Progress with new drugs for RA

[Guest guest]

Progress with new drugs for RA

Rheumawire

Jun 23, 2004 Zosia Chustecka

Berlin, Germany - Progress with several new drugs under development for

rheumatoid arthritis (RA) was discussed at the recent EULAR 2004

meeting. All of them have novel mechanisms of actions, thus representing

new approaches to therapy.

Furthest ahead in the race to the market are rituximab (Roche/Genentech)

and abatacept (CTLA4g, Bristol-Myers Squibb). Both products are in phase

3 clinical trials, so launches are possible by late 2005, but more

likely in 2006.

Rituximab may have an advantage when going through the approval process,

as it is already marketed for use in lymphoma and consequently already

has a large safety data bank, whereas abatacept is a completely new

chemical entity. However, abatacept may complete its clinical

development program first. It is currently in 2 pivotal phase 3 clinical

trials, Dr Larry Moreland (University of Alabama, Birmingham) told the

meeting: in patients with RA refractory to methotrexate and in patients

with RA who have failed treatment with TNF inhibitors. Both are due to

be completed in the fall of this year, he said.

Already, the companies involved are preparing the ground among

rheumatologists, with explanations of the science involved detailed at

exhibition booths and at satellite symposia held during the meeting. The

2 drugs act on completely different cell populationsrituximab depletes B

cells, which produce the autoantibodies that propagate the autoimmune

attack in RA, whereas abatacept is a costimulation blocker that inhibits

T-cell activation.

Presentations on both drugs at the meeting focused on data from phase 2

studies in RA, 2 of which have already been published in the New England

Journal of Medicinethe one on rituximab only last week [1], the one on

abatacept late last year [2], as previously reported by rheumawire. In

both cases, accompanying editorials hailed the new drugs as " promising "

new approaches to the treatment of RA.

Rituximab is also being investigated in the treatment of systemic lupus

erythematosus (SLE), and its B-cell-depletion approach is also

considered to have potential in other autoimmune diseases. Abatacept is

also being investigated in clinical trials in lupus and psoriasis.

Slightly further behind in development, in early phase 3 trials with a

launch expected in 2007, is the anti-interleukin-6 receptor antibody MRA

(originally developed at Osaka University, now being developed in

collaboration by Chugai and Roche). It has also shown efficacy in

rheumatoid arthritis in a phase 2 trial (the CHARISMA study) and in

juvenile idiopathic arthritis, as previously reported by rheumawire.

Reviewing these data at the EULAR meeting [3], Prof Sir Ravinder Maini

(Kennedy Institute of Rheumatology, Imperial College, London) commented

that the drug has been shown " efficacious in a short-term study in

suppressing signs, symptoms, and acute-phase proteins and holds promise

as a therapeutic option for RA. Preliminary trials have also shown

impressive responses in juvenile chronic arthritis. " The product is also

being explored in other potential indications, including Castleman's

disease, Crohn's disease, and multiple myeloma.

Further back in development is an interleukin-15 antibody (Humax,

AMG-714, Amgen). At the EULAR meeting, Prof Iain McInnes presented data

from a phase 1/2 study in 24 patients with active RA who were failing on

disease-modifying antirheumatic drugs (DMARDs). These patients stopped

taking their DMARDS for 4 weeks and underwent a trial of monotherapy

with the IL-15 antibody for 12 weeks. ACR20 responses were seen in 60%

of patients, ACR50 in 37.5%, and ACR70 in 25% of patients, which was

" rather surprising " as this was monotherapy, McInnes commented, but he

also pointed out that the trial was not placebo controlled. A phase 2

clinical trial is now in progress, with a phase 3 trial planned for next

year. Speculating on the positioning of the product, McInnes suggested

it could be targeted at patients who are only partial responders to TNF

therapy or perhaps other disease population subsets. The IL-15-antibody

approach may also have potential in other conditions, he added,

including psoriasis, psoriatic arthritis, inflammatory bowel disease,

pulmonary inflammation, and transplant rejection.

