dmt update practical help to dmt management in ms...dmt update practical help to dmt management in...

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DMT UPDATE

Practical help to

DMT management in MS Regional MS Summit 2018

A Wundes, MD

Medical Director Neurology

UW MS Center

University of Washington, Seattle, WA

DISCLAIMER

Research funding: Biogen, Alkermes

Handout of 2017 talk is in your package: Comprehensive practical guide to

DMT decision making reviewing all drugs

Not a comprehensive review

Not equal weight to all drugs

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OBJECTIVES

• Review AAN DMT guidelines

• Learn about the 2017 /2018 DMT updates

• Case-based examples of DMT decision making

Rae-Grant et al. Neurology 2018:90:777-788

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AAN DMT Practice Guidelines

Recommendations

• 17 on starting DMT

• 10 on switching DMT for breakthrough dz

• 3 on stopping DMT

A = “must”

B = “should”

C = “may”

Neurology 2018;90:777-788

4x “MUST” Clinicians must…

1. Ascertain and incorporate patients’ preferences re safety, route of administration, lifestyle, cost, efficacy, common AE and tolerability in choice of DMT

2. Engage in an ongoing dialogue re treatment decisions throughout the disease course

3. Counsel patients on DMTs to notify providers of new or worsening symptoms

4. Counsel that there is an increased risk of relapse or MRI dz activity within 6 months of D/C natalizumab

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Starting DMT “SHOULD”

• Discuss & if interested prescribe DMT for CIS if ≥2 brain lesions

• Prescribe alemtuzumab, fingolimod or natalizumab if highly active

• Not prescribe mitoxantrone unless benefits greatly outweigh risks

• Offer ocrelizumab to PPMS “who are likely to benefit unless risks outweigh benefits”

• Monitor adherence, AE, tolerability, safety and effectiveness; should follow pt at least annually or per REMS

“MAY”

• Recommend serial MRI at least annually 1st 5 years and close follow up rather than DMT for CIS/RRMS not on DMT and stable x2y

• Initiate NTZ only if reasonable chance benefit if JCV ab pos >0.9

• Direct to financial support programs or recommend AZA/cladribine

“SHOULD”

• Monitor MRI

• Discuss switch if 1 or more relapses or, 2 or more unequivocal new MRI lesions or increased disability over 1 year period - if long enough on and adherent to DMT

• Discuss oral or less frequent injectable DMT if intolerable AE or injection fatigue

• Discuss undefined malignancy and infection risk with newer DMTs without long-term safety data

• Switch to alternative DMT if on NTZ and JCV ab pos, esp if >0.9

• Check NTZ antibodies if infusion reactions or break through dz

Switching DMT

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Stopping DMT “SHOULD”

• Advocate for MS patients who are stable on DMT to continue their current DMT unless D/C DMT trial warranted

• Counsel pts who are stable and want to stop DMT for need for ongoing FU and periodic re-evaluation D/C DMT

• Assess likelihood of future relapse in SPMS d/t age, dz duration, relapse hx and MRI activity

“MAY” advise D/C DMT SPMS w/o relapse or gd+ lesion and not ambulatory for at least 2 years

• Review risk of continuation vs D/C DMT in CIS who have not progressed to MS

“Real life case”

• 44yo male engineer with outside dx MS

• My assessment CIS rather than MS

• Partial TM 2011 sensory sx, Lhermitte gd+ C2-3 lesion

• Brain MRI minimal WM changes

• CSF results?

• PMH: Low Vit D, HLP, BMI 34, MVA 2015

• No dz activity while on glatiramer acetate x 7 years

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A. Treatment success, should stay on DMT

B. Counsel could consider DMT D/C trial

C. Stop DMT b/o did not progress to MS

AAN Patient DMT Guide

Find a copy of the AAN Patient Guide included in your materials

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DISEASE MODIFYING THERAPIES

2017-2018 UPDATES

Glatiramer Acetate

• Now 2 generics available

– Glatopa®

– Mylan®

• Both available in daily 20 mg and 40 mg TIW formulations

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Daclizumab/Zinbryta®

• Voluntarily withdrawn from market 3/2018 for safety concerns: 12x brain infections

Oral agents

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Fingolimod / Gilenya®

• Once daily po 0.5 mg

• FDA approved in 2010

• 231,000+ patients to date (536K PY)

Spingosine-1-phosphate receptor modulator Prevents egress of lymphocytes from lymph nodes

Fingolimod-related PML

• Exposure: 231,000

• PML cases: n=19 (excluding cases NTZ ≤6m PML dx)

• Risk factors: Treatment duration

1:5,000 if rx >2 years (18/94K)

<1:10,000 overall

• PI update:

– Most cases in pts > 2 years rx

– Some cases dx’ed by MRI while initially asymptomatic

Novartis Medical Information Service, PI update 12/2017

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Report of 15 PML cases as of August 2017

• Mean age 53 (n=5 <50yo), MS duration 4-35 years

• 14/15 clinical sx whereas 1 identified d/t MRI findings

• 2/15 possible confounders: prior cancer, prior IS for UC

• 4/14 ALC ≤ 0.2

• 3 deaths, others deficits aphasia, mobility, cognition

Fingolimod-related PML

• No specific clinical features or guidelines at this point

• Lymphocyte counts and subsets appear not associated

• Challenge of weighing PML risk vs possibly inappropriate modification of effective MS treatment

• Patient, provider and staff education and vigilance

– Importance of clinical and MRI surveillance

– Stop drug immediately if concerns for PML

– PML sx can resemble MS relapse but tend to be slowly and persistently progressive

– Red flags clinically: subacute cognitive, language, seizures

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26yo M engineer

• ON age 12 (his mom dx’ed with MS 1y earlier)

• ON age 18

• Overall thus far favorable clinical course, EDSS 1

• IFNb-1a sc (Rebif®) x 1.5 years, d/c “pill easier”

• FGL since 2015

53yo Female • MS x 15 y

• Established care 2013 while on FGL x 1 year

• Prior DMT

– IFNb-1a (Rebif®) x 2 y, D/C “relapses” q3m, stress high

– NTZ (Tysabri®) x 36 inf, D/C after JCV ab conversion

• Main sx mood, pain, fatigue, some imbalance

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Chengde Pham et al. BMJ Case Reports 2017

