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Posts Tagged ‘Actemra’

ACR 1I recently had the privilege to attend the annual meeting of the American College of Rheumatology. Considerable time was spent in the exhibit hall since, in addition to presenting a research paper, I was also volunteering at the booth of the Rheumatoid Patient Foundation.

The exhibit hall was overwhelming and the cavernous room was dominated by pharmaceutical companies. There were dozens of exhibits from large to small companies including, but not limited to, the following who provide many of the major biological treatments for RA:

ACR 2These pharmaceutical companies commanded the majority of the space and had professionally designed exhibits replete with multimedia presentations, large colorful signs and displays hanging from the ceiling, leather lounge chairs, espresso bars, snacks, colorful print materials, conference rooms, and an army of 20-30 sales representatives each. The rumor floating around was that these traveling exhibits cost upwards of $100,000 each in addition to the staff and other associated costs. They replace them every year. It is evident that the big pharmaceutical companies, especially those with expensive biological drugs on the market for RA, have vast amounts of funds to spend on sales and these exhibits. Based on this level of spending, it is obvious that this is big business and it is important for these companies to interact with the doctors and other health care providers who attend this conference in an effort to increase the sales of their drugs.

I enjoyed free espressos from Genentech/Roche each day – the manufacturer of my current RA medication Rituxan. One day while drinking my coffee and looking over research materials on Rituxan, a sales representative approached me obviously expecting me to be a doctor. I told her that I was a patient advocate who was actually taking Rituxan. She literally took a step backwards and told me that she was sorry and hoped I felt better. I laughed and said thanks and grabbed some print materials on clinical trail results and side effects. This awkward moment drove home the potential disconnect between the company sales force and patients. In spite of this brief and awkward interaction, the pharmaceutical companies must be commended for several things.

ACR 3Most of the research and development (R&D) behind these biological treatments for RA were paid for by the pharmaceutical companies. Oftentimes, the basic research, paid for by government or private foundation money, starts with a university-based researcher. These basic ideas lead to potential new treatments and the drug companies take over the onerous and lengthy task of developing and trying out new drugs. For biological drugs, this process may take years. And for every drug that makes it to market, there may be dozens that fail. Such development processes are extremely expensive and those costs are passed onto the patient in the cost of the drug. During the conference I was able to speak with several companies about RA treatments that are in Phase III Clinical trails (the last phase before seeking government approval). The concern is about who is going to pay for the R&D once pharmaceutical companies go over the so-called patent cliff in the next few years when their patents run out and they start to loose market share and profits.

Another patient benefit provided by the pharmaceutical companies for expensive biological treatments for RA are co-pay assistance plans. All of the companies listed above have such plans and they pay out millions of dollars each year helping patients be able afford treatments that can cost between $16,000 – $40,000 a year. This assistance, while extremely beneficial to those who need it, also demonstrates the large profit margins built into the “retail” costs of the drugs.

During the conference, I also met several consultants who are contracted by pharmaceutical companies to conduct research related to patient reactions and opinions about their products. While one may cynically infer that the companies are simply trying to increase their market share by pressuring the patients to ask for their drug, it was clear from the consultants that they genuinely want to increase the positive interactions between patients and the pharmaceutical companies in an effort to improve patient care and future drug development.

Yes, pharmaceutical companies are huge for-profit entities with a major goal of making money for shareholders. And the companies with major biological treatments for RA make enormous profits (Humira sales alone for the 4th quarter of 2012 were $2.7 billion). But they also bear the brunt of the R&D process, help with co-pays, and appear to seek patient interaction. As the patent cliff approaches, time will tell how it will impact these companies and the future of RA drug development.

ACR 4

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For those who live with type I diabetes, injecting insulin multiple times a day becomes a regular routine. But rheumatoid arthritis patients are also likely to face using needles to administer a variety of medications.

After receiving a diagnosis, there is a progression of RA treatments recommended by the American College of Rheumatology (ACR)[i] that usually begin with chemical-based disease modifying drugs (DMARDs) like methotrexate, sulfasalazine, leflunomide (Arava), and hydroxychloroquine (Plaquenil). All of these drugs are available in pill form. Even though available in pill form, many people cannot tolerate the side effects of the most commonly used DMARD, methotrexate, as it is prone to cause nausea. Methotrexate is also available in an injectable liquid form and many rheumatologists will prescribe this form when side effects can’t be tolerated. If this is the case, the patient must learn to self-inject…

…Read more at http://rheumatoidarthritis.net/living/prepare-poked-needles-ra-treatments-go-hand-hand/

