Oral Cladribine

Safety Issues

Gavin Giovannoni Blizard Institute of Cell and Molecular Science Barts and The London School of Medicine and Dentistry Safety = Benefits - Risks Established therapies

Fingolimod Glatiramer Acetate Interferon beta Mitoxantrone Natalizumab

Fingolimod Fingolimod (FTY720): Mode of Action Sphingosine 1-phosphate (S1P) receptor modulator

S1P Prevents T cell receptor invasion of CNS T cell FTY720-P LN FTY720 results in FTY720 traps internalisation of the circulating receptor S1P1 lymphocytes

This blocks lymphocyte in peripheral egress from lymph nodes lymph nodes while sparing immune surveillance by circulating memory T cells Kappos L et al. N Engl J Med 2010;362:387-401 Main observations from safety assessments • Transient reduction in heart rate upon treatment initiation with fingolimod: • Mean reduction of 8bpm for fingolimod 0.5 mg • Increase in mean blood pressure: • Mean increase of 2 mmHg for fingolimod 0.5 mg • Cases of macular edema (patients): • < 1% for fingolimod • Majority of cases detected within 4 months of study entry • Elevations of liver enzymes: • ALT ≥ 3 x ULN: ~8% fingolimod 0.5 mg • No cases reflective of serious drug-induced liver injury • Non-clinically relevant change in pulmonary function tests:

• Mean decrease from baseline FEV1 is ~2% fingolimod 0.5 mg

• No change in any group in mean FVC or DLCO values • Two deaths • Disseminated VZV • HSV encephalitis Kappos L et al. N Engl J Med 2010;362:387-401 Malignancies

Phase III placebo-controlled All studies (D2301) Placebo Fingolimod Fingolimod

0.5 mg 1.25 mg 0.5 mg 1.25 mg

N=418 N=425 N=429 N=1176 N=1302 Basal cell carcinoma 3 (0.7) 4 (0.9) 1 (0.2) 9 (0.8) 5 (0.4) Squamous cell ca. skin - - 1 (0.2) 1 (0.1) 1 (0.1) Malignant melanoma 1 (0.2) - 1 (0.2) 3 (0.3) 5 (0.4) Breast cancer 3 (0.7) - 1 (0.2) 3 (0.3) 3 (0.3) Cervix carcinoma 1 (0.2) - - - -

Endometrial carcinoma 1 (0.2) - - - - Prostate cancer 1 (0.2) - - - - Ovarian epithelial cancer - - - 1 (0.1) - Total 10 (2.4) 4 (0.9) 4 (0.9) 17 (1.4) 14 (1.1)

No increase in the risk of malignancies observed in clinical development program (however long-term follow-up needed)

Presentation FDA-Advisory Committee Meeting June 10, 2010 FTY720 FREEDOMS II Study Case of severe hemorrhagic focal encephalitis

• 28-year-old woman with mild RRMS • Hemorrhagic and centrally necrotic focal encephalitis after 7 months of treatment with fingolimod • Spatially separated new and active typical MS lesions occurring during and after antibiotic treatment, as well as continued clinical and cMRI improvement of the temporo- occipital lesion after discontinuation of antibiotics, argued for an autoimmune or, possibly, undetected viral etiology

Leypoldt F et a. Neurology 2009;72:1022-1024 FTY720 FREEDOMS II Study Case of severe hemorrhagic focal encephalitis

Leypoldt F et a. Neurology 2009;72:1022-1024 Mitoxantrone Hartung et al. Lancet 2002:360:2018-25. Treatment-related leukaemia MITOXANTRONE

Mistry et al. Engl J Med. 2005 Apr 14;352(15):1529-38. Treatment-related leukaemia MITOXANTRONE

mitoxantrone

Mitoxantrone Natalizumab Treatment – disease modifying: NATALIZUMAB

Natalizumab Polman et al. N Engl J Med 2006;354:899-910. NATALIZUMAB Progressive multifocal leukoencephalopathy

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74. Natalizumab

reduction in annualised relapse rate 81% vs. placebo over 2 years (p < 0.001)

reduction in the risk of disability progression, sustained for 24 weeks, as 64% assessed over 2 years (p =0.008)

