h $ ~ ; Ø8 Ì { ï u Yà 8 øÉ Ü # C * ëÛ h Ø / e 4 æ P e æ / ] R Ë +¨ M H M X M X L Ø X u } Page 4 of 111 I. M H M X7 J I B x v n h4 Ü @ x− x v n h qa gp Ü b N c 4%,

of 111

29 3 31

PMDA

PMDAPMDA

添付資料1

of 111

. .................................................................................... 3

........................................................................................................... 4

................................................................................... 4

. ........................ 6

............................................................................................... 7

........................................................................................................... 8

. .................................. 70

............................................................................................. 71

............................................................................................................. 71

.

......... 108

............................................................... 109

............................................................................... 109

....................... 110

of 111

I.

I

of 111 I.

−

−

3

4

3

3

5

point to consider

−

PMDA NIHS

ICH CMC

3

4

PMDA

of 111 I.

NIHS

PMDA

PMDA NIHS

−

24 26

27 28

of 111 II.

II

of 111 II.

3

1

PMDA NIHS

NIHS

2

PMDA NIHS

PMDA

PMDA

3

PMDA NIHS

of 111 II.

PMDA

NIHS

of 111 II.

27 3 31

PMDA

PMDAPMDA

of 111 II.

24

PMDA

PMDA

1) 1)

of 111 II.

............................................................. 13 ......................................................................................................................... 16 ......................................................................................................................... 16

......................................................................................................... 17 ............................................................................. 20

1. ................................................................................................ 21 2. ............................................................................................ 22 3. ................................................................................................................ 25 4. ............................................................................................................................ 26 5. ............................................................................................................................ 27 6. ............................................................ 28

............................................. 30 1. ............................................................................................................................ 31 2. ............................................................................................................................ 37

......................... 40 ..................................................................................................... 43

..................................................................................... 44 1. .................................................................................................................... 46 2. .................................................................................................... 47 3. ........................................................................................ 48 4. ................................ 52 5. ............................................................................................................ 54 6. ............................................................................................................ 56 7. .................................................................................................... 57 8. ............................................................................................................ 59 9. ........................................................................................ 60 10. .......................................................................................................... 60 11. .................. 61 12. .......................................................................................... 64 13. .............................................................................................. 65

of 111 II.

14. .......................................................................................................................... 66 15. .................................................................................................................. 66

of 111 II.

of 111 II.

......................................................................................................................... 16

......................................................................................................................... 16 ......................................................................................................... 17

............................................................................. 20 1. ................................................................................................ 21

1.1. ............................................................................................................. 21

1.2. ............................................................................................................. 21

2. ............................................................................................ 22 2.1. ..................................................................... 22

2.2. ............................................................................................. 22

2.3. ............................................................. 23

2.4. ................................................. 24

2.5. ......................................................................................... 25

3. ................................................................................................................ 25 4. ............................................................................................................................ 26 5. ............................................................................................................................ 27

5.1. ................................................. 27

5.2. ................................................................. 27

5.3. ............................................................................................................. 27

5.4. ......................................... 28

6. ............................................................ 28 ............................................. 30

1. ............................................................................................................................ 31 1.1. ..................................................................................................................... 31

1.2. ..................................................................................................................... 32

1.3. ......................................................................................................... 34

1.4. ..................................................................................................... 37

2. ............................................................................................................................ 37 2.1. ..................................................................................................................... 37

2.2. ......................................................................................................... 37

2.3. ..................................................................................................... 39

of 111 II.

ICH ICH Q3A R2 Q3B R2 Q6A

DDS

DDS

of 111 II.

DDS

mRNA

RNA

RNA

DNA RNA

of 111 II.

HPLC LC/MS

DDS

drug delivery system

HPLC LC

high performance liquid chromatography

ICH

EU International Conference on Harmonisation of

Technical Requirements for Registration of Pharmaceuticals for Human Use

MS

mass spectroscopy

OO

Base

NPO N

Me

Me

of 111 II.

siRNA

small interfering RNA RNA RNA

of 111 II.

of 111 II.

1.

1.1. RNA

siRNA

1.2.

of 111 II.

2.

2.1.

[1]

[2]

[1] Perspect. Drug Discovery Des., 1996, 4, 17-40.

