discussing neda as an individualized treatment goal
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Discussing individualized treatment goals: the physician’s perspective
Gavin Giovannoni
Barts and The London
Disclosures
I have received personal compensation for participating on Advisory
Boards in relation to clinical trial design, trial steering committees and
data and safety monitoring committees from: Abbvie, Almirall, Bayer-
Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime,
Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono,
Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma
and Vertex Pharmaceuticals.
Definitions
• DAF = disease activity free
• NEDD (oncology) = No evident detectable disease • Minimal detectable disease
• Biochemically detectable disease
• PCR detectable disease
• NEDA (MS) = No evident disease activity
• T2T = treat-to-target (rheumatology)
• Zeto = zero tolerance
Conclusions / Questions – September 2012
• What should NEDA look like?
• Absence of any clinical and biomarker evidence of disease activity
• Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions
• What about brain atrophy and CSF neurofilament levels?
• Should the definition be stage specific?
• CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS
• What do we do about post-inflammatory neurodegeneraton?
• What about the potential effects of superimposed accelerated ,or premature, aging?
• How do we define an appropriate baseline for comparison?
• We need to optimise the time fore re-base lining MRI when looking for a change; this will need to be agent specific.
• How do we deal with the difference between maintenance and induction therapies?
• Maintenance - absence of NEDA status indicated non-response
• Induction – absence of NEDA status indicates a time to retreat.
• How do we standardise (or improve) on the metrics?
38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London Glatiramer acetate treatment for 3 years (good adherence and tolerance) Relapse with a mild left sensory loss Referred to me for a second opinion Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk) Mild persistent flu-like side effects and lymphopenia 12/12’s neutralizing antibodies screen negative Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol
Teacher
38-year-old teacher with relapsing–remitting MS
As a result of fatigue and cognitive problems she is forced to take
early retirement Although fully functional she develops depression and anxiety In her spare time she spends a lot of time on the web and becomes
an expert patient Widely read
Net savvy; regular follower of www.ms-res.org
Teacher X
NICE (UK) guidelines for the prescribing of natalizumab
Natalizumab is recommended as an option for the treatment only of rapidly evolving severe relapsing–remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year,
and one or more gadolinium-enhancing lesions on brain magnetic
resonance imaging (MRI) or a significant increase in T2 lesion load
compared with a previous MRI.
1st-line or naïve MSers or 2nd-line (IFN-beta or GA failures)
NICE - Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis; August 2007.
NICE (UK) guidelines for the prescribing of fingolimod
Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:
1. they have an unchanged or increased relapse rate or on-going severe relapses compared with the previous year despite treatment with beta interferon, and
2. the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.
NICE Fingolimod: final appraisal determination document; 16 March 2012 .
The NICE (UK) relapsing MS DMT doughnut
CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.
Clinically-inactive or MRI-active RRMS
CIS
RIS or asymptomatic MS
Suboptimal responders?
Clinically active RRMS
IFN β or GA
IFN β
Highly-active or rapidly evolving severe RRMS
Fingolimod Natalizumab
Relapsing-MS
Active Inactive Highly-active Rapidly-evolving severe
Bermel et al. Ann Neurol 2012. Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
Teacher X
Teacher X
Questions: the Mser’s perspective
To make an informed decision MSers need to ask and understand the following questions:
1. Are you sure that you have MS?
2. What types of MS do you have?
3. What prognostic group do you fall into?
4. What is the risk of not having any treatment?
5. Do you have active MS?
6. Am I eligible for treatment with a DMT?
7. Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?
8. Do you understand the concept of treat-2-target of NEDA?
Question: Are you sure that you have MS?
• MS misdiagnosis rate of ~5%
CDMS 485/518 (94%) - SENSITIVITY = True+ve /(True+ve + False-ve) Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988 Jul;78(1):39-44.
• MS mimics
NMO
Shimizu et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum.
Neurology. 2010 Oct 19;75(16):1423-7.
