Highlights from the American Academy of Neurology’s 2014 Annual Meeting

FDA-Approved Medications for MS

Results of a prospective evaluation of the use of the Avonex Pen autoinjector to self-administer Avonex® (interferon beta-1a) intramuscularly were reported. Users’ self-reports demonstrated that fear of injection decreased from 17.5 percent to only 2.4 percent at month 12 and the proportion of those requiring assistance for injections decreased from 10 percent to 5.2 percent.

Betaseron® (interferon beta-1a) was the first drug approved by the FDA for the long-term treatment of MS. In the BENEFIT trial, individuals with clinically isolated syndrome (CIS) who were randomized to receive early treatment with Betaseron did not advance to clinically definite MS (CDMS) as quickly as those who began treatment at a later time. Study participants who began Betaseron early also experienced lower relapse rates than those who were treated at a later time. Patient-reported outcomes on Quality of Life (QoL) remained high for both groups of treated patients.

A two-year extension study of the GALA trial assessed the efficacy and safety of Copaxone® (glatiramer acetate) at its newer 40-mg dose, injected subcutaneously three-times weekly. This open-label extension study observed the effects of this higher-dosed, less-frequent administration in participants with RRMS (the dose and administration originally approved was 20 mg injected subcutaneously once daily). The study concluded that early treatment with this newer dosing of Copaxone lowered the risk of relapse as well as the rates of disability progression (relative to starting the therapy at a later time). Safety data were similar to Copaxone’s “well-established safety profile” and adverse events were noted to be generally mild.

The majority of people with relapsing forms of MS using the Rebismart autoinjector to self-administer Rebif® (interferon beta-1a) rated the convenience of the device positively. In a separate study, researchers conducted a post-hoc analysis of the PRISMS study, looking at the data to determine the relapse rates of patients on Rebif versus placebo over the course of one year. The study concluded that treatment with Rebif “was associated with rapid onset of action over zero to three months despite titration” (titration refers to starting at a lower dose and increasing to a full dose over time). Treated patients improved to a rate of 39-percent fewer relapses over the first year compared to placebo.

Two of the most important factors contributing to a good outcome in Tysabri® (natalizumab)-treated individuals diagnosed with progressive multifocal leukoencephalopathy (PML-a rare but severe complication of treatment) are early diagnosis and treatment. A case was reported of a patient who was successfully treated after being diagnosed with PML following six years of treatment with Tysabri. In this specific instance, the patient went to the hospital following a disturbance in his gait. After PML was diagnosed, he underwent the prescribed therapy to remove Tysabri from his system (through plasma exchange). According to the study, “The patient was clinically stable during the entire period and the initial gait disturbance diminished after a few weeks.”

Only 9.1 percent of individuals treated with Tysabri who had an EDSS score of ≥2 had progressed to an EDSS score of ≥4, six years later. Additionally, in the AFFIRM study, Tysabri was shown to increase the probability of confirmed improvement in walking speed (CIWS). A post-hoc analysis found that patients with a confirmed improvement in walking speed had better self-reported physical functioning.

The rate of serious infections or of opportunistic infections in patients treated with Aubagio® (teriflunomide) for up to 12 years did not differ from those treated with placebo. (An opportunistic infection is one caused by an organism that does not normally affect a person with a healthy immune system, but may cause illness in a person with a compromised immune system.)

Another study looked at two Phase III trials of Aubagio, the TEMSO and TOWER studies, to evaluate the drug’s effect on clinical MS-disease activity in 2,251 study participants. A post-hoc analysis of these studies was performed to determine the proportion of patients who remained free of clinical MS-disease activity while taking Aubagio. The study concluded that this approved disease-modifying therapy reduces the risk of clinical disease activity with consistent effectiveness across a wide range of patients with relapsing forms of MS.

Only 1.7 percent of patients with relapsing-remitting MS (RRMS) beginning treatment with Gilenya® (fingolimod, FTY720) experienced cardiac rhythm abnormalities. These findings are consistent with previous studies. Up to 7,000 individuals with RRMS will be enrolled in this one-week, open-label “START” study. In 200 of the study participants, additional diagnostics were required; these included a 24-hour electrocardiogram (ECG) while being screened for the study and at baseline, i.e., the start of the study. Cardiologists evaluated these ECG recordings.

