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>>You talk about therapeutic dose, MTD like this would be a small molecule drug - i think once it blocks cd47 and creates signal to immune system - dose may not matter much.
I doubt that is the case - we are not talking an all-or-nothing process by any means.
Too low a dose and the "do not eat me" signal will very likely be maintained.
Sort of drug that might not even have an obvious DLT.
Not sure how they will determine dosing in the intratumoral trial.
>>I'm pretty sure there could be one DLT in a given dose and still progress higher if additional pts at that dose did okay (i.e. usually need 2 DLT to call it a MTD)
To get to the vicinity of 18 patients by ASH, I think you would need five or six dose cohorts. So that would be something like 6x3 or 5x3+4. If they were seeing multiple DLTs then things slow up a lot and it is hard to imagine he could confidently project 18 by ASH.
Clearly he misspoke. If it's in lymphoma, then it's not yet in the expansion phase. Later in the broadcast he talked about it being in the initial phase. There is literally not enough time elapsed for it to be in the expansion phase.
From his earlier talk, projecting to have somewhere around 18 subjects at ASH ("a meaningful number") means they must have not yet encountered any instances of DLT given their 3+3 design.
>>TRIL > TTI-621 in expansion phase
I think he might have misspoken there - later they say they are still in the dose escalation phase which makes much more sense.
>TRIL
Pretty neat experiment showing at least the possibility that their drug could also activate T-cells, which would be important for a long-term response.
But it's quite a distance from this experiment to demonstrating the same thing happening in the clinic. So I'd put this in the "increases potential upside" bucket rather than the "this makes it more likely to work" bucket.
Thanks for finding that encouraging article.
Peter
I'd call that loose journalistic language rather than an actual mistake.
This is the offending sentence I was complaining about:
The mistake I had in mind related specifically to the drugs being developed.
There is definitely a link between drug-induced liver injury and daily dose.
See this link - about 80% of DILI occurs with daily doses of 50mg or more, and the real danger comes with lipophilic drugs with doses in excess of 100 mg.
http://www.gwicu.com/Assets/Articles/Drug%20Induced%20Liver%20Injury.pdf
My recollection is that all the drugs first approved but then withdrawn for liver tox had significant daily doses.
Agreed re Botox, although perhaps the article meant no new drugs that weren't already approved for other indications. Not just Botox but also Topamax were already approved drugs that got new indications for migraine.
The mistake I was after related specifically to the CGRP drugs.
Peter
I think you have to distinguish between LFT abnormalities as an idiosyncratic reaction to a drug, and those that might relate to the drug's intended activities. We've not seen class effects here, and so my strong belief is that the hep tox in FGEN's earlier trial was specific to that particular compound. The FDA obviously looked at this closely, and with some 1400 patients in Phase 1/2 trials severe idiosyncratic reactions seem unlikely (although obviously still possible with low incidence). The very high potency of the drug (meaning very low absolute dosages) significantly decreases the possibility of idiosyncratic liver tox.
Now ESRD patients do indeed have low LFTs - that seems to be a reflection of their disease. They often have low LFTs even when they should have high LFTs - e.g., when they have HCV or HBV infections. So if we were to magically cure their renal disease, we would actually expect their LFTs (as a population) to increase. Not saying that's what is actually happening here, but it conceivably might be part of the story, namely that the increased LFTs actually reflect improved metabolism.
At the end of the day, for me the MACE endpoints are always going to be more of a concern than these modest increases in LFTs.
Peter
Quiz:
>>Overview of CGRP migraine programs:
What's the significant error in that article?
>>Couldn't the same blurb be written about a dozen other biotech companies?
But Ariad is far less risky than most - brigatinib is close to 100% for approval and is (narrowly) BIC, albeit a year or so behind alectinib in terms of commercialization. Plus ponatinib should provide a steