New Treatment Options for MS Patients: Understanding risks versus benefits

Transcription

1 New Treatment Options for MS Patients: Understanding risks versus benefits By Michael A. Meyer, MD Department of Neurology, Sisters Hospital, Buffalo, NY

2 Objectives: 1. to understand fundamentals of MS diagnosis and clinical presentation 2. to understand MS disease pathophysiology 3. to understand risk versus benefits of new treatment options

3 Worldwide there are 2.5 million people with MS

4 1838: first illustration of MS lesions

5 MS : multiple demyelinating lesions in space and time within the CNS

6 During a 10-year follow-up, multiple sclerosis was diagnosed in 38 percent of patients with a first episode of optic neuritis who were enrolled in the Optic Neuritis Treatment Trial

7 A 45-year-old man with multiple sclerosis presented with worsening weakness in his right leg and double vision. Neurologic examination revealed horizontal diplopia during lateral gaze in both eyes. This patient had internuclear ophthalmoplegia in both eyes due to demyelinating lesions.

8 MS: peri-ventricular lesions

9 MRI : Coronal FLAIR

10 T1 Black Holes

11 MRI : Axial T1

12 Post-vaccinal central demyelination:

13 post-vaccinal encephalomyelitis:

14 Components of the perivascular inflammatory infiltrates include CD3+ T cells

15 left: blood vessel, with red cells in the lumen of an acute lesion, is ringed by small lymphocytes middle: actively demyelinating lesion in the spinal cord of a mouse with acute experimental autoimmune encephalitis right : acute plaque is completely demyelinated and contains numerous transected, damaged axons (arrows) that form spheroids.

16 Lymphocytic Invasion into white matter fiber tracts:

17 Re-Myelination is a slow repair process:

18 TREATMENT OPTIONS for MS: Steroid IV infusions

19 TREATMENT OPTIONS FOR MS: Avonex (Interferon Beta 1a)

20 INTERFERONS: AVONEX: In controlled clinical trials in relapsing MS, those taking the medication had a reduced risk of disability progression, experienced fewer exacerbations, and showed a reduction in number and size of active lesions in the brain (as shown on MRI) when compared with the group taking a placebo. BETA-SERON : patients on interferon beta-1b had no increase in total lesion area, as shown on MRI, in contrast to the placebo group, that had a significant increase. REBIF: A controlled clinical trial in relapsing-remitting MS compared three groups those receiving 22mcg three times per week, those receiving 44mcg three times a week, and those receiving placebo. Over the two-year study, the two experimental groups demonstrated a lower relapse rate, prolonged time to first relapse, a higher proportion of relapse-free patients, a lower number of active lesions on MRI, and delay in progression of disability, when compared to the placebo group.

21 TREATMENT OPTIONS FOR MS: Copaxone Glatiramer acetate is a synthetic protein that simulates myelin basic protein, a component of the myelin that insulates nerve fibers in the brain and spinal cord. This drug seems to block myelin-damaging T-cells through a mechanism that is not completely understood. In controlled clinical trials with relapsing-remitting MS, those taking the glatiramer acetate had a significant reduction in annual relapse rate and a reduction in new lesions as shown on magnetic resonance imaging (MRI), when compared to control subjects who were given a placebo

22 NATALIZUMAB (Tysabri):

23 Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment:..the risk of PML was highest among patients who had all three risk factors (positive status with respect to anti JC virus antibodies, prior use of immunosuppressants, and natalizumab treatment for 25 to 48 months), with an estimated incidence of 11.1 cases per 1000 patients (1 in 90 incidence!!!)

24 PML & JC Virus :

25 HIV associated PML:

26 Progressive Multifocal Leukoencephalopathy

27 Tysabri antibody is directed against alpha4beta1 integrins, which link inflammatory lymphocytes to vascular endothelial cells bearing VCAM1

28 JC viremia after IV natalizumab:

29 α4β1 Integrin Acts as a Cell Receptor for Murine Polyomavirus at the Postattachment Level

30 IDSP sequence on VCAM-1 critical for alpha4beta1 integrin binding:

31 Integrins from inflammatory lymphocytes bind to endothelial cells via VCAM1:

32 JC Polyoma Virus:

33 The viral coat protein VP1 has a IDSP binding site homologue (DSP in red, below)

34 DSP amino acid sequence (yellow):

35 VP1 coat protein :

36 DSP sequence (yellow) homologous to IDSP binding site for VCAM1 to alpha4 integrin:

37 VP1 Pentameric viral capsid ( 1 of 72 coating the JC virus)

38 Proposed model for JC viral latency by binding to alpha4 integrins at the viral coat protein DSP sequence:

39 Tyrsabri likely disrupts integrin binding of the JC virus, disrupting latency and causing JC viremia

40 Latent JC bound to Integrins (left) JC viremia (right)

41 NOVANTRONE (mitoxantrone) Warnings and Precautions In response to post-marketing findings, the FDA has added a black box warning to the prescribing information for this medication: Cardiotoxicity Secondary acute myelogenous leukemia (AML)

42 TECFIDERA: Tecfidera (dymethyl fumarate ) Description: Tecfidera is an oral therapy contained in capsules taken two times per day. Tecfidera, formerly known as BG-12, is dimethyl fumarate, a formulation that was developed specifically for use by people with multiple sclerosis. A chemically related compound, called Fumaderm (dimethyl fumarate and fumaric acid esters), has been used at higher doses for decades in Germany to treat acute flare-ups of psoriasis. Although its exact mechanism of action is not known, Tecfidera is thought to inhibit immune cells and molecules, and may have anti-oxidant properties that could be protective against damage to the brain and spinal cord.

43 FINGOLIMOD: Gilenya is a new class of medication called a sphingosine 1- phosphate receptor modulator, which is thought to act by retaining certain white blood cells (lymphocytes) in the lymph nodes, thereby preventing those cells from crossing the blood-brain barrier into the central nervous system (CNS). Preventing the entry of these cells into the CNS reduces inflammatory damage to nerve cells.

44 Fingolimod (Gilenya):All those starting treatment with Gilenya should have an electrocardiogram prior to dosing and after the 6- hour observation period. During the observation period, blood pressure and heart rate should be measured hourly.

45 Fingolimod reduces T cell egress from lymph nodes:

46 AUBAGIO (teriflunomide) Aubagio (teriflunomide), a pyrimidine synthesis inhibitor, is an oral compound that inhibits the function of specific immune cells that have been implicated in MS. It is related to leflunomide, a drug used to treat rheumatoid arthritis. Aubagio can inhibit a key enzyme required by white blood cells (lymphocytes) which in turn reduces the proliferation of T and B immune cells that are active in MS and also inhibits the production of immune messenger chemicals by T cells.

47 Aubagio : hepatotoxicity Warnings and Precautions The prescribing information contains a boxed warning about the potential for liver damage (hepatotoxicity). Severe liver injury, including fatal liver failure has been reported in patients taking leflunomide to treat rheumatoid arthritis, and a similar risk would be expected with Aubagio (teriflunomide) because of the similarities between the two medication

48 References: Neurol Int Jul 22;5(3):e14 N Engl J Med May 17;366(20): doi: /NEJMoa