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?