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An increase in the therapeutic arsenal against MS

Over the past four years, a number of immune treatments have become available. They are second-line treatments for patients with relapsing-remitting MS.
Lemtrada®  (alemtuzumab)
Lemtrada® is a monoclonal antibody that acts against CD-52, an antigen present  on the surface of many T and B lymphocytes. This causes lymphocyte depopulation and repopulation, which alters both their number and properties. 
Lemtrada®  is given intravenously for five days during the first year and for three days during the second year. The treatment then need only be repeated in the event of renewed disease activity.
Two major studies were performed to compare its effectiveness with that of an active comparator (IFN ß-1a, Rebif® 44µg, three per week, given subcutaneously).
  • The CARE-MS I study was performed on patients who had never received therapy. A 55% reduction in the annualised relapse rate (ARR) was noted over two years of treatment with Lemtrada®. Statistically, the difference in sustained accumulation of disability (SAD) was insignificant.
  • The CARE-MS II study was performed on patients suffering from attacks despite having been previously treated with interferon beta or glatiramer acetate. Compared with the IFN ß-1a treatment, a 49% decrease in ARR over a two-year period was noted, as well as a 42% decrease in SAD. Also, the number of patients with sustained reduction in disability (SRD) was 29% in patients treated with Lemtrada®, against 13% in those treated with Rebif®.
The 7-year follow-up data for both studies confirmed persistent efficacy. The EDSS score remained stable or improved in 78% of the MS-CARE I patients and 73% of the MS-CARE II patients compared with the initial score.
Side effects occurred on IV administration, or were delayed and had an auto-immune basis. 90% of the patients reacted to infusion. The reaction was usually slight to moderate and treated by the simultaneous administration of paracetamol, methylprednisolone and an antihistaminic drug. The symptoms chiefly included headaches, mild nausea, an itchy rash and an impression of fever. During lymphocyte repopulation, auto-immune events sometimes occurred, often between the second and fourth year following administration. The most frequent manifestations were thyroid problems (36%), a fall in platelet count with a risk of bleeding (1%) and auto-immune kidney disease (0.3%). Monthly blood and urine tests are required to detect these side effects.
Finally, the risk of infection, among other things with shingles, increases during a one-month period following administration. In this case, treatment with Acyclovir is recommended.
Mavenclad® (cladribine)

Mavenclad®  causes a long-lasting reduction in the number of lymphocytes. B and T lymphocyte depopulation is selective due to the fact that these cells contain a higher amount  of the activating enzyme.

Mavenclad® is taken orally and the dose depends on body weight. The drug is taken for 4 or 5 days in the first and second month and the treatment is repeated after 1 year. No tablets need to be taken during the third and fourth years.

  • Effectiveness was demonstrated by the CLARITY study, in which Mavenclad® was compared with a placebo over a period of 2 years. Initially, 2 doses were assessed, of 3.5 and 5.25 mg/kg. All results relate to the commercially sold dose, which is 3.5mg/kg.
  • Cladribine treatment reduced ARR by 57.6% and 79.7% of the subjects remained free from attacks after two years, against 60.9% of those taking a placebo. The proportion of progression-free patients at the end of 6 months (EDSS score) increased by 47%. The number of patients who had not suffered attacks over a period of 2 years was 80%. The NEDA* rate was 47%.

The main side-effect of cladribine is lymphopenia. The lymphocyte count is therefore checked prior to beginning the treatment, then during the second and sixth months before completing each
cycle. Shingles also occurs more frequently. Although care must be taken to avoid infections, there was no increase in rare infections during this study.

Ocrevus® (ocrelizumab)
Ocrevus® is a monoclonal antibody that specifically targets CD20+ B cells. This causes B lymphocyte depopulation. However, the cells which preserve long-term immune memory are not affected.
Ocrelizumab is administered intravenously every 6 months.
  • 2 Phase III studies (OPERA I & II) assessed the drug’s efficacy compared with an active treatment with IFN ß-1a (Rebif® 44µg, 3/week, given subcutaneously). Both studies yielded similar results: a reduction in ARR (46%/47%), a 40% increase in the number of patients whose disease had not progressed in 6 months (OPERA I & II). NEDA was achieved in 47.9 and 47.5% of cases respectively.
  • Finally, the ORATORIO study should be mentioned, during which the use of ocrelizumab as a first-line treatment in primary progressive MS significantly reduced (25%) the number of patients whose disability continued to progress after 6 months (CDP).

Reactions may occur at the time of administration and drugs therefore need to be given preventively (as in the case of Lemtrada®). These side effects mainly occur at the time of the first administration. Particular attention needs to be paid to infections, especially Hepatitis B, which must be excluded prior to beginning the study. However, the studies show that severe side effects, especially severe infections, occur with about the same frequency as in the case of treatment with interferon beta-1a or a placebo.

Dr. Danny Decoo

*NEDA: No Evidence of Disease Activity
This is a new goal in the treatment of multiple sclerosis. Patients with relapsing-remitting MS are treated with disease-modifying drugs (DMDs) so that they achieve a state in which:
  • they have no relapses
  • their disability does not increase (as measured on the EDSS scale)
  • no new or active (enhancing) lesions appear on their MRI scans.