TNF)

inhibitors, B-cell-depleting agents, and inhibitors of T-cell stimulation,

that have come to market. However, questions still remain, such as:

When should a biologic agent be started?

When (or if) should a biologic agent be stopped if the patient is doing

well?

When (and which) biologic agent should be used if the patient does not

exhibit adequate response to the first agent?

What is the incidence of long-term side effects (both medical and economic)

that occur in patients treated with biologics?

Although the definitive answers to these questions are not yet available,

this article describes some of the " work in progress " with available agents

and will review reports of several new drugs in clinical development.

Interim data from many of these studies were previously presented at the

European League Against Rheumatism (EULAR) 2007: The Annual European

Congress of Rheumatology meeting in Barcelona, Spain, in June 2007.

Abstracts from that meeting are available online at:

http://www.eular.org/index.cfm?framePage=/Abstracts.cfm.

Update on Anti-TNF Agents

Infliximab

The Behandel Strategien (BeST) study was reported by van der Kooij.[1] This

study addressed 3 treatment issues:

Whether initial treatment with the combination of methotrexate (MTX) and

infliximab (IFX) was superior to use of MTX or other disease-modifying

antirheumatic drugs (DMARDs) alone;

Whether IFX could be discontinued in patients with a very good response; and

How many patients would remain in good control in the absence of IFX at

least 2 years after treatment discontinuation.

Due to the complexity of the study, it is easiest to analyze the data in

terms of whether IFX was started " early " or " late " in the RA disease course:

At the beginning of the study, patients in the early IFX therapy group had

mean Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ)

scores that were higher compared with the scores reported in the late IFX

therapy group; and

Four years after the start of the study, more than 50% of patients in the

early IFX group had discontinued their IFX therapy and continued with DAS <

2.4.

An analysis of x-rays from this study compared early with late IFX patients

and found significantly less progression of joint damage in those patients

treated early in the disease process. The study authors concluded that

initial treatment with MTX and IFX in patients with early-onset RA is more

effective than reserving MTX and IFX for patients who failed on previous

DMARDs.

This conclusion implies that all patients with RA should receive IFX early

in the disease process, and was discussed among the meeting participants.

There was agreement that aggressive treatment was necessary in the early-RA

patient. The early-RA patient should be carefully monitored and escalated to

biologics if disease is not under control (DAS < 2.4). The study does

indicate that some patients who received " initial " IFX therapy can be

discontinued successfully.

Etanercept

The 4-year data from the Trial of Etanercept and Methotrexate with

Radiographic and Patient Outcomes (TEMPO) was presented.[2] TEMPO compared a

combination of MTX and etanercept (ETN) with each of the monotherapies. The

most recent observation, a longitudinal and DAS remission analysis over 3

years, suggested that the combination resulted in lower disease activity

than either treatments used as monotherapy.

The 3-year blinded study was followed by a 1-year, open-label extension

treatment with combination therapy:

The changes in total Sharp score were lower after combination therapy than

with monotherapy during the previous year (year 2-3 of TEMPO). This was

pronounced and significant for the MTX monotherapy group; and Erosions and

joint space narrowing demonstrated similar results.

The study authors concluded that regardless of disease duration, after 3

years of combination therapy with ETN and MTX in the group of patients with

moderate RA disease activity, further radiographic progression was halted

with improved clinical outcomes. Furthermore, for early RA, patients treated

with combination or ETN alone achieved similar levels of disease remission.

In a late-breaking abstract Emery and colleagues[3] reported the remission

rates from the 1-year results of the COmbination of Methotrexate and

ETanercept in Active Early Rheumatoid Arthritis (COMET) trial. This is the

first major trial to look at remission as an endpoint. Key points include:

Patients had less than 2 years of disease duration and were MTX-naive;

263 patients were randomized to MTX or MTX plus ETN;

At week 52, 48% of the patients on combination therapy had achieved ACR70

compared with 28% on MTX only; and

Similar results were found when the data were analyzed for DAS < 2.6.

Key points during the discussion of this study were:

Determination of the clinical/laboratory features that predicted the need

for continued ETN; and

Whether the ETN must be continued indefinitely in view of realistic economic

considerations.

Lee and colleagues[4] reported that patients with early RA (less than 3

years) who were treated for at least 1 year with a TNF inhibitor and then

discontinued their TNF inhibitor in the CORRONA database were likely to

remain relatively stable for the next 6 months. These results support the

results from the BeST and the TEMPO trials, as described above. It is

anticipated that further analyses of these trials will shed more light on

the benefit of ETN for RA disease remission.

