R&D pipeline bursting with new SLE treatments

[Guest guest]

May 18, 2004

R & D pipeline bursting with new SLE treatments

New York, NY - Despite the fact that it's been 40 years since a new

treatment was approved to treat systemic lupus erythematosus (SLE), the

development pipeline is bursting with drugs aimed at blocking various immune

responses that drive this disease, according to new data presented here at

the 7th International Congress on Systemic Lupus Erythematosus and Related

Conditions.

With current therapies for SLE, " we are not meeting our therapeutic goals to

improve specificity, improve efficacy, and reduce toxicity, " says Dr I

Daikh (University of California, San Francisco). " The overarching point is

that we hope to achieve all of these goals by having more targeted therapy. "

Important new targets for immune suppression in SLE include T cells, B

cells, and the activated protein C (APC) receptor that sets off the immune

response. " We are fortunate to have drugs in the pipeline that target all of

these interactions, " Daikh says.

Costimulation blocker CTLA41G

Costimulation blocker CTLA4Ig (under development by Bristol-Myers Squibb

[bMS]) has been tested with good results in rheumatoid arthritis (RA) and

psoriasis and has been shown to prevent renal disease in murine lupus, Daikh

says.

It works by blocking a costimulatory signal that is required for optimum

activation of T cells, he explained. The activation of T cells and the

secondary activation of other important cells, such as macrophages and B

cells, lead to the inflammatory cascade resulting in the release of TNF and

other cytokines.

So far, the data on SLE for this compound come from experimental work. In a

murine study of advanced renal disease [1], researchers found that mice

lived longer, although renal disease plateaued when either CTLA418 or

cyclophosphamide (Cytoxan®, BMS) was used alone. But when the 2 drugs were

used together, there was a " dramatic and prompt reduction in renal disease

and proteinuria " and survival improved as well, he says.

Specifically, survival was 94% with the combination, compared with 36% with

either drug alone. CTLA418 inhibits T cells, while cyclophosphamide produces

a marked diminution of B cells, Daikh explains. " These are encouraging data,

but only 1 way of blocking immune response, " he says.

" Questions about CTLA418 and other new drugs in the pipeline include what

the effects on immune regulation and immune competence are, what the optimal

timing and targets for specific therapies are, and how best to combine

traditional and biologic therapies, " he says.

Blocking proinflammatory cytokines in SLE

Another crucial question remains as well, says Dr f S Smolen (Medical

University of Vienna, Austria) [2]. " We do not know, despite all the

progress in the past decade, what the mechanism is that leads to

metamorphosis from autoimmunity to autoimmune disease, " he says.

Specifically, researchers are still not clear what drives the tissue

destruction in SLE.

Proinflammatory cytokines, including tumor necrosis factor alpha (TNF-),

IL-1, and IL-6, may play a role in SLE, but they have gotten " little

attention with respect to tissue damage and little attention in regard to

becoming targets for therapeutic interventions, " he says.

Both IL-6 and IL-1 are elevated in SLE, but despite the fact that there are

products that block these cytokines, " I am not aware of any studies in SLE, "

he says. For example, anakinra (Kineret®, Amgen) targets IL-1 and is

approved for use in rheumatoid arthritis (RA), and there is an anti-IL6

antibody, MRA (in development by Chugai), in late clinical trials for RA.

However, it's TNF that " is at the apex of cytokines by inducing IL-12 and

IL-6 . . . and is very important with respect to activation of the whole

spectrum of inflammation, " Smolen says. And of course, there are now 3 TNF

inhibitors available commerciallyinfliximab (Remicade®, Centocor),

etanercept (Enbrel®, Immunex/Wyeth), adalimumab (HumiraTM, Abbot

Laboratories)approved for use in rheumatoid arthritis and also some other

conditions.

Making the case for TNF inhibition

While considered controversial to many in the rheumatology world, Smolen

says that TNF blockade may be an option for SLE. Making the case for this

approach, he points out that TNF is elevated in SLE, correlates with disease

activity, is bioactive, and is overexpressed in involved organs: " So why not

use blockers to inhibit it? "

However, he warns that blocking TNF " may be beneficial in autoimmunity and

experimental lupus, but it also may be dangerous. " Some research shows that

" sustained TNF therapy does not prevent severe renal disease [and]

TNF-deficient mice have severe lupus due to the fact that they lack TNF. " In

addition, approximately 0.2% of patients treated with TNF blockers develop

drug-induced lupuslike syndrome, he noted, but all of the patients have

recovered and there was no renal or nervous system involvement.