1 AFFIRM Highly Active* (n= 148 for natalizumab, 61 for PBO)

*Patients with ³ 2 relapses and ³ 1 Gd+ lesion in year prior to entry

1. Natalizumab SmPC Natalizumab PML Incidence Estimates by Treatment Epoch

3.0

2.5 2.45 2.29

2.02 1.99

patients 2.0 1.96

1.73 1.55 1.5 1.47 1.43 1.28

1.0 0.99 0.76

0.64 Incidence per 1000 per Incidence 0.5 0.54 0.37

0.11 0.0 0.01 0.04 Post 1-12 13-24 25-36 37-48 49-60 Marketing Infusions Infusions Infusions Infusions Infusions

Calculations based on exposure through August 31st 2011 and 159 confirmed cases as of 1st September 2011

*Yousry TA, et al. N Engl J Med. 2006;354:924-933. Manufacturer Data on File Use of Natalizumab in the Post-Marketing Setting*

Worldwide post-marketing data from 23 Nov 2004 to 30 June 2011 Overall 88,100 Exposure ≥12 Months 58,500

≥18 Months 48,100

≥24 Months 38,700 165,500 Patient-Years of Natalizumab exposure ≥30 Months 30,100

≥36 Months 22,700

≥42 Months 13,800 Patients Patients

*Post-marketing data includes patients exposed since 23 November 2004. This excludes a total of 4,700 patients exposed in clinical trials; 2,100 exposed for >12 months; 1,900 exposed for >18 months; 1,600 exposed for >24 months; 1,300 were exposed >30 months; 1,000 were exposed >36 months; and 700 were exposed >42 months. Exposure are estimates and may not fully reflect treatment interruptions that are used in certain patients. PML Risk PML is rare and likely caused by interplay between multiple factors

Patients at higher risk of developing PML are likely those: Immunomodulating therapy 1. Who have JC virus and have the pathogenic form of the virus (i.e. has an altered NCCR and has a Immune function Host genetic factors pathogenic mutation in VP1). 2. AND who have a compromised immune system that permits viral replication in the brain VP1 mutations NCCR rearrangements 3. AND who may have other risk factors such as host genetic factors that make them susceptible to JC virus infection and/or PML development UK population-based seroprevalence study of the human polyomaviruses: BKV , JCV and the simian polyomavirus SV40

Knowles et al. Journal of Medical Virology 71:115–123 (2003) Prior disease modifying treatments for MS

~50 % of PML cases have had prior chemotherapy exposure both in Europe and US

28 cases – Clifford et al. Lancet Neurol. 2010 Apr;9(4):438-46. 42 cases – Clifford et al; AAN 2010.

Slide courtesy of David Clifford A Risk Stratification Tool

Anti-JCV Antibody Status

Negative Positive

Prior Immunosuppressant Use

No Yes

Natalizumab Treatment Natalizumab Treatment >2 Years >2 Years

No Yes No Yes

Lowest Highest

Relative PML Risk Risk Stratification Tool: Prior IS Use, Treatment Duration, and Anti-JCV Antibody Status Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

Khatri et al. Neurology 2009;72:402–409 Emerging therapies

Alemtuzumab BG12 Laquinomod Teriflunomide Alemtuzumab Coles et al. Mult Scler. 1998;4:232-8. N Engl J Med 2008;359:1786-801. Humoral autoimmunity syndromes as a complication of Alemtuzumab therapy: associated with immune reconstitution post lymphocyte depletion

• Alemtuzumab (anti-CD52) • Grave’s disease ~30% • Immune-mediated thrombocytopaenia (ITP) ~2-3% • 6 cases (1 fatal) • Goodpasture’s syndrome – 3 cases • Immune-mediated neutropaenia – 1 case • Well described in other clinical settings • AIDS & HAART • Chemotherapy • Bone marrow transplantation • Anti-TPO Abs and raised baseline IL21 predictive of post- alemtuzumab autoimmunity • Possibly related to imbalance between regulatory, memory and naïve T cell reconstitution BG12 BG-12: MoA

