Overview of Current and Emerging Small Molecules and Monoclonal Antibodies in MS Clyde E. Markowitz,...

Overview of Current and Emerging Small Molecules and Monoclonal

Antibodies in MS

Clyde E. Markowitz, MD

Director, Multiple Sclerosis Center

University of Pennsylvania

Philadelphia, Pennsylvania

Introduction

• Traditional 1st-line MS therapies reduce relapse rates and slow progression

– But are only partially effective

– Require self-injection

– Some have bothersome side effects

• The 1st oral small-molecule therapy (fingolimod) and the 1st monoclonal antibody (natalizumab) have now been integrated into MS treatment

– Greater potency? More concerning side effects?

– Many new small molecules and monoclonal antibodies are in development

Case Study• 30-year-old woman has occasional numbness and tingling in

left hand for past 6 months. Now presents with optic neuritis

• MRI shows multiple T2 hyperintensities in corona radiata and cervical spinal cord

• Results of other evaluations consistent with clinically isolated syndrome

• After resolution of optic neuritis on corticosteroids, started on glatiramer acetate 20 mg/day

• 7 months later, she experiences an episode of imbalance and difficulty walking

– Treated with corticosteroids

– She has residual symptoms but she is still able to ambulate

Case Study

• She is switched to IFN β-1b 250 µg SC every other day

• 10 months later, she presents with decreased sensation in her right foot, worsening and extending up her leg over the course of 3 days

• She complains about injection-site reactions and flu-like symptoms

• She is reluctant to continue on injectable medication

Case StudyMRI

She is a possible candidate for small molecule or monoclonal antibody therapyShe is a possible candidate for small molecule or monoclonal antibody therapy

Slide courtesy of Clyde E. Markowitz, MD.

Oral Small-Molecule Therapies

Oral Agents

• Currently approved– Fingolimod

• Investigational– Laquinimod– Teriflunomide– Dimethyl fumarate (BG-12)– Cladribine

FingolimodThe 1st Oral MS Therapy

• Sphingosine-1-phosphate (S1P) receptor modulator1

– Binds to S1P receptors on lymphocytes– Receptors are internalized and degraded– Lymphocytes are sequestered in secondary lymphoid

organs Affects naive T-cells, central memory T-cells but not

effector T-cells• Possible CNS effect2

– Neurons, astrocytes, oligodendrocytes, and microglia express S1P receptors

• Approved dose: 0.5 mg orally once daily3

• Terminal half-life: 6–9 days3

1. Mehling M, et al. Neurology. 2011;76(suppl 3):S20-S27. 2. Osinde M, et al. 22nd ECTRIMS; September 27-30, 2006; Madrid, Spain. Abstract P792. 3. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.

FingolimodPhase III TRANSFORMS Trial

Decreased number of T2 and Gd-enhanced lesions on MRI

Cohen JA, et al. N Engl J Med. 2010;362:402-415.

Fingolimod 0.5 mg/dn = 429


IFNβ-1a IM 30 μg QWn = 431

P value vs IFN

Annualized relapse rate

0.16 (-52%)

0.20 (-38%)

0.33 <.001

Relapse-free 83% 80% 69% <.001

Disability progression-free

94% 93% 92% NS

% change in brain volume -0.31 -0.30 -0.45 <.001

N = 1292 RRMS + ≥1 recent relapse12-month data

FingolimodPhase III FREEDOMS I Trial

Kappos L, et al. N Engl J Med. 2010;362:387-401.


