The Next Generation of MS Pharmacotherapy

BOSTON—New treatment approaches showed benefit in managing relapsing-remitting multiple sclerosis (RRMS) in clinical trials presented at the 59th Annual Meeting of the American Academy of Neurology. Currently available disease-modifying treatments for RRMS—interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, and natalizumab—are approved for use as single-agent treatments to reduce the risk of relapse. Unfortunately, these therapies do not reverse existing neurologic damage or prevent permanent disability. Investigations have focused on new uses for existing therapies, primarily in combination regimens, as well as development of novel treatments for RRMS.

EXPANDING USES OF AVAILABLE THERAPIES

A combination of minocycline and glatiramer was more effective than glatiramer alone in reducing the number of T1 lesions on MRI. Minocycline is an inexpensive second-generation tetracycline commonly used to treat urinary tract infections, severe acne, rosacea, gonorrhea, chlamydia, and tick fever, among other conditions. However, it has also been shown in animal models of MS to reduce inflammation and to preserve axons and retinal ganglion cells.

Luanne Metz, MD, of Foothills Medical Center in Calgary, Alberta presented data from a randomized, double-blind study of glatiramer 20 mg/day plus either 100 mg of minocycline or matched placebo twice daily. Study participants were 44 adults with RRMS, with evidence of active disease and no prior exposure to glatiramer. The patients were assessed by MRI at months 1, 3, 8 and 9. At baseline, the two groups were well matched except for a nonsignificant trend in which the minocycline group had a higher rate than expected of T1-enhancing lesions on MRI.

Despite the slight imbalance at baseline, the minocycline group had a rapid decline in T1-enhancing lesions, ultimately leading to 63% fewer lesions after treatment compared with glatiramer alone. The mean number of gadolinium-enhancing lesions decreased from 7.5 at baseline to 1.47 at months 8 and 9 of glatiramer/minocycline. The group treated with glatiramer alone had an average of 2.5 lesions at baseline and 2.95 lesions at months 8 and 9.

In addition, Dr. Metz reported that the combination arm was associated with 65% fewer new and enlarging T2 lesions (mean of 1.84 versus 5.14), a trend that approached statistical significance. At month 9, there was no difference between groups in the number or proportion of black holes on brain MRI that had evolved from acute lesions at month 1 or 3. There was a 42% reduction in risk of relapse in the combination arm, although this was not statistically significant. The combination regimen was well tolerated with no significant differences between the two groups with regard to adverse events.

Dr. Metz concluded, “Our findings suggest a consistent trend toward benefit for minocycline as an add-on therapy to glatiramer.”

INTERFERON BETA-1A PLUS PIOGLITAZONE

Pioglitazone, an oral insulin-sensitizing drug commonly used to treat type 2 diabetes, showed benefit when added to interferon beta-1a in RRMS patients. Results of the one-year, phase I, double-blind, placebo-controlled trial presented by Claudia Kaiser, PhD, of the University of Illinois in Chicago showed that pioglitazone 30 mg/day was safe and reduced disease progression in 22 RRMS patients. Dr. Kaiser explained that previous research has shown pioglitazone to have strong anti-inflammatory components, including effects on T cells and glial cells, as well as metabolic effects.

“We couldn’t see any effect on the total volume of T1 lesions; however, to our surprise, after comparing the FLAIR [fluid-attenuated inversion recovery] sequences after one year, we could see a 3% increase in the placebo group and a 7% decrease in the [pioglitazone] group, which is statistically significant,” noted Dr. Kaiser. In addition, less gray matter atrophy was observed in the pioglitazone group (3.1%) than in the placebo group (5.8%).

Treatment had no significant effects on Expanded Disability Status Scale (EDSS). “However, it was quite interesting to see our results on the MSFC [the Multiple Sclerosis Functional Composite],” said Dr. Kaiser. The MSFC includes quantitative measures of leg function/ambulation, arm and hand function, and cognitive function. “Our placebo group performed fairly well on the MSFC, and our [pioglitazone] group actually showed a significant improvement out to month 5 and an almost-significant improvement out to the end of the trial.” She hypothesized that the reason for the discrepancy in results on the EDSS and the MSFC is that only the MSFC includes evaluation of cognitive function.

Pioglitazone was safe and well tolerated. There were no cases of liver toxicity, edema, or hypoglycemia.

Dr. Kaiser concluded, “Further trials in secondary progressive MS or other relapsing-remitting MS patients are warranted.”

