Looking Into the Crystal Ball

1. Looking Into the Crystal Ball Promising Research in Multiple Sclerosis Treatment

2. What do we need to study in MS? • Why do people get MS? • Why do people get different types of MS? • Why does the course of MS vary so much? • What actual cells are abnormal in MS? • What are the protein targets in MS? • What parts of our brain or immune system can we change to alter the course of MS? • How do we make life better for MS Patients?

3. Why do People get MS? • Genetics studies • Environmental Studies

4. Genetic Studies Twins studies- If one identical twin has MS, the likelihood of the other getting it is 25-35%. If one Fraternal Twin has MS, the likelihood of the other getting it is only 2-3 % 20% of people with MS have a family member with MS Some ethnic groups seem to be less likely to get MS than others- Asians

5. Genetic Studies • HLA- DR 2 gene is seen in about 60% of people with MS • Two other genes of the immune system- IL-2 Receptor and IL-7 Receptor genes have a small association with MS • Many other genes are likely to play a role and are being studied at present • Likely a risk factor based on more than one genetic factor

6. Environmental Studies • Sunlight • Epstein-Barr Virus • Chlamydia Pneumoniae • Radon? • Vitamin D • Other viruses and bacteria • Other environmental proteins or chemicals

7. Why do people get different types of MS? • Direct Brain studies • MRI studies • Blood Studies • Changes in the pattern of the spinal fluid in more progressive MS • Comparing the severity of the course of the disease to other measures • Finding better measures of disease progress

8. Direct Brain Studies • Samples of brains from MS patients studied to compare the different types of brain lesions seen. • 4 different sub-types recognized • Attempts to compare to clinical course are not yet completely successful • Some are also attempting to compare the MRI findings of these types. • Problems- MRIs aren’t as useful on people who have died • People who have biopsies done to diagnose their MS have an unusual type of MS or a biopsy would not be needed

9. MRI studies • MRI is a good tool to look at MS, but no single MRI measure correlates well with the clinical picture of MS (some people with really bad looking MRIs have mild disease and Vice-versa) • New MRI techniques- MR Spectroscopy, Magnetization Transfer Imaging, Functional MRI, and other tools may help measure disease activity in other ways.

10. Basic Science • Answering the questions of actual molecular causes and activity in MS allows for the identification of ways of changing the disease • Animal Models that we can manipulate • Blood studies • Tissue cultures • DNA studies

11. What cells or parts of Cells are abnormal in MS? Inflammation- T cells and B cells and adhesion Molecules Oxidative Stress- Free radical production Repair mechanisms Early cell death Loss of Axons- the role of myelin in maintaining axons

12. What are the protein targets in MS • Different protein Targets in different types of MS? • The same target for everyone? • Spreading of targets as the disease progresses?

13. How can we alter the course of MS? • Identifying target actions by the above studies • Developing drugs that alter the actions uncovered by other studies • Testing drugs in animal models and then in humans • Looking at the risk-benefit ratio of different drugs. • What about repair?

14. Phases of drug trials • Phase I- can this drug be safely given to people or to people with this disease? Usually a small study looking at safety only • Phase II- finding a dose that can be given and using a group of people to see if this looks as if it might be effective • Phase III- large controlled trial to determine if this drug is actually beneficial in the disease • Phase IV- testing of the drug after it is found to be useful to understand better all the side effects and uses of the drug

15. Drugs for RRMS in phase III trials • Cladribine • Teraflunamide • Fingolimod • BG- 12 • Laquinimod • Alemtuzumab (Campath) • Combination Avonex and Copaxone

16. Cladribine • Oral Drug that blocks a certain type of T-cell • Didn’t work in Secondary progressive MS • Phase 3 trial ongoing in Relapsing MS • Major risk of infection

17. Teriflunomide • Oral Medication with promising results in the Phase II trials • Phase III study ongoing • Blocks the proliferation of Lymphocytes so that the immune response is not as great to a given protein • Similar to a drug given in Rheumatoid Arthritis • Concerns about Liver toxicity and infections

18. Fingolimod • Oral drug that prevents lymphocytes from leaving the lymph nodes S-1P inhibitor • Phase 2 trial with 50% reduction in clinical disease activity • Two Phase 3 trials are ongoing • Safety concerns- heart block, melanoma, retinal problems, asthma, increased risk of infections, liver problems

