Analysis of Lemtrada data by researchers at Queen Mary University suggests issues in T/B cell repopulation dynamics

In a post titled Unpublished Data May Point to Link Between Lemtrada and Other Autoimmune Diseases in MS Patients , Multiple Sclerosis News Today began with text:



Previously unpublished results of clinical trials of Lemtrada (alemtuzumab) appears to contain key information as to why many multiple sclerosis patients who use it [Lemtrada] develop other autoimmune diseases.

Researchers looked at the immune cell mix after Lemtrada depleted many of those cells. They discovered that certain B-cells repopulate the body earlier than key regulatory T-cells, leading to an imbalanced immune system that is prone to turn on itself.

Although the findings pertained specifically to Lemtrada, they suggest that naturally occurring immune cell imbalance could lead to autoimmune diseases, researchers said.




This news blurb was based on a scientific paper titled Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab
appearing in JAMA Neurol., published online June 12, 2017. doi:10.1001/jamaneurol.2017.0676. The first named author is David Baker, Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England.

The work is summarized at Jamanetwork in the following way:


Results Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (−80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.

Conclusions and Relevance Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.



The multiple sclerosis news today website indicated that the data analyzed by the Queen Mary University people was obtained through a Freedom of Information request to the European Medicines Agency, thereby making this story relevant to intellectual property:


Researchers from Queen Mary University of London used a Freedom of Information request to the European Medicines Agency to obtain full results of the Phase 3 clinical trials of Lemtrada.

Scientists know that many people who take Lemtrada develop autoimmune diseases. Those who conducted the trials had presented some of the unpublished information at conferences, but had yet to submit studies involving those results to scientific journals.

“We were very surprised to find such important information on B-cell dynamics were only partially described and remained unpublished, even though they were observed and analysed several years ago following the pivotal Phase 3 trials,” Klaus Schmierer, the senior author of the study, said in a press release.



The second sentence of the press release [available at https://www.eurekalert.org/pub_releases/2017-06/qmuo-put061217.php ] noted "there is an almost 50% chance of secondary autoimmune diseases..."

Separately, an article in medpagetoday by Judy George begins:


In an analysis of previously unpublished phase III data, U.K. researchers reported a massive, rapid repopulation of a subset of B cells without effective T-cell regulation in patients with multiple sclerosis (MS) treated with alemtuzumab (Lemtrada), which might have created an environment for secondary autoimmune disease.

Examining lymphocyte reconstitution data from the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) studies, Klaus Schmierer, PhD, FRCP, of Queen Mary University of London, and colleagues found that alemtuzumab depleted CD4 T cells by more than 95%, including regulatory cells and CD8 T cells, which remained well below reference levels throughout the trials. Although the drug also initially depleted CD19 B cells by more than 85%, immature B cells increased by 180% and converted to mature B cells over time. These changes were associated with the rapid development of alemtuzumab-binding and alemtuzumab-neutralizing antibodies and subsequent secondary B-cell autoimmunity. This B-cell hyperpopulation masked a long-term depletion of CD19 memory B cells that may underpin the efficacy of alemtuzumab in MS, the researchers reported in JAMA Neurology.



link: https://www.medpagetoday.com/neurology/multiplesclerosis/66037

**Separately, from an editorial by Steinman about the matter