OTHER INTERFERON BETA-1A COMBINATION TRIALS

Two other clinical trials looked at possible combination regimens using interferon beta-1a but failed to find significant benefit. In fact, one of the studies showed that adding atorva­statin, a commonly used lipid-lowering agent, increased MS progression.

Gary Birnbaum, MD, Director of the MS Treatment and Research Center at the Minneapolis Clinic of Neurology in Golden Valley, Minnesota, randomized 24 adults with stable MS who were being treated with interferon beta-1a to add six months of placebo, atorvastatin 40 mg/day, or atorvastatin 80 mg/day. New and enhancing MRI lesions and/or relapses occurred in nine of 13 patients taking either dose of atorvastatin and in one of nine controls. Two of the patients taking high-dose atorva­statin discontinued treatment due to myalgias and transaminase elevations. “Combination treatment of MS with subcutaneous interferon beta-1a and atorva­statin, while well tolerated, resulted in increased MRI and clinical disease activity,” Dr. Birnbaum observed.

Jeffrey Cohen, MD, of the Cleveland Clinic in Solon, Ohio, presented the Avonex Combination Trial (ACT). This was a randomized, controlled, multicenter phase IV study in which the drug was combined with oral methotrexate, IV methylprednisolone, or both, in 313 patients with active RRMS despite treatment with interferon beta-1a.

At 12-month follow-up, results were favorable for all three therapies, but no differences had reached statistical significance. Further analysis is ongoing.

NOVEL THERAPIES FOR MS

Fampridine

Fampridine may improve motor function, particularly walking speed, in patients with MS, according to a phase III, placebo-controlled study presented by Andrew Goodman, MD, Director of the Rochester Multiple Sclerosis Clinic in New York. Fampridine closes potassium channels on demyelinated axons and helps to restore the axon’s ability to transmit impulses by preventing potassium leakage.

In the study, Dr. Goodman and colleagues randomized patients to 10 mg of oral sustained-release fampridine twice daily or placebo for 14 weeks. Participants were 301 adults with definite MS who were able to complete a timed 25-foot walk within 8 to 45 seconds. Use of stable concomitant medications was permitted.

More than one-third of treated patients (34.8%) had consistent improvement in walking speed as measured on the MS Walking Scale-12 (MSWS-12), compared with only 8.3% of controls. Walking speed increased by a mean of 25.2% in the fampridine group compared with 4.7% in the placebo group. A significant improvement in walking speed was maintained throughout the treatment period and was seen in patients with all types of MS.

 Two patients had serious adverse events leading to treatment discontinuation, including anxiety in one patient and seizure during urosepsis in another patient. The most common side effects included falls, urinary tract infection, dizziness, insomnia, fatigue, nausea, upper respiratory tract infection, asthenia, back pain, balance disorder, and headache.

Dr. Goodman concluded, “A significant proportion of MS patients treated with fampridine experienced consistently improved walking speed during 14 weeks of treatment. Improvement in the MSWS-12 score among responders appears to validate the clinical meaningfulness of this improvement.”

Laquinimod

High-dose laquinimod showed significant activity against RRMS on MRI measures of disease activity in a phase IIb trial. Laquinimod is a new orally available immunomodulatory disease-modifying drug for RRMS.

Giancarlo Comi, MD, of the Scientific Institute and University Ospedale San Raffaele in Milan, and colleagues randomized 306 patients with RRMS to 0.3 or 0.6 mg/day laquinimod in a 36-week, double-blind, multicenter study. During weeks 24 through 36, high-dose laquinimod produced a 40% reduction in the cumulative number of enhancing lesions, compared with placebo. Dr. Comi noted, “When we look at the timetable of the changes … they first start to be evident (even though the difference is not yet significant) at the first examination [and at] week 12, and [then] they continually increase over time.” The difference in efficacy became statistically significant after week 24. The effect of low-dose laquinimod did not reach statistical significance, but fell between that of placebo and the high-dose arm.

There were nonsignificant trends favoring the high dose over placebo on clinical measures including annual relapse rate, proportion of patients who were relapse-free, and time to first relapse. Laquinimod was generally well tolerated; however, reversible, dose-dependent liver enzyme elevations were observed.

Rituximab

Rituximab, a monoclonal antibody approved for use in non-Hodgkin’s lymphoma and rheumatoid arthritis, showed safety and efficacy in phase I and II trials.

Amit Bar-Or, MD, Assistant Professor of Neurology and Neurosurgery at the Montreal Neurological Institute, presented data from a 48-week follow-up from a phase I, open-label, multicenter, 72-week trial in which he and colleagues treated 26 RRMS patients with two IV infusions of rituximab given six months apart.

