Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'

Fundación Ramón Areces
Fundación Ramón Areces Organización sin ánimo de lucro
Biomaterials and biotechnology: 
From the discovery of the first 
angiogenesis inhibitors to the 
development of controlled drug 
delivery systems and the foundation 
of tissue engineering 
Dr. Robert S. Langer 
David H. Koch Institute Professor 
Massachusetts Institute of Technology
“Anti-angiogenesis” 
(Dormant Tumor) 
New Capillaries 
T A F
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
TUMOR 
POLYMER 
1.5mm 
4mm 
1mm
“The agent to be released is a small 
molecule with a molecular weight no larger 
than a few hundred. One would not expect 
that macromolecules e.g. proteins, could be 
released because of their extremely small 
permeation rates through polymers.” 
Adv. Poly. Sci., 1977
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
10 20 30 40 50 60 70 80 90 100 
Days 
% Protein Released 
90 
80 
70 
60 
50 
40 
30 
20 
10 
Lysozyme 
Soybean Trypsin Inhibitor 
Alkaline Phosphatase 
Catalase 
Langer & Folkman, Nature, 1976
80 
60 
40 
20 
0 
Cumulative Percent release 
0 10 20 30 40 50 
Days
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
TUMOR 
POLYMER 
1.5mm 
4mm 
1mm
Rabbit corneal pocket assay 
-CDI 
+CDI 
Langer et al, Science, 1976
Angiogenesis inhibitors approved for clinical use 
Date Approved Drug Disease 
February 2004 Avastin (Bevacizumab) Colorectal Cancer 
November 2004 Tarceva (Erlotinib) Lung Cancer 
December 2004 Macugen Macular Degeneration 
December 2005 Nexavar (Sorafenib) Kidney Cancer 
December 2005 Revlimid Myelodysplastic Syndrome 
January 2006 Sutent (Sunitinib) Gastric (GIST), Kidney Cancer 
June 2006 Lucentis Macular Degeneration 
May 2007 Torisel (CCI-779) Kidney Cancer 
November 2007 Nexavar (Sorafenib) Hepatocellular Carcinoma 
February 2008 Avastin Breast Cancer 
May 2009 Avastin Glioblastoma 
November 2010 Afinitor Giant Cell Astrocytoma 
April 2011 Zactima (Vandetanib) Medullary Thyroid Cancer 
May 2011 Sutent Pancreatic Neuroendocrine Tumors 
November 2011 Eylea (Aflibercept) Macular Degeneration 
January 2012 Axitinib (AG-013736) Kidney Cancer 
July 2012 Afinitor Breast Cancer 
September 2012 Eylea (Aflibercept) Central Retinal Vein Occlusion 
January 2013 Avastin Metastatic Colorectal Cancer 
February 2013 Pomalyst (Pomalidomide) Multiple Myeloma 
April 2014 Cyramza Advanced Stomach Cancer 
August 2014 Avastin (Bevacizumab) Cervical Cancer
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Overview of targeted therapies 
Technology Example Approved 
drugs 
Payload 
Single 
molecules 
Humira 20 1 molecule 
Nanoparticle 
conjugates 
0 103 - 105 
molecules
Coating nanoparticles with 
polyethylene glycol (PEG) 
PEG chains 
Biodegradable core + drugs
1 5 50 500 5000 
Diameter 
(nm) 
Intensity
In vitro phagocytosis of surface-modified 
polymeric particles 
Rat alveolar macrophages - 1hr 
Polymeric 
particles 
without PEG 
PEG 
(20,000 M.W. 
Single chain) 
PEG 
(5000 M.W. 
Single chain) 
PEG 
(5000 M.W. 
Triple chain)
Gref, R., Minamitake, Y., Peracchia, M., Trubetshoy, V. 
Torchillin, V., Langer, R. Biodegradable long-circulating 
polymeric nanospheres, Science, 263: 1600-1603, 1994.
