MULTIPLE SCLEROSIS PROGRAM
To improve the lives of patients suffering from multiple sclerosis.
UCLA MS Clinical Services, an integral part of the overall Multiple Sclerosis Program at UCLA, serves the neurologist or primary care physician's referral needs by:
- Providing a full range of diagnostic services for patients experiencing symptoms with no definitive diagnosis
- Providing a second opinion for patients who have been diagnosed with multiple sclerosis
- Providing the referring neurologist with an individualized treatment plan for the MS patient with a confirmed diagnosis
- Providing access to clinical trials in MS
MS patients are seen by dedicated specialists with decades of combined experience and/or fellowship training in the diagnosis and treatment of this difficult disease. UCLA is a designated MS Comprehensive Care Center.
Rhonda Voskuhl, M.D., Jack H. Skirball Chair in MS Research and Director of the M.S. Program at UCLA, is an internationally recognized expert in MS, focusing on translational work by moving from the bedside (clinical observations) to the bench (research) to the bedside (novel clinical trials). Four translational clinical trials have been conducted by Dr. Voskuhl based on work originating in her research lab, with two of these trials involving many sites across the U.S. See UCLA Dept of Neurology?s MS Research website for more information. In 2013, Dr. Voskuhl was one of five finalists for the Barancik Prize from the National MS Society, an award recognizing the Most Innovative MS Researcher in the World. Dr. Voskuhl's patient care focus is giving second opinions on diagnosis of complex cases as well as on major changes in MS treatment management. She also trains post doctoral fellows, graduate students and undergraduates on clinical MS.
Barbara Giesser, M.D., clinical director of UCLA MS Clinical Services, specializes in MS patient care. The clinical program offers many treatments that can impact disease course, ameliorate symptoms, improve function, and enhance quality of life. Treatments are available for pain, spasticity, fatigue, genitourinary dysfunction and other impairments due to MS. Her direction has been central to establishing UCLA as an MS Comprehesive Care Center. She has also designed trials related to exercise in MS.
Callene Momtazee, M.D., specializes in MS patient care and provides consultative, diagnostic and management services. She has also been involved in MS trials at UCLA.
- Full consultative reports are provided in writing to referring physicians in a timely manner.
- At UCLA, state-of-the-art neuroimaging is performed by expert neuroradiologists. Other sophisticated diagnostic testing is available, when appropriate.
- A certified MS nurse specialist participates in the patient's treatment regimen, attending clinic with physicians and providing support and guidance for patient issues that include bladder and bowel management, and medication issues.
- An internationally recognized research group which discovers novel MS treatments through basic science then translates them to the clinic in the form of clinical trials. For more information about clinical trials go to www.clinicaltrials.gov websites searching for estriol and MS or exercise and MS.
The Marilyn Hilton Multiple Sclerosis Achievement Center at UCLA (MSAC)
As an adjunct service to the diagnostic, treatment and consultative services provided, UCLA also offers access to this unique center that provides rehabilitative, recreational, and education services in a small group setting. The center, a joint effort of the National Multiple Sclerosis Society (Southern California Chapter) and the UCLA Department of Neurology, offers a broad continuum of care that will complement the medical management of MS.
The overall purpose of the center is to help individuals with MS address the daily life struggles large and small inherent with the disease to improve health-related quality of life. The center's approach is to provide a range of services in a day-program format for members with all types of MS conditions including prevention of secondary medical conditions; improvement or maintenance of functional abilities and mobility; improvement of family relations, self-esteem, and emotional status; reduce social isolation and minimize hospitalizations, provide respite for care partners and prevent premature institutionalization. Participants undergo an intake evaluation and an individual treatment plan is designed for each person, and will attend one day a week (Tuesday through Friday) on the day that is best suited to their individual needs.
Other programs of the MSAC include a 12 week course for persons newly diagnosed with MS, a cognitive rehabilitation program, classes in fall prevention, and a one time comprehensive assessment for person who live outside the Los Angeles area.