Fingolimod1.25 mg/dn = 429

Placebo n = 418

P value vs Placebo


0.18 (-54%)

0.16 (-60%)

0.40 <.001

Relapse-free 70% 75% 46% <.001

Disability progression-free

82% 83% 76%

.03 for 0.5 mg

.01 for 1.25 mg

% change in brain volume

-0.84 -0.89 -1.31 <.001

N = 1272 RRMS + ≥1 relapse in past year or ≥2 in past 2 years; EDSS ≤5.524-month data

Decreased number of T2 and Gd-enhanced lesions on MRI

Fingolimod Ongoing Trials

• FREEDOMS II (phase III)1

– Relapsing-remitting MS– 2 years– Fingolimod 0.5 mg/d vs placebo (1.25 mg/d dropped)

• INFORMS (phase III)2

– Primary-progressive MS– ≥3 years– Fingolimod 0.5 or 1.25 mg/d vs placebo

• FREEDOMS Extension study3

1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://www.clinicaltrials.gov/ct2/show/NCT00355134?term=fingolimod+AND+FREEDOMS&rank=2. 2. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://www.clinicaltrials.gov/ct2/show/NCT00731692?term=fingolimod&cond=primary-progressive+MS&phase=2&rank=1. 3.ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://www.clinicaltrials.gov/ct2/show/NCT00662649?term=fingolimod&cond=MS&phase=2&rank=4.

Fingolimod Safety Profile

Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen JA, et al. N Engl J Med. 2010;362:402-415. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.

• Bradycardia (1–6 hours after 1st dose), atrioventricular block

• Blood pressure increases

• Infections

• Macular edema

• Malignancies (mostly skin cancer)

• Peripheral-blood lymphocyte count reductions (MOA)

• ALT increases (≥3 x ULN in 7%–8.5%)

• Mild forced expiratory volume (FEV1) reductions

• Drug interactions (ketoconazole, antineoplastic/immuno-suppressive drugs, vaccines, drugs affecting heart rate)

Fingolimod Monitoring• Laboratory

– CBC + differential– Liver enzymes/bilirubin (baseline and if symptomatic)– Baseline anti-varicella-zoster virus IgG/IgM (if negative, vaccinate and

delay fingolimod 1 month)• Ophthalmologic exam

– Baseline and at 3–4 months– Repeat if patient reports visual disturbance

• Cardiac– EKG if cardiac risk factors, slow/irregular heartbeat, or taking beta-

blockers, calcium channel blockers, or antiarrhythmics – 6-hour observation after 1st dosing– Blood pressure

• Spirometry/diffusing capacity of the lung for carbon monoxide– If clinically indicated

Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.

Laquinimod

• Novel oral immunomodulatory agent (quinoline-3-carboxamide)

• High oral bioavailability1

– 0.6 mg orally once daily2

• Structurally related to roquinimex1

– Unlike roquinimex, does not increase risk of myocardial infarction, serositis

• FDA fast-track review status

1. Polman C, et al. Neurology. 2005;64:987-991. 2. Comi G, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii.

Laquinimod Mechanism of Action

• Induces Th1 to Th2 shift; inhibits proinflammatory cytokine production1,2

• Inhibits leukocyte migration into CNS1

• Deactivates microglia and macrophages3

• Suppresses NFκB pathway in B-cells and NK cells2

• Increases brain-derived neurotrophic factor 11-fold (possible neuroprotection)4

• Not immunosuppressive: cellular/humoral immune responses remain intact1

1. Brück W, et al. J Neurol Sci. 2011;306:173-179. 2. Gurevich M, et al. 62nd AAN; April 10-17, 2011; Toronto, Ontario, Canada. Abstract P04.208. 3. Wang J, et al. 62nd AAN; April 10-17, 2011; Toronto, Ontario, Canada. Abstract P04.222. 4. Thöne J, et al. 62nd AAN; April 10-17, 2010; Toronto, Ontario, Canada. Abstract PD5.004.

Laquinimod Phase III ALLEGRO Trial

N = 1106 RRMS; 24-month data

Comi G, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Gever J. MedPage Today. April 14, 2011. Accessed July 21, 2011 at: http://www.medpagetoday.com/MeetingCoverage/AAN/25935?pfc.

