What’s New in Research in GBS and CIDP?Kenneth C. Gorson, M.D.Professor of Neurology

Tufts University School of Medicine, Boston MA

Chair, Global Medical Advisory BoardGBS/CIDP Foundation International

Boston Regional SymposiaOctober 5, 2019

International GBS Outcome Study (IGOS)PI: Bart Jacobs, M.D., Ph.D., Erasmus University, The Netherlands

A patient-oriented, prospective, worldwide study on GBS.

Aim is to understand and predict the clinical course in individual patients, and to develop better and personalized treatment for GBS.

Examples of specific research aims: Improve the diagnostic criteria for GBS (subtypes) Identify the causes and risk factors for developing GBS Identify genetic and other biomarkers for disease progression Prediction of the recovery after treatment in individual patients Evaluate the effect of new treatments in subgroups of patients Identify and predict the long-term consequences of GBS

GOAL: Prospectively follow 1000 GBS patients over > 1 year

IGOS – a global study>150 hospitals from 21 countries have contributed

IGOS – a prospective cohort study in 2000 patients with GBS

Time line (weeks)

Clinical data

Serum samples

DNA

Nerve physiology

Cerebrospinal fluid

0 1 2 26 524 13 104 1568

Treatment data

Outcome measures• GBS disability score• (Rasch) MRC sum score• Rasch-built Overall Disability Score (RODS)• (Rasch) Fatigue Severity Score (FSS)• Visual analogue score for pain• EQ-5D-5L

0

200

400

600

800

1000

1200

1400

1600

1800

2000

may Jul Oct Jan2013

Apr Jul Oct Jan2014

Apr Jul Oct Jan2015

Apr Jul Oct Jan2016

Apr Jul Oct Jan2017

Apr July Oct Jan2018

April Jul Oct Jan2019

April June

IGOS-1000(June 2012 - June 2015)

IGOS-2000(June 2015 - )

June 2019n=1773n=1000

Number of patients included in IGOS

124 new inclusions last year

IGOS Protocol

Regional variation

IGOS DK epidemiol

Zika studies

Diagnostic criteria

Other

Epidemiological Clinical/diagnosis

NCS data description

NCS criteria subtypes

Diagnostic criteria

Pathogen subtypes

Prognosic value

Other

Electrophysiology

Preceding infections

Anti-glycolipid abs

Anti-protein abs

IVIg PK/PD studies

Genomic/Proteomics

Other

Laboratory

Treatment practice

I-SID in severe GBS

IVIg in mild GBS

CER new drugs

RCT designing

Other

Treatment

mEGOS/EGRIS

Rasch MRC/I-RODS

Propensity score

New progn models

Long-term outcome

Other

Outcome measures Prognostic models

Published in Brain

Published in J Neurol

Published in NeurologyLab testing (Rotterdam)

Lab testing(Glasgow) Submitted to JNNP

Data analysis

Data analysis

Data collection

Paper preparation

Data analysis

Paper preparation Data analysis

• Papers : 4 published, 1 submitted, 4 aim to submit in 2019• Studies : 11 projects ongoing at present

IGOS Research Program

Update IGOS biobank

• Entry serum samples from 824/1000 patients• Stored aliquoted in Micronics system in -80 C• Entry samples aliquoted into 15 vials• Planned Research projects:

• 2x 150 µl• 2x 300 µl

• 1x 100 µl

• 5x 100 µl

• 5x 200 µl

• External back-up (Glasgow, Dhakka)

Reserved for first research projects:

The “Big 5” preceding infections: CMV, EBV, HEV, Zika, Mycoplasma

Campylobactor jejuni; IgG and albumin levels

Anti-ganglioside, glycolipid antibodies

IGOS Patient and study cohort

Christine Verboon et al. Neurology 2019;93:e59-e76

©

What is the Current Treatment Practice in GBS Patients?

Country-specific initial treatment of severely affected patients with Guillain-Barré syndrome (GBS)

Christine Verboon et al. Neurology 2019;93:e59-e76

What is the Current Treatment Practice in GBS Patients?

