* Mode of administration: IM (Intramuscular); IV (intravenous); O (oral); SQ (subcutaneous); T (topical: applies to ointment, cream, gel)


These companies had run up against the placebo effect -- a major problem in such trials. For one thing, when the trial is designed to test the drug on one lesion and the placebo on another (say one on each side of the abdomen), the patient's expectations can actually result in marked improvement of both lesions. For another, when patients are applying the medication themselves, they have been known to use both the drug and the placebo on the same lesion -- or to get them mixed up.

But there's more to it than that: Remember that psoriasis comes and goes in an unpredictable manner that can't be planned for when designing a trial. And, it's known to be affected beneficially by sunlight, so it's usually worse in the winter than it is in the summer. Any clinical trial that spans the seasons is surely asking for trouble.

That's what The Immune Response Corp.'s investigators discovered when they analyzed the first Phase II clinical trial of the firm's therapeutic vaccine IR502. This trial, which was completed in December 1996, tested the putative vaccine (consisting of two CD8 T cell receptor peptides combined with an adjuvant) in patients with moderate-to-severe psoriasis. This vaccine was injected, a route of administration that presumably should not encounter the placebo effects seen with topical drugs. Nonetheless, there was a marked placebo effect: All the patients improved. This trial also spanned the seasons, lasting from January through August. Many of the patients, as it turned out, were treated in the spring and summer.

But Immune Response didn't accept defeat: Buoyed by patients' positive response to the vaccine, and cognizant of the seasonal nature of the disease, the firm conducted another Phase II trial, in which the patients once again exhibited clinical improvement. That trial was completed in May 1998; since then, Immune Response has put the vaccine on the back burner, waiting for a partner to fund further development.


Two other biotech firms stuck it out in the face of setbacks: Both Seragen Inc. and BioCryst Pharmaceuticals Inc. ran into difficulties during Phase II trials --and neither had to do with a placebo problem.

Seragen's trial had to be halted after one of the patients developed a blood clot (from which that person recovered). After the FDA found no links between the product and the adverse event, it lifted the clinical hold. However, Seragen decided not to resume the trial: The company had already treated a sufficient number of patients to see that its IL-2 fusion protein (Ontak) was producing statistically significant results -- it was able to reduce both disease severity and lesion thickness.

Psoriasis Drug Trials That Have Been Discontinued Or Put On Hold

Company	Product Name	Product Type	Mode Of Action		Indication (Mode Of Administration)*	Outcome
Chemex Pharmaceuticals (Access Pharmaceuticals)	Methotrezate	Zinc salt of methotrexate	Antifolate; arrests cell growth		Severe psoriasis (T)	Minimal benefit in Phase I trial; program discontinued 1993
Immune Response	IR502	Two CD8 T cell receptor peptides, combined with adjuvant; therapeutic vaccine	Inhibits or down-regulates T cells		Moderate-to-severe psoriasis (IM)	In 1st Phase II trial, completed 12/96, product did not perform statistically better than control; in 2nd Phase II trial, completed 5/98, patients exhibited clinical improvement; company is seeking partner for further development
Protein Design Labs	Nuvion (HuM291)	Humanized Mab that targets the CD3 antigen on T cells	Induces apoptosis of activated T cells		Moderate-to-severe psoriasis (IV)	In Phase I/II trial, patients experienced symptoms of cytokine release syndrome; product development discontinued 6/01
Sphinx Pharmaceuticals (Eli Lilly)	Kynac	Protein kinase C inhibitor	Key intracellular enzyme that regulates proliferation, among other cellular processes		Plaque psoriasis (T)	Effect on psoriatic lesions not clinically meaningful; product development discontinued 1993
Sugen (Pharmacia)	SU5271	Synthetic small molecule signal transduction inhibitor	Interrupts epidermal growth factor (EGF) signal transduction by binding to EGF receptor; blocks growth of keratinocytes		Plaque-type psoriasis (T)	Phase I/II trial data were not compelling; product development was put on hold (1999)
Vertex Pharmaceuticals	VX-497	Rationally designed drug that inhibits inosine monophosphate dehydrogenase (IMPDH), a cellular enzyme that is essential for production of guanine nucleotides	Blocks DNA synthesis, thus proliferation of lymphocytes		Severe chronic plaque-type psoriasis (O)	Initiated Phase II clinical trial 1/99; apparently dropped clinical development in favor of  2nd generation IMPDH inhibitor, VX-148 (plans to initiate Phase II trial by end of 2001)

* Mode of administration: IM (Intramuscular); IV (intravenous); O (oral); SQ (subcutaneous); T (topical: applies to ointment, cream, gel)


Ligand Pharmaceuticals Inc., which subsequently acquired Seragen, ran another study and also found positive results. It's unclear, though, whether Ligand will follow through with large-scale trials.