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My rheumatologist reiterated with me yesterday that I have a tough to treat case of RA – called refractory RA. She displayed disappointment that all of the treatment plans we’ve tried over the years have not had the intended impact. We’ve cycled through four TNF inhibitors (Enbrel, Cimzia, Humira, and Remicade), Orencia, and Actemra. And that’s in addition to various DMARDs including sulphasalzine, azathioprine, and leflunomide (Arava). The reasons for stopping the use of these drugs runs the gamut of lack of efficacy to intolerable side effects. My doctor was apologetic, felt bad I wasn’t helped by all of the treatment plans, and genuinely expressed concern for the impact RA has had on my life recently. But I reassured her that I trusted her medical judgement and that the impact comes over time allowing time to adjust. I appreciated her empathy and deep desire to help.

We discussed the few remaining options which includes Xeljanz, Kineret, and Rituxan. Xeljanz (tofacitinib) was approved in the United States but not approved in Europe. We both felt that more data was needed on this “oral biologic” before giving it a try. Kineret, or anakinra is a biological response modifier that targets interleukin 1. My rheumy said that is not used that much anymore because of more effective options. A recently published report indicates that a Swedish company just purchased the rights for Kineret from biological pharmaceutical giant Amgen. Such a move seems like Amgen is dumping the drug likely because it is not profitable and is moving onto other new drugs. After much discussion, we both agreed to try Rituxan and I will continue to inject 20mg of methotrexate weekly. 

As I was describing my new treatment regimen to friends and family, I found myself trying to explain the drugs, how they are administered, how they act to treat RA, and the possible side effects. As I read more about these drugs, it struck me as interesting that both medicines were originally developed to treat certain forms of cancer. Methotrexate is a chemotherapy drug developed in the 1950s and is still used to treat forms of leukemia, breast cancer, lung cancer, non-Hodgkin lymphoma, and head and neck cancers (see American Cancer Society). It stops the growth of cancer cells by affecting their metabolism. Given the immunosuppressing nature of methotrexate, it is now commonly used in lower doses to treat various autoimmune diseases including rheumatoid arthritis. It’s also used to treat tubal ectopic pregnancies by inducing abortion. In spite of the low doses used in treating RA, some of the chemotherapy side effects remain including hair loss and nausea. This paints a picture of a rather toxic medicine! But I’ve been injecting 20mg weekly for some time now and seem to tolerate it rather well.

Rituxan is also known by the names MabThera and Rituxamab. This monoclonal antibody is a biological medicine that was originally developed in the late 1990s to target the protein CD20 present in certain phases of B lymphocytes. It was originally approved for the treatment of B cell related lymphomas and leukemias (see the Rituxan website). In the early 2000s, it was shown in clinical trials to be effective in treating rheumatoid arthritis and gained FDA approval for use in refractory RA cases in 2006. The involvement of B cells in autoimmune diseases likely led to the investigation of Rituxan as a treatment for RA. The side effect profile appears similar to other biologicals but with some additional infusion side effects requiring some pre-medications along with a few more rare serious infections.

The use of cancer drugs to treat RA points to the connection of both diseases to the immune system. It also demonstrates the serious nature of RA. Given the fact that both methotrexate and Rituxan were originally designed to treat certain cancers, and that they are now secondarily being used to treat RA, may point to the fact that a much larger proportion of research funding goes to cancer (see this earlier post). While I don’t mind receiving the “leftovers” or being an “afterthought” if the medicines effectively treat RA, the ideal would be for the development of new treatments or even cures specifically designed for the processes involved in autoimmune diseases. In the meantime, I’ll go to the infusion clinic and begin Rituxan infusions along with cancer patients and see if it can take care of this refractory case of RA!

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fragment of antibodyWith the research net being cast widely and deeply by researchers and pharmaceutical companies, it’s clear that the currently approved treatments for rheumatoid arthritis are not having the intended impact on all patients (see this recent post on lack of remission). Unlike some infectious diseases where there is a treatment that often results in a cure (e.g. tuberculosis) or eradication via a vaccine (e.g. polio), no such remedy currently exists for RA. Last year I wrote a post about the large variety of biological treatments for RA that are currently in the development and testing pipeline. And this did not even include the myriad of small molecule drugs being developed to target the so-called JAK-STAT pathways of which Xeljanz (tofacitinib) is the only one currently approved in the United States but not approved in Europe.