Initial

• 61yo on FGL x 3y, previously D/C NTZ d/t JCV ab +

• HA/neck pain (coughing ), N, vertigo, 10 kg WL x 2wk

• R beat nystagmus, quickly became confused

• MRI extensive PF leptomeningeal nodular enhancement, edema w/ mass effect and early cerebellar tonsillar herniation

• CSF via external ventricle drain Cryptococcus +

• Antifungal iv/po, D/C FGL, VP shunt

• MRI improved at 6 wks but new UI and new MRI lesions bifrontal, ?fungal, ?IRIS, ?MS, iv/po steroids 6 wk

Initial

Cryptococcus meningitis

• Overall risk 0.11/100 PY in post-marketing setting

• More cases than PML cases

• Unlike PML, any age group (27-68yo)

• Usually after longer FGL exposure (16 m – 5 years)

• 1/3 without meningeal sx

Novartis Medical Information Services

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PI Updates – Infections / Cancer

Serious and life-threatening infections have occurred

• Varicella zoster, herpes simplex and cryptococcus infections incl fatal meningitis, encephalitis and disseminated infections

• Consider when atypical MS relapse and organ failure

Increased risk basal cell cancer and melanoma

• Vigilance skin lesions

• PI recommends advising pts to use sun protection

PI update 12/2017 + 5/2018

PI Updates – Bradycardia 1st dose

• Max decrease usually within 1st 6h, usually asymptomatic and recovers, though not baseline 8-10h

• D/t physiological diurnal rhythm 2nd period HR w/i 24h

• Pre-existing ischemic heart dz, h/o MI, CHF, CVA, uncontrolled HTN, recurrent syncope, severe untreated OSA

Evaluate by cardiologist before FDO

Overnight continuous ECG monitoring

• Transient similar but to lesser reduction HR following dosing in 1st 2-4 weeks

PI update 5/2018

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Pediatric MS

PI Updates

• RRMS patients age 10 or older

• Recommended all vaccinations per guidelines before FGL

• If ≤40 kg: 0.25 mg once daily

• Pediatrics pts ≥10y + ≥40kg: 0.5 mg once daily 82% reduction AAR1

53% reduction new T2 lesions1

66% reduction gd+ lesions1

Ongoing open-label study

Chitnis et al. ECTRIMS 2017; manuscript under review. PI update 5/2018

Baseline labs with VZV status and if needed VZV vaccination before starting agent

Pay attention to co-medications and co-morbidities - DM, uveitis risk of ME↑ - Co-meds HR↓

Lymphopenia not associated with infections

Risk of opportunistic infections

Increased PML rate after 2 years of treatment

Fingolimod: Clinical Pearls

oral 0.5 once daily Gilenya®

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Teriflunomide/Aubagio®

Once daily po – 7 vs 14 mg

FDA approved in 2012 for RRMS and CIS

84,000 patients to date (162K PY)

Closely related to leflunomide (for RA)

Blocks de novo pyrimidine synthesis

→ cytostatic effect on proliferating T and B cells

1 PML Case on Teriflunomide

Due to teriflunomide vs carry-over from natalizumab?

Some PML cases reported on leflunomide1

Stopped NTZ #33

JCV ab pos index 3.6

EDSS 1.0

MRI @ 6wk stable

DMT hiatus x 5+m

Started TFL

R-sided weakness, aphasia @ 10 wk

EDSS 3.5

MRI suspicious PML

CSF JCV DNA+

11 copies/ml

(false-positive?)

Chelation therapy

Clinical and MRI progression

PML-IRIS suspected; 3 day IVMP

Eventually improvement, EDSS 1.0

Started on GA

Lorefice et al, Neurology 2018:90:1-3. 1 FAERS: n=24, Sanofi n=7 PML in RA with prior IS

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• 54yo black woman dx’ed with follicular lymphoma

• Teriflunomide x 8 months

• No RF other than age

• Per Authors

– 50-54yo: 7 FL /100,000

– 10 cases on teriflunomide*

– 82 cases on leflunomide*

Landais et al, Mult Scler Rel Dis 2017;17:92-94 (*VegiBase: WHO global database AE reports)

Lymphoma on Teriflunomide

• Hypersensitivity/skin pooled clinical trials: 16.1% vs 14.3% plc1

• Severe skin reactions reported – 7x Steven Johnson Syndrome in post-market setting2

– 84x skin exfoliation in post-market setting2

– 1 fatal TEN report in post-market setting3

1 Leist et al. Pooled safety data 4 clinical studies (n=3044) AAN 2014, 2 FAERS, 3 Gerschenfeld. MS Journal 2015

46y F

MS x 10y

IFN, DMF dc’ed for tolerability

Teriflunomide

Day 19 transient FLS x 5 days

Day 28 fever, asthenia, D/C drug

Day 30 respiratory failure

Day 34 TEN suspected

Day 39 death

Teriflunomide: Skin Reactions

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Teriflunomide: Clinical Pearls oral 7 or 14 mg once daily Aubagio®

Pregnancy category X (need reliable contraception)

Rule out latent TB

Monthly LFT monitoring x6 months

Monitor CBCdiff

Risk of serious skin reactions

Expedited elimination protocol if needed

Dimethyl fumarate / Tecfidera®

• Orally 240 mg twice daily


• 311,000+ patients to date (544+K PY)

• Activates nuclear factor 2 (Nrf2) pathway; response to oxidative stress

• Th1 → Th2 shift

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DMF-related PML

• Exposure: 311,000

• PML cases: n=5

• Risk factors: Prolonged lymphopenia, age

• PI updates:

– Majority of PML cases ALC <0.5, some <0.8

– In other MS drugs some cases of early PML dx based on MRI findings in asymptomatic pts, usually better outcome

Biogen Medical Information Service, PI update 12/2017

• 1 death, other survival but no specifics available • Low CSF JCV viral copies: 2x 12 ultrasensitive JCV PCR!

DMF-related PML Cases

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DMF-induced Lymphopenia

Mean ALC↓ by 30% in 1st y

and stabilized above LLN

9.4% Mod (0.5 - <0.8) 2.1% Severe (<0.5)

ALC in 1st year predictive for severe, prolonged lymphopenia

Fox et al. Pooled safety data 4 clinical studies (ph II, 2 ph III, extension; n=2512, K PY) ECTRIMS 2017

• All ALC >0.8 in 1st year 0.1%

• ALC <0.8 in 1st year 12%

• ALC <0.5 in 1st year 51%

Strong correlation of ALC with CD4 and CD8 subsets

Recovery Lymphopenia after D/C

After D/C

6 months after D/C with severe, prolonged lymphopenia (n=34)

At least 1x ALC >0.8: 41%

At least 1x ALC >LLN: 24%

Severe, prolonged lymphopenia on DMF Moderate, prolonged lymphopenia on DMF

Fox et al. Pooled safety data 4 clinical studies (ph II, 2 ph III, extension; n=2512, K PY) ECTRIMS 2017

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Slower taper may help with side effects

Montelukast (Singulair) for GI side effects

Aspirin or anti-histamine for flushing

Monitor lymphocyte counts and LFT

Rare PML cases

Dimethyl fumarate: Clinical Pearls

oral 240 mg twice daily Tecfidera®

Infusions

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Natalizumab / Tysabri®

• Once monthly infusion


• REMS program required (TOUCH)

• 181,300 patients to date

Monoclonal antibody to α 4 integrin = VLA-4 Prevents extravasation of T-cells and monocytes into CNS

“Real life case” 35 yo AA male professional

• Natalizumab since 2012

• Past glatiramer acetate x 3y, D/C for ISR, 1 relapse, MRI

• JCV ab 1x POS 0.45 in 2/2013, then 12x neg by 11/2015

• EDSS 2.0

4/2018 re-established care after 2.5 y hiatus d/t insurance

• Last MRI 5/2015

• JCV ab tested x3, remained negative

Safety monitoring up to date?

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• Exposure: 181,300 (638K PY)

• PML cases: n=763 in MS (Crohn’s n=3)

• Risk factors

– JCV antibody status

– Prior immunosuppression

– Natalizumab treatment duration

• PI update 4/2018 JCV antibody index

Natalizumab-related PML

Biogen Safety Update March 2018

PML risk algorithm

Koendgen Biogen ECTRIMS 2016

Wait 2 weeks after PLEX to avoid false-neg result

Wait 6 months after IVIG to avoid false-pos result

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PML risk algorithm

1:10,000 - regardless of rx duration and prior use of IS 5 PML cases worldwide reported




PML risk algorithm

1: 5,000 1: 325 Koendgen Biogen ECTRIMS 2016



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PML risk algorithm

• Highest PML risk ! • JCV ab index does

not apply!

1: 3,333

1: 120




• TOUCH data as of 6/1/2017

• Included JCV ab positive patients only

• SID (standard interval): average dosing ≥3 and <5 wk

• EID (extended interval): average dosing >5 and ≤12 wk

• NO info available re JCV ab index or efficacy data!

Zhovtis, ACTRIMS 2018 platform

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Baseline demographics all groups:

• Age 43-44

• 5-6% prior IS

• EID: slightly higher total # and duration NTZ

94%

risk

88%

risk

Zhovtis, ACTRIMS 2018 platform & Zhovtis ACTRIMS + AAN 2018 poster

• Most EID pts switched from SID after >2 years treatment

• Relative small dosing interval; average EID 35-43 days vs SID 30-31 days

• No efficacy data available

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Personalized NTZ dosing?

John Foley, AAN 2018 poster

NTZ concentration varied 100-fold

Mean concentration lower in EID

NTZ concentration affected by cycle

length and body weight (BMI↓, conc ↑)

Retrospective chart review (6m):

self-reported relapse and MRI change

without difference EID vs SID

Single PML case in this cohort:

Particularly high concentration (low BMI)

JCV infection of granule cell neurons in the cerebellum

• AKA JC virus granule cell neuronopathy [JCV GCN]

• Cerebellar dfct: ataxia, incoordination, apraxia, visual sx

• MRI: cerebellar atrophy

• DX: MRI w/wo, CSF for JC viral DNA

• Distinct from PML but can occur with and without PML

• Should be managed similarly to PML

Tysabri® PI; Koralnik Ann Neurology 2005

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Acute retinal necrosis (ARN): • Fulminant viral infection of retina

• Decreased visual acuity, redness, or eye pain

• Refer PROMPTLY for retinal screening for ARN

• Some cases occurred with CNS herpes meningitis /encephalitis

• Serious cases of ARN led to blindness of one or both eyes

• Following ARN, consider discontinuation of TYSABRI

Immunosuppression/infections: • <1% pt with opportunistic infections:

• Pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, candida pneumonia

Additional PI Updates Natalizumab

Tysabri ® PI

Natalizumab: Clinical Pearls iv once monthly Tysabri®

Check JCV antibody in blood regularly

Check brain MRI regularly

Any new neurologic symptom or new MRI

lesion on natalizumab is concerning for PML

Concerns for reactivation and rebound MS

disease activity when stopping drug

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Ocrelizumab / Ocrevus®

• Infusion q6 months

• FDA approved March 2017 for RRMS and PPMS

• Total exposure n= 40,000+ (15+K PY)

Monoclonal antibody to CD20 on B lymphocytes B cell depletion

Bar-Or AAN 2018

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Open-label extension RRMS trials

OCR / OCR

IFN / OCR

OCR / OCR

IFN / OCR

Change EDSS from baseline

Open label extension Double blind

Open label extension Double blind

Time to onset to Confirmed Disability Improvement

Immature data

Hauser et al.