Migraine
Kleinschmidt-DeMasters et al. PML complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74
Question: what types of MS do you have?
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907-11.
RRMS R-SPMS/NR-SPMS PPMS RPMS
relapsing forms of MS vs. non-relapsing MS
Question: what prognostic group do you fall into?
Good prognosis Poor prognosis
Young
Female sex
“Unifocal” onset
Isolated sensory symptom (optic neuritis, sensory)
Full recovery from attack
Long interval to second relapse
No disability after 5 years
Normal MRI / low lesion load
No posterior fossa lesions
No brain atrophy
CSF negative for OCBs
Older age of onset
Male sex
“Multifocal“ onset
Efferent system affected (motor, cerebellar, bladder)
Partial or no recovery from a relapse
High relapse rate in the first 2 years
Disability after 5 years
Abnormal MRI with large lesion load
Posterior fossa lesions
Brain atrophy
CSF positive for OCBs
Genomic factors (e.g. ApoE4)
Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288
The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.
The exact relationship between MRI findings and the clinical status of the patient is unknown.
Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;
Brex PA et al. N Engl J Med. 2002;346:158-164.
Baseline number of brain lesions predicts progression to EDSS Score ≥3.0
Queen Square Study
Question: what prognostic group do you fall into?
Favourable
Indeterminate
Poor
time Aim of
treatment
Question: What is the risk of not having any treatment?
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
Up to 75% increased annualized divorce rate4
Life expectancy is reduced by 5-10 years5
7.5x greater than suicide rate than the general population6
2 out of 3 patients with RRMS were unemployed due to the disease7
Utilit
y
EDSS Status
EDSS and utilitya show a significant inverse relationship1,b
aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.
1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6.
7. Morales-Gonzales. Mult Scler. 2004;10:47-54.
Question: do you have active MS?
vs.
1
2
3
Clinical
MRI
Biomarkers
Question: am I eligible for treatment with a DMT?
• MSer
• Neurologist
• Payers
• Regulator
Question: Am I eligible for treatment with a DMT?
MS is an autoimmune disease hypothesis
15-20 year experiment
“T2T-NEDA & early ”
Question: Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?
What is your treatment philosophy? maintenance-escalation vs. induction
survival analysis
Treatment Selection
Choose therapy
X Y Z
Define the individual MSer’s disease
Treatment failure?
yes
The individual Mser: • MS prognosis • Life style and goals • Your goals for therapy
Individual Mser’s measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers?
Monitoring
Therapy: • Maintenance vs. Induction
• Moderate efficacy (1st-line) • Intermediate efficacy (2nd-line) • High-efficacy (3rd-line)
Monitoring: • Clinical
• Relapse • Disability progression • Risk profile for serious AEs
• MRI • T2 & T1-Gd • Brain Atrophy
• Biomarkers • NABs • CSF NF
no
Treatment Ladder
1st-line A
1st-line B
1st-line C
1st-line D
1st-line E
2nd-line N
2nd-line M
3rd-line y
3rd-line X
A population approach: arguing by analogy
Relapsing-MS
Active Inactive Highly-active Rapidly-evolving severe
Active Inactive HA RES
A population of newly diagnosed CISers/MSers
Long-term outcomes under the current Rx paradigm
Long-term outcomes under the T2T-NEDA paradigm
Giovannoni & Cutter; Lancet Neurol 2006; 5: 887–94.
T2T-NEDA diffusion curve
• MSer
• Neurologist
• Payers
• Regulator
Conclusions / Questions - December 2013
1. What should NEDA look like?
2. Should the definition be stage specific?
3. What do we do about post-inflammatory neurodegeneraton?
4. What about the potential effects of superimposed accelerated , or premature, aging?
5. How do we define an appropriate baseline for comparison?
6. How do we deal with the difference between maintenance and induction therapies?
7. How do we standardise (or improve) on the metrics?
8. How do we communicate these concepts to our colleagues and more importantly MSers?
9. How can we facilitate the adoption of the T2T-NEDA paradigm?