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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.

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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.

Plaquenil

Plaquenil

By A. G. Moore

One of the first medications a lupus patient may be offered is Plaquenil. While every drug has side effects, Plaquenil is generally considered to be “safer” than many other medicines prescribed to treat lupus.

Researchers are finding out more about this drug all the time; the current state of science indicates that Plaquenil is effective against lupus, and some other inflammatory diseases, because it creates an inhospitable environment for some actors in the immune process. In this way Plaquenil inhibits the immune response and thus also inhibits inflammation.

Though Plaquenil is considered to be relatively “safe”, there are several populations in whom great care should be taken before the  medicine is prescribed. If you are over the age of 60, the chance for retinal damage increases. If you have psoriasis or porphyria, taking this drug may exacerbate your condition. Anyone with reduced liver or kidney function should also consider carefully if the risks of the drugs outweigh its benefits. Plaquenil can be extremely dangerous for children, especially children under the age of 6. People who have a metabolic disorder called G6PD run the risk of developing severe anemia on Plaquenil therapy.

The most commonly addressed side effect of Plaquenil therapy is retinal damage. Every responsible opinion I have read prescribes a visual screening before therapy begins and then a re-check several weeks later. While it is rare for eye damage to occur, especially if therapy lasts less than five years, it is important to keep in mind that once damage occurs, it is most likely irreversible. And the changes in the retina may not be noticed subjectively but can be detected by sophisticated testing in the ophthalmologist’s office. Many doctors recommend a yearly check-up; some recommend six months. If I were on Plaquenil I would go for six months because I’d like to detect damage before it goes very far.

With all of the warnings listed above (this is just a partial list of possible side effects) it would seem that Plaquenil is a dreadful drug. It really isn’t for most people. Lupus is a dreadful disease and sometimes you have to take out a big gun to control it. Plaquenil is actually one of the smaller guns in the arsenal against lupus.

Originally used as a treatment for malaria, Plaquenil is useful not only in treating SLE (though not severe SLE), but also other inflammatory diseases. The drug is supposed to be particularly effective at treating discoid lupus.

All of the sources I consulted implicate higher-dose and longer-term Plaquenil treatment in increased risk of eye damage. So if you are on Plaquenil for many years, certainly as many as 8, your doctor might begin a conversation with you about switching to an alternative treatment.

Several helpful sources I used in order to get information for this article were:

Plaquenil Data Sheet: http://www.medsafe.govt.nz/profs/datasheet/p/Plaqueniltab.pdf
eyeupdate.com: http://www.eyeupdate.com/plaquenil-updates.html
and
PDRhealth: http://www.pdrhealth.com/drugs/plaquenil

I think anybody contemplating taking this medication should read and understand each of these sources. In making this recommendation I am operating on the theory that, though we may not know everything the doctor knows, we always should be vigilant in supervising our own medical care.


Plaquenil and Quinoric

By A. G. Moore 
10/20/2014
This week I read several posts on Lupus UK which addressed the question of whether Quinoric was as effective as Plaquenil in treating lupus. Several people on the site suggested that the only difference between the two drugs was in the “filler” added to the active ingredient, hydroxychloroquine. And several people added that their pharmacist, or doctor, had assured them the preparations were “identical”. Which suggests to me a larger issue: are generics and substitute formulations for established drugs truly “identical” in formulation and do they behave identically when consumed?

In an effort to examine the interchangeability of generics for established drugs, I took a close look at Plaquenil and Quinoric. Are these two “identical”? Can one drug be substituted seamlessly for the other? I found a list of constituent ingredients for each of these drugs so I could make a comparison.

Both drugs, I discovered, do contain the same active ingredient in equal quantity: 200 mgs of hydroxychloroquine. The differences between the drugs, as some people suspected, is in the “fillers”. So I looked at those “fillers”.

