2013 ms research update
DESCRIPTION
Dr. Jody Corey-Bloom's (UCSD) MS Research update from the 2013 Annual Meeting of Members for the National MS Society, Pacific South Coast ChapterTRANSCRIPT
MS Research Update 2012
NMSS Annual MeetingDana Point, CA
Jody Corey-Bloom, MD, PhD
University of California, San Diego
What is MS?· MS is an immune-mediated disease
of the brain and spinal cord
- 350,000 affected in US- 8,500-10,000 new cases/yr
· Immune system attacks and destroys myelin and axons
· Characterized by demyelination and axonal loss
· Demyelinating plaques: well-demarcated areas characterized by loss of myelin
3
MS Plaques
4
6
MS: Symptoms and Signs
• Related to distribution of lesions (“plaques”) within the
nervous system
• Weakness, incoordination
• Fatigue
• Sensory symptoms including pain
• Disturbance of sphincter control
• Sexual dysfunction
• Loss of vision or double vision
• Emotional disturbances
• Cognitive impairment
7
Epidemiology
• Prevalence that ranges between 2 and 150 per 100,000
depending on the country or specific population
• Primarily a disease of Northern and Central Europeans
and their descendants
• Though some ethnic groups at low risk: Samis,
Turkmen, amerindians, Canadian Hutterites, Maori
• Climate, sunlight, intake of Vitamin D
• Rare in East Asia and unknown in blacks in Africa
• Migration in children before the age of 15 years adopt the
risks of the new locale
8
Genetics & Gender
• 12-20 times more common among those with an affected family member
• Identical twins = 40% concordance rate
• Average population 1:500 prevalence
• Women 2:1
• Association between MS and MHC alleles DR15 and DQ6.
• Protective loci such as HLA-C554 and HLA-DRB1*11
9
Clinical course of MS
• Well-defined attacks or “exacerbations”• Improvement• Recovery
• Periods of remission• Unpredictable progression
11
Progression of MS
• 70% initially relapsing remitting
• 20-30% remain relapsing remitting• 40% transition to a slow, chronic progression
• 10-20% chronic progressive from outset
• 20% benign
MS Progression
EARLY· Inflammation· Demyelination· Plaques
LATE· Increasing tissue
destruction· Axonal loss· Atrophy
RELAPSES DISABILITY
13
MS Treatment Goals
• Prevent relapses
• Decrease severity and shorten relapses
• Decrease disability
• Slow or prevent conversion from RR to SP
14
Disease-Modifying Therapy (DMT)
• Interferons
• Copaxone®• Novantrone®• Tysabri®• Gilenya®• Aubagio®
Avonex® Betaseron® Extavia® Rebif®
15
MS DMTs
• Successful phase III trials in relapsing MS• All agents
• Successful CIS phase III trials • IFN s and GA (CHAMPS, ETOMS, BENEFIT, PreCise)
• Successful SPMS phase III trials • SC IFN -1b (double-dose IM IFN -1a trial, 1º outcome
not accepted)
• Long-term data, although imperfect, suggests benefit for IFN s and GA for at least 5–16 yrs
16
MS DMTs: Agents have pros and cons
• IFN -1b: long track record, positive trials for multiple subtypes; neutralizing antibody (NAb) issue
• IM IFN -1a: most convenient; low NAb rate; efficacy issue
• SC IFN -1a: very positive relapsing trial; least frequent SC dosing; NAb issue
• GA: good side effect profile; no NAb issue; delayed onset; daily injection
17
MS DMTs: Agents have pros and cons
• Natalizumab (Tysabri®):
• Very positive relapsing trial
• PML issue (323 cases, January 2013); IRIS
• Returned to market with more restrictive use• Elaborate consent form, TOUCH enrollment• Ongoing assessment required• Limited infusion centers
• Monotherapy, no associated immunosuppression
• Use in those who cannot use or who failed immunomodulation
18
MS DMTs: Agents have pros and cons
• Fingolimod (Gilenya®):
• Sphingosine-1-phospate receptor modulator
• -Induces sequestration of WBCs in lymph nodes
• Once daily, oral agent; very positive relapsing trials
• Extensive REMS: baseline and ongoing assessments
• -cardiac issues, 6 hour/longer first-dose monitoring• -ophthalmologic evaluation at baseline, 3 months• -VZV antibodies• -liver toxicity
19
2012: Significant Advances in MS Research
• approval of a second oral therapy for MS