• BG-12 inhibits the expression of cytokines and adhesion molecules1–3 O • BG-12 activates the Nrf2 transcriptional pathway, which plays a key role in the O oxidative stress response and immune O homoeostasis4–7 O • Activation of the Nrf2 pathway is neuroprotective. In Nrf2 knockouts myelin is cystic with preserved oligo cell bodes, astrocyes are activated, and gliotic8 • Long-term use in many patients in Germany (psoriasis) supports long-term safety

1. Wierinckx A, et al. J Neuroimmunol 2005;166:132–43 6. Venugopal R, et al. Oncogene 1998;17:3145–56 2. Loewe R, et al. J Invest Dermatol 2001;117:1363–68 7. Chen XL, et al. Am J Physiol Heart Circ Physiol 2006;290: 3. Schilling S, et al. Clin Exp Immunol 2006;145:101–07 H1862–70 4. Lukashev M, et al. Mult Scler 2007;13 (suppl 2):S149 8. Hubbs AF, et al. Am J Pathol 2007; 170: 2068–76 5. Itoh K, et al. Biochem Biophys Res Commun 1997;236:313–22 Phase II study: key efficacy outcomes

Primary outcome ● BG-12 240 mg three times daily significantly reduced the number of Gd-enhancing lesions compared with placebo

5

4 69% reduction p<0.0001 3

2

1

0 placebo BG-12 120 mg BG-12 120 mg BG-12 240 mg once daily three times daily three times daily

● BG-12 240 mg three times daily also significantly reduced the number of new or enlarging T2-hyperintense (p<0.001) and new T1-hypointense lesions (p=0.014)

Kappos L, et al. Lancet 2008;372:1463–72 Phase II study: key safety outcomes

Placebo BG-12 120 mg BG-12 120 mg BG-12 240 mg (N=65) once daily three times three times (N=64) daily (N=64) daily (N=63) Flushing 6 (9%) 34 (53%) 31 (48%) 25 (40%)

Multiple sclerosis 16 (25%) 11 (17%) 20 (31%) 12 (19%) relapse Headache 7 (11%) 5 (8%) 11 (17%) 13 (21%)

Nasopharyngitis 10 (15%) 7 (11%) 6 (9%) 7 (11%)

Nausea 5 (8%) 1 (2%) 9 (14%) 10 (16%)

Diarrhea 3 (5%) 6 (9%) 5 (8%) 7 (11%)

Pruritis 5 (8%) 6 (9%) 5 (8%) 6 (10%)

Upper abdominal 2 (3%) 5 (8%) 4 (6%) 9 (14%) pain Hot flush 0 5 (8%) 1 (2%) 6 (10%)

Abdominal pain 0 2 (3%) 2 (3%) 6 (10%)

Kappos L, et al. Lancet 2008;372:1463–72 Laquinimod Laquinimod: MOA

• Laquinimod is a derivative of linomide, a quinolone-derived immunomodulator

• Preclinical data demonstrate both immunomodulatory and neuroprotective properties: • Reduces inflammation in the CNS1 • Induces myelin and axonal preservation1 • Protects from demyelination in the cuprizone model2 • Reduces astrogliosis1 • Reduces clinical signs of EAE3 1. Wegner C, et al. J Neuroimmunol 2010;227:133-43 • Preserves immune surveillance in 2. Bruck W et al. AAN 2011; Poster P05.030 patients4 3. Wegner C et al. AAN 2011; Poster PD6.010 4. Lund et al. AAN 2011; Poster P02.198 • NFkB inhibition5 5. Gurevich et al. J Neuroimmunol 2010; 221:87-94

ALLEGRO/BRAVO: key clinical outcomes

ALLEGRO: ARR1 ALLEGRO: disability progression1

RRR: 23%

p=0.0024

ARR

BRAVO: ARR2 BRAVO: disability progression2

RRR (uncorrected): 17.7%; NS Risk of disability progression reduced by RRR (corrected): 21.3% p<0.05 ●