Researchers also looked at the effects of Gilenya on reducing the amount of brain-volume loss in individuals with MS who were treated with Gilenya in Phase III and extension trials. The study concluded that the annualized percentage of brain-volume change (PBVC) for all patients individually showed a consistently low rate of brain atrophy versus placebo in the Phase III trials (FREEDOMS and FREEDOMS II) as well as versus Avonex in the one-year extension study (TRANSFORMS). According to the authors, this supports previous observations from individual studies.

About half of individuals (most with relapsing-remitting MS [RRMS]) taking Tecfidera™ (dimethyl fumarate) reported experiencing gastrointestinal symptoms and about half reported flushing. These rates were similar to those found in prior clinical trials. Sixteen percent discontinued treatment due to these side-effects, a rate that was slightly higher than found in previous studies. Efforts to reduce these symptoms are ongoing.

The use of Tecfidera is frequently associated with gastrointestinal (GI) symptoms, including abdominal discomfort, diarrhea, nausea, and vomiting. Within a group of four individuals who took the oral asthma medication montelukast, 10 mg once daily (while continuing treatment with Tecfidera), GI symptoms decreased within 72 hours and the improvement persisted for 30 days. Symptom severity, as measured by the Gastrointestinal Symptom Rating Scale (GSRS), decreased by 81 percent.

A four-year follow-up was conducted to determine the integrated clinical efficacy results of three studies using Tecfidera in treating RRMS. The studies included the Phase III DEFINE and CONFIRM studies, as well as the five-year ENDORSE extension study. Results of this analysis show that both low relapse rates and low disability progression continued during the four-year follow-up. These are in addition to the neuroradiologic efficacy (as found through MRI scans) and an acceptable safety profile.

MS Treatments under Review by the FDA

Efficacy was better in individuals receiving Plegridy™ (PEGylated interferon beta-1a) every two weeks than those receiving it every four weeks in the second year of ADVANCE, a Phase II study of 1,512 people with RRMS. The safety profile was consistent with both year one of ADVANCE and with other beta interferons.

Versus placebo, both dose frequencies of Plegridy (once every two weeks and once every four weeks) significantly reduced the risk of 12-week confirmed disability progression by 38 percent with both dosages, and significantly reduced the annualized relapse rate by 36 percent and 28 percent, respectively. Given the lower risk of disability at year one, the authors of the study suggest that Plegridy may improve recovery following relapses.

Four-year follow-up data from the ongoing CARE-MS extension study found that in years zero to four, 35 percent of individuals receiving Lemtrada® (alemtuzumab, formerly Campath) experienced a thyroid adverse event, a well-known risk of treatment with the drug. None of these events resulted in discontinuation of treatment with Lemtrada, and most of the thyroid-related adverse events were treated with conventional treatment. The incidence of events peaked at month 36 and decreased thereafter. Ongoing patient education and quarterly laboratory monitoring allow for timely detection and treatment.

Three-year follow-up data from the CARE-MS II extension study demonstrated that Lemtrada has a durable treatment effect. Eighty percent of individuals with RRMS who received two yearly courses of the drug in the CARE-MS II trial did not receive a third course of treatment. Seventy percent of EDSS scores were stable or improved at year three, compared to the baseline measurement upon entry into the trial.

Impairments in visual function can impact disability in individuals diagnosed with RRMS. In the CARE-MS II study, individuals taking Lemtrada had improved visual outcomes as compared to those taking Rebif.

Studies in Progressive MS

In a randomized trial of 20 adults with chronic-progressive MS, both arm use and neuroplasticity (the brain’s capacity to change and adapt) improved using a therapy called constraint-induced movement therapy (CI). This therapy forces the use of the affected arm by restraining the unaffected arm in a sling. These results suggest that CI therapy may counteract the progressive loss of function as well as central nervous system (CNS) degeneration in progressive MS.

