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Posts Tagged ‘Bristol-Myers Squibb’

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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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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Measurement of Erythrocyte Sedimentation Rate ...

The answer to this question eluded me over the years with the wide variety of RA medicines I’ve taken. It came up this week when my wife asked it again after seeing me go through a particularly long and nasty flare. I reminded her that there is no cure, only treatments for RA. But it did raise my curiosity.

In an attempt to answer this question, I went back to the Orencia package insert[i] – those 20 page, 5 point font documents that every pharmaceutical company puts inside their medicines – to try to find some answers. Bristol Myers Squibb likes to include a copy of these inserts every time they send me something in the mail. Most people probably don’t read these lengthy, highly technical documents that include information on dosage, indications, administration, warnings, side effects, and efficacy. There are likely some regulatory guidelines from the government dictating their contents since at the bottom of the document it says, “The Instructions for Use has been approved by the U.S. Food and Drug Administration”.  I dug through the insert until finding the section on clinical response – in other words, how well does it work?

Most clinical researchers use a variety of tools to gauge RA drug efficacy. The Health Assessment Questionnaire – Disability Index (HAQ-DI) which is a short version of the full HAQ is one such measure.[ii] Here’s a link to an online version of the HAQ. Many rheumatologists have their patients complete a HAQ and I remember doing this at my very first visit. Another commonly used tool to assess is the Disease Activity Score 28 or DAS28. It uses a count of the number of tender and swollen joints plus either a sedimentation rate (ESR) or c-reactive protein (CRP) blood test of inflammation. There is also an online version of DAS28 and an app for the iPhone. According to one site, “A DAS28 score higher than 5.1 is indicative of high disease activity, whereas a DAS28 below 3.2 indicates low disease activity. A patient is considered to be in remission if they have a DAS28 lower than 2.6.”[iii]

According to the online DAS28, I currently have high disease activity. One of the clinical studies on Orencia reported in the insert, “…a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo.” The proportions reported were 41% of patients on Orencia/Methotrexate reached a DAS28 of less than 2.6 compared to 23% of placebo patients. That means that a larger proportion of patients, 59%, did not reach remission.

I’ve been on Orencia plus Arava for 11 months now and am not currently in that minority who reached remission. In fact, just the opposite has happened. It’s hard to tell at this point if this combination of disease modifying drugs is not working for me or it’s just a nasty flare induced by too much work in the past few months. But this will be a conversation my rheumy and I will have at our next visit in early December. I am very hesitant to try yet another treatment regimen as I’ve already been through a truck load. But my rheumy encouraged me there’s still hope and other treatments to try and her goal is remission.


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It seems that with the FDA approval of Xeljanz this week, most of the attention for new treatments for RA is focused on orally administered protein kinase inhibitors.[i] This attention is not unwarranted in that Xeljanz is the first oral treatment for RA approved in over 10 years. The kinase inhibitor drugs are complex molecules that impact some part of the biological pathways involved in cancer and immune diseases.[ii] With all the hoopla around Xeljanz, I wondered what was going on in the world of new biological treatments for RA.

antibodies

Most biological treatments for autoimmune diseases are focused on signaling pathways involved with immune cells. These signals are typically carried by proteins including cytokines. In autoimmune diseases, it is thought that the pathways and associated cytokines are out of whack resulting in an overactive immune response in which a person’s own tissue comes under attack. Tumor necrosis factor (TNF) is a cytokine that has been the target of many recent biological treatments for RA. The most popular biological treatments for RA are Enbrel, Humira, and Remicade which all attempt to block TNF with antibody proteins. The large size of these sensitive proteins means that they must be injected or infused into the body rather than be ingested orally. Other biological treatments approved for RA include Orencia targeting the protein called B7 which reduces T cell stimulation, Rituxan which targets the protein CD-20 in B cell pathways, and the newest one Actemera which targets interleukin 6 (IL-6).

