Journal club

Dr Ranjith kumar

resident in neurology

Gandhi medical College.

Oral drugs in multiple sclerosis

• Oral formulations are long awaited for 2.5 millions of MS patients world wide

• Ease of administration.

• Improved adherence

• Reduce restrictions on life style.

FREEDOMS

FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis

fingolimod• Chemical derivative of myriocin, fungus Isaria sinclairii, Chinese

traditional medicine, lymphopenia-inducing effect.

FTY720 or 2-amino-2-(2-[4-oct ylphenyl]ethyl)-1,3-propanediol hydrochloride

• When fingolimod enters the bloodstream, rapidly phosphorylated , resembles the lysophospholipid sphingosine-1-phosphate (S1P).

• S1P has five known receptors-S1P1, S1P2, S1P3, S1P4, and S1P5

• Neurogenesis, cardiovascular development, vasoregulation, endothelial- cell function, and leukocyte migration

fingolimod

• Phosphorylated fingolimod binds to all S1P receptors except S1P2.

• S1P1, the predominant S1P receptor expressed on lymphocytes, is a major regulator of lymphocyte migration because S1P1 signaling is required for extra vascular lymphocytes to emigrate from tissues

• mechanism by which fingolimod acts on S1P1 is more complex.

• The drug probably acts initially as an agonist of S1P1,but it results in rapid internalization and the sustained loss of the receptor’s surface expression

Fingolimod -effects

• Fingolimod interferes with T-cell migration.• Prevents lymphocytes from leaving lymph nodes and

other tissues. • The sequestration of T and B lymphocytes in lymphoid

tissues results in the nearly complete disappearance of lymphocytes, but not myeloid leukocytes, from the blood. This process is reversible.

• Lymphocytes reappear in the blood after the cessation of treatment, indicating that fingolimod does not kill lymphocytes

• fingolimod has been found to modulate oligodendrocyte maturation and astroglia proliferation in vitro.

Study design and randomisation

• Phase III, double blind, placebo controlled study.

• Randomly assigned in 1:1:1 ratio to receive either 0.5 mg or 1.5mg of fingolimod capsule or placebo daily for 24 months

• EDSS

• MSCF

Inclusion criteria

• age of 18 to 55 years;• a diagnosis of multiple sclerosis, according to

the revised McDonald criteria• a relapsing–remitting course• one or more documented relapses in the

previous year or two or more in the previous 2 years;

• a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS; which ranges from 0 to 10, with higher scores indicating greater disability)

Exclusion criteria

• relapse or corticosteroid treatment within 30 days before randomization

• active infection, macular edema, diabetes mellitus, immune suppression (drug- or disease-induced), or clinically significant systemic disease.

• Interferon-beta or glatiramer acetate therapy had to have been stopped 3 or more months before randomization

Study Procedures and End Points

• Clinical assessments were performed at screening and at randomization (baseline)

• study visits, including safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomization.

• The EDSS score was determined every 3 months, and the MSFC z score every 6 months.

• Standardized MRI scans were obtained at the screening visit and at 6, 12, and 24 months and were analyzed centrally at the Multiple Sclerosis–MRI Evaluation Center at the University Hospital in Basel, Switzerland

• The primary end point was the annualized relapse rate, defined as the number of confirmed relapses per year

• The key secondary end point was the time to confirmed disability progression

Secondary endpoints

• time to a first relapse, time to disability progression (confirmed after 6 months)

• changes in the EDSS score and MSFC z score23 between baseline and 24 months

• number of gadolinium-enhancing lesions, proportion of patients free from gadolinium- enhancing lesions

• number of new or enlarged lesions on T2-weighted MRI scans, proportion of patients free from new or enlarged lesions on T2- weighted scans

• volumes of hyper intense lesions on T2-weighted scans and hypo intense lesions on T1-weighted scans,

• change in brain volume between baseline and 24 months, and safety and tolerability measures

Statistical analysis

• Log rank test

• Null hypothesis

• Binomial regression

• Kaplan mier curves

Study Population

• From January 2006 through August 2007, a total of 1272 patients were randomly assigned to a study group at 138 centers in 22 countries.

• Baseline characteristics were similar across the three study groups

• .In total, 1033 patients (81.2%) completed the 24-month study, with 945 (74.3%) still receiving the assigned study drug.

• The study drug was discontinued in proportionately fewer patients in the group receiving 0.5 mg of fingolimod (18.8%) than in the group receiving 1.25 mg of fingolimod (30.5%) or in the placebo group (27.5%).

conclusion

• Oral fingolimod as compared with placebo had superior efficacy in this 24-month study involving patients with relapsing–remitting multiple sclerosis.