Pixantrone (PIX) is under investigation as an alternative for the effective but cardio-toxic drug Novantrone® (mitoxantrone or MIX) in the treatment of aggressive RRMS or secondary-progressive MS (SPMS). In a Phase I/II study of 18 patients with aggressive disease, pixantrone was as effective as Novantrone with less cardiotoxicity. According to the study abstract, pixantrone is structurally similar to Novantrone and both drugs have similar immunosuppressive properties in animal studies. However, the authors state that pixantrone is less toxic to the heart.

In a Phase II double–blind, placebo-controlled study of 20 people with SPMS, SR-CRH-01 was well tolerated and resulted in significant improvements in several secondary endpoints. These endpoints included the MS Functional Composite (MSFC), the Timed 25-Foot Walk, and the mean 9-Hole Peg Test (9-HPT). SR-CRH-01 is a stabilized, neuropeptide, also known as Aimspro®. Larger, longer-term studies are warranted given these promising results.

The ALLEGRO and BRAVO trials studied the effects of Laquinimod on individuals with RRMS. Pooled data from these trials were examined to determine the effect of Laquinimod confirmed disability progression (CDP) in several subgroups, including a group with the least favorable MSFC scores. The results were encouraging and suggest that Laquinimod may benefit people with progressive types of MS. Laquinimod is an experimental oral medication that works as an immunomodulator.

A retrospective evaluation of clinical outcomes of individuals with SPMS demonstrated that 48 percent stabilized and 36 percent significantly improved following treatment with Rituxan® (rituximab). No significant adverse events were reported. While Rituxan is not likely to continue in development for the treatment of MS, these data support continued development of the next-generation anti-CD20 monoclonal antibodies.

Other Experimental Treatments for MS

Vitamin D
A total of 158 people with MS (most with RRMS) were treated with either 1 mcg of Alfacalcidol (a Vitamin D analog) once daily for six months, or with a placebo. Patients in the Alfacalcidol-treated group had a reduced number of relapses compared to the placebo group. They also experienced a significant improvement in fatigue, based on the Fatigue Improvement Scale (FIS), compared to the placebo group. Quality of Life scales were positively affected as well. No serious adverse events occurred in either arm of the study.

Stem Cell Transplant
The safety and feasibility of autologous (from the patient) mesenchymal stem cell transplant is being studied in STREAMS, a Phase II trial of individuals with highly active MS. No adverse events have been seen in the five patients who have been infused to date (a total of 15 patients will be recruited). Preliminary results support the safety and feasibility of mesenchymal stem cell transplant in this population. No data are available to indicate whether their MS was affected.

Ofatumumab
Results from MIRROR, a 12-week Phase II study, comparing several doses of Ofatumumab (also known as Arzerra®) in RRMS were reported. Significant reductions in new gadolinium-enhancing lesions were seen in all treatment groups compared to placebo. Five serious adverse events were reported, all in the highest dose treatment group. No cases of PML were observed. Ofatumumab (also known as Arzerra®) is an anti-CD20 monoclonal antibody given via IV.

Anti-LINGO-1
The design of SYNERGY, a Phase II trial studying the safety and efficacy of the anti-LINGO-1 monoclonal antibody BIIB033, was presented. A total of 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 are expected to aid in the decisions on further development of this drug for CNS neuroprotection or repair. 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.

Daclizumab HYP
Results of the SELECT and SELECT Extension studies indicate that treatment with Daclizumab HYP (High Yield Process) may result in a reduction in the rate of brain atrophy in MS patients, suggesting the drug may have a long-term neuroprotective effect. Daclizumab (also known as Zenapax®) is a genetically engineered monoclonal antibody that is administered via IV and is being studied in individuals with RRMS and SPMS.

Siponomid (BAF312) is an oral drug that is in the same class of drugs as Gilenya. Safety and efficacy results from the BOLD extension study in individuals with RRMS demonstrated sustained efficacy. These findings were consistent with the core BOLD study. No new safety concerns were identified.