Targeting 
molecule
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Manufacture: Pre-clinical, clinical 
and commercial scale-up 
Scale up for pre-clinical, 
clinical and commercial 
development 
Current manufacturing scales 
Laboratory 1-10 g 
Tox 500 g 
Phase 1 5 kg
Human PK Data and clinical efficacy: (A) PK profile of Bind-014 at different 
doses (B)PK profile of BIND-014 versus DTXL at same dose. (C) PK Data (D) 
MRI of patient after treatment 
0 20 40 60 
100000 
10000 
1000 
100 
10 
1 
Time (hr) 
Total Docetaxel Conc 
in Plasma (ng/mL) 
BIND-014; 30 mg/m2 
Taxotere; 30 mg/m2 
0 5 10 
Before After Before After 
100000 
10000 
1000 
100 
Time (hr) 
Total Docetaxel Conc 
in Plasma (ng/mL) 
3.5 mg/m2 
7 mg/m2 
15 mg/m2 
30 mg/m2
Accurin targeted nanoparticles are engineered 
for optimal targeting by two complementary 
mechanisms 
EPR only 
EPR + binding 
Labeled Accurins administered to a mouse with two PC3 prostate xenograft 
tumors: PSMA- and PSMA+
Accurin targeted nanoparticles increase 
tumor drug targeting and improve efficacy 
Science Translational Medicine, April 2012, 
Hrkach et al 
Clinical Cancer Research, June 2012, Zamboni et al 
Targeted nanoparticles demonstrate significant increase in tumor drug concentrations over 
parent drug (docetaxel) 
Targeted nanoparticles result in tumor regression compared to tumor growth for parent drug 
and non-targeted nanoparticles
Genetic medicine 
 DNA – Turn Genes “on” 
 siRNA – Turn Genes “off”
The gene medicine bottleneck: 
Delivery 
“There are only three problems in 
gene therapy: delivery, delivery, and 
delivery.” 
—Inder Verma, 1999
Previous approaches 
 Lipids (no more than 30 were used) 
 Our approach – chemical libraries using 
novel synthesis approaches – more than 
1,000 used
1000’s of new polymers and lipid-like 
materials developed 
O 
O 
O 
O O 
O O 
O O 
O 
O 
O 
O 
O O 
O 
O 
O 
O 
O 
O 
O 
O 
O O 
O O 
O 
O 
O 
O 
O 
O O 
O O O 
O 
O O 
O 
O 
O 
O 
O 
O 
O O O 
O 
O O 
O O 
O 
O 
O 
O 
O O 
O 
O 
O 
O 
O 
O O 
O O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O O 
O 
O 
O 
O O 
O O O 
O 
A 
B 
C 
D 
E 
F 
J 
K 
L 
M 
O 
P 
Q 
R 
S 
T 
U 
Z 
AA 
O O 
O O 
BB 
O O 
O O 
O O 
F O 
O O 
O 
O 
F 
F 
F 
O O 
O 
O O 
II 
JJ 
KK 
LL 
O 
O O O O O O O 
O 
O O 
O 
O 
F O 
F 
F 
F 
F 
F 
F 
F 
PP 
O NH2 
O 
O 
O 
O NH2 
O NH2 
O NH2 
O NH2 
NH2 
O 
NH2 
O 
O NH2 
O 
NH2 
O 
NH2 
O 
O 
NH2 
O 
NH2 
O 
O 
NH2 
O 
NH2 
O 
NH2 
NH2 
O 
O 
NH2 
O 
O 
O 
NH2 
O 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
HO 
HO NH2 
NH2 
OH 
NH2 
OH 
