6 Avoidable IND Killers in Nonclinical Development 👀 — Transcript

Full transcript

1. 0:00Good morning everyone. Today we are
2. 0:01talking about IND killers. And so we're
3. 0:03going to go through a couple of the
4. 0:04things that can potentially put an IND
5. 0:07on clinical hold, not get you a
6. 0:09clearance or an IND approval to go FIH
7. 0:11or into clinical trials. And the biggest
8. 0:13takeaway from this is that every one of
9. 0:17these is avoidable. Um and so we'll go
10. 0:21through them here on the right. The
11. 0:22first one that we're going to talk about
12. 0:23is missing TK data. If if you know me,
13. 0:25if you follow my LinkedIn content, if
14. 0:27you've taken my course, um the complete
15. 0:29guide to nonclinical development, uh you
16. 0:31know that TK data, I talk about it all
17. 0:33the time. It's a critical thing. Being
18. 0:35able to correlate toxicity to exposure
19. 0:37is the foundation of having a defensible
20. 0:41regulatory narrative and regulatory
21. 0:42submission that will pass um review at
22. 0:45any regulatory agency, not just the FDA.
23. 0:48tox having to talk data, having TK data
24. 0:50on all of your tox studies, on your
25. 0:52pharmarmacology studies, on your PK
26. 0:54studies is critical to being able to
27. 0:56correlate any toxicity to exposure and
28. 0:58then to correlate any toxicity to
29. 1:00efficacious exposure and then
30. 1:02translating that to the clinic. Another
31. 1:05one is unexplained deaths. So having
32. 1:07deaths that happen without being able to
33. 1:09justify that those deaths didn't weren't
34. 1:11caused by your drug. That is where we
35. 1:13want to be able to understand um these
36. 1:15things. So a lot of times when you have
37. 1:16a death it can be exposure driven high
38. 1:19exposure it can be misdosing uh for
39. 1:21example or vage you can misdose and the
40. 1:23animal can die it could be due to just
41. 1:25the animal species um why an animal died
42. 1:28then there's doubt for the reviewer that
43. 1:31um it could be due to your drug and
44. 1:33that's going to be a big no no. You're
45. 1:35going to have to be able to to
46. 1:37understand that. you're gonna have to
47. 1:39they're going to want you to dig down
48. 1:40deep into that and understand why these
49. 1:43deaths did or were not were or were not
50. 1:45caused by your drug. Another one is
51. 1:48irreversible organ toxicity. This is
52. 1:50especially uh important in chronic
53. 1:52dosing. If we want to chronic dose in
54. 1:54patients, we need to understand if
55. 1:56there's any organ toxicity that can't be
56. 1:58reversed upon dose and sessation. If
57. 2:00organ tox can't be reversed, then that
58. 2:02is usually a big sign that that dose or
59. 2:05that exposure is is too toxic to be able
60. 2:08to go up to humans and and if you don't
61. 2:09have an adequate uh safety factor or
62. 2:12exposure margin to be able to compare
63. 2:14that back to animals, you're going to
64. 2:16have a tough time justifying that your
65. 2:17drug is able to go first in human
66. 2:21species specific findings not relatable
67. 2:23to humans. So, a lot of you might know
68. 2:25that for like the GLP1s that came out,
69. 2:27there was a black box about uh thyroid
70. 2:29cancer, a lot of the findings in the
71. 2:32rodent um studies, carcinogenic studies
72. 2:35and the tox studies showed tumors being
73. 2:38formed. History of thyroid cancer or
74. 2:40issues with their thyroid shouldn't be
75. 2:42taken. The GLP-1s. So, rodent thyroids,
76. 2:45they dysfunction in the human with their
77. 2:47thyroid that might mimic the function
78. 2:49that happens in the rat. Um, and so
79. 2:51there is a potential for thyroid cancer.
80. 2:53But species specific findings like that,
81. 2:56um, that aren't relatable to humans,
82. 2:59they are usually very toxic. They are
83. 3:02usually, uh, something that you
84. 3:05definitely have to clinically monitor.