BioCryst's problem didn't even involve patients. In June 1995, an error popped up in the analysis of Phase II data on the topical version of its small molecule drug candidate BCX-34. The company had thought its results were statistically significant -- but that conclusion went out the window after it discovered that faulty randomization codes had counted some placebo results as drug-induced.

Unbowed, the firm went back into the clinic with its topical drug, shepherding it all the way through Phase III trials. Once again, however, the results weren't statistically significant. BioCryst also tried an oral formulation of BCX-34, but discontinued the program early last year when it found that the dose levels being used weren't adequate enough to inhibit the activity of its target enzyme purine nucleoside phosphorylase (PNP), which is specifically required for normal DNA synthesis in T cells.

Since then, BioCryst has in-licensed a series of more powerful PNP inhibitors from Albert Einstein College of Medicine of Yeshiva University and New Zealand-based Industrial Research Ltd. BioCryst is just about to launch the first clinical trial of its new lead candidate, BCX-1777, but not in psoriasis. Instead, the company is testing BCX-1777 in acute lymphoblastic leukemia (ALL), a T-cell proliferative disease. Why? "There's an important medical need for a new treatment for ALL," explained J. Claude Bennett, BioCryst's president and COO. "There's not a good second-line therapy. Once these patients are in remission, there's not much that can be done [in terms of maintenance therapy]." The company is hoping to establish BCX-1777's safety and efficacy profile in the ALL trials, too, where it will be administered intravenously. As to psoriasis? Because "there are now at least three good drugs that can achieve a 75 percent response rate in psoriasis, to take them on we need to first establish a base in ALL," Bennett said.


Phase II clinical trials ended up being a sticking point for Isis Pharmaceuticals Inc., too -- but, like Immune Response and several other biotech companies striving to develop therapies for this difficult disease, Isis forged ahead. The company's first product, ISIS 2302, is an antisense oligonucleotide designed to inhibit intercellular adhesion molecule-1 (ICAM-1), which plays a role in immune cell activation and trafficking to sites of inflammation.

Isis initially tested an intravenous formulation of the ICAM-1 inhibitor in psoriasis patients, but by the end of Phase II trials it was obvious that very little of the drug was actually getting to the dermal and epidermal skin layers. Importantly, however, Isis did see a modest clinical benefit -- so it switched to a topical formulation.

This appears to work. The Phase II trial results, reported at the 2nd Joint Meeting of the International Psoriasis Symposium and the European Congress on Psoriasis, held in San Francisco in June 2001, demonstrated that ISIS 2302 was able to penetrate psoriatic lesions and reduce plaque thickness. And, although not quite statistically significant (due to a high placebo response), the data showed a strong trend favoring a relationship between increased concentrations of the drug and reduction of plaque thickness (induration). The trend was encouraging enough that Isis is now starting to gather the data from a larger study with the highest (4% cream) drug concentration. The company should be presenting these at the American Academy of Dermatology meeting in February 2002, said F. Andrew Dorr, Isis' vice president and chief medical officer.