NH2 
OH 
HO 
NH2 
OH 
HO 
HO NH2 
NH2 
HO NH2 
HO 
HO 
HO 
NH2 
NH2 
OH 
NH2 
HO 
OH 
NH2 
HO 
NH2 
HO 
O 
NH2 
OH 
NH2 
NH2 
HO 
NH2 
NH2 
OH 
HO 
NH2 
HO 
NH2 
HO 
HO 
NH2 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
63 
64 
65 
66 
67 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
NH2 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
N 
H 
H 
N 
N 
H 
H 
N 
N 
H 
H 
60 N 
61 
62 
N 
H 
HN NH 
Si NH2 
O 
O 
Si NH2 
O 
O 
O 
N 
H 
N 
H 
N 
H 
N 
H 
N 
H 
HN 
O 
O 
H 
N 
HN 
O 
N 
H 
NH 
O 
O 
O 
NH 
H 
N 
N 
H 
N 
H 
N N 
H 
S 
NH2 
68 
69 
70 
71 
72 
73 
74 
N NH2 
N 
NH2 
N 
N NH2 
N NH2 
N 
NH2 
NH2 
N NH2 
N 
HO 
NH2 
N 
HO 
NH2 
N 
NH2 
N NH2 
N NH2 
HO 
HO 
N NH2 
N 
NH2 
O 
N 
NH2 
O N NH2 
O N NH2 
87 
88 
89 
90 
91 
92 
93 
94 
NH2 
F 
F 
F 
F 
F 
F 
N NH2 
N 
HN 
N 
NH2 
75 
76 
77 
78 
79 
80 
81 
82 
83 
84 
85 
86
Formulations induce long duration, 
reversible knockdown in mice, rats, guinea 
pigs, and primates 
1.8 
1.6 
1.4 
1.2 
1.0 
0.8 
0.6 
0.4 
0.2 
0.0 
0 10 20 30 40 50 60 70 80 90 100 110 
Time (d) 
Relative FVII Protein 
siCont siFVII
LP-siCont 2.5 LP-siApoB 2.5 LP-siApoB 6.25 
mg/kg mg/kg mg/kg 
1.4 
0.8 
0.0 
Lipoprotein Relative to Pre-Dose
Fully reversible, specific liver 
knockdown 
1.8 
1.6 
1.4 
1.2 
1.0 
0.8 
0.6 
0.4 
0.2 
0.0 
0 10 20 30 40 50 60 70 80 90 100 110 
Time (d) 
Relative FVII Protein 
siCont siFVII 
Dose 1 Dose 2 Dose 3 
No evidence of reduced activity upon repeat administration
Improved lipidoid libraries 
H2N NH2 
O 
+ R 
90 oC 
Created library of 150 new compounds 
R R 
OH HO 
 10 different commercially available epoxide-terminated 
tails 
 Selection of amines from original lipidoid library 
with bias towards good performing amines from 
previous libraries 
 Tested FIRST IN VITRO 
N N 
HO OH 
R R
2-3 orders of magnitude more efficient 
delivery of siRNA in mice APO E independent 
NH 
O 
N 
HN 
N 
N 
NH 
O N 
H 
O 
NH 
O 
O 
NH 
1.2 
1 
0.8 
0.6 
0.4 
0.2 
0 
PBS 1mg/kg 
siLuc 
0.1 
mg/kg 
0.03 
mg/kg 
0.01 
mg/kg 
0.003 
mg/kg 
6 mg/kg 3 mg/kg 1.5 
mg/kg 
C12-200 LNP01 
Relative FVII Expression 
Dose (Entrapped siRNA Content)
Single dose knockdown of TTR in 
Primates at <0.03 mg/kg 
Relative TTR/GAPDH mRNA Level
Ten different siRNAs formulated in one 
nanoparticle inhibit ten different hepatic 
mRNAs 
LNP12-Pool of 10 
1.5 
1.0 
0.5 
Pool of 10 
Luciferase 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
Luciferase 
Pool of 10 
0.0 
PCSK9 
FVII 
ApoB 
TTR 
Xbp1 
SORT1 
TTC39B 
Rab5c 
ITG1 
ApoC3 
Target mRNA 