• progression of other emerging therapies through the development pipeline
• launch of the International Progressive MS Collaborative• speed research on progressive forms of MS
• completion of the first human trial of an experimental therapy targeting myelin repair
• advances in understanding of factors that trigger MS
20
PROGRESSING TOWARD STOPPING MS
• Funding of clinical trials:• Vitamin D, riluzole, phenytoin, antioxidants
• Projects focused on “biomarkers” to aid better diagnosis and treatment decisions
• Collaboration in a cross-disease drug screening initiative aimed at discovering compounds to stop nerve and brain degeneration
• In partnership with Merck Serono, Fast Forward provided funding for research into small molecules for CNS repair and neuroprotection
21
Other Important 2012 Results
• FDA Approves Oral Aubagio® (Teriflunomide, Genzyme)
• Two potential therapies before the FDA
• BG-12
• Alemtuzumab
• Tysabri® label updated to include lab test to stratify risk and enhance treatment decisions
• Phase II results of ocrelizumab in relapsing MS
TREATMENT PIPELINE
22
Other Important 2012 Results
• FDA Approves Oral Aubagio® (Teriflunomide, Genzyme)
• Two potential therapies before the FDA
• BG-12
• Alemtuzumab
• Tysabri® label updated to include lab test to stratify risk and enhance treatment decisions
• Phase II results of ocrelizumab in relapsing MS
TREATMENT PIPELINE
Teriflunomide (Aubagio®)
Active metabolite of leflunomide (approved for treatment of rheumatoid arthritis)
Inhibits pyrimidine synthesis and T-cell division
Oral agent, once daily
TEMSO, TENERE, TOWER Phase 3 trials; also TOPIC (early MS, CIS) and TERACLES (adjunct to interferon)
Modest efficacy; good safety profile (LFTs, hair)
Teratogenic in rabbits, rats; Pregnancy Category X
Rapid clearance requires cholestyramine, activated charcoal
Genzyme (Sanofi)
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
Teriflunomide: Phase III TOWER Study
Placebo(n = 388)
Teraflunomide 7 mg(n = 407)
Teraflunomide 14 mg
(n = 370)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.501
0.389
0.319
AR
R
TOWER = Teriflunomide Oral in people With relapsing multiplE scleRosis; RRR = relative risk reductionKappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]
Primary Endpoint: ARR
RRR: 22.3%P = 0.0183
RRR: 36.3%P = 0.0001
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
TOWER: Treatment-Emergent AEs
Preferred term, %Placebo(n = 385)
Teriflunomide7 mg (n = 409)
Teriflunomide14 mg (n = 371)
HeadacheLeading to discontinuation
10.90.3
14.70
12.40
Increased ALT Leading to discontinuation
8.31.6
11.22.9
14.02.4
Alopecia (hair thinning)Leading to discontinuation
4.40.3
10.30
13.51.6
DiarrheaLeading to discontinuation
7.30.3
12.01.0
11.10.8
NauseaLeading to discontinuation
8.80
8.30
10.20.8
NeutropeniaLeading to discontinuation
2.90
7.11.0
9.42.2
ALT = alanine aminotransferaseKappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]
26
Other Important 2012 Results
• FDA Approves Oral Aubagio® (Teriflunomide, Genzyme)
• Two potential therapies before the FDA
• BG-12
• Alemtuzumab
• Tysabri® label updated to include lab test to stratify risk and enhance treatment decisions
• Phase II results of ocrelizumab in relapsing MS
TREATMENT PIPELINE
BG-12
Oral formulation of dimethylfumarate; BID dosing
>30 years of use of fumaric acids in the treatment of psoriasis (both topical and oral)
Anti-inflammatory effects
Inhibits expression of adhesion molecules and proinflammatory cytokines; induces a Th1 to Th2 shift
Potential neuroprotective effects
Activates the Nrf2 pathway and induces antioxidant enzyme production
Biogen
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
BG-12: Pooled Phase III DEFINE and CONFIRM Trials
Gold R, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 151].
Study Design
aPatent numbers are based on the placebo, BG-12 BID, and BG-12 TID groups (GA group is not included).bAll comparisons were vs placebo.CSubset of patients from selected sites with MRI testing capability.
