The study info is still useful, but I just got some more details about IDH305. It was confirmed that Novartis dropped development of it and all trials are suspended. Dosing levels were found to need to be fairly high and that side effects were an issue, in particular liver function. They had 1 patient that had near fatal liver complications that resolved once the drug was stopped which prompted a major FDA review and resulted in Novartis pulling the plug.
Thanks for the additional information. I noticed there is still one trial registered at clinicaltrials.gov for IDH305 that doesn't say "suspended", but the status is "not yet open", anticipated study start date is April 2018, and this listing was updated in September of this year. But who knows whether it will open then or not, given the situation.
If you look at the trial history it shows that it had been listed as 'recruiting'. Also Novartis pulled IDH305 off their website. The PI I got this info from is more tied with Agios, but also was involved with novartis and said that even the active patients were not going to receive the drug even under compasionate care. So sounded like they have pretty solidly 'pulled the plug'.
That's odd. I've never seen a trial go from "recruiting" to "not yet recruiting" before. Going from "recruiting" to "suspended" would have been more honest, if that's the case.
Scratch that, I clicked on the wrong section. IDH305 is still showing on the Novartis website.
In general it sounded like a big part of the decision was financial (the FDA review changed timelines/oversight/costs) so maybe if other IDH inhibitors show benefit then Novartis might get back into it?
Another interesting nugget that I just found out from getting a 2-hg MRS research scan is that the PI's have been see a number of grade 2 and 3 patients that have very stable levels of 2-hg for years and then at recurrence they see small MRI flair changes but sudden tumor wide increases in 2-hg levels. In not a subclonal expansion pattern. Their hypothesis is that a tumor wide environment change occurs that re-initiates cancerous growth.
The nature study also commented on this indirectly in regards to tumor microenvironment being critical and seeing almost opposite effects in vitro vs vivo.
That is interesting, and perhaps those patients would be the ones that would respond to a mutant IDH1 inhibitor. On the other hand, clearly some tumors evolve beyond the point of being driven by mutant IDH1/2-HG, for example those secondary GBMs that lose the mutant allele of IDH1, and still manage to proliferate just like any grade 4 glioma does.
IDH-mutant gliomas tend to become more like IDH-non mutant glioblastomas as they evolve, for example they often undergo deletion of CDKN2A/B during malignant progression, which is a classic copy number alteration found in IDH1 non-mutant glioblastoma. Loss of the mutant copy of IDH1 could be viewed as another step in this progression, and this could only happen when the tumor has acquired enough new driver mutations or other alterations that they no longer depend on mutant IDH1 or 2-HG as drivers.
In my view it seems like IDH1-mutant tumors reach a point of no return, late in their evolution, where mutant IDH1 is no longer important, and in these cases applying a mutant IDH1 inhibitor would be of little use.
I have no doubt that mutant IDH1 inhibitors are useful in some cases, but highly doubtful they'd be useful across the board in all cases of IDH1-mutant glioma.
Sorry I didn't explain that very well. I definitely agree with you about malignant progression and so did the PI and she also strongly felt that the role for IDH inhibitors is much more likely to be to treat grade 2/3 and hopefully to slow or stop malignant progression.
What I was trying to say is that what they have seen in many cases of grade 2 or 3 where the patient was being followed and getting MRI and 2-hg scans every 3-4 months, that when the patient has a recurrence that 2-hg is elevated across the tumor -- including when there has been malignant transformation and including when the MRI has only a focal region of contrast enhancement.
So it seems to indicate that instead of the idea that CT/RT kills most of the active cells but that a subcolony is created that grows from 1 or a few more mutated cells, that possibly most of the tumor cells stay stable for a period of time and then something triggers a widespread change and both the primary cells and the subclonal cells are 're-activated'.
It certainly has a bit of a chicken/egg problem though since for instance a subclonal expansion could be what actually provides the 'trigger'. So at this point it is just a really interesting clue, and not necessarily something actionable.
They published a good paper on their MRS 2-HG work and in figure 3 showed some of the data in regard to the 'clue' that growth is happening more tumor wide.
I found this recent (published in April 2018) interesting study on the pharmacodynamics of IDH1 inhibitors. It is a small study (only 8 patients) but it uses the Novartis idh305 drug. If the drug was pulled due to it's unwanted impacts on liver function, then you would think they would not be using it in further studies?
The study info is still useful, but I just got some more details about IDH305. It was confirmed that Novartis dropped development of it and all trials are suspended. Dosing levels were found to need to be fairly high and that side effects were an issue, in particular liver function. They had 1 patient that had near fatal liver complications that resolved once the drug was stopped which prompted a major FDA review and resulted in Novartis pulling the plug.