Mild to moderate infusion-related events were observed. Dr. Bar-Or described five adverse events, including an infusion-site reaction, asthenia, a tooth fracture, and two cases of headache. Other drug-related events included headaches, chills, hypertension, and throat irritation. Mild to moderate respiratory infections occurred. One patient discontinued the study due to headache.

On secondary efficacy outcome measures, rituximab significantly reduced the lesion count on MRI and the risk of relapse. Dr. Bar-Or concluded that in patients with active RRMS, over the 48-week observation period, rituximab was safe and generally well tolerated. He added that it was associated with “decreases in gadolinium-enhancing lesions, T2 metrics, and relapse rate.”

Commenting on the mechanism by which rituximab exerts its activity in MS, Dr. Bar-Or said, “The question of how the selective depletion of B cells may be impacting the inflammatory aspect of MS is a fascinating question. In addition to hopefully representing a viable and attractive treatment modality for the future, [rituximab] is teaching us something very important about the role of B cells in the disease.” He noted, “This regimen resulted in rapid and sustained B cell depletion in all patients…. The onset of the effect is rapid and evident about four weeks into therapy, suggesting that ri­tuximab’s effect is unlikely to be antibody mediated.”

In a double-blind, 48-week, phase II study, Stephen L. Hauser, MD, Chairman and Professor of the Department of Neurology at the University of California, San Francisco, randomized 104 patients with RRMS to either two infusions of rituximab two weeks apart or placebo. The two groups were well balanced for baseline characteristics with the exception that the rituximab group had more gadolinium-enhancing lesions on MRI at baseline and the placebo group showed more inactive lesions on MRI at baseline.

Rituximab produced a 90% reduction in total cumulative gadolinium-enhancing lesions. Dr. Hauser noted that the reduction in lesion count was evident by week 12 and sustained at each assessment thereafter. Rituximab also reduced secondary MRI outcomes including the proportion of patients with new gadolinium-enhancing lesions and the accumulation of new T2 lesion volume.

During a six-month period, ri­tuximab reduced the relative risk of relapse by 58% compared with placebo; 14.5% of the rituximab patients experienced at least one relapse during the six-month period, compared to 34.3% of the patients receiving placebo.

Infusion-associated reactions were the only adverse event more common with rituximab than placebo. Acute infusion reactions occurred within 24 hours of administration in a high proportion of patients at the first infusion. Most reactions were mild to moderate, typically manifesting as chills, nausea, pruritus, pyrexia, pharyngitis, or throat irritation. There was one serious case of pyrexia but no grade 4 events. Dr. Hauser pointed out that in rheumatoid arthritis trials, IV methylprednisolone has been used successfully to limit infusion reactions, but it was not used in his study. Infections occurred in a similar proportion of both groups; most were mild to moderate, though some severe infections were reported.

Based on these findings, a phase III trial is warranted. In addition, “these data provide the proof of principle that B cells clearly play a central role in pathophysiology of RRMS,” said Dr. Hauser.

Claude Genain, MD, Associate Adjunct Professor in the Department of Neurology at the University of California, San Francisco presented an investigator-initiated, open-label, single-center trial of rituximab in 10 patients with neuromyelitis optica. Nine patients received two infusions of rituximab two weeks apart, and four patients repeated this cycle of treatment. After a median posttreatment follow-up of six months, three patients had myelitis relapses at 2.6 to 7.3 weeks after the first cycle; however, none relapsed after a second cycle of treatment. The posttreatment relapse rate was only one third of the pretreatment rate. Rituximab had no significant effect on EDSS. Three patients had mild infusion reactions, and there were no serious infections.

Anu Jacob, MD, of the Mayo Clinic in Rochester, Minnesota, presented a retrospective analysis of rituximab in three men and 21 women with neuromyelitis optica. All of the patients received two to four infusions of rituximab 375 mg/m2 at weekly intervals. At a median of 22 months’ follow-up, the posttreatment relapse rate was 0.2, compared with 1.6 relapses pretreatment, and EDSS scores had stabilized or improved in 91% of patients. Six patients experienced infusion-related adverse ­effects, which were not dose limiting. Two patients died of intercurrent infections at 10 and 12 months after treatment. Eighteen patients were continuing rituximab treatment at the most recent follow-up.

Alemtuzumab

Despite raising some safety concerns, the CAMMS223 study showed alemtuzumab to be reasonably safe and superior to interferon beta-1a in a head-to-head randomized comparison of patients with early and active MS.

