Actemra

Report by Linda Kvastad

Target and molecular mechanism

Mechanism of disease
Rheumatoid arthritis (Ra) affects about 1% of the worlds adults. The disease usually starts when the patient is between 20 to 40 years old. Ra is an auto-immune disease, which means that the bodys immune system starts to attack the bodys own tissue. In Ra patients white blood cells (leukocytes), that are a part of the immune response, infiltrate the joint synovium which is the space between bones in a joint. Among the infiltrating leukocytes there are autoimmune CD4 T cells, which recognize the bodys own tissue. Upon recognition the autoimmune CD4 T cells will become activated with help from dendritic cells. When activated the CD4 T cells will in turn activate B cells and macrophages. The macrophages that accumulate in the synovium will secrete pro-inflammatory cytokines, which are small signaling molecules which act as communication between cells of the immune system. These cytokines e.g. TNF-, IL-6, IL-1 and IL-7 will attract more leukocytes to the synovium. All this will lead to and sustain an inflammation of the joint, which will eventually cause tissue erosion and destruction of the cartilage of the joint [1].

Drug target
Ra is caused by an overactive immune response at certain sites such as the joint synovium. This will result in too much cytokines at the site e.g. IL-6 and TNF. There will also be too much B and T cell activity at the site. All these will cause Ra symptoms and there are different drugs which focus on these targets, see Figure 1. Actemra is one of these and its target is the IL-6 receptor [2].

Figure 1 Different drug targets for Ra and the corresponding drugs [2].

Mechanism of action
In the body the cytokine IL-6 binds to its receptor, the IL-6 receptor, these then associates with glycoprotein 130 (gp130). This leads to downstream signaling which in turn activate certain genes. For example, in precursor B cells IL-6 signaling is involved in their differentiation into antibody secreting plasma cells. Actemra has the ability to bind to both membrane bound and soluble IL-6 receptors, and thus blocking the IL-6 signaling pathway, see Figure 2 [3].

Figure 2 Actemra binds to both membrane bound and soluble IL-6 receptors and block the IL-6 signaling pathway into the cell [3].

Actemra compared to other Rheumatoid arthritis drugs

When deciding on a treatment for Ra there is a lot of drugs out there to choose between. A common one is Methotrexate, which is a small organic molecule. It can be taken orally or subcutaneously to avoid adverse effect in the gastrointestinal tract and it is administered weekly. It is cheaper than biopharmaceuticals and works to improve about 50% of the patients; it has also proven to work well with biopharmaceuticals to improve their efficacy. Rituxan is another drug for Ra treatment; it is a chimeric monoclonal antibody against CD20, which means it depletes the body of B-cells. It is taken intravenously with two infusions two weeks apart and the effect will last up to six months. As Actemra, Rituxan is administered at a hospital, and both have a risk at eliciting an immunogenic response, since they are not 100% human. Humira and Enbrel are both anti-TNF drugs, they can both be administered at home [4]. Personally I think that the best way to treat Ra is to investigate each patient individually. For example, maybe one patient has much more elevated levels of IL-6 than TNF; in that case Actemra would be better than the anti-TNF drugs.

Drug substance and formulation

Production
Actemra is a humanized monoclonal antibody at 148 kDa. It is manufactured in a fed-batch system using mammalian cells. To make a humanized antibody the DNA form the complementary determining regions (CDRs) from an animal (e.g. mouse) antibody are grafted into DNA for a human antibody, in the case of Actemra they were grafted to an IgG1 antibody [3]. There are different subclasses of IgG antibodies in the human body, the IgG1 class is the most abundant and versatile of the human IgGs. Compared to the other IgGs it is intermediate in its capacity to activate

complement (proteins involved in inflammatory response), its susceptibility to proteolysis and its movement flexibility [1]. By making a humanized antibody, instead of a chimeric one, the risk that the patient will have an antigenic response is reduced, since the humanized antibody has a lower probability to be recognized as a pathogen by the immune system [3].

Figure 3 Actemra is a humanized monoclonal antibody. Antibody constructed from human genome (green) and mouse genome (purple). The CDRs are showed as thin purple bands on the Actemra antibody [3].

Administration
Treatment with Actemra is administered intravenous at hospital under observation from medical staff, because there is a small risk of anaphylactic shock. The administration of the drug takes about one hour, and the patient will have to return to the hospital to get a new infusion on a monthly basis. Normally the patient will start off with a lower dose at 4mg/kg to observe potential side effects and increase dosage later on, during several studies on Actemra it has been shown that the most effective dose is around 8mg/kg [4]. Actemra is a biologic Disease Modifying Anti-Rheumatic Drug (DMARD) and today this is not commonly used as a first line therapy, which is due to the biological DMARDs side effect profile and their costs. Instead the first line treatment is often non-biological DMARDs. Actemra is used today by adult patients who have moderately to severe active Ra, and who has failed to respond to anti-TNF treatment or non-biological DMARDs [5].

