ssif safety update

L09: Safety Issues

Gavin Giovannoni

Blizard Institute of Cell and Molecular Science

Barts and The London School of Medicine and Dentistry

Safety = Benefits - Risks

Safety issues

• Misdiagnosis • Interferon-beta / glatiramer acetate • Fingolimod • Mitoxantrone • Natalizumab • Emerging therapies

– Alemtuzumab – BG12 – Teriflunomide – Laquinimod

Misdiagnosis

Lennon et al. Lancet 2004;364:2106-12.

NMO

What constitutes a useful diagnostic test or set of criteria?

TARGET DISORDER

PRESENT ABSENT

DIAGNOSTIC

TEST RESULT

+ a b a + b

- c d c + d

a + c b + d a + b + c + d

From these we determine the sensitivity and specificity as follows:

SENSITIVITY = a/(a+c) > 80%

SPECIFICITY = d/(b+d) > 80%

Neurobiol Aging 1998; 19:109-116.

A clinico-pathoanatomical study of multiple sclerosis diagnosis

SENSITIVITY = True+ve /(True+ve + False-ve)

Eye Department, Hvidovre Hospital, Denmark.

• Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%).

• Clinical diagnosis had been established by a neurologist in all cases.

• Erroneous diagnosis included a variety of other neurological disorders.

• Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS:

– post mortem confirmation of MS was obtained in circa 66%.

– The remainder the error pattern was similar to the above.

Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.

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

PML complicating treatment with natalizumab and IFNb-1a for MS

Established therapies

Interferon beta Glatiramer Acetate

Fingolimod Mitoxantrone Natalizumab

Interferon beta

What is the diagnosis?

Take special care with Interferon-beta-1b: If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use interferon beta-1b. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like interferon-beta-1b. See also 4. Possible side effects.

Glatiramer Acetate

Fingolimod

?

Could sudden death be due to MS?

Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion

Barnett & Prinea. Ann Neurol 2004;55:458–468.

Sudden death in multiple sclerosis (SUDMUS)

www.adverseevents.com

www.adverseevents.com

We need to define a new entity:

SUDMUS Sudden death in multiple sclerosis

Mitoxantrone

Mitoxantrone-related leukaemia

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

Treatment-related leukaemia mitoxantrone

mitoxantrone

Mitoxantrone

1 in 244

1 in 108

/MITOXANTRONE

Natalizumab

Natalizumab

Progressive multifocal leukoencephalopathy (PML)

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

359 cases -30th April 2013 83 (23%) died 276 (77%) alive

Mild disability – 10% Moderate disability – 50% Severe disability – 40%

5% NAbs – infusion reactions

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

Natalizumab PML risk stratification tool

Anti-JC virus antibody status

Negative Positive

Prior immunosuppressant use

Natalizumab treatment

>2 Years

Natalizumab treatment

>2 Years

No Yes

No Yes No Yes

Lowest Highest Relative PML Risk

< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887

Mitoxantrone

Azathioprine

Methotrexate

Cyclophosphamide

Mycophenolate

Cladribine

Rituximab

Etc.

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

N Engl J Med 2008;359:1786-801. Coles et al. Mult Scler. 1998;4:232-8.

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%

• Goodpasture’s syndrome – 3 cases

• Immune-mediated neutropaenia – 1 case

• Immune-mediated haemolytic anaemia

• 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

Tranexamic Acid

Predicting autoimmunity following treatment of MS with alemtuzumab

• 30% of alemtuzumab-treated pts develop autoimmune side-effects (primarily thyroid disease and idiopathic thrombocytopenia)

• Aim: To define predictive factors for autoimmune side-effects

• Sera of 141 pts screened at baseline for 8 different cytokines/chemokines

A combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients at low risk of developing autoimmunity following treatment with alemtuzumab

Jones JL, et al. ECTRIMS 2011, Amsterdam. P1009

Sensitivity NPV Specificity PPV

IL-21 alone 81 84 70 66

IL-7 alone 76 76 54 54

CCL21 alone 63 65 49 47

IL-21 or IL-7 98 97 41 55

IL-21 OR IL-7 OR CCL21

98 91 12 45

Given that pts may elect to receive treatment based

on results of this test – most weight given to

minimizing false negative results. Combining IL-21

and IL-7 into a single test offers improved test

accuracy over IL-21 alone. CCL21 did not improve

test accuracy

0

10

20

30

40

IL-7

Autoimmunity No autoimmunity

0

500

1000

1500

IL-2

1

1.0

Se

nsit

ivit

y

0.8

0.6

0.4

0.2

0.0 0.0 0.2 0.4 0.6 0.8 1.0

1.0

Se

nsit

ivit

y

0.8

0.6

0.4

0.2

0.0 0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

IL-21 and IL-7 levels in sera

of pts who did or did not

develop autoimmunity

Receiver operating

characteristic (ROC) curves

BG12

Laquinimod

Teriflunomide

Teriflunomide - safety

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

Other issues

Other issues

• Pregnancy

• Contraception

• Travel

– Vaccinations

– Anti-malarials

• Drug interactions

• Pharmacogenomics

Conclusions

Safety = Benefits - Risks

• High unemployment rates; 50% unemployed within 10 years of diagnosis.

• High divorce rates; at least double the average

• 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 irreversible disability levels of EDSS 4, 6, and 7, respectively3

• Life expectancy is reduced by 5–10 years4

Uti

lity

EDSS Status

EDSS and utilitya show a significant inverse relationship

1,b

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

MS is a debilitating disease

66

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