AAN 2018

Time to cognitive decline Pooled RRMS phase III trials

Patients on OCR had significantly lower risk (HR 0.6) of sustained cognitive decline at 12 and 24 wks compared to pts on IFN

- mITT cohort; both 4% and 10% SDMT cut off

- Pts at risk of progression (EDSS 4.0)2

- similar trend in patients with baseline cognitive difficulties

Cohen et al. Platform AAN 2018 , 2: Benedict at al. Poster AAN 2018

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Infection and PML risk

• Some increase URI, LRI, skin and herpes infections

• To date 1 opportunistic infections (systemic Pasteurella infection), none in trials

• Hepatitis B reactivation warning (anti-CD20 rx)

• Boxed warning PML

– To date no PML cases d/t OCR

– 3 carry-over PML cases (NTZ, fingolimod)

– RTX approved 1997 for NHL, CLL, RA, PA, >4 million pt PML not only in hematological malignancies but also RA n=9, SLE n=12, MS n=1; est risk in RA 1:20,000+

Hauser et al. AAN 2018, Borie Semin Arthritis Rheum 2015

Vaccinations

• Recommendation to complete vaccines 6 week BEFORE

• No live vaccines while on OCR

• Antibodies against common viral/bacterial antigens were maintained x 2 years in pivotal trials

Responses to vaccines while fully B-cell depleted by ocrelizumab

Bar-Or et al. AAN 2018

Tetanus 23-PPV Influenza

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In phase III trials more malignancies in OCR compared to control groups (IFN, PLC), primarily breast CA

Thus far incidence rates malignancies and breast cancer remain within range of epidemiologic background

Appears that comparator groups lower than expected incidences

Malignancies

Any malignancy per 100 PY compared to Danish MS registry Breast CA OCR vs 3 MS registries

Hauser et al. Platform presentation AAN 2018

Deaths

• 40+K pts treated to date

• Incidence of fatalities 4/2017 – 3/2018: 0.28 per 100 PY

• No obvious pattern reported

If interested, detailed information included as supplemental slides

Phase 3

OPERA I/II

trials*

Phase 3

ORATORIO

trial*

All OCR

MS clinical

trials†

Post-

marketing

setting‡

French cohort

study

(n=27+K)

US retrosp

study

(n=30K)

Incidence rate

per 100-PY

0.07 0.25 0.169 0.2806 0.37 0.9

0.73 PMS

0.32 RRMS

Genentech Medical Information Services May 2018

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Ocrelizumab: Clinical Pearls iv once every 6 months Ocrevus®

Infusion reactions: premedication, slow titration

Hepatitis B testing required

Consider more extensive baseline lab screening

Consider pneumonia/Hep B vaccination

UW Medicine MS Center Located on NWH campus

1536 N 115th St

Seattle, WA 98133

Phone: 206.598.3344

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© 2018 Genentech, Inc. All rights reserved.

Post-marketing experience: PML

As of April 2018, we have confirmed 3 carry-over cases of PML in MS patients treated with

ocrelizumab1

■ The first case (May 2017) was from a compassionate-use program in an anti-JCV-

positive patient who was switched to ocrelizumab after 36 infusions of

natalizumab.2 Assessment of the information resulted in the case being reported to

regulators as related to natalizumab and not ocrelizumab.

■ The second case (April 2018), occurred in a patient who had increasingly worsening

neurological symptoms and MRI changes prior to discontinuing treatment with

fingolimod in December 2017. The patient started treatment with ocrelizumab in

March/April 2018. In April 2018, MRI changes, worsening clinical presentation, and

JCV DNA in the CSF confirmed the diagnosis of PML. The case was reported to

regulators as a carry-over PML from fingolimod as assessed by the physician3

■ The third case (April 2018) occurred in a JCV+ patient who was previously treated with

natalizumab for 7 years. Due to MRI changes and worsening clinical symptoms,

natalizumab was discontinued in February 2018. The patient received a single infusion

of ocrelizumab in April 2018. The case was reported by the physician as a carry-over

PML from natalizumab3

■ As described in the prescribing information, PML remains an important potential risk4

JCV=John Cunningham virus; MS=multiple sclerosis; PML=progressive multifocal leukoencephalopathy.

1. Hauser SL, et al. Presented at: AAN Meeting 2018 (Platform presentation ( S36.001) 2. Hauser SL, et al. Presented at: 7th Joint ECTRIMS-ACTRIMS Meeting 2017 (Poster P676). 3. Genentech, data on file. 4. Ocrevus® [prescribing information]. South San Francisco, CA: Genentech, Inc, a Member of the Roche Group; March 2017.


Fatalities summary: Phase 2 and Phase 3 clinical trials (controlled treatment period)

As of January 2016, eight fatalities occurred in the OCR groups and five fatalities occurred in the control

groups

■ OPERA I and II studies, controlled treatment period

• One fatality occurred in the OCR group (completed suicide) and two fatalities in the IFN β-1a group

(completed suicide, mechanical ileus)

■ ORATORIO study, controlled treatment period

• Four fatalities occurred in the OCR group (pneumonia, pulmonary embolism, aspiration pneumonia,

metastatic pancreatic cancer) and three fatalities in the placebo group (traffic accident, aspiration

pneumonia, sudden cardiac death)

■ Phase 2 study

• Among three fatalities in the OCR group, one occurred during the controlled treatment period (systemic

inflammatory response syndrome) and two (unknown cause, injury) during the safety follow-up, more

than 1 year after the final dose of OCR

■ There was no increase in fatalities in OCR-treated patients versus controls in the clinical trials

66

OPERA (pooled)* ORATORIO†

IFN β-1a

incidence rate‡

(95% CI)

OCR

incidence rate‡

(95% CI)

Placebo

incidence rate‡

(95% CI)

OCR

incidence rate‡

(95% CI)

OCR controlled

treatment period 0.14 (0.02, 0.52) 0.07 (0, 0.38) 0.41 (0.08, 1.20) 0.25 (0.07, 0.64)

*Two identical Phase 3, global, randomized, double-blind, double-dummy studies with a 96-week controlled period during which 1,656 patients with relapsing forms of MS received either

intravenous OCR (600 mg) every 24 weeks or subcutaneous IFN β-1a (44 μg) three times weekly.†A Phase 3, global, randomized, double-blind study with a ≥120-week controlled period

during which 732 patients with primary progressive MS received either intravenous OCR (600 mg) or placebo every 24 weeks (2:1 randomization). ‡All data are reported as incidence rates per 100 patient-years (95% CI).

CI=confidence interval; IFN β-1a=interferon beta-1a; MS=multiple sclerosis; OCR=ocrelizumab.