Weinblatt and colleagues[5] reported that increasing the dose of ETN from 50

mg/week to 100 mg/week did not yield statistically significant improvement

in patient outcomes.

Adalimumab

Weinblatt and colleagues[6] presented data from their study on the safety,

efficacy, and remission profiles of patients with RA receiving adalimumab

(ADA) for up to 7 years. They showed that:

A total of 1469 patients were treated with ADA plus MTX for ? 30 days and up

to 7 years (5720 patient-years);

After 6 months of therapy, all efficacy measures showed significant

improvements vs baseline as nonresponders were switched to other therapies;

After 1 year of therapy, further improvements were observed in most

measures, except the patients' Global Assessment of Functioning (GAF) and

HAQ[7]; and

The percentage of patients achieving clinical remission (ACR70 or DAS < 2.6)

continued to increase after 2 or more years of continuous treatment with ADA

plus MTX.

Burmester and colleagues[8] reported that switching to ADA after

TNF-antagonist failure was effective and well tolerated in patients with RA.

In RA patients, the ACR50 was 41% and 33%, respectively, in patients who

were TNF-naive or who experienced TNF (ETN or IFX) failures.

Update on Risks Associated With TNF Inhibitors

The presentation by Greenberg[9] was the result of the study investigating

the use of TNF inhibitors and risk for malignancy in 8072 RA patients

representing over 15,495 patient-years. They found a 2-fold increased risk

in skin cancer but not in other solid tumors.

Setoguchi and colleagues[10] presented data showing that TNF antagonists may

increase the incidence of heart failure in elderly patients with RA,

although a potential confounding contribution of the RA disease to heart

failure has not been defined. The study authors recommended that larger,

detailed studies are needed to better define the effect of RA severity on

heart failure and the effect of TNF use in subgroups of patients that do not

present with structural heart disease.

There are relatively few studies on the effects of TNF-inhibitor use on

pregnancy. and colleagues[11] updated that multiple observations of

congenital abnormalities in the offspring of mothers who were administered

anti-TNF during pregnancy have been reported to the US Food and Drug

Administration (FDA). Although the actual risk is difficult to calculate, it

is important to counsel patients of childbearing age about appropriate

precautions in regard to pregnancy and the potential risks associated with

TNF agents.

Costimulatory Modulator

Abatacept is a recombinant fusion protein that binds CD80/86 and inhibits

T-cell activation. Kremer and colleagues[12] and Westhovens and

colleagues[13] presented data from the Abatacept in Inadequate Responders to

Methotrexate (AIM) trial and Abatacept Trial in Treatment of Anti-TNF

Inadequate Responders (ATTAIN), which updated the long-term efficacy and

safety results of abatacept through 3-5 years of treatment. They reported

that:

An ACR50 of 60% was noted at year 3;

Abatacept provides durable improvement in treatment response and disease

status, and a consistent safety profile through 3 years in MTX-inadequate

responders and in anti-TNF-inadequate responders; and

The data suggest that the efficacy benefits of abatacept may increase over

time.

Schiff and colleagues[14] also reported the response to influenza vaccine in

RA patients treated with abatacept in the Abatacept Researched in Rheumatoid

Arthritis Patients with an Inadequate anti-TNF response to Validate

Effectiveness (ARRIVE) trial. The study demonstrated that 75% of

abatacept-treated RA patients responded to at least 1 strain of influenza

virus, demonstrating that abatacept does not abrogate the ability of RA

patients to mount an immune response to influenza immunization. The titers

of the antibodies were lower than in age-matched controls. The study authors

suggested that patients should receive necessary vaccinations prior to

starting abatacept (or other biologic agents).

Update on B-Cell-Depleting Agents

Rituximab (RTX) is a chimeric mononclonal antibody to CD20 that reduces the

number of circulating B-cells B cells. Keystone and colleagues[15] and Emery

and colleagues[16] reported the benefits of repeated treatment courses of

RTX in patients with RA who previously had an inadequate response (or

intolerance) to 1 or more TNF inhibitors. Since September 2006, a total of

571 RA patients with a prior inadequate response or intolerance to 1 or more

TNF inhibitors have been exposed to repeated courses of RTX (1000 mg x 2 for

all courses) in the clinical program. Of these:

Two hundred ten patients received ? 3 courses of RTX.

