Biosimilars – “Generics” for Biological Treatments for RA

Etanercept (Enbrel) structure (Photo credit: Wikipedia)

It was recently announced that Etacept was being launched in India by the generic drug company Cipla as a “biosimilar” to Enbrel (Etanercept). This new biological drug is designed to treat rheumatoid arthritis and other rheumatic conditions and is being manufactured by China-based Shanghai CP Guojian Pharmaceutical Company Ltd. It is supposed to cost 30% less than Enbrel. The approval of this biosimilar in India is not without controversy as biotechnology companies are complaining that Cipla did not follow the standards for approval (see this article).

In the United States, patent exclusivity for biological drugs is set at 12 years. This is designed to protect the expensive and time consuming processes involved in developing and testing these complex biological treatments. However, there is an approaching “patent cliff” (see this excellent article on biosimilars). Of all biologicals used for a variety of diseases, Humira, Enbrel, Remicade, and Rituxan are among the most profitable biologicals on the market. These drugs will lose their patent protection in the next few years. Once the patent cliff is reached, large pharmaceutical companies stand to lose billions of dollars in sales (see this article). The Biologics Price Competition and Innovation Act (BPCIA) of 2009 was built into the Patient Protection and Affordable Care Act (“Obamacare”) and is designed to speed up the process of approval for biosimilars. Large generic drug manufacturers are beginning to ramp up to enter the biosimilar market

Over the next few years, we will likely begin to see a slew of biosimilars for RA begin to hit the market worldwide. The potential savings to patients and insurance companies will competitively drive the market (see this article). Decisions about starting or switching to the biosimilars will need to be made. The efficacy and safety of these look-alike drugs will be questioned. This will also drive large pharmaceutical drug companies to research and develop new drugs for RA in order to maintain a competitive edge.

Refractory RA – When Treatments Fail to Work

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.

Stem Cell Treatment for RA?

Stem Cells

A reader of this blog recently sent me information about a clinical trial involving stem cells as a treatment for rheumatoid arthritis. This prompted me to investigate further.

The American National Institutes of Health has a great descriptive website on stem cells. Stem cells are of interest to researchers since they are able to grow into a variety of different types of cells. They are proposed to be used for cell therapy – cells injected into a patient to impact a process, and regenerative therapy – cells used to regrow or repair damaged tissue. They are theorized to have great potential but that potential has been sought without much success for many years.

There is also a controversy with stem cells having to do with the harvesting of stem cells from embryonic tissue. This harvesting is typically done in vitro meaning that embryos are fertilized and grown in a lab. For those who believe life begins at conception, such harvesting is repugnant. The other type of stem cell harvesting is from adult tissue. Adult harvested stem cells can come from a variety of tissues.

The clinical trial in question is from a company called TiGenix which is a European cell therapy company based in Belgium. They only use adult stem cells harvested from fat or adipose tissue. They claim that their stem cells are less likely to result in immune system reactions resulting in rejection of the cells by the patient. Their stem cell Cx611 was used in a Phase II clinical trial to investigate safety and efficacy for rheumatoid arthritis.  One interesting aspect of this particular clinical trial is that they used patients with “refractory” RA – patients who failed to respond to biologic treatments. The patients receiving the stem cell treatment displayed lower disease activity than those receiving a placebo and safety data was positive. Here is a link to the press release and a link to a detailed presentation about the company’s foray into stem cell research for autoimmune diseases. The stem cells are theorized to impact the biological processes involved with RA induced inflammation and tissue damage. In summarizing the clinical trial, they stated,

“These results are remarkable, as they constitute the first ever signal of clinical activity of a cell therapy in RA. Moreover, this was achieved in the probably most refractory RA patient population ever evaluated in clinical studies.”

Check out this recent blog post from Diana at My RA Diary for a more detailed explanation of stem cell research and RA. In her post, she does an excellent job of outlining the potential of stem cells as a treatment. She cites research and posts some nice videos and diagrams.

It is exciting that researchers are investigating stem cell therapy as a potential treatment for RA. I suspect that we are years away from knowing if it will become a reality. But the Phase II clinical trial conducted in Europe is a promising step in the right direction.

