Where Toxicology Fits in Drug Development — From Discovery to Approval 🔬 — Transcript

Full transcript

1. 0:00Good morning toxsters.
2. 0:02I don't know if that's going to stick,
3. 0:03but we're going to give it a shot.
4. 0:04Anyway, today we are going to talk about
5. 0:06something that I put in module one of my
6. 0:08course on nonclinical Academy and it is
7. 0:10where does toxicology fit in the drug
8. 0:12development pipeline? A lot of people
9. 0:14think that it's a very niche space
10. 0:17within the pipeline. You you know, you
11. 0:20create the molecule and then you
12. 0:21optimize it. You do your your
13. 0:23pharmacology studies, your efficacy
14. 0:25studies. Then you do tox in this one
15. 0:26little space and then you get approved
16. 0:30for uh FIH for clinical trials. You go
17. 0:32to your clinical trials. You market it.
18. 0:33You're off to the races. You're good to
19. 0:34go. Um but it's actually not how it
20. 0:37works in practice and nonclinical and
21. 0:40toxicology specifically is actually
22. 0:42prevalent in most stages of the drug
23. 0:44development pipeline if not every stage
24. 0:47of the pipeline. And so this graphic you
25. 0:49can see is a good representation of
26. 0:51where tox actually hits and what what
27. 0:54points it comes into play. Uh so if you
28. 0:56start here at the top, you can see the
29. 0:58discovery. You know, we we make the
30. 0:59molecules. Um there's a lot of
31. 1:01chemistry. Biologic, there might be um
32. 1:04clones that are being made, cells that
33. 1:06are being made. Um you know, this is the
34. 1:08very beginning touchpoint where we we
35. 1:11may have a drug, we might not have a
36. 1:12drug. We're looking at affinity, we're
37. 1:14looking at binding, we're looking at all
38. 1:15these things and trying to pick one of
39. 1:18them to move forward.
40. 1:20Tox has become increasingly more
41. 1:21prevalent in this phase. Specifically
42. 1:24discovery tox is a a pretty good sort of
43. 1:27area that people specialize in. I have a
44. 1:29colleague that actually is solely works
45. 1:32as a toxicologist in discovery tox.
46. 1:34She's said that told me that it She's
47. 1:36actually never run a tox study because
48. 1:38all of her work is done at this very
49. 1:39early stage. Um so there's a lot that
50. 1:42you can do in this very beginning step
51. 1:45um that has to do with toxicology and
52. 1:47de-risking the molecule. Nowadays, it's
53. 1:50all about how best you can de-risk a
54. 1:52molecule versus how fast you can get to
55. 1:54the clinic.
56. 2:04that we're not going to have a
57. 2:06showstopper later on. Specifically in
58. 2:08tox is a major category. A lot of other
59. 2:10spaces, too. But that's one of the major
60. 2:13uh red flags or and/or green flags.
61. 2:15And then after discovery, we get into
62. 2:17lead up. So we go through all these
63. 2:19molecules and we decide, okay, we found
64. 2:22the one.
65. 2:23We are going to move this one on. We're
66. 2:24going to optimize it. So we're going to
67. 2:26optimize formulation. We're going to
68. 2:27optimize structure. We're going to
69. 2:28optimize PK. We're going to optimize
70. 2:30pretty much everything about it and
71. 2:32develop it so that we can push it
72. 2:33forward. We're going to create bigger
73. 2:34batches of the material, research
74. 2:36batches so that we can put it into
75. 2:38animals. We can run assays. We can do
76. 2:40whatever we need to do. And so at this
77. 2:42stage, between this stage and around the
78. 2:44preclinical space where you start doing
79. 2:46your pharmacology studies, this is where
80. 2:47we start to try to understand off-target
81. 2:49toxicity. So is there um a kinase that
82. 2:54it's hitting? Is there uh any CV risk in
83. 2:57terms of a herd channel or certain
84. 2:59things that it's inhibiting that's going
85. 3:00to cause downstream effects?
86. 3:02Um this is where we do off-target tox.
87. 3:04This can can include, like I said,
88. 3:06kinase panels, safety panels. Um
89. 3:08biologics, we do tissue cross-reactivity
90. 3:10assays. Um are there any other tissues
91. 3:12where this particular target receptor is
92. 3:15present that's going to cause a concern?