There are literally thousands of clinical trials related to RA occurring around the world[iii] and finding specific information related to new possible biological treatments is difficult for someone outside the research community. It seems that pharmaceutical companies are somewhat elusive with drug development. They want to maintain some level of trade secrecy, publish results in the peer-reviewed research world, and give out just enough information for investors to get excited. With a little snooping that would not have been possible 15 years ago in the early stages of the internet, I found that there are some important clinical trials going on for new biological treatments. In some cases, I had to create a login to access certain journals or use my university library access to find information.

B cell lymphocytes and their signaling proteins appear to be one of the main targets of recent biological drug development.[iv][v]. It seems that IL-6 and CD-20 are the most researched parts of the RA biochemical pathway. I found 17 biologicals that show promise and are in various stages of testing. Below is a list of some of the biologicals I found. Most of their scientific names end in “MAB” because they are monoclonal antibodies meaning that they are cloned proteins coming from one type of immune cell. Genetically engineered mice are used in the complex production process.

We see the usual set of major pharmaceutical players, who already have the lion’s share of the RA drug market, doing most of the testing of these new drugs demonstrating that there is big money to be had in this area. Sometimes smaller companies develop the drug and the rights are purchased by a large company who then funds the extensive clinical trails. Not all of these experimental drugs will obtain approval and make it to market.

It is a good thing for patients that the search for new biological and chemical treatments for RA continues. The wide variety of biologicals targeting different biochemical pathways may ultimately result in more patients responding to treatment. With over 1.5 million RA patients and as one of the leading causes of disability in the United States, treatments are needed that improve the quality of life and reduce disability. In spite of the proliferation of treatments, I still hold out hope for a real cure to this insidious disease.

IL-6 Inhibitors

Sarilumab is being developed by Sanofi in Europe. It shows promise in clinical trials in treating RA with infections the most common side effect.[vi]

BMS-945429 is an experimental drug from Bristol Meyers Squibb that also targets IL-6.[vii] It is made in yeast cells instead of the standard medium for making other biologicals-hamster ovaries. It shows promise in treating RA.[viii]

Sirukumab, being tested by GlaxoSmithKline, is an IL-6 inhibitor to which RA patients show a good response.[ix] Side effects include infections, gastrointestinal problems, and blood problems.[x]

Olokizumab is being developed in Europe by UCB which also developed the TNF blocker Cimzia. [xi] It shows promise in early trials with side effects including headache and blood problems.[xii]

GSK315234, also from GlaxoSmithKline, targets interleukin 6 (IL-6) and is in early clinical trials. [xiii] [xiv]

CD-20 Inhibitors

Like Rituxin, the antibody Ofatumumab (trade name Azerra also known as HuMax-CD20) targets the B cell protein CD-20. It is already approved for leukemia but is being tested in clinical trials for rheumatoid arthritis.[xv] It is produced by GlaxoSmithKline.

Pfizer, in partnership with Emergent, announced the development of a biological which also targets CD-20. It is currently called SBI-087 (PF-05230895).[xvi] It is in clinical trial for the treatment of RA.[xvii]

While not a completely new biological, Pfizer is testing an antibody called PF-05280586 that is similar to Rituxin. These are called “biosimilars” and other companies around the world are trying to get in on the action by developing their own Rituxin look-alikes.[xviii]

IL-20 Inhibitors

The monoclonal antibody NNC 0109-0012 targets interleukin 20 (IL-20). Clinical trials occurred in Europe and are funded by the company Novo Nordisk. Early results show that this biological positively impacted RA symptoms while showing the typical safety profile of other biologicals including increased infections and injection reactions.[xix]

IL-17 Inhibitors

Secukinumab, developed by Novartis, targets the cytokine interleukin 17 (IL-17).[xx] It is in clinical trial for several autoimmune diseases including RA in which some improvement was seen with typical side effect profiles for other biologicals.[xxi] [xxii]

Ixekizumab, from Eli Lily and Co., also targets IL-17 and is being tested for RA and plaque psoriasis.[xxiii] Early results demonstrate impact on RA symptoms along with typical side effects including infections.[xxiv]

B Cell Activating Factor (BAFF) Inhibitors

Tabalumab, from Eli Lily and Co., is being developed as a treatment for autoimmune diseases and some cancers. It shows some efficacy at reducing RA symptoms yet includes infections as a side effect.[xxv]

