D Rog, P Talot & K Vernon - Complexity of DMDs

1. The clinical and non-clinical management
of the complexity of DMDs
Paul Talbot, Consultant Neurologist
David Rog, Consultant Neurologist
Karen Vernon, MS Nurse Consultant
Manchester Centre for Clinical Neurosciences
@ Salford Royal NHS Foundation Trust

2. Since September 2016
• 1 NICE approved DMTs
• 1 DMT withdrawn for safety concerns
• Expanded Blueteq requirements
• DMT treatment algorithm (finally)
• Revised MS diagnostic guidelines

3. Frequency of administration Trade name Generic name (Some) Investigational Names
Weekly Avonex Interferon beta-1a IM ---
Fortnightly Plegridy Interferon beta-1a SC Pegylated (Peg) Interferon
Alternate days Betaferon Interferon beta-1b SC ---
Alternate days Extavia Interferon beta-1b SC ---
Thrice weekly Rebif 22mcg / 44 mcg Interferon beta-1a SC
Once daily Copaxone 20 Glatiramer Acetate Copolymer-1
Thrice weekly Copaxone 40 Glatiramer Acetate Copolymer -1
Once daily Gilenya Fingolimod FTY720
Once daily Aubagio Teriflunomide ---
Twice daily Tecfidera Dimethyl Fumarate BG-12
5 days monthly for 2 months
years 1 and 2 based upon weight
Mavenclad Cladribine
4 weekly Tysabri Natalizumab Antegren
6 monthly after initial dose split
over 2 weeks
Ocrevus Ocrelizumab
Yearly for 2 cycles* Lemtrada Alemtuzumab Campath-1H (MabCampath)
see individual SPCs at https://www.medicines.org.uk/emc accessed 24th June 2018

4. Selected DMT exposures
DMT Approximate global total
patient years of exposure
Approximate global total
number of patients
exposed
Censor date
Interferon Beta 1a SC1
Interferon Beta 1a IM2
1,616,700 (European)
>2,297,919 (Globally) >491,850
3rd May 2018
31st May 2018
Natalizumab2 >658,895 >184,900 31st May 2018
Fingolimod3 >566,000 >255,000 31st May 2018
Teriflunomide4
>186000
> 93000 August 2018
December 2017
Dimethyl fumarate2 >625000 >340000 31st July 2018
Alemtuzumab5 > 20000
> (approx 4000 in UK)
July 2018
September 2018
Cladribine tablets6 > 3000 post licence
Ocrelizumab7 > 17150 >39900 July 2018
1 Harty et al. ECTRIMS 2018, Poster 914. 2 Biogen, data on file. 3 Novartis data on file. 4 Lebrun-Frenay et al. EAN 2018, Poster 2070. 5
Sanofi Genzyme internal data. 6 Merck data on file 7 Vukusic et al ECTRIMS 2018 Poster 600 (Model-based estimate using drug
dispensary information (non-USA) and claims databases (USA) from July 2018)

5. Disease Modifying Treatments in
clinical practice
• When to start?
• What to start?
• When to switch?
• How to switch?
• When to stop DMTs (period)
• Managing complications
especially non-neurological
Monitoring
Familyplanning
Reimbursement
Risksvsbenefits

6. Wider clinical network for MS DMT patients
NB Patients, in extremis, attend local hospitals in a hub and spoke model, so building a clinical network of peer-to-peer support eg local
haematologist to “your” haematologist can be very useful, could save time and facilitate management.
Based on screening investigations and adverse events described for MS DMTs see individual SPCs at https://www.medicines.org.uk/emc accessed 8th February 2018
Haematologist
Obstetrician
Ophthalmologist
Respiratory
Infectious diseases
Microbiologist
Endocrinologist /
Endocrine Surgeon
Gastroenterologist /
Hepatologist
Nephrologist
Respiratory
Infectious diseases
Microbiologist
Cardiologist
Ophthalmologist
Dermatologist
Consul
tant
neurol
ogists
MS Nurses
Physioth
erapists
and
occupati
onal
therapist
s
GP’s
Speech and
language
therapists;
psychologist
s; dieticians;
social care
and
continence
specialists
Patient
MS
Neurologist
(and General
Neurologist) MS
Specialist
Nurse
GP
MS
Coordinator
Pharmacist(s)
Neuro-
radiologist
MS
Infusion
Nurse

