By David N. Leff

If ever there was a disease where the remedy can be worse than the malady, psoriasis is it. It¿s not life threatening, but some of its current therapies are.

Yet psoriatic patients put up with these toxic treatments because their debility is so afflicted that with moderate to severe psoriasis they sometimes feel that life isn¿t worth living. Their skin, from scalp to elbows, knees and other broad areas of their bodies, is covered with unsightly, unbearably itchy expanses of reddened inflammation, capped by piled-up plaques ¿ silvery scales that flake off continually. Psoriasis condemns some 7 million American sufferers to constant, acute embarrassment and frequent profound depression. (See BioWorld Today, Jan. 18, 2001, p. 1.)

Because dermatologists interpret psoriasis as an overexuberant assault by an errant immune system, they prescribe immunosuppressant drugs to tamp down psoriatic stretches of the body¿s skin. Of these, the preferred therapeutic is cyclosporine.

¿Cyclosporine is the gold standard of psoriasis therapeutics for clearing moderate to severe disease,¿ observed clinical research dermatologist Alice Gottlieb. ¿There¿s no other FDA-approved anti-psoriatic reported to date that has that good a profile.¿

She defines clearance ¿as a 75 percent or more drop in the standard research rating of psoriasis severity. It¿s the kind of near-total improvement that makes a patient in shorts or swimsuit feel great. While they¿re taking cyclosporine, they can forget they have the disease.¿

But cyclosporine, Gottlieb added, ¿also confers kidney toxicity, and possibly immunosuppression, with its risk of serious infection.¿ She directs the Clinical Research Center at the University of Medicine and Dentistry of New Jersey¿s Robert Wood Johnson Medical School in New Brunswick. The current issue of The Lancet, dated June 9, 2001, carries an article of which Gottlieb is senior author. Its title: ¿Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial.¿

Infliximab, better known by its trade name, Remicade, is a product of the biotech company Centocor Inc. in Malvern, Pa., now part of Johnson & Johnson. The firm¿s executive director of medical affairs, Thomas Schaible, explained that the drug¿s word segments ¿ infl-ixi-mab ¿ stand respectively for inflammation, chimeric and monoclonal antibody. The antibody reacts with tumor necrosis factor-alpha; chimeric denotes its mixed mouse-human features.

80 Percent Skin Clearance: A Socko Response¿

Gottlieb initiated the 10-week, Phase II, double-blind, placebo-controlled clinical study. It enrolled 33 psoriatic patients, ages 18 to 75. One-third received intravenous infusions of lower-dose infliximab, another 11, higher-dose, and the final third a placebo.

¿Treatment with infliximab,¿ she told BioWorld Today, ¿resulted in a high proportion of patients ¿ around 80 percent ¿ clearing their disease within six to eight weeks. That¿s a socko response. It makes infliximab¿s clinical effects comparable to cyclosporine. In terms of safety, at the higher dose, there was some incidence of mild headaches.¿

Besides this basic clinical outcome, Gottlieb pointed to a scientific payoff. ¿Consider infliximab as a therapeutic probe into the pathogenesis of psoriasis, because it is targeted to react with TNF-alpha. The fact that we cleared 80 percent of these patients with monotherapy directed against TNF-alpha demonstrates that among the many cytokines that are elevated in psoriasis, TNF-alpha must be playing a pivotal role in the generation of psoriatic plaques. That makes a very powerful statement.¿

What led Gottlieb and her co-authors to indict TNF-alpha was ¿a mixture of science and serendipity. First of all,¿ she pointed out, ¿we knew the inflammatory response in psoriatic plaques is initiated, at least in part, by activated T lymphocytes in the epidermis and dermis. These T calls make a lot of inflammatory cytokines, one of which is TNF-alpha. Its level, and that of other cytokines ¿ notably interleukin-6 and -8 ¿ is elevated in the psoriatic lesions, but not in the normal skin of psoriatic patients. TNF-alpha enhances leukocyte migration into the skin. It activates neutrophils, upregulates a number of intracellular transcription factors, and induces acute-phase reactants in other liver proteins.

¿The clinical challenge of psoriasis,¿ Gottlieb observed, ¿is not in clearing the disease. It¿s finding something that¿s safe and effective for its long-term management. And in general, that¿s where the biologics¿ niche will be ¿ a treatment you can give someone who gets the disease in their 20s.¿

Her 10-week study, reported in The Lancet, is now continuing with the same cohort of patients, this time in an open-label trial. ¿We have two goals in this stage,¿ she said. ¿Obviously, we had to offer infliximab treatment to those patients who initially got placebo. We had to offer them the real thing in real time. That ethical step was one goal. The other, to determine the relapse rate. So we asked: Does retreatment work? How long does the remission last?¿ To look at relapse rate, obviously, we followed them till they relapsed. And at that point they got retreated.

¿The second phase of this study,¿ Gottlieb summed up, ¿is work in progress. And Centocor is planning a full Phase III multicenter study of infliximab for psoriasis.¿

FDA Talks Treat Phase III Design, Timing

¿We¿re still discussing the final Phase III study design with FDA,¿ Schaible observed. ¿Given the considerations around coming to an agreement with FDA,¿ he continued, ¿and getting protocols to institutional review boards, we¿ll probably start enrolling patients in the first quarter of 2002 ¿ I would suspect in the 500-to-1,000-cohort range.¿

He has worked on developing Centocor¿s infliximab/Remicade for the past six years. For more than the last two years, the drug, approved by FDA, has been in routine clinical practice, treating rheumatoid arthritis (RA) and Crohn¿s disease. In RA, Schaible pointed out, ¿the monoclonal drug is given in combination with immunosuppressants, such as methotrexate. In Crohn¿s, it can be either Remicade monotherapy or in combination. The drug¿s annual cost,¿ he added, ¿is in the $10,000 to $12,000 range on RA.

¿The clinical effects in both indications are dramatic,¿ Schaible went on. ¿It¿s very similar to what Gottlieb reported in her psoriasis trials. Not only did we see a clinical benefit, but also an end-organ benefit: in RA, inhibition of joint destruction; in Crohn¿s, healing of the gastrointestinal mucosa.¿

Gottlieb concluded: ¿The high degree of efficacy and rapid response we¿ve seen in psoriasis patients treated with infliximab far exceeded our expectations.¿