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Epratuzumab: Targeting B-Cells To Treat SLE

As research laboratories across the world investigate new lupus treatments, efforts increasingly focus on suppressing B-cell activity.  B-cells are major actors in the normal immune response.  With lupus, the immune response is not normal and neither is the behavior of B-Cells.  During an active disease phase, the immune system attacks organs and wreaks havoc. B-cells play an important role in this process.
Historically, lupus medicines have sought to control the aberrant immune response by tamping down the entire immune system.  Established remedies (for example: glucocorticoids  and cyclophosphamide) are not very specific in suppressing the immune system. Instead of acting on the parts of the system that are especially aggressive, older medicines depress the general immune response. While this approach is often effective in controlling symptoms, it can sometimes have a devastating impact on the overall health of the patient.
An analogy to the traditional approach might be found in the case of a broken light switch. In order to repair the switch, an electrician could shut down all the circuits in a house. This certainly would insure that electricity isn’t flowing to the broken switch–it would also insure that electricity isn’t flowing anywhere else in the house, either. A total shutdown might have far-reaching consequences–melting ice cream, for instance.  However, if the electrician decided to shut off only the circuit associated with the broken switch–that is, if she/he targeted the problem area–disruption in the household would be minimized.
That’s the principle behind targeted B-cell suppression. If only B-cells are affected, the impact on the patient might not be as widespread as it would be if an older generation, immune-suppressant drugs were administered.
The problem with new generation, B-cell-targeting drugs is that, so far, they haven’t proven to be very effective. This is the case with belumimab and rituximab. While both of these drugs are prescribed at present and do help people in certain situations, neither has lived up to its early promise.
Epratuzumab is a B-cell-targeting drug with a difference. This drug doesn’t try to suppress all B-cell activity.  It is designed to address only a specific part of the B-cell: CD-22, which is on the surface of the cell.
It is believed that a major benefit of epratuzumab over other B-cell-targeting drugs may be that it does not depopulate all of the B-cells in the course of treatment. It seems that epratuzumab only eliminates “up to 45% of circulating B-cells“.  Rituximab, on the other hand, eliminates  greater than 90% of circulating B-cells.  Since B-cells are essential for a robust immune response, wiping these cells out increases the risk of infection. Keeping viable B-cells might help to limit that risk.
Epratuzumab has gone through Phases I and Phase II clinical trials. Phase III is currently underway.  A January 2013 article published in the Annals of Rheumatology describes the drug as promising. The journal reports that epratuzumab was well tolerated by study participants, even at high doses (2400 mg. week); also, the journal reports, trial subjects who received the medication experienced better outcomes than the control group that received placebo.
In February 2015 Euroscan (a European evaluating organization) issued a report on the safety of epratuzumab and side effects experienced by study subjects. Side effects were noted to have occurred as follows: 10% experienced conjunctivitis; 45% upper respiratory infections; 28% diarrhea and 28%  headache; 14% experienced migraine and 34% caught a cold; 24% experienced nausea; 24% had bronchitis; dizziness was reported by 10%; 10% ran a fever; sinusitis was reported in 31%; abdominal pain occurred in  31%; 10% had chest pain; 10 % had a cough.
Phase III of the epratuzumab clinical trial has 1400 participants; these patients have moderate to severe SLE. The final report on Phase III will be issued in 2019.  The drug’s manufacturer, UCB and Immunomedics is optimistic, based on the results of  Phase I and Phase II.  UCB reports that study participants who received epratuzumab showed a  “24.9% treatment advantage over placebo”.
Will epratuzumab  be a ‘magic bullet’ for lupus patients? A lot of people certainly hope so. Clinical trials and actual practice will prove whether or not this hope is misplaced.
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Rituximab Update