Psoriasis Drug Trials: Active Programs**

Company	Product Name	Product Type	Mode of Action	Indication (Mode Of Administration)	Clinical Status
Abgenix	ABX-IL8	Fully human Mab; blocks activity of interleukin-8 (IL-8)	IL-8 contributes to inflammatory process; levels can be elevated 150X in psoriatic tissue; IL-8 is growth factor for proliferating skin cells; IL-8 is also an angiogenesis factor	Moderate-to-severe psoriasis (IV)	Phase IIa trial results statistically significant; initiated Phase IIb trial 3/01
Angiotech Pharmaceuticals	Micellar Paclitaxel Injection	Yew tree-derived semisynthetic taxoid	Paclitaxel is anti-microtubule agent (inhibits cell growth); also inhibits inflammatory cell response and angiogenesis	Severe psoriasis (IV)	Initiated Phase II study at NCI 11/00
Biogen	Amevive (alefacept)	Fusion protein; human LFA-3 IgG1 fusion protein (a.k.a., LFA3TIP)	Blocks activation of T cells by interfering with LFA3/CD2 co-stimulatory pathway; binds to CD2 on T cell	Moderate-to-severe chronic plaque psoriasis (IV or IM)	Under regulatory review; FDA and European Agency for the Evaluation of Medicinal Products both accepted applications for review 10/01
Centocor (Johnson & Johnson)	Remicade (infliximab)	Chimeric Mab to tumor necrosis factor-alpha	Blocks TNF-alpha (key inflammatory mediator)	Moderate-to-severe psoriasis (IV)	Investigator-initiated Phase II study at the University of Medicine and Dentistry of New Jersey demonstrated high degree of efficacy, rapid response and sustained benefit
Connetics	Olux	Foam formulation of super high potency topical steroid (clobetasol proprionate)	Reduces inflammation; also has immunosuppressive and anti-proliferative effects	Mild-to-moderate body psoriasis (T)	Statistically significant results in Phase IV clinical trial 11/01: company will file sNDA by 1/02 (product 1st approved by FDA for treating corticosteroid-responsive scalp psoriasis in 5/00)
Corixa	PVAC	Heat-killed Mycobacterium vaccae extract	Immunomodulator	Moderate-to-severe psoriasis (ID)	Failed to meet primary endpoint of Phase II study 2/01 but did show clinical benefit

* Mode of administration: ID (intradermal); IM (intramuscular); IV (intravenous); O (oral); SQ (subcutaneous); T (topical: applies to ointment, cream, gel)
** Excludes phototherapies.


"As a platform for dermatological disease, topical antisense is very promising as it has the ability to target specific molecules involved in skin disease without systemic toxicity," commented Utah's Krueger, who presented the trial results in June.

That's what Isis is counting on: Also in June, the company started a Phase II trial in mild-to-moderate psoriasis using a topical formulation of a second-generation antisense drug, ISIS 104838, targeted against tumor necrosis factor-alpha (TNF-alpha). It's also planning a trial in moderate-to-severe disease -- where the drug will be administered subcutaneously -- which should start no later than the second quarter of 2002, according to Dorr.

"Oligonucleotides given topically distribute to both the epidermis and the dermis, but without a lot of systemic uptake," Dorr explained. With ISIS 2302, "We get good uptake into the endothelium of the blood vessels (where ICAM is found) in the dermis, but the drug goes no further into the circulation," he continued. But TNF-alpha is another story: "We're not sure where the target cell is. It could be in the skin, or systemic, or both."


In fact, targeting TNF-alpha could be just the ticket. There's ample proof that it's a major player in inflammatory diseases -- and that biotech drugs are able to gum it up. Best-selling rheumatoid arthritis drugs Enbrel and Remicade both block TNF-alpha. And, excitingly, there's every sign that they'll work in psoriasis, too.

It even appears that Enbrel is an effective therapy for psoriatic arthritis, a devastating disease that combines the stiffness and joint destruction of arthritis with the inflamed, scaly patches of psoriasis. Data from a three month clinical trial demonstrated that 87 percent of patients given Enbrel saw an improvement in their disease, compared with 23 percent of patients who received placebo. Enbrel was also effective at clearing plaques: 40 percent of patients saw their psoriasis clear by 50 percent or more; 20 percent of the patients saw a 75 percent or higher improvement. Reportedly, Immunex Corp. is exploring Enbrel's use in psoriasis as well.

In July 2001 Immunex filed a supplemental BLA for Enbrel's use in treating psoriatic arthritis (either alone or in combination with methotrexate). According to Mark Lebwohl, professor and chairman of dermatology at Mount Sinai Medical Center, one out of every 10 psoriasis patients he examines suffers from psoriatic arthritis. (It affects about 300,000 individuals in the U.S.) "My hope is that we are one step closer to treating a disease that has not yet seen adequate treatment," he said. It's no wonder that physicians are enthusiastic: The FDA has never before reviewed a drug specifically for treating psoriatic arthritis.

Meanwhile, Centocor Inc.'s Remicade is producing "socko" results in psoriatic patients, according to Alice Gottlieb, professor of medicine and W.H. Conzen Chair in clinical pharmacology at the University of Medicine and Dentistry of New Jersey (UMDNJ) - Robert Wood Johnson Medical School.

