In the last few years biologic therapy has shown promise in the treatment of psoriasis. Many TNF blockers (adalimumab, etanercept, infliximab) are now indicated in severe cases that do not respond to other therapies.

On September 25, 2009 the U.S. FDA approved ustekinumab (Stelara, manufactured by Centocor Ortho Biotech Inc, a subsidiary of Johnson & Johnson) for the treatment of plaque psoriasis.

Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23,  and it is administered by subcutaneous route.

The UK’s National Institute for Health and Clinical Excellence issued a guidance that recommended ustekinumab use in the following clinical setting:

Severe psoriasis that has not responded to standard systemyc therapies including ciclosporin, methotrexate and PUVA(psoralen and long-wave ultraviolet radiation). Ustekinumab (Stelara), may also be considered in patients intolerant or have a contraindication to these treatments.

Ustekinumab (Stelara) mechanism of action in psoriasis

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The figure shows how ustekinumab (CNTO) blocks interleukin 12 (IL-12) and interleukin 23 (IL-23), these cytokines are involved in T-cell activation and promote immune response.

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Further reading

Efficacy and safety of ustekinumab in patients with psoriasis: PHOENIX 1 and PHOENIX 2 trials. National electronic Library for Medicines, NHS.

Review: Treatments for psoriasis and risk of malignancy. National electronic Library for Medicines, NHS.

In addition to the updated Boxed Warning, FDA is requiring several other changes to the prescribing information for TNF blockers to warn of and mitigate the risks associated with these drugs. These changes are based on additional safety reviews and include a(n):

Source.  FDA alert: Information for Healthcare Professionals: Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi).

This 2008 video was an alert on possible association between TNF blockers and the development of lymphomas. At that time, the FDA was in the middle of an ongoing safety review, and did not take any regulatory action.

Further reading

Follow-up to the June 4, 2008 Early Communication about the Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)

Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia)

He illustrates some examples of autoimmune diseases such as: multiple sclerosis, asthma, treatment of rheumatoid arthritis with etanercept, and others.

Inflammation and autoimmunity: new understandings and therapies.

By Andrew Chan, M.D., Ph.D. Vice President. Immunology and antibody engineering. Genentech

Rituximab

The UK’s National Institute for Health and Clinical Excellence (NICE) issued yesterday a guidance on the use of rituximab as first line treatment for chronic lymphocytic leukemia.

From the institute’s press release:

“The guidance recommends that rituximab should be considered as a possible first treatment for people with chronic lymphocytic leukemia who are able to take fludarabine in combination with cyclophosphamide.
Rituximab should only be used in combination with fludarabine and cyclophosphamide. Rituximab is not recommended in combination with any other cancer chemotherapy agents as a first treatment for chronic  lymphocytic leukaemia.”

Read full NICE guidance

The first approved TNF alpha blocker was etanercept (Enbrel) in May 1998. Then came infliximab (Remicade) in November 1999, while adalimumab (HUMIRA) was approved in December 2002.

TNF alpha, a key cytokine for the development of the inflammatory response

An excerpt from the excellent “ Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy” by D. Golan , A.H. Tashjian , E. J. Armstrong and A.  W Armstrong

Tumor necrosis factor-α (TNF-α) is a cytokine central to many aspects of the inflammatory response. Macrophages, mast cells, and activated T_H cells (especially T_H1 cells) secrete TNF-α. TNF-α stimulates macrophages to produce cytotoxic metabolites, thereby increasing phagocytic killing activity.

TNF-α has been implicated in numerous autoimmune diseases. Rheumatoid arthritis, psoriasis, and Crohn’s disease are three disorders in which inhibition of TNF-α has demonstrated therapeutic efficacy. Rheumatoid arthritis illustrates the central role of TNF-α in the pathophysiology of autoimmune diseases. Although the initial stimulus for joint inflammation is still debated, it is thought that macrophages in a diseased joint secrete TNF-α, which activates endothelial cells, other monocytes, and synovial fibroblasts. Activated endothelial cells up-regulate adhesion molecule expression, resulting in recruitment of inflammatory cells to the joint. Monocyte activation has a positive feedback effect on T-cell and synovial fibroblast activation. Activated synovial fibroblasts secrete interleukins, which recruit additional inflammatory cells. With time, the synovium hypertrophies and forms a pannus that leads to destruction of bone and cartilage in the joint, causing the characteristic deformity and pain of rheumatoid arthritis.

