New approaches to RA: natalizumab, eculizumab, and R406

[Guest guest]

Rheumawire

Feb 10, 2004

Drug development

New approaches to RA: natalizumab, eculizumab, and R406

Several new drugs with novel mechanisms of action are being investigated

for use in rheumatoid arthritis (RA). The selective-adhesion-molecule

antagonist natalizumab (Antegren®, Biogen Idec and Elan) and the oral

syk kinase inhibitor R406 (Rigel Pharmaceuticals) are both about to

start phase 2 clinical trials, while the complement blocker eculizumab

(ion) has just completed a second phase 2 trial, yielding results

similar to the first.

Natalizumab is to be evaluated in a phase 2 trial in RA in patients with

moderate to severe disease already receiving methotrexate. Administered

intravenously, this product has already been tested in Crohn's disease

and multiple sclerosis (MS) in clinical trials involving more than 4000

patients. It's the first of a new class of drugs that act as inhibitors

of selective adhesion molecules (SAM), say the manufacturers. These

molecules, found on the surface of immune cells, are thought to play an

important role in the migration of these cells out of the bloodstream

and into areas of inflammation.

Natalizumab, a humanized monoclonal antibody, is an 4 antagonist and

binds to the specific adhesion molecule 4 integrin. " The drug was

designed to selectively inhibit immune cells from leaving the

bloodstream and to prevent these cells from migrating into tissuethe

gastrointestinal tract in Crohn's disease, the brain in MS, and the

joints in RAwhere they may cause or maintain inflammation, " say the

companies. They recently announced successful results from a phase 3

maintenance trial in Crohn's disease. A phase 3 trial in MS is ongoing.

Results from earlier clinical trials in both conditions were published

last year in the New England Journal of Medicine [1, 2]. At the time, an

accompanying editorial noted that 4 integrins have been implicated in

several inflammatory conditions, including RA, and that treatment with

antagonists may lead to an improvement in at least some of these

diseases [3].

Also about to start a phase 2 trial in RA is the oral syk kinase

inhibitor R406. The drug works by blocking mast cells and B cells that

promote swelling and the inflammatory response, and Rigel says that

results from preclinical studies suggest it will be a safe and potent

disease-modifying antirheumatic drug (DMARD).

Meanwhile, eculizumab, a humanized antibody that acts as a complement

blocker, recently completed a second phase 2 trial in RA. The trial

involved 350 patients already taking either methotrexate or leflunomide,

and the new product was added on in 1 of 2 dosing regimens and compared

with placebo over a period of 6 months. Preliminary results released by

the manufacturer show that eculizumab reached its primary efficacy end

pointa significant improvement in ACR20 score after 6 months of

therapyin 1 of the 2 treatment arms, which involved monthly dosing.

However, the other armin which the drug was administered 2 times each

monthdid not reach statistical significance.

These results are similar to those seen in an earlier phase 2a trial,

which had involved 209 patients already taking methotrexate. At first

glance, the finding of a significant improvement with monthly dosing,

but not with twice-monthly dosing, seems " counterintuitive, " says

ion chief executive Leonard Bell, but the same trend was seen in

both trials and the results need to be analyzed further. He added that

in the first trial, certain patients seem to respond better to the

treatment (irrespective of dose) than others. The company plans to

present the results at a forthcoming scientific conference and is

deciding what to do next in the area of RA.

Eculizumab is also being developed for use in paroxysmal nocturnal

hemoglobinuria (PNH), in which red blood cells are highly susceptible to

lysis that is mediated by complement. Results from a trial in 11

patients with PNH published last week in the New England Journal of

Medicine [4] show that the drug, given over a period of 12 weeks,

reduced intravascular hemolysis, hemoglobinuria, and the need for

transfusion and was associated with an improvement in quality of life.

Zosia Chustecka

Sources

1. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's

disease. N Engl J Med 2003 Jan 2; 348(1):24-32.

2. DH, Khan OA, Sheremata WA, et al. A controlled trial of

natalizumab for relapsing multiple sclerosis. N Engl J Med 2003 Jan 2;

348(1):15-23.

3. von Andrian UH, Engelhardt B. Alpha4 integrins as therapeutic targets

in autoimmune disease. N Engl J Med 2003 Jan 2; 348(1):68-72.

4. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis

and transfusion requirements in patients with paroxysmal nocturnal

hemoglobinuria. N Engl J Med 2004 Feb 5; 350(6):552-9.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org