For more information go to the MSAC website at: www.msac.ucla.edu or call 310-267-4071.
Contact for Referral
Please call the UCLA Neurology Clinic at 310-794-1195 to arrange an appointment for your patient. You can ask for one of the specialists by name, or ask to speak with the MS physician for initial phone consultation. For information about MS clinical trials, call 310-206-2176.
YouTube - Promising new multiple sclerosis drug
Summary of the Estriol Treatment Trial in RRMS:
Presented at the American Academy of Neurology on April 29, 2014
This was a double blinded, placebo controlled trial conducted at 16 sites across the U.S. Eligible patients were female, between ages 18 and 50, with actively relapsing disease, and an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.
Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) versus glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants' estriol levels, and assessed for relapses and disabilities.
A total of 82 patients received glatiramer acetate (Copaxone) plus estriol, and 76 patients received glatiramer acetate (Copaxone) plus placebo. Baseline characteristics were similar in both patient groups. Participants' mean age was approximately 38, and their mean EDSS score was 2.2. The treatment was safe and well tolerated. Estriol levels in serum were in a mid pregnancy range in the estriol plus glatiramer acetate treated group.
The primary outcome measure of annualized relapse rate was achieved after 12 months of treatment, with the relapse rate 47% lower among patients receiving estriol and glatiramer acetate as compared with patients receiving placebo and glatiramer acetate. Beyond month 12 of treatment, the group receiving estriol and glatiramer acetate continued to have few relapses and few gadolinium-enhancing lesions on MRI. Thus, their disease activity remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate showed expected effects of this standard of care treatment on relapses by month 24. However, there remained a 32% reduction in relapses in the estriol plus glatiramer acetate group as compared to the placebo plus glatiramer acetate group at month 24.
By 12 months of treatment, scores on the widely used cognitive test, the Paced Auditory Serial Addition Test (PASAT), were significantly improved among patients receiving estriol and glatiramer acetate. After 12 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores to the end of study at month 24, while participants receiving placebo plus glatiramer acetate began to show improved PASAT scores by month 24.
Frequently Asked Questions:
Did you design the study as a combination therapy in order to prevent participants from being on placebo only?
Yes. Since the primary outcome was relapses and since relapses occur less than every year in most patients, the treatment duration had to be at least 2 years. Since drugs are available for MS that reduce relapses, trials of 2 years duration usually do not have a placebo only treatment arm. Notably, trials which add on a new treatment to an FDA approved drug are much more challenging than past trials which compared a new treatment to placebo only. Indeed, all of the approved drugs for relapses in MS were originally approved based on their benefit as compared to placebo alone.
Evidence regarding how difficult combination trials can be comes from work by others in a large study combining glatiramer acetate (Copaxone) injections with interferon injections (Avonex). This study showed no additive clinical effects despite treatment for 3 years duration and having large sample sizes of 250-400 patients per treatment (Lublin, et. al., Annals of Neurology, 2013).
The estriol trial had 80 patients in each treatment group (Copaxone + Estriol vs. Copaxone + Placebo) and showed a significant clinical effect on relapses within only 12 months. This significant clinical effect with only 80 subjects per treatment arm is striking with respect to its timing and potency. Most of the approved MS drugs using sample sizes of this size could only find an effect on a surrogate marker of relapses (like MRI markers), with only a trend of an effect on relapses themselves.
Why did you select Copaxone as the disease modifying therapy for your study?
At the time that we designed our study, it was known that Copaxone takes a while to start working after one starts treatment. Specifically, after starting Copaxone treatment, it can take 6-9 months to reduce enhancing lesions on brain MRI by about 50%. This was in contrast to high dose interferons, (another option at the time), which takes about 1-3 months to reduce enhancing lesions by about 80%. Enhancing lesions on brain MRI were known to be a surrogate indicator of relapses. Thus, we hypothesized that we would have an opportunity to see an effect of adding on estriol to Copaxone on relapses, particularly within the first year of treatment in patients who had just started taking Copaxone. That is precisely what happened.