[2] Org. Process Res. Dev., 2002, 6, 798-806.

2.2.

of 111 II.

2.3.

[3-5] LC-MS

of 111 II.

HPLC

HPLC HPLC

[3] Chromatographia, 2010, 72, 215-223.

[4] J. Chromatogr. A, 2011, 1218, 5609-5617.

[5] Anal. Bioanal. Chem., 2012, 403, 1333-1342.

2.4. ICH Q3A R2

of 111 II.

ICH Q3A R2

2

2.5.

2 RNA

[6]

[6] J. Pharm. Sci., 2000, 89, 443-456.

3.

of 111 II.

ICH Q6B

4.

DDS

pH

[7]

[7] Anal. Chem., 2000, 72, 5092-5096.

of 111 II.

5.

5.1.

ICH Q5E

5.2.

[8]

[8] Anal. Biochem., 2011, 414, 47-57.

5.3.

ICH Q7 Q11

of 111 II.

5.4.

failure sequences

[9, 10]

[9] Rapid Commun. Mass Spectrom., 1993, 7, 195-200.

[10] Anal. Chem., 1996, 68, 941-946.

6.

DDS

ICH Q8 R2 Q9 Q10 Q11

of 111 II.

of 111 II.

1.

1.1.

5.3.

of 111 II.

ICH Q5E

1.2.

of 111 II.

2.3.

ICH Q3A R2 M7 step 4

ICH Q3C R3

ICH Q3D step 3

of 111 II.

1.3.

ICH Q6A

ICH Q2 R1

(1) (2) (3) (4)

(5)

of 111 II.

ICH Q3A R2

of 111 II.

ICH Q3A R2

ICH Q3A R2 M7 step 4

ICH Q3C R3

ICH Q3D step 3

(6)

(7) (8) (9)

of 111 II.

ICH Q6A

(10)

(11)

ICHQ6A Q6B

1.4. ICH Q1

2.

2.1.

2.2.

ICH Q6ADDS

of 111 II.

ICH Q2 R1

(1) (2) (3)

1.3.

(4)

1.3. ICH Q3B R2 ICH Q3D step 3

(5)

1.3.

(6)

(7)

of 111 II.

ICH Q6B

2.3. ICH Q1

of 111 II.

( )

of 111 II.

............................................................................................................... 43

............................................................................................... 44 1. .............................................................................................................................. 46 2. .............................................................................................................. 47

2.1 ............................................................................................................ 47 2.2 ................................ 47 2.3 ........................................................................ 47

3. .................................................................................................. 48 3.1 ............................................................................................................ 48 3.2 / ................................................................................................... 49 3.3 / ....................................................................................................................... 50 3.4 / ............................................................................................... 50 3.5 ........................................................................................................................ 51 3.6 ................................................................................ 51 3.7 ........................................................................................................................ 52

4. .......................................... 52 4.1 ........................................................................ 52 4.2 ................................................................................................ 53

4.2.1 ................................................................................................. 53 4.2.2 ......................................................................................... 54

5. ...................................................................................................................... 54 5.1 ........................................................................................................ 54 5.2 ................................................................................................ 55 5.3 ........................................................................................................ 55

6. ...................................................................................................................... 56 6.1 ........................................................................................................ 56 6.2 .................................................................................... 56 6.3 in vivo ............................................................................................ 57 6.4 ........................................................................................................ 57

7. .............................................................................................................. 57 7.1 ................................................................................................................ 57 7.2 ............................................................................................................ 58 7.3 ................................................................................................ 59

8. ...................................................................................................................... 59 8.1 .................................................................................... 59

9. .................................................................................................. 60 9.1 .................................................................................... 60

10. .................................................................................................................... 60 10.1 ................................................................................... 61

11. ............................ 61

of 111 II.

11.1 RNA .............. 61 11.2 RNA ... 62

11.2.1 in silico ............................................................... 62 11.2.2 in vitro ................................................................ 63

12. .................................................................................................... 64 12.1 ........................................................................... 64 12.2 ............................................................................... 64

13. ........................................................................................................ 65 13.1 ....................................................................................................... 65 13.2 ................................... 65

14. .................................................................................................................................... 66 15. ............................................................................................................................ 66

of 111 II.

RNA

aPTT Activated Partial Thromboplastin Time

DNA Deoxyribonucleic Acid

HED Human Equivalent Dose

ICH EU The International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

mRNA RNA Messenger Ribonucleic Acid

LOAEL Lowest Observed Adverse Effect Level

LOEL Lowest Observed Effect Level

MABEL Minimal Anticipated Biological Effect Level

MFD Maximum Feasible Dose

MTD Maximum Tolerated Dose

NHP Non-human Primate

NOAEL No Observed Adverse Effect Level

NOEL No Observed Effect Level

PD Pharmacodynamics

RNA Ribonucleic Acid

siRNA small interfering RNA

UTR Untranslated Region

of 111 II.

of 111 II.

1.

RNA

3R

of 111 II.

2.

siRNA

2.1

2.2

2.3

of 111 II.

3.

3.1

in vitro in vivo

GLP

GLP

of 111 II.

in vitro

ICH S9

3.2 /

2

2 2

2

1

2

2

of 111 II.

1

2

3.3 / ICH S4

ICH S6(R1)

3.4 /

NOAEL -

of 111 II.

3.5 ICH M3(R2)

siRNA mRNA

mRNA mRNA

3.6

of 111 II.

ICH M3(R2) Q&A

3.7

23

4.

4.1

ICH S6(R1) ICH S7A

of 111 II.

4.2

4.2.1

19

20 21 35S

14C14CO2

ADME

ICH S6(R1) ICH M3(R2) ICH S3B

of 111 II.

4.2.2

/

5.

5.1

NOEL LOEL NOAEL LOAEL

MTD

of 111 II.

ICH M3(R2)

5.2 MTD ICH M3(R2) ICH S6(R1)

5.3 ICH M3(R2)

3

4

/ 3.6 4.2

KYNAMRO®

22

of 111 II.

2

6.

ICH M7

ICH M7

DNA

DNA

6.1

In vivo

DNA

6.2

of 111 II.

DNA DNA

6.3 in vivo

6.4 in vitro

in vivo

7.

7.1

of 111 II.

ICH S5 R2

DNA

DNA

7.2

NHP NHP

of 111 II.

NHP

7.3

ICH S9

8.

8.1 ICH S1A

ICH S1A ICH M3(R2)

DNA

DNA

in vitro

of 111 II.

9.

9.1

ICH M3(R2)

10.

22 4.2.1

ICH

S8

3.7

of 111 II.

10.1

ICH S8

11.

siRNA RNA

11.1 RNA RNA

of 111 II.

11.2 RNA

in silico

in vitro

in silico in vitro

11.2.1 in silico

In silico RNA

,

In silico

siRNA

7 RNA

23 in silico

of 111 II.

11.2.2 in vitro In silico in vitro

in

vitro

In vitro

in silico

in vitro

In vitro

in silico

in vitro

of 111 II.

12.

12.1

12.2

NOAEL

HED

3

MABEL

of 111 II.

13.

ICH M3(R2)

ICH M3(R2)

13.1

13.2 a)

in vitro /

in silico in vitro

b)

ICH M3(R2)

ICH M3(R2)

c)

3.4 ICH M3(R2)

6

of 111 II.

14.

1

2

24

24

25 aPTT

25 26 27

15.

1. ICH M3(R2)22 2 19

0219 4

2. ICH S1A9 4 14 315 ICH S1B

20 11 27 1127001

20 11 27 1127001

3. ICH S2(R1)24 9 20 0920 2

4. ICH S3A8 7 2 443

of 111 II.

