Hype and hope of psoriasis biologics examined.
Alongside the well-warranted excitement, however, psoriasis experts at the Ninth International Psoriasis Symposium also voiced their concerns about the costs of the new medications, their potential for adverse effects, and their ability to be combined with one another or with older drugs.
Currently, three of the new biologics have been approved by the Food and Drug Administration: etanercept (Enbrel), for psoriatic arthritis and rheumatoid arthritis (RA) in both adults and children; infliximab (Remicade), approved for Crohn's disease and RA; and most recently, alefacept (Amevive), which is the only one officially approved for psoriasis. More approvals are expected in the next few years.
The highly specific nature of the biologics is supposed to reduce the risk of toxicity and adverse effects associated with older, systemic immunosuppressants such as methotrexate and cyclosporine, Dr. Menno de Rie said at the meeting, sponsored by the Skin Disease Education Foundation. The SDEF and this newspaper are wholly owned subsidiaries of Elsevier.
Nevertheless, one should not be lulled into thinking that targeted biologics are trouble free. "TNF [tumor necrosis factor] inhibitors do have adverse effects," said Dr. de Rie, of the University of Amsterdam.
The major adverse events include immune reactions at or around the site or injection, autoimmune phenomena, and infections, including tuberculosis, granulomas, and lymphomas. The latter is particularly disturbing.
Though the absolute numbers are still small, Dr. de Rie noted that the etanercept clinical trials show a two- to threefold increase in lymphoma among patients on active treatment, compared with placebo. In the infliximab trials, the increase was six-to ninefold. For adalimumab, a drug that has not yet hit the psoriasis market, there was a fivefold increase.
In terms of treatment-related infections, Dr. de Rie explained that "TNF-[alpha] is crucial for killing bacteria. Macrophages produce TNF-[alpha], and it is also important for natural killer cells. If you block TNF-[alpha], it could have negative effects, which is a cause for concern."
On the basis of data submitted to the FDA, there is a treatment-associated tuberculosis rate of 82 per 170,000 treated patients for infliximab, and of 11 per 104,000 for etanercept. While the latter is consistent with general background incidence rates, the former is somewhat higher.
In general, the side-effect profiles of the biologics are quite acceptable, given the devastating day-to-day impact of severe psoriasis. But at the same time, it is important to keep potential side effects in mind and to monitor patients closely.
When it comes to rapidly clearing severe psoriasis, the biologics deliver "socko" efficacy, as Dr. Alice Gottlieb likes to say.
"The future holds far better things than we have now, but ... for those of use who actually use the targeted biologics, they really have an impact on real peoples' lives. We can clear psoriasis," said Dr. Gottlieb, chair of clinical pharmacology at Robert Wood Johnson Medical School, New Brunswick, N.J.
The clinical trials seem to bear out her assertion. In one phase II trial, 59% of patients with moderate to severe psoriasis treated with 50 mg etanercept twice weekly for 24 weeks had 75% reductions in Psoriasis Area and Severity Index (PASI) scores. The "PASI 75" has been the primary therapeutic end point in all of the major biologics' trials, and 49% of patients on the 50-mg dose reached this milestone within 12 weeks. At 25 mg, etanercept was not as effective, with only 34% of patients reaching PASI 75. In the placebo group, only 4% reached PASI 75 at 24 weeks.
Infliximab gives similar results. In the multicenter Study of Psoriasis Infliximab (Remicade) Induction Therapy (SPIRIT) trial, 88% of patients given 5 mg/kg at baseline and at weeks 2 and 6 reached the PASI 75 level of clearance within 10 weeks, compared with 5.9% in the placebo group and 72% in the group receiving 3 mg/kg.
How long do patients remain clear? On infliximab, at least, one-third of patients maintained a PASI 75 level of clearance for months beyond the 10-week study period without any additional therapy.
Alefacept, the only biologic approved for psoriasis, seems to work more gradually than some of its biologic classmates. Given as intravenous infusions or intramuscular injections in courses of 12 weekly doses, alefacept seldom produces the rapid clearance seen with infliximab. But the phase III data indicate that 33% of patients will achieve PASI 75 level clearance after a single 12-week course of intramuscular injections, and 43% will get there with two courses. The numbers were similar with the intravenous form of the drug.
Alefacept-treated patients often stay clear for as long as a year without additional therapy, said Dr. Mark Lebwohl, chairman of dermatology at Mount Sinai School of Medicine, New York. In a cohort of patients achieving PASI 75 with two courses of alefacept, the median duration of remission--defined as maintaining PASI reductions of 50% or better--was well over 1 year. "You can maintain very big reductions in PASI over very long periods with this drug," said Dr. Lebwohl.
The alefacept study showed that side effects were very rare. In a cohort of more than 1,200 patients receiving a first course, chills were the only adverse event that showed a greater incidence in the alefacept group than in the placebo group (6% vs. 1%). Other common side effects were headache, rhinitis, pharyngitis, and pruritus. There were no serious adverse events in any of the alefacept studies, and the incidence of the minor side effects does not seem to increase with repeated courses of therapy.
