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Friday, June 5, 2015

Highlights from the American Academy of Neurology's 2015 Annual Meeting - includes PPMS updates

The American Academy of Neurology's (AAN's) 67th Annual Meeting took place in Washington, DC April 18th-25th. The AAN is an association of more than 27,000 neurologists and neuroscience professionals dedicated to advancing the care of individuals with neurologic disease. Every year, these professionals gather to hear the latest findings in research and treatments for neurological conditions, including multiple sclerosis (MS). To follow are some important highlights.

Clinical Trials

Daclizumab HYP - The DECIDE Trial of RRMS


Daclizumab high-yield process (HYP) is a new therapy that has been studied in relapsing-remitting multiple sclerosis (RRMS). It is a humanized monoclonal antibody against CD25, a receptor on T cells that is thought to become activated in MS. Daclizumab is believed to work by selectively targeting these activated T cells without causing general T-cell depletion.

This therapy results in a "reversible modulation" of the immune system. This means that while the medication alters the immune-system response to slow the attack caused by MS on myelin and nerves (axons) of the brain and spinal cord, it does so without causing permanent changes to immune system function. DECIDE was a randomized, double-blind, active-controlled study ("active-controlled" denotes that the control group was given an existing treatment that has already been shown to be effective, versus a placebo, which has no active ingredients). This study compares DAC HYP 150mg injected subcutaneously once every four weeks, to intramuscular interferon once weekly. The primary endpoint was the annualized relapse rate (ARR). A total of 1,841 patients were randomized into the study.

Treatment with DAC HYP versus interferon resulted in a 45-percent reduction in the ARR and a 41-percent reduction in the proportion of patients who relapsed. MRI outcomes were also positive favoring DAC HYP as this agent brought about a 54-percent reduction in the number of new/enlarging T2 lesions (more intense lesions, which are areas of inflammation). Furthermore, DAC HYP reduced the risk of confirmed disability by 16 percent. The benefits of this drug compared to interferon were seen in many subgroups of patients - men, women, both older and younger than 35, and irrespective of prior treatment with interferon. The authors concluded that DAC HYP demonstrated superior efficacy compared with weekly interferon across key clinical, radiographic, and patient-reported MS outcome measures in relapsing MS patients.
A variety of side effects and adverse events were seen with this agent. Infections, significant skin reactions, and liver effects were observed. The side-effect profile and safety issues will warrant careful monitoring if this medication is approved.

Immediately following the AAN meeting, the United States Food and Drug Administration (FDA) accepted for review the Biologics License Application (BLA) requesting marketing approval of Daclizumab HYP for relapsing forms of MS. If approved, this will be marketed under the brand name Zinbryta™.

Gilenya® (fingolimod) - The INFORMS Trial of PPMS


Gilenya is an FDA-approved oral treatment for MS that blocks lymphocytes from exiting lymph nodes and reaching the nervous system. It is approved for RRMS, and was studied in a large, randomized, double-blind, placebo-controlled trial called INFORMS, to assess efficacy in patients with primary-progressive MS (PPMS). A novel primary composite endpoint was used, based on increase in disability as measured by the Expanded Disability Status Scale (EDSS), the 25-Foot Timed-Walk Test (T25FW), and the 9-Hole Peg Test (9-HPT). Other key endpoints were the formation of new lesions and percent brain volume change (PBVC), or brain atrophy (the shrinking or reduction of brain volume).

INFORMS was a three-year trial that randomized 970 patients, and was adequately powered (that is, enough patients were included and enough measurements were made) to assess the primary endpoint. Unfortunately, none of the endpoints were met. Gilenya did not prevent the accumulation of disability in patients with PPMS any greater than placebo. Furthermore, PBVC did not differ between the Gilenya and placebo groups.

Unsurprisingly, given this agent's success in preventing relapses and new MRI lesions in RRMS patients, there were fewer new MRI lesions seen in the Gilenya-treated patients. The safety results were generally consistent with fingolimod in prior MS trials. It is disappointing that Gilenya did not significantly slow disease progression in PPMS. These findings have important implications for the understanding of PPMS, and will no doubt allow researchers to refine how PPMS is studied moving forward.


MD1003 - High-Dose Biotin in Progressive MS


Biotin is a vitamin involved in key steps of energy metabolism and fatty acid synthesis, though most people think of it as being "good for hair and nails." Among other actions, biotin activates an enzyme in myelin synthesis. Using this hypothesis and building upon data from a small, open-label pilot study, MD1003, a high-dose biotin preparation of 300 mg/day, was studied in a Phase III trial of patients diagnosed with secondary-progressive MS (SPMS) or PPMS. (This dose is hundreds of times higher than what can typically be purchased as a supplement of this vitamin.) In a relatively small study, 154 patients were randomized to high-dose biotin or placebo.