7. Complexity of DMTs
• Infection (Paul)
• Autoimmune (David)
• Malignancy (David)
• Non-clinical issues (Karen)

8. Infections with MS DMDs
Paul Talbot
MS Consultant
Manchester Centre for Clinical Neurosciences
@ Salford Royal NHS Foundation Trust

9. Which infections?
• Mode of action
– Don’t be fooled!
• Use prior to MS
– Worse case scenario
• Clinical trials
– False reassurance?
• Post-marketing observational studies, passive surveillance
& cohort studies
– Rare serious v common milder infections…

10. MS DMDs
• BRACE are safe
• Tysabri, Gilenya, Aubagio,
Tecfidera, Lemtrada, Mavenclad,
Ocrevus…
– PML and other opportunistic (and
community acquired) infections…

11. Take home messages
• Prevention is better than cure
• Clinical vigilance is king
• Low threshold for investigation

12. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing issues
Beta-interferons None [or reduced?]
except at injection
sites
Antiviral action?
No PML
Age-appropriate vaccines
on therapy
FBC FBC every 6 months Near-term [days-to-weeks] effects on
immune system
Immediate switch
Copaxone None except at
injection sites
No PML
Age-appropriate vaccines
on therapy
None None Near-term [days-to-weeks] effects on
immune system
Immediate switch

13. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Tysabri All 79% v 79% on placebo
Severe 3% v 3% on placebo
URTIs
VZV/HSV encephalitis/myelitis and
acute retinal necrosis
PML
[1 in 10,000 to >1 in 100]
No live attenuated vaccines
on therapy [?]
FBC
JCV Ab titre
Consider VZV
Avoid if JCV Ab +ve?
FBC every infusion
JCV Ab titre every 6 months
MRI annually and every 3-6
months if high risk
Consider increasing infusion
interval up to 8 weeks
Mid-term [weeks-to-
months] effect on immune
system
Risk of rebound
LP required if PML risk
before switching to
Lemtrada, Mavenclad,
Ocrevus [Gilenya?]
Switch at time of next
Tysabri infusion [>4-8
weeks?]

14. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Gilenya All 69% v 72% on placebo
Severe 2% v 3% on placebo
VZV, HSV & cryptococcus
encephalitis/meningitis
PML
[<1 in 10,000]
No live attenuated vaccines
on therapy
VZV 4 weeks prior to initiation
FBC
HIV, HCV, HBV, VZV, TB
Consider JCV
Delay if active infection
FBC every 6 months
Consider JCV Ab every 6
months
if -ve at baseline
Consider stopping/alternate
day if lymphocyte count 0.2 or
below
Consider stopping if severe or
frequent infections
Mid-term [weeks-to-
months] effect on immune
system
Risk of rebound
LP required if switching
from Tysabri because of
‘carry-over’ PML risk [?]
Switch once lymphocyte
count LLN [>4-10 weeks?]

15. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Aubagio All 42% v 47% placebo [?]
Severe 2% v 2% on placebo
HSV
?TB
No PML [cases with related drug
for other conditions]
No live attenuated
vaccines on therapy
FBC
HIV
Consider TB [CXR and
Quantiferon] if at risk
Consider HCV, HBV
Delay if active infection
FBC every 6 months
Consider accelerated elimination if
severe infection
Long-term [months-to-years]
effect on immune system
Switch at 4 weeks?
[following accelerated
elimination]
Tecfidera All 60% v 58% on placebo
Severe 2% v 2% on placebo
PML
[<1 in 10,000]
No live attenuated
vaccines on therapy
FBC
Consider JCV
FBC every 3-6 months
Consider JCV Ab every 6 months
if -ve at baseline
Consider stopping/half dose
if lymphocyte count 0.5 or below
for 6 months
Near-term [days-to-weeks]
effects on immune system
Switch once lymphocyte
count LLN [>4 weeks?]

16. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Lemtrada All 73% v 53% on Rebif
Severe 3% vs 1% on Rebif
Respiratory
Urinary tract
Superficial fungal
HSV [16% v 3% Rebif]
Primary VZV
VZV reactivation
HBV/HCV [excluded]
Listeria meningitis
TB reactivation
HPV
No PML [cases in other conditions]
No live attenuated vaccines on
therapy
Vaccination at least 6 weeks
prior to initiation
HSV prophylaxis
Listeria prophylaxis
Consider revaccination when
immune competence is restored
FBC
HIV, VZV
TB
Consider HBV,HCV
Consider JCV
Delay if active infection
FBC every month for 4
years after last infusion
Cx screening (annually
?)
Consider JCV Ab every 6
months
if -ve at baseline
Consider delaying
retreatment?
Long-term [months-to-
years] effect on immune
system
LP required if switching
from Tysabri because of
‘carry-over’ PML risk
Avoid switch to Tysabri
Switch >6 months after
last infusion?

17. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Mavenclad All 48% v 43% on placebo
Severe 2% v 3% on placebo
HZV [2% v 0% on placebo]
No PML [cases in other conditions]
No live attenuated vaccines
on therapy
Vaccination at 4 -6 weeks
prior to initiation
Consider revaccination when
immune competence is
restored
FBC
HIV, VZV, HCV, HBV
TB
Consider JCV
Lymphocyte count 1.0 or above
before treatment
Delay if active infection
Consider JCV Ab every
6 months
if -ve at baseline
Lymphocyte count 0.8
or above before
retreatment
[Delay up to 6 months]
If lymphocyte count
drops to below 0.2
start herpesvirus
prophylaxis
Long-term [months-to-
years] effect on immune
system
LP required if switching
from Tysabri because of
‘carry-over’ PML risk
Avoid switch to Tysabri
Switch once lymphocyte
count LLN [>6 months?]

18. MS DMDs
DMD Infection risk Vaccination Screening Monitoring Sequencing
Ocrevus All 60% v 53% on Rebif
Severe 1% v 3% on Rebif
Respiratory [15% v 11% Rebif]
HSV [6% v 3% Rebif]
VZV reactivation
HBV reactivation [other CD20 Mabs]
TB reactivation
No PML [cases in other CD20 Mabs
for other conditions - not NMOSD]
No live attenuated vaccines on
therapy
Vaccination at least 6 weeks
prior to initiation
FBC
IGs
HIV, VZV, HBV
Consider HCV
TB
Consider JCV
Delay if active infection
FBC every 6 months
Consider IGs
Consider JCV Ab every 6
months
if -ve at baseline
Consider increasing
infusion interval [CD19
count LLN?]
Long-term [months-to-
years] effect on immune
system
LP required if switching
from Tysabri because of
‘carry-over’ PML risk
Avoid switch to Tysabri
[?]
Switch once CD19 count
LLN? [>6 months?]

19. Tysabri-induced PML
• 1st case in 2015
– Missed diagnosis with fatal
outcome
• Risk management
– Individualized risk
assessments
– Increased infusion intervals
– MRI reporting

20. Tysabri-induced PML
• 2nd case in 2017
– 47yr female
– Started Tysabri in 2011 [57 infusions to date, 6-weekly for 18 months]
• No relapses or MRI activity
• JCV Ab +ve [titre 2.4]1
– 2 week h/o episodic tingling right face o/e mild gait ataxia
– Next infusion imminent
• CSF JCV PCR +ve
• MRI
1Risk of PML >1 in 100 [?]

21. MRI
Diagnosis
6 months
3 months

22. Risk management
• Switch all at risk
• Start Tysabri only if JCV Ab –ve

23. Risk management
• Informed consent, education & communication
– Individualized risk-benefit
– MS DMD/CG MDT meetings
• Avoidance
– Choice of DMD
– Screening tests
– Vaccination and prophylaxis
– Sequencing of DMDs
• Monitoring
– Risk factors
– Blood tests, MRI etc
– Clinical vigilance

24. Autoimmune complications with
MS DMDs and cancer considerations
David Rog
MS Consultant
Manchester Centre for Clinical Neurosciences
@ Salford Royal NHS Foundation Trust

26. Case 1

27. Question 1
• What is the likely diagnosis?
1) Hyperthyroidism
2) Hypothyroidism
3) Non-thyroidal illness

28. Case 2
You are asked to comment on these thyroid function tests, performed in a patient
with secondary progressive MS (it isn’t clear why they were done). She isn’t taking a
DMT, but is on every supplement available…
The patient is asymptomatic and examination is normal.
Ardabilygazir et al. Cureus 10(6): e2845. DOI 10.7759/cureus.2845
01/06/2016 Ref range
TSH 0.02 (↓) (0.27-4.2)
Free T4 7.8 (↑) (0.9-1.8)
Free T3 7.38 (↑) (1.8-4.6)

