The director of the Comprehensive Multiple Sclerosis Center at Thomas Jefferson University provided insight on the potential effect cladribine could have on multiple sclerosis.
Thomas Leist, MD
In the treatment of multiple sclerosis (MS), the concept of essentially resetting the immune system has gained ground in recent years. In theory, this type of therapy would allow for short-term treatment, followed by long periods of disease remission, in which patients would still hold a biologic treatment effect.
Thomas Leist, MD, the director of the Comprehensive Multiple Sclerosis Center at Thomas Jefferson University, has been involved in the clinical development of one of these therapies, cladribine. A purine analog, it is a synthetic agent that targets lymphocytes and selectively suppresses the immune system, with the goal of depleting lymphocytes in order to “reset” the immune system. It has been studied in a pair of phase 3 trials, as well as an extension trial.
To provide further insight into the development and potential of this therapy, Leist spoke with NeurologyLive about it, as well as the concept of the therapy’s mechanism of action.
Thomas Leist, MD: We have a new approach in multiple sclerosis where we utilize agents that are given in short treatment courses, lead to a reduction of immune cells, and, ultimately, will lead to repopulation of these immune cells. The whole concept behind these treatments is the fact that we try to reset the immune system in MS in a direction of a non-self-aggressive, non-self-reactive immune system.
The agent that we have been studying in that particular area is alemtuzumab (Lemtrada, Sanofi Genzyme). We have also, more recently, been studying cladribine (Mavenclad, EMD Serono), but that has not yet come to the market in the United States but is licensed in Europe. This agent has been studied in 2 phase 3 trials and 1 extension trial. The first of the phase 3 trials was the CLARITY trial, the second was the ORACLE trial—which was a trial with patients at the time of a first event, treated with cladribine.
The ORACLE trial, the clinically isolated syndrome (CIS) trial, has been the trial with a quite significant reduction in of the risk of patients to progress to clinically definite MS—so, patients having a second event. The trial has also shown that it delays the likelihood of patients having a next MRI lesion, which matches the 2010 MacDonald Criteria, or the 2005 MacDonald Criteria.
This is a new approach toward the treatment of multiple sclerosis where we give agents that take away autoreactive immune cells and will enable a recrudescence, a growing up, of the immune system that is non-self-reactive. Obviously, these agents are associated with a reduction of immune cells, and so an infection risk is a potential concern. As we looked at cladribine development, this infection risk was higher during a relatively short period of time when patients had low lymphocyte counts. In general, with cladribine, the lymphocyte counts are low-ish, but Grade 3 and Grade 4 lymphopenias have only been observed in a small number of patients.
Cladribine is dosed orally, it is a weight-based dosed in 10-mg tablets that is then adjusted to the weight of the patients. The cumulative dose given in 2 treatment cycles is 3.5 kg over 2 years. Cladribine has had positive results in CIS, but also in relapsing-remitting patients. There, we have the CLARITY trial. The CLARITY trial has been a standard trial and has also had a long-term extension of its original study.
One of the interesting things about the cladribine development program is the fact that, initially, this product was submitted to the FDA based on 1 trial. In that particular trial, the CLARITY trial, there was a small oncologic risk, which gained concern. Since then, obviously, the ORACLE trial has been completed, and also the extension trial of the CLARITY trial—this oncologic risk has not repeated itself in the larger cohort. And because the product development was interrupted, we now have long-term follow-up data for cladribine, up to 5 or 6 years after the actual dosing, and no oncologic risk has at this, point in time, emerged.
One of the questions that potentially arise when using such therapies that are given for short-term cycles followed by long-term disease remission is whether there is a potential utility of such agents—in the main group of individuals that get it, such as women—could allow protection from multiple sclerosis, even at the time when somebody would, for example, consider pregnancy because there is no medication available. Obviously, more data are needed around this, but at least from an intellectual point of view, this is an interesting approach or thinking, that one could control the disease in absence of medication, and then go on with other pursuits in life and other important endeavors.
If we look at cladribine in totality, it is an agent that leads to a relatively lymphocyte-specific action, and this is based on its activity. Cladribine is only active in cells that are relatively deficient of certain enzymes, and these are the lymphocytes. So, the effect of cladribine is significantly directed toward lymphocytes. For example, if we look at the effect of circulating blood cells, then platelets and neutrophils are only minimally affected—lymphocytes are affected, they are reduced, both B and T cells. This reduction of B and T cells is as I have already briefly mentioned, normally at the level of a Grade 2 toxicity not at a level 3 or 4, so a relatively shallow depletion. It has also been observed that the clinically effect is not really dependent on the degree of lymphocyte depletion, so even after replenishing lymphocytes, the biologic effect of cladribine resides in the patient, even though the lymphocyte counts have normalized. This has to do with this concept that one takes T cells and B cells that are autoreactive away from the body and lets a more naïve immune system to grow back.
Cladribine has now been approved in the European community, in Australia, and other jurisdictions including Canada. It is not yet approved in the United States, it is in front of the FDA now. It will be interesting to see how the FDA is going to respond to this particular product, particularly also since this may be an agent that, potentially, could be used relatively early in patients, based on the data from the ORACLE study. From that point of view, it gets closer to whatever terminology we like, a conditioning agent or an induction agent, an agent that potentially at the very earliest stages of multiple sclerosis would reset the autoreactive response and kind of step back to a pre-MS state. Obviously, these are relatively strong statements, but they have to be revisited and looked at. This is a different approach from the currently available maintenance medications where ongoing treatment is needed to maintain a biologic effect.
Transcripted edited for clarity.