Laquinimod 0.6 mg/d vs Placebo

Annualized relapse rate 0.304 vs 0.395—23% reductionRR = 0.770; 95% CI 0.650–0.911; P = .0024

Disability progression (EDSS) 36% reductionHR = 0.641; 95% CI 0.452–0.908; P = .0122)

Brain atrophy 33% reduction (P <.0001)

Mean cumulative Gd-enhancing lesions

37% reduction (P = .0003)

Mean cumulative T2 lesions 30% reduction (P = .0002)

Abbreviations: EDSS, Expanded Disability Status Scale; RRMS, relapsing-remitting MS.

Laquinimod Ongoing Trials

• BRAVO (phase III)1

– Relapsing-remitting MS (N = 1200)

– Laquinimod 0.6 mg/day vs oral placebo vs IFNβ-1a 30 µg IM once weekly Double-blind for laquinimod vs placebo; rater-blind for

IFN reference arm Primary outcome: relapse rate

– Results expected Q3 2011

• 3 open-label extension studies2

1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00605215?term=BRAVO+Study%3A+Laquinimod+Double+Blind+Placebo+Controlled&rank=1. 2. ClinicalTrials.gov. 2011. Accessed July 21, 2011 at: http://www.clinicaltrials.gov/ct2/show/NCT01047319?term=laquinimod&cond=multiple+sclerosis&rank=1, http://www.clinicaltrials.gov/ct2/show/NCT00745615?term=laquinimod&cond=multiple+sclerosis&rank=5, and http://www.clinicaltrials.gov/ct2/show/NCT00988052?term=laquinimod&cond=multiple+sclerosis&rank=4.

Laquinimod Safety Profile

Adverse events in phase II and III studies

• Transient dose-related ALT increases1,2

• Budd-Chiari syndrome (single case in patient with underlying hypercoagulability)1

• Abdominal/back pain,2 chest pain, arthralgias1

• Herpes infections1

• No cardiac events1,2

1. Comi G, et al. Lancet. 2008;371:2085-2092. 2. Gever J. MedPage Today. April 14, 2011. Accessed July 21, 2011 at: http://www.medpagetoday.com/MeetingCoverage/AAN/25935?pfc.

Laquinimod Metabolism/Drug Interactions

• Metabolized by CYP3A4 (low affinity)

• Strong CYP3A4 inhibitors (eg, ketoconazole) may slow laquinimod metabolism

• Unlikely to cause competitive inhibition with other CYP3A4 substrates

Preiningerova J. Expert Opin Investig Drugs. 2009;18:985-989.

Teriflunomide• Active metabolite of leflunomide (approved for

rheumatoid arthritis since 1998)• Noncompetitive reversible inhibition of mitochondrial

enzyme dihydro-orotate dehydrogenase (de novo pyrimidine synthesis pathway)

• Cytostatic for proliferating T- and B-cells; noncytotoxic• Inhibits protein kinase activity

– Decreased T-cell proliferation, activation, cytokine production

• Half-life: 2 weeks– Rapid clearance requires cholestyramine

Warneke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340.

TeriflunomidePhase III TEMSO Trial

N = 1088 relapsing MS (RRMS or SPMS with relapses)

2-year study

Placebo Teriflunomide (7 mg/d)

Teriflunomide (14 mg/d)


0.539 0.37031.2% reduction

P = .0002

0.36931.5% reduction

P = .0005

12-week sustained disability

27.3% 21.7%23.7% reduction

P = NS

20.2%29.8% reduction

P = .0279

Change in volume of white matter

-3.741 -0.635P = .0609

2.406P = .0002

Brain MRI total lesion volume

39% reductionP = .032

67% reductionP = .0003

Miller A, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.002. Wolinsky JS, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.003. Gever J. MedPage Today. April 16, 2011. Accessed July 21, 2011 at: http://www.medpagetoday. O'Connor P, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Abstract 79.