Anti TNF agents molecular characteristics

Etanercept (Enbrel): Soluble TNF receptor fusion protein. As you can see in the image, etanercept molecule consists of 2 extracellular domains of human soluble TNF receptor p75 that binds to TNF and a Fc fragment of human IgG that serves as a stabilizer.

Infliximab (Remicade): chimeric human-mouse anti-TNF alpha  . This drug is 25% murinal (mouse) derived and 75% human. The binding epitope for TNF is of murine origin while the IgG fragment is of human origin.

Adalimumab (HUMIRA- Human Monoclonal Antibody in Rheumatoid Arthritis-): fully human anti-tumor necrosis factor alpha monoclonal antibody produced by phage-display technology.

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The TNF alpha inhibitors share therapeutic uses

This chart shows the latest (May 2009) information on the FDA approved uses of  three selected TNF alpha blockers.

Source: FDA.gov

Newer TNF alpha blockers

Certolizumab pegol (Cimzia): pegylated humanized Fab’ fragment that binds tumor necrosis factor alpha. FDA approved it in April 2008  for the treatment of Crohn’s disease.

Golimumab (Simponi). Approved in April 2009 for: moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.

TNF blockers adverse effects: risks of tuberculosis reactivation and invasive fungal infections

TNF inhibitors have a number of known side effects, mainly related to their immunosuppressant activity.

Since TNF is a important cytokine when fighting against tuberculosis, these drugs can reactivate a latent tuberculosis infection.

The official FDA presentation below discusses adverse effects associated with TNF blockers: infections (tuberculosis, histoplasmosis and other invasive fungal infections) , congestive heart failure, neurologic events, malignancies and autoimmunity.

Download PPT file

This is a FDA patient safety alert video, warning about the risk of serious fungal infections in patients receiving TNF alpha inhibitors.

Also, the UK’s National Institute for Health and Clinical Excellence (NICE) issued in February 2009 an update of the rheumatoid arthritis clinical guideline.

The following slideshow is a clear and accurate introduction on the topic:

(ignore the first slide error message and move to the second)

Download PPT file: “Antibodies as drugs”

Cancer treatment

The following image summarizes the latest drug developments on targeted therapy against cancer. The diagram shows the mechanism of action of several drugs, some of them are monoclonal antibodies while others are small molecules.

From the excellent article: Targeted Treatments: A New generation of Cancer Treatments. American Family Physician, 2008.

FDA-approved monoclonal antibodies for cancer treatment

Source: Mayo Clinic

Therapeutic antibodies in rheumatology

The monoclonal revolution has touched musculoskeletal diseases too. Infliximab and adalimumab have been approved by the FDA for the treatment of psoriasis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis and ulcerative colitis. Etanercept is a fusion protein produced through expression of recombinant DNA with very similar indications. Recently (August 2009), the FDA added a boxed warning on the increased risk of lymphoma in TNF blockers users.

These three drugs share their mechanism of action: they reduce or even neutralize the effect of TNF (Tissue Necrosis Factor), they are known as TNF inhibitors. The image below shows the key role TNF plays in the pathogenesis of rheumatoid arthritis.

Source:  Clinical Therapeutics: Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis. NEJM, 2006.

Some videos on the future of mAbs

This video shows how monoclonal antibodies can be used to the entry of influenza virus into the host cell.

From bench to bedside, Ron Levy, MD, professor of Medicine at Stanford discusses past and future of mAbs for the treatment of cancer. Wendy Harpham, a participant in the early clinical trials of Rituxan, provides a patient’s perspective.