The vast majority of approved RA biological treatments focus on inhibiting the tumor necrosis factor (TNF) alpha molecule which is overactive in autoimmune patients. The TNF blockers Enbrel, Remicade, and Humira account for the majority of biological prescriptions and control a vast portion of the market. The newer TNF blockers Simponi and Cimzia have recently joined the fray. Other parts of the involved biological pathways have been targeted for treatment including costimulatory protein CD-40 (Rituxan), interleukin 6 or IL-6 (Actemra), and T cell lymphocytes (Orencia).

In spite of the major focus on TNF alpha, a Belgium company called Ablynx now proposes that over the next few years, the “Anti-IL-6 pathway will dominate as the preferred biologic after anti-TNFα treatment.” They predict that 16% of the RA biological market will consist of IL-6 inhibitors by the year 2021. This focusing on IL-6 signaling pathways was proposed in 2008. In addition to Actemra (tocilizumab) which is currently approved in the U.S. and Europe, other antibody treatments targeting IL-6 are being developed including sarilumab by Sanofi and Regeneron, sirukumab by GlaxoSmithKline, and clazakizumab by Bristol Myers Squibb.

Ablynx is currently completing Phase II clinical trials of an IL-6 inhibitor called ALX-0061 and the results show strong treatment efficacy and safety profiles. Instead of being made of large monoclonal antibody (MAB) molecules like most of the current biological medicines, the company Ablynx focuses on producing smaller components called “nanobodies” or fragments of antibodies (FAB) (see this Scientific American article). FABs are cheaper to produce, may produce fewer side effects, and are less prone to breakdown in harsh environments. Ablynx clones the human FABs in llamas before isolating the molecules (see this report).

It is heartening that much research continues on the development and testing of treatments for RA.

Creative Commons photo credit, public domain: http://commons.wikimedia.org/wiki/File:1K4C.png

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English: insulin resistance model

English: insulin resistance model (Photo credit: Wikipedia)

In two earlier blog posts (I and II), I outlined a fairly common extra articular complication of rheumatoid arthritis called metabolic syndrome which is associated with increases in insulin resistance, type II diabetes and cardiovascular disease. Although all of the connections are not fully understood, it is clear to researchers that the systemic inflammation brought about by RA can contribute to metabolic malfunctioning (see this scientific review).

Since I was writing about these topics, it should come as no surprise that metabolic syndrome has become an issue for me. This originally came to the surface when I was receiving Actemra infusions every month. One of the listed side effects of Actemra is an increase in blood pressure and lipids. My rheumy began regularly checking these parameters and we began to see an increase in hypertension and the lipid test results were high and rising over time. I already knew that my cholesterol was borderline going into the use of Actemra. But the dramatic changes, coupled with the lack of efficacy of Actemra in treating RA, were enough to cease using it after five months. But even after stopping Actemra and going on a low fat diet to try to lower cholesterol, the test results kept coming back high. At their peaks over the past few months, my total cholesterol was 293 (target is below 200), high density lipoproteins (HDL) or “good” cholesterol was 33 (target is above 40), low density lipoproteins (LDL) or “bad” cholesterol was 226 (target is below 100), and triglycerides was 469 (target is below 150). The fact that triglycerides were high points to the fact that sugars were going unused and were being converted into long term storage molecules. Insulin resistance was occurring and I was headed towards type II diabetes as my general practitioner pointed out.

My rheumatologist and general practitioner both agreed that metabolic syndrome was a real danger and we developed a comprehensive plan to treat it. I did not want to develop type II diabetes and I felt like a ticking time bomb for a heart attack or stroke. This all seemed surreal as these issues don’t run in my family and I was not really overweight. My body mass index (BMI) was 24.4 which is still in the low category – albeit at the high end (see this simple online BMI calculator). The major culprit must have been the systemic inflammation caused by RA.

My general practitioner commented that eating a low fat diet does not do much to lower cholesterol and that since my triglycerides were high and insulin resistance a real threat, he suggested cutting back on sugars and starches. After much investigation, I found an excellent book on insulin resistance diets. I began to analyze my eating habits and found out that I was eating far too many processed sugars and starches. I’ve learned to keep total carbohydrates to about 30 grams per meal, balance quality carbs with low fat proteins (about a 2 to 1 ratio of carbs to proteins), and snack regularly when hungry. I’ve learned that American diets are full of processed sugars and starches that can wreak havoc on someone with metabolic syndrome. There’s been a complete change in mindset in how I eat. I avoided Atkins, South Beach, and Paleo diets as they are not necessarily designed for insulin resistance and may be difficult to follow long term. A balance in macronutrients – quality carbs from whole grains, proteins, and fats – seems to be the best approach. Of course, I can eat all the green vegetables I want. 🙂

Exercise is another way to stave off insulin resistance as muscles can burn through large amounts of unused glucose in the bloodstream (see this article). RA patients often have trouble remaining physically active that was the case with me over the past few years. While RA is currently active and not under control, I have attempted to go on walks several times a week and started doing some fairly light resistance band exercises when my joints and energy levels permitted. The only medication that was used was a daily dose of the cholesterol lowering statin drug atorvastatin (Lipitor).