Alemtuzumab is an anti-CD52 monoclonal antibody that is currently indicated for the treatment of B-cell chronic lymphocytic leu­kemia (B-CLL) in patients who have been treated with alkylating agents and were treated unsuccessfully with fludarabine. Alasdair Coles, PhD, of Addenbrooke’s Hospital in Cambridge, UK, explained that he and his colleagues have been using alemtuzumab in open-label studies of various subtypes of MS since 1991 and have concluded that it is a powerful immunotherapy that is most effective when given early in the course of MS.

Dr. Coles’ two-year study compared high and low doses of alemtuzumab with interferon beta-1a. The study protocol allowed an optional third alemtuzumab treatment to be administered at month 24 if the treating physician deemed it necessary and if hematologic criteria were met. IV corticosteroids were given prior to antibody infusion to suppress anticipated infusion-related side effects. Patients in the interferon arm also received corticosteroids so that the two treatment arms would be balanced.

During the study, one patient died of an intracranial hemorrhage secondary to idiopathic thrombocytopenic purpura (ITP). Dr. Coles said the occurrence was “a complication of alemtuzumab treatment that we had not previously seen in any of our open-label studies, and we were not prepared for.” In a separate presentation, Herman Sullivan, MD, of Michigan Medical, PC in Grand Rapids, provided details of this and subsequent ITP cases in the CAMSS223 trial. Of the 216 treated patients, six (2.8%) developed ITP. Increased monitoring led to earlier identification and treatment of ITP in the other patients, all of whom are in remission with normal platelet counts. None of the patients required splenectomy, nor was there lasting ITP-related morbidity. Alemtuzumab was also associated with infusion reactions (mostly grade 1 or 2) and with Graves’ disease. There was no significant increase in risk of infection.

As a result of the treatment-related death, study investigators were advised to discontinue alemtuzumab dosing. At that point, all but two patients had received 12-month treatment, so follow-up and efficacy analyses continued. Dr. Coles presented two-year follow-up data.

Alemtuzumab was associated with a 70% to 90% lower risk of relapse, as compared with interferon, and a 66% to 88% lower risk of fixed disability at six months. Whereas the interferon group had small but statistically significant increases in disability over two years, Dr. Coles noted “a startling reduction in disability that was highly statistically significant both in the median and mean EDSS of the group on alemtuzumab, suggesting that something about this treatment is either permitting or promoting recovery.” More than half of the patients treated with alemtuzumab had reductions in disability over the course of the study. All three treatment arms showed a reduction in MRI T2 lesion load, but the reduction was of a greater magnitude in those patients being treated with alemtuzumab.

Dr. Coles said, “We would conclude that alemtuzumab has unambiguously superior efficacy over interferon in the prevention of relapses and the prevention of accumulation of disability. We further report here the unprecedented finding that patients on alemtuzumab treatment showed an improvement in their disability.” Dr. Coles plans two additional studies starting this year to assess safety and efficacy of alemtuzumab in treatment-naive and treatment-experienced patients.

Daclizumab

A retrospective chart review presented by Eman N. Ali, MD, a neurologist in Brookline, Massachussetts, suggested that daclizumab may have improved or stabilized disability in patients with MS. However, the study lacked a control group and failed to show statistically significant benefit compared with baseline on any of its outcome measures.

Daclizumab is a human monoclonal antibody directed against the interleukin-2 receptor alpha subunit (IL-2Ra) that is expressed on activated T cells. By blocking IL-2R, daclizumab limits T-cell expansion, thus reducing brain inflammation in MS.

Dr. Ali reviewed the charts of 55 patients (40 with RRMS and 15 with secondary progressive MS) treated with daclizumab 1 mg/pg IV monthly for at least six months. These patients had previously developed breakthrough disease while taking conventional immunomodulatory therapies. Mean duration of daclizumab therapy was 13 months (maximum, 28 months).

At follow-up, EDSS scores had stabilized or improved in 39 patients (71%) overall, 63% had an activity-free MRI, and 71% were relapse-free. However, Dr. Ali did not find statistically significant changes from baseline to on-treatment rates of stabilization, improvement of EDSS score, activity-free MRI, or relapse.

Fatigue, gastrointestinal upset, and rash were the most common side effects. Mild upper respiratory infections and urinary tract infections were observed. Patients rated the tolerability of the drug as an average 1.87 on a visual analog scale (0 = well tolerated; 10 = not tolerated).

According to Dr. Ali, randomized controlled study is needed for further evaluation of any potential benefit of daclizumab in the treatment of MS.

NR