Viewing Gilenya from the CCSVI perspective
written for CCSVI Alliance by Al Ossorio
While CCSVI treatment is quite different from pharmaceutical treatment for MS, in some cases they do share common scientific assumptions and pragmatic goals. CCSVI Alliance will share an interesting analysis of the scientific basis and treatment goals of CCSVI and the new oral MS drug, Gilenya.
Please note that this analysis is in no way an endorsement of or recommendation for Gilenya. Side effects of powerful whole-body immunosuppressants like Gilenya are significantly different from the side effects of endovascular procedures like CCSVI treatment. CCSVI Alliance believes that each patient should assess the risks and benefits of any treatment in consultation with their doctor.
From a CCSVI perspective, we often think of pharmaceutical approaches to MS as distant if not wholly separate from the CCSVI/endovascular approach to MS. Of course, both are aimed at managing/reducing MS, but beyond this, clearing stenoses through angioplasty seems virtually unrelated to the idea of fundamentally altering the body’s immunological biochemistry through the introduction of powerful foreign substances, whether injected or swallowed.
In fact, however, drugs like Gilenya share important and interesting common scientific assumptions, goals, and theory with CCSVI. Let’s take a quick look at Gilenya and see how its medical action (what makes it work) is consistent with and potentially complementary to CCSVI theory and treatment.
Gilenya (fingolimod) background:
Gilenya is a whole-body (global) immunosuppressant that was initially considered a candidate to help reduce rejection rates in organ (kidney) transplants. However, due to adverse side effects, its investigation as an organ transplant drug was halted (1). At lower doses, however, Gilenya was deemed safer, and was reintroduced as an MS drug.
How Gilenya works in MS
As with some other MS drugs (for example, Copaxone), no one is certain exactly how Gilenya works (2). However, several of the drug’s "actions" have been studied in detail, and it is likely that the following two key actions are central to Gilenya’s efficacy as an MS disease modifying drug:
1. Gilenya suppresses the immune system by sequestering lymphocytes in the lymphatic system (3).
Lymphocytes (a form of white blood cells) are fundamental to our entire immune system, and, depending on the body's needs, can transform into either T-cells or B-cells. Lymphocytes enter the blood stream from the lymphatic system, can travel freely in the blood stream, and can enter CNS tissue through blood vessels. By locking lymphocytes in the lymph nodes (the lymph nodes are in the lymphatic system, which is separate from but connects with the vascular system), Gilenya prevents many of the lymphocytes from ever entering the blood stream and thus from migrating into the CNS (3).
2. Gilenya may decrease endothelial permeability (3).
The endothelium is a thin sheath of cells that line the inner walls of blood vessels. Lymphocytes (and other material) traveling in the blood vessels typically move into the CNS through mechanisms at least partially controlled by the endothelium. By making the endothelium less permeable, it is likely true that fewer lymphocytes will enter CNS tissue (and remember, lymphocytes (especially T-cells and B-cells) are central to the immunologic activity associated with MS).
In sum, Gilenya: 1) decreases the number of lymphocytes in the blood stream; and 2) makes it harder for those lymphocytes to enter the CNS.
How Gilenya's action is consistent with CCSVI Theory
CCSVI theory holds that poor blood flow causes abnormal permeability of the blood vessels in the CNS (4). Abnormal permeability allows contents of the blood vessels (lymphocytes, erythrocytes (red blood cells), and other organic material in the blood stream) to "leak" into the CNS. The presence of this leaked material either activates or exacerbates the immune system response we see in MS (4). The goal of CCSVI treatment is to remove the stenoses causing blood flow irregularity that results in blood vessel damage and abnormal endothelial permeability. By freeing up the blood flow out of the brain and spine, the health and normal permeability of the endothelium may be restored, and abnormal leakage of material from the veins into the CNS reduced.
So how does this all relate to Gilenya? Because Gilenya greatly reduces the number of lymphocytes in the blood stream, one would expect fewer lymphocytes to leak into the CNS as a result of CCSVI damage to blood vessels. Also, because CCSVI theory holds that damage to the endothelium is the likely source of these leaks (4), the fact that Gilenya helps decrease endothelial permeability is consistent with the goal of CCSVI in reducing abnormal endothelial permeability.
Thus, two key actions of Gilenya are consistent with (and potentially complementary to) CCSVI theory.
What about Treatment?
The real proof of any approach to MS is not in its underlying theory, but in how effective the resulting treatment is. Here’s where CCSVI and Gilenya differ: Gilenya has undergone many years of research and testing, while CCSVI treatment is still in the very earliest stages of research.
Gilenya was first synthesized in the early 1990s. As an MS drug, it has undergone a series of open label, single and double blinded clinical studies. Novartis, the drug maker, mentions over 4,500 patient hours of data about Gilenya, and that Gilenya has been studied in about 2,600 MS patients.
In contrast, there is only one published study on CCSVI treatment – an open label study involving 65 patients. Fortunately, the results of this study were sufficiently compelling to raise the interest of a wide range of researchers and physicians around the world, several of whom are now either planning or actively recruiting patients for double-blinded CCSVI treatment clinical trials.
It should be noted, however, that rigorous clinical trials of CCSVI treatment are substantially more complex, expensive, and ethically challenging than the vast majority of pharmaceutical trials. Designing and performing a “sham” surgery, for example, is an order of magnitude more complex and expensive than handing out a sugar pill. Moreover, while molecules and substances like Gilenya can be patented and “owned” by pharmaceutical companies with the resources to invest in expensive and time-consuming clinical trials, no one “owns” the basic endovascular techniques used in CCSVI treatment, and at present no single resource-rich organization is currently marshalling the personnel and funding for CCSVI clinical trials (the US. National Multiple Sclerosis Society has thus far declined to fund any clinical trials of CCSVI treatment).
This is all the more reason to publicly and privately applaud and support the courageous physicians and researchers like http://clinicaltrials.gov/ct2/show/NCT01201707?term=ccsvi&rank=1 Dr. Gary Siskin and http://clinicaltrials.gov/ct2/show/NCT01089686 Dr. Manish Mehta, both of whom are now recruiting for double-blind clinical trials of CCSVI treatment.
What about the Side Effects of Gilenya and CCSVI Treatment? Gilenya may cause serious side effects such as “slow heart rate (bradycardia or bradyarrhythmia), infections, macular edema, breathing, and liver problems” (1). Further, because Gilenya is a global immunosuppressant (which means it in no way directly targets MS; rather, its efficacy is a result of systemic changes to the entire immune system), it may affect any given individual’s immune system in unpredictable ways.
Because clinical trial data on CCSVI treatment is limited, the risks of CCSVI treatment remain largely unknown. While angioplasty is now commonplace and is generally considered quite safe, there are important differences in performing angioplasty for arterial conditions as opposed to venous conditions (the latter is sometimes referred to as “venoplasty.”). For those interested in unique CCSVI treatment risks, we suggest you visit CCSVI Alliance’s “Treatment and Risk” section on the CCSVI.org website, which provides a very thorough discussion of potential CCSVI treatment risks. Note, however, that until clinical data is available, the frequency that any of these risks will actually occur is not known.
References
1. www.novartisclinicaltrials.com/webapp/.../displayFile.do?trialResult=2375
2. http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
3. http://www.medscape.com/viewarticle/574422_print
4. Simka, M. Blood Brain Barrier Compromise with Endothelial Inflammation may lead to Autoimmune Loss of Myelin during Multiple Sclerosis (2009). Current Neurovascular Research, 2009, 6, 1-8