Gottlieb, who started the Psoriasis Clinic Research Center at UMDNJ in 1995, conducted a small Phase II trial of Remicade in patients with moderate-to-severe psoriasis (covering at least five percent of the body surface). And the results, published in the June 9, 2001 issue of The Lancet, were fabulous. "The high degree of efficacy and rapid response seen in patients treated with Remicade far exceeded our expectations," she said. "It's clear that TNF-alpha plays a role in psoriasis."

In the 10-week trial, 33 patients received infusions of Remicade or placebo at baseline and at weeks two and six. The data showed that 82 percent of the patients receiving 5 mg/kg of the drug and 91 percent of patients receiving 10 mg/kg (vs 18 percent of the placebo group) achieved the primary endpoint -- a good, excellent or clear Physician's Global Assessment (PGA) rating -- at week 10. "Our primary endpoint ['good or better'] was too conservative, actually," Gottlieb said. "We should have picked 'excellent' [75-99 percent clearing]."

Psoriasis Drug Trials: Active Programs**

Company	Product Name	Product Type	Mode of Action	Indication (Mode Of Administration)	Clinical Status
Genentech and Xoma	Xanelim (efalizumab)	Humanized Mab targeted to T cells (anti CD11a)	Inhibits binding of T cells to other cell types; blocks receptor's binding to adhesion molecules on endothelial cells and inhibits T-cell activation	Moderate-to-severe psoriasis (SQ; initially IV)	Positive results demonstrated in 2 pivotal Phase III trials, which both hit primary endpoints in preliminary analysis 5/01; FDA requested additional study (manufacturing equivalence) 10/01 that will delay BLA filing
Genmab	HuMax-CD4	Fully human Mab; targets CD4 receptor on T cells	Interferes with inflammatory process	Psoriasis (IV)	Phase II results presented at American College Of Rheumatology conference on 11/12/01
Icos (partnered with Biogen)	IC747	Oral, small molecule LFA-1 antagonist; leukocyte function-associated antigen-1 is a cell adhesion molecule that promotes T cell migration and activation	Inhibits T cell activation and migration	Psoriasis (O)	Initiated Phase I trial 7/01
Idec Pharmaceuticals	IDEC-114	Primatized anti-B7-1 (CD80) Mab; binds to CD80 co-stimulatory molecule on antigen-presenting cells (B cells)	Causes either apoptosis or anergy; inhibits binding of APC cells and T cells, thus blocks second signal for T-cell activation	Moderate-to-severe psoriasis (IV)	Initiated Phase II trial 1/01
Idec Pharmaceuticals	IDEC-131	Humanized anti-CD154 (anti-CD40L) Mab (targets CD40 on T cells)	Targets CD154-CD40 pathway (regulates interaction between B and T cells)	Moderate-to-severe psoriasis (IV)	Initiated Phase II trial 1/01
Immunex	Enbrel (etanercept)	Dimeric fusion protein; recombinant soluble p75 tumor necrosis factor receptor (TNFr) linked to Fc portion of human IgG1 (TNF inhibitor)	Binds TNF, one of dominate cytokines that play important role in both normal immune function and cascade of reactions that cause inflammation	Psoriatic arthritis (+/- methotrexate) (IV)	Supplemental BLA (sBLA) filed in US 7/01; supplemental NDS (new drug submission) filed in Canada 7/01 (Will be 1st product ever reviewed by FDA to treat psoriatic arthritis)

* Mode of administration: ID (intradermal); IM (intramuscular); IV (intravenous); O (oral); SQ (subcutaneous); T (topical: applies to ointment, cream, gel)
** Excludes phototherapies.


Gottlieb also assessed disease severity using the Psoriasis Area Severity Index (PASI). According to this secondary endpoint, 82 percent of patients receiving the low dose of Remicade and 73 percent of those getting the high dose (vs 18 percent on placebo) achieved a 75 percent improvement (the "gold standard" in psoriasis trials). "This response rate is comparable to cyclosporine," according to Gottlieb.

Moreover, preliminary long-term data presented in June at the international psoriasis meeting in San Francisco demonstrated that Remicade may provide a sustained high level of efficacy for more than eight months in these patients -- and that it's quick acting, able to achieve a statistically significant response within two weeks. "With one IV infusion, we're already half way there. The overwhelming majority [of patients] cleared by week 6. At the end [of the study], they all do," Gottlieb explained. The full long-term analysis of this trial will be completed once all enrolled patients reach the 12-month point.

