ARTICLE IN BRIEF
A randomized combination trial of estriol, a pregnancy hormone, showed promising results for female patients with relapsing-remitting multiple sclerosis. Within 12 months, there was a 47-percent reduction in annualized relapse rate in the estriol plus glatiramer acetate group versus glatiramer acetate alone.
PHILADELPHIA—Based on a clinical observation that many women with multiple sclerosis (MS) experience a significant reduction in relapses during their third trimester of pregnancy, researchers at the University of California–Los Angeles School of Medicine (UCLA) have spent years testing estriol (a pregnancy hormone) to determine a potential therapeutic role.
“Estriol is one of three naturally produced estrogen hormones; it is created by the fetal placental unit, so it is not present in women unless they become pregnant,” said Rhonda Voskuhl, MD, Jack H. Skirball chair in multiple sclerosis research and director of the Multiple Sclerosis Program at the David Geffen School of Medicine at UCLA, who has spearheaded this research in her lab. “Estriol reaches very high levels in the third trimester, and then it drops precipitously after delivery. So we thought that the high levels of estriol in pregnancy could be mediating relapse protection,” explained Dr. Voskuhl. “The hormone also has a lower side-effect profile than many of the other treatments that have been tried,” she added.
At the 2014 AAN Annual Meeting in Philadelphia, Dr. Voskuhl and colleagues presented data from a double-blind, multicenter, combination trial, which compared oral estriol as an add-on therapy with glatiramer acetate injection (Copaxone) versus glatiramer acetate alone in women (ages 18–50) with relapsing-remitting MS.
“Within 12 months of giving estriol in combination with glatiramer acetate injections, we reached our primary outcome measure, with a 47-percent reduction in annualized relapse rate in the estriol add-on group,” Dr. Voskuhl said. The patients taking estriol also showed significant improvements in cognitive function. The difference between the comparison groups became less marked in the second year as patients taking glatiramer acetate also started showing benefit, she added.
The study had approximately 80 subjects in each treatment arm, making it smaller than many Phase III studies. Also, she said, all past MS trials for US Food and Drug Administration (FDA) approval have shown a reduction in relapses as compared to a placebo-only treatment arm.
“It is much more difficult to show an ‘add-on’ effect of a treatment in a combination study since the placebo arm includes a treatment known to be effective. Our study's ability to find significant improvements in relapses and cognition speaks to the robustness of the estriol effect. Together, this suggests that estriol treatment might be working through a mechanism that is different than the other available anti-inflammatory drugs,” mainly neuroprotection.
THE STUDY FINDINGS
Dr. Voskuhl and colleagues began researching estriol for MS using an EAE (experimental autoimmune encephalomyelitis) mouse model and then conducted a pilot trial involving 10 women with MS. “We did a lot of work — and other groups did as well — showing that estriol is not only anti-inflammatory, but also neuroprotective,” she said.
Their current trial included 164 women from 15 sites throughout the US who had the disease about 3 years. Nearly all (99.4 percent) of the women had at least one relapse in the preceding 24 months, with 29.4 percent having at least one enhancing lesion on a single screening MRI. The mean Expanded Disability Status Scale (EDSS) score for the participants was 2.2 (0=normal neurological exam, 10=death).
The researchers found that within one year, there was a 47 percent reduction in annualized relapse rates in the estriol combination group compared to the placebo with glatiramer acetate injection group (p = 0.03). “There were very few relapses and few gadolinium enhancing lesions on MRI in the estriol plus glatiramer acetate injection group after 12 months, with this low annualized relapse rate in the estriol plus glatiramer acetate injection group continuing from month 12 to 24,” said Dr. Voskuhl. By month 24, the glatiramer acetate plus placebo group began to show a reduction in relapses, thus decreasing the difference between the two groups to 32 percent (p = 0.15).
The secondary outcome measure for this trial was cognitive testing of processing speed using the Paced Auditory Serial Addition Test at 3 and 2 seconds (PASAT3 and PASAT2). At one year of treatment, the investigators reported a significant improvement (p = 0.04) in cognitive test scores — a 5–6 percent improvement (3 points) over baseline scores in the estriol plus glatiramer acetate injection group compared to the placebo plus glatiramer acetate injection group. Those who scored the lowest at baseline (below 55) had a 12 percent improvement (6–7 points), while those with a score above 55 at baseline (maximum score is 60) showed no change.
“By the second year, the estriol add-on group had a ‘floor effect’ and a ‘ceiling effect,’ respectively, where there were so few relapses left that they couldn't be reduced further, and the cognitive testing scores were so high after 12 months that they couldn't be improved further, while at the same time, the glatiramer acetate plus placebo arm started kicking in, and we started to eventually see less differences between the groups at month 24,” she said.
This raises the question, she added, of whether patients with even more relapsing disease activity or lower cognitive tests should be included in future studies. There also need to be studies based on estriol alone to see if it works as a monotherapy, she said.
Another question, she said, is which trials the US Food and Drug Administration (FDA) will want to see in order to have this as an FDA approved drug for MS? “The possible indications could be either/or a reduction in relapses or an improvement in cognition.
“A key difference with estriol is that it's both anti-inflammatory and neuroprotective in the MS model, whereas all the drugs we have now for MS are only anti-inflammatory,” she said. Dr. Voskuhl and colleagues are currently testing testosterone, which is converted to estrogen in the brain, for male MS patients to see if it will be similarly neuroprotective. “This research on sex differences in the MS model is consistent with the new NIH policy just announced in Nature describing their focus on research involving sex differences in physiology and disease.”
It's also important to note that this research began as a clinical observation, said Dr. Voskuhl, stressing the importance of what she called the “bedside to bench to bedside” approach, rather than the traditional “bench to bedside” where research ideas originate with a cloned molecule or a high throughput screen of thousands of compounds in the lab.
Commenting on the study, Regina Berkovich, MD, PhD, an assistant professor of clinical neurology at the University of Southern California (USC) Keck School of Medicine in Los Angeles, said that MS specialists have long been “intrigued by the potentially protective effects of pregnancy on MS, as there is relatively reduced disease activity during this period.”
This two-year combination study was well designed, she added, “to authenticate the effects of add-on oral estriol in women with relapsing remitting multiple sclerosis.” Notably, the study subjects — women between 18 and 50 years old — are representative of the largest part of the MS population, Dr. Berkovich told Neurology Today, so these findings may have potentially broad implications.
She called the 47 percent reduction in the primary outcome of annualized relapse rates in the estriol combination group “remarkable.”
“As a principal investigator of another investigator-initiated study, I can say that the seemingly modest significance (p = 0.03) is still very meaningful when it comes to a relatively small clinical study.” She noted that her colleagues at the AAN Annual Meeting were similarly impressed with Dr. Voskuhl's findings.
These results really reiterate “that there is a lot of room for improvement of efficacy of the already approved disease-modifying compounds for MS,” said Dr. Berkovich.
Annette M. Langer-Gould, MD, PhD, a research scientist at Kaiser-Permanente and a clinical assistant professor at USC Keck School of Medicine, said that although this study and its results were “interesting from a biological perspective, from a practical perspective, I don't see a market for this type of product because this was already such a difficult study to enroll,” she added, noting the hesitation among the MS population to use this type of hormonal treatment.
One avenue in the future, she said, would be “to develop estriol-like compounds that act on certain receptors — more selective estrogen-binding, estriol-like compounds that don't have the same type of side effects as a hormonal therapy.”