Current Treatment Practice of GBS:Summary of Findings

• 92% of 1023 GBS patients received IVIg, PE or other immunotherapy

• 75% of patients with mild GBS were treated (who were able to walk at nadir)

• 76% with Miller Fisher Variant (uniformly good prognosis)• 83% of other GBS variants• 35% who did not improve were treated again (no data to

support this)

Brain, Volume 141, Issue 10, October 2018, Pages 2866–2877, https://doi.org/10.1093/brain/awy232The content of this slide may be subject to copyright: please see the slide notes for details.

Age and gender distribution of IGOS cohort. *P < 0.05 for difference in number of males and females per age ...

Geographic Variation of GBS

Brain, Volume 141, Issue 10, October 2018, Pages 2866–2877, https://doi.org/10.1093/brain/awy232The content of this slide may be subject to copyright: please see the slide notes for details.

Clinical course during 1-year follow-up.

Geographic Variation of GBS

Brain, Volume 141, Issue 10, October 2018, Pages 2866–2877, https://doi.org/10.1093/brain/awy232

Clinical variants (Week 2) (A) and antecedent events (B) in different geographical areas.Geographic Variation in GBS

Brain, Volume 141, Issue 10, October 2018, Pages 2866–2877, https://doi.org/10.1093/brain/awy232The content of this slide may be subject to copyright: please see the slide notes for details.

Kaplan-Meier analysis of time to walk unaided in different geographical areas. Geographic Variation in GBS

Regional Variation of Guillain-Barre Syndrome:Summary of Findings

• 69% with classical sensorimotor GBS in USA/Europe• 69% pure motor GBS in Bangladesh (BD)• 22% Miller Fisher Syndrome and overlap with GBS in

Asian cohort• 55% with demyelinating pattern in USA/Europe• 36% axonal subtype in BD vs. 6% in USA/Europe

• Younger, frequently pure motor, trend to poorer recovery• Able to walk (Grade 2 GBS disability score) and mortality:

• 91% in Asia; 2% mortality• 83% in USA/Europe; 5% mortality• 69% in BD; 17% mortality (most never treated)

• Factors related to geography have major influence on disease

Acknowledgements to IGOS Consortium and sponsorsUSA K. Gorson, D. Cornblath, K. Sheikh

UK G. Chavada, A. Davidson, R. Hughes, H. Willison

Bangladesh Z. Islam, B. Islam, Q. Deen Md

Italy E. Nobile-Orazio

Denmark T. Harbo

Spain I. Illa, L. Querol

Germany H.P. Hartung, H. Lehmann

Argentina R. Reisin

Japan S. Kusunoki

Malaysia N. Shahrizaila

Canada T. Feasby

France Y. Pereon

Belgium P. van den Bergh

Taiwan S. Hshieh

South-Africa K. Bateman

China Y. Wang

Australia S. Reddel

Greece D. Efthimios

Brazil A. Barreira, W. Junior

Steering committee, country coordinatorsB. v.d. Berg, C. Verboon, M. van Woerkom, J. Roodbol,

A. Doets, P. van Doorn, S. Leonhard, M. Mandarakas

S. Arends

Coordinating center at Erasmus MC

Sponsors

Switzerland P. Ripellino

Second IVIg Dose in GBS patients with poor prognosis (SID-GBS)

• Randomized, placebo-controlled trial

• 60 participating hospitals in the Netherlands

SID-GBS FlowchartInclusion: Day 1

IVIg standard treatment

Check prognosis Day 7

Good prognosis Poor prognosis

No second IVIg dose

Second IVIg dose

No additionaltreatment

4 weeks primary endpointFollow-up, 8, 12 and 26 weeks

Randomization

Predictors Categories Score

Age ≤40 0 (years) 41-60 0.5

>60 1

Diarrhoea absent 0

(≤ 4 weeks) present 1

GBS disability score 0-1 1

(at 2 weeks) 2 2

3 3

4 4

5 5

EGOS 1 - 7

A clinical prognostic scoring system for GBS

Erasmus GBS outcome score (EGOS) Chance unable to walk at 6 months according to EGOS (N=762)

