Receptor Mediated Transport of Biotherapeutics Across the Blood-Brain-Barrier - Clinical Proof of Safety & Efficacy in Pediatric Patients with ...
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Receptor Mediated Transport of Biotherapeutics
Across the Blood-Brain-Barrier –
Clinical Proof of Safety & Efficacy in Pediatric Patients
with Severe MPS I
7th World CNS Summit, February 2019
Why Are We Here Today?
Biotherapeutics Brain and CNS Lysosomal storage
diseases
Alzheimer’s disease
Parkinson’s disease
Neuro-Oncology
Neuro-Inflammation
• >$160B market and growing versus • The blood-brain-barrier prevents entry of large
stagnation on small molecules molecules into the brain
• >140 recombinant proteins FDA • The brain is the last organ not yet directly
approved, 40% in rare diseases, many for addressed by biotherapeutics
severe and life threatening diseases
• Bringing biologics across the BBB opens an
• Higher COGS offset by premium pricing avenue for treating many severe CNS diseases
2
QUESTION:
How Much of an i.v. Injected Recombinant Antibody Enters The Brain?
⚫ 0%?
⚫ 0.001%?
⚫ 0.01%?
⚫ 0.1%
⚫ 1%
⚫ 10%
3
Common Misinterpretations Measuring Brain Uptake of Antibodies
Company Z measured uptake of a therapeutic antibody for AD following SQ
injection in the mouse
PLASMA Exposure BRAIN Exposure
(ug/mL) (ng/g)
25 250
10 mg/kg
20 200
10 mg/kg
15 150
10 100
5 50
3 mg/kg 3 mg/kg
0 0
0 6 12 18 24 0 6 12 18 24
Hours after SQ injection Hours after SQ injection
4
The Brain Blood/Plasma Volume
(inside the head - outside the brain)
5
Brain Uptake After Correction For Brain Plasma Volume
Observations
1
• Correction for the brain plasma volume shows the BBB
0.8 penetration for antibody generally is ZERO.
• Some antibodies enter the brain under disease
0.6 conditions that disrupt the BBB integrity
• Some antibodies enter the brain by inducing vascular
0.4 edema (TI = 1)
0.2
0
0 6 12 18 24
Hours after SQ injection
6
QUESTION:
How Much of an Injected Recombinant Antibody Enters The Brain?
Macaque brain stained with
Anti Macaque IgG
Macaca fascilularis
Serum IgG 8-19g/L
Brain IgG if 0.01%
0.8-1.9 ug/g
crossed the BBB
7
Clinically Applied Methods of Delivery of Macromolecules Across
The Blood-Brain-Barrier
Intrathecal Delivery Intracerebroventricular Intravenous Delivery
Delivery
Drug is administered via Drug is administered
Drug is administered
a catheter into the brain intravenously and enters
into the cerebrospinal
ventricle from where it the CNS via the highly
space from where it has
has to diffuse into the branched vascular bed in
to diffuse across the Pia
brain parenchymal space the brain
Pater into the brain
parenchyma
8ArmaGen’s Trojan Horse Technology
ArmaGen’s technology mimics the transcytosis of insulin into the brain by developing a non-
competitive anti insulin receptor antibody that ferries effector molecules into the brain
Brain
Endothelial cell BBB
Insulin Vasculature
receptor Therapeutic
Pancreas Insulin fusion protein
Effector molecules
Carrier mAbs
Enzymes Antibodies Peptides Nucleic Acids
1
Receptor-targeting
mAb (InsR)
9Comparison of BBB Receptor Mediated Transcytosis Platforms
FFYGGSRG
Genentech/
ArmaGen Denali JCR Pharma Abbvie Angiochem Bioasis
Roche
mAb fusion BsAb (TfR/BACE) mAb fusion 8-19 AA peptide 12 AA peptide of
Format F-STAR Fcab DVD-Ig
protein mAb-Aptamer protein ligand melanotransferrin
Target Insulin Receptor Human Transferrin Receptor LRP-1 LRP-1
Not published,
Affinity 0.3 nM 30-250 nM high 1-13 nM 1000 nM unknown
likely low
Human
~1000 infusions None None ~48 infusions None yes None
exposure
Validation Phase II PoC preclinical Preclinical Phase I Preclinical Failed in phase 1 preclinical
Efficacious
1 – 3 mg/kg 40-50 mg/kg 50 mg/kg ? 20 mg/kg + na 17 mg/kg
dose
Safety unknown. Paclitaxel Acquired in 2002
Potential concern Inability to Safety unknown. No correlation
Duplicates conjugate in from Biomarin,
of hypoglycemia establish safe Effect of M6PR between
ArmaGen clinical later abandoned.