Teriflunomide Ongoing Trials

• TOWER (phase III)– Relapsing MS (N = 1110)– 2 years– Primary outcome: annualized relapse rate– Teriflunomide 7 or 14 mg vs placebo

• TENERE (phase III)– Relapsing MS (N = 300)– 48 weeks– Primary outcome: time to treatment failure (relapse or

dropout)– Teriflunomide 7 or 14 mg vs IFN β-1a 44 μg SC 3x weekly

ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00751881?term=tower+%2B+teriflunomide&rank=1 and http://clinicaltrials.gov/ct2/show/NCT00883337?term=tenere++.

Teriflunomide Ongoing Trials

• TOPIC (phase III)

– Clinically isolated syndrome (N = 780)

– 2 years

– Primary outcome: conversion to clinically definite MS (2nd attack)

– Teriflunomide 7 or 14 mg vs placebo• Long-term extensions

• Phase II combination therapy trials ongoing

ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00622700?term=topic+%2B+teriflunomide&rank=1, http://clinicaltrials.gov/ct2/show/NCT00228163?term=extension+%2B+teriflunomide&rank=2 and http://clinicaltrials.gov/ct2/show/NCT00803049?term=teriflunomide&rank=9.

Teriflunomide Safety Profile• Adverse effects in phase II study1

– ALT elevations– Nasopharyngitis– Alopecia– Nausea, diarrhea– Paresthesias– Back pain, limb pain, arthralgias

• Hepatic metabolism2

• Inhibits CYP2C9, enhancing warfarin’s anticoagulative effects2

• Teratogenic in animal studies, so washout with cholestyramine/activated charcoal and confirmation of plasma level <0.02 mg/L recommended before conception1

1. O’Connor PW, et al. Neurology. 2006;66:894-900. 2. Warneke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340.

Dimethyl Fumarate (BG-12)

• Exact mechanism of action is unclear

– Inhibits expression of proinflammatory adhesion molecules and chemokines1

– Suppresses macrophage function2

– Increases Nrf2 DNA binding (possible neuroprotection)3

– Suppresses inflammatory activation of astrocytes and C6 glioma cells3

• FDA fast-track review status

1. Moharregh-Khiabani D, et al. Curr Neuropharmacol. 2009;7:60-64. 2. Bista P, et al. 61st AAN; April 25-May 2, 2009; Seattle, Wash. Abstract P09.114. 3. Lin SX, et al. ASN Neuro. 2011; Epub ahead of print.

Dimethyl Fumarate Phase III DEFINE Trial

• Relapsing-remitting MS (N >1200)

• Dimethyl fumarate 240 mg 2 or 3 times daily vs placebo for 2 years

• Preliminary data reported only via press release to date

– Significant reduction in proportion relapsing at 2 years for both treatment arms

– Both treatment arms showed positive results on all secondary outcomes Relapse rate

MRI outcomes

Expanded Disability Status Scale progressionClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00420212?term=multiple+sclerosis+%2B+define&rank=1. NMSS. April 14, 2011. Accessed July 21, 2011 at: http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=4903.

Dimethyl Fumarate Ongoing Trials

• CONFIRM (phase III)1

– Relapsing-remitting (N = 1232)

– Dimethyl fumarate 240 mg 2 or 3 times per day vs placebo vs glatiramer acetatefor 2 years

– Primary outcome: relapse rate– Results in 2nd half of 2011

• 2-year extension study2

1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00451451?term=fumarate+%2B+confirm&rank=1. 2. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00835770?term=fumarate+%2B+extension+study+%2B+multiple+sclerosis&rank=1.

Dimethyl Fumarate Safety Profile

• Nausea, diarrhea, abdominal pain

• Flushing

• Headache

• Fatigue

• Adverse events are dose-related

Kappos L, et al. Lancet. 2008;372:1463-1472.