Creative Commons Photo Credit: http://commons.wikimedia.org/wiki/File:Human_embryonic_stem_cells_only_A.png

Brush Those Teeth-Periodontal Disease and RA

Several years ago after an 8 year hiatus, I finally made a visit to my dentist. The hygienist and dentist noted that my gums were red and tender – I had periodontal disease. They used a probe to measure the depth of the pockets between the gums and teeth. There were quite a few pockets that were deeper than desired and it was recommended that I get a “deep cleaning” and then move to a cleaning every 3 months. The deep cleaning required lidocaine shots to numb the nerves since the cleaning tools would probe deep. Realizing that there must be inflammation involved, I started speculating about a possible connection with RA.

Like RA, periodontal disease is an inflammatory condition that can include gum inflammation and eventually damage to tissue and tooth loss. The National Institute of Dental and Cranofacial Research indicate that it is thought to be caused by opportunistic bacterial infections in the mouth. A recent review of studies by researchers in Australia found relationships between periodontal disease and inflammatory blood markers like ESR, C-reactive protein, and interleukin 1 which are all implicated in RA. Associations between periodontal disease and joint destruction from RA have been found (see this study). Some researchers noted connections between the biochemical processes of RA and periodontal disease. A study published in the Annuals of the Rheumatic Diseases in Europe showed that a common blood marker for RA, anti-citrullinated antibodies (anti-CCP), is related to periodontal disease. Other researchers demonstrated that the bacteria Porphyromonas gingivalis, which is one of the pathogens involved in periodontal disease, is linked to anti-CCP antibodies. Another group of researchers indicated that people with RA have a significantly higher rate of periodontal disease than control populations. While there are statistical correlations between RA and periodontal disease, it is not proven that periodontal infections are a cause of RA. The link between the two continues to be explored by dental and rheumatology researchers.

Based on these findings, it is important for RA patients take good care of their mouth in order to avoid diseased gums and teeth. If RA-caused joint damage in the fingers and wrist make it difficult to brush and floss, it may be necessary to use some adaptive tools like an electric toothbrush, a floss holder, and water jet systems. I use an elective toothbrush and let the motor do the hard work. I’ve now gotten the periodontal disease under control and my dentist is letting me go back to 6 month cleanings.

Creative Commons photo credit: http://www.flickr.com/photos/ephotion/39301156/

Living within Limitations

Gardening has been a favorite outdoor activity for years. This love of the ground and raising plants began in 6th grade when I dug up a spot in our yard and planted a vegetable garden. Tomatoes grew like weeds and the joy that came with watching and nurturing plants sank deep in my psyche like tap roots.

As a twenty something high school teacher, summers were spent operating a small landscaping business. I had a truck and hired several high school students as laborers. We would plant shrubs and trees, build retaining walls, and haul bulk items like top soil, rock, and mulch. During this phase of life, I also regularly ran 20-30 miles per week and participated in 5Ks periodically. I never felt better!

Every home we lived in over the years would get hours of loving care in terms of landscaping and gardening. Redoing lawns, building greenhouses, planting flowers, edging and mulching planting beds, planting trees and shrubs, and building fences (see photo) were just a part of life.

Thirty years later and living with rheumatoid arthritis has dramatically changed these activities. This fact was recently evident when my wife started edging a planter bed and digging up sod in order to plant new flowers and lay mulch. In the past, I would’ve been in the thick of this kind of work. She began the digging knowing that I couldn’t help. We were delighted when our wonderful neighbor came over and started helping edge and pulling up sod. Instead of just passively standing by watching someone else do the work, I decided to work on bonsai gardening. The kind of work needed to maintain bonsai – pruning, watering, etc. - is doable given the impact of RA on my joints and energy levels. My dwarf Cedar of Lebanon and Western Red Cedar bonsai seem to be doing very well (see photo).

I can no longer dig sod or haul mulch, but I can still get my hands dirty and nurture plants – just on a much smaller scale!

Diagnose Early, Treat Aggressively, Monitor Carefully

My first systemic autoimmune symptom was in 2004 – I was not formally referred to a rheumatologist. Three years later I had ankle surgeries in both ankles which later was attributed to RA. Again, I was not referred to a rheumatologist. In late 2008 I started having additional symptoms that drove me to my primary care physician. He put all the symptom pieces together and immediately sent me to a rheumatologist resulting in a formal diagnosis five years after the first symptoms appeared. After diagnosis, I progressed rather quickly through a series of treatments (that journey continues today but that’s a story for another post). Now I am nowhere near clinical remission and have a severe level of disease activity that caused permanent joint damage and is dramatically impacting my life. I only wish I knew more about RA back in 2004. The good news is that there are some quality resources available that are designed to encourage early diagnosis and aggressive treatment.