The median period between treatment courses 1 and 2 was 37.9 weeks, and 42.1

weeks between courses 2 and 3.

Efficacy data were available for 97 patients who, at the time of analysis,

had reached at least 24 weeks' follow-up post course 3.

An ACR50 of 45% to 50% was noted after courses 2 and 3, which exceeded the

ACR50 of 35% noted during the first course of RTX. This probably reflects

the dropout of patients with low response or intolerance of RTX.

In patients who have received up to 4 courses of therapy, the immunoglobulin

(Ig)M and IgG levels decreased, but a clear causal relationship with

infections (mostly upper respiratory tract) has not been established.

Update on Emerging Biologic Agents for RA

Certolizumab Pegol

The Routine Assessment of Patient Index Data (RAPID)1 and 2 studies assessed

certolizumab pegol (CZP) as monotherapy and in combination with MTX.[17-19]

These studies demonstrated that:

In RAPID1, 400 mg CZP every 4 weeks were administered, whereas in RAPID2,

200 mg CZP were administered biweekly after an initial 400-mg loading dose;

In both the RAPID1 and 2 studies, CZP was associated with improvements in

the ACR20/50/70 measures, although there were no differences between the CZP

200-mg and 400-mg doses; and

Significant inhibition of radiographic progression was demonstrated.[20]

Ofatumumab

Ofatumumab is a human monoclonal anti-CD20 IgG1 antibody. Østergaard and

colleagues[21] presented a phase 2 study involving 225 RA patients with

incomplete DMARD responses. ACR50 in the 20% to 25% range was achieved with

the 700-mg and 1000-mg doses.

Ocrelizumab

Genovese and colleagues[22] presented dosing studies of ocrelizumab, a novel

humanized anti-CD20 monoclonal antibody. Although predominantly a safety

study, clinical assessments showed ACR50 responses of 30% in the 10-mg (x 2)

group, whereas a lower response between 20% and 25% was evident in the

higher-dose (50-mg and 200-mg) groups. These clinical observations may be

fortuitous because a dose-related decrease in B-cell numbers and increased

serum B-cell activity factor (BAFF) were noted. Overall:

Ocrelizumab was well tolerated with similar adverse events across different

dose ranges; and

Infusion-associated adverse events were noted but did not show a

dose-dependent relationship.

Tocilizumab

Frey and colleagues[23] reported that targeting the interleukin (IL)-6

receptor with tocilizumab (4 mg or 8 mg every 4 weeks with MTX) led to

clinical improvement in health-associated quality of life, including

fatigue. During the late-breaking abstracts, Genovese and colleagues[24]

reported that IL-6 receptor inhibition reduced disease activity in the

TOWARD trial, a 2-arm, double-blind, placebo-controlled study designed to

evaluate the safety and efficacy of tocilizumab plus DMARDs compared with

placebo plus DMARDs in RA patients. These studies showed that:

The ACR50 was 38% vs 9% in placebo;

Only 1% of the patients in the tocilizumab group showed elevated liver

function tests (over 3-fold normal); and

Patients experienced a rapid drop in C-reactive protein levels and an early

decrease in symptoms of joint pain, which appeared to be comparable to TNF

inhibitors and more rapid than B-cell depletion.

Denosumab

Inhibition of radiographic bone erosion by denosumab, an anti-RANKL human

monoclonal antibody, was reported.[25] Results from 60 mg and 180 mg

subcutaneous denosumab administered at 2-month intervals showed:

Six-month MRI indicated that there is a significant decrease in the

proportion of patients with increasing erosion in the 80-mg group;

A decrease in the erosion score was noted with both denosumab dosages; and

However, the study revealed minimal symptomatic response among treated

patients.

Conclusions

Overall, data on treatments for RA focused on reanalysis of data from

ongoing clinical trials. It is vital that we retain the ability to switch

safely between TNF agents, B-cell-depleting agents, or inhibitors of T-cell

costimulation.

Data supporting the potential for patients with early RA (less than 3 years)

to be weaned off their biologic therapy were presented. Because some

patients with early RA can achieve disease " remission " with MTX only,

although a significantly greater number of patients achieve disease

remission with MTX in combination with a biologic agent, it will be

important to use clinical and laboratory markers to identify which patients

need to start biologics early and which patients can be tapered off

biologics when they achieve remission.