1 2 3 4 5 6 7

EGOS

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pred

icte

d fr

actio

n no

t wal

king

at 6

mon

ths

AUC 0.85

SID-GBS

• 244 GBS patients included

• 88 with poor prognosis randomized to 2nd

course IVIg or placebo

• Results and conclusions presented at PNS meeting June 2019

SID-GBS: Findings• 2nd course of IVIg INEFFECTIVE in

hastening recovery at 4 weeks and 6 months• 6 month disability scores identical between the

groups• Proportion of patients walking at 6 months

identical • All secondary outcome measures identical• Serious adverse events more common in 2nd

IVIg dose group

No indication for 2nd course of IVIg in severe GBS

COMPLEMENT INHIBITION AS A THERAPEUTIC TARGET IN GBS

Dr Amy DavidsonProf. Hugh WillisonOn Behalf of the ICA-GBS consortium

Halstead et al

Complement Cascade

• Plasma proteins forming part of the innate immune system

• Triggered by anti-ganglioside antibodies• Cause nerve damage via disruption of the plasma

membrane and intracellular calcium influx

Complement in a Mouse

• GBS mouse models have shown that early application of complement inhibitors prevents nerve damage

Eculizumab

• Fully humanised recombinant monoclonal antibody• Neutralizes C5 in the complement cascade

• Current indications: PNH and aHUSSide Effects:• Risk from encapsulated bacteria

• Neisseria meningitides• Infusion reactions• Headache• GI upset

Image provided by Alexion Pharmaceuticals, Inc.

SAFETY AND EFFICACY OF ECULIZUMAB IN GUILLAIN-BARRÉ SYNDROME: AMULTICENTRE, DOUBLE-BLIND, RANDOMISED PHASE 2 TRIAL (JET STUDY)

JET Study: Findings

Eculizumab (n=23) Placebo (n=11)

Between-group difference (95% CI)

p value

Primary outcomeAble to walk 5 m independently (functional grade ≤2)

Week 4, % (90% CI) 61% (42 to 78) 45% (20 to 73) 15% (−20 to 51) ..

Number of patients 14/23 5/11 .. ..

Secondary outcomesImprovement by one functional grade*†

Week 4, % (95% CI) 66% (39 to 86) 61% (27 to 87) 5% (−31 to 40) 0·801

Patients with data 22 11 .. ..

Week 24, % (95% CI) 95% (70 to 99) 91% (45 to 99) 4% (−17 to 24) 0·710

Patients with data 22 9 .. ..Able to walk 5 m independently (functional grade ≤2), sensitivity analysis*†

Week 4, % (95% CI) 65% (37 to 85) 45% (16 to 79) 20% (−19 to 58) 0·325

Patients with data 22 11 .. ..

Week 24, % (95% CI) 92% (67 to 98) 72% (32 to 93) 20% (−14 to 54) 0·187

Patients with data 22 9 .. ..Time to improvement by one functional grade (days)

Median (95% CI) 19·0 (9·0 to 35·0)

22·0 (7·0 to 59·0) −3·0‡ 0·542

Patients with data 23 11 .. ..Able to run (functional grade ≤1)§

Week 24, % (95% CI) 74% (52 to 90) 18% (2 to 52) 56% (27 to 85) 0·004

JET Study: Conclusions• Eculizumab safe and well tolerated in GBS• No significant benefit in 4 week or 6 month primary outcome measure (walking independently)

• All secondary outcome measures also negative, EXCEPT:

• Percentage of patients who could run (? distance) at 6 months significantly greater in Eculizumab group

• Larger trials are needed

Annexon Complement Inhibitor Trial

• ANX005 novel complement inhibitor• Blocks C1q- the beginning of the complement cascade• Placebo controlled trial Phase I/II ongoing in Bangladesh• Pivotal Phase II/III trial to begin next year in US and

Europe (with IVIg)• Recently approved for “fast track” designation from FDA

ANX005 reduces free C1q levels in CSF at doses > 18 mg/kgCSF C1q inhibition important to efficacy due to nerve root involvement in GBS