93. 3:18We start to do this very early on in
94. 3:20this space
95. 3:21um while we start to do our pharmacology
96. 3:23work. And then as we move through the
97. 3:25pipeline, we start getting into more
98. 3:27We're getting ready for tox. We're
99. 3:28gearing up for non-GLP studies. So we're
100. 3:31going to run some genotox studies, maybe
101. 3:33some acute tox, maybe some PK, some
102. 3:35single dose tox. Try to get a little bit
103. 3:37more understanding. Um
104. 3:39Certain compounds might have a higher
105. 3:41risk for genotoxicity. Some might have
106. 3:43lower risk. Some might have higher risk
107. 3:45for cardiotoxicity. These are all things
108. 3:47that you might assess as early on as
109. 3:49possible within in vitro assays.
110. 3:51Um particularly with all the NAMs on the
111. 3:54alternative animal methods that are here
112. 3:56these days, this is something that um
113. 3:59is becoming more and more prevalent
114. 4:00early on because there are all these
115. 4:01things that we can do again to de-risk
116. 4:04the molecule um
117. 4:06using things that are not animals. Uh we
118. 4:08can do that all all up here.
119. 4:11And then we get into the the big bread
120. 4:12and butter of the nonclinical. Um
121. 4:14this is uh this is sort of where it
122. 4:16might get bumpy. You're starting to do
123. 4:17your repeat dose tox, your GLP tox, your
124. 4:20safety farm. You're starting to put
125. 4:21together a program and a package that
126. 4:23you're going to submit to the FDA or any
127. 4:25other regulatory agency and hopefully
128. 4:27get their approval and sign-off that
129. 4:29yes, you've de-risked it. You've shown
130. 4:31that it's safe enough to go into humans
131. 4:32for the first time.
132. 4:34Um you've shown adequate exposure
133. 4:35margins. You've shown uh that if there
134. 4:38is any toxicity concern that you have a
135. 4:41way to monitor it in the clinic.
136. 4:44You run your GLP studies. You're in
137. 4:46compliance. You have your GMP material.
138. 4:49You are good to go. This is where this
139. 4:51all happens. So this, you know, this is
140. 4:53the meat and potatoes Well, this is the
141. 4:55meat of the meat and potatoes of
142. 4:57toxicology in the drug development
143. 4:59pipeline. But a lot of the early stuff
144. 5:01feeds into this as well. You know, early
145. 5:03on you might do a non-GLP genotox study.
146. 5:06Uh but when we get to this part, the IND
147. 5:07enabling phase, you're going to want to
148. 5:09run your GLP genotox study. And then you
149. 5:11want to complete the whole battery. So
150. 5:12you might have to run most of the
151. 5:14battery at this stage, 2/3 of it
152. 5:16perhaps, and then run your in vivo or
153. 5:18your last your last piece of that
154. 5:19genotox study to support a phase two.
155. 5:22And so there's a lot of things that
156. 5:23might come up and down within this
157. 5:25ladder.
158. 5:26And then once you've gone
159. 5:28through your IND studies um and you've
160. 5:30gotten your IND clearance, you go into
161. 5:32clinical trials. Um
162. 5:34like I said here, you've made it, but
163. 5:35you really haven't. This is the very
164. 5:37first space. You're in healthy
165. 5:38volunteers. And unless you're in a
166. 5:40different indication, for example,
167. 5:41oncology, you go right into patients for
168. 5:43ethical reasons. But between here and
169. 5:45phase two, typically where you start to
170. 5:47run your chronic toxicity studies. So
171. 5:49your six-month rodent or your nine-month
172. 5:51non-rodent studies. This is to support
173. 5:53chronic indications. If you don't have
174. 5:55You're not going into a chronic
175. 5:56indication, not be a need for it. You
176. 5:58can justify it, get a waiver, do a
177. 6:00weight of evidence. Um but typically if
178. 6:02you are doing a chronic indication, this
179. 6:04is where you would run that. And that's
180. 6:05to support phase two and/or phase three.
181. 6:08And but ultimately it's because phase
182. 6:10two and phase three, you're going into
183. 6:12patients and you're going to start to do
184. 6:14um potentially commercialized a regimen
185. 6:17of dosing. So if your indication calls
186. 6:20for six months of dosing of the drug,
187. 6:22you're going to need to do your chronic
188. 6:24tox study to support that so that you
189. 6:26have the animal data prior to initiating
190. 6:28those studies in particular. And that's
191. 6:30why that is usually um done at that
192. 6:32point versus early on
193. 6:34uh because your phase ones are a little
194. 6:35bit shorter. Usually have a SAD or MAD,
195. 6:38which is a single ascending dose or a
196. 6:39multi ascending dose clinical trials. Um
197. 6:42and those are usually shorter term and
198. 6:44so you don't need as long of toxicology
199. 6:47studies to support those.