Dr. Gottlieb reported that 58% of patients on the highest dose of etanercept (5 mg/kg) had some type of noninfectious adverse event, compared with 49% in the placebo group. Upper respiratory infections, headache, and injection site reactions were the most common. For infliximab, the numbers were slightly higher: 79% of patients in the 5 mg/kg group had one or more adverse effects, compared with 63% in the placebo group.
For both drugs, these were primarily mild, well tolerated, and self-resolving. "There were only four reasonably serious adverse events [in the SPIRIT infliximab trial]: one squamous cell carcinoma, one case of cholecystitis/cholelithiasis, one case of diverticulitis, [and] one case of sepsis with pyelonephritis," said Dr. Gottlieb.
Some patients will develop antibodies to these drugs, resulting in injection-site inflammatory reactions. This tends to be inversely dose dependent, at least for infliximab. Patients treated with the higher dosage were less likely to develop antibodies and have these reactions.
Much of the concern about serious adverse events such as lymphoma and tuberculosis comes from trials in patients with rheumatoid arthritis. In aggregate, 35% of RA patients treated with etanercept had significant infections, including tuberculosis.
But Dr. Gottlieb stressed that RA is quite different from psoriasis: RA patients tend to be older, sicker, and generally more susceptible to a variety of ailments than are those with psoriasis. This is especially important to keep in mind when looking at the issue of treatment-associated lymphoma.
Taking all the etanercept trials together, including those of RA, results in an observed 11% incidence of lymphoma in the treatment group, compared with 5% in the control group. But Dr. Gottlieb stressed that RA confers a doubled risk of lymphoma, compared with the general population. Psoriasis does not confer a risk increase, so data from RA trials may not apply to psoriasis.
Demyelinization and optic neuritis can occur with etanercept, but the absolute incidence is still low, estimated at between 2 and 6 per 100,000 treated patients. In general it is not a worry unless a patient has multiple sclerosis, in which case etanercept is contraindicated.
Antinuclear antibody-positive lupus occurs with a greater frequency in etanercept-treated patients than in control patients, but this is generally well tolerated. "It is like drug-induced lupus or 'old-people' lupus, with bone aches, but no CNS or renal symptoms. It is pretty rare and not very intense," said Dr. Gottlieb.
As for congestive heart failure (CHF), the other major side-effect concern, she added that one of two large etanercept trials showed a trend toward worse cardiovascular outcomes in patients with preexisting conditions on active therapy. But there is no definitive evidence that the drug causes CHF. "Don't start etanercept in patients with existing CHF," she said. "It won't make it better, and could make it worse."
The biologics pose a direct challenge to the dermatologic profession, according to Dr. Alan Menter, chair of dermatology at Baylor University Medical Center, Dallas. "Are dermatologists ready to step up to the plate and be recognized as medical specialists alongside their rheumatologic and gastroenterologic colleagues? I certainly hope so," he said.
"We have done a reasonably good job of clearing patients in the short term. But clearly, we need better long-term control, just like in diabetes or asthma. Our treatments still fall short on long-term management," Dr. Menter said.
RELATED ARTICLE: Biologics: Progress at a Price?
The big problem for psoriasis biologics could be that all of that fastacting, highly targeted, low-risk impact comes at a price: The biologics are far more expensive than the old standby drugs for psoriasis.
All of the available agents will cost somebody between $10,000 and $30,000 per patient per year. Though they will likely reduce the burden of side effects, these new drugs are not necessarily more effective than mainstays like methotrexate, cyclosporine, and retinoids. Consequently, third-party payers haven't exactly been jumping over one another to get them in their formularies.
Economic considerations are already starting to drive how alefacept is used clinically, said Dr. Lebwohl at the symposium. Although the intramuscular form is therapeutically equivalent to the intravenous form, and most dermatologists are far more comfortable with intramuscular injection than with the intravenous infusion, some insurers want clinicians to go intravenous because it is cheaper. "You use roughly half the amount [of alefacept] with the IV, so it is cheaper. But there is no therapeutic reason to go one way or the other."
In this age of bang-for-the-buck reasoning, careful patient selection becomes essential. It is still too soon to determine which psoriasis patients are the best candidates for biologics.
"Psoriasis is a very heterogeneous disease, and we need to realize that we are treating very different kinds of people. Some patients do not respond at all, or only minimally," said Dr. de Rie.
"It would be nice if we had the information at the outset on which patients will respond to which agents. But right now we don't," he added. To date, none of these drugs has been tested outside of moderate to severe stable plaque psoriasis vulgaris. No one knows how well the drugs will perform against other forms of the disease.
BY ERIK GOLDMAN
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|Title Annotation:||Across Specialties|
|Publication:||Clinical Psychiatry News|
|Date:||Mar 1, 2004|
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