Posted Thursday, December 8, 2011
News from the Multiple Sclerosis Association of America
This year's joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) was extremely well attended. More than 7,000 professionals attended the meeting, which featured more than 1,000 presentations - all in a whirlwind three-and-a-half days.
The following highlights review only a few of the many topics discussed at the meeting, but they reflect research of ongoing interest to the entire MS community.
Phase III Results For New Drugs and Related Studies
The most notable event was the release of data from Phase III trials for five drugs, all of which were tested in relapsing-remitting MS (RRMS). These drugs have been discussed previously in MSAA's "Research Update," appearing annually in The Motivator. The most recent update may be found in the Summer/Fall 2011 issue.
Alemtuzumab (Lemtrada®, formerly Campath)
This drug is administered in one course yearly by intravenous infusion over three-to-five consecutive days. It is a humanized monoclonal antibody that targets a protein present on the surface of mature lymphocytes and is approved for the treatment of B-cell leukemia.
Results from the Phase III CARE-MS I study compared Lemtrada to Rebif® over a two-year period. The study showed that trial participants treated with Lemtrada had an Annual Relapse Rate (ARR) that was 55-percent lower than for individuals taking Rebif, as well as an increased reduction in T2-hyperintense lesion volume (as indicated by the "hyper" prefix, this refers to lesions with increased intensity). No difference was observed between the two drugs in the ability to reduce the progression of disability.
The Phase III CARE-MS II study tested Lemtrada against Rebif in patients who relapsed while on a therapy for MS. The results were released a few weeks after the meeting. The press release indicates that patients taking Lemtrada during the two-year study period experienced a 49-percent reduction in relapse rate compared to those taking Rebif. The Lemtrada group also had a 42-percent reduction in the risk of sustained accumulation (worsening) of disability as measured by the EDSS. ("EDSS" refers to the Kurtzke Expanded Disability Status Scale, which measures disability in numbers from 1 to 10.)
BG-12 (dimethyl fumarate)
BG-12 is an oral medication taken daily. It may have a distinct dual mechanism of action. First, it is an immunomodulator with anti-inflammatory properties. This induces anti-inflammatory cytokines (small proteins that may stimulate or inhibit the function of other cells) and appears to suppress damaging macrophage cell activity. Second, BG-12 may also have neuroprotective effects.
The DEFINE Phase III study tested 240 mg of drug given either twice or three times daily, compared to an inactive placebo. The treated group had an approximate 50-percent reduction in the proportion of patients who had relapsed at the end of two years compared to those taking a placebo. The ARR was reduced by 48 to 53 percent; the mean number of T2-hyperintense lesions was reduced by 73 to 85 percent; and the mean number of new T1-hypointense lesions (as indicated by the "hypo" prefix, this refers to lesions with a lower intensity) was reduced by 63 to 72 percent.
Laquinimod is an oral medication taken once daily. It has been granted Fast Track status by the United States Food and Drug Administration (FDA). Although its exact mechanism of action is unknown, it is an immunomodulator, apparently through its effects on cytokines and interleukins. It enhances T-regulatory cell activity, which reduces Th1-inflammatory T-cell activity. It also appears to reduce white blood cell penetration of the central nervous system (CNS). In addition to its immunomodulatory actions, laquinimod may have neuroprotective effects in people with MS.
The BRAVO Phase III trial did not meet its primary endpoint of reducing ARR relative to placebo. However, after adjustment for baseline differences (for clinical factors associated with relapse rate that were imbalanced between the three treatment groups), there was a 33.5-percent decrease in three-month disability progression and 40.6-percent decrease at six months. These reductions are compared to Avonex®, which showed a 29-percent decrease compared to the placebo group. Approximately 12 percent of the placebo group showed a confirmed six-month disability progression, compared with approximately 7 percent on laquinimod and 8 percent on Avonex. The group receiving laquinimod had significantly lower brain atrophy (a loss of brain volume due to cell death and demyelination) during this period; it was 1.25 percent with Avonex, 1.14 percent with placebo, and 0.83 percent with laquinimod.