19. BG00012 • Oral drug similar to a psoriasis drug called Fumaderm • Phase 2 trial was promising- showed a reduction in inflammatory activity by 68% by MRI • Phase 3 trial is ongoing- compares BG12 with copaxone and placebo • Concerns about Kidney and liver function and low blood counts

20. Laquinimod • Oral drug that acts as an immunomodulator. • Mechanism of action isn’t certain • Phase 2 trial showed a reduction of active lesions by 50% and new lesions by 44% • Phase 3 trial ongoing • Side effect profile is fairly mild at present, but some concern about Liver problems or low blood counts

21. Combi-RX • Does combining Copaxone and interferon work better than either drug alone? • Study to compare Avonex to Copaxone to both drugs combined • No placebo Group, but everyone takes injections for both

22. Alemtuzumab (Campath) • IV drug given for 5 days once a year. • Phase II trial showed a reduction in relapses of about 70% compared to Rebif • Risk of Grave’s Disease • Risk of ITP • Risk of unusual infections • Not useful in SPMS

23. RRMS drugs in Phase II trials • CDP 323 • Rituximab/ Ocrelizumab • Daclizumab • Estriol

24. CDP 323 • VLA-4 inhibitor • Likely to work like Tysabri to decrease influx of inflammatory cells into the nervous system. • Initial studies are promising • Phase II trial open to RRMS or SPMS with Relapses

25. Daclizumab • Antibody against the IL-2 Receptor • Conflicting studies- phase I open label with the IV form looks a little more promising than the the Phase II trial with the subcutaneous injection

26. Rituximab • An antibody against the B cells- used in a lot of different autoimmune diseases • Phase II trial showed a major reduction in active lesions compared to placebo • The humanized version of the drug, Ocrelizumab is now in Phase II testing

27. Estriol • Because it is well known that pregnant women do better than normal during their pregnancy, studies into different estrogens have begun. • A mouse study with Estriol, an estrogen found in high quantities in pregnant women showed a good effect • Phase II trial in combination with Copaxone is ongoing

28. Secondary Progressive MS • ABT-874—antibody that inhibits certain protiens that promote immunity. Now in phase II trial in SPMS • MBP8298—synthetic protein fragment or peptide may make immune system tolerant of myelin. Phase II/III study in SPMS is underway

29. Primary Progressive MS • Rituximab trial did not show any significant difference, but some hint that certain subgroups of PPMS might benefit • Fingolimod trial started in PPMS

30. How do we make life better for MS Patients? • Symptomatic Treatments • Rehabilitation • New devices to improve mobility

31. Fampridine • Known as 4 amino Pyridine or 4-AP, this drug is believed to improve function through the damaged parts of the brain. • Recent study showed an improvement in walking speed in about 40% of peole who tried it • Presently being presented to the FDA for possible approval

32. Provigil and R-Modafanil • Some suggestion of assistance in fatigue • We plan to study it in cognitive function in the near future.

33. Rehabilitation • Many ongoing studies to evaluate exercise for MS patients • Cognitive re-training studies • Walk-aide • New electronic walking devices used for paraplegic patients

34. Future directions of Research • Repair and regeneration of new myelin • Stop the ongoing degeneration and atrophy and preserve dying cells • Find more specific ways to block the immune response in MS only

35. Stem Cells • Some types of stem cells can be used to replace the bone marrow if a person undergoes chemotherapy and has her own Bone marrow wiped out. • Commonly done in cancer patients, but with a lot of toxicity and risk • Studied in severe, rapidly worsening MS

36. Mesenchymal Stem Cells • This is a technique of taking bone marrow stem cells from a person, changing them by growing them in culture, and and the n injecting them back into the blood of a person with MS. • May alter the immune response to change the course of MS, possibility of also aiding in repair

37. Stem Cell Repair • One of the most exciting theories is to use stem cells for repair- encourage the cells to become a new cell that will replace a damaged cell- new myelin producing cells, or new brain cells • Need to find ways to stimulate the proper types of cells, get the cells to right places in the brain, encourage them to actually replace the damaged cells, and to stop growing when they are at the right density. • Lots of research needs to be done to figure out how this would best be used.

38. What to know about clinical trials • Placebo Control • Need for comparisons and clinical accuracy • Trying a drug that might not work • Unforeseen side effects