Genentech, data on file.

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Fatalities summary: Post-marketing experience

■ The number of post-marketing patients exposed to OCR is based on estimated total

number of vials sold, as well as US claims data

■ Overall exposure is calculated in patient-years on OCR

■ Fatalities based on reports in the Roche safety database with patients suffering from

relapsing and progressive multiple sclerosis treated with OCR post-marketing in the

designated market period. There was no pattern observed*

*The causes of the post-marketing fatalities are as follows: Unknown cause (n=21), aspiration pneumonia (n=2), myocardial infarction (n=2), sepsis (n=2), urosepsis (n=2), cardiac disord

er (n=1), brain herniation (n=1), pulmonary embolism (n=1), opioid overdose (n=1), sudden death (n=1), acute kidney injury (n=1), cardiogenic shock with circulatory collapse and urinary

tract infection (n=1), epilepsy with status epilepticus (n=1), cellulitis with pneumonia, sepsis and urinary tract infection (n=1), asthenia with chest paint, pyrexia, and decreased appetite (n

=1), cerebral hemorrhage (n=1), influenza (n=1), lung cancer with metastases to bone and metastases to CNS (n=1), acute respiratory failure with urosepsis (n=1), respiratory failure (n=

1). †Two reports were invalidated after March 17, 2018. Reported causes of death for these patients were unknown (n=1) and respiratory failure (n=1). ‡Expressed per 100 patient-years.

CI=confidence interval; CNS=central nervous system; MS=multiple sclerosis; OCR=ocrelizumab.


67

Market period

Estimated patients

on OCR by end

of period

Exposure

patient-years

Fatalities

(n) Crude

incidence rate‡ 95% CI

Apr 2017 –

March 17, 2018 ~37,000 15,682 44† 0.2806

0.2039,

0.3766


Fatalities summary: Post-marketing setting

■ >40,000 patients have been treated with ocrelizumab as of March 17, 2018, including >37,000

in the post-marketing setting outside of clinical trials1

■ In the post-marketing setting, the incidence rate of fatalities was 0.2806 per 100 patient-years during

the period April 2017 to March 17, 2018

■ The FDA-approved prescribing information2 remains the primary source for known and potential risks

associated with ocrelizumab for the treatment of MS

■ A total of 49 fatalities have been reported outside of clinical trials from April 2017-March 31, 2018.

• 44 fatalities were reported outside of clinical trials from April 2017-March 17, 2018. Two of those reports were

subsequently invalidated‡

• 7 additional fatalities were reported after March 17th and through March 31, 2018.

■ No pattern was observed.

■ 26 fatalities were reported between January 1 and March 31, 20181

• Female (n=17) and male (n=9)1

• MS (n=7), RMS (n=4), PMS (n=3), PPMS (n=6), and RRMS (n=6)1

• Causes of death included: unknown cause (n=15), urosepsis (n=2), aspiration pneumonia (n=1),

cellulitis/pneumonia/UTI sepsis (n=1), influenza (n=1), intracerebral hemorrhage (n=1), metastatic liver

cancer (n=1), metastatic lung cancer (n=1), suicide (n=1), heart attack (n=1), and myocardial infarction

(n=1)1,*†

*Some investigations remain ongoing and information may be subject to change; MS type and cause of death were as reported verbatim by the reporter.1

†Per regulation,3 all cases of unknown or uncaptured causality are reported as ocrelizumab-related. ‡Patient did not receive Roche drug

FDA=US Food and Drug Administration; MS=multiple sclerosis; PMS=progressive multiple sclerosis; PPMS=primary progressive multiple sclerosis; RMS=relapsing multiple sclerosis; RR

MS=relapsing-remitting multiple sclerosis; UTI=urinary tract infection.

1. Genentech, data on file; 2. Ocrevus® [prescribing information]. South San Francisco, CA: Genentech, Inc, a Member of the Roche Group; March 2017; 3. US Food & Drug Administr

ation. CFR — Code of Federal Regulations Title 21. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.80. Accessed November 2017.

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Fatalities summary: All settings

■ Published estimates of the mortality rate in the MS population range from 0.37 per 100

patient-years2 to 0.9 per 100 patient-years3 based on an observational study in France

(n=27,603)2 and a retrospective study in the US (30,402 MS patients from the

OptumInsight Research database)3

■ The incidence rates of fatalities are derived from varied sources and are intended to

provide context. Confounding factors that may influence mortality have not been

accounted for and, therefore, no direct comparisons should be made. Such factors may

include, but are not limited to, type of MS, age, gender, disease duration, geographical

region, population size, drug exposure, comorbid conditions, treatment history, and

duration of follow-up

69

*Incidence rate during the controlled treatment period in patients randomized to OCR. †Includes all patients exposed to ocrelizumab in the global and US MS clinical trials except Ensemble; excludes patients in compassionate use program ‡April 2017 to March 17, 2018.

MS=multiple sclerosis; OCR=ocrelizumab; US=United States.

1. Genentech, data on file; 2. Leray E, et al. PLoS One 2015;10(7):e0132033; 3. Goodin DS, et al. PLoS One 2014;9(8):e105207.

Phase 3 OPERA I/II

trials*

Phase 3

ORATORIO trial*

All OCR MS

clinical trials†

Post-marketing

setting‡

Incidence rate per

100-patient years

in OCR-treated

patients1

0.07 0.25 0.169 0.2806


Mortality in patients with MS: French observational study

■ A French, multicenter, observational study evaluated 27,603 patients enrolled in the EDMUS

database*. The mortality rate was 0.37 (95% CI 0.36–0.39) per 100 patient-years (1,569 deaths)

■ Patients with progressive onset of MS had higher mortality rates compared with patients with

relapsing onset (0.73 [95% CI 0.67–0.81] per 100 patient-years vs 0.32 [95% CI 0.30–0.33] per 100

patient-years, respectively)

*The EDMUS database captured demographic and longitudinal clinical data for MS patients. For this study, EDMUS was linked to two national registers

(Répertoire national d'identification des personnes physiques [RNIPP] and the national death register [INSERM-CepiDc]) in order to ascertain death and causes of death.

