Phase III Trial Results (Alemtuzumab & Laquinimod)

From the NMSS's website, the results of Phase III trials:

First, Alemtuzumab:

Sanofi and its subsidiary Genzyme have announced that the experimental intravenous therapy alemtuzumab (with a proposed brand name Lemtrada,™) met one of two primary endpoints by significantly reducing relapse rates in a two-year study comparing two annual cycles of alemtuzumab against standard subcutaneous dosing of Rebif^® (interferon beta-1a, EMD Serono Inc. and Pfizer). The study, called CARE-MS I, involved 581 people with early relapsing-remitting MS. The study did not meet its second primary endpoint of slowing disease progression compared to Rebif. The results were announced in July 11 press release. Data analysis is ongoing and the company expects to provide a full report at an upcoming medical meeting. Another trial of alemtuzumab, called CARE-MS-II, is currently underway.
Background: Multiple sclerosis involves immune system attacks against brain and spinal cord tissues. Alemtuzumab is a humanized monoclonal antibody directed at CD52 (a protein on the surface of immune cells) that is currently approved by the U.S. FDA for the treatment of B-cell chronic lymphocytic leukemia. Its ability to target immune cells led investigators to test its potential as a treatment for relapsing-remitting MS. An earlier phase II study compared two dose levels of alemtuzumab with Rebif in 334 subjects with relapsing-remitting MS who had never taken any other disease-modifying therapies. Those taking alemtuzumab had a 74% reduction in the risk of MS relapse compared with those on Rebif, and a 71% reduction in the risk for sustained accumulation of disability (New England Journal of Medicine 2008 359;17: 30-45).
Dosing was temporarily suspended in the Phase II study due to the occurrence of immune thrombocytopenic purpura (ITP), a rare condition in which low blood platelet counts can lead to abnormal bleeding. After the first cases of ITP occurred, one of which was fatal, Genzyme implemented a patient safety monitoring program which includes patient and physician education and regular contacts with patients. Two phase III studies comparing alemtuzumab with Rebif were then launched.
In June 2010, it was announced that alemtuzumab had been designated by the FDA as a “Fast Track Product.” This designation should expedite its future review by the FDA after the company submits results of the phase III trials. The press release stated that the company expects to file for regulatory approval of alemtuzumab for MS in early 2012.
This Study: In the CARE-MS I study, approximately 581 people with early, active relapsing-remitting MS, who had never received disease-modifying therapy to treat their MS, were randomly assigned to receive alemtuzumab or Rebif. Alemtuzumab was given by intravenous infusion for 5 days initially and for 3 days one year later. Those on Rebif received the standard dose of 3-times weekly subcutaneous injections. According to the press release, after two years the relapse rate of those on alemtuzumab was reduced by 55 percent compared to those on Rebif. After two years, 8 percent of those on alemtuzumab had an increase in their EDSS score (a standard scale of physical disability) compared to 11 percent on Rebif – a difference that was not statistically significant.
According to the press release, the most common adverse event associated with alemtuzumab in the CARE-MS I study included reactions associated with infusions (such as headache, rash, fever, flushing, hives and chills). There were more infections in those taking alemtuzumab, predominantly mild to moderate, and there were no fatal infections. Less than 20 percent on alemtuzumab developed autoimmune thyroid-related problems and less than one percent developed ITP.
In the ongoing CARE-MS II study, approximately 1200 subjects at over 250 study sites have been randomly assigned to receive one of two alemtuzumab treatment regimens, or Rebif.
Comment: These positive results are the first reported from this Phase III study of alemtuzumab. Full details and evaluation of this study, and from another Phase III study now underway, should help define the safety and promise of alemtuzumab as a potential new therapy for relapsing MS.

Next,  Laquinimod:

Teva Pharmaceutical Industries Ltd. and Active Biotech announced in a press release that the phase III BRAVO study, in which the experimental oral drug laquinimod was tested against inactive placebo in a study involving over 1300 people with relapsing-remitting MS, did not reach its primary goal of reducing the average number of relapses in a year. However, when the investigators adjusted the data to correct for differences in magnetic resonance imaging characteristics at the start of the study, a significant reduction in average annual relapse rate was observed in the group receiving the laquinimod. Further analysis is ongoing, and the results are being submitted for presentation at a scientific meeting later this year. The companies state that they plan to submit applications to regulatory authorities for the treatment of MS in the United States and European Union.
Background: Multiple sclerosis occurs when the immune system mistakenly attacks nerve fiber-insulating myelin and other brain and spinal cord tissues. Laquinimod is a monoclonal antibody believed to affect the immune attack. In an earlier phase II study involving 306 people with relapsing-remitting MS, oral laquinimod reduced disease activity by 40.4% compared with inactive placebo. (Lancet 2008; 371: 2085–92) In one phase III study – the ALLEGRO study – laquinimod reduced the annual relapse rate in those completing the trial by 23%, compared to those on placebo. (Late-Breaking News – American Academy of Neurology, 2011)
The Study: In the BRAVO study, participants were randomly assigned to receive either laquinimod 0.6 mg (one capsule daily), inactive placebo, or Avonex® (interferon beta-1a, Biogen Idec) 30 mcg/wk for 24 months. The primary goal of the study was to determine the effect of laquinimod on the rate of relapses. Secondary goals included impacts on disease activity as observed on MRI scans, and accumulation of disability. Laquinimod was not directly compared to Avonex, but just to the inactive placebo.
Laquinimod did not reduce the annualized relapse rate significantly more than placebo. According to the press release, there were differences in MRI characteristics between the treatment groups at the beginning of the study, and when the data were adjusted to account for these differences, laquinimod was found to reduce annualized relapse rate, disability progression (as measured by the EDSS scale of disease activity), and brain tissue volume loss significantly more than placebo. No details were released related to safety, except to state that “laquinimod demonstrated a favorable safety and tolerability profile compared to placebo.”
According to the companies, further analysis is ongoing, and the results are being submitted for presentation at a scientific meeting later in the year. The companies plan to submit applications to regulatory authorities for the treatment of MS in the United States and European Union. The complete data from the BRAVO and ALLEGRO studies should help define the safety and promise of laquinimod as a potential new oral therapy for relapsing-remitting MS.

Always nice to know what progress is being made!