There are a number of potentially devastating disorders much more common to one gender than the other. Males are much more likely to develop autism, while females are nine times more likely than men to contract systemic lupus erythematosus (SLE), and are also at higher risk of multiple sclerosis (MS) and other autoimmune disorders. Both autism and SLE have a definite genetic component, but there are other factors that contribute even more to the appearance of these diseases.
Because of the genetic factor, one out of five of people with lupus have a parent or sibling who already has or may contract lupus, and about one in 20 children born to sufferers will get it themselves.
SLE is, in fact, a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks normal, healthy tissues. There is no cure or completely effective treatment, and the only available therapies are those that ameliorate the many symptoms.
The disease is commonly referred to as “lupus,” the Latin word for “wolf.” When SLE was just beginning to be recognized as a medical disorder, it was thought that it was caused by a wolf bite – probably because of the distinctive symmetrical red or purplish scaly rash that at least half of those with the disease develop on their faces, also referred to as a “butterfly rash.”
SLE can affect nearly every organ system in the body and in some cases can be fatal, said Prof. Edna Mozes, a senior immunologist and chemist at Rehovot’s Weizmann Institute of Science in a recent interview with The Jerusalem Post. Mozes has devoted the past two decades to the study of SLE and developed a promising experimental drug called hCDR1, or Edratide, that is going into Phase IIb trials for the US Food and Drug Administration. “It was supposed to be called Ednatide, after my name, but in the end it became Edratide,” she said.
Unlike MS, which affects the central nervous system, lupus can strike the kidneys, skin, joints, lungs, brain heart and blood cells, she said. It can also affect women’s fertility.
About five million people around the world have some type of lupus – SLE affects more than a million Americans, with around 10,000 patients dying of active lupus each year. There are also a few hundred Israeli lupus patients, the vast majority being women in their fertile years. It strikes African Americans and people of Chinese and Japanese origin somewhat more than Caucasians, Mozes said. Although sufferers may have a variety of symptoms, the most common ones include extreme fatigue, painful or swollen joints (arthritis), skin rashes, unexplained fever and kidney problems.
There is no single test for SLE. There are 11 criteria for the diagnosis of lupus and only if at least four of them are positive is the patient diagnosed as a lupus patient. A blood test for antinuclear antibodies (ANA) can help, as these are found in the vast majority of SLE patients, but there are people who test negative for ANA and nevertheless have lupus, and also those who test positive for the antibodies and don’t have lupus.
Thus, it can take months or even years until the diagnosis is confirmed. Patients may even be diagnosed with other autoimmune connective tissue diseases before the medical team settles on lupus. Current treatments include corticosteroids and cytotoxic immune suppressants, which are sometimes effective but involve side effects such as osteoporosis, high blood pressure, suppression of bone marrow activity and a higher risk of cancer.
In a series of publications, Mozes and her team reported that a synthetic peptide that they designed and prepared could effectively cure lupus in mice. They further demonstrated the mechanism by which treatment with their peptide resulted in the remission of the disease.
“There are dogs and mice that get SLE as well as humans,” said Mozes, who added that former president George H.W. Bush’s dog came down with the disease and was treated for it.
As for why 90 percent of patients are women, Mozes explained that the female sex hormone estrogen is certainly a factor, but other elements that are involved include genetic, environmental, hormonal and stress factors.
MOZES, WHO was born in Haifa to parents of Lithuanian origin who settled in pre-state Israel, grew up in Tel Aviv. Her mother was a housewife and her father, Josef Zimberg, the CEO of the Haaretz newspaper. A sister, Drora Goldblatt, also did her doctorate at Weizmann and works for the Health Ministry. Edna studied bacteriology, chemistry and parasitology at the Hebrew University of Jerusalem, completed her doctorate at Weizmann and then did postdoctoral research at Stanford University in California (where she was the only female postdoctorate fellow at that time in her field) before returning to Rehovot.
“I didn’t want to be a physician, but immunology very much interested me, and both my parents encouraged me a lot. When I started studying the immune system, nobody knew very much about its complexity. To me, the immune system was like magic, and fascinating.
I started by investi- gating the genetic control of the i m m u n e response.”
Eventually she got into SLE and myasthenia gravis – another autoimmune disease (composed of the Greek words for “muscle weakness”).
Its most famous victim was Greek shipping tycoon Aristotle Onassis, who married American First Lady Jacqueline Kennedy after her husband John Kennedy was murdered.
The muscle weakness, including in the eyelids, is caused by circulating antibodies that block acetylcholine receptors where the nerves connect with the muscles. There is no effective drug to treat the disease, and when it kills it’s usually because the complications affect respiration.
As for SLE, at first the Weizmann team had to learn about the disease. “We didn’t know the cause of SLE, but were intrigued that some mice get SLE spontaneously when they are eight or 10 months old. We developed a mouse model in which the rodents are always affected, and could follow the disease development.
We found that we were able to control it with our synthetic peptide, hCDR1, that down-regulates the SLE-related autoimmune process.
The peptide doesn’t destroy cells that are not related to the autoimmune disease and therefore it is specific to SLE in its function. The drug has to be injected once a week and not swallowed, but in the future, it could become an oral pill. It works well when given orally to mice, but the rodent’s gastrointestinal system is different than [that of] humans.”
After it was found to improve significantly the nervous systems and kidneys of mice (over 40 peer-reviewed journal articles have been published on hCDR1), the drug went on to early clinical trials with encouraging results. Teva performed three clinical trials involving over 400 patients, and the drug was found to be very safe. In the last study that Teva performed, on hundreds of patients, the drug failed what is known as the “primary endpoint,” which is the key indicator in the study, but it showed a “secondary endpoint” effect – usually an experimental endpoint.
Because it failed the primary endpoint, Teva returned the drug to Weizmann.
Timing is everything, and shortly after Teva returned the drug, the FDA changed its guidelines and now required trials on lupus to have as their primary endpoint one of two endpoints – one of them being the secondary endpoint in the Teva trial and which showed a positive effect.
Yet the FDA approval process is very long.
The drug has so far proven to be very safe, and to have no side effects. If all goes well, said Mozes, Edratide could come on the market around 2019. It is now owned by XTL Biopharmaceuticals, a company based in Herzliya Pituah whose chief executive officer is Josh Levine.
“The only lupus drug approved by the FDA to be put on the market in the past 50 years is Benlysta of Human Genome Sciences/ GlaxoSmithKline,” said Levine. “It is not a breakthrough drug. There is an unclear correlation between the SLE auto-antibodies and disease severity. It is estimated that only about 15 percent to 20% of lupus patients are candidates for Benlysta, and the launch of the drug in March 2011 has been slower than expected due to unclear patient selection and questionable cost effectiveness.” Levine said the cost of that SLE drug is high, at tens of thousands of dollars per year.
“Edratide targets an earlier stage of the SLE process than Benlysta. There a large number of SLE patients that live for a relatively long time with a lousy quality of life and with no effective treatment” added Levine, who made aliya from New York in 2000 and previously worked for Teva before joining XTL.
The Herzliya Pituah biotech company is also working on experimental drugs to treat multiple myeloma and schizophrenia. If the firm succeeds in making a difference, patients around the world will beat a path to its door.