RandomizationN = 2,307a
DEFINE1:1:1 (N = 1,237)
CONFIRM1:1:1:1 (N = 1,070)a
EDSS
MRI cohort (N = 1,046)a,c
DEFINE (N = 540)CONFIRM (N = 506)a
BG-12 240 mg BID PO (n = 773)b
BG-12 240 mg TID PO (n = 761)b
Placebo PO (n = 773)
GA 20 mg QD SC (CONFIRM only, n = 360)b
Year 2Year 1
√√ √ √ √ √ √ √ √
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
BG-12: Pooled Efficacy Analysis of DEFINE and CONFIRM
Endpoint, 2 yrs PLACEBO BG-12 BID BG-12 TID
ARR,Reduced vs placebo
0.37 0.19*49%
0.19*49%
Mean Gd+ lesions,Reduced vs placebo
0.3*83%
0.4*70%
Mean new T2,Reduced vs placebo
16.8 3.7*78%
4.5*73%
New T1 hypointense,Reduced vs placebo
6.3 2.2*65%
2.3*64%
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
Selmaj K, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract P484]
BG-12: Pooled Safety Analysis of DEFINE and CONFIRM
Similar safety profile and discontinuation rates across placebo and both BG-12 groups– Similar incidence of renal and hepatic AEs
AEs associated with BG-12: – Most common: flushing and GI events– No increased risk of serious infections– Decreased mean WBC (by ~10%) and
lymphocyte count (by ~30%) at 1 yr(within normal limits)
WBC = white blood cells
Alemtuzumab (Campath, Lemtrada®)
Approved for treatment of B-cell chronic lymphocytic leukemia; anti-CD52 (cell-surface glycoprotein expressed on T- and B-lymphocytes); yearly infusion
Prolonged depletion of cells; median recovery time to baseline levels:
- CD4+ T cells: 61 months
- CD8+ T cells: 30 months
- B cells: 3 to 6 months
CARE-MS 1, CARE-MS 2
high level of efficacy in reducing relapses
Sanofi
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
CARE-MS I Disease Activity Status: The New Endpoint?Proportion of Patients Free of MS Disease Activity
A significantly greater proportion of patients were disease-free with alemtuzumab vs IFNβ-1a in CARE-MS I
Giovanonni G, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 173]
Clinical disease activity-free MRI activity-free MS disease activity-free0
20
40
60
80
56.0
42.0
27.0
74.0
51.0
39.0
SC IFNβ-1a Alemtuzumab 12 mg
Pat
ien
ts (
%)
P < 0.0001
P = 0.0388
P = 0.0064
© 2012 PRIME Education, Inc. (PRIME®). All Rights Reserved.
Autoimmunity With Alemtuzumab in RRMS
Alemtuzumab Clinical Development Program
Head-to-head studies vs IFN-1a with ≥ 2 years follow up Safety monitoring effective in detecting early autoimmunity Thyroid events common: 36.4%
– Mostly manageable– Peaked during the third year and diminished thereafter
ITP occurred infrequently: 1.5%– Majority manageable
Anti-GBM disease and other nephropathies uncommon– Renal function improved with treatment
ITP = immune thrombocytopenia purpura; GBM = anti-glomerular basement membrane Fox EJ, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract P1005]
36
Other Important 2012 Results
• FDA Approves Oral Aubagio® (Teriflunomide, Genzyme)
• Two potential therapies before the FDA
• BG-12
• Alemtuzumab
• Tysabri® label updated to include lab test to stratify risk and enhance treatment decisions
• Phase II results of ocrelizumab in relapsing MS
TREATMENT PIPELINE
37
38
Other Important 2012 Results
• FDA Approves Oral Aubagio® (Teriflunomide, Genzyme)
• Two potential therapies before the FDA
• BG-12
• Alemtuzumab
• Tysabri® label updated to include lab test to stratify risk and enhance treatment decisions
• Phase II results of ocrelizumab in relapsing MS
TREATMENT PIPELINE
Ocrelizumab: Phase II Trial anti-CD20; IV q 6 months
1. Kappos L, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster P114. 2. Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.