Small organic molecule or biopharmaceutical

Non-biological DMARDs are small organic molecules compared to the much larger biological DMARDs e.g. the protein drug Actemra. There are a lot of differences between them, as shown in Table 1 [6]. Small organic molecule Intra and extra cellular target Can reach entire body Oral administration possible Carcinogenic substances possible Development cost high Production cost low 6% success rate in phase I-III Immune reactions rare Biopharmaceuticals Extra cellular targets Limited distribution Intravenous administration Not carcinogenic Development cost low Production cost high 25% success rate in phase I-III Immunogenic effects possible

Table 1 Differences between non-biological DMARDs (small organic molecules) and biological DMARDs (Biopharmaceuticals).

Risk and benefit analysis

Adverse effects
As always when taking a medicinal drug, the benefits and the risk of adverse effect must be taken into account. Among the patients taking Actemra very common adverse effects, more than one in ten, are elevated levels of cholesterol and infections in the upper respiratory tract. Common adverse effects, less than one in a hundred and more than one in ten, are hypertension, neutropenia, leukopenia and headaches. An uncommon adverse effect, more than one in a thousand and less than one in a hundred, is gastric ulcers [7].

Benefits
Patients with Ra that takes Actemra gain an improved quality of life due a slower disease progression and lessening of pain in joints. Also patients, who didnt respond to the available treatments before Actemra, which was about 50% of the Ra patients, now have an alternative treatment to avoid joint destruction and loss of joint function [4] [5].

Efficacy
In a comparative study of patients taking Methotrexate and Actemra, se Figure 4, it was shown that patients using Actemra had a higher ACR (American College of Rheumatology) score. For example, ACR20 means that the patients taking the drug had a 20% or more decrease in number of swollen/tender joints, and a 20% improvement in the following measures; ESR (Erythrocyte Sedimentation Rate, how fast red blood cells can sediment), CRP (C-reactive protein, found in blood, increased levels found during inflammation), physicians global assessment of disease, patients global assessment of physical function, patients global assessment of disease [4].

Figure 4 Comparison between Methotrexate and Actemra (Tocilizumab) using ACR score [4].

Patent and marketing

The patent situation for Actemra is different depending on which country you look at. In some countries the patent has not expired and in some it has, although efforts are being made to extend the patents. Actemra is patented in three different patent families, as a receptor protein for human B cell stimulation factor 2 (IL-6 receptor), as a reconstituted human antibody against human IL-6 receptor and as a rheumatoid arthritis remedy containing IL-6 antagonist as active ingredient. To continue to protect Actemra even after the patents expire, the use of data exclusivity is used. This means that it will probably be too expensive and time consuming for a generic company to acquire pharmaceutical data needed to apply for the marketing of a drug. Not surprisingly, there are no generic versions of Actemra on the market today [8]. The drug is marketed under Actemra outside of Europe and as RoActemra within Europe. Roche is the company responsible for the marketing and Actemra has its own homepage with information for the patients and patient stories showing the benefits of the drug [2].

Literature sources
[1] P. Parham, The Immune System, 3:rd ed., New York: Garland Science, Taylor & Francis Group, LLC, 2009. [2] "Actemra," 1 12 2011. [Online]. Available: http://www.actemra.com/actemra/rheumatoid-arthritis/ra.html. [3] "RoActemra," 1 12 2011. [Online]. Available: http://www.roactemra.com/portal/roactemra/mechanism_of_action?_requestid=185186. [4] G. Jones and C. Ding, "Tocilizumab: A Review of Its Safety and Efficacy in Rheumatoid Arthritis," Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders, vol. 3, pp. 81-89, 2010. [5] J. M. Kahlenberg and D. A. Fox, "Advances in the Medical Treatment of Rheumatoid Arthritis," Hand Clin., vol. 27(1), pp. 11-20, 2011. [6] "Roche," 1 12 2011. [Online]. Available: http://www.roche.com/biotechnology.html. [7] "FASS," 1 12 2011. [Online]. Available: http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=20080125000011&DocTypeID=7&UserTypeID=2. [8] "Genericsweb," 1 12 2011. [Online]. Available: http://www.genericsweb.com/index.php?object_id=762.