The Barrow Neurological Institute published its Phase 2 trial design online today for their pending early stage investigation of Actemra™ (tocilizumab) in people diagnosed with ALS.  The investigators are primarily seeking to understand whether the immunomodulatory compound can be tolerated in ALS patients “without causing too many side effects.” This trial is similar to an earlier clinical trial conducted at the University of California in Los Angeles in 8 PALS. The earlier trial showed Actemra to be effective in reducing the levels of specific pro-inflammatory markers, but was neither powered to measure nor reported on any potential effect on disease progression.

The Barrows sponsored clinical trial is not currently enrolling, but four ALS clinics will enroll a total of 24 PALS.   It is important to note that while the study is placebo controlled, it does not follow the standard 50:50 ratios. In this trial, two-thirds of participants (16 of the 24) will be given Actemra intravenously, while the remainder (8) will receive a placebo.  Many clinical trials in ALS are moving toward having fewer people on placebo, especially in early stage research. For example, the ALS Therapy Development Institute’s trial of Gilenya, another immune system targeted compound, randomized two-thirds of its participants in the active treatment arm of the study.

What is Actemra (tocilizumab)?

For more than 20 years now, researchers have shown the immune system to be operating differently in people diagnosed with ALS. While it is not generally believed that ALS is caused by a faulty immune system, many researchers believe that the immune system may be playing a role in disease progression following onset. There have been a number of preclinical and clinical experiments conducted on compounds which may alter the function of the immune system in ALS patients and restore it to a more normal state.  Actemra is an FDA-approved compound for the treatment of rheumatoid arthritis, an autoimmune disease. It is thought to provide benefit by blocking the receptor for a specific substance (interleukin 6) known to play a role in the activation of specific immune cells, such as T cells, which may play a role in the progression of ALS due to aberrant behavior.  

The makers of Actemra, Roche, are exploring the application of the drug in a number of different additional disorders, including scleroderma, for which they were recently granted breakthrough therapy designation by the FDA.  Roche’s subsidiary biotechnology company, Genentech, is collaborating with Barrows on this clinical trial. Actemra is an immunosuppressive monoclonal antibody which will be delivered intravenously in this clinical trial.

What were the results from the earlier trial at UCLA of tocilizumab in PALS?

The UCLA trial of tocilizumab in ALS patients occurred several years ago, with results published in 2012. That study enrolled a total of 8 people diagnosed with ALS and 5 healthy controls. Prior to dosing participants with the drug, researchers in the earlier study separated participants into two groups depending on the level of interleukin 6 (IL6) in blood serum samples collected. This led to the 8 PALS being separated into two groups, with one having increased expression IL6 prior to treatment and the other with either normal or decreased expression prior to treatment.  The UCLA team reported that treatment with Actemra reduced IL6 levels in patients who showed elevated levels before treatment. Several other markers of inflammation were also measured and reported.  A follow up study in 11 PALS was also done to confirm the original potential impact of Actemra on levels of IL6 found in blood serum. In summary, the trial found Actemra to be effective in modifying the expression of pro-inflammatory cytokines and chemokines in those patients with elevated levels prior to treatment. No claims of efficacy on disease progression in either study were made.  

What is the difference between these two trials?

Both of the trials were designed to measure specific biomarkers of how the immune system is operating in ALS patients by measuring, among others, the levels of the protein IL6. In the UCLA study, measurements were made from blood serum samples collected from participants, whereas in the Barrows trial, investigators will collect and investigate markers of immune system activity from both blood and cerebral spinal fluid samples collected from participants. In addition, in the UCLA trial Actemra was only given once, whereas in the current trial, it may be administered up to three times in the active compound arm of the trial. Neither study was powered or designed to adequately measure the efficacy of Actemra on disease progression. 

Bottom line:

Neither the earlier UCLA trial nor the current Barrows trial were designed to measure efficacy of tocilizumab on disease progression. The UCLA trial on tocilizumab was both very small and very short, whereas this new trial will include a larger cohort and exposure to the drug will occur for a longer period of time (up to 3 doses). Therefore, the Barrows trial should provide greater information on how Actemra affects specific markers of inflammation in ALS patients over a longer period of time as well as if multiple doses with the compound produce any safety concerns.

It is not known if Actemra (tocilizumab) is an effective treatment for ALS. The Barrows trial is a safety and tolerability study only, and it is unlikely to produce sufficient evidence to support any specific claims of efficacy on disease progression. It should produce a significant amount of biomarker data building on the earlier UCLA trial. The ALS Therapy Development Institute will continue to monitor this clinical trial. To receive updates about the status of this trial, please subscribe to our global ALS clinical trial database.

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