CONFIDENTIAL 30

Dose-dependent increase in CSF ANX005 levels Dose-dependent decrease in CSF free C1q

1 8 3 6 7 50 .1

1

1 0

1 0 0

D o s e (m g /K g )

CS

F A

NX

00

5 (

ug

/mL

)

P re -d o s e P la c e b o 1 8 3 6 7 50 .0 1

0 .1

1

1 0

1 0 0

D o s e (m g /K g )

CS

F C

1q

(u

g/m

L)

P o s t d o s e d 5 -8

ANX005 induces early improvement of MRC score, that is dose-dependent

CONFIDENTIAL 31

Placeb

o 3 9 18 36 75-20

0

20

40

Mean Change in MRCDay 8 from Baseline

Mea

n ch

ange

in M

RC

Dose

• ANX005 results in improvement of muscle strength (MRC sum-score) within 1 week of treatment

• MRC score at day 8 is a major predictor of future functional outcomes (mEGOS)

ANX005 provided larger treatment effect in Phase 1b patients more similar to Western world patients

32

GBS-DS MRC I-RODS

CONFIDENTIAL

2 4 6 8-10

0

10

20

30

40

MRC change from baselineMRC > 18 at baseline

Time (Wks)

Mea

n ch

ange

in M

RC

Placebo N=3 ANX005 N=5

0 2 4 6 81

2

3

4

5

Mean GBS-DSMRC >18 at baseline

Time (Wks)

Mea

n G

BS-

DS

Placebo N=3 ANX005 N=5

0 2 4 6 80

10

20

30

40

Change from baseline in I-RODSMRC > 18 at baseline

Time (Wks)

Mea

n ch

ange

in I-

RODS

Placebo N=3 ANX005 N=5

Update in GBS Research• IGOS

• Enormous prospective data collected with biobank• Will answer fundamental questions about the biology, diagnosis,

treatment responses and prognosis for GBS and variants• SID Trial

• No 2nd dose of IVIg in GBS patients with poor prognosis• Novel treatments for GBS on the horizon

• Eculizumab• ANX005- FDA fast track application

• Much of this work could not have been done without support from the GBS/CIDP Foundation International (Your Support!)

2019

1. Clinical2. Treatment

CIDP Research UpdateAre we making progress?

1958

Clinical and diagnostic updates:1. How can CIDP be better defined2. How can CIDP be better followed

• Supporting data:• CSF: Albuminocytologic dissociation • MRI: Nerve root enlargement or enhancement• Histology: Segmental demyelination or inflammation • Clinical improvement with immunomodulating agents

“Typical” CIDP• Clinical features:

• Relatively symmetric proximal and distal weakness and numbness• Hyporeflexia or areflexia• Evolving over > 2 months in a progressive or relapsing pattern

• Electrophysiologic features:• Evidence of peripheral nerve demyelination

• Exclusionary: No hereditary neuropathy, malignancy, MAG, MMN, or other explanation

But not all patients are “typical”

“Atypical” CIDPStill considered CIDP but with different features

Distal acquired demyelinating symmetric (DADS)

Asymmetric (Lewis–Sumner syndrome, MADSAM)

Pure motor

Pure sensory (including chronic immune sensory polyradiculopathy, CISP)

There is an ongoing need to better define CIDP

• 15 sets of CIDP diagnostic criteria have been developed

Diagnostic criteria can helpCriteria Year

Dyck 1975

Barohn 1989

Albers and Kelly 1989

AAN 1991

Saperstein 2001

INCAT 2001

INCAT 2002

Thaisetthawatkul 2002

Magda/Neuropathy Association

2003

Van den Bergh 2004

Fisher 2005

ENFS/PNS 2006

Koski 2009

Laughlin/Mayo 2009

Revised EFNS/PNS

2010 Sensitivity1 73 – 91%Specificity1 66 - 88%

1Breiner A, Brannagan TH 3rd. Comparison of sensitivity and specificity among 15 criteria for CIDP. Muscle Nerve.2014 Jul;50(1):40-6.