Mice, 0.1mg/kg of each siRNA, 48h post tail vein injection
Next generation LNPs: Remarkable 
potency improvements with novel 
lipids 
Novel LNPs set new benchmark for systemic RNAi with ~100 fold improved 
potency 
 Efficacy in pre-clinical models following single IV injection 
 Each LNP comprised of distinct cationic lipid component 
 Improvements in potency has resulted in single digit /kg ED50 
Dlin-MC3-DMA-b 
MIT MIT 
DLin-KC2-DMA-b 
FVII siRNA Dose (mg/kg) 
ED50 
DLinDAP 
0.1 1 10 
120 
100 
80 
60 
40 
20 
0 
% Residual Factor VII 
DLinDMA 
98N12-5(I) 
DLin-K-DMA 
DLin-KC2-DMA-a 
0.01 
C12-200 
0.001 
MD1 
0.0001 
1st Generation LNPs 
 ALN-VSP (Phase I Completed) 
 ALN-TTR01 (Phase I) 
2nd Generation LNPs 
 ALN-PCS (CTA Filed) 
 ALN-TTR02 (IND, H2 ’11) 
MIT 
Yizhou, D et al 
PNAS 2014
Optimized 7C1 forms small, consistent, 
stable particles 
siRN 
A 
7C1 
C14PEG2000 
35-55 nm 
100 
nm 
Microfluidics 
1 10 100 1000 
25 
20 
15 
10 
5 
0 
Diameter (nm) 
Percent Volume 
Batch 1 
Batch 2 
Batch 3 
Batch 4 
1 10 100 1000 
25 
20 
15 
10 
5 
0 
Diameter (nm) 
Percent Volume 
0 Days 
14 Days 
40 Days 
Consistent Stable 
Dahlman et al, Nature Nanotechnology
7C1 reduces endothelial mRNA at doses 
100x lower than other technology 
50% Silencing 0.017 mg/kg 
1.5 
1.0 
0.5 
0.0 
0.001 0.010 0.100 1 
siVE-cad Dose (mg/kg) 
VE-cad/GapDH mRNA 
Heart ECs 
Renal ECs 
Lung ECs 
Dahlman et al, Nature Nanotechnology 
0 10 20 30 40 
1.4 
1.2 
1.0 
0.8 
0.6 
0.4 
0.2 
0.0 
Days Following Single 0.6 mg/kg Injection 
ICAM-2/GapDH mRNA 
Silencing >3 weeks
Prototype device 
Silicon Nitride 
or Dioxide 
Cathode 
Silicon 
Active 
Substance Anode
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Reservoir activation 
 SEM of a reservoir – 
electrode system 
before application of 
an electric potential
Reservoir activation 
 SEMs taken after application of 1.04 volts vs. SCE in PBS
Single compound release 
40 
30 
20 
10 
0 
Release Rate 
1 2 3 4 5 6 7 
Time (days) 
Fluorescein (ng/min)
Multiple compound release 
Time (Hours) 
60 
40 
30 
20 
10 
0 
Release Rate 
50 
Fluorescein (ng/min) 
45Ca++ (5xNCi/min) 
10 20 30 40 50 60 70
Clinical trial 
 Chips are communicated with over a special 
frequency called the Medical Implant 
Communications Service Band, approved by both 
the FCC and the FDA. 
 A patient or doctor enters a special computer code 
to administer or change the dose. 
 Bidirectional communications link between the chip 
and receiver enables the upload of status 
information, including confirmation of dose delivery, 
battery life, etc.