The primary endpoint of the study was defined as the proportion of patients who improved at nine months, with a confirmation of the improvement at 12 months. Improvement was defined as either a decrease in EDSS (Expanded Disability Status Scale) or an improvement in T25FW (timed 25-foot walk) of at least 20 percent.

The primary endpoint was met, with 12.6 percent of patients in the MD1003 arm showing an improvement of EDSS or T25FW at nine months and confirmed at 12 months, compared to none of the patients in the placebo arm. The primary endpoint was supported by secondary analyses showing evidence for a decrease in the risk of disease progression. These numbers are encouraging, although it is important to note that the decrease in disability experienced by the MD1003 group, and the disease progression seen in the placebo group, were both so small, they would be virtually undetectable in clinical practice. MD1003 was well tolerated. The overall incidence of adverse events was similar across the two groups. One patient treated with MD1003 died from suicide; however, this event was not considered to be related to the drug.

These results suggest a possible therapeutic effect of high-dose biotin in progressive MS, and merit further study. Though this trial gives initial support for its potential use, a larger trial will need to be done to truly understand whether biotin is an effective treatment in progressive MS. Noting that the dose of biotin studied would require taking hundreds of commercially-available pills of this vitamin, it is certainly not recommended that patients begin such a regimen at the present time. Studies also need to determine if any toxic effects could result from taking such high doses of this vitamin.

Neuroprotection in Optic Neuritis


Anti-LINGO-1 - The RENEW Trial


Anti-LINGO-1 is an agent under investigation for its potential remyelinative properties, after animal studies showed that it blocks this protein responsible for stopping the growth of myelin. Agents aimed at remyelination would repair or regrow myelin, the protective covering of the nerves, which is damaged by MS.

RENEW was a Phase II, randomized, double-blind, placebo-controlled, study of Anti-LINGO-1 in subjects experiencing their first episode of acute optic neuritis (AON). An equal number of subjects were randomized to receive either a placebo or anti-LINGO-1 (100 mg/kg) once every four weeks for six total doses. Follow-up extended 12 weeks after the last dose.

The primary outcome of RENEW was an assessment of recovery of optic-nerve function measured by the speed at which the nerve conducts visual signals. This was studied by evaluating a test called Full Field Visual Evoked Potential (FF-VEP) in participants treated with anti-LINGO-1, compared with placebo. Patients who were treated with at least five of the six doses of anti-LINGO-1 showed a 34-percent improvement in optic-nerve conduction latency (delay in the speed of the visual signal) at week 24, compared with placebo. Further recovery in optic-nerve conduction was observed at the last study visit (week 32), with a statistically significant 41-percent improvement. Together, the data demonstrate evidence of treatment effect with continuous improvement observed 12 weeks following the last study dose. There was no effect on key secondary endpoints, including actual recovery of visual function.

These data are the first evidence of functional remyelination in patients treated with anti-LINGO-1, and justify further study in the ongoing SYNERGY trial, in which 396 subjects with active RRMS or SPMS will be randomized to intravenous (IV) infusions of this experimental medication or placebo. All subjects will also receive once-weekly injections of Avonex. Results will provide clinical information about this drug's efficacy for neuroprotection or repair within the central nervous system (CNS), which consists of the brain, spinal cord, and optic nerves. The results will also address two fundamental questions: 1) Are the effects seen in the optic neuritis study replicable in other areas of the nervous system? And 2) Does this translate to improved function in patients with MS either in the short or long term?

Phenytoin in Acute Optic Neuritis


Phenytoin is an anti-epileptic medication that has been available for decades. It has also been shown to be neuroprotective in experimental models of inflammatory demyelination. A Phase II clinical trial assessed whether phenytoin could be neuroprotective in acute optic neuritis (AON). The study was comprised of 86 people with AON randomized within two weeks of symptom onset to receive either phenytoin (4 mg/kg/day) or placebo for three months. The primary outcome of this AON study was an evaluation of the structure of the retinal nerve fiber layer (RNFL) and macular volume (MV) at six months. Visual function, optic-nerve imaging, and visual evoked potentials were also measured.

Of the original 86 participants, 81 were followed to study end. In these patients, the average adjusted affected eye RNFL thickness at six months was higher in the active group versus placebo, resulting in a 30-percent protective-treatment effect. Adjusted MV (macular volume) showed a 34-percent protective-treatment effect. Vision generally recovered well, with no significant difference in visual outcomes between the treatment groups.