5. ICH S4 58 10 88 ICH S4A

11 4 5 655

6. ICH S5A ICH S5B9 4 14 316 ICH S5B(M)

1212 27 1834

7. ICH S6(R1)24 3 23 0323 1

8. ICH S7A 13 6 21902

9. ICH S8 184 18 0418001

10. ICH S922 6 4 0604 1

11. 3 1 29 4

12. 10 6 26 496

13. ( )9 11 1 24

14. 24 4 2 0402 1

15. Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with investigational medical products. EMEA/CHMP/SWP/ 28367/07

16. Sims J. Member of ABPI/BIA Early Stage Clinical Trials Taskforce. Calculation of the Minimum Anticipated Biological Effect Level (MABEL) and 1st dose in human. In: EMEA Workshop on the Guideline for first-in human clinical trials for potential high-risk medicinal products. 12 June 2007 London. Available from:

of 111 II.

http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500010862.pdf

17. Guidance for Industry;Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (CDER/FDA,July 2005)

18. Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther. 281, 810–816 (1997)

19. Yu RZ, Geary RS, Levin AA, Pharmacokinetics and pharmacodynamics of antisense origonucleotides. In Pharmacokinetics and Pharmacodynamics of Biotech Drugs, ed. Meibohm B, WILEY-VCH Verlag GmbH & Co. KGaA, pp 93-120, 2011.

20. Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos. 31, 1419-1428 (2003)

21. Black LE, Degeorge JJ, Cavagnaro JA, Jordan A, Ahn CH. Regulatory considerations for evaluating the pharmacology and toxicology of antisense drugs. Antisense Res Dev. 3, 399-404 (1993)

22. Mipomersen (Kynamro®) FDA

23. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol, 21, 635-637 (2003)

24. Levin AA, and Henry SP, Tocicology of oligonucleotide therapeutics and understanding the relevance of the toxicities. In Preclinical Safety Evaluation of Biopharmaceuticals, ed. Cavagnaro JA, John Wiley & Sons, Inc., pp 537-574, 2008.

of 111 II.

25. Henry SP, Novotny W, Leeds J, Auletta C, Kornbrust DJ. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev. 7, 503-510 (1997)

26. Sheehan JP, Lan HC. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood 92, 1617-1625 (1998)

27. Sheehan JP, Phan TM. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. Biochemistry. 40, 4980-4989 (2001)

of 111 III.

III

of 111 III.

3

ICH

4

PMDA NIHS

5

PMDA

PMDA

of 111 III.

29 3 31

PMDA

PMDAPMDA

of 111 .

PMDA24

24

26

28

PMDA

of 111 .

..................................................... 75 ......................................................................................................................... 77 ......................................................................................................................... 77

......................................................................................................... 78 1. ............................................................................................................................ 80 2. ............................................................................................................................ 86

..................................................... 89 ..................................................................................................... 91

..................................................................................... 92 1. .................................................................................................................... 93 2. .................................................................................................................... 94 3. .................................................................................................................... 94 4. ........................................................................................................ 95 5. ................................................................ 99 6. ............................................................................................................ 99 7. .......................................................................................................... 100 8. .................................................................................................. 101 9. .......................................................................................................... 102 10. .................................................................................... 103 11. ........................................................................................................ 103 12. ............................................................................................................ 103 13. ................ 103 14. ................................................................................................ 104 15. ........................................................................................................................ 104 16. ................................................................................................................ 105

of 111 .

of 111 .

......................................................................................................................... 77

......................................................................................................................... 77 ......................................................................................................... 78

1. ............................................................................................................................ 80 1.1. ..................................................................................................................... 80 1.2. ..................................................................................................................... 81 1.3. ......................................................................................................... 83 1.4. ..................................................................................................... 86

2. ............................................................................................................................ 86 2.1. ..................................................................................................................... 86 2.2. ......................................................................................................... 87 2.3. ..................................................................................................... 88

of 111 .

ICH ICH Q3A R2 Q3B R2 Q6A

DDS

mRNA

of 111 .

RNA

RNA

DNA RNA

of 111 .

HPLC LC/MS

DDS

drug delivery system

HPLC LC

high performance liquid chromatography

ICH

The International Council for Harmonisation of Technical

Requirements for Pharmaceuticals for Human Use

MS

mass spectroscopy

siRNA

small interfering RNA RNA RNA

OO

Base

NPO N

Me

Me

of 111 .

1.

1.1.

of 111 .

ICH Q5E

1.2.

of 111 .

ICH Q3A R2 M7 M7

ICH M7

of 111 .

ICH Q3C R5

ICH Q3D

1.3.

ICH Q6A

ICH Q2 R1

(1)

of 111 .

(2) (3) (4)

(5)

ICH Q3A R2

of 111 .

