ssif safety update
TRANSCRIPT
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