Post on 13-May-2022
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