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
[iii]http://onlinelibrary.wiley.com/doi/10.1002/jps.23154/abstract;jsessionid=9D413E4C15671EACC3C15C618871AA0F.d02t04
[iv]http://www.clevelandclinicmeded.com/online/webcasts/bcelltherapies/eular-2012/perspectives-on-emerging-b-cell-therapies/webcast.asp
[v] http://www.clevelandclinicmeded.com/online/webcasts/rheumatology-highlights-report/2011-acr/b-and-t-cell/webcast.asp
[viii] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.2
[ix] http://www.pharmpro.com/News/Feeds/2012/08/pharmaceutical-companies-glaxosmithkline-gsk-announces-start-of-phase-iii-programme-of-siru/
[x] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.2
[xi]http://www.cslrecruitment.com/News/UCB_confirms_results_for_olokizumab_in_rheumatoid_arthritis_study/cid-1057.aspx
[xii] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.2
[xiii] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.3
[xiv] http://www.bioportfolio.com/resources/trial/88920/Phase-Ii-Study-Evaluating-The-Safety-And-Efficacy-Of-Gsk315234-In-Patients.html
[xv] http://www.gsk-clinicalstudyregister.com/quick-search-list.jsp?tab=protocols&phase=All&studyType=All&population=All&marketing=All&status=All&country=All&item=ofatumumab&letterrange=L-P&type=compound
[xvi] http://www.news-medical.net/news/20100112/Pfizer-commences-SBI-087-Phase-2-clinical-trial-for-RA.aspx
[xix]http://www.docguide.com/novel-human-monoclonal-igg4-antibody-reduces-disease-activity-patients-active-ra?tsid=5
[xx] http://www.clevelandclinicmeded.com/online/webcasts/rheumatology-highlights-report/2011-acr/b-and-t-cell/webcast.asp
[xxii]http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.4&setC=2®Track=1
[xxv] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.6
[xxvi] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.5
[xxvii] http://www.healio.com/orthopedics/biologics/journals/ORTHO/%7BF0904E01-0380-4F87-8907-61A6A6B458D5%7D/New-and-Upcoming-Biologic-Agents-for-Rheumatoid-Arthritis
[xxx] http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2109&sj=2109.07&sc=2109.07.7
Excellent research effort, Andrew. You really dug in! Thanks for sharing what you learned with the rest of us; knowing that medical scientists are still working in earnest on finding an effective treatment for RA is encouraging. And perhaps, in the end, they’ll actually stumble upon a cure!
I hope this finds you feeling better. You’ve really been through the wringer lately! Wishing you plenty of rest, far more comfort, and lots of calm.
Thanks for the kind comments Wren. This little bit of research was a nice Veteran’s Day diversion that was actually relaxing. I had a second hip injection today and I can already tell that it feels better. I started a low dose of amitriptyline last week (I think I remember you saying you take nortriptyline which is similar). It’s worked wonders and I’ve slept like a baby…first time in months! I feel like I’m slowly coming back to “baseline.”
Hope you’re doing well.
You did a fantastic job in digging up really important information, Andrew. Thank you so much for your efforts!
I am forever astonished by the advances made in treatment. I keep saying that I never thought I’d see this in my lifetime and although that statement may be getting old, the miracle of it all hasn’t for me. there is so much hope these days…
Still holding out for a real cure!
[...] treatments. This is evident in the that a slew of new medications are being tested (see earlier post) and the recent approval of Xeljanz. I just have to keep reminding myself that I’m not a failure [...]