At my most recent blood tests last week, the cholesterol and triglycerides are finally within normal parameters – total cholesterol = 136 (target below 200), HDL = 46 (target above 40), LDL = 70 (target below 100), and triglycerides = 99 (target below 150). Cholesterol was down and insulin resistance was no longer an issue! In addition to the dramatic decreases in lipids, my blood pressure has decreased and I’ve lost 10-12 pounds in two months. The spare tire from my waistline is disappearing and my BMI is decreasing. My general practitioner wanted to make sure that I was not prediabetic so he ran a fasting blood glucose test and it came back within the normal range. Thyroid function was also tested since it has so much to do with metabolism and everything came back normal. While it’s impossible to pin the improved metabolic markers on any one treatment or prevention, the systematic and aggressive approaches are probably acting in concert with one another.

Unfortunately, these metabolic syndrome treatments and lifestyle changes have not had a dramatic impact on RA symptoms as they remain uncontrolled. In fact, I predict that if systemic inflammation from RA gets under control, it will help with metabolic issues. But that is another battle that my rheumy and I are systematically tackling right now.

If you have RA, it is critical that you and your doctor regularly monitor your blood pressure, lipids, body weight, and glucose levels to make sure that metabolic syndrome is not running amok. If problems persist, then please be proactive by treating and preventing these extra articular symptoms from having a serious impact on your health and life span.

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struktura infliximabu

struktura infliximabu (Photo credit: Wikipedia)

It is becoming increasingly clear that a substantial proportion of RA patients fail to respond to the more common treatment regimens including combinations of DMARDs (methotrexate, Arava, etc.) and TNF inhibitors (Enbrel, Humira, Remicade, etc). As recently noted by researchers,

“However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor.” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669237/)

The television advertisements in the United States for these drugs show happy, active people. It is heartening that many RA patients receive excellent results from DMARDs and anti-TNF medications. But I seem to have found myself in the 20-40% group of non-responders. Apparently there is a name for this…Refractory RA.

Refractory in the medical sense means “resistant to treatment or cure” (http://www.merriam-webster.com/dictionary/refractory). According to the National Institutes of Health,

“Refractory disease is defined as failure to attain a predefined target, which is now accepted to be remission or, at least, a low disease activity state.” (http://www.ncbi.nlm.nih.gov/pubmed/21570496)

Since remission is embedded within this definition, it must be clearly operationalized. The predefined target for remission of RA is from the recently revised ACR-EULAR criteria. In order to be technically in remission,

At any time point, patient must satisfy all of the following:

Tender joint count – equal or less than 1
Swollen joint count – equal or less than1
C-reactive protein – equal or less than 1 mg/dl
Patient global assessment – equal or less than 1 (on a 0–10 scale) (p. 581)

These are the stringent criteria applied for clinical trials of newly developed drugs. But applied to currently approved drugs, do patients on these drugs reach remission status? In a review of several studies, the use of traditional DMARDs like methotrexate result in between 35-65% of patients reaching remission. Other comparison studies demonstrated remission rates within a range of 24% with methotrexate alone to 64% with Humira. In one recently published study in China, only 25% of patients achieved remission status using the ACR-EULAR criteria. Many of the remission rate studies were conducted using the old criteria before 2010. Whatever standard is used, it is clear that there are a considerable number of patients who are not in remission.

Biological medicines that are not in the TNF inhibitor class like Xeljanz, Rituxan, and Actemra, are commonly recommended for refractory RA (see studies linked to each medicine above). In the United Kingdom, failure of TNF inhibitors leads to a recommendation to use Rituxan (see http://guidance.nice.org.uk/TA195). But these “second tier” biologicals don’t always result in patients reaching remission status. All one needs to do is read the prescribing information for each of these drugs to quickly realize that many patients in the clinical trials did not reach ACR-EULAR remission status. This is actually the case for all approved RA drugs.