Cladribine Approval Status• Approved in Australia and Russia; rejected in EU

• FDA rejected approval

– Single phase III CLARITY trial1

Significant reductions in relapse rate, brain lesion counts, and 3-month sustained disability

Lymphocytopenia, infections/infestations (especially herpes zoster)

– FDA requested additional data to clarify safety and risk-benefit profile

– Manufacturer has chosen to no longer pursue development of oral cladribine for MS

1. Giovannoni G, et al. N Engl J Med. 2010;362:416-426.

Monoclonal Antibodies

Monoclonal Antibodies

• Currently approved

– Natalizumab

• Investigational

– Alemtuzumab

– Rituximab and ocrelizumab

– Daclizumab

Natalizumab

• Humanized monoclonal antibody targeting α4 subunit of α4β1 and α4β7 integrins on leukocytes, preventing them from binding their receptors on vascular endothelial cells1

– May prevent migration of leukocytes across endothelial cells of blood-brain barrier1

• Phase III trial (AFFIRM)2

– 68% reduction in relapse rate

– 83% reduction in new/enlarging hyperintense T2 lesions

– 92% reduction in Gd-enhancing lesions

– 42% reduction in risk of sustained progression of disability

• 300 mg IV infusion given over 1 hour every 4 weeks1

1. Tysabri [PI]. Cambridge, Mass: Biogen Idec; 2011. 2. Polman CH, et al. N Engl J Med. 2006;354:899-910.

NatalizumabProgressive Multifocal Leukoencephalopathy

• Viral brain infection (JC virus)1

• Overall incidence is 1.23 cases per 1000 patients treated2

– Incidence varies with presence of risk factors

• Progresses to severe disability or death1

• Plasma exchange helps clear natalizumab1

- Is followed by immune reconstitution inflammatory syndrome in almost all cases1

• TOUCH prescribing program1

• Natalizumab used only after failure of other options1

1. Tysabri [PI]. Cambridge, Mass: Biogen Idec; 2011. 2. Sandrock A, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Poster P03.248.

NatalizumabPML Risk Factors

• Duration of use/number of infusions

– 1.53 cases per 1000 patients treated with ≥12 infusions

– 2.41 cases per 1000 patients treated with ≥24 infusions

• JC virus antibodies

– About 55% of MS patients are Ab positive

– 2.24 cases per 1000 patients if Ab positive

– ≤0.11 cases per 1000 patients if Ab negative (theoretic; all cases Ab+)

• Prior immunosuppressive (IS) therapy

– Increases risk 4-fold

• Risk is further increased if ≥1 risk factors

– 4.5 cases per 1000 patients if history of IS therapy + natalizumab use ≥2 years

– 8.1 cases per 1000 patients if history of IS therapy + Ab positive + natalizumab use ≥2 years

Abbreviation: PML, progressive multifocal leukoencephalopathy.

Sandrock A, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Poster P03.248.

Alemtuzumab

• Humanized monoclonal antibody directed against CD52 antigen – CD52 is a cell-surface glycoprotein of unknown

function, present on most T-cells, B-cells, NK cells, dendritic cells, eosinophils, monocytes, macrophages

• Depletes CD52-expressing cells

• Stabilizes blood-brain barrier

• Annual infusion (3 or 5 days) given with corticosteroids

• Fast-track FDA status

Bielekova B, et al. Neurology. 2010;74:S31-S40.

Alemtuzumab’sEffects on the Immune System

• Within 1 hour after single 5- to 10-mg dose, lymphocytes and monocytes are no longer detectable in circulation1

1. Coles A, et al. J Neurol. 2006;253:98-108. 2. Thompson SA, et al. J Clin Immunol. 2010;30:99-105.

Median Time to Recovery After Discontinuation of Alemtuzumab

CD4+ T-cells1 61 months

CD8+ T-cells1 30 months

Monocytes1 3 months

B-cells1,2 3 months

• B-cells rise to 165% of pretreatment levels after 12 months posttreatment2

Alemtuzumab5-Year Follow-Up of Phase II CAMMS223

Alemtuzumab(Combined

Data*)

IFN β-1a44 µg SC TIW

Annualized relapse rateYears 0–5Years 3–5

0.110.14

0.350.28

Relapse-free 72% 41%

Change from baseline in EDSS -0.30 +0.46

Patients free of sustained accumulation of disability

87%† 62%†

Free of clinical disease activity 65% 27%*Alemtuzumab 12 or 24 mg/day for 5 days in month 1 and 3 days in month 12; 3 additional days in month 24 at physician’s discretion. †P <.0001; P values were not reported for the other comparisons.

