MANAGED CARE June 2003. ©MediMedia USA
New therapies that manipulate the immune system offer hope to patients and pose challenges to managed care.
Psoriasis treatment is undergoing a revolutionary change. In the past, serendipity played a major role in the development of new therapies. Recently this has all changed. Rapid developments in the field of proteinomics and genetic modification of organisms, fueled by the fear of the cumulative effects of even minor toxicities, (a dominant consideration when faced with treating a disease for 40 to 50 years), has led to the creation of effective and safer biologic drugs.
This disease affects nearly 2 percent of the general population in the U.S. Although several chromosomes appear to have genetic links, it appears that there is a strong genetic link with three loci in particular: loci 6q, 17q, and 4 q. Although it is primarily a skin disorder, between 10 and 30 percent of people with psoriasis express the joint form of the disease that is termed psoriatic arthritis. Although not everyone with the genetic tendency to develop the disease expresses it, there are known triggers such as stress, medications (lithium, antimalarials, Indocin, Inderal and quinidine), infections and injuries to the skin. The histologic hallmarks of psoriasis include hyperproliferation, inflammatory cell infiltrates, vascular proliferation and abnormal keratinocyte differentiation.
Psoriasis is characterized by a dramatically reduced cell cycle where keratinocyte transit time is decreased from 27 to 4 days. This rapid cell proliferation causes the typical plaques of skin to build up.
Until recently, common teaching emphasized that the hallmark of psoriasis, keratinocyte hyperproliferation and abnormal differentiation of the epidermis, was the primary cause of psoriasis, and that the inflammatory component was only a response. The thinking has changed as recent discoveries have focused on the immune system as the primary trigger for the epidermal reaction. In fact, it is now clear that psoriasis is the most common T-cell mediated inflammatory disorder in man.
There are five different types of skin psoriasis. Usually people suffer from only one type at a time. Occasionally two types will be present, or conversion from one type to another may occur. The five types are:
- Plaque, characterized by large, well defined areas of red raised skin, typically affecting elbows, knees, scalp, trunk and nails.
- Guttate, individual drop-sized areas of red lesions.
- Inverse, characterized by red, inflamed, dry, smooth areas, often in creases and folds of the skin, that lack scaling.
- Erythrodermic, widespread areas of fiery red skin, occurring periodically.
- Pustular, characterized by hand and palm involvement of reddened skin but may become generalized and widespread.
Previously there were only suppressive therapies for psoriasis. Traditional therapies revolve around the notion of "coat and cook," meaning that most people with psoriasis are treated with either topical agents or UV radiation.
Traditional topical agents
There are numerous topical agents including emollients, salicylic acid, coal tar, Dithranol, steroids, vitamin D analogues and tazarotene.
Other popular treatments include phototherapy with ultraviolet B radiation, either alone or in combination with oral or topical administration of psoralens.
Systemic therapy includes methotrexate, acitretin, cyclosporin and hydroxyurea, all of which are associated with numerous side effects and contraindications.
All of the above traditional approaches are now subject to what may be termed a disruptive innovation, namely the use of biologic agents. The revolutionary increase in the knowledge of the immunologic pathways involved in psoriasis along with the ability to manipulate the genomic processes within Chinese hamster ovary (CHO) cells to create designer proteins has led to exciting and novel approaches to this age-old disease.
The new agents target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of psoriasis. Interestingly enough, it was through serendipity again that the role of the T-lymphocyte was discovered to be a key element of psoriasis. The use of DAB389IL-2, a diphtheria-IL-2 fusion protein with an affinity for just the IL-2 receptor present only on the T-lymphocyte, led to the clinical resolution of coexistent psoriasis after being prescribed for an unrelated disease. Although one study has suggested that DAB389IL2 may be too toxic for long-term use in psoriasis, it led investigators to other pathways to modify cellular immune responses. In general, protein-based therapeutics fall into three classes: antibodies, recombinant cytokines and fusion proteins.
The first FDA-approved biologic drug for psoriasis, alefacept (Amevive, from Biogen), is a dimeric fusion protein produced by recombinant DNA technology in a CHO cell. Alefacept interferes with lymphocyte activation by binding to the lymphocyte antigen CD2 and interfering with LFA-3/CD2 interaction. It is administered weekly, either 7.5 mg intravenously or 15 mg intramuscularly.
Although not entirely understood, TNF-alpha plays a significant role in the development of psoriasis. The exact trigger is not known, but it is known that TNF-alpha is a proinflammatory cytokine produced by numerous cells in the skin (including activated T cells, keratinocytes, macrophages and Langerhans cells). TNF-alpha can induce the production of several interleukines, including IL-1, IL-6 and IL-8, as well as other mediators. IL-1 can then induce further synthesis of cytokines, propagating the inflammatory process. IL-6 is known to be a T and B cell growth factor and is involved in the proliferation of keratinocytes. IL-8 also induces keratinocyte proliferation and activates T cells and neutrophils.
