Key data from the 9th International Psoriasis Symposium: June 23, 2003
Broadband UVB Speeds Benefit of Alefacept
Data presented by John Koo, MD, Psoriasis Treatment Center, University of California, San Francisco Medical Center, San Francisco, California
Broadband (BB) ultraviolet B (UVB) light substantially accelerates response to alefacept, according to a randomized, controlled trial. The median PASI reduction after 24 weeks of follow-up in this study was 50% for alefacept monotherapy but more than 70% when alefacept was combined with BB UVB. Although these differences are likely to narrow with additional follow-up based on previous experience with alefacept monotherapy, the difference in the early response was marked.
Alefacept Alone Versus Alefacept Plus BB UVB
Thirty patients with chronic psoriasis entered the trial. The median baseline PASI score was 8. The mean body surface involvement was 10%. Patients were randomized to alefacept alone, alefacept plus BB UVB for 6 weeks, or alefacept plus BB UVB for 12 weeks. Alefacept injections were administered on a once-weekly schedule over 12 weeks. Those on 6 weeks of phototherapy received a mean 3318 mjoules/cm2 versus 10,229 mjoules/cm2 in those treated for 12 weeks.
PASI >50% in Majority of Patients by 5 Weeks
In the combination treatment groups, 37% of patients had already achieved a 50% or greater PASI reduction by 4 weeks. The proportion climbed to more than 50% by 5 weeks. For patients who achieved a 50% or greater PASI reduction 2 weeks after the last dose, the vast majority maintained this benefit throughout this 3-month period.
The combination of alefacept and BB UVB was well tolerated with no reports of serious adverse events, including opportunistic infections. The trial data indicate that this combination is safe, effective, and appears to accelerate clinical benefits relative to alefacept alone.
Coding: The Emerging Fight for Biologics
Data presented by David M. Pariser, MD, Professor, Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia
With the introduction of new therapies for psoriasis has come expected payer resistance to reimbursement. Many of these agents are appropriate for first-line therapy in individuals with moderate to severe psoriasis, but some payers are expected to demand pre-approval for their use. A soon-to-be-released consensus statement by the American Academy of Dermatologists (AAD) stating that patients do not have to fail other systemic therapies to be considered candidates for use of biologics is likely to aid physicians in accessing the best new therapies for their patients.
Publication of the AAD consensus statement in the Journal of the AAD, expected in July, will strengthen the basis on which to make claims. Manufacturers of biologics and the National Psoriasis Foundation (NPF) may serve as additional resources if third party payers deny access. Many manufacturers cooperate in providing data that can be submitted to medical directors to support the superiority of these newer drugs. They may also help enroll patients in financial assistance programs when a claim denial cannot be reversed. The NPF is working hard nationally to support access to the most effective therapies.
Reaching the Responsible Party
It is important to recognize that many payers are responsive to individual needs when contacted directly by physicians. To advocate for patients, it is helpful to reach the individual who is responsible for changing policy, often the medical director of the insurance plan.
Biologics require a shift in practice for many physicians inexperienced with ordering and billing for intravenous medications, but with slight modification in office practices and proper coding for these services this transition can easily be made. Resources such as the AAD, NPF, and drug manufacturers themselves can be powerful resources to help physicians help patients.
Anti-Sense Therapies to Treat Psoriasis: The Genomic Evolution
Data presented by Gerald Krueger, MD, Professor, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
Efforts to move antisense therapies forward in psoriasis have already led to the first clinical trial. Antisense impairs messenger RNA (mRNA) from delivering its signal from DNA to produce biologically active proteins. In psoriasis, the goal is to inhibit the proteins that underlie overexpression of inflammatory cytokines, such as interferon gamma or tissue necrosis factor (TNF) alpha.
The clinical trial was performed with 2302-CS14, a small interfering RNA (siRNA), that, when applied topically to skin, enters target cells to block mRNA translation of intracellular adhesion molecule (ICAM-1). In human skin models on nude mice, 2302-CS14 was highly effective for blocking the inflammatory response induced by TNF alpha. Although it was ineffective in 18 psoriatics participating in a pilot study, it was safe, and investigators remain convinced of its potential based on the promise of experimental models.
Biologics: Efficacy in Refractory Psoriatics
Data presented in a poster by Enno Christophers, MD, Klinikum an der Universitдt Kiel, Kiel, Germany
In patients who are refractory or contraindicated for traditional therapies, the efficacy of alefacept remains highly significant relative to placebo, according to a subgroup analysis from the phase III trials. In these two trials, which led to Food and Drug Administration approval of alefacept in January, 2003, there was highly significant reductions in PASI scores and improvements in quality of life overall, but the new subgroup studies demonstrate that improvements in PASI scores remained highly significant even in those refractory or unsuitable to methotrexate, cyclosporine, or other potent anti-psoriasis drugs.
