Researching New Treatments

The United States spend around 130 billion dollars each year on medical and pharmaceutical research. Why then has it been over 50 years since a new treatment for lupus has been approved and brought to market?

Before we can begin to figure out what needs to be done and why researching and developing new treatments for lupus is important it helps to understand a bit about what the disease is and how it affects people. Lupus is an autoimmune disease in which your immune system attacks your own organs and tissue much the same way it would an infection- basically you are allergic to yourself. Lupus can affect any organ in the body and among the most commonly attacked organs are the skin, joints, lungs, and kidneys. 90% of lupus patients are female, most often diagnosed during their childbearing years. There is no known cure and the symptoms of the disease are often life diminishing and potentially life ending, especially when involved organs include the kidneys, lungs, heart, or liver.

There are only three medications currently approved for the treatment of lupus: aspirin, prednisone, and plaquenil. All of these have dangerous side effects which can be as problematic as the symptoms they are intended to treat. Aspirin is a common cause of stomach problems ranging from nausea to severe stomach ulcers and also acts as a blood thinner which can make it more difficult for blood to clot when someone has an injury such as a cut. It is also one of the most common drug allergies seen.

Plaquenil is an anti-malarial with common side effects such as Nausea, stomach cramps, decreased appetite, diarrhea, dizziness, and headache. Other side effects often seen with plaquenil include fast heartbeat, hair loss/color change, mental/mood changes, ringing in the ears/hearing loss. Among the most serious side effects though are blurred vision and glaucoma. Then there is the most commonly prescribed drug for lupus- prednisone. Prednisone is a steroid medication which often causes changes in mood, weight gain, difficulty fighting infections, and brittle bones. As you can see, these drugs cause as many problems as they solve.
We desperately need to find newer, safer, and less toxic treatments for lupus. In order to do this we need to increase funding for research into new treatments for this disease and others like it.

I am a lupus patient and also a research patient. The primary medications for controlling and managing my lupus are Imuran, an anti-rejection drug being used off label to help prevent further kidney involvement and what I think of as my miracle drug, Lymphostat-B. Lymphostat-B, also known as BenLysta is an investigational drug currently being studied for the treatment of lupus.

Before discussing BenLysta and how it affects me specifically, it might be helpful to know a little about how pharmaceutical research and development works. There are many different things that go into developing new treatments and many different people involved at each stage from the conception of the idea to it becoming available for use. It starts with the scientists and pharmacists who develop an idea or model for a new treatment for a disease or class of diseases and ends finally with the patients who receive the drug during clinical trials that test for safety and efficacy of the treatment before the Food and Drug Administration will consider it for approval.
I interviewed Lu Anne Novello, the Director of Clinical Operations for Human Genome Sciences. Human Genome Sciences is the research group developing BenLysta in partnership with the pharmaceutical company Glaxo-Smith Kline. She has worked in pharmaceutical research for 27 years after graduating from the University Of Connecticut School Of Pharmacy in 1982 with her Doctorate of Pharmacy. Ms. Novello explained how research projects are chosen:
"Drug or biologics can be specifically engineered based on a model or an existing protein and then tested on a specific target. Or a compound could theoretically have more than one therapeutic target. In that instance preclinical studies (work in tissue or animal models) are conducted to help define what indications may have the greatest chance for success in humans. The identified disease areas are also evaluated to determine medical need. The following are considered: how many patients have the disease, how many other products are currently on the market and might your drug have a benefit (greater safety or better efficacy) than what is currently available. Often multiple indications for a product are pursued in parallel. The first one that completes the required testing will be submitted to the regulatory agencies as the initial NDA (New Drug Application) or BLA (Biologic License Application). Other indications are then submitted later in supplemental filings. She also explained to me that all treatments, both chemical and biologic, are subject to many levels of testing before ever being tested in human subjects during clinical trials. All new drugs are put through a series of preclinical experiments testing both the drugs potency and how it acts against different sets of cells. This is done first in a dish, then in rodents, and finally in primates before ever being tested in humans. At each stage of this process different doses are tested for safety and whenever possible for efficacy."

After the preclinical trials are completed the new treatment is ready for tests in humans. There are four different phases of clinical trials which are conducted in humans.

Phase one trials are done in a very small number of, usually healthy, people in order to test for safety (side effects and toxicity) and pharmacokinetics (level of drug in the bloodstream). At this stage there are generally a couple of different dosing levels evaluated in different subject groups. If these tests are successful the drug may move on to phase two studies.

