How Biologic Agents Work

The introduction of biologics has dramatically changed how moderate-to-severe psoriasis can be treated. Biologic therapies are immunomodulators, meaning they can alter the functions of your immune system by either suppressing or enhancing certain built-in responses. This novel approach contrasts the one taken by traditional oral or systemic therapies that exert a general suppressing effect on the entire immune system. Consequently, the effect of wide-spread immune suppression prevents the use of conventional systemic agents at high doses due to their potentially severe negative side-effects. Theoretically, the more specific the target to be blocked is, the less interference there will be with other biological functions, making the drug safer and more effective.

Biologics are bioengineered from living things - human and/or animal proteins. The technique has been used for a long time in manufacturing drugs, such as insulin or interferon. Biologics agents used for psoriasis have been developed based on the current understanding of the abnormal immune system responses that contribute to the disease. As such, they are designed to 'target' specific parts of the immune system. The goal of biologic therapy is to diminish or immobilize certain immune responses that are triggering the psoriasis, while causing minimal adverse side-effects, without having to broadly weaken the immune system.

Each of the available biologic agents works differently and has distinct advantages and disadvantages. Consequently, your treating physician will assess which medication is best suited for you based on individual evaluation.

In rare cases, serious side-effects from treatment with biologics have been reported, even fatalities have been linked with use. If you have a pre-existing condition, such as tuberculosis (TB), heart disease, hepatitis B, or other serious illnesses, your risk for rare side-effects from treatment with biologics increases. Also suspected is their potential for increasing cancer risk through their effects on the body's immune system. Because these drugs have only been in existence for a relatively short period of time, long-term data on their safety is still being collected and will not be known for some time.

Biologic therapy is very costly and generally not a viable treatment option, unless private insurance coverage can be obtained or compassionate patient programs are offered. The biologics that are approved for use in treating adults with moderate-to-severe psoriasis can be divided into three broad categories: tumor necrosis factor-alpha (TNF-a) inhibitors, which interfere with the chemical messengers that are sent from T cells to skin cells, T cell modulators that target T cells directly and cytokine inhibitors that disrupt specific intercellular communications.

• Infliximab (Remicade®)
• Etanercept (Enbrel®)
• Adalimumab (Humira®)

• Alefacept (Amevive®)
• Efalizumab (Raptiva®)

• Ustekinumab (Stelara®)
• ABT-874 (under development)

Your body naturally produces the protein TNF-a to trigger white blood cells to fight infections. For most individuals, this immune response is temporary and causes inflammation in the affected area to rid the infection, then your body eliminates the TNF-a. However, in the case of autoimmune disorders, such as psoriasis, your body overproduces the TNF-a protein and causes more white blood cells to converge and build-up, leading to excessive inflammation at the affected sites. By blocking and inhibiting the effects of TNF- a, these drugs reduce inflammation and other signs and symptoms that are associated with psoriasis.

Recent regulatory information regarding the use of TNF blocking agents:

March 14, 2008 - Amgen Inc. and Wyeth Pharmaceuticals, makers of Enbrel®, added a boxed warning to its prescribing information to further strengthen and clarify information regarding the risk of infections, including tuberculosis (TB) in patients taking Enbrel®; namely the new recommendation involves screening for latent (hidden) tuberculosis infection before beginning treatment. The complete box warning: http://www.fda.gov/medwatch/safety/2008/AmgenDearHCPLetter.pdf

June 4, 2008 - The US FDA is investigating the possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. Reported cases involved individuals who were treated with TNF blockers for juvenile rheumatoid arthritis, Crohn's disease or other autoimmune diseases. The early communication: http://www.fda.gov/cder/drug/early_comm/TNF_blockers.htm

September 4, 2008 - The US FDA announced that the makers of TNF-a inhibitors must strengthen existing warning and educate prescribers about the risk of fungal infection in patients treated with these agents. The press release: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01879.html

T cell Modulators

In psoriasis, T cells in the immune system become over activated and migrate to psoriasis plaques, which in turn trigger inflammatory responses by the body. T cell modulators work directly on T cells by blocking one of its receptors. This specific targeted therapeutic approach interferes with T cell activation and disrupts the chain of events that causes the inflammatory reactions seen in psoriasis.

Cytokine Inhibitors

Additional insights into what causes psoriasis have led to the development of targeted biological therapies. Ustekinumab, along with another drug that is under development (ABT-874), specifically target cytokines, in particular interleukin-12 (IL-12) and interleukin-23 (IL-23). Interleukins are naturally occurring proteins that help to regulate the body’ immune responses, and they have been implicated as key contributors to inflammatory disorders, such as psoriasis. Cytokine inhibitors are a new class of drugs that prevent IL-12 and IL-23 from binding to receptors on T cells, thereby interfering with the chemical messaging pathways that trigger inflammation.

Recent regulatory information regarding the use of T cell modulators:

October 16, 2008 - The U.S. FDA announced labeling changes for efalizumab (Raptiva®) to include a "black box" warning, the FDA's sternest warning, about the risk of life-threatening infections. The new information will highlight the risk of opportunistic infections that include bacterial sepsis (an infection of the bloodstream that can affect organs throughout the body), viral meningitis (inflammation of the brain), invasive fungal disease, and progressive multifocal leukoencephalopathy (PML) (a rare brain infection). The press release:
http://www.fda.gov/bbs/topics/NEWS/2008/NEW01905.html

February 19, 2009 - The European Medicines Agency (EMEA) recommends suspension of the Marketing Authorization for efalizuman (Raptiva®). The press release:
http://www.emea.europa.eu/humandocs/Humans/EPAR/raptiva/raptiva.htm

February 19, 2009 - The U.S. FDA issues a public health advisory concerning three confirmed, and one possible report of progressive multifocal leukoencephalopathy (PML), a rare brain infection, in patients using efalizumab (Raptiva®). The press release:
http://www.fda.gov/cder/drug/advisory/efalizumab.htm

February 20, 2009 - Efalizumab (Raptiva®) has been removed from the Canadian market by the manufacturer (EMD Serono) due to safety concerns. Read the full Health Canada Advisory at:
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/raptiva_2_pc-cp-eng.pdf

April 8, 2009 - Genentech announces a phased voluntary withdrawal of efalizumab (Raptiva®) from the U.S. market. The company's decision is based on the association of Raptiva® with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease of the central nervous system. FDA statement:
http://www.fda.gov/bbs/topics/NEWS/2009/NEW01992.html