29. Case 2
A “treatment” is stopped – what has happened?
Ardabilygazir et al. Cureus 10(6): e2845. DOI 10.7759/cureus.2845
01/06/2016 07/06/2016 Ref range
TSH 0.02 2.00 (0.27-4.2)
Free T4 7.8 1.3 (0.9-1.8)
Free T3 7.38 3.05 (1.8-4.6)
High dose Biotin was stopped

30. Non-exhaustive list of assays that may be affected by Biotin* (1 of 2)
ANAEMIA
EPO
Ferritin
Folate
Vitamin B12
CARDIOLOGY
BNP
CK-MB
D-Dimer
Myoglobin
NT-proBNP
Troponin I
Troponin T
ENDOCRINOLOGY
ACTH
AMH
Androstenedione
Cortisol
C-Peptide
DHEA-s
Estradiol
Estriol, unconj.
FSH, LH
HbA1c
HCG
hGH
IGF-1
IGFBP-3
Inhibin A
Insulin
PAPP-A
PlGF
Progesterone
Prolactin
SHBG
Testosterone
Anti TG
Anti TPO
Anti-TSHr
Calcitonin
T3, FT3
T4, FT4
TBG
Tg
TSH
T-Uptake
* Specifically MD1003 http://medday-lab.com accessed 4th November 2018
BONE METABOLISM
Anti-CCP
Beta cross Laps
Osteocalcin
PTH
P1NP
Pyrilinks-D
Vitamin D
LIVER FIBROSIS
Hyaluronic acid
PIIINP
TIMP-1

31. Non-exhaustive list of assays that may be affected by Biotin* (2 of 2)
* Specifically MD1003 http://medday-lab.com accessed 4th November 2018
ONCOLOGY
ACE
AFP
β-microglobuline
BR 27.29
CA 125
CA 15-3
CA 19.9
CA 72-4
Cyfra 21-1
HE4
HER-2/neu
Gastrin
NSE
PAP
ProGRP
PSA
S100
sFlt-1
TPS
SEPSIS /
INFLAMMATION
C1 inhibitor
C3, C4
CRP
IgA, IgE, IgG, IgM
IL6, IL8, IL10
LBP
Prealbumin
Procalcitonin
TNF-α
Transferrin
INFECTIOUS DISEASES
Ag HBe
Ag HBs
Anti-HAV
Anti-HBc
Anti-HBc IgM
Anti-Hbe
Anti-HBs
Anti-HCV 2
Anti-HIV 1/2
C. Difficile Toxin A&B
CMV IgG, IgM
H. Pylori IgG
Herpes I & II IgG
HIV Ag p24
HIV Ag Confirm.
HIV Combo
HSV-1/2 IgG
Rubella IgG, IgM
Syphilis
Toxo Avidity
Toxo IgG, IgM
NB Therapeutics
drugs and drugs
of abuse and
toxicology not
listed separately

33. Systematic Review of Malignancies in MS (2015)1
• Estimates for incidence and prevalence varied
substantially for most cancers.
• In population-based studies, cervical, breast, and
digestive cancers had the highest incidence.
• Risk of meningiomas and urinary system cancers
appeared higher than expected, while the risks of
pancreatic, ovarian, prostate and testicular
cancer were lower than expected.
Conclusion: inconsistencies in study design, and
relative paucity of age, sex and ethnicity-specific risk
estimates from which the strong impact of age on
the incidence of cancers can be assessed.
1 Marrie et al MSJ 2015, Vol. 21(3) 294–304

34. Malignancy rates in treatment groups of phase 3 MS DMT placebo-controlled trials
Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015

35. Malignancy rates in placebo groups of phase 3 MS DMT placebo-controlled trials
Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015

36. Malignancy risk differences in Phase 3 clinical trials of MS DMTs
Pakpoor et al. Neurol Neuroimmunol
Neuroinflamm 2015