• EFNS/PNS 2010 for clinical trials

• In clinical practice, can help organize the diagnostic process

• Not perfect. • Updates are needed, especially with

what is known about atypical CIDP

• Even then, will they capture the true spectrum of CIDP?

What are the clinical boundaries of CIDP?Currently running national registries

• More than 1300 patients collectively within 8 separate registries• Databases vary with extensiveness of:

• Clinical data• Diagnostic data• Follow-up• Collection of biomaterials

Italy Netherlands France Japan

srerbadsad

GermanyNorway

IndiaBelgium

Serbia/ MontenegroSpain

INCbase• Harmonize current registry protocols• Develop a central database that interacts with current registries• Central database will be known as INCbase

INCbase Objectives:• Define variation of CIDP phenotypes• Improve diagnostic criteria • Develop treatment prediction models • Allow studies on pathogenesis• Improve clinimetrics• Biomarker exploration

Workshop report231th International Workshop: International Standard for CIDP Registry

and BiobankFilip Eftimov, Carina Bunschoten, Yusuf Rajabally, Luis Querol;

participants of the 231th ENMC workshop1

1. Eftimov, Bunschoten, Rajabally, Querol et al. Neuromusuclar disorders. Manuscript in preparation.

2. http://www.enmc.org/publications/workshop-reports/international-standard-cidp-registry-and-biobank

Clinimetrics: The science of clinical measurements

Why is this so important?1. Clinical trials: obvious importance2. Routine clinical care:

• For right or wrong, a high degree of importance is placed on improvement following immunotherapy

• Can we be more objective?• Can traditional tools be supplemented?

• Support the diagnosis• Justify ongoing immune therapy• Monitoring for disease worsening• Monitor for relapse after therapy is stopped

Clinimetrics:How can patients be followed over time?

PeriNomS study group. 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands. Neuromuscul Disord. 2013

• Developed for patients with inflammatory neuropathies

• Captures clinically meaningful changes over time

• May be a good way define a patient as a treatment responder

• Completed in 3 minutes or less

PeriNomS Study Group. Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness. Neurology. 2014.van Nes SI et al. R-ODS for immune-mediated peripheral neuropathies. Neurology. 2011.

• Sensitive tool for assessing clinically relevant changes in patients with CIDP

• Reliable measure of global strength in CIDP, not limited to upper limb or exclusively motor function

• Completed in less than 2 minutes

Vanhoutte EK. Vigorimeter grip strength in CIDP: a responsive tool that rapidly measures the effect of IVIG--the ICE study. Eur J Neurol.2013. PeriNomS Study Group. Neurology. 2014.

Martin Vigorimeter

Jamar Dynamometer

CIDP Treatment:Where are we?

What we know:• IVIg works• Corticosteroids work

What we don’t know:• Best dose• Best frequency• Combination therapy• Duration of treatment• How personalize maintenance

CIDP Treatment:Where are we?• Dosing/frequency studies for IVIg

• Pro-CID Trial• DRIP Trial

• Treatment Related Fluctuations (TRFs)• GRIPPER Trial

• Combining proven effective treatments (IVIg + IVMP)• OPTIC Trial

• Role of SCIg as chronic therapy in CIDP• PATH Trial• Facilitated SCIg

Active Trial:Efficacy and safety of 3 different doses of IVIg (NewGam) in

CIDP (ProCID study)1• Sponsor: Octapharma• Location: 44 centers in Canada, EU, Russia, Ukraine and Australia• Purpose: Explore different IVIg dosing options in CIDP• Study design

• Prospective, double blind, randomized, phase III study• After dependency phase all receive loading dose 2.0 g/kg IVIG (NewGam)• The randomized to 0.5 g/kg or 1.0 g/kg or 2.0 g/kg IVIG (NewGam)• 7 maintenance infusions at 3-week intervals