CI=confidence interval; EDMUS=European Database for Multiple Sclerosis; MS=multiple sclerosis.

Leray E, et al. PLoS One 2015;10(7):e0132033.

70

Kaplan-Meier estimated survival curves in patients with MS

(observed) and the general French population (expected)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

Years from MS clinical onset

Su

rviv

al

pro

ba

bilit

y (

%)

Observed survival

Expected survival

6/5/2018

36


Mortality in patients with MS: US retrospective study

■ A US retrospective study enrolled 30,402 patients with MS and 89,818 non-MS

comparators* from the OptumInsight Research healthcare claims database

■ Cause of death information was obtained from death certificates

■ The difference in mortality rates for MS patients and non-MS comparators was primarily

due to infections, cardiovascular causes, and pulmonary problems

*MS and non-MS comparators were matched based on age/residence at index year and gender.

CI=confidence interval; MS=multiple sclerosis; US=United States.

Goodin DS, et al. PLoS One 2014;9(8):e105207.

71

Patients with MS Non-MS controls

Overall mortality rate per

100-patient years (95% CI)1 0.9 (0.86–0.95) 0.45 (0.43–0.46)

Number of deaths 1,579 2,332


Additional Details Regarding Fatalities

January–March 2018 Reports

6/5/2018

37


Fatalities: Spontaneous reports in post-approval setting* (slide 1 of 4)

AERS

identifier

Gender,

age (y)

MS

diagnosis

OCR

infusions

Time between

last OCR

infusion and fatality

Cause of death as

reported to FDA Additional information

2053832 F, NR RRMS 2 48 d Unk Prior fingolimod; death

believed to be suicide

2053170 F, 68 RRMS 2 21 d Unk Prior GA, dimethyl

fumarate

2051610 M, 51 MS Unk Unk Cellulitis, pneumonia,

and UTI sepsis

Prior NTZ

1959821 M, 69 RRMS 2 59 d Unk Death secondary

to serious UTI

2055539 F, 55 PMS 2 99 d Aspiration pneumonia Prior IFN β-1a,

dimethyl fumarate

2059001 F, 55 RMS 1† 30 d Metastatic liver cancer Prior GA

2058077 F, 59 PMS 2 >81 d Unk Prior GA, NTZ

2059852 F, 35 RRMS 2 ≥22 d Intracerebral

hemorrhage left frontal

and parietal cortex

Prior IFN β-1b,

pulse IV MP, and

plasmapheresis; autopsy

done

*For January to March 2018; reported by physician unless otherwise noted. †One 300 mg infusion.

AERS=adverse event reporting system; d=days; F=female; FDA=US Food and Drug Administration; GA=glatiramer acetate; IFN β-1a=interferon beta-1a;

IFN β-1b=interferon beta-1b; IV=intravenous; M=male; MP=methylprednisolone; MS=multiple sclerosis; NR=not reported; NTZ=natalizumab; OCR=ocrelizumab; PMS=progressive multiple scl

erosis; RMS=relapsing multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis; Unk=unknown; UTI=urinary tract infection; y=years.


73



AERS

identifier

Gender,

age (y)

MS

diagnosis

OCR

infusions

Time between

last OCR


Cause of death as

reported to FDA Additional information

2062369 M, 70 PMS 2 88 d Unk Case reported by nurse;

prior IFN β-1a, IFN β-1b,

and GA

2063857 F, 43 PPMS 2 Unk Unk Prior IFN β-1a;

autopsy done

2066961 F, 49 MS 2 >150 d Influenza Past medical

history unknown

2068341 M, 67 MS Unk Unk Urosepsis Past medical

history unknown

2070864 M, 81 PPMS 2 80 d Metastatic lung

cancer

Case reported by

nurse; prior IFN β-1a,

mitoxantrone plus IFN

β-1a combination, MTX, and

mycophenolate mofetil

2073386 F, 45 RRMS 2 158 d Unk Prior GA and fingolimod

*For January to March 2018; reported by physician unless otherwise noted.

AERS=adverse event reporting system; d=days; F=female; FDA=US Food and Drug Administration; GA=glatiramer acetate; IFN β-1a=interferon beta-1a;

IFN β-1b=interferon beta-1b; M=male; MS=multiple sclerosis; MTX=methotrexate; OCR=ocrelizumab; PMS=progressive multiple sclerosis; PPMS=primary progressive multiple sclerosis;

RRMS=relapsing-remitting multiple sclerosis; Unk=unknown; y=years.


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AERS

identifier

Gender,

age (y)

MS

diagnosis

OCR

infusions

Time between

last OCR


Cause of death as

reported to FDA

Additional

information

2074292 F, 62 PPMS 2 >153 d Unk Prior IFN β-1b and

GA

2078616 F, approx. 64 MS Unk Unk Unk Reported by friend of

patient; past medical

history unknown

2079460 F, approx. 71 RMS Unk Unk Unk Past medical history

unknown

2080264 F, 57 PPMS 2 32 d Myocardial infarction Reported by a nurse;

prior GA

2080272 M, 28 PPMS 2 10 d Urosepsis secondary

to bladder infection

Reported by a nurse

2089979 M, 65 MS Unk Unk Unk Prior IFN β-1b


AERS=adverse event reporting system; d=days; F=female; FDA=US Food and Drug Administration; GA=glatiramer acetate; IFN β-1b=interferon beta-1b; M=male; MS=multiple sclerosis

; OCR=ocrelizumab; PPMS=primary progressive multiple sclerosis; RMS=relapsing multiple sclerosis; Unk=unknown; y=years.


75



AERS identifier

Gender,

age (y)

MS

diagnosis

OCR

infusions

Time between

last OCR


Cause of death as

reported to FDA

2092457 F, 64 MS 2 9 d Unk

2094528 F, 70 MS 1 3 d Unk

2096961 M, 57 RRMS Unk Unk Suicide

2097002 M, 50 RMS 2 >5 days Heart attack

2097115 F, 36 RMS 2 44 d Unk

2093565 F, 62 PPMS 2 79 d Unk


AERS=adverse event reporting system; d=days; F=female; FDA=US Food and Drug Administration; M=male; MS=multiple sclerosis; OCR=ocrelizumab; PPMS=primary progressive mult

iple sclerosis; RMS=relapsing multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis Unk=unknown; y=years.