Are there plans to conduct any head to head comparator studies pitting estriol against Copaxone or any other DMT?
There are several options being weighed in regard to future studies of estriol as an add on to a currently approved MS drug or to use estriol by itself as a monotherapy. Such trials are not mutually exclusive and could both be done. Several factors will have a role in the ultimate design(s), including who funds each study. If a pharmaceutical company that makes a currently approved drug funds a study, then they might want to use estriol in combination with their drug in an attempt to increase overall efficacy. If another entity funds a trial, they may be interested in developing estriol as a monotherapy, essentially competing with currently approved drugs. Both studies are needed.
Do estradiol or estrone also have these positive effects on MS?
The effects of these other types of estrogens are not known since trials of these agents have not been published. The least is known about estrone, while more is known about estradiol since it is the estrogen of the ovulatory cycle and synthetic mimics of it can be found in oral contraceptives and hormone replacement therapy. In the MS model, estradiol treatment ameliorates disease if given at a high enough dose. The problem with using estradiol at a high dose is that it is a strong stimulator of estrogen receptor alpha (ER alpha), and it is known that high levels of ER alpha stimulation promotes breast cancer, uterine endometrial cancer and blood clotting. Thus, it is unlikely that estradiol can be used at a high enough dose in MS to reduce MS disease without having toxic side effects. When oral contraceptives (OCPs)were assessed for their effects on MS incidence, no effect was shown, but in that study the dose of estrogen was not considered, with some OCPs even being progesterone only with no estrogen. Even "low dose" estrogen containing OCPs contain levels of estradiol that are far below pregnancy levels. They must in order to be safe. There is no solid evidence that such low doses of estradiol as in OCPs offer any significant disease modification in MS. Estriol, on the other hand, is unique in that it is not an estrogen of the ovulatory cycle, but is made only during pregnancy. It binds to ER beta more than to ER alpha. ER beta stimulation is known to counter toxic effects of ER alpha stimulation. Thus, a balance is achieved whereby toxic effects are avoided with estriol treatment based on preferentially binding to ER beta over ER alpha. Indeed, estriol has been known to be the safest of the estrogens for decades where it was used widely in Europe and Asia for HRT. It was generally used however at only 2 mg per day and our study has used estriol at a higher dose (8 mg/day) to induce a late pregnancy level in the blood. There were some previous studies that used estriol at 8 to 16 mg per day for HRT, so evidence for safety at 8mg/day exists. However large data sets of post marketing experience at 8 mg per day are not yet available. Notably, new drugs developed for MS generally come with no post marketing experience, with safety assessed only during trials. Often unexpected toxicities arise in trials of these agents. In our pilot estriol trial and in our multicenter estriol trial, both using 8mg per day, estriol treatment was safe. However, consultation with a gynecologist is always needed with estriol use, as should be the case with the use any estrogen.
Does menopause play a role in MS in women?
There is no evidence that loss of endogenous estrogen during menopause is associated with an increase in MS relapses. However, it remains unknown if menopause can play a role in MS worsening in terms of disability progression. Women with MS may do worse with regard to their MS during menopause, but there are other factors such as menopausal symptoms and aging that could contribute to the worsening. A controlled trial to test if estriol treatment may halt such worsening is needed. Interestingly, younger women who do not have MS and who undergo surgical menopause experience cognitive problems and these cognitive problems are improved with estrogen treatment. This suggests that endogenous estrogen of the ovulatory cycle could favorably affect cognition. This conclusion is supported by ovariectomy and estrogen replacement studies in healthy rats and mice. In these experiments, estrogen treatment causes prouting of new nerve fibers (axons and dendrites) and their connections (synapses) in cognitive areas of the brain. Such sprouting and reestablishment of connections has also been shown in mice with the MS model when they were treated with estriol. Further study is warranted to assess an effect of menopause and estriol treatment on cognitive problems and other disabilities in MS.
Can I start taking estriol now for my MS?