One such resource is an online presentation from Dr. Martin Jan Bergman, a rheumatologist from Drexel University. He recently gave an excellent, relatively short, and non-technical presentation in October 2012 titled Rheumatoid Arthritis: Diagnosis, Treatment and Monitoring. The presentation was sponsored by Quest Diagnostics. His presentation is a superb resource for primary care physicians, RA patients, and care givers to better understand the disease and treatment processes.

One key point made by Dr. Bergman is that RA is more serious than most people think and there is a lack of public awareness of this severity. He points out that RA leads to disability, reduced work capacity, and lower quality of life. He strongly asserts that RA is a lethal disease and he shows how the survival rates of patients with high RA disease activity is similar to coronary artery disease and Hodgkin’s lymphoma. RA also brings about an increased risk of heart attacks, strokes, infection, and lymphoma.

Dr. Bergman is emphatic about early and aggressive diagnosis and treatment of RA. His says that his most common referrers are orthopedic surgeons but argues that this is often too late and primary care providers need to be more aware of RA symptoms. He stated that “there’s no such thing as arthritis- it’s a field of study.” He compares the loose use of the term arthritis to getting a diagnosis of a “belly problem” for a heart attack. With over 100 kinds of arthritis, keying in on the exact nature of the symptoms and diagnostic keys is critical to helping the patient. He discusses common diagnostic tests but warns that lab tests are normal in 35% of patients with RA. Common inflammatory tests like ESR and CRP are also normal 40% of time and should never be used to exclude a diagnosis.

Once diagnosed with RA, Dr. Bergman states that it should be treated aggressively. Waiting only results in permanent loss of function and poorer responses to treatment over time. He describes how the ACR/EULAR classification criteria should be used and he states that monitoring the disease using detailed criteria rather than just asking patients how they’re feeling provides a quicker response to treatments. His goal is to get patients as close to “normal” as possible.

Awareness of these issues discussed by Dr. Bergman is critically important for patients’ well-being. I only hope that more physicians will diagnose early, treat aggressively, and monitor carefully. Patients and care givers will find Dr. Bergman’s presentation enlightening.

Creative Commons Photo Credit: http://www.flickr.com/photos/67272961@N03/6123892769/

Can’t Turn a Blind Eye to RA

There are a few people with whom I can be completely open and transparent about the impacts of RA on a regular basis. There are others who are on a “need to know” basis. And then there are some from whom I try to hide my symptoms mostly from fear of being misunderstood, judged, or penalized. Being in a place where treatments are not working and symptoms are significantly impacting daily life and work, it’s much harder to follow this approach.

A while back, someone sent a note to my blog expressing the notion that my approach to writing about RA was too negative and that they had lived with RA for many years and got along just fine. It’s wonderful that this person has this experience. But that has not been my experience nor is it the experience of a large proportion of people with RA. This comment prompted me to go back and reread my posts reflecting on my journey over the past few years. While many posts were about research related to RA, there were personal posts of celebration along with posts describing the realities of symptoms and treatments.

The Rheumatoid Patient Foundation just published a white paper about the results from a patient survey. The results of this survey clearly paint a picture of patients regularly experiencing symptoms that impact daily life in spite of receiving treatment. The collective voice of patients is critical for developing and implementing effective treatments.

The idiom “turn a blind eye” reportedly came from an admiral who refused to withdraw in the heat of battle. Using this approach in medical situations can lead to serious consequences. Read this excellent article from the Center for Bioethics and Human Dignity at Trinity International University on the topic.

I can’t turn a blind eye to my own RA symptoms, its impact on my life, or the impact of RA on millions of sufferers in the world. Therefore, I vow to accurately share my experiences with those around me as it is appropriate and with the online community via this blog. This will be done in as balanced an effort as possible.

Creative Commons Photo Credit: http://www.flickr.com/photos/kubina/138205823/