Zenapax is administered via intravenous infusion every four weeks and has also been studied when given in subcutaneous injections. It is a genetically engineered monoclonal antibody that binds to CD25, a receptor on T cells that is thought to become activated in MS. Zenapax is believed to selectively target these activated T cells without causing general T-cell depletion. It is approved by the FDA for use in rheumatoid arthritis and other autoimmune diseases.
The SELECT trial results showed a decrease in ARR of 54 percent and a decrease in disability progression of 57 percent, as compared to placebo. The proportion of patients who were relapse-free at one year was 63 percent for placebo and 80 percent with Zenapax . The confirmed three-month disability progression was reduced to 6 to 8 percent (in the two groups receiving one of two dose levels of Zenapax ) from 14 percent for placebo. The number of new lesions was also decreased, from 4.8 with placebo to 1.0 to 1.5 in the treated groups. A significant improvement in secondary outcomes was also seen in the treated groups, including physical function, disability progression, and T2-hyperintense lesion burden as shown on magnetic resonance imaging (MRI).
Teriflunomide is an oral medication taken daily. It is an immunomodulator that affects the production of T and B cells. It inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. It may inhibit nerve degeneration by reducing the production of free radicals, possibly decreasing the risk of infections and other complications linked to chemotherapy-like drugs.
Open-label extension studies of this drug, now under FDA review in the United States, showed a 31-percent decrease in the ARR versus placebo, and a reduction in disability progression of 29.8 percent versus placebo. The EDSS remained stable for the group given the higher dose of 14 mg/day, and rose only moderately among those on 7 mg-dose per day.
Ocrelizumab is administered via intravenous infusion. It is a monoclonal antibody that binds to a receptor on the surface of B cells. These cells are then destroyed and their levels in the circulation are decreased. Similar to the drug Rituxan (another anti-CD20 monoclonal antibody), ocrelizumab has the potential advantage of being a more humanized antibody than Rituxan.
While Phase III studies have largely been the topic of this article so far, the results of an important Phase II study reported at the meeting indicated that ocrelizumab maintained a significant reduction in disease activity in patients with RRMS for almost two years.
A Phase III clinical program (ORCHESTRA) is underway, which will test the drug in people with RRMS (Opera I and II) and in people with PPMS (Oratorio). According to www.clinicaltrials.gov, the PPMS portion of this program has two treatment arms (ocrelizumab and placebo) and will evaluate the efficacy and safety of ocrelizumab in patients with primary progressive multiple sclerosis . The blinded treatment period will be more than two years (at least 120 weeks), followed by an open-label treatment for patients in both groups who (in the opinion of the investigators) could benefit from further or newly initiated ocrelizumab treatment. This study is expected to take up to five and half years to complete.
Tysabri is administered via intravenous infusion every four weeks. It is approved for all individuals with relapsing types of MS. This drug is generally recommended for patients who have not responded adequately to, or who cannot tolerate, another treatment for MS.
This laboratory-produced monoclonal antibody acts against a molecule involved in the activation and function of lymphocytes (immune-system cells produced to fight infection and disease) and their migration into the CNS. Recent data suggest that it may also enhance remyelination and stabilize damage to the myelin sheath (the protective covering of the nerves). Preliminary results suggest that the drug may actually produce an improvement in function.
Discontinuing Tysabri to reduce the risk of Progressive Multifocal Leukoencephalopathy (PML), an often-fatal viral infection of the brain, was associated with a rapid return of MS disease activity. A report from the Cleveland Clinic indicated that more than half of patients in the RESTORE trial who switched to methylprednisolone (a steroid) or Copaxone® for six months, relapsed or developed new gadolinium-enhancing lesions. This was also true for four of 14 patients who switched to Avonex.
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