Despite these misgivings, TNF inhibition has already been tried in SLE, and

while the results come from an open-label trial in only 6 patients, they

suggest that there was some benefit. All 6 SLE patients had moderate disease

activity with lupus arthritis, lupus nephritis, or both, and were refractory

to standard therapy. They received 4 doses of infliximab 300 mg at weeks 0,

2, 6, and 10.

" In days to weeks, every single patient went into remission with regard to

swollen joints, but 6 to 8 weeks after the last dose, there was a recurrence

of arthritis, " Smolen told the meeting. In the patients with nephritis,

proteinuria decreased (by 50% to 90%) and remained decreased even when

treatment ceased. SLE disease activity scores also fell. Importantly,

steroid dose was reduced by 50% at 52 weeks.

The treatment appeared to be safe, Smolen commented. There were no infusion

reactions, but there were several urinary tract infections and there was a

transient increase in anti-dsDNA antibodies, but no flares, he said.

TNF blockade in SLE " may not be that dangerous, but this is only an open

trial and we can only know the truth by doing controlled trials, " he

continued. There are 2 sides to every story, he reminded the audience, but

he concluded that TNF blockade " may be safe and efficacious in SLE, and

these data warrant a controlled trial. "

" This is a provocative and compelling study, " Daikh commented.

More data on rituximab in SLE

Another approach to SLE under investigation is B-cell depletion with

rituximab (Rituxan®, Genentech Inc). Several small trials in SLE patients

with this agent have already been reported, and at the New York meeting a

trial of rituximab with cyclophosphamide in 11 patients with severe SLE was

reported by a Swedish group [3].

All the patients were female, with an average age of 32 and a mean follow-up

time of 16 months. Seven patients had lupus nephritis, 1 had seropositive

arthritis, and 1 had Quincke's edema, Dr Iva Gunnarson (Karolinska Hospital,

Stockholm, Sweden) told the meeting. All the patients had failed

conventional immunosuppressive therapy and received 4 weekly infusions of

375 mg/m2 of rituximab, 2 infusions of cyclophosphamide at 0.5 mg/m2, and a

time-limited increase of corticosteroids.

At 6 months, SLE Disease Activity Index (SLEDAI) and the SLE Activity

Measure (SLAM), decreased significantly, and the dose of prednisone these

patients were taking was reduced. Anti-DNA antibodies fell in most of the

patients, Gunnarson commented, but she noted that they were not elevated in

all patients at inception. IgG, IgA, and IgM remained stable. Renal biopsy

data after treatment showed that 2 patients transformed into mild disease,

and there was a significant decrease in renal activity over 6 months. In

addition, proteinuria decreased in most patients, and all patients were

shown to be responders at 4 to 6 months. Moreover, skin manifestation

improved and the Quincke's edema disappeared, she said.

" Rituximab was well-tolerated in our patients, and we saw very few side

effects, " Gunnarson told the meeting. The side effects included limited

herpes zoster and an infusion reaction in 1 patient. " These are very

promising data, " she concluded.

Mann

Sources

1. Daikh DI. Presentation: Session on new treatments. New York, NY: 7th

International Congress on Systemic Lupus Erythematosus and Related

Conditions: Session on long-term outcome: heart and vessels; May 9-13,

2004:NA.

2. Smolen JS. Presentation: Session on new treatments. New York, NY: 7th

International Congress on Systemic Lupus Erythematosus and Related

Conditions: Session on new treatments; May 9-13, 2004:NA.

3. Gunnarson I, Welin Henriksson E, Sundelin B, et al. Presentation:

Rituximab plus cyclophosphamide in severe SLE: promising results in 11

patients who failed conventional immunosuppressive therapy. New York, NY:

7th International Congress on Systemic Lupus Erythematous and Related

Conditions: Session on long-term outcome: heart and vessels; May 9--13,

2004:Abstract 49A.