200. 6:49But for your phase two, phase three in
201. 6:50your patients, that's where you're going
202. 6:52to need that.
203. 6:53And then keep going down this pathway
204. 6:55here. You can see reproductive tox is
205. 6:57right before phase three. Sometimes some
206. 6:59of these studies might be need to be
207. 7:00done prior to phase two depending on
208. 7:02your molecule. But for the most part,
209. 7:04they could be done prior to phase three.
210. 7:05This includes your fertility studies,
211. 7:07your uh embryo fetal development
212. 7:10studies, your PPND, pre- and post-natal
213. 7:13development studies. This all gets done
214. 7:15before here. Um and so there's a lot of
215. 7:18waivers that you can do for this, too.
216. 7:19There's a lot of weight of evidence. But
217. 7:21you might need an entire dart package uh
218. 7:23for your reproduct reprotox to be able
219. 7:26to justify going into phase three. And
220. 7:29an interesting thing is that you can't
221. 7:31do uh reprotox or repro safety
222. 7:33assessment on humans because it's it's
223. 7:35not ethical. And so the data from the
224. 7:38reprotox studies directly gets put on
225. 7:40that label. Uh so the rabbits, the rat
226. 7:43or what have you, whatever species
227. 7:44you're using your reprotox, that data
228. 7:46actually gets put right on the label. So
229. 7:48it's very interesting.
230. 7:50And then going even further down before
231. 7:52your NDA or BLA, you have your
232. 7:54carcinogenicity studies. These are
233. 7:56usually your longer term studies. So six
234. 7:58months two years. Um and the whole
235. 8:00battery approach and weight of evidence
236. 8:01approach for these as well. These are uh
237. 8:04usually at this phase because they take
238. 8:06so long to do and you normally need them
239. 8:08for marketing versus needing them to
240. 8:10support a phase two or phase three
241. 8:12um because it's to understand understand
242. 8:14more long-term effects of your compound
243. 8:16and if it's going to cause cancer. Um so
244. 8:19like I said, these take roughly two
245. 8:20years in life, which means that the
246. 8:22study as a whole could be up to three
247. 8:24years. And so you actually start these a
248. 8:26little bit earlier on to be able to
249. 8:27support this stage right here.
250. 8:30But that's basically the whole pipeline
251. 8:32of nonclinical and toxicology and where
252. 8:35it fits in. And you can see all the
253. 8:36different spaces that it fits. And one
254. 8:39of my later videos, I'll show you um a
255. 8:41nonclinical toxicologist uh the
256. 8:43different functional areas that I deal
257. 8:45with on a daily basis. Uh it's pretty
258. 8:47much all of them. We we touch every
259. 8:48touchpoint in terms of clinical, CMC,
260. 8:51regulatory,
261. 8:53um pharmacology, research, you name it.
262. 8:56Um it's kind of the same way with this
263. 8:57pathway. Every single piece of the drug
264. 9:00drug development pipeline, nonclinical
265. 9:01toxicology touches in one way or
266. 9:03another. So it's present from start all
267. 9:05the way to finish. And so it's critical
268. 9:07to understand what those points are, how
269. 9:09they play into the tox package as a
270. 9:11whole, and how they play into the drug
271. 9:13development or the development of that
272. 9:15drug as a whole as well. If you want
273. 9:17more information, like I said, this is
274. 9:18one module in my course. You can go to
275. 9:20nonclinical.academy to learn more. Uh
276. 9:23there's several tiers. It's very
277. 9:24comprehensive. It's called the complete
278. 9:25guide to nonclinical development. And
279. 9:28it's 60 plus hours of content over 14
280. 9:30modules. There's real-life case studies,
281. 9:33downloadable resources, downloadable
282. 9:35guides. It's all there uh and you
283. 9:37basically get what we just talked about,
284. 9:39but in much more depth. Uh and you get
285. 9:41me right by your side. So check it out
286. 9:43when we're done here and I hope you
287. 9:45enjoyed the video.