TNF-alpha also stimulates the production of intracellular adhesion molecule-1 (ICAM-1) and may increase the production of other adhesion molecules which play a role in plaque formation. In addition, TNF-alpha can induce the expression of vascular endothelial growth factor (VEGF) that in turn can stimulate angiogenesis, leading to the characteristic deep red color of psoriasis.
Investigating TNF inhibitors
Another approach to psoriasis is inhibiting the TNF cascade. Although none of the three current TNF inhibitors has been approved for the nonarthritic manifestations of psoriasis, they are all undergoing studies for this indication.
- Etanercept (Enbrel), a TNF-receptor-Ig fusion protein from Amgen;
- Infliximab (Remicaid) a chimeric anti-TNF-alpha monoclonal antibody from Centocor; and
- Aalimumab (Humira) a fully human anti-TNF monoclonal antibody from Abbott.
Of these, only Enbrel has been approved by the FDA for use in psoriatic arthritis. The others are in clinical trials for this condition, and all of these drugs are being evaluated for their effects in psoriasis. In addition, efalizumab (Raptiva, from Genentech/Xoma), a monoclonal antibody against a T-cell receptor (CD11a), is being considered by the FDA for approval for psoriasis and is in phase II trials for psoriatic arthritis.
Goal: minimum 75% reduction
Finally, studies are under way with antisense oligonucleotides to ICAM-1. These substances target intracellular pathways that cannot be reached with protein-based approaches.
When considering the use of biologic drugs in the treatment of psoriasis, it is important to understand the usual study endpoint, the Psoriasis Area and Severity Index (PASI). The published studies typically involve patients with psoriasis involving at least 10 percent of their body surface area. They then evaluate whether there was a 50-percent improvement (PASI-50), a 75-percent improvement (PASI-75), "almost clear" or "clear" response. A reduction of 75 percent or more is considered ideal.
The pivotal phase 3 trial for Amevive (Journal of the American Academy of Dermatology Dec 2002, vol 47, number 6), cites a net response (after subtracting the placebo response rate) of 10 percent for a PASI-75 two weeks after the completion of one course of therapy and a total 21 percent "clear" or "almost clear" response rate two weeks after two courses of therapy. There was no placebo arm for the two courses of Amevive but the "net" after subtracting the placebo effect is probably in the teens.
Better, but more costly
The cost of the biologic drugs will be considerably higher than current treatments. According to the initial mailings to MCOs from the manufacturer, Amevive will cost between $8,400 (IV) and $11,940 (IM) (AWP) per 12-week course, depending on the method of administration. It is anticipated that a course will provide about seven months of response leading to a first year cost of up to $24,000 for just the drug. In addition, there are mandatory lab tests and administration and provider fees.
The TNF category typically runs in the same range of $16,000–$20,000 and even more per year for the approved indications. For psoriasis, the total yearly costs may be lower because the TNF inhibitors appear to put psoriasis into remission. This results in a cost of nearly $84,000 for each person who receives a PASI-75 in the first course.
Will there be a significant demand for the biologic drugs? The size of the manufacturing plant may give an indication. The latest addition to the Biogen plant in Raleigh includes two 17,000-liter bioreactors.
How will managed care fit these expensive biologic treatments for psoriasis into medical necessity benefit language? Are the study results large enough for managed care plans to consider these drugs for coverage? Will they replace the existing therapies and thus save other costs? Do these treatments actually improve health, or are they only improving a cosmetic condition? Since the existing FDA-approved drug (as well as the other anticipated biologics) is approved for moderate to severe psoriasis, how will an MCO determine how severe the psoriasis is? Will MCOs demand full body photos to evaluate the extent of disease? If payment is denied, how will the appeal process resolve the issues? How will the employers view this new expense? Will they demand a new category of benefits with higher patient financial responsibility? Should MCOs set the expectation that patients should demonstrate a response prior to paying for the drug, thus decreasing the cost per improved patient? Should these drugs be paid for under the medical or pharmacy benefit?
Amevive will be administered in a physician's office, so how will physician reimbursement be structured? Will MCOs pay the expected markup on the drug to the physicians or will they insist that the drug be distributed from a specialty pharmacy with direct billing to the MCO by the pharmacy? Will MCOs attempt to push patients toward a self-administered approach or deny the IM form and approve the less expensive IV form? Once other drugs are approved by the FDA, will MCOs set a "preferred agent" in order to create rebate and positioning opportunities?
The future is clear: Psoriasis is rapidly becoming a "biologic" disease, as did rheumatoid arthritis, multiple sclerosis, and hepatitis C. The ability to manipulate the immune system selectively to clear psoriasis is nearby.
Although the approved drug is lacking in the number of patients demonstrating a PASI-75 or more, it clearly shows that medicine is close to mending the heartbreak of psoriasis! The developments are exciting, but also challenging to MCOs and society.