• Rates of relapse, progression of clinical disability, and MRI evidence of inflammatory lesion activity and tissue destruction were all significantly reduced with the use of fingolimod.

• The two doses of fingolimod had similar efficacy, and adverse events may be less frequent with the 0.5-mg dose than with the 1.25-mg dose

CLARITY

Cladribine Tablets Treating Multiple Sclerosis Orally

Mode of action

• Cladribine is resistant to the enzyme adenosine deaminase, which causes an accumulation of toxic deoxyribonucleotides in lymphocytes, resulting in relatively selective longtermdepletion of CD4+ and CD8+ T cells

• Cladribine is administered in two or four short courses annually, whereas fingolimod is given daily, both drugs were associated with persistent lymphocytopenia.

Patients• From April 20, 2005, to January 18, 2007, we recruited patients from

155 clinical centers in 32countries

• Patients were eligible if they had received a diagnosis of relapsing–remitting multiplesclerosis (according to the McDonald criteria), had lesions consistent with multiple sclerosis on magnetic resonance imaging (MRI) ,had had at least one relapse within 12 months before study entry, and had a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale .

• Patients were excluded from the study if two or more previous disease-modifying therapies had failed or if they had received immunosuppressive therapy at any time before study entry or cytokinebased therapy, intravenous immune globulin therapy, or plasmapheresis within 3 months before study entry.

Study design• 96- week, phase 3, double-blind, placebo-controlled,multicenter trial.• Eligible patients were assigned in an approximate1:1:1 ratio to

receive one of two cumulative doses of cladribine over 96 weeks (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo

• The study drugs were administered orally as short courses, each consisting of one or two 10-mg cladribine tablets or matching placebo given once daily for the first 4 or 5 days of a 28-day period.

• In the first 48-week treatment period, patients received either two courses of cladribine, followed by two courses of placebo (in the 3.5-mg group); four courses of cladribine (in the 5.25-mg group); or four courses of placebo (in the placebo group), starting at day 1 and at weeks 5, 9, and 13 (8 to 20 days of treatment).

• In the second 48-week period, both cladribine groups received two courses of cladribine, and the placebo group received two courses of placebo, starting at weeks 48 and 52 (8 to 10 days of treatment)

conclusion

• This study showed that short course treatment with cladribine tablets for only 8 to 20 days per year provided a significant benefit for patients with relapsing–remitting multiple sclerosis

TRANSFORMS

• Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis

Study design

• 12-month, phase 3, multi center, randomized, double-blind, double-dummy, parallel group study.

• From May 2006 through September 2007, a total of 1292 patients underwent randomization at 172 clinical centers in 18 countries.

• Patients were randomly assigned to 12 months of treatment with oral fingolimod, at a daily dose of either 1.25 or 0.5 mg, or intramuscular interferon beta-1a (Avonex, Biogen Idec), at a weekly dose of 30 μg

conclusions

• study showed that once-daily oral fingolimod had superior efficacy to interferon beta-1a administered by weekly intramuscular injection.

• Fingolimod was associated with clearly identified adverse events, some of which may be dose-related.

• The absence of dose related differences in efficacy in this study requires further evaluation in the 2-year, placebo-controlled phase 3 trials.

Critical analysis

• How do these therapies measure up against the existing treatments?

• Are all the longer-term adverse effects known?

• What do these drug trials tell us about multiple sclerosis and our treatment goals?

• Both cladribine (in the CLARITY trial) and fingolimod (in the FREEDOMS trial) were highly effective against placebo over a 2-year period.

• fingolimod was more effective than intramuscular interferon beta-1a over a 12-month period (in the TRANSFORMS trial)

• Adverse effects were similar in all three trials of cladribine and fingolimod.

• rates of events leading to discontinuation of a study drug were low but still at least twice as frequent with high dose cladribine (7.9% for the 5.25-mg dose) and fingolimod (10% and 14% for the 1.25-mg dose).

• Close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects

• Change the emphasis of the immune response from activation of pro inflammatory type 1 helper T cells to activation of anti inflammatory type 2 helper T cells

• Both cladribine and fingolimod are targeting inflammation, the key driver of immune injury in multiple sclerosis.

• Both natalizumab, which blocks lymphocyte access to endothelium in the central nervous system, and the anti-CD52 monoclonal antibody alemtuzumab, which destroys T and B cells, have shown impressive reductions in disease activity.

• Insights from these trials and others treating the initial stages of disease suggest that early direct targeting of the immune system offers the best hope for the prevention of later disability

• New horizon for patients with relapsing–remitting multiple sclerosis and a welcome increase in the range of treatment options.

• What are the long-term goals of this new phase of therapy?

• Time will determine the long-term effectiveness of these treatments in delaying the development of irreversible disability.

Thank you