Coles A, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster 410. Twyman C, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.003.

Untreated RRMS (N = 334)

Alemtuzumab Phase III CARE-MS I Trial

Recently completed but reported only in press release form1,2

• Treatment-naive relapsing-remitting MS (N = 581)

• Alemtuzumab 12 mg/day x 5 days + 3 days at month 12 vs IFN β-1a SC 44 μg for 2 years (rater blinded)

• 55% reduction in relapse rate (P <.0001)

• Time to 6-month sustained accumulation of disability not significantly different

• Proportion of patients with sustained increase in disability not significantly different (8% vs 11%; HR = 0.70; P = .22)

– Few patients accumulated disability at the rate expected based on earlier trials, which may have reduced ability to detect significant treatment effect on this endpoint

1. Gandey A. Medscape Today July 12, 2011. Accessed July 22, 2011 at: http://www.medscape.com/viewarticle/746184. 2. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://www.clinicaltrials.gov/ct2/show/NCT00530348?term=alemtuzumab+AND+multiple+sclerosis&rank=4.

Alemtuzumab Ongoing Phase III Trials

• CARE-MS II

– MS with relapse during IFN or glatiramer acetate and ≥2 attacks in past 24 months or ≥1 attack in past 12 months (N ≅ 840)

– Alemtuzumab 12-mg dose (24-mg dose dropped) vs IFN β-1a SC 44 μg for 2 years (rater-blinded)

• CARE-MS extension

– N ≅ 1500

– 5 years

– Can receive additional cycles if resumed disease activity

ClinicalTrials.gov. 2011. Accessed July 20, 2011 at: http://clinicaltrials.gov/ct2/show/NCT00548405?term=alemtuzumab+%2B+multiple+sclerosis+%2B+care&rank=1 and http://clinicaltrials.gov/ct2/show/NCT00930553?term=alemtuzumab+%2B+multiple+sclerosis+%2B+care&rank=4.

Alemtuzumab Safety Profile

• Cytokine release syndrome: fever, rash, headache, nausea/vomiting, rigor1,2

• Autoimmune disease (primarily thyroid dysfunction): 30%1,2

• Immune thrombocytopenic purpura: ~3%1,2

• Goodpasture’s syndrome: at least 2 cases3

• Infections (~66%): upper and lower respiratory tract, urinary tract, herpes, influenza2

• Cancers: Burkitt’s lymphoma, breast cancer, cervical cancer2

• Serious infusion reactions: 1.4%2

1. Minager A, et al. Expert Opin Biol Ther. 2010;10:421-429. 2. CAMMS223 Investigators. N Engl J Med. 2008;359:1786-1801. 3. Buttmann M. Expert Rev Neurother. 2010;10:791-809.

Alemtuzumab Monitoring

• Complete blood count monthly1

• Thyroid-stimulating hormone every 3−4 months1

• Pretreatment: hydroxyzine or diphenhydramine, meperidine, acetaminophen1

• Posttreatment: prophylactic acyclovir, trimethoprim/sulfamethoxazole x 6 months1

• Creatinine and urinalysis screening2

• Autoimmunity screen? – Increased IL-21, autoantibodies, genetic2

1. Hunter SF, et al. 61st AAN; April 25-May 2, 2009; Seattle, Washington. Poster P07.147. 2. Clyde Markowitz, MD, personal communication, July 2011.