Group APlacebo
Group BOCR 600 mg
Group COCR 2000 mg
Relative reduction in Gd+ lesions vs placebo*
89%
P <.0001
96%
P <.0001
Annualized relapse rate (ARR)
0.637 0.12580% reduction
P = .0005
0.16973% reduction
P = .0014
Cycle 1 (Weeks 0–24)1
Cycle 2 (Weeks 0–24)—all groups taking ocrelizumab2
• ARR = 0.112 in Group B, 0.256 in Group C• 80% and 73% relapse-free, respectively
*Both ocrelizumab arms were also significantly superior to IFN.
Ocrelizumab Ongoing Phase III Trials
• OPERA I and II1 – Relapsing-remitting MS (N = 800 each)– Ocrelizumab 2 x 300 mg IV followed by 600 mg IV
every 24 weeks vs IFNβ-1a 44 μg SC 3 times weekly
– Primary outcome: annualized RR at 96 weeks;
• ORATORIO2
– Primary-progressive MS (N = 630)– Ocrelizumab 600 mg IV every 24 weeks vs placebo– Age 18–50 years, EDSS 3.0–6.5, abnormal CSF– Primary outcome: time to sustained progression
1. Clyde Markowitz, MD, personal communication, July 2011. 2. Montalban X, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P04.186.
Ocrelizumab Safety Profile
• Infusion reactions occurred in 34% and 46% of the 2 ocrelizumab arms in the phase II trial vs 9.3% of placebo arm at 1st infusion– Rates comparable to placebo at 2nd infusion
• 1 death from brain edema after systemic inflammatory response syndrome with multiorgan failure 12 weeks after starting ocrelizumab
• Rates of infection similar to placebo
Kappos L, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster P114. 2. Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.
42
Other Important 2012 Results
• International Progressive MS Collaborative• To expedite the development of effective disease
modifying and symptom management therapies for progressive forms of MS
• New project to develop improved tools for tracking MS disability, progression, and benefits of therapies
• Discovery that fibrinogen, a blood-clotting protein, may play an early role in triggering inflammation by microglia that leads to nerve fiber damage in a mouse model of MS
• Novel strategy for stopping MS damage?
UNDERSTANDING MS
43
PROGRESS TOWARD RESTORING WHAT’S BEEN LOST
• New studies into the potential of adult skin cells and umbilical cord cells as a source of CNS repair cells
• Cutting-edge research to discover new targets to stimulate myelin repair
• Clinical trials testing the ability of cannabis to treat spasticity, aspirin to fight fatigue, and innovative rehabilitation and exercise programs aimed at improving mobility, fatigue, spasticity and cognitive problems
• Advanced MRI analysis to determine how the brain regions associated with pain are affected by MS
44
Other Important 2012 Results
• Trial of experimental anti-LINGO to stimulate myelin repair
• Trial of patients’ own adult stem cells
• New therapies to stimulate myelin repair in MS
CNS PROTECTION & REPAIR
45
BIIB033 (anti-LINGO-1, Biogen Idec)
• anti-LINGO-1 is an antibody that inhibits LINGO-1—an important negative regulator of myelination
• first human phase I trial of BIIB033
• 64 healthy adult volunteers and 42 people with relapsing or secondary-progressive MS
• no serious adverse events
• headache was the most frequently AE reported
• authors concluded that the results support advancing this myelin repair strategy into a phase II clinical trial
46
Other Important 2012 Results
• Trial of experimental anti-LINGO to stimulate myelin repair
• Trial of patients’ own adult stem cells
• New therapies to stimulate myelin repair in MS
CNS PROTECTION & REPAIR
47
Autologous mesenchymal stem cells for the treatment of secondary progressive MS Connick et al, 2012
• small clinical trial from the UK; 10 people with secondary progressive MS
• autologous mesenchymal stromal (bone marrow) cells IV
• primary objective to assess feasibility and safety; secondary objectives to assess clinical efficacy
• • patients assessed at 3-6 month intervals before and after
• findings suggested that IV administration of autologous mesenchymal stem cells to patients with secondary progressive multiple sclerosis was feasible and safe
48
Hemopoietic stem cell transplantation (HSCT) or bone
marrow transplantation or autologous stem cell
transplantation
49
Other Important 2012 Results
• Trial of experimental anti-LINGO to stimulate myelin repair
• Trial of patients’ own adult stem cells