Plaquenil (Manufacturer Sanofi. List derived from:http://www.drugs.com/pro/plaquenil.html)

Calcium Phosphate, Dibasic, Anhydrous

Hypromelloses

Magnesium Stearate

Polyethylene glycol 400

Polysorbate 80

Starch, Corn

Titanium Dioxide

Quinoric (Manufacturer Bristol Labs. List derived from

Maize Starch

Calcium Hydrogen Phosphate dihydrate

Colloidal anhydrous silica

Polysorbate 80

Purified Tale

Magnesium stearate

Hypromellose

Titanium dioxide

Macrogol 6000

While the two lists of constituent ingredients are similar, they certainly are not the same. But the question remains, do these differences matter? I took a look at one ingredient that appears to be almost identical.: PEG.

On the Plaquenil list PEG (Polyethylene glycol) is described as Polyethylene glycol 400. On the Quinoric list PEG comes in a different formulation: Macrogol 6000. In industry, these two forms of PEG have different uses because they interact with environments differently. One, Macrogol 6000, is commonly used as a laxative, among other things. The other, Polyethylene glycol 400, has a lower molecular weight and is more liquid: this chemical is often used in printer ink, as well as in pharmaceuticl preparations. It’s impossible for me to say if these two forms of PEG are processed identically in the human body.

There’s one “filler” included on the list for Quinoric which is not included on the list for Plaquenil: silica (Colloidal anydrous silica). Silica is abundant in the environment. This compound has been linked to a numboer of autimmune diseases. Whether inhaled, absorbed through the skin or ingested orally, silica has a well-established association with lupus and rheumatoid arthritis, among other other inflammatory conditions. Silica is almost ubiquitous. It’s in soaps, cleaning products, paints and other common household items. Some sources that discuss silica’s role in autoimmunity are: http://ntp.niehs.nih.gov/NTP/Noms/Support_Docs

And

http://books.google.com/books?id=eP49JCMVWKMC&pg=PA55&lpg=PA55&
So, I ask,  what is silica doing in a preparation that’s prescribed for people who have lupus?

There is a pat response to this and other questions I raise in this essay: these substances are harmless, they are inactive and largely inert. They serve merely as vehicles for delivery of crucial medication.

I’m going to refute these glib reassurances by turning to Dr. Phil Lieberman of the American Academy of Asthma, Allergy & Immunology. Dr. Liebermans is asked about an adverse reaction a patient had to one constituent ingredient in Quinoric: Macrolog 6000. The doctor responds: “..it is best to try and avoid polyethylene glycol as carefully as possible. This is a difficult task given the ubiquitous nature of these substances, but it is clearly the safest strategy to employ.”( see: http://www.aaaai.org/ask-the-expert/anaphylaxis-to-polyethylene-glycol.aspx ).

I’m not a chemist, pharmacist or doctor. But I do know what the word identical means. And I do know that when there is a change in formulation—say from PEG 400 to Macrolog 6000—it’s because one formulation behaves differently from another. And if two substances are not the same, then they are not the same.

Plaquenil and Quinoric are prescribed for a very particular population, a population of people who have heightened immune responses. Allergies, even rare allergies, are common in this population. Extreme caution should be taken when introducing any new element into the environment of someone with such a heightened and unpredictable response to potential antagonists.

Plaquenil and Quinoric are not identical; they may not be absorbed the same into the bloodstream, or processed in exactly the same way by the digestive system. There may be constituent ingredients that are irritating in one and not the other.

This issue is not unique to Plaquenil and Quinoric; the issue of interchangeability between knock-off drugs and brand name drugs is one that affects every single person who has to take medicine: that is, all of us. Glib rejoinders that medicines are “identical” do not address the matter. More honest would be an admission that there are differences in manufacturing and processing between knock-offs and brand drugs. For most people, in most cases, these differences may have no consequence. However, there’s no telling how a particular formulation will be tolerated by a particular individual.

This is the truth—perhaps not convenient, but nonetheless true. And truth is something every patient has a right to expect from a medical provider.