37. DMT (alphabetical
by generic name)
Contraindications Special precautions and precautions for use (in relation to malignancy)
Alemtuzumab --- Caution should be exercised in initiating LEMTRADA therapy in patients with pre-existing and/or
an on-going malignancy.
Annual HPV screening be completed annually for female patients.
Cladribine Active malignancy An individual benefit-risk evaluation should be performed before initiating in patients with prior
malignancy. Patients treated should be advised to follow standard cancer screening guidelines.
Dimethyl fumarate --- ------
Fingolimod Known active
malignancies
Fingolimod…increases the risk of developing lymphomas and other malignancies, particularly
those of the skin. Physicians should carefully monitor patients, especially those with concurrent
conditions or known factors, such as previous immunosuppressive therapy. If this risk is
suspected, discontinuation of treatment should be considered by the physician on a case-by-
case basis
Vigilance for skin lesions is warranted and a medical evaluation of the skin is recommended at
initiation, and then every 6 to 12 months taking into consideration clinical judgement. The
patient should be referred to a dermatologist in case suspicious lesions are detected.
Cautioned against exposure to sunlight without protection. These patients should not receive
concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy
MS DMT Summary of product characteristics and malignancy advice (1 of 2)
Summary of Product characteristics for each product accessed at https://www.medicines.org.uk/emc on 4th November 2018

38. DMT
(alphabetical by
generic name)
Contraindications Special precautions and precautions for use (in relation to
malignancy)
Glatiramer acetate --- ------
Interferon beta 1a/1b --- ------
Natalizumab Known active malignancies, except
for patients with cutaneous basal
cell carcinoma.
Observation over longer treatment periods… [>2 years]… is required before
any effect of natalizumab on malignancies can be excluded
Ocrelizumab Known active malignancies Individual benefit risk should be considered in patients with known risk
factors for malignancies and in patients who are being actively monitored
for recurrence of malignancy. Patients with a known active malignancy
should not be treated with Ocrevus (see section 4.3). Patients should follow
standard breast cancer screening per local guidelines
Teriflunomide --- There does not appear to be an increased risk of malignancy with
teriflunomide in the clinical trial experience. The risk of malignancy,
particularly lymphoproliferative disorders, is increased with use of some
other agents that affect the immune system (class effect).
MS DMT Summary of product characteristics and malignancy advice (1 of 2)
Summary of Product characteristics for each product accessed at https://www.medicines.org.uk/emc on 4th November 2018

39. “Non-clinical” complexity
Karen Vernon
MS Nurse Consultant
Manchester Centre for Clinical Neurosciences
@ Salford Royal NHS Foundation Trust

40. Or learning to spin plates!

41. THE OLD DAYS
Patient
MS CNS
MS
NEUROLOGISTHOMHOMECARE
COMPANY

42. Wider clinical network for MS DMT patients
NB Patients, in extremis, attend local hospitals in a hub and spoke model, so building a clinical network of peer-to-peer support eg local
haematologist to “your” haematologist can be very useful, could save time and facilitate management.
Based on screening investigations and adverse events described for MS DMTs see individual SPCs at https://www.medicines.org.uk/emc accessed 8th February 2018
Haematologist
Obstetrician
Ophthalmologist
Respiratory
Infectious diseases
Microbiologist
Endocrinologist /
Endocrine Surgeon
Gastroenterologist /
Hepatologist
Nephrologist
Respiratory
Infectious diseases
Microbiologist
Cardiologist
Ophthalmologist
Dermatologist

43. Todays reality re DMTs
from a service perspective
Positive
• Ever expanding “speciality” circle
• More people involved
• Increasing knowledge set of nurses
• Development of new roles within team
• Management acknowledgement
Not so positive
• Lack of IT infrastructure to
support complexity of care
• More people involved
• Clinical governance issues
• Time spent “chasing”
– Results
– Nurses
– Consultants
– Patients
• “DMT” nurses

44. MDT
Concern Reality

45. What’s next
• Complexity of DMTs here to stay
• Sequencing of drugs:
– Clear information of patients DMT history
• Tolerability
• Compliance with regime
– Knowledge of patients PMH
– Knowledge of patients social history
• Homeless? Drug user? Travelling?
• Expansion/development of “none traditional” MS team roles
– Positive or negative?

46. The End

47. References
• Summary of Product Characteristics 2018
• Immunisation in Patients with MS. Cahill et al. Neurol Bull 2010
• Infections in Patients receiving MS Disease-Modifying Therapies. Grebenciucova et al. Curr Neurol Neurosci Rep 2017
• MS treatment and infectious issues: update. Winkelmann et al. Clinical and Experimental Immunology 2013
• The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. Pardo & Jones. J Neurol 2017
• Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study. Wijnands et al. JNNP 2018
• Opportunistic Infections and Other Risks with Newer Multiple Sclerosis Therapies. Ann Neurol 2009
• Infectious Complications of Multiple Sclerosis Therapies. Hersh. The Neurology Report 2014