Simponi is a recently approved human monoclonal antibody for the treatment of rheumatic diseases. Its indications include:

• Moderately to severely active Rheumatoid Arthritis (RA) in adults, in combination with methotrexate.
• Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate.
• Active Ankylosing Spondylitis in adults (AS).

According to the FDA, histoplasmosis and other invasive fungal infections are not consistently recognized in patients under other TNF-α blockers such as Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). This has resulted in delays in appropriate antifungal treatment, which in some cases has lead to death. The agency also added  a Boxed Warning to this group of medications,  alerting about an increased risk of  lymphoma.

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

Source

MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Simponi (golimumab)

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

• Neuropathic pain.
• Epilepsy in patients who have partial seizures that cannot be controlled with their current treatment.
• Generalized anxiety disorder.

In June 21, 2007; the US Food and Drug Administration approved Lyrica as the first drug for the treatment of fibromyalgia, a year later duloxetine (Cymbalta) became the second.

On 23 April 2009, the European Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of an extension of indication that would include fibromyalgia treatment as a new indication for Lyrica.

Pfizer requested a re-examination of the opinion. After considering the grounds for this request,
the CHMP re-examined the initial opinion, and confirmed the refusal of the marketing authorisation
on 23 July 2009.

The CHMP was concerned that the benefits of Lyrica in fibromyalgia had not been shown in either the short or the long term. There were no consistent or relevant reductions in pain or other symptoms in the short-term studies, and the maintenance of Lyrica’s effect was not shown in the longer study. The Committee was also concerned that the safety and effectiveness of Lyrica had not been shown in patients from the EU.

Bottom line:

EMEA didn’t approve an extension of indication for Lyrica to include the treatment of fibromyalgia.

Other approved indications (neuropathic pain, generalized anxiety disorder, epilepsy) for Lyrica remain with no changes.

Andrew Moore, from the Nuffield Department of Anaesthetics at the University of Oxford, discusses the available evidence on the use of rubefacients for acute and chronic pain.

Listen Podcast

Further reading on rubefacients

Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ 2004; 328(7446):995.

European CHMP issues positive opinion on Qutenza® (capsaicin) patch for peripheral neuropathic pain in non-diabetic patients. National electronic Library for Medicines.

Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials. National electronic Library for Medicines.

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.

The authors used a self-control case series analysis to study nearly 400,000 women from the UK General Practice Research Database. They included women prescribed oral alendronate or risedronate in a period of 2 years (between December 2006 and December 2008).

“We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.”

Quoting the conclusions of another related paper; Relation of Bisphosphonate Therapies and Risk of Developing Atrial Fibrillation, American Journal of Cardiology:

“In conclusion, in a long-term study of >47,000 patients, we were unable to find an association between bisphosphonate therapy and AF. However, patients who received bisphosphonates were older and had more cardiovascular disease that we suspect accounts for the increased arrhythmia risk reported in other trials.”

As you can read in a previous post, FDA issued an update some months ago on the topic.

Pharmacist Matt Robinson at his excellent “Prescribing advice for GP’s” commented the most relevant points of the guidance:

This guideline recommends that treatment is started early during active disease in order to minimise damage to joints.

A combination of disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate and one other DMARD are recommended to be started within 3 months of the onset of persistent symptoms. In addition, a short course of a steroid is recommended to provide symptomatic relief during a flare.

The guideline also details the place in therapy for analgesics (including non-steroidal anti-inflammatory drugs), long-term steroids and biological agents.

Finally, the guideline recommends that people with rheumatoid arthritis are offered access to a multi-disciplinary team (MDT) including:

• specialist occupational therapy if they have trouble with daily activities or hand function
• specialist physiotherapy to improve general fitness, flexibility and strength
• a podiatrist if they have particular foot problems

Action: Primary care clinicians should be aware of these new guidelines. Clinicians who see patients with rheumatoid arthritis will find this information useful.

Full PDF can be downloaded here: Rheumatoid arthritis. NICE guideline

adalimumab (Humira)  is  accepted  for  restricted  use  in  NHS  Scotland,  in  combination  with methotrexate, for the treatment of active polyarticular juvenile idiopathic arthritis in adolescents aged 13-17  years  who  have  an  inadequate  response  to  one  or more  disease-modifying  anti-rheumatic drugs (DMARDs).  Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

It should be  restricted  to use within specialist rheumatology services (including  those working within the network  for paediatric rheumatology).   Adalimumab is one of  three TNF-antagonists  listed  in  the British National Formulary  for Children as drugs  that  suppress  the  rheumatic disease process, and one of two of those drugs licensed for active polyarticular juvenile idiopathic arthritis.

The Scottish Medicines Consortium  has  previously  accepted  this  product  for  restricted  use  for  this indication in adults.