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...
Transcript of 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...
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Page 1 of 111
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PMDA
PMDAPMDA
添付資料1
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. .................................................................................... 3
........................................................................................................... 4
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. ........................ 6
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........................................................................................................... 8
. .................................. 70
............................................................................................. 71
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.
......... 108
............................................................... 109
............................................................................... 109
....................... 110
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I.
I
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−
−
3
4
3
3
5
point to consider
−
PMDA NIHS
ICH CMC
3
4
PMDA
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NIHS
PMDA
PMDA NIHS
−
24 26
27 28
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II
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3
1
PMDA NIHS
NIHS
2
PMDA NIHS
PMDA
PMDA
3
PMDA NIHS
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PMDA
NIHS
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27 3 31
PMDA
PMDAPMDA
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24
PMDA
PMDA
1) 1)
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............................................................. 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
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14. .......................................................................................................................... 66 15. .................................................................................................................. 66
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......................................................................................................................... 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
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ICH ICH Q3A R2 Q3B R2 Q6A
DDS
DDS
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DDS
mRNA
RNA
RNA
DNA RNA
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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
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siRNA
small interfering RNA RNA RNA
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1.
1.1. RNA
siRNA
1.2.
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Page 22 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.
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2.3.
[3-5] LC-MS
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Page 24 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
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ICH Q3A R2
2
2.5.
2 RNA
[6]
[6] J. Pharm. Sci., 2000, 89, 443-456.
3.
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ICH Q6B
4.
DDS
pH
[7]
[7] Anal. Chem., 2000, 72, 5092-5096.
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5.
5.1.
ICH Q5E
5.2.
[8]
[8] Anal. Biochem., 2011, 414, 47-57.
5.3.
ICH Q7 Q11
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Page 28 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
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1.
1.1.
5.3.
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ICH Q5E
1.2.
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2.3.
ICH Q3A R2 M7 step 4
ICH Q3C R3
ICH Q3D step 3
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1.3.
ICH Q6A
ICH Q2 R1
(1) (2) (3) (4)
(5)
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ICH Q3A R2
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ICH Q3A R2
ICH Q3A R2 M7 step 4
ICH Q3C R3
ICH Q3D step 3
(6)
(7) (8) (9)
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ICH Q6A
(10)
(11)
ICHQ6A Q6B
1.4. ICH Q1
2.
2.1.
2.2.
ICH Q6ADDS
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ICH Q2 R1
(1) (2) (3)
1.3.
(4)
1.3. ICH Q3B R2 ICH Q3D step 3
(5)
1.3.
(6)
(7)
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ICH Q6B
2.3. ICH Q1
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( )
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............................................................................................................... 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
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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
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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
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1.
RNA
3R
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2.
siRNA
2.1
2.2
2.3
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3.
3.1
in vitro in vivo
GLP
GLP
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in vitro
ICH S9
3.2 /
2
2 2
2
1
2
2
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Page 50 of 111 II.
1
2
3.3 / ICH S4
ICH S6(R1)
3.4 /
NOAEL -
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3.5 ICH M3(R2)
siRNA mRNA
mRNA mRNA
3.6
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ICH M3(R2) Q&A
3.7
23
4.
4.1
ICH S6(R1) ICH S7A
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4.2
4.2.1
19
20 21 35S
14C14CO2
ADME
ICH S6(R1) ICH M3(R2) ICH S3B
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4.2.2
/
5.
5.1
NOEL LOEL NOAEL LOAEL
MTD
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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
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2
6.
ICH M7
ICH M7
DNA
DNA
6.1
In vivo
DNA
6.2
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DNA DNA
6.3 in vivo
6.4 in vitro
in vivo
7.
7.1
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ICH S5 R2
DNA
DNA
7.2
NHP NHP
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NHP
7.3
ICH S9
8.
8.1 ICH S1A
ICH S1A ICH M3(R2)
DNA
DNA
in vitro
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9.
9.1
ICH M3(R2)
10.
22 4.2.1
ICH
S8
3.7
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10.1
ICH S8
11.
siRNA RNA
11.1 RNA RNA
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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
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11.2.2 in vitro In silico in vitro
in
vitro
In vitro
in silico
in vitro
In vitro
in silico
in vitro
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12.
12.1
12.2
NOAEL
HED
3
MABEL
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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
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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
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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:
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Page 68 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.
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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)
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III
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Page 71 of 111 III.
3
ICH
4
PMDA NIHS
5
PMDA
PMDA
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29 3 31
PMDA
PMDAPMDA
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PMDA24
24
26
28
PMDA
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..................................................... 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
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......................................................................................................................... 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
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ICH ICH Q3A R2 Q3B R2 Q6A
DDS
mRNA
-
Page 78 of 111 .
RNA
RNA
DNA RNA
-
Page 79 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
-
Page 80 of 111 .
1.
1.1.
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Page 81 of 111 .
ICH Q5E
1.2.
-
Page 82 of 111 .
ICH Q3A R2 M7 M7
ICH M7
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Page 83 of 111 .
ICH Q3C R5
ICH Q3D
1.3.
ICH Q6A
ICH Q2 R1
(1)
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Page 84 of 111 .
(2) (3) (4)
(5)
ICH Q3A R2
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Page 85 of 111 .
ICH Q3A R2
ICH Q3A R2 M7
ICH Q3C R5
ICH Q3D
(6)
-
Page 86 of 111 .
(7) (8) (9)
ICH Q6A
(10)
(11)
1.4. ICH Q1
2.
2.1.
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Page 87 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)
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Page 88 of 111 .
(7)
2.3. ICH Q1
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Page 89 of 111 . .
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Page 90 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
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Page 91 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
-
Page 92 of 111 .
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Page 93 of 111 .
1.
ICH
ICH S6(R1)
ICH S6(R1)
RNA
3R
-
Page 94 of 111 .
2.
DDS
mRNA
3.
3.1
3.2
-
Page 95 of 111 .
3.3
4.
4.1
in vitro in vivo
-
Page 96 of 111 .
in vitro
ICH S9
4.2 /
2
2
2
2
-
Page 97 of 111 .
1
1
1
4.3 /
ICH S6(R1)
4.4 /
NOAEL -
-
Page 98 of 111 .
ICH S6(R1)
ICH M3(R2)
4.5 ICH M3(R2)
4.6
-
Page 99 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)
-
Page 100 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)
-
Page 101 of 111 .
in vitro
In vivo
DNA DNA
7.2 In vivo
8.
8.1
ICH S5 R2
DNA
DNA
-
Page 102 of 111 .
8.2
ICH S5(R2)
NHP NHP
NHP
9.
9.1 ICH S1A
DNA DNA
ICH S1A ICH M3(R2)
-
Page 103 of 111 .
10.
ICH M3(R2)
11.
ICH S8
12.
ICH S10
ICH S10
13.
in silico in vitro
in vivo
-
Page 104 of 111 .
FIH
14.
ICH
M3(R2)
ICH M3(R2)
III
DNA
15.
1
2
20
-
Page 105 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
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Page 106 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.
-
Page 107 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)
-
Page 108 of 111 IV.
IV
-
Page 109 of 111 IV.
TK PK
14.
DNA DNA
“ ”
DNA
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Page 110 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
-
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