ReplyDeleteThanks for the additional information. I noticed there is still one trial registered at clinicaltrials.gov for IDH305 that doesn't say "suspended", but the status is "not yet open", anticipated study start date is April 2018, and this listing was updated in September of this year. But who knows whether it will open then or not, given the situation.
Deletehttps://clinicaltrials.gov/ct2/show/NCT02977689
If you look at the trial history it shows that it had been listed as 'recruiting'. Also Novartis pulled IDH305 off their website. The PI I got this info from is more tied with Agios, but also was involved with novartis and said that even the active patients were not going to receive the drug even under compasionate care. So sounded like they have pretty solidly 'pulled the plug'.
DeleteThat's odd. I've never seen a trial go from "recruiting" to "not yet recruiting" before. Going from "recruiting" to "suspended" would have been more honest, if that's the case.
DeleteScratch that, I clicked on the wrong section. IDH305 is still showing on the Novartis website.
ReplyDeleteIn general it sounded like a big part of the decision was financial (the FDA review changed timelines/oversight/costs) so maybe if other IDH inhibitors show benefit then Novartis might get back into it?
More on mutant IDH1 inhibitors (in vivo)
ReplyDeletehttps://www.nature.com/articles/s41598-017-14065-w
A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit
Another interesting nugget that I just found out from getting a 2-hg MRS research scan is that the PI's have been see a number of grade 2 and 3 patients that have very stable levels of 2-hg for years and then at recurrence they see small MRI flair changes but sudden tumor wide increases in 2-hg levels. In not a subclonal expansion pattern. Their hypothesis is that a tumor wide environment change occurs that re-initiates cancerous growth.
ReplyDeleteThe nature study also commented on this indirectly in regards to tumor microenvironment being critical and seeing almost opposite effects in vitro vs vivo.
Intriguing!
That is interesting, and perhaps those patients would be the ones that would respond to a mutant IDH1 inhibitor. On the other hand, clearly some tumors evolve beyond the point of being driven by mutant IDH1/2-HG, for example those secondary GBMs that lose the mutant allele of IDH1, and still manage to proliferate just like any grade 4 glioma does.
DeleteIDH-mutant gliomas tend to become more like IDH-non mutant glioblastomas as they evolve, for example they often undergo deletion of CDKN2A/B during malignant progression, which is a classic copy number alteration found in IDH1 non-mutant glioblastoma. Loss of the mutant copy of IDH1 could be viewed as another step in this progression, and this could only happen when the tumor has acquired enough new driver mutations or other alterations that they no longer depend on mutant IDH1 or 2-HG as drivers.
In my view it seems like IDH1-mutant tumors reach a point of no return, late in their evolution, where mutant IDH1 is no longer important, and in these cases applying a mutant IDH1 inhibitor would be of little use.
I have no doubt that mutant IDH1 inhibitors are useful in some cases, but highly doubtful they'd be useful across the board in all cases of IDH1-mutant glioma.
Sorry I didn't explain that very well. I definitely agree with you about malignant progression and so did the PI and she also strongly felt that the role for IDH inhibitors is much more likely to be to treat grade 2/3 and hopefully to slow or stop malignant progression.
DeleteWhat I was trying to say is that what they have seen in many cases of grade 2 or 3 where the patient was being followed and getting MRI and 2-hg scans every 3-4 months, that when the patient has a recurrence that 2-hg is elevated across the tumor -- including when there has been malignant transformation and including when the MRI has only a focal region of contrast enhancement.
So it seems to indicate that instead of the idea that CT/RT kills most of the active cells but that a subcolony is created that grows from 1 or a few more mutated cells, that possibly most of the tumor cells stay stable for a period of time and then something triggers a widespread change and both the primary cells and the subclonal cells are 're-activated'.
It certainly has a bit of a chicken/egg problem though since for instance a subclonal expansion could be what actually provides the 'trigger'. So at this point it is just a really interesting clue, and not necessarily something actionable.
They published a good paper on their MRS 2-HG work and in figure 3 showed some of the data in regard to the 'clue' that growth is happening more tumor wide.
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477829/
I found this recent (published in April 2018) interesting study on the pharmacodynamics of IDH1 inhibitors. It is a small study (only 8 patients) but it uses the Novartis idh305 drug. If the drug was pulled due to it's unwanted impacts on liver function, then you would think they would not be using it in further studies?
ReplyDeletehttps://www.nature.com/articles/s41467-018-03905-6#Sec8
The published study was based on this trial:
Deletehttps://clinicaltrials.gov/ct2/show/NCT02381886
which started in 2015. The data in the study was probably collected before any of the IDH305 trials were suspended.