This is an intriguing study that may have broad implications, as it found that the administration of a well-known, relatively safe drug seemed to be neuro-protective in the period directly following optic neuritis. Similar to anti-LINGO-1, further studies will need to be done to clarify whether this effect is translatable to other areas of the nervous system and whether this will, in turn, lead to preservation of neurologic function.

Long-Term Extension Studies

Lemtrada® (alemtuzumab) - Update from the Care MS II Extension for RRMS
Lemtrada is a monoclonal antibody given by IV infusion that was approved by the FDA in 2014 for the treatment of relapsing MS. In the CARE-MS II trial, Lemtrada had superior benefit versus subcutaneous interferon beta-1a, including improved MRI outcomes over two years, in RRMS patients who had relapsed on prior therapy. A total of 393 (92.9 percent) CARE-MS II Lemtrada-treated patients entered the extension study; data are available through four years from the first treatment, and follow-up is ongoing. Through four years, 67.7 percent of patients received only the initial two courses of treatment, 24.2 percent received the initial two treatments plus one additional course, and 7.4 percent received the initial two treatments plus two additional courses. In Year 3 and Year 4, almost 90 percent of patients were free of new gadolinium-enhancing lesions, and two-thirds of patients did not have new T2 lesions.

Aubagio®'s (teriflunomide) 14-Year Extension Study for RRMS



Aubagio is a once-daily oral immunomodulator approved for the treatment of RRMS. In the core Phase II study, patients with relapsing MS were randomized equally to Aubagio 14mg, Aubagio 7mg, or placebo. After completing the 36-week core study, patients could enter the long-term open-label extension. In the extension, patients who were taking one of the two doses of Aubagio continued on their same therapy; those previously treated with placebo were reallocated in equal numbers to Aubagio 14mg or 7mg.

Of the 179 patients originally randomized, 147 entered the extension study. Including treatment in the core and extension studies, patients received Aubagio for up to 576 weeks (11 years). During the study, annualized relapse rates (ARR) remained low in both groups, and the percentage of patients free from relapse during the extension was greater in the 14-mg group (51.5 percent) versus the 7-mg group (39.5 percent). Patients had minimal increases in EDSS score following up to 528 weeks (more than 10 years) of treatment. No new/unexpected adverse events were identified following long-term Aubagio treatment, and the safety and tolerability profile was consistent with other clinical studies.

Although long-term extension trials are always limited by the fact that patients who are doing well on a particular treatment are more apt to stay on it, this study provides support for the use of Aubagio -- one of the more recently approved therapies -- over the long term. Relapse rates remained low in both treatment groups that were followed up to 12 years, and patients in both groups had minimal progression, similar to what was seen in the Phase III trials.

Data on Treatment Decisions

Anti-JCV Antibody Index in Tysabri® (natalizumab)-Treated Patients


Multiple risk factors are now known for developing Tysabri-associated progressive multifocal leukoencephalopathy (PML), a viral brain infection caused by the JC virus. These risk factors include the presence of anti-JCV antibodies, prior immunosuppressant use, and duration of Tysabri treatment -- especially beyond two years. In previous analyses, the anti-JCV antibody index was able to differentiate the risk of PML in patients who were positive for the anti-JCV antibody, but without a history of immunosuppressant use.

This current analyses involved data from clinical studies and post-marketing sources as of March 2014. Data were available for 101 Tysabri-treated PML patients with blood samples collected six months prior to PML diagnosis. For patients with no history of immunosuppressant use, with anti-JCV antibody index at or below thresholds of 0.9 to 1.5, PML risk was approximately 0.1 to 0.2 per 1,000 patients during the first two years of Tysabri treatment; it ranged from 0.5 to 1.1 per 1,000 patients who had taken Tysabri for more than two years and up to four years; and from 0.6 to 1.4 per 1,000 patients who had taken Tysabri for more than four years and up to six years. For patients with no history of immunosuppressant use with an index greater than 1.5, PML risk was approximately 1.2 per 1,000 patients during the first two years of Tysabri treatment, 8.8 per 1,000 patients between two and four years, and 10.1 per 1,000 patients between four and six years.

Consistent with previous findings, this updated analysis suggests the anti-JCV antibody index may differentiate PML risk in anti-JCV antibody positive patients with no history of immunosuppressant use. Patients with a JC index less than 1.5 maintained a low risk for developing PML over the course of the study, as opposed to those with a high index where the risk was seen to increase greatly over time.


Data on Discontinuing Treatment


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