• New therapies to stimulate myelin repair in MS• Researchers at University of Edinburgh funded to find
compounds that can stimulate a molecule called RXR-gamma that is “turned on” following myelin damage and may play a role in forming new myelin
CNS PROTECTION & REPAIR
50
Other Important 2012 Results
• Balance/eye movement training improves MS symptoms
• Rehabilitation technique improves memory
• Weight training improves walking and quality of life
• Fast Forward and Concert Pharmaceuticals collaborate on C-21191, a substance with the potential for treating spasticity and pain in MS
• Small study reports benefit of marijuana on MS spasticity
• CCSVI research continues
REHABILITATION AND MANAGING SYMPTOMS
51
Short-term effects of medicinal cannabis therapy on spasticity in MS
52
Short-term effects of medicinal cannabis therapy on spasticity in MS
• randomized, placebo-controlled, crossover design
• short-term safety (particularly neuropsychiatric side effects) in addition to spasticity, cognitive, and global ratings
• treatment with either placebo or active product for three days with daily ratings (phase I)---eleven day washout period---crossover to other treatment (Phase II)
53
Short-term effects of medicinal cannabis therapy on spasticity in MS
WashoutPHASE I PHASE IIDays 1, 2, 3 Days 15, 16, 17Days 4-14
Spasticity/Mobility Measures
Cognitive Battery/Neuropsychiatric EffectsTreatment Emergent Effects
QOLSafety/Plasma levels
54
Smoked cannabis for spasticity in MS: a randomized, placebo-controlled trial Corey-Bloom et al, 2012
Placebo Cannabis
55
Other Important 2012 Results
• Balance/eye movement training improves MS symptoms
• Rehabilitation technique improves memory
• Weight training improves walking and quality of life
• Fast Forward and Concert Pharmaceuticals collaborate on C-21191, a substance with the potential for treating spasticity and pain in MS
• Small study reports benefit of marijuana on MS spasticity
• CCSVI research continues
REHABILITATION AND MANAGING SYMPTOMS
56
CCSVI
57
Prevalence of CCSVI in MS and OND: CoSMo Study
• Methods• 35 centers (N = 1816):
• MS (n = 1202)• HC (n = 382)• OND (n = 232)
• Standardized criteria for CCSVI• central blind evaluation • Dx compared between the local
and one central sonologist• Conclusions
• CCSVI not assoc w/ MS or OND• No significant difference in
prevalence among 3 groups
Comi G, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 167]
All subjects
Local Reading
MS HC OND0
20
40
60
80
100
3.26 2.13 3.1
CC
SV
I Pre
va
len
ce
(%
)
ns
ns
MS HC OND0
20
40
60
80
100
15.88 11.973.1
CC
SV
I Pre
va
len
ce
(%
)
ns
ns
58
CCSVI: Research Progress
• At this point, no connection has been confirmed between CCSVI and MS
• In fact, CCSVI appears to occur in many people who do not have MS
• Although some individuals who have MS have undergone surgical procedures for CCSVI, there has not yet been a controlled trial to determine its effectiveness in treating the symptoms or course of the disease.
• U.S. FDA has issued a safety communication about potential risks associated with procedures and devices ussed to treat CCSVI (May 2012)
59
PROGRESS TOWARD ENDING MS FOREVER
• International summit on vitamin D in MS
• Funding for an enhanced MS DNA core resource bank—genetic susceptibility to MS; control of disease course
• Supported research on role of bacteria in MS
• Launched a new, $100,000 annual cash prize to recognize scientists whose work in MS research has demonstrated outstanding innovation and originality: The Barancik Prize for Innovation in MS
60
Other Important 2012 Results
• Breakthrough in understanding gene activities• Data from ENCODE, funded by the National Human
Genome Research Institute (NHGRI), describes function of the human genome; may greatly enhance understanding of the influence of genes on MS
• Studies further understanding of vitamin D and MS risk• high levels of vitamin D associated with reduced risk• low blood levels associated with greater risk of MS
disability
• Clues as to how Epstein-Barr virus may play role in MS• Latent virus might indirectly stimulate MS disease
activity
61
2012: Fantastic Year for MS Research!
• National MS Society Comprehensive Strategy
• Stopping MS
• Restoring function
• Ending MS forever
• Invested $44 million in over 350 new and ongoing projects
62
from Gary Larson, The
Far Side.