33.5% (p=0.044) vs placebo

ARR *ARRs corrected for baseline imbalances in MRI activity between groups

im IFN beta-1a

1. Comi G, et al. AAN 2011 2. Press release 2011 ALLEGRO: key safety findings Laquinimod Placebo TEAEs, n (%)* (n=550) (n=556) Increased ALT** 38 (6.9%) 15 (2.7%) Abdominal pain 32 (5.8%) 16 (2.9%) Back pain 90 (16.4%) 50 (9%) Cough 41 (7.5%) 25 (4.5%) Urinary tract infection 40 (7.3%) 25 (4.5%) Diarrhoea 44 (8%) 34 (6.1%) Headache 125 (22.7%) 99 (17.8%) Insomnia 36 (6.5%) 31 (5.6%) Arthralgia 47 (8.5%) 42 (7.6%) Nausea 34 (6.2%) 32 (5.8%) Depression 31 (5.6%) 35 (6.3%) Nasopharyngitis 101 (18.4%) 118 (21.2%) Upper respiratory tract infection 42 (7.6%) 48 (8.6%) Pain in extremity 35 (6.4%) 38 (6.8%) Influenza 33 (6%) 44 (7.9%) *TEAEs by MedDRA preferred term occurring at ≥5% in any group; ranked by decreasing order of risk ratio**Reported as an adverse event, not necessarily a 3xULN elevation Comi G, et al. AAN 2011

Teriflunomide Teriflunomide

• Active metabolite of leflunomide (leflunomide licensed for treating RA since 1998) • Inhibits pyrimidine synthesis by binding to the enzyme dihydro-orotate dehydrogenase (DHODH) in T cells and other rapidly dividing cell populations.1 • Also been shown to alter the tyrosine kinase activation of calcium mobilisation in an experimental model of autoimmune neuritis.2 • May inhibit inflammatory cell migration into the CNS and promotion of Th2 class switching.3

Adapted from Tallantyre E, Evangelou N, Constantinescu C et al, Int MS Journal 2008; 15:62 - 68 O’Connor et al. N Engl J Med 2011;365:1293-303. Teriflunomide - safety

O’Connor et al. N Engl J Med 2011;365:1293-303. Failed therapies

Cladribine Significant reductions in relapse rates (primary outcome, ITT)

0.40 57.6% reduction 54.5% reduction vs placebo vs placebo p<0.001 p<0.001 0.30 0.33

0.20

0.15 0.10 0.14

Annualised relapse rate (95% (95% CI) rate relapse Annualised 0.00 Placebo Cladribine Cladribine (n=437) 3.5 mg/kg 5.25 mg/kg (n=433) (n=456)

ITT, intent-to-treat population AEs of special interest: malignancies

Cladribine Cladribine Cladribine Preferred term, Placebo 3.5 mg/kg 5.25 mg/kg overall n (%) patients (n=435) (n=430) (n=454) (n=884) During study Malignant melanoma 0 0.2 (1) 0 0.1 (1) Ovarian cancer 0 0.2 (1) 0 0.1 (1) Pancreatic carcinoma, metastatic 0 0.2 (1) 0 0.1 (1) During post-study surveillance Choriocarcinoma 0 0 0.2 (1) 0.1 (1)

. The standardised incidence ratio (SIR) matched for country/gender/age1 was 0.99 (95% CI: 0.25, 2.70) . Reliable risk estimate is not possible in a 2 year clinical trial setting for events: . With a long latency . With a low incidence . Further characterization of this potential risk . CLARITY extension study . Post-marketing surveillance (PASS)

1International Agency for Research on Cancer database (1998–2002) and the Globocan 2002 database

Risks vs. Benefits

Cladribine Tablets approved in Russia on July 12th 2010 Cladribine Tablets approved in Australia on September 3rd 2010 Cladribine tablets

• The EMA committee gave a negative opinion, recommending that cladribine tablets should not be granted a marketing authorisation. • Following this feedback and a similar decision from the US FDA, the manufacturer decided to no longer pursue the global approval process of cladribine tablets Efficacy is maintained in the high-disease activity (HAD) population (≥2 relapses and ≥ 1 T1 Gd+ lesions)

Annualized relapse rate Relapse-free patients (%)