During the second phase the drug is tested in patients with the target indication. This is the first time that the drug is used in patients who have the condition the drug is being developed to treat. Like in phase one, different dosages are looked at for safety but now it is being looked at for efficacy in humans as well. The researchers want to see if the drug behaves as predicted and is safe for patients who are afflicted with a given condition. Because phase two is in large part evaluating safety it is conducted in a small number of patients studies during this phase are considered “underpowered” meaning there is still a risk of statistical error. A drug could possibly be effective but appear not to be due to the small sample size, or vice versa- it may appear effective but turn out not to be any more effective than a placebo or a current standard of care.

Next, if phase two has been successful, is phase three which the new drug will be tested in a larger number of patients. This round of trials examines the drug’s efficacy against current standard of care as well as providing further data on the safety of the drug in a larger number of its’ intended recipients. There are generally at least two different phase three studies and all of these should show comparable results. If these trials show the drug to be safe, effective, and have the potential for improvement in the standard of care for patients then the data is submitted to the FDA and other regulatory authorities for approval.

In addition to Lu Anne Novello, I interviewed Kathy Benish. Ms Benish is the Research Administrator for Kentucky Research. Kentucky Research is a research department involved with conducting clinical trials and is a part of the Kentuckiana Center for Better Bone & Joint Health run by Dr. Steven Stern. She is also the nurse and coordinator overseeing the study I am in and explained the role of the doctor’s offices or clinics in the research process, “The Dr.'s office/clinic is where the trials are being conducted. We are pivotal in getting new drugs to market or approved drugs for a new indication to market, new treatments for patients, and offer treatment options to patients that otherwise would not be available”.

Kentucky Research is currently involved in several clinical trials for lupus and rheumatoid arthritis and in response to being asked what she saw as being most important to help increase the development of new, more effective, and safer treatments for diseases such as lupus Ms. Benish said patient education and involvement is important along and funding for research. “Cost is a huge factor in developing new drugs” then added, “Insurance companies are reluctant to cover patients if they are in a trial. This is a big factor in patient recruitment.” Insurance companies’ refusal to cover patients in studies adds to a patient’s out of pocket medical costs and acts as a deterrent to potential recipients sometimes making it harder to recruit participants for clinical trials. This is despite the fact the group developing the treatment covers the costs for treatment, labs, and visits to the study doctor.

Funding the research for new treatments is one of the biggest problems and something that needs to change. The National Institute of Health publishes its’ research expenditures on its' website each year. It lists what it actually spent on lupus research in 2008 as 126million dollars and includes a projection of 129million in 2009 and 130million in 2010. In contrast, the same page lists 245million in actual spending on herpes and related conditions in 2008 with spending predictions of 251million in 2009 and 255million in 2010.

I stated before that I am both a lupus patient and a research patient. I have been part of a phase four or post-market study for Imitrex and phase three studies for Relpax and Amerge. These are three different migraine medications. These have all come out in the past 20 years along with other medications such as Zolmig, Treximet, and several others. While I am grateful to have these drugs available it perplexes me as to why we have made so many advances in how to treat a migraine yet there has been nothing new for lupus?

Thankfully that may change soon. The study drug I am on for my lupus has successfully completed phase three testing and is expected to be submitted to the FDA and European regulating agencies in the first half of 2010 and may be available for doctors to use in the treatment of lupus patients later in the year.

This study has been very rewarding to be a part of in a couple of ways. First, it actually helps my lupus. I have been on this drug since before it actually had a name. It was simply LBSL-99 when I began receiving it during the first phase two trials over six years ago and was also referred to as Lymphostat-B, probably because it acts by inhibits the biological activity of B-lymphocyte stimulator in order to suppress the immune system. Before receiving the drug I had many days where I was in so much pain and so ill I could not even walk down the stairs at home, much less work or think about finishing my degree. After the first few treatments I began to feel an improvement in my pain and energy levels and my labs started to improve. After six months I tried returning to work and was able to survive the Christmas season in retail. I still have bad days or weeks at times but thanks to BenLysta, my miracle drug, those days are fewer and more manageable.

The real reason why this study has been so rewarding for me is knowing that by participating in this trial and acting as a “human guinea pig”, as my friends have referred to me before, I am helping other lupus patients. I get asked quite often by my fellow “lupies” what the medication is like and if it really helps. Without a doubt it has helped me and when one of my friends who also has lupus thanked me for trying the drug out first it made me smile because I realized that I wasn’t just helping myself, I was helping them too. One of the comments made by Kathy Benish in her interview was, “without patients, we could not do the trials and new drugs would not come to fruition”.

Participating in the trial for BenLysta has taught me many things and has motivated me to return to school and pursue a degree in pharmacology. Even more, it has shown me that there is something that can be done to improve the quality of life for the millions of people worldwide who are living with lupus. We just need to prioritize how we’re spending precious research dollars and pay a little more attention to a disease that is life diminishing, and in about 15% of cases life ending.