Also in phase 2 trials is an interleukin-1 trap (Regeneron). Actually,

the product has already completed a phase 2 study that showed efficacy

in moderate to severe RA, Dr Clifton Bingham (Seligman Center for

Advanced Therapeutics, New York University Hospital for Joint Diseases,

NY) told the meeting, but the formulation that was used caused

injection-site reactions. The reactions were thought to be due to a

sodium citrate component that has now been removed, and the new

reformulated product will be tested again in a phase 2 trial, he told

rheumawire. Commenting on the results obtained already, in a trial of

201 patients followed for 12 weeks [3], Bingham said: " I am encouraged

by results showing bioactivity and the improvement in signs and

symptoms, and I look forward to further studies at higher doses. " In a

veiled reference to the interleukin-1 antagonist anakinra (Kineret®,

Amgen), already on the market, he added: " We've never seen what an

effective IL-1 blocker can do in rheumatoid arthritis. "

A new DMARD from Japan, T-614 (Toyama Chemical) was introduced at the

meeting by Dr Masako Hara (Tokyo Women's Medical University, Japan) [4].

This is a novel type of DMARD, characterized by inhibitory effects on

immunoglobulin production in B cells, without suppression of

proliferative responses, but the drug also inhibits cytokine production

by macrophages and synovial cells, Hara explained. She presented data

from a late phase 2 trial in 209 patients and from a phase 3 trial in

376 RA patients, in which the new drug (at 50 mg/day) was compared with

both placebo and sulfasalazine (1000 mg/day) for 28 weeks [5]. The

primary end point was ACR20 response, achieved by 62.5% of patients in

the group taking T-614, which was comparable to that seen in the

sulfasalazine group (58.1%) and significantly superior to the placebo

group. The response to the drug was quick, with 13.5% of patients

showing efficacy within 4 weeks, she said, and efficacy was seen even in

patients who had previously responded poorly to methotrexate (52.9% of

these patients achieved an ACR response). Hara noted, however, that

elevations in liver enzymes were seen " frequently " in the group taking

T-614, although the elevations were transient and improved on

discontinuation. She commented to rheumawire that patients will need

monitoring for liver enzymes while taking this drug but expects the

problem to be less frequent than is currently seen with leflunomide and

methotrexate. Hara concluded that T-614 " is expected to be a useful,

novel DMARD even for methotrexate-resistant patients. " Fumio Matsuoka

from Toyama Chemical told rheumawire that the drug was available for

licensing outside of Japan.

Separately, Neurogen Corporation announced recently that it is unlikely

to continue developing the oral C5a antagonist NGD-200-1 for rheumatoid

arthritis, after a phase 2a trial in 49 patients failed to meet its

primary end point. As C5a is a naturally occurring peptide with

proinflammatory functions mediated through the G-coupled protein C5a

receptor, the company had hoped that inhibiting the activation of the

C5a receptor might work to treat rheumatoid arthritis by blocking the

inflammatory response and breakdown of tissue.

However, preliminary results from the phase 2a trial showed no

significant effect on C-reactive protein (CRP) levels, the primary end

point, or on most of the secondary end points reflecting signs and

severity of the disease. A post hoc analysis of the ACR20 responses

showed a significant effect at the highest dose tested (100 mg/day), but

the dose levels that would need to be developed would not " permit a

sufficient therapeutic window, " the company believes, as the drug had

already shown in previous studies an inhibition of cytochrome P450

enzymes involved in drug metabolism, which could lead to drug-drug

interactions. Earlier this year, a phase 2 trial of the same drug in 142

asthma patients also failed to show a significant benefit.

Sources

JCW, Szczepanski L, Szechinski J, et al

Efficacy of B-cell-targeted therapy with rituximab in patients with

rheumatoid arthritis N Engl J Med 2004; 350:2572-2581

Kremer JM, Westhovens R, Leon M, et al Treatment of

rheumatoid arthritis by selective inhibition of T-cell activation with

fusion protein CTLA4Ig N Engl J Med 2003 Nov 13; 349(20):1907-191

Maini RN Anti-IL6 receptor therapy: rationale and

early results in rheumatoid arthritis. Presented at: EULAR 2004; Berlin,

Germany; June 9-12, 2004. Abstract SP0074.

Hara M, Abe T, Sugawara S, et al A phase III

double-blind comparative study to evaluate the efficacy and safety of

T-614, a newly developed DMARD. Presented at: EULAR 2004; Berlin,

Germany; June 9-12, 2004. Abstract OPO109.

Bingham CO, Genovese M, Moreland L, et al Treatment of

moderate to severe rheumatoid arthritis with IL-1 trap. Presented at:

EULAR 2004; Berlin, Germany; June 9-12, 2004. Abstract OPO108.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org