Rheumatology researchers in Portugal recently stated,

“During the last decade we have experienced exciting developments regarding the approval of new treatment options but few patients are reaching sustained remission and refractory patients continue to be a problem. Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by closely monitoring disease activity, using well defined and accepted composite measures, and by early and optimized use of DMARDs, including biologics.” (http://www.ncbi.nlm.nih.gov/pubmed/21570496)

This quote sums up the problem which remains. A large proportion of RA patients who are currently on biological and DMARD medication combinations do not achieve remission status – they have Refractory RA. This evidence lends credence to the fact that more work needs to be done in order to develop treatments that result in true remission. Ultimately, a cure should be the goal for this insidious disease.

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A weird thing happened at my Actemra (tocilizumab) infusion last Friday…I was dog tired and started dozing off in the chair when all of a sudden about half way through the infusion I got a rapid burst of energy. I went home feeling great and even mowed my front yard! But by Saturday night it was all over and I was back to feeling terrible – it was a great tease!

My rheumatologist always states that her goal is for me to not pay much attention to RA throughout the day. If the RA is causing issues to which I must attend during the day, then she believes that the medications aren’t working well. For the past five months since starting Actemra, I can clearly state that RA persistently reminds me that it’s present. I knew in the back of my mind that a change may be needed. But after being through so many RA treatments over the past 4 ½ years, I’m very hesitant to switch medications because I’m getting to the point where choices are limited. Below are some factors that are working towards a change.

  1. Doctor recommendation. I don’t tend raise the issue of switching medicines and instead rely on my rheumatologist to broach the subject. Call me gun shy – I just want to make sure that we give a treatment a fair shot before moving on. Part of that hesitancy is based on the fact that we’re running out of options. After last month’s discussion and a recent set of blood tests a few days ago, my rheumatologist contacted me and wants me to stop the current combination of Actemra infusions and leflunomide (Arava).
  2. Your body. My rheumatologist always asks me how I’m feeling in terms of joint pain, swelling, fatigue. She understands that I know my body better than anyone else and takes that into account. She even asked me yesterday, “Do you think the Actemra is working – if not, I’m fleshing out a super Plan B.” I have to admit that it does not seem to be working well. I’ve had increasing joint pain and swelling with over 28 joints impacted. Using the ubiquitous DAS28 tool for measuring RA disease activity (an online calculator is available), I currently have high disease activity.
  3. Increase in Inflammatory Blood Markers. A sharp increase in inflammatory blood markers may demonstrate that the disease is becoming more active (see this study on the correlation). For the first time ever since being diagnosed with RA, I had a high C Reactive Protein test last week. While blood tests like sedimentation rate and C reactive protein are not always accurate indicators of disease as some RA patients like myself tend to not show high results (see this study), they can serve as some gauge of disease activity and are used for clinical trials (see this post from RA Warrior for more info). If the level of general inflammation in my body is increasing while taking certain medications, it may be a sign that they are not working well.
  4. Side Effects. Many side effects of RA medications are tolerable. But sometimes side effects can have too great of an impact. Such is my case with Actemra as we’ve seen a steady increase in cholesterol, triglycerides, and blood pressure since starting infusions. Roche, the maker of Actemra, lists these side effects in the prescribing information as “Adverse Reactions” seen in at least 5% of the population taking the drug. While these side effects are not listed as “Warnings” which include more acute issues like serious infections and gastrointestinal perforations, my rheumatologist believes that they are serious enough to warrant a switch in medication.
  5. Others Around You. Sometimes we can’t see the “forest for the trees” so to speak and we need others to observe how we are doing. I will tend to put my head in the sand and march on like nothing is wrong. As the British say, “hold a stiff upper lip” or “keep calm and carry on.” I’m fortunate to have a wife who can observe changes over time and call it like it is. She recently questioned the efficacy of the Actemra/Arava combination.

4109461394_1be7f99342All of the information above tends to be pointing towards the fact that Actemra is not working for me and that it’s time to move on. The choices are becoming limited as it appears that Rituxin infusions and the newly approved Xeljanz are the only biological treatments currently on the market that I haven’t yet tried. Rituxan is an entirely different kind of biological which is usually reserved for patients who don’t respond to the more common biological treatments. Xeljanz is brand new and lacks long term efficacy and safety data in the open market.

Last December I wrote a post about how Orencia was not working and the switch over to Actemra. Five short months later I’m at the same place of limbo trying to figure out the next plan of attack.

Creative Commons Photo Credit: http://www.flickr.com/photos/carolyncoles/4109461394/sizes/m/

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