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AERS

identifier Comment

2053832 A female patient with RRMS and past medical history significant for depression and prior treatment with

fingolimod received ocrelizumab in October 2017, with the day 15 infusion being administered on November 13,

2017. Patient tolerated infusions well without any changes in vital signs. The patient died on December 31,

2017, with cause of death unknown but believed by physician to be suicide and unrelated to ocrelizumab.

2053170 A 68-year-old female with RRMS with an initial EDSS of 2 and past medical history significant for sarcoidosis,

IBS, hypertension, hypersensitivity lung disease, prediabetes, psoriasis, COPD and pulmonary nodules, and on

multiple concomitant mediations, received prior MS medications of glatiramer acetate and dimethyl fumarate.

Patient had been administered two infusions of ocrelizumab: one on June 24, 2017, and the other on July 10,

2017. She tolerated both well. Patient passed away on July 31, 2017, from unknown cause. Provider stated it

was unknown whether death was related to ocrelizumab due to comorbid conditions.

2051610 A 51-year-old male patient with MS on hospice care, who initiated ocrelizumab on an unknown date, passed

away on December 16, 2017. Prior MS treatment included natalizumab. Cause of death is reported as cellulitis,

pneumonia, and UTI sepsis. Autopsy was not performed. Provider believes death is not related to ocrelizumab.

1959821 A 69-year-old male with RRMS (EDSS of 6) had a past medical history significant for multiple UTIs, Merkel cell

carcinoma of the neck (treated with chemotherapy), myocardial infarction in 2010, and three strokes: two in 2013

and one in 2014. Patient received ocrelizumab June 27, 2017, and September 11, 2017. Patient developed a

UTI after initial infusion, which led to delay between infusions. Patient passed away on November 9, 2017,

secondary to a serious UTI. Causality was assessed as unknown.

*For January to March 2018; additional information is still being sought on some of these reports.

AERS=adverse event reporting system; COPD=chronic obstructive pulmonary disease; EDSS=Expanded Disability Status Scale; IBS=inflammatory bowel syndrome;

MS=multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis; UTI=urinary tract infection.


77



AERS

identifier Comment

2055539 A 55-year-old female patient with progressive MS requiring wheelchair use had prior MS medications of IFN β-

1a and dimethyl fumarate. Patient received two infusions of ocrelizumab on September 18, 2017, and October 3,

2017. Of note, provider mentioned that, prior to the ocrelizumab infusion, she was only able to walk 10–20 feet,

and several weeks after her last infusion, she was walking up to 40 feet. Patient passed away due to aspiration

pneumonia on January 8, 2018. No autopsy was performed. Causality between ocrelizumab and death was

reported as possibly related.

2059001 A 55-year-old female patient with RMS and previously on glatiramer acetate had one infusion of ocrelizumab on

July 7, 2017. The patient passed away on August 6, 2017. Cause of death was reported as metastatic liver

cancer. The physician believes cancer and death are not related to ocrelizumab.

2058077 A 59-year-old female with progressive MS (wheelchair-bound) had a past medical history significant for

prediabetes, hypertension, recurrent UTIs, bed sores, and recurrent respiratory infections. Prior MS medications

were glatiramer acetate and natalizumab. Natalizumab was discontinued in June 2017 due to JCV+ (index of

0.42). Patient had two infusions of ocrelizumab on July 26, 2017, and August 11, 2017. Patient tolerated

infusions without issue. Patient passed away in November of unknown cause. Provider believes that death is

unrelated to ocrelizumab.


AERS=adverse event reporting system; IFN β-1a=interferon beta-1a; JCV=John Cunningham virus; MS=multiple sclerosis; RMS=relapsing multiple sclerosis; UTI=urinary tract infection.


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40



AERS

identifier Comment

2059852 A 35-year-old female patient diagnosed with RRMS for the past 12 years had prior MS medications of IFN β-1b,

pulse intravenous methylprednisolone, and plasmapheresis. Patient was also on multiple concomitant pain

medications. Patient received two infusions of ocrelizumab in August and September 2017. On October 16,

2017, she was reported as receiving day 4 of her usual 5-day IVIG. On October 17, 2017, she did not make her

appointment for day 5 of IVIG, but did report severe headache. She was admitted to hospital on October 18,

2017, due to nausea, vomiting, photophobia, and neck stiffness. On October 22, 2017, she died in hospital due

to intracerebral hemorrhage of the left frontal and parietal cortex. The physician reviewed the autopsy and

determined the death to be due to IVIG and to be not associated with ocrelizumab.

2062369 A 70-year-old male with progressive MS, wheelchair-bound for the past 8 years, received prior MS medications

of IFN β-1a, IFN β-1b, and glatiramer acetate. Past medical history included hip replacement, paroxysmal atrial

fibrillation, colostomy, suprapubic urostomy, and sacral ulcers. Patient was also on multiple symptom-controlling

concomitant medications. Patient had two infusions of ocrelizumab on August 7, 2017, and September 7, 2017.

Patient contracted pneumonia between first and second infusions and passed away on December 4, 2017.

Provider believes death is not related to ocrelizumab.

2063857 A 43-year-old female with PPMS and an EDSS of 9, prior MS medications of IFN β-1a, and past medical history

significant for UTIs, received two infusions of ocrelizumab on December 26, 2017, and January 9, 2018. She

passed away on an unknown date due to an unknown cause. The reporting physician knew very few details

surrounding the death. It was mentioned that “she might have had a pulmonary embolism because she did not

move very much.” Autopsy was performed, and results would be available in 6–8 weeks. The physician

assessed death as possibly related to ocrelizumab.


AERS=adverse event reporting system; EDSS=Expanded Disability Status Scale; IFN β-1a=interferon beta-1a; IFN β-1b=interferon beta-1b; IVIG=intravenous immunoglobulin;

MS=multiple sclerosis; PPMS=primary progressive multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis; UTI=urinary tract infection.


