Trimesta (oral estriol)
For decades, women with multiple sclerosis have noticed that they tend to do better while they are pregnant. That has led to an experimental drug for the disease that's based on a hormone associated with pregnancy.
The hormone is a form of estrogen called estriol. It's abundant in a woman's body only when she is pregnant. Adding estriol to treatment with an existing MS drug cut relapses by 47 percent in a study of 158 women presented at the American Academy of Neurology meeting in April.
The result is "quite remarkable," says Rhonda Voskuhl, an author of the study and a neurologist at the University of California, Los Angeles. It suggests that estriol could greatly enhance the effectiveness of current MS drugs, Voskuhl says. Those drugs, which are designed to modulate the immune system, can cost up to $60,000 a year.
Multiple sclerosis is a disease that damages the myelin sheath covering nerve fibers. Researchers believe the damage is caused at least in part because the body's own immune cells begin attacking myelin. About 400,000 people in the United States have multiple sclerosis, with symptoms ranging from muscle weakness or paralysis to difficulty thinking.
The new research on estriol was inspired by decades of anecdotal reports from women like Melissa Sherak Glasser of Woodland Hills, Calif. Glasser is 41 now, but was diagnosed with MS when she was just 15.
She remembers putting one hand into a tub of bathwater to check the temperature and being surprised that it felt cold. "Then I put my other hand in and it was burning hot and I thought OK, something's wrong," she says.
An MRI scan showed that Glasser had MS. But Glasser didn't let the disease slow her down much. She was a cheerleader in high school, then went to college and graduate school and got married, despite relapses that caused temporary blindness, vertigo and difficulty walking.
When Glasser was in her mid-20s, she got pregnant. And one day, during an episode of morning sickness, she realized something surprising: her MS symptoms had gone away. "I felt so horrible with all the pregnancy hormones, and I had to laugh," she says.
Glasser reported this to neurologists at UCLA who had been monitoring her MS since she was diagnosed more than a decade earlier. They weren't surprised. They'd heard stories like that before from women with MS. And pregnancy's effect on MS symptoms had been confirmed by a large scientific study in 1998.
So by the time Glasser became pregnant for the first time (she has four children now and was free of MS symptoms during all four pregnancies), Voskuhl and other researchers were already hard at work trying to identify the factor that was protecting pregnant women with MS. "If we could just figure it out, we would have an inroad to a major discovery," Voskuhl says.
The researchers knew that during pregnancy, a woman's immune system changes. "Pregnancy involves a fetus, which has half of the father's proteins on it," Voskuhl says. "So it's half foreign. In order to not reject that half-foreign fetus, the mother's immune system shifts."
Voskuhl figured that whatever was causing that shift was also protecting the woman's nerve fibers from MS. And she suspected a key factor was the hormone estriol.
So the researchers gave estriol to mice with multiple sclerosis and waited to see whether it would help them. "And indeed it did," Voskuhl says. "The mice were not paralyzed, they were walking around fine. It was just a dramatic reduction in their disease." Doses of the pregnancy hormone even worked in male mice.
Voskuhl was confident that estriol could help people with MS. But it took more than a decade to find out.
Drug companies weren't interested in estriol because it isn't a patented chemical, Voskuhl says. So she turned to the National Institutes of Health, the National Multiple Sclerosis Society and foundations, including one set up by the family of Melissa Sherak Glasser.
Ultimately, Voskuhl got the millions of dollars she needed to conduct a two-year trial of estriol in women who also were taking the widely used MS drug Copaxone. The success of that trial clears the way for a much larger study that can be submitted to the Food and Drug Administration for approval.
Glasser is confident that estriol will ultimately be approved as a treatment for MS and hopes to be one of the first people in the U.S. to get a prescription.
Source: Copyright 2014 NPR (02/06/14)
Female hormone estriol, combined with Copaxone, reduces MS relapse rate by nearly 50 percent(30/04/14)
A study conducted by Dr. Rhonda Voskuhl, a UCLA neurologist, shows that combining estriol, a female hormone, with Copaxone, a medication currently used to treat multiple sclerosis, reduced the relapse rate of MS by nearly 50 percent with only one year of treatment.
Voskuhl presented the results of the preliminary Phase II clinical trial today at the annual meeting of the American Academy of Neurology in Philadelphia.
The randomized, double-blind, placebo-controlled trial involved 158 women with relapsing-remitting MS. At 16 sites across the U.S., one group of women was treated with Copaxone, a commonly prescribed, standard-of-care drug for MS, and an 8 milligram estriol pill each day; others received Copaxone and a daily placebo pill. After 12 months of treatment, the relapse rate for the Copaxone-plus-estriol group was 47 percent lower than that of the group that took Copaxone plus a placebo.
The test also showed that women who were taking Copaxone plus estriol scored higher on cognitive tests after one year than did women who were taking Copaxone and the placebo.
Voskuhl found that, after two years, patients taking Copaxone and the placebo began to show improvement, but those results took longer to appear and were not as strong as those of the group taking Copaxone plus estriol.
MS is an autoimmune and neurodegenerative disease that affects 400,000 people in the U.S. Relapsing-remitting MS, the most common form, can result in such permanent disabilities as loss of vision, paralysis and cognitive problems.
Current MS medications, which can cost patients up to $60,000 per year, have succeeded in reducing relapses and slowing the progression of the disease to some degree, but they do not halt the disease.