Odds ratio = 2.10 0.8 RR to relapse=0.56 P=0.024 67.2% reduction 80 0.6 P<0.001 0.67 60 0.4 70% 40 0.2 46% 0.22 20 0 Placebo Cladribine 0 (n=41) 3.5 mg/kg Placebo Cladribine (n=50) (n=41) 3.5 mg/kg (n=50)

Mean number of active T1 Gd+ lesions per patient per scan Time to 3-month confirmed EDSS progression (months)

3 Prolongation by 15 8.1 months, NS 2 2.50 90% reduction P<0.001 10 13.5

1 5 0.25 5.4 0 0 Placebo Cladribine Placebo Cladribine (n=41) 3.5 mg/kg (n=41) 3.5 mg/kg (n=50) (±0.05) (n=50) CLARITY Extension Study

Primary Objective: Evaluate Safety and Tolerability of extended treatment with oral cladribine in subjects completing CLARITY Trial: Randomized, double-blind, PBO-controlled, multinational, 2-year EXTENSION study to CLARITY, Phase IIIb MS Population: RRMS subjects completing CLARITY study

Trial Design

CLARITY (STUDY 25643) EXTENSION TO CLARITY (STUDY 27820) YEAR 1 YEAR 2 All YEAR 1 of EXTENSION YEAR 2 of EXTENSION R A PLACEBO PLACEBO CLADRIBINE tablets CLADRIBINE tablets N (4 courses) (2 courses) (2 courses) (2 courses) D O CLADRIBINE tablets CLADRIBINE tablets M CLADRIBINE tablets CLADRIBINE (2 courses clad.) (2 courses) I (2 courses clad + tablets Z 2 courses PBO) (2 courses) PLACEBO PLACEBO A (2 courses) (2 courses) T I CLADRIBINE tablets LOW-DOSE CLADRIBINE CLADRIBINE (2 courses) (2 courses) O CLADRIBINE tablets tablets N (4 courses) (2 courses) PLACEBO PLACEBO (2 courses) (2 courses)

1:1:1 Cladribine:Cladribine:PBO 2:1 Cladribine:PBO www.ms-res.org www.ms-res.org Lessons from high risk therapies

BMT Autologous bone marrow transplantation

Autoreactive T Cell

Non-autoreactive T Cell Results of BMT in MS: EBMT Registry

• 183 registrants: • 178 transplanted Very effective therapy • ~54% SP, 12% RR, 10% RP, 18% PPMS Stops relapses and MRI activity • Median age 34 Does not prevent 2⁰ progression • Median disease duration* 6.7 years Some cures reported • 163/178 peripheral blood ASCT • 126 mobilized with Cy/G-CSF • 76 conditioned with BEAM & ATG Treatment related mortality = 5.3% • 30 BEAM alone Mortality 2º to progressive MS = 4.7%

• 97 CD34 “purging”

Saccardi et al Mult Scler 12:814, 2006 *Date of diagnosis to HSCT Conclusions Safety = Benefits - Risks

MS is a severely debilitating disease

EDSS and utilitya show a significant inverse relationship1,b • MS is one of the most common causes of neurological disability in young adults2 • Natural history studies indicate

that it takes a median time of 8, 20, and 30 years to reach the

Utility irreversible disability levels of EDSS 4, 6, and 7, respectively3 • Life expectancy is reduced by 5–10 years4

EDSS Status

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bError bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5. EDSS, expanded disability status scale 1 Adapted from Orme M et al. Value In Health 2007;10:54–60; 2 WHO and MSIF http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747 Accessed October 6, 2010; 3 Confavreaux C and Compston A, Mcalpine’s multiple sclerosis, 4th edn 2005; 4 Compston A et al. Lancet 2008; 372: 1502–17 59 Conclusions

• MS is serious debilitating disease • Risk: benefits • Tolerability vs. serious AEs • Defined and undefined risks • Risks • Active surveillance • Manage risks • LFTs and blood monitoring • JCV serology & PLEX for PML • VZV vaccination pre-fingolimod & SOPs for starting and monitoring treatment • Platelet, TFTs and urine monitoring for alemtuzumab • Individualise treatments • 1st vs. 2nd vs. 3rd line treatments • Maintenance-escalation vs. induction strategies