85. 3:07They're something that the FDA
86. 3:08definitely red flags. This is a very
87. 3:12important one. Your noal drives
88. 3:14everything after it, meaning that it
89. 3:16drives your exposure margins. It drives
90. 3:18your clinical starting. If you have
91. 3:20missing TK data and you can't establish
92. 3:22a no, uh, you're dead in the water right
93. 3:24there. So, a flat dose response. What we
94. 3:27want to see in our tox studies,
95. 3:28especially when we get to GOP, is that
96. 3:30we can see a dose response in toxicity
97. 3:32from the the low dose to the mid dose to
98. 3:34the high dose. And that we can see that
99. 3:36as exposure or CAX increases, the
100. 3:39toxicity increases. And so, we can
101. 3:42narrow down and understand where the
102. 3:44changes are happening and be able to
103. 3:46translate that into the clinic. If you
104. 3:48have a flat, you haven't run your non
105. 3:49GLOP studies adequately enough to uh
106. 3:52have a dose range that is narrowed
107. 3:54enough to provide an accurate noal. And
108. 3:58sometimes the FDA, they really want to
109. 3:59see a no or a dose level that doesn't
110. 4:02have any effects so that they can
111. 4:04understand where that threshold is where
112. 4:06toxicity starts and then where adverse
113. 4:08toxic based on your your uh indication
114. 4:11in your patient population can
115. 4:12definitely be an IMD killer. um oncology
116. 4:15compounds, oncology indications, and
117. 4:18particularly small molecule, your
118. 4:19exposure margins are going to be at
119. 4:21least 10x or higher uh depending on your
120. 4:23patient population. And so if it's too
121. 4:25narrow, then that's going to impact your
122. 4:28clinical dose escalation. That's going
123. 4:30to impact your clinical monitoring plan,
124. 4:31your translation of toxicity to the
125. 4:33clinic, and everything that basically
126. 4:35that comes after it. Sometimes narrower
127. 4:38exposure margins can be justified. Um,
128. 4:41but more often than not, you're going to
129. 4:42want to make sure that you've run your
130. 4:43nonclinical intoxicity, whether it's
131. 4:46your MTD or your dose range finding
132. 4:48study, your DRF, and then making sure
133. 4:50you have the right doses to be able to
134. 4:52have adequate exposure margins within
135. 4:53your GLP to justify uh a sufficient NOAL
136. 4:58and a sufficient exposure that goes with
137. 4:59that NOAL to support clinical
138. 5:01development. And so, like I said, the
139. 5:04takeaway from all of this is that these
140. 5:06are avoidable upfront, right? Missing TK
141. 5:08data. Add TK to every dose and every
142. 5:10study that you that you run. Unexplained
143. 5:13death. Make sure that you do your on
144. 5:15offtarget safety assessments. You do
145. 5:17your safety panels. You understand your
146. 5:19CRO. Vetting your CRO and the technical
147. 5:22capabilities is critical. Irreversible
148. 5:25organ toxicity. Um this is something
149. 5:27that can be mitigated within your study
150. 5:30design. Species specific findings not
151. 5:32related to humans. This takes a lot of
152. 5:33weight of evidence and literature
153. 5:35research. Flat dose response. This all
154. 5:37has to do with dose selection and being
155. 5:38able to make sure that you have
156. 5:39well-designed studies of study or you
157. 5:41designing an IND because all of this
158. 5:43these things fall together and create
159. 5:45this well-rounded puzzle to be able to
160. 5:48support a sufficient uh nonclinical
161. 5:51development package that has sufficient
162. 5:53noses sufficient exposure margin
163. 5:55sufficient TK data uh sufficient
164. 5:57justification for any deaths sufficient
165. 5:59justification for any irreversible organ
166. 6:02toxicity and how you plan to mitigate
167. 6:04that in the clinic. So that's it for
168. 6:05today. Hope uh you guys had a great time
169. 6:08learning about these IND killers. If you
170. 6:10want to go a little bit further into
171. 6:11this, we talk more about it in my
172. 6:13course, the complete guide to
173. 6:14nonclinical development. I tagged it in
174. 6:16the description below. Take a look.
175. 6:18There's a free preview on there so you
176. 6:19can see what's in it. It's 60 plus hours
177. 6:22of content over 14 modules covering the
178. 6:24the whole spectrum of nonclinical
179. 6:25development. Um and we talk a lot about
180. 6:27IND and IND killers.