Clinical trial 
 8 patients 
 PTH (compliance with injections is 25%) 
 Small office procedure to implant 
 Some pharmacokinetics (less variability) 
and Ca, PINP, CTX measures as daily 
injections
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'
Gates Foundation grants 
Phase I: Feasibility 
 Granted in December 2012, term: 13 months 
 Purpose: to develop a personal fertility control system 
with emphasis for use by women living in Developing 
World countries as a means to effectively plan their 
families 
 Amount: $1,579,750 
Phase II: Detail Design 
 Granted in January 2014, Term: 13 months 
 Purpose: to develop a personal system that enables 
women to regulate their fertility 
 Amount: $4,614,648
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  • 1. Biomaterials and biotechnology: From the discovery of the first angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering Dr. Robert S. Langer David H. Koch Institute Professor Massachusetts Institute of Technology
  • 5. “The agent to be released is a small molecule with a molecular weight no larger than a few hundred. One would not expect that macromolecules e.g. proteins, could be released because of their extremely small permeation rates through polymers.” Adv. Poly. Sci., 1977
  • 7. 10 20 30 40 50 60 70 80 90 100 Days % Protein Released 90 80 70 60 50 40 30 20 10 Lysozyme Soybean Trypsin Inhibitor Alkaline Phosphatase Catalase Langer & Folkman, Nature, 1976
  • 8. 80 60 40 20 0 Cumulative Percent release 0 10 20 30 40 50 Days
  • 13. Rabbit corneal pocket assay -CDI +CDI Langer et al, Science, 1976
  • 14. Angiogenesis inhibitors approved for clinical use Date Approved Drug Disease February 2004 Avastin (Bevacizumab) Colorectal Cancer November 2004 Tarceva (Erlotinib) Lung Cancer December 2004 Macugen Macular Degeneration December 2005 Nexavar (Sorafenib) Kidney Cancer December 2005 Revlimid Myelodysplastic Syndrome January 2006 Sutent (Sunitinib) Gastric (GIST), Kidney Cancer June 2006 Lucentis Macular Degeneration May 2007 Torisel (CCI-779) Kidney Cancer November 2007 Nexavar (Sorafenib) Hepatocellular Carcinoma February 2008 Avastin Breast Cancer May 2009 Avastin Glioblastoma November 2010 Afinitor Giant Cell Astrocytoma April 2011 Zactima (Vandetanib) Medullary Thyroid Cancer May 2011 Sutent Pancreatic Neuroendocrine Tumors November 2011 Eylea (Aflibercept) Macular Degeneration January 2012 Axitinib (AG-013736) Kidney Cancer July 2012 Afinitor Breast Cancer September 2012 Eylea (Aflibercept) Central Retinal Vein Occlusion January 2013 Avastin Metastatic Colorectal Cancer February 2013 Pomalyst (Pomalidomide) Multiple Myeloma April 2014 Cyramza Advanced Stomach Cancer August 2014 Avastin (Bevacizumab) Cervical Cancer
  • 16. Overview of targeted therapies Technology Example Approved drugs Payload Single molecules Humira 20 1 molecule Nanoparticle conjugates 0 103 - 105 molecules
  • 17. Coating nanoparticles with polyethylene glycol (PEG) PEG chains Biodegradable core + drugs
  • 18. 1 5 50 500 5000 Diameter (nm) Intensity
  • 19. In vitro phagocytosis of surface-modified polymeric particles Rat alveolar macrophages - 1hr Polymeric particles without PEG PEG (20,000 M.W. Single chain) PEG (5000 M.W. Single chain) PEG (5000 M.W. Triple chain)
  • 20. Gref, R., Minamitake, Y., Peracchia, M., Trubetshoy, V. Torchillin, V., Langer, R. Biodegradable long-circulating polymeric nanospheres, Science, 263: 1600-1603, 1994.