B-Cells and CD20 in MS• B-cell role: antigen presentation, cytokine production,

antibody secretion (plasma cells)1,2

• CD20: transmembrane protein

– Functions as Ca+2-permeable cation channel and has role in B-cell proliferation3

– Present on premature, immature, mature, activated, and memory B-cells and small subset of normal/neoplastic T-cells (low density)2

Not on plasma cells2

– Not shed after antibody binding2

• CD19 also present on pre−B-cells2

1. McFarland HF. N Engl J Med. 2008;358:664-665. 2. Dalakas MC. Neurology. 2008;70: 2252-2260. 3. Uchida J, et al. Int Immunol. 2004;16:119-129.

Rituximab

• IgG1 chimeric anti-CD20 monoclonal antibody1

• Approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, refractory rheumatoid arthritis (with methotrexate)1

– Indication for MS not being pursued• Rapid depletion of B-cells2

– B-cells remain depleted for about 6 months2

– Naive B-cells return more quickly than memory B-cells3

1. Rituxan [PI]. South San Francisco, Calif: Genentech; 2011. 2. Hauser SL, et al. N Engl J Med. 2008;358:676. 3. Roll P, et al. Arthritis Rheum. 2006;54:2377-2386.

Rituximab in RRMS48-Week Phase II Study

N = 104

Rituximab dose: 1000 mg IV days 1 and 15

Hauser SL, et al. N Engl J Med. 2008;358:676-688.

Placebo (n = 35)

Rituximab

(n = 69)

P value

Mean number of Gd-enhancing lesions

5.5 0.5 <.001

Mean Δ in volume of T2 lesions from baseline to week 36 (mm3)

417.8 -175.4 .004

Patients with relapses 40% 20.3% .04

Adjusted annualized relapse rate 0.7 0.4 .08

• 95% reduction from baseline in CD19+ B-cells at weeks 2–24; 30.7% of baseline at 48 weeks

• 24.1% had human antichimeric antibodies at week 48

Rituximab in PPMS96-Week Phase II/III Study

N = 439 PPMS with abnormal cerebrospinal fluid, EDSS 2.0–6.5

Rituximab 1000 mg IV days 1 and 15 every 24 weeks (n = 292) vs placebo (n = 147)

Hawker K, et al. Ann Neurol. 2009;66:460-471.

Placebo Rituximab P Value

Disease progression at 96 weeks 38.5% 30.2% NS

In age <51 years HR = 0.52 .010

In patients with Gd+ lesions HR = 0.41 .007

In age <51 + Gd+ lesions HR = 0.33 .009

Median Δ T2 lesion volume (mm3) 809.5 302.0 .001

Median Δ brain volume -14.0 -13.1 NS

Longer time to progression if shorter (≤3 years) disease duration; no gender effect

Rituximab Safety Profile

• Infusion reactions: fever, chills, rigors, flu-like symptoms, hypotension, nausea, pruritus, asthenia1

• Infections (respiratory tract, urinary tract)1

• Progressive multifocal leukoencephalopathy– Majority in patients using rituximab in combination with

chemotherapy for hematologic malignancies or in patients with prior or concurrent immunosuppressive therapy

1. Hauser SL, et al. N Engl J Med. 2008;358:676-688.

Humanized Anti-CD20 Monoclonal Antibodies

• Ocrelizumab – Enhanced antibody-dependent cell-mediated

cytotoxicity; reduced complement-dependent cytotoxicity

– Binds to different overlapping epitope

• Ofatumumab – Binds to more proximal CD20 portions

– Increased complement-dependent cytotoxicity

Buttmann M. Expert Rev Neurother. 2010;10:791-809.

Ocrelizumab 48-Week Phase II Trial

Relapsing-Remitting MS (N = 220)

Study Protocol

Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.