"Based on the results of this study, Centocor [ a Johnson & Johnson company] is pursuing it," Gottlieb continued. "We need to see Remicade's long-term efficacy and safety as a monotherapy."

While blocking the pro-inflammatory cytokine TNF-alpha looks like a sure hit, there's another approach to treating the root cause of psoriasis that also looks like a winner: Blocking T-cell activation in the first place. That's how both Xanelim and Amevive work (among others).

Xanelim, being developed by Genentech Inc. and Xoma Ltd., is a humanized monoclonal antibody (anti-CD11a) designed to bind with a subunit of the LFA-1 receptor on the surface of the T cell. In theory, blocking this receptor should prevent T-cell activation. And Biogen Inc.'s Amevive (LFA3TIP) is a fusion protein that binds the CD2 receptor on T cells, thus interfering with the LFA-3/CD2 co-stimulatory bridge. (Please refer to the diagram above for details.)

Just five months ago, in mid-June, it wasn't clear which product would take the upper hand. Presentations of Phase III data on both drugs at the international psoriasis meeting in San Francisco were encouraging. Thirty-nine percent of patients who received the low dose of Xanelim showed a 75 percent improvement in the PASI score after 12 weeks; 40 percent of patients receiving two intravenous courses of Amevive also showed a 75 percent or greater improvement in the PASI score two weeks after completion of a 12-week course of treatment.

But in early October, the FDA threw Xoma and Genentech a curve: The agency now requires the companies to conduct an additional pharmacokinetics study to confirm head-to-head equivalence of the material used for clinical trials and that which will be manufactured large-scale. This delay pushed Xanelim's time line back considerably: The companies now say they won't be filing a BLA until the summer of 2002.

That makes it a sure bet that Amevive will be first up for regulatory review: Biogen filed for approval in the U.S. and Europe in August 2001; both applications have been accepted.

Psoriasis Drug Trials: Active Programs**

Company	Product Name	Product Type	Mode of Action	Indication (Mode Of Administration)	Clinical Status
Isis Pharmaceuticals	ISIS 2302	Antisense inhibitor of ICAM-1 (intercellular adhesion molecule-1)	Interferes with activation of T cells and trafficking of those cells to sites of inflammation	To reduce thickness of plaques in mild-to-moderate psoriasis (T)	Phase II trial results not statistically significant 6/01; company is conducting 2nd trial at highest dose level used in 1st trial
Isis Pharmaceuticals	ISIS 104838	2nd generation antisense inhibitor of TNF-alpha	Inhibits TNF-alpha, a known pro-inflammatory cytokine	To reduce thickness of plaques in mild-to-moderate psoriasis (T)	Initiated Phase II trial 6/01
Ligand Pharmaceuticals	Targretin Capsules (bexarotene)	Synthetic retinoid analog	Selectively activates retinoid X receptors; reduces cell proliferation and hyperproliferation	Moderate-to-severe plaque psoriasis in patients with prior therapies (O)	Positive results in Phase II trial 3/01
MedImmune (collaboration with BioTransplant)	MEDI-507 (siplizumab)	Humanized Mab that binds to CD2 receptor on T cells and NK cells	Suppresses function of T and NK cells	Moderate-to-severe plaque psoriasis (IV and SQ)	Phase II trial ongoing; initiated Phase I PK/PD study 7/01
Protein Design Labs	Zenapax (dacluzimab)	Humanized Mab that binds to CD25 subunit (a.k.a., TAC or p55 alpha) of the high-affinity IL-2 receptor expressed on activated T cells	IL-2 receptor antagonist; inhibits IL-2 mediated activation of T cells	Moderate-to-severe psoriasis (to maintain remission following clearance by cyclosporine) (IV)	Phase II trial results expected 1Q:02
Seragen (Ligand Pharmaceuticals)	Ontak (denileukin diftitox)	IL-2 fusion protein; diphtheria toxin Fragment A-Fragment B genetically fused to human IL-2	Targets high affinity IL-2 receptors on activated T cells	Moderate-to-severe plaque psoriasis (IV)	Ligand reported positive results of pilot study 3/01 (Note: Seragen earlier took this product through Phase II trials, and reported positive results in 11/96)