Others

Pateclizumab, by Genentech and Roche, targets a set of cytokines called lymphotoxin (LT)-alpha Inhibitors. It shows promise in treating RA. It is also being tested by co-administering it along with a TNF blocker like Enbrel. Side effects include headache and gastrointestinal issues but no serious infections.[xxvi]

Denosumab is an antibody from Amgen that targets the production of RANKL, a protein that signals bone erosion. It is currently approved under the trade name Prolia for the treatment of osteoporosis and is currently under clinical trial for the treatment of RA.[xxvii] But problems with the drug have held up the use of Denosumab for osteoporosis let alone other diseases.[xxviii]

Ozoralizumab, developed by Ablynx in Europe, is a new TNF blocker that shows promise in treating RA and may compete with Humira and Enbrel if approved.[xxix][xxx]

Stelara (Ustekinumab), developed by Janssen, is already approved for the treatment of psoriasis. It targets interleukins 12 and 23 (IL-12, IL-23). It is in clinical trial for RA.[xxxi]

Fezakinumab, being developed by Pfizer, targets interleukin 22 and is in clinical trial for RA.[xxxii]

Creative Commons Photo Credit: http://commons.wikimedia.org/wiki/File:Chimeric_and_humanized_antibodies.svg

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I’ve been on four biological medicines over the past 3 ½ years to treat rheumatoid arthritis. I’m thankful for these complex drugs as it’s clear that they slowed disease progression. I’m currently taking Orencia. After a recent Orencia infusion, my insurance company sent an Explanation of Benefits (EOB) form showing the cost and coverage of the medicine and infusion services (see a photo of the form). The form shows that the charges billed by the infusion clinic for the Orencia was $4,425 for 1,000 mg of medicine. I’m curious about the source of this cost and can only assume that this is the cost suggested by the drug manufacturer Bristol-Myers Squibb…sort of like a “suggested retail price.” The adjustments made by the clinic were for $2,609.25 making the final cost of the drug that the insurance company agreed to pay $1,815.75. The mark-up on Orencia must be huge if the adjustment was almost 59% less than the original cost. Insurance companies obviously know the price structures to medicines and know what price pharmaceutical companies and clinics will actually accept in order to cover their costs. The clinic also charged $367 for the infusion which included the nurse and equipment. My insurance company agreed to pay $260 for these services. The total cost of this infusion was $2,076.29. A total annual cost of such infusion treatments would be $24,912. And that does not include other costs associated with my RA treatment including other medicines, doctor visits, blood tests, imaging, and surgeries.

I had already met my deductible for the year so there were no out-of-pocket expenses this time. However, pharmaceutical companies know that deductibles and co-pays can present huge financial challenges to patients and many offer co-pay assistance. Bristol-Myers Squibb provides an assistance plan where they will pay all but $5 of each infusion co-pay costs (just for the medicine, not the clinic costs). They actually sent me a debit card and loaded it with “cash” ready to be used to pay the clinic any co-pays not covered by insurance. I used this card to pay for thousands of dollars of co-pay costs to the clinic during the first six months of the year.

Biological medicines are understandably expensive because of the complex manufacturing processes involved. Such medicines also have extended patent protection over chemical pharmaceuticals in order to help drug companies recoup the extensive cost of research and development. Those costs are passed onto the patient. Every time an Orencia commercial comes on the TV, I wonder about the cost of publicity – a relatively new thing in the pharmaceutical industry.

The wild difference in charged costs versus covered costs as shown on the EOB can only make one wonder about drug company profit margins. Clearly biologicals are big business. In 2010, Amgen’s Enbrel had over $3 billion in sales just in the United States.[i] This represented 23% of Amgen’s annual sales. Humira is projected to be the world’s biggest revenue drug by 2016 with over $10 billion in annual sales.[ii]

The real cost of Orencia isn’t a mystery that I will likely solve any time soon. There are numerous business and political players involved. I’m just thankful for a medicine to treat RA, insurance coverage, and co-pay coverage by the pharmaceutical company.

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