Liabilities (mitigated by molecule resulted saturation at 50 receptor affinity
technology, development. No Mtf mediated
infusion in 5% in a shift to mAb- mg/kg dose and brain
unknown CNS results posted on brain delivery
dextrose/saline) aptamer fusions unknown exposure
benefit clinicaltrials.gov inconclusive
10Not All Receptors Are Alike - Insulin Receptor vs Transferrin Receptor
Expression across specis Immunohistochemistry of rhesus brains
Receptor (4w chronic dosing of anti TfR antibody)
Mouse Rat Monkey Human
Expression 30 mg/kg AGT-6 Control
Anterior thalamus Occipital cortex
InsR abs.* 0.8 1.5
TfR abs 5.2 2.3
InsR (rel.) 53 64 44 100
GFAP (astrogliosis)
TfR (rel.) 226 339 n.m. 100
* pmol/mg tissue
Target-related safety profile
⚫ Transferrin receptor: Lysis of reticulocytes IBA1 (microglia activation)
H & E staining of sciatic nerve
expression/cell
Relative TfR
Demyelination
11Biggest limitation:
For humans, we do not have a biomarker of substrate
reduction or pharmacodynamic activity in the brain
Solution:
Demonstrate neurocognitive effect in patients using
clinical endpoints
12ArmaGen Uses Its Platform to Address the Neurological and
Somatic Symptoms in Lysosomal Storage Diseases
Healthy individual
lysosome
nucleus
Enzyme
dysfunction LSD
(monogenic)
Somatic Symptoms
Hepatosplenomegaly, skeletal deformities, joint
stiffness, corneal clouding, impaired hearing,
lysosome
nucleus cardiac dysfunction, retarded growth, pain,
respiratory and ear infections
Neurological Symptoms
Retarded cognitive development, low DQ,
⚫ Substrate inclusion bodies cause pathology
spasticity, loss of speech, behavioral
in tissues, organs, CNS and bones
abnormalities, impaired socialization
⚫ ~ 80 LSDs known; ~ 40 with CNS pathology
13ArmaGen’s Value Proposition is Driven By The Outstanding
Unmet Medical Need in Lysosomal Storage Diseases
Standard ERT Unmet need
P
Naked Y Neurocognitive decline
enzyme
DQ/IQ
Age (years)
ArmaGen
Trojan horse
InsR mAb
(BBB)
Naked P P Neurological
enzyme stabilization/improvement
14ArmaGen’s LSD Portfolio
AGT-181 (MPS I)
AGT-182 (MPS-II)
AGT-183 (MLD)
AGT-184 (MPS IIIa)
AGT-194 (Batten type I)
AGT-192 (Tay Sachs)
AGT-187 (MPS IIIb)
AGT-189 (NP-A/B)
AGT-195 (GM1G)
Discovery IND Phase I Phase II Phase III
15AGT-181 for the Treatment of MPS I
InsR mAb
FDA granted Fast Track
designation to AGT-181 for
the treatment of MPS I
on November 29, 2017
Laronidase
AGT-181
mAb Anti human InsR
Enzyme Laronidase
Indication MPS I (Hurler)
Status End of phase 2
Approved somatic
Aldurazyme
therapy
16Preclinical Validation of AGT-181
Demonstration of AGT-m181 Activity in a Mouse Model of MPS I
A Reduction of GAGs or lysosomal inclusion B Restoration of enzyme activity in brain
bodies in brain and other organs (1 hr post infusion)
Enzyme activity (nmol/h/mg protein)
Saline AGT-m181
Electron microscopy of Hurler mouse brain
Substrate reduction in central and somatic organs
Liver Spleen Heart Kidney Brain
Saline
>95% 80% 36% 20% 73% AGT-m181
8 weeks of AGT-m181 treatment in adult Hurler mice Boado RJ, et al. Molecular Pharmaceutics 2011;8:1342-1350
18Preclinical Confirmation of BBB Passage in Rhesus monkey
using AGT-181 (clinical asset for MPS I)
Aldurazyme® AGT-181
Brain Whole Body Brain Whole Body