79



AERS

identifier Comment

2066961 A 49 year old female with MS (bedridden) started ocrelizumab on an unknown date and received a second

infusion on August 7, 2017. On December 30, 2017 she developed pneumonia and influenza. Ocrelizumab was

discontinued due to the adverse events. On January 4, 2018, the pneumonia resolved. On an unspecified date,

she passed away with influenza. Physician assessed that the pneumonia was related to ocrelizumab but

influenza was not related.

2068341 A 67-year-old male with MS with unknown past medical history or concomitant medications started ocrelizumab

on an unknown date. The patient was diagnosed with a bladder infection on an unknown date. On December 2,

2017, he was diagnosed with urosepsis; he died on December 11, 2017. Causality was assessed as unknown

by the physician.

2070864 An 81-year-old male with PPMS (EDSS of 8.0) with past medical history significant for an approximately 50-year

history of smoking, subdural hematoma after a fall in July 2015, and Alzheimer's disease previously received IFN

β-1a, mitoxantrone, and methotrexate. The patient received two infusions of ocrelizumab on October 16, 2017,

and October 30, 2017. The patient was diagnosed with metastatic lung cancer on January 5, 2018, and passed

away secondary to this on January 18, 2018. The provider does not believe that the cancer or death were

related to ocrelizumab.

2073386 A 45-year-old female patient diagnosed with RRMS and had prior MS medications of glatiramer acetate and

fingolimod was wheelchair-bound, had difficulty communicating, and was on palliative care. She was given two

infusions of ocrelizumab on August 18, 2017, and September 1, 2017. Patient died due to an unknown cause on

February 6, 2018. The physician assessed that death was not related to ocrelizumab.


AERS=adverse event reporting system; EDSS=Expanded Disability Status Scale; IFN β-1a=interferon beta-1a; MS=multiple sclerosis; PPMS=primary progressive multiple sclerosis; RR

MS=relapsing-remitting multiple sclerosis.


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AERS

identifier Comment

2074292 A 62-year-old chronically ill female with a 30-year history of PPMS was nonambulatory and had a past medical

history significant for decubitus ulcers and pneumonia. Past drugs included IFN β-1b and glatiramer acetate. In

June 2017, the patient started ocrelizumab and received the second infusion in July 2017. It was reported that

she progressively went downhill following the infusion. In January 2018, patient passed away of unknown cause.

Causality was assessed as unknown.

2078616 An approximately 64-year-old female patient with unknown medical history and concomitant medications started

ocrelizumab on an unknown date. The patient died due to unknown cause on an unknown date.

2079460 An approximately 71-year-old female patient with RMS and unknown medical history, concurrent conditions,

concomitant medications, or past drugs started ocrelizumab on an unknown date. On January 14, 2018, she died

due to unknown cause. The reporter did not state the causality between death and ocrelizumab.

2080264 A 57-year-old female patient diagnosed with PPMS had baseline severe cognitive issues (nonverbal) and was

cared for by family. Past medical history included seizures. Prior MS medications included glatiramer acetate.

Patient started ocrelizumab on December 18, 2017, and received her second infusion on January 2, 2018. On

February 3, 2018, the patient passed away secondary to a myocardial infarction. The nurse assessed the

myocardial infarction as not related to ocrelizumab.

81


AERS=adverse event reporting system; IFN β-1b=interferon beta-1b; MS=multiple sclerosis; PPMS=primary progressive multiple sclerosis; RMS=relapsing multiple sclerosis.




AERS

identifier Comment

2080272 A 28-year-old male with PPMS and a past medical history of chronic bladder infections and UTIs and multiple

concomitant pain, antianxiety, and antispasmodic medications received ocrelizumab in June 2017 and January

23, 2018. Patient was diagnosed with bladder infection and developed urosepsis on January 31, 2018. Patient

died on February 2, 2018. Nurse believed that the patient's ability to fight the infection might have been

compromised, but causality between death and ocrelizumab is reported as unknown.

2089979 A 65-year-old male with MS previously on IFN β-1b started ocrelizumab in June 2017. The patient passed away

on March 5, 2018. Cause of death is unknown. Causality was not reported.

2092457 A 64-year-old female patient with MS (EDSS 7.0) with past medical history significant for diabetes, hypertension,

and tobacco received ocrelizumab on August 7, 2017 and August 22, 2017. Patient passed away on August 31,

2017, due to unknown cause. The physician assessed the causality as unknown.

2094528 An approximately 70-year-old female with MS passed away 3 days after her first infusion of ocrelizumab.

Contact with prescriber has been unsuccessful thus far and Roche Genentech continues to try and obtain further

information about this case.


AERS=adverse event reporting system; EDSS=Expanded Disability Status Scale; IFN β-1b=interferon beta-1b; MS=multiple sclerosis; PPMS=primary progressive multiple sclerosis; UTI

=urinary tract infection.


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42



AERS

identifier Comment

2096961 An approximately 57-year-old male with RRMS diagnosed in December 2017 (tumefactive, ambulatory with mild

weakness) started ocrelizumab on an unknown date. Patient passed away due to suicide. Causality was stated

as unrelated.

2097002 An approximately 50-year-old male with RMS (left-sided hemiparesis) and past medical history significant for

diabetes, obesity, and atrial fibrillation on dabigatran etexilate, digoxin, diltiazem, lisinopril, metformin, and

metoprolol received ocrelizumab on July 12, 2017, and July 26, 2017. Patient passed away from a severe heart

attack in August 2017. Autopsy is pending. Causality was not reported.

2097115 A 36-year-old female with RMS (EDSS of 2) and past medical history significant for hyperlipidemia received

ocrelizumab on January 17, 2018, and February 5, 2018. On March 21, 2018, the patient had shortness of

breath, became diaphoretic, and collapsed at home. Patient could not be revived. Cause of death is unknown.

Autopsy is pending.

2093565 A 62 year old female patient with PPMS being treated with ocrelizumab received a 300 mg ocrelizumab infusion

on October 29, 2017. The patient passed away on January 16, 2018. Cause of death is unknown and causality

was not reported.


AERS=adverse event reporting system; EDSS=Expanded Disability Status Scale; MS=multiple sclerosis; RMS=relapsing multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis;

UTI=urinary tract infection.


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