In September of 2012 I posted a blog about a biologic, Rituximab.  Some researchers had hoped this medication would prove to be an effective treatment for SLE.  Unfortunately, Rituximab  did not live up to expectations. However, the drug has been used to treat SLE  in rescue situations.  As such, it is tried when other options have failed. In many of these cases, Rituximab has been effective, especially when used along with  other drugs.
Even though clinical trials of Rituximab have not yielded promising results, investigation continues to see if it might be useful as part of a regimen with other lupus treatments.  As  experience with Rituximab accumulates–in doctors’ practices and in trials–data  is collected about potential side effects.  It is important for physicians and patients to be alert to these so that prompt action may be taken, if necessary.
A 2015 Hindawi Journal article reports a case of early-onset neutropenia and thrombocytopenia that was associated with the administration of Rituximab. The patient’s treating physicians entertained the possibility that these conditions may not have been caused by Rituximab but may have been a manifestation of SLE.  This analysis was rejected because the patient’s clinical profile did not support the conclusion.
This case of early-onset neutropenia and thrombocytopenia associated with Rituximab is unusual, if not unique. The authors of the Hindawi article contemplate the possibility that the side effects  may have also occurred in other cases but were not detected.
In any event, both  neutropenia and thrombocytopenia were transient in this case.  The  conditions cleared up 12 days after Rituximab therapy stopped.
risk of neutropenia is infection; a risk of thrombocytopenia is bleeding.
One thing that should be remembered as side effects of Rituximab are discussed: the medicine is used for very sick people, people who may not have many other options. Side effects will likely not be a reason to avoid treatment, but being aware of those side effects may help to keep the patient safe while treatment proceeds.

Accelerating Medicines Partnership

The US government, Big Pharma and non-profit organizations have agreed to work together in a novel approach to finding effective treatments for lupus and other diseases. Called AMP (Accelerating Medicines Partnership), the collaboration would involve pooling research and information in the early stages.  All “partners” in the project would be able to learn from the work of others in the group.  The emphasis would be on finding biomarkers that would aid in the development of targeting drugs.

AMP grew out of the frustration of patients and doctors.  Access to effective drugs for devastating diseases, such as lupus and Alzheimer’s, is woefully limited.  Progress in finding new treatments has been slow. One of the reasons for this, some have suggested, is that competing firms doing research often duplicate the efforts of each and thus waste valuable time.  If all the research results could be pooled and both private and public resources dedicated to exploiting those results, progress might be realized.

The unique aspect of AMP is that although competing private companies would pool information on the early end of research efforts, at some point competing companies would separate and develop their own products. These, then, could be sold for profit. Pooling information would no longer be part of the process.

While AMP seems to offer great potential for advances in the treatment of certain diseases (the list is limited to lupus, Alzheimer’s, rheumatoid arthritis and diabetes), there are some researchers who question the approach.  Dr. Michael D. Lockshin, at the Hospital for Special Surgery in New York, wonders if the AMP approach for lupus is too narrow in focus.  Dr. Lockshin explains that lupus is a disease of many manifestations. He believes that effective treatments for lupus may emerge from AMP but that to eradicate the disease completely,  “...you will need to go into other fields.”

AMP is projected to continue for five years.  Results are scheduled to be reviewed regularly. Whatever questions may be raised about narrow focus or eventual profits reaped, one thing is certain: millions of people will benefit if this collaboration yields effective treatment for even one of the targeted diseases.

Lupus and Clinical Trials


 By A. G. Moore 11/23/2013
 Melingue_Jenner
 
 Edward Jenner injecting James Phipps, his gardener's
 son, with cowpox
 Lithograph by Gaston Melengue
 Wikimedia Commons, public domain, Copyright expired