Dose (mg/kg) 0.58 Dose (mg/kg) 1.2
Brain activity (U/mg) 0 Brain activity (U/mg) 2.4
Fold normal brain Fold normal brain
0% 160-480%
activity activity
Whole body autoradiography at 2 hours after IV injection
19Clinical PoC with AGT-181: A 52-Week Phase I/II Trial for the Treatment of Severe Untransplanted MPS I Patients with AGT-181
MPS I Subpopulations & Current Treatment Paradigm
Scheie Hurler-Scheie Hurler Hurler
(MPS IS) (MPS IHS) (MPS IH) (MPS IH)
MPS I
Few Hurler patients are
Hurler- untransplanted and treated with
Scheie Hurler
Scheie laronidase only
(5%) (>60%)
(20%) (South America, MENA, India)
Attenuated Severe Target population for PoC trial
in Brazil
Stem cell
Laronidase transplantation
21AGT-181-101 Proof of Concept Trial Outline in Pediatric
MPS I Patients
⚫ Pediatric MPS I patients who were on laronidase
were immediately switched to AGT-181 and
treated with weekly infusions of 1, 3 or 6 mg/kg for
6 months.
Endpoints investigated
⚫ Safety and pharmacokinetic properties.
⚫ Age-appropriate neurocognitive testing.
⚫ Total urinary, plasma and CSF GAGs.
⚫ Liver and spleen volume (MRI).
⚫ Growth velocity, shoulder ROM.
⚫ Neuroimaging (MRI and MRI DTI).
⚫ 6MWT, FVC, mean left ventricular mass.
22Cognitive Stabilization or Improvement versus the Expected
Decline Based on Natural History
Natural history DQ change on AGT-181 compared to Natural
history
Krivit et al. 1999
Natural History AGT-181
Bayley MDI
5.0 3.4
0.0
(5.0) (1.2)
ΔDQ /Year
(10.0)
(10.0)
(15.0)
Age (years) (20.0)
(25.0)
(20.5)
110
100
Shapiro et al. 2018 Severe MPS I Severe MPS I Severe MPS I Severe MPS I
90 Krivit et al. Shapiro et al. Att.
Bayley (DQ)
80
70
60
50
Conclusion: Stabilization of DQ is observed in
40
30 AGT-181 treated pediatric patients as opposed
20 to the decline observed in natural history
10
0 studies of untransplanted untreated MPS IH
0 10 20 30 40 50 60 70 80 90 100
patients
Age (months)
23DQ Stabilization or Improvement In Individual Patients Versus
Baseline Compared With Natural History
Change in DQ after 52 weeks vs BL
15 Patient 213*
10 207
202
5
205 206 211 214 215 203* 204*
216
0
-5 Avg. ΔDQ Giugliani et al. 2018 (AGT-181)
-10
Avg. ΔDQ Shapiro et al. 2018 (natural history)
-15
-20
Avg. ΔDQ Krivit et al. 1999 (natural history)
-25
AGT-181 response rate compared to natural history average * Attenuated MPS I
Natural History AGT-181-101
Study DQ change Responders % RR
Krivit et al. 1999 -20.5 10/11 90.9
Shapiro et al. 2018 -10 9/11 81.8
24Summary of Cognitive Changes Observed in All Patients in Context
of Natural History Data
The Hurler-Scheie population clearly
80 separates from the severe Hurler
70 population and experienced even 213
more dramatic benefit
Age Equivalent in months
60 204
203
50
40 Trajectory for each patient is
indicated by a
30 • green arrow (Hurler)
205 216 • Blue arrow (Hurler-Scheie)
20 206T
214 207 215
10
202
211
0
0 10 20 30 40 50 60 70 80 90 100 110 140 150 160 170 180 190
Chronological age in months
(Shapiro et al., 2017)
⚫ Each of the patients’ longitudinal age equivalent trajectory is indicated by an arrow –
chronological age over change in age-equivalent score and put into the context of the DQ of
untransplanted Hurler children from a cross sectional study published by Elsa Shapiro.