ICH Q3A R2

ICH Q3A R2 M7

ICH Q3C R5

ICH Q3D

(6)

of 111 .

(7) (8) (9)

ICH Q6A

(10)

(11)

1.4. ICH Q1

2.

2.1.

of 111 .

2.2.

ICH Q6A

ICH Q2 R1

(1) (2) (3)

1.3.

(4)

1.3. ICH Q3B R2 M7 ICH Q3D

(5) 1.3.

(6)

of 111 .

(7)

2.3. ICH Q1

of 111 . .

of 111 .

..................................................................................................... 91

..................................................................................... 92 1. .................................................................................................................... 93 2. .................................................................................................................... 94 3. .................................................................................................................... 94

3.1 .................................................................................................. 94 3.2 ...................................... 94 3.3 .............................................................. 95

4. ........................................................................................................ 95 4.1 .................................................................................................. 95 4.2 / ......................................................................................... 96 4.3 / ............................................................................................................. 97 4.4 / ..................................................................................... 97 4.5 .............................................................................................................. 98 4.6 ...................................................................... 98 4.7 .............................................................................................................. 99

5. ................................................................ 99 5.1 .................................................................................................. 99 5.2 ...................................................................................... 99

5.2.1 ....................................................................................................... 99 5.2.2 ............................................................................... 99

6. ............................................................................................................ 99 6.1 ...................................................................................... 99 6.2 ............................................................................................ 100

7. .......................................................................................................... 100 7.1 .................................................................................... 100 7.2 In vivo ................................................................................ 101

8. .................................................................................................. 101 8.1 .................................................................................................... 101 8.2 ................................................................................................................ 102

9. .......................................................................................................... 102 9.1 ........................................................................................ 102

10. .................................................................................... 103 11. ........................................................................................................ 103 12. ............................................................................................................ 103 13. ................ 103 14. ................................................................................................ 104 15. ........................................................................................................................ 104 16. ................................................................................................................ 105

of 111 .

RNA

aPTT Activated Partial Thromboplastin Time

DNA Deoxyribonucleic Acid

HED Human Equivalent Dose

ICH

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

mRNA RNA Messenger Ribonucleic Acid

LOAEL Lowest Observed Adverse Effect Level

LOEL Lowest Observed Effect Level

MABEL Minimal Anticipated Biological Effect Level

MFD Maximum Feasible Dose

MTD Maximum Tolerated Dose

NHP Non-human Primate

NOAEL No Observed Adverse Effect Level

NOEL No Observed Effect Level

PD Pharmacodynamics

RNA Ribonucleic Acid

siRNA small interfering RNA

UTR Untranslated Region

of 111 .

of 111 .

1.

ICH

ICH S6(R1)

ICH S6(R1)

RNA

3R

of 111 .

2.

DDS

mRNA

3.

3.1

3.2

of 111 .

3.3

4.

4.1

in vitro in vivo

of 111 .

in vitro

ICH S9

4.2 /

2

2

2

2

of 111 .

1

1

1

4.3 /

ICH S6(R1)

4.4 /

NOAEL -

of 111 .

ICH S6(R1)

ICH M3(R2)

4.5 ICH M3(R2)

4.6

of 111 .

4.7 18 ICH S6(R1)

5.

5.1 ICH S6(R1) ICH S7A

5.2 5.2.1

ICH S6(R1) ICH M3(R2) ICH S3B

5.2.2

6.

6.1 MTD ICH M3(R2) ICH S6(R1)

of 111 .

6.2 ICH M3(R2)

4

5

/

2

7.

DNA

19

ICH M7

ICH M7

7.1

ICH S2(R1) ICH M3(R2)

of 111 .

in vitro

In vivo

DNA DNA

7.2 In vivo

8.

8.1

ICH S5 R2

DNA

DNA

of 111 .

8.2

ICH S5(R2)

NHP NHP

NHP

9.

9.1 ICH S1A

DNA DNA

ICH S1A ICH M3(R2)

of 111 .

10.

ICH M3(R2)

11.

ICH S8

12.

ICH S10

ICH S10

13.

in silico in vitro

in vivo

of 111 .

FIH

14.

ICH

M3(R2)

ICH M3(R2)

III

DNA

15.