• Outcome- Percentage of responders at week 24 in the 1.0 g/kg group- Percentage of responders at week 24 in the 0.5 g/kg and 2 gm/kg group relative to

baseline and compared to the 1.0 g/kg arm• Study time frame

• Estimated enrollment: 140• Anticipated completion: End of 2019

1. Cornblath DR et al. POLY(RADICULO)NEUROPATHY (ProCID STUDY) – DESIGN OF A PHASE 3 STUDY. Abstract presented at the Peripheral Nerve Society Meeting, July , 2017, Barcelona, Spain

1 Kazatchkine, NEJM 2001; 2 Rajabally, JPNS 2006; 3 Roopenian, Nat Rev Immunol 2007; 4 Patwa, Clin Ex Immunol 2014

1 wk 2 wks

month3 wks

5 wks

What is the optimal dose and interval?

Optimal dose and interval is unknown1-4

Hypothesis IgG levels

Kuitwaard et al., JPNS 2018

Rapid response to each IVIg dose but also rapid wear-off

1. Pollard JD and Armati PJ. J Peripher Nerv Syst 2011;16:15-23

Wear off in a patient treated with monthly IVIg1

DRIP TRIAL

• More frequent low dosing of IVIg ⇒ more stable serum IgG levels ⇒ better efficacy & less adverse events

Comparison:

normal dose and interval IVIg vs.

½ dose and ½ interval IVIg

Study outline

Primary and secondary outcome

Primary outcome measure: Vigorimeter

Primary endpoint:Difference > 8 kPa in the change in Vigorimeter from baseline in favour of the half dose and interval group considered as a clinically relevant improvement

Secondary outcome measures: R-ODS, R-FSS, SF-36 (S)AEs, IgG levels

1 Merkies et al., JNNP 2010

Change in Vigorimeter from baseline

Mean change in Vigorimeter from baseline

ConclusionMore frequent, lower dose IVIg:

• Does not improve the efficacy of IVIg in CIDP

• Does not result in a decrease in the amount of patients reporting common side effects

Hypothesis of smoothing IgG levels between IVIg infusions probably wrong?

Jeffrey Allen MDUniversity of MinnesotaMinneapolis, MN, USA

IVIG TREATMENT RELATED FLUCTUATIONS IN CIDP USING

DAILY GRIP STRENGTH MEASUREMENTS

On behalf of the GRIPPER study team

Background• IVIG efficacy for CIDP treatment has been well

established• Some patients develop treatment related fluctuations

(TRF) during IVIG exposure1

1. Pollard and Armati. JPNS 2011;16:15-23.

TRF: Cyclic or periodic improvement or decline at some interval after IVIG

ObjectiveIdentify the extent and frequency of IVIG treatment related fluctuations in patients with CIDP

What we hope to learn from GRIPPER

• A better understanding of disease activity status• A better understanding of how to optimize

treatment

GRIPPER Data Collection

Separating “noise” from TRFs

Separating “noise” from TRFs

Patients stratified as:• High fluctuaters if TRFs in ≥ 1/3rd of

cycles• Low/no fluctuaters if TRFs in < 1/3rd of

cycles

Timing of TRFs

• 3-day averaged grip strength peaked between day 9 & 12 • At day 18 grip strength returned to and remained at or

near baseline until the next IVIG

Active Trial:Optimal treatment in CIDP (OPTIC) trial1

• Location: Dutch neuromuscular centers• Purpose: Explore combination of IVIg + corticosteroids in CIDP • Study design

• Open label• Newly diagnosed patients• Treatment for 18 weeks, then stop

• Primary endpoint • Drug free remission at 1 year

• Results• Enrollment: 21 enrolled and 17 completed protocol• At 1 year 56% in remission• 25% had initial improvement and then relapsed (at 1, 3, 5, and 8 months)

• Follow up• Based upon these results intent to proceed with randomized controlled trial• IVIg + methylprednisolone vs IVIg + placebo

1. Bunschoten C et al. Abstract presented at the Peripheral Nerve Society Meeting, July , 2017, Barcelona, Spain

Subcutaneous Immunoglobulin (SCIg)

Allows for more convenient treatment scheduleAdministered 1-2 times/weekPotentially fewer side effects? Fewer TRFs and less wearing off effects