Sixty years ago, when Flannery O’Connor learned she had lupus, one medication was available to treat her disease: hydrocortisone. Twenty years before her diagnosis, Edward O’Connor, her father, learned that he had lupus.  For him there was no treatment. Times have changed since Flannery and her father battled lupus. Today the list of treatment options is long. These options exist because researchers have worked tirelessly to solve the lupus puzzle and because they were aided in their efforts by the participation of countless lupus patients in clinical trials. While much of the work researchers do takes place in the laboratory, the proving ground for their investment is the clinical trial. Currently there are clinical trials underway that are exploring new theories in lupus therapy. One of these theories has been described by Dr. Timothy Niewold, who is a scientist affiliated with the Mayo Clinic. Dr. Niewold is investigating the role of interferon in lupus. There is clear evidence that in some people levels of interferon rise with disease activity. In certain instances, lupus has actually been precipitated by administration of interferon (for an unrelated illness). With the apparent association between interferon levels and lupus, it has been suggested that decreasing interferon production might temper symptoms of the disease. Drugs are being designed that are supposed to do just that. Targeting interferon is one example of the trend in lupus treatment to zero in on specific components of the immune response–rather than suppressing the entire immune system. When Flannery O’Connor was prescribed hydrocortisone, the drug was effective because it stopped her immune system from attacking her organs. However, shutting down the whole immune system is a rather blunt way of dealing with autoimmunity. It’s kind of like trying to weed the front lawn with a scythe; maybe the job gets done, but a whole lot of grass and flowers are sacrificed in the process. Shutting down the immune system can have devastating consequences. It is hoped that by targeting specific actors in the system, treatment may not only be more effective but may have less dramatic side effects. One of the interferon-targeting drugs currently under investigation is sifalimumab. Dr. Niewold (of the Mayo Clinic) explains that an important aspect of research on interferon-targeting medications is understanding how this cytokine acts in people from different ethnic backgrounds. As sifalimumab goes through its different trials, it is becoming clear that interferon does not have equal significance for all ethnic groups. For example, interferon activation in African American SLE patients is dependent on the presence of autoantibodies; this is not true for European Americans. Dr. Niewold states: “This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.” Targeting specific aspects of the immune system is the theory behind the development of other lupus therapies. B and T cells, for example, are known to be very aggressive in active lupus. Belimumab , currently prescribed for certain types of lupus, targets B cells and Abatacept, which is an RA drug under consideration for lupus, targets T cells. Both drugs are currently in clinical trials. Clinical trials are essential if new therapies are to come on the market. They also may be of help to those who volunteer as subjects, because there is possibly the opportunity to receive novel and effective treatment. However, every person who volunteers as a subject should be clear about the goals of the study for which they have been recruited. Not every study has as a primary endpoint improvement in participants’ disease status. Some studies examine other aspects of drug development. Volunteers should never lose sight of the fact that participation may carry with it significant risks. One research paper I came across illustrates the importance of being informed before becoming a volunteer. This paper gives the results of a clinical trial in which sifalimumab was studied. The primary purpose of the trial is described: “..to evaluate the safety and tolerability of multiple doses of intravenous (IV) sifalimumab in patients with moderate-to-severe SLE.” Secondary objectives of the trial are also described: “..to evaluate the PK (Pharmacokinetics) and immunogenicity” of the drug. Only as a third and almost incidental objective is observation of the effect sifalimumab has on disease activity. The research paper describes this third objective in the following words: “…measurements of disease activity…were included only as an exploratory end point… ” The clinical trial described by this research paper has obvious significance for lupus treatment; finding out dose tolerance and learning about adverse side effects are important pieces in the development of a possibly valuable lupus intervention. However, these are findings that have general importance and likely will not immediately benefit study participants. It does not seem that those who conducted the study expected subjects in the clinical trial to experience sustained improvement in disease status; that was not the study’s defined prime objective. This leads me to repeat the following: if you are considering being a volunteer in a clinical trial, make sure you understand what it is that the researchers hope to learn from that trial. Does the trial offer participants an opportunity to reap the benefits of new lupus treatment, or are participants merely being mined, as it were, for information that may contribute some day to a good lupus intervention? Know that there are risks associated with participation. In the study described above, for example, some participants did die. Whether or not these deaths were attributable to sifalimumab is not certain, though, as the paper states, for at least two of the deaths, “… a potential role of the drug in contributing to the infection cannot be excluded.” Without clinical trials there cannot be new drugs to treat lupus. Volunteers for these trials are essential if the trials are to succeed. However, if you choose to become a subject, be clear about what it is you are submitting to. And then, if you are satisfied with the risk/reward ratio, go for it. You and everyone else with lupus may benefit.

Neutrophil Extracellular Trap

Neutrophil Extracellular Traps 

By A. G. Moore

This isn’t about basketball or hair management; this is about autoimmunity. It seems that one of the latest cuplrits to be discovered in the search for lupus antagonists is something called the neutrophil extracellular trap(see http://www.jimmunol.org/content/187/1/538.short).  Neutophils are the most plentiful disease-fighting cells in the immune system. The role of neutrophils is to attack and kill invading organisms. These highly motivated soldiers in the immune system’s army are willing to commit suicide in order to fulfill their mission. They do this by releasing chemicals between the cells. The chemicals from different neutrophils join together and form a trap, which serves as a kind of net to capture and destroy pathogens. In order to release enough of the deadly material to be effective, the neutrophil has to deplete its own supply and die. It does so willingly.

Unfortunately, this ally of the body, in waging war, sometimes does damage to the very organism it seeks to protect. When the NETs (neutrophil extracelluar traps) are floating around in the bloodstream they can cause inflammation.

The discovery of the role that NETs play in the development of inflammation is very important to understanding the mechanism which precipitates lupus flares. The more researchers understand this process, the closer they get to thwarting the process. Not only may it be possible to design better therapies so that many of the damaging effects of lupus can be avoided; it may also be possible, with an understanding of the role that NETs play in inflammation, to find a cure and maybe even prevent lupus.