1

2

20

of 111 .

20

21 aPTT

22 23 24

16.

1. ICH M3(R2)22 2 19

0219 4

2. ICH S1A9 4 14 315 ICH S1B

20 11 27 1127001

20 11 27 1127001

3. ICH S2(R1)24 9 20 0920 2

4. ICH S3A8 7 2 443

5. ICH S4 58 10 88 ICH S4A

11 4 5 655

6. ICH S5A ICH S5B9 4 14 316 ICH S5B(M)

1212 27 1834

7. ICH S6(R1)24 3 23 0323 1

8. ICH S7A 13 6 21902

of 111 .

9. ICH S8 184 18 0418001

10. ICH S922 6 4 0604 1

11. 3 1 29 4

12. 10 6 26 496

13. ( )9 11 1 24

14. 24 4 2 0402 1

15. Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with investigational medical products. EMEA/CHMP/SWP/ 28367/07

16. Sims J. Member of ABPI/BIA Early Stage Clinical Trials Taskforce. Calculation of the Minimum Anticipated Biological Effect Level (MABEL) and 1st dose in human. In: EMEA Workshop on the Guideline for first-in human clinical trials for potential high-risk medicinal products. 12 June 2007 London. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500010862.pdf

17. Guidance for Industry; Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (CDER/FDA,July 2005)

18. Mipomersen (Kynamro®) FDA

19. ®

20. Levin AA, and Henry SP, Toxicology of oligonucleotide therapeutics and understanding the relevance of the toxicities. In Preclinical Safety Evaluation of Biopharmaceuticals, ed. Cavagnaro JA, John Wiley & Sons, Inc., pp 537-574, 2008.

of 111 .

21. Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther. 281, 810–816 (1997)

22. Henry SP, Novotny W, Leeds J, Auletta C, Kornbrust DJ. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev. 7, 503-510 (1997)

23. Sheehan JP, Lan HC. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood 92, 1617-1625 (1998)

24. Sheehan JP, Phan TM. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. Biochemistry. 40, 4980-4989 (2001)

of 111 IV.

IV

of 111 IV.

TK PK

14.

DNA DNA

“ ”

DNA

of 111 IV.

2016 9

eteplirsen

4

FDA 1 2

2016 12 nusinersen FDA

3

LDL

1 LDL

1

4 C-III

5 N-

siRNA 3

6

7

4

of 111 IV.

8

1. Railroading at the FDA, Nat. Med., 22 (2016) 1193–1193.

2. Patient need versus evidence: a balancing act, The Lancet, 388 (2016) 1350.

3. E. Dolgin, Spinal muscular atrophy approval boosts antisense drugs, Nat.

Biotechnol., 35 (2017) 99–100.

4. E.P. van Poelgeest, M.R. Hodges, M. Moerland, Y. Tessier, A.A. Levin, R. Persson,

M.W. Lindholm, K. Dumong Erichsen, H. Ørum, A.F. Cohen, J. Burggraaf,

Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9

(PCSK9): a first-in-human randomized, placebo-controlled trial, Br. J. Clin.

Pharmacol., 80 (2015) 1350–1361.

5. S.T. Crooke, B.F. Baker, T.J. Kwoh, W. Cheng, D.J. Schulz, S. Xia, N. Salgado,

H.-H. Bui, C.E. Hart, S.A. Burel, H.S. Younis, R.S. Geary, S.P. Henry, S. Bhanot,

Integrated Safety Assessment of 2’-O-Methoxyethyl Chimeric Antisense

Oligonucleotides in NonHuman Primates and Healthy Human Volunteers, Mol.

Ther., 24 (2016) 1771–1782.

6. K. Garber, Alnylam terminates revusiran program, stock plunges, Nat. Biotechnol.,

34 (2016) 1213–1214.

7. S.P. Henry, M.V. Templin, N. Gillett, J. Rojko, A.A. Levin, Correlation of toxicity

and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to

inhibit ICAM-1, Toxicol. Pathol., 27 (1999) 95–100.

8. K.S. Frazier, Antisense oligonucleotide therapies: the promise and the challenges

from a toxicologic pathologist’s perspective, Toxicol. Pathol., 43 (2015) 78–89.

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