"I'm very excited by these results," said Voskuhl, who is director of the UCLA Department of Neurology's Multiple Sclerosis Program. "Currently, all of the available drugs reduce immune attacks on the brain, but none of them protects the brain. Estriol is particularly promising because it both reduces attacks and protects the brain directly. It's a two-pronged approach — an anti-inflammatory prong to reduce the attacks, and a neuroprotective prong to make the brain suffer less damage in case of an attack."
Earlier work by Voskuhl showed that, in mouse models with MS, estriol repaired brain cells by increasing the connections, or synapses, between neurons, which improved the transmission of information between the cells.
Estriol is also promising because it has an established safety record — it has been used for years in Europe and Asia as a hormone replacement therapy for women with menopausal symptoms — and it can be given as a pill, rather than as a shot, as most MS medications are. Although the pill is not yet approved for use in the U.S., the fact that it already exists and is a generic should dramatically reduce the cost of treatment, said Voskuhl, who holds the Jack H. Skirball Chair for Multiple Sclerosis at UCLA.
As a potential therapy for multiple sclerosis, estriol has had an unusual evolution. For decades, women with MS and their doctors noticed a curious thing: When they became pregnant, they experienced a sharp drop in their MS relapses, more of a drop than is observed with most of the currently approved MS treatments. That anecdotal evidence continued to mount over the years, and a landmark paper by a European group in 1998 described the protective effect of pregnancy on MS.
Intrigued by those findings, Voskuhl in 1996 conducted animal studies that identified estriol, which spikes during a woman's pregnancy, as playing a role in protecting the body from MS. Estriol is virtually undetectable in the body until pregnancy, when its production spikes; it is thought that the hormone helps suppress a woman's immune system during pregnancy so that the body doesn't treat the fetus as a harmful "invader."
"The fetal brain, as it develops, would benefit if there were a neuroprotective substance circulating in the blood of pregnant moms," Voskuhl said. "If there were a possible injury during pregnancy, the baby's brain may undergo less damage. While having a substance like estriol that is both anti-inflammatory and neuroprotective would help ensure fetal survival, this substance would also be ideal for a mom with MS who also needs an anti-inflammatory and a neuroprotective substance."
Voskuhl followed that discovery with a 2002 pilot study in which 10 non-pregnant women with MS were given estriol pills. During the course of the study, the women experienced a 70 percent drop in the number of inflammatory brain lesions, which are a hallmark of MS.
"Most potential drugs go from the laboratory bench to the patient bedside," Voskuhl said. "In the case of estriol, though, it went from the bedside — patients talking to their doctors — to the lab bench, and then back to the bedside, in the form of a clinical trial. It's important that patients keep the lines of communication open to their doctors in letting them they know what makes them better. And it's important that we doctors listen."
Although Voskuhl said the results are promising, she added that they must be validated in a larger, Phase III trial.
Funding for the study was provided by the National Institutes of Health, the National Multiple Sclerosis Society, the Sherak Family Foundation, the Jack H. Skirball Foundation and the Conrad N. Hilton Foundation. The biotechnology company Synthetic Biologics Inc. provided and distributed the estriol and placebo pills to the 16 clinical sites.
Source: UCLA Newsroom © 2014 UCLA All Rights Reserved (30/04/14)
Synthetic Biologics Inc. has announced that the U.S. Patent & Trademark Office has issued U.S. Patent No. 8658627 entitled Pregnancy Hormone Combination for Treatment of Autoimmune Diseases to the Regents of the University of California (UCLA). The patent includes claims to the use of the Company's drug candidate Trimesta™ (oral estriol) in conjunction with a gestagen for the treatment of multiple sclerosis (MS) and other autoimmune diseases. The patent also includes a claim for the administration of Trimesta™ a gestagen and a third standard of care MS agent such as glatiramer acetate injection (Copaxone®) interferon beta-1a (Avonex® Rebif®) interferon beta-1b (Betaseron® Extavia®) or sphingosine-1-phosphate receptor modulator (Gilenya®). Through its wholly owned subsidiary Synthetic Biologics holds the exclusive license to the newly issued U.S. Patent 8658627 as well as U.S. Patents 8372826 and 6936599 and pending patents for MS and other autoimmune diseases covering the uses of its oral estriol candidate Trimesta™.
In an on-going randomized double-blind placebo-controlled Phase II clinical trial for the treatment of women with relapsing-remitting MS patients enrolled at 15 centers in the U.S. are administered either Trimesta™ in combination with Copaxone® and progesterone (a gestagen) or receive a placebo plus Copaxone®. Lead Principal Investigator of the clinical trial Rhonda Voskuhl M.D. Professor Department of Neurology Jack H. Skirball Chair in Multiple Sclerosis Research and Director Multiple Sclerosis Program at the UCLA School of Medicine is scheduled to present topline results from this trial at the American Academy of Neurology's (AAN) 66th Annual Meeting in Philadelphia on April 29 & 30 2014 as part of the AAN Emerging Science program. The clinical trial is supported by grants exceeding $8 million awarded primarily by the National Multiple Sclerosis Society (NMSS) in partnership with the NMSS's Southern California chapter and the National Institutes of Health.
"Claims in this new patent further expand Synthetic Biologics' intellectual property related to our oral estriol candidate Trimesta™ for the treatment of MS and other autoimmune diseases" stated Jeffrey Riley Chief Executive Officer at Synthetic Biologics. "Our objective has been to continue to strengthen our intellectual property covering oral estriol and this patent is an achievement in that direction."
Source: Synthetic Biologics Inc (11/03/14)