Lancet Neurol2018;17:35-46

PATH Trial

PATH Trial: Outcome

CIDP treatment: SCIg

N=172Relapse +

discontinuationRelapse only

Placebo 63% 56%

Low dose (0.2 g/kg) 39% 33%

High dose (0.4 g/kg) 33% 19%

• Facilitated SCIG is an Ig treatment that allows up to once-a-month (every 2-4 weeks) dosing in a single SC infusion site1

• A second or third site can be used based on tolerability and total volume• If more than one site is used, divide the Recombinant Human Hyaluronidase equally between sites

• Potential to address attributes of IVIG and SCIG, including:• Frequency of therapy sessions for conventional SCIG• Number of needle sticks for conventional SCIG• Decreased bioavailability of conventional SCIG relative to IVIG• Large peak-to-trough variation for monthly IVIG• Increased risk of systemic adverse reactions for monthly IVIG

Facilitated SCIG

Components of fSCIG:

Recombinant Human Hyaluronidase (rHuPH20)• Enhances dispersion and absorption of

Ig, allowing for greater volumes to be delivered in a SC infusion site

Immune Globulin Infusion (Human) 10%• Provides the therapeutic effect

fSCIG = Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase ; FDA=Food and Drug Administration; Ig=immunoglobulin; PIDD=primary immunodeficiency disease; SC=subcutaneous.1. HYQVIA Prescribing Information, Westlake Village, CA: Baxalta US Inc.

Hyaluronan: Fills Space Between Structural Components of the SC Tissue

Figure adapted from Frost et al. 2007SC=subcutaneous.1. Frost GI. Expert Opin Drug Deliv. 2007;4:427-440. 2. Bookbinder LH, et al. J Control Release. 2006;114:230-241. 3. Shapiro SD, et al. J Clin Invest. 1991;87(5):1828-1834. 4. Toyama BH, Hetzer MW. Nat Rev Mol Cell Biol. 2013;14(1):55-61. 5. HYQVIA Prescribing Information, Westlake Village, CA: Baxalta US Inc.

Epidermis/Dermis

Subcutaneous Tissue

Collagen Fiber

• Maintains structure of SC tissue

• Slow turnover (years)

Capillary Lymphatic Vessel

Structural Components

Hyaluronan(Blue substance)

• This polymer fills the space between the structural components

• Fast turnover (hours to days)

• Causes resistance to bulk fluid flow through the SC tissue

Elastin Fiber

How does the Hy in HYQVIA work?

73 | Title | DD/MM/YY | Confidential - for internal use only

ADVANCE-CIDP 1: Study Design

Placebo(rHuPH20 + 0.25% Human Albumin in Lactated Ringer’s Solution)

IGIV Rescue (Entry into Epoch 2)

Completion(End of Epoch 1)

Relapse?

Relapse?

No

No

Yes

Epoch 1: SC Treatment Period

TargetN=148 Evaluable

HYQVIA (rHuPH20 + IGI,10%)Stable on

IGIV for 12 weeks or more

Screening and

Pre-SC Baseline Target

N=232 EnrolledN=174

Randomized

Open-label long term safety study

(ADVANCE-CIDP 3)SCIG 10%

Completion(End of Epoch 1)

Randomization (1:1)

CIDP diagnostic criteria are widely available, infrequently used: INCBase data will hopefully address

Clinimetrics has made major recent advancements I-RODS disability and Grip strength testing Supplement to history and neurological examination Not just for clinical trials

DRIP trial: Is it better to treat with smaller but more frequent IVIg doses? NO

GRIPPER study: How often does wear off occur? A LOT What does that tell us about treatment optimization?

TREATMENT CAN BE INDIVIDUALIZED ProCID trial: Does IVIg dose matter in CIDP treatment?

OPTIC trial: Is the addition of corticosteroids to IVIg beneficial? PATH trial: SCIg is effective for CIDP maintenance therapy

ADVANCE CIDP 1: Future role of facilitated SCIg

Update in CIDP Research