25Summary of Change in Age Equivalence (months) Observed
Hurler Patients
Change in cognitive age-equivalent score at latest assessment versus baseline
Age Cognitive Receptive Expressive Fine motor Gross motor W*
(Y) (M) Lg. (M) lg. (M) (M) (M)
PT BL BL latest BL latest BL latest BL latest BL latest
1-202+ 9.1 0.6 4.66 0.5 4.33 0.6 7 0.5 16 6 11 52
1-206 3.1 25 23 7 4.3 8 6 28 34 18 18 76
1-205 5.0 19 25 19 22 19 31 23 25 14 18 52
1-207# 5.9 10 16 0.5 10 7 3.6 16 17 13 17 26
1-211 2.9 10 8 5 9 8 12 10 11 7 7 26
1-211 2.9 10 4.67 5 0.5 8 6 10 7 7 6 52
1-214 2.0 13 20 4.3 16 7 17 11 22 13 19 52
1-215 12.1 25 25 16 15 8 14 33 18 15 15 52
1-216 7.8 27 28 10 19 18 21 35 33 21 18 52
+ Baseline
Improvement by at least 3 months
ND, first tested at week 13 Stabilization (± 1 month)
* Week at which latest assessment was conducted
# High neutralizing antibody titer Deterioration by at least 3 months
26Unexpected Somatic Differentiation - Changes in Organ Volume
9 of the 11 patients had been on laronidase for at least 1 year
A, spleen B, liver
Pt. 202 204 205 206 207 203 211 214 213 215 216 202 204 205 206 207 203 211 214 213 215 216
27Summary of Adverse Events Part B: 26 weeks of treatment, ~ 290 infusions • AEs were reported for 12/13 patients; the vast majority were related to the underlying disease • Most common (both drug related and unrelated) included: upper respiratory infection (9 pt), hypoglycemia (6 pt), gastroenteritis, impetigo, pyrexia (4 pt), diarrhea (3 pt) • Hypoglycemia and infusion reactions were the events most commonly considered drug related • 11 SAEs, all not drug related, included: Sinusitis, pneumonia, respiratory infection, asthma, possible cord compression, respiratory apnea, acute otitis and respiratory dysfunction Hypoglycemia • Hypoglycemic events (observed in 6 patients) were defined as blood glucose
Differentiation of AGT-181 against Laronidase Observed
from Various AGT-181 Trials Including Compassionate Use
Improved cognitive
Improved and motor function,
socialization skills language
neurobehavior
Improvement in sinus
Improvement of symptoms
short term memory
Amelioration of
Favorable immuno- retinopathy
genicity profile
Improved shoulder
ROM, joint stiffness
Decreased
hepatosplenomegaly Improved
echocardiogram
Improvement in
tendon reflexes
Decreased joint pain
Cognitive/CNS
Somatic/orthopedic
29Key Takeaways
Clinical Validation of Platforms to transport Biologics across the BBB
⚫ SAFETY: Many neurologic diseases are of chronic nature – Validation of
platform safety is as important as validation of efficacy
⚫ EFFICACY: In the absence of validated biomarkers requires measurement
of clinically relevant CNS endpoints
⚫ Proof of Concept: AGT-181 is the first large molecule that demonstrates
both safety and clinical efficacy in the CNS in a phase 2 clinical trial
⚫ Validation Pitfalls: Be mindful of them when measuring brain uptake of
large molecules. In vitro models of BBB passage not reflect the complexity
of the BBB in living organisms
30Acknowledgements
All patients and their parents ArmaGen, Agoura Hills, CA, USA
Hospital de Clinicas, Porto Alegre, Brazil • William Pardridge
• Roberto Giugliani • Ruben Boado
• Luciana Giugliani
• Larissa Pozzebon da Silva
• Solanger Perrone
• Fabiano Poswar
University of Minnesota, Minneapolis,
MN, USA
• Julie Eisengart
• Igor Nestrasil
• Elsa Shapiro
Adv. Res. Imaging, Durham, NC, USA
• Steven Chen
Neurocog Trials, Durham, NC, USA
• Carmen Sanchez
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