  • 23. Manufacture: Pre-clinical, clinical and commercial scale-up Scale up for pre-clinical, clinical and commercial development Current manufacturing scales Laboratory 1-10 g Tox 500 g Phase 1 5 kg
  • 24. Human PK Data and clinical efficacy: (A) PK profile of Bind-014 at different doses (B)PK profile of BIND-014 versus DTXL at same dose. (C) PK Data (D) MRI of patient after treatment 0 20 40 60 100000 10000 1000 100 10 1 Time (hr) Total Docetaxel Conc in Plasma (ng/mL) BIND-014; 30 mg/m2 Taxotere; 30 mg/m2 0 5 10 Before After Before After 100000 10000 1000 100 Time (hr) Total Docetaxel Conc in Plasma (ng/mL) 3.5 mg/m2 7 mg/m2 15 mg/m2 30 mg/m2
  • 25. Accurin targeted nanoparticles are engineered for optimal targeting by two complementary mechanisms EPR only EPR + binding Labeled Accurins administered to a mouse with two PC3 prostate xenograft tumors: PSMA- and PSMA+
  • 26. Accurin targeted nanoparticles increase tumor drug targeting and improve efficacy Science Translational Medicine, April 2012, Hrkach et al Clinical Cancer Research, June 2012, Zamboni et al Targeted nanoparticles demonstrate significant increase in tumor drug concentrations over parent drug (docetaxel) Targeted nanoparticles result in tumor regression compared to tumor growth for parent drug and non-targeted nanoparticles
  • 27. Genetic medicine  DNA – Turn Genes “on”  siRNA – Turn Genes “off”
  • 28. The gene medicine bottleneck: Delivery “There are only three problems in gene therapy: delivery, delivery, and delivery.” —Inder Verma, 1999
  • 29. Previous approaches  Lipids (no more than 30 were used)  Our approach – chemical libraries using novel synthesis approaches – more than 1,000 used
  • 30. 1000’s of new polymers and lipid-like materials developed O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O A B C D E F J K L M O P Q R S T U Z AA O O O O BB O O O O O O F O O O O O F F F O O O O O II JJ KK LL O O O O O O O O O O O O O F O F F F F F F F PP O NH2 O O O O NH2 O NH2 O NH2 O NH2 NH2 O NH2 O O NH2 O NH2 O NH2 O O NH2 O NH2 O O NH2 O NH2 O NH2 NH2 O O NH2 O O O NH2 O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 HO HO NH2 NH2 OH NH2 OH NH2 OH HO NH2 OH HO HO NH2 NH2 HO NH2 HO HO HO NH2 NH2 OH NH2 HO OH NH2 HO NH2 HO O NH2 OH NH2 NH2 HO NH2 NH2 OH HO NH2 HO NH2 HO HO NH2 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 63 64 65 66 67 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 N H H N N H H N N H H 60 N 61 62 N H HN NH Si NH2 O O Si NH2 O O O N H N H N H N H N H HN O O H N HN O N H NH O O O NH H N N H N H N N H S NH2 68 69 70 71 72 73 74 N NH2 N NH2 N N NH2 N NH2 N NH2 NH2 N NH2 N HO NH2 N HO NH2 N NH2 N NH2 N NH2 HO HO N NH2 N NH2 O N NH2 O N NH2 O N NH2 87 88 89 90 91 92 93 94 NH2 F F F F F F N NH2 N HN N NH2 75 76 77 78 79 80 81 82 83 84 85 86
  • 31. Formulations induce long duration, reversible knockdown in mice, rats, guinea pigs, and primates 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 70 80 90 100 110 Time (d) Relative FVII Protein siCont siFVII
  • 32. LP-siCont 2.5 LP-siApoB 2.5 LP-siApoB 6.25 mg/kg mg/kg mg/kg 1.4 0.8 0.0 Lipoprotein Relative to Pre-Dose
  • 33. Fully reversible, specific liver knockdown 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 70 80 90 100 110 Time (d) Relative FVII Protein siCont siFVII Dose 1 Dose 2 Dose 3 No evidence of reduced activity upon repeat administration
  • 34. Improved lipidoid libraries H2N NH2 O + R 90 oC Created library of 150 new compounds R R OH HO  10 different commercially available epoxide-terminated tails  Selection of amines from original lipidoid library with bias towards good performing amines from previous libraries  Tested FIRST IN VITRO N N HO OH R R