In the two phase III trials, one conducted with intravenous (IV) administration and the other with intramuscular (IM) administration, over 1,000 patients were randomized to alefacept or placebo. Of these, 706 were refractory (no change or worse after treatment) or contraindicated to traditional therapies. Approximately 4% were refractory to cyclosporine, 10% to methotrexate, 10% to retinoids, 11% to PUVA, and 20% to UVB. When combined with patients contraindicated to these medications, usually because of side effects, the proportion of patients who were not candidates for these therapies rose to 32%, 30%, 36%, 12% and 20%, respectively. Two thirds of patients were contraindicated for at least one therapy.
Response Rates in Refractory Patients
In the subgroup of patients who were refractory to or had contraindications to conventional systemic therapies, up to 33% achieved a PASI score reduction of 75% or greater on alefacept, compared to maximum placebo response of 11%. In those who were refractory or had contraindications to three or more conventional medications, a 75% or greater PASI reduction was achieved in 26% of alefacept patients versus 7% of the placebo group
Consistent with phase III benefits overall, the subgroup analysis demonstrates that alefacept is effective even in patients who have limited therapeutic options based on lack of prior response, toxicity, or comorbidities. The data are reassuring in regard to the role of biologics in meaningfully increasing opportunities for disease control.
National Survey Documents Burden of Psoriasis
Data presented by Gail M. Zimmerman, President and CEO, National Psoriasis Foundation, Portland, Oregon
One of the most comprehensive surveys of psoriasis ever undertaken in the United States has confirmed that moderate to severe psoriasis exerts a significant adverse influence on many activities of daily life. The survey was conducted through telephone interviews with 27,000 randomly selected individuals. Sponsored by the National Psoriasis Foundation (NPF), the survey produced an estimated prevalence of psoriasis in U.S. adults of 2.1%, or approximately 4.5 million individuals. Of these, approximately one third have moderate to severe psoriasis, defined as lesions covering at least 3% of body surface area.
In a detailed questionnaire administered to 1798 individuals with moderate to severe psoriasis, of whom 571 were members of the NPF, 75% identified psoriasis as a moderate to large problem in their life. Approximately one quarter reported that their disease had caused them to alter or stop normal daily activities, and 40% reported that they made clothing choices specifically to hide their condition.
78% of Respondents Avoid Traditional Systemic Therapy
The need for safer and more effective therapies was underscored by the finding that 33% of patients are very unsatisfied with their current therapies. Complete satisfaction was uncommon, and 78% reported that they avoided the more aggressive therapies currently available because of concern about side effects or lack of efficacy. These results conflicted with a separate survey of dermatologists who estimated far greater patient satisfaction with currently available treatments. However, dermatologists did acknowledge that psoriasis is a serious problem. This empathy may explain why patients expressed greater satisfaction with their physician than the available therapies.
The 4.5 million estimated psoriatics is lower than the previous NPF estimate of 6 million, but the estimated 1 million with psoriatic arthritis is higher. The finding that dermatologists see about twice as many psoriatics as rheumatologists was cited as a potential source of inadequate diagnosis of joint symptoms.
IL-12: Clinical Data and Theoretical Mechanism
Data presented by Kevin D. Cooper, MD, Director, Skin Research Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio
The results of an initial phase I trial with an anti-interleukin 12 (IL-12) monoclonal antibody may have serendipitously generated new insight into the heterogeneity of response to systemic therapies. When high responders were compared to low responders, baseline cytokine levels in psoriatic lesions were found to differ significantly. In particular, those with high levels of tissue necrosis factor (TNF) alpha, IL-10, or monocyte chemoattractant protein (MCP-1) achieved very large and durable reductions in PASI scores on the anti-IL-12 therapy when compared to those with lower levels of these cytokines.
The studies with an anti-IL-12 monoclonal antibody, conducted on a phase I protocol in 18 patients, were based on experimental evidence that this cytokine has an important role in upregulating release of interferon gamma, another cytokine strongly implicated in the pathogenesis of psoriasis. This mechanism of action was substantiated by marked reductions in interferon gamma levels observed in in vitro trials with this agent, but interpatient differences in response by baseline cytokine abnormalities could be important for better targeting of biologics. This premise is being actively pursued.