Pregnancy while Taking a DMT

Despite a requirement for reliable contraception, 83 pregnancies were reported in women who were either (A) taking Aubagio during clinical trials, or (B) partners of men taking Aubagio during clinical trials. Upon learning of pregnancy, women were instructed to discontinue Aubagio and undergo a procedure that results in rapid elimination of the drug. Pregnancy outcomes were consistent with those in the non-MS population. No structural or functional problems have been reported in any of the infants exposed to Aubagio in the context of these clinical trials.

Women with RRMS planning to become pregnant are advised to discontinue treatment with Tysabri before conception. However, it is known that there is a high risk of severe relapse following discontinuation of Tysabri and that these relapses frequently require high-dose steroid treatment to manage. Results of a prospective controlled study of 97 women with RRMS who did not discontinue treatment during their pregnancy were reported. When compared to both healthy and disease-matched control groups, the rates of major malformation, low birth weight, and premature birth did not differ significantly. It will be important to weigh the risks and benefits of continuation of treatment with Tysabri against the risks and benefits of high-dose steroid treatment during pregnancy.

Only 16 percent of women with MS who responded to a reproductive-events questionnaire said the reason they did not want to become pregnant was because of their concerns about raising a child as a parent with MS. Other reasons recorded: 30 percent did not want children; 24 percent were unsuccessful in trying to become pregnant; 18 percent did not have a spouse; 5 percent were considering pregnancy; and 3 percent had adopted.

A retrospective analysis of population-based databases in British Columbia found no evidence that infants born to fathers who were exposed to Betaseron or Copaxone around the time of conception were associated with altered birth weight or gestational age. An Italian study found that infants of fathers with MS taking one of these same DMTs (Betaseron or Copaxone) around the time of conception had similar outcomes to infants of fathers with MS who did not take these drugs (ever or around the time of conception). No differences were observed in: birth weight or length; the frequency of pre-term delivery; or the incidence of spontaneous abortion. No pregnancy or delivery complications, or infant malformations, were reported following exposure to these drugs.

Cognition

A study of 48 people with RRMS found that MS relapses did not cause a significant decline in tests measuring cognitive functions.

Treatment with Tysabri has been shown to be superior to placebo in preserving cognitive function during the first two years of therapy. An interim analysis of data from an observational study of 63 patients treated with Tysabri continuously for more than two years suggests that treatment can preserve and possibly improve cognitive function beyond two years of continuous therapy.

Examples of Other Interesting Studies

An estimated 2 to 10 percent of all cases of MS are diagnosed before the age of 18 (pediatric MS). In Hispanics, one study found that pediatric onset occurred in 18 percent of the 348 people with MS included in the study.

In an observational study of 681 people diagnosed with MS, smoking cessation was found to significantly reduce the risk of progression (either to EDSS of 6 or to SPMS).

In a group of 70 people with RRMS, individuals with high-sodium intake were 3.4 times more likely to develop a new lesion and had an average of eight more T2 lesions on MRI than those with low- or moderate-sodium intake. People with medium- or high-sodium intakes had a 2.75 to 3.95-fold greater chance of experiencing a worsening of their disease than those with low-sodium intake. The findings were replicated in a separate study of 52 people with MS.

Previous studies have estimated the prevalence rate of taste dysfunction to be 1 percent in MS. This study of 73 people with MS and matched controls found that almost 22 percent of people with MS exhibited taste dysfunction. All types of taste were affected, including sweet, sour, bitter, and salty.

Please see MSAA’s MS Research Update for additional details on the FDA-approved disease-modifying therapies, experimental treatments, and other MS research. For more information or to speak with a trained Helpline consultant, please call MSAA at (800) 532-7667. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.

Written by Margaret M. McCormick, RN, BSN, MSCN
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer and Creative Director

Editor’s note: MSAA does not endorse or recommend any specific products or therapies. Readers are advised to consult their physician before making any changes to their medication, diet, exercise, or other treatment regimen. Initial study results from therapeutic agents under investigation should be considered as preliminary, since additional studies and/or evaluations may be needed to prove the safety and efficacy of these agents. Please note that the different lengths of text dedicated to each topic should in no way be considered as favoritism toward any one product. The information given in this article is just a sampling of various highlights from the AAN meeting.