  • 35. 2-3 orders of magnitude more efficient delivery of siRNA in mice APO E independent NH O N HN N N NH O N H O NH O O NH 1.2 1 0.8 0.6 0.4 0.2 0 PBS 1mg/kg siLuc 0.1 mg/kg 0.03 mg/kg 0.01 mg/kg 0.003 mg/kg 6 mg/kg 3 mg/kg 1.5 mg/kg C12-200 LNP01 Relative FVII Expression Dose (Entrapped siRNA Content)
  • 36. Single dose knockdown of TTR in Primates at <0.03 mg/kg Relative TTR/GAPDH mRNA Level
  • 37. Ten different siRNAs formulated in one nanoparticle inhibit ten different hepatic mRNAs LNP12-Pool of 10 1.5 1.0 0.5 Pool of 10 Luciferase Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 Luciferase Pool of 10 0.0 PCSK9 FVII ApoB TTR Xbp1 SORT1 TTC39B Rab5c ITG1 ApoC3 Target mRNA Mice, 0.1mg/kg of each siRNA, 48h post tail vein injection
  • 38. Next generation LNPs: Remarkable potency improvements with novel lipids Novel LNPs set new benchmark for systemic RNAi with ~100 fold improved potency  Efficacy in pre-clinical models following single IV injection  Each LNP comprised of distinct cationic lipid component  Improvements in potency has resulted in single digit /kg ED50 Dlin-MC3-DMA-b MIT MIT DLin-KC2-DMA-b FVII siRNA Dose (mg/kg) ED50 DLinDAP 0.1 1 10 120 100 80 60 40 20 0 % Residual Factor VII DLinDMA 98N12-5(I) DLin-K-DMA DLin-KC2-DMA-a 0.01 C12-200 0.001 MD1 0.0001 1st Generation LNPs  ALN-VSP (Phase I Completed)  ALN-TTR01 (Phase I) 2nd Generation LNPs  ALN-PCS (CTA Filed)  ALN-TTR02 (IND, H2 ’11) MIT Yizhou, D et al PNAS 2014
  • 39. Optimized 7C1 forms small, consistent, stable particles siRN A 7C1 C14PEG2000 35-55 nm 100 nm Microfluidics 1 10 100 1000 25 20 15 10 5 0 Diameter (nm) Percent Volume Batch 1 Batch 2 Batch 3 Batch 4 1 10 100 1000 25 20 15 10 5 0 Diameter (nm) Percent Volume 0 Days 14 Days 40 Days Consistent Stable Dahlman et al, Nature Nanotechnology
  • 40. 7C1 reduces endothelial mRNA at doses 100x lower than other technology 50% Silencing 0.017 mg/kg 1.5 1.0 0.5 0.0 0.001 0.010 0.100 1 siVE-cad Dose (mg/kg) VE-cad/GapDH mRNA Heart ECs Renal ECs Lung ECs Dahlman et al, Nature Nanotechnology 0 10 20 30 40 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Days Following Single 0.6 mg/kg Injection ICAM-2/GapDH mRNA Silencing >3 weeks
  • 41. Prototype device Silicon Nitride or Dioxide Cathode Silicon Active Substance Anode
  • 43. Reservoir activation  SEM of a reservoir – electrode system before application of an electric potential
  • 44. Reservoir activation  SEMs taken after application of 1.04 volts vs. SCE in PBS
  • 45. Single compound release 40 30 20 10 0 Release Rate 1 2 3 4 5 6 7 Time (days) Fluorescein (ng/min)
  • 46. Multiple compound release Time (Hours) 60 40 30 20 10 0 Release Rate 50 Fluorescein (ng/min) 45Ca++ (5xNCi/min) 10 20 30 40 50 60 70
  • 47. Clinical trial  Chips are communicated with over a special frequency called the Medical Implant Communications Service Band, approved by both the FCC and the FDA.  A patient or doctor enters a special computer code to administer or change the dose.  Bidirectional communications link between the chip and receiver enables the upload of status information, including confirmation of dose delivery, battery life, etc.
  • 48. Clinical trial  8 patients  PTH (compliance with injections is 25%)  Small office procedure to implant  Some pharmacokinetics (less variability) and Ca, PINP, CTX measures as daily injections
  • 51. Gates Foundation grants Phase I: Feasibility  Granted in December 2012, term: 13 months  Purpose: to develop a personal fertility control system with emphasis for use by women living in Developing World countries as a means to effectively plan their families  Amount: $1,579,750 Phase II: Detail Design  Granted in January 2014, Term: 13 months  Purpose: to develop a personal system that enables women to regulate their fertility  Amount: $4,614,648