Cycle 1 (Weeks 0–24)

Cycle 2 (Weeks 25–48)

Group ADouble-blind

Placebo on days 1 and 15 Ocrelizumab 300 mg IV on days 1 and 15 (600 mg total)

Group BDouble-blind

Ocrelizumab 300 mg IV on days 1 and 15 (600 mg total)


Group CDouble-blind



Group DOpen-label

IFN β-1a 30 µg IM once weekly Ocrelizumab 300 mg IV on days 1 and 15 (600 mg total)

Ocrelizumab Phase II Trial

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

Δ T2 lesion volume NS NS

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 relapse rate at 96 weeks; time to

sustained disability progression • 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

If EDSS ≤5, disease duration <10 years If EDSS >5, disease duration <15 years

– 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.

OfatumumabPhase I/II Dose-Finding Study

• Relapsing-remitting MS and 1 of the following (N = 38)

– ≥2 relapses in past 2 years

– ≥1 relapse in past 1 year

– 1 relapse in year 2 plus 1 Gd+ brain lesion in past year

• Ofatumumab 100, 300, or 700 mg IV at weeks 0 and 2 vs placebo

• New Gd+ lesions from weeks 8–24: 0.04 for ofatumumab (combined) vs 9.69 for placebo

– Relative risk reduction 99.8% (95% CI 94.7%–100%; P <.001)

• No safety signals

Sorensen P, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P01.265.

Daclizumab• Humanized IgG1 monoclonal antibody against IL-

2R chain (CD25)1,2

– CD25 is expressed on activated T-cells and B-cells, but these cell counts only modestly affected1,2

– Increases CD56bright NK cell function and number1,2

• Approved for renal transplant rejection but marketing discontinued

1. Schippling S, et al. Intl MS J. 2008;15:94-98. 2. Stüve O, et al. Lancet Neurol. 2010;9:337-338.

Daclizumab 24-Week Phase II CHOICE Trial

• Other small phase II trials document clinical and MRI benefits2,3

– 1–2 mg/kg every 2–4 weeks (IV or SC)

1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Bielekova B, et al. Arch Neurol. 2009;66:483-489. 3. Rose JW, et al. Neurology. 2007;69:785-789.

IFN + Placebo (n = 77)

IFN + Daclizumab 1 mg/kg SC

q4wk (n = 78)

IFN +Daclizumab2 mg/kg SC

q2wk (n = 75)

Mean number new/enlarged Gd+ lesions

4.75 3.5825% reduction

P = NS

1.3272% reduction

P = .004

Mean number new/enlarged T2 lesions

3.4 2.2P = NS

1.1P = .007

Unadjusted annualized relapse rate

0.86 0.5832% reduction

P = NS

0.4943% reduction

P = NS

Relapsing-remitting MS with ≥1 relapse or Gd+ lesions on IFN (N = 230)1

Daclizumab Safety Profile• Rash

• Lymphadenopathy

• Infections

• Fever

• Headache • Mouth ulcers• Elevations of bilirubin, hepatic enzymes, autoantibodies

– Monitoring: routine blood tests

Wynn D, et al. Lancet Neurol. 2010;9:381-390. Bielekova B, et al. Arch Neurol. 2009;66:483-489. Rose JW, et al. Neurology. 2007;69:785-789. Schippling S, et al. Intl MS J. 2008;15:94-98.

Conclusions

Conclusions

• New MS therapies are on the horizon

– Will expand choices for treatment, and options for routes of administration and dosing schedules

– Will add to treatment complexity– Personalized medicine

• Novel mechanisms of action will raise concern about unknown, rare, or long-term safety issues

– Risk:benefit ratio analysis• Future focus

– Optimal drug selection, induction/combination strategies, when/how to switch, CNS repair strategies To be discussed in the next webcast in this series

Thank you for your participation.

To earn CME/CE credit, please complete the posttest and evaluation. (Click link in the navigation bar above

or to the left of the slide presentation.)

Your feedback is appreciated and will help us continue to provide you with clinically relevant

educational activities that meet your specific needs.

Overview of Current and Emerging Small Molecules and Monoclonal Antibodies in MS Clyde E. Markowitz,...

Documents

Transcript of Overview of Current and Emerging Small Molecules and Monoclonal Antibodies in MS Clyde E. Markowitz,...