Estriol is not FDA approved in the U.S. so it is not available in pharmacies. It can be attained from compounding pharmacies, but these are not FDA regulated. To get FDA approval, another trial in MS must be done. We are raising money for that trial now and have a trial design ready for launch. Currently, prior to that study and prior to FDA approval, we cannot recommend that MS patients start taking estriol since efficacy for a given indication has not yet been proven in MS. We hope to get funding within the next 6 months, so the trial can be begin. The next trial could be completed within 3 years after its initiation.
There are fewer men diagnosed with MS than women and, from what I have understand, they appear to have a much more aggressive or progressive disease course. Is that true and if so, do male hormones play a role?
While men are less likely to get MS, when they get it, it tends to be more disabling or progressive in its course. This worse disability progression in men is not due to testosterone since we and others have shown that testosterone treatment is beneficial in MS models. Further, when we conducted a trial of testosterone treatment in men with MS to increase their blood levels of testosterone from low normal to high normal range, we found that testosterone supplementation significantly slowed brain atrophy on MRI, a biomarker of disability. Further, Bove et al. showed that men with lower testosterone levels have higher disability scores and do worse in cognitive testing over the subsequent two years. We are now raising money to do a larger, multicenter, placebo controlled trial of testosterone treatment in men with MS. The goal of the trial will be to prove that testosterone supplementation halts brain atrophy and slows disability accumulation in men. In addition, these men should experience the known beneficial effects of testosterone treatment including improved muscle mass and strength, less fatigue, improved sexual function, improved bone mineral density and an improvement in cognition as has been observed in elderly men. Why testosterone treatment halts brain atrophy and may halt disability progression is likely due to the fact that testosterone is converted to estrogen in the brain. While boosting testosterone levels in men with MS is very promising, until the next trial of testosterone treatment in MS men is funded and completed, we cannot currently recommend testosterone supplementation as a disease modifier in men with MS. The decision to take supplemental testosterone should be made in consultation with an internist and avoided in men with pre-existing prostate cancer or ischemic heart disease.
So the question remains, what makes MS men have a more rapid rate of progressive disability if it is not testosterone? Recently, we have published in the Proceedings of the National Academy of Sciences a paper showing an effect of sex chromosome gene expression in the brain using the MS mouse model. A gene on the X chromosome (Toll like receptor-7) expressed in cells in the brain (neurons) that can cause cell death during injury is expressed at higher levels in males (XY) versus females (XX) due to maternal imprinting of the one X gene in males. This may contribute to why MS men have a more progression course of disease, or respond worse to a given immune attack during MS. Finding new treatments to modulate this gene may lead to a treatment that will halt disease progression in both men and women with MS.
Why don't more groups study sex effects in disease?
This will soon change. The NIH recently announced that it is now implementing a new policy whereby sex differences in disease can no longer be ignored in NIH grants. This was published as a Nature paper in March of 2014, referencing our work in MS (3 of the total of 15 articles by Dr. Voskuhl and an additional 2 more by Dr. Arnold, her collaborator at UCLA), and discussing the estriol trial in the narrative as an example of success using this approach. Sex differences in disease lead to more than minor adjustments to doses medications depending upon whether one is female or male. Rather, sex differences in disease can hold major clues in understanding the basic pathogenesis of disease and thereby lead to novel treatments for both sexes. This novel conceptual approach has been spearheaded by Dr. Voskuhl and her collaborators for over a decade at UCLA.
Do women of childbearing age show any improvement in MS if they are on birth control?
No. see above. The type of estrogen used and the dose of estrogen is critical.
What are your next steps regarding basic and clinical research with estriol and MS?
In addition searching for funding to support the next estriol trial in women with MS (and the next testosterone trial in men with MS), we are well into the development of a "next generation estriol" that will bind only to ER beta receptor, with no binding to ER alpha receptor. This could be used in the subset of MS women at higher risk for breast cancer, uterine cancer or blood clotting since it would not bind to the estrogen receptor that contributes to these toxicities. Phase I trials are soon approaching to test our lead ER beta ligand in MS. Basic science into why estriol and testosterone have neuroprotective effects are a major goal. The major unmet need in the MS field is to find a neuroprotective treatment for MS. Once the first neuroprotective treatment is discovered, it can be unraveled and understood so that many more can follow. Thus, we are aggressively pursuing the precise cells and pathways involved in the neuroprotective effects of estriol and testosterone in MS.
Can estriol potentially be useful in other diseases?
Other autoimmune diseases which are known to improve during pregnancy, such as rheumatoid arthritis and psoriasis warrant investigation of estriol as a treatment in the form of a clinical trial.
Other neurological disease, particularly those which involve cognitive decline, such as Alzheimer's disease or cognitive decline associated with menopause, each warrant investigation of estriol as a treatment in the form of a clinical trial.
What other research endeavors are active in your lab?
SUMMARY of PROJECTS in the Voskuhl lab: THE NEXT STEPS
1. In addition to raising $15 million and designing the next estriol trial as required by the FDA to bring estriol to the market in the U.S., we are actively involved in the following other areas of research.
2. In our recently completed multicenter trial of estriol in women with MS where we found significant beneficial effects on relapses and cognition, we acquired brain MRI scans. These MRI scans now need to be assessed for whether estriol treatment slowed or halted gray matter atrophy, a biomarker for permanent disability including cognitive function. Funds needed: $250,000
3. A trial focusing on whether estriol treatment can improve cognition in not only RRMS, but also in progressive MS is needed. We have begun that trial, and it is ongoing at 4 sites across the U.S. Based on our results in the relapse trial, we know that this new trial is on target with regard to its optimal design and outcomes. In this trial, estriol treatment can be added on to other standard of care MS treatments (not just Copaxone, but also interferons or the new orals) or estriol can be used in people on no other MS treatments. The treatment duration is one year, and the primary outcome is cognitive testing. Based on data collected thus far, we now have an exact number with regard to how many patients are needed for that trial. It needs to be expanded and more clinical sites are needed. Funds needed: $900,000.
4. Given our extremely promising data from trials of estriol for women and testosterone for men with MS with respect to identifying an MS treatment that is not merely anti-inflammatory via suppressing immune cells in the blood, but rather one that can go to the brain to bind cells therein (astrocytes, oligodendrocytes, neurons, microglia) to provide neuroprotection and/or neural repair, we are aggressively continuing our pursuit of how these treatments work. Once the first neuroprotective drug for MS is established, understanding its mechanism of protection will lead to more drugs in the future targeting this mechanism. Funds needed: $500,000
5. As mentioned above, we are planning and raising funds for a large multicenter trial of testosterone treatment for men with MS. Funds needed: $8 million
6. Using the MS model in basic science experiments, we have identified a gene on the X chromosome that is expressed in the brain that may help us understand why men tend to have a more progression course of disease. Finding new treatments to regulate this gene may lead to a treatment that will halt disease progression, with relevance to other neurodegenerative diseases that demonstrate gradual progressive worsening. Funds needed: $400,000.
7. Using the MS model in basic science experiments, we have identified a gene on the X chromosome that is expressed in immune cells that may contribute to why women are more susceptible to developing MS and what contributes to relapses. Finding new treatments to modulate this gene may lead to a treatment that will reduce relapsing disease, with relevance to other autoimmune diseases characterized by an increased susceptibility in females. Funds needed: $400,000
8. Consistent with this focus on finding ways to halt disease progression, we are now dissecting through neurological pathways in the MS model to discover disability specific generic treatments for MS. This work is currently funded by the Conrad N. Hilton Foundation.
In conclusion, thank you for your interest in our MS research which is driven by clinical observations, which are unraveled and understood at the laboratory bench, leading to new treatments in the form of clinical trials. This is our MISSION: Bedside to Bench to Bedside research that leads to new treatments to halt MS, with relevance to other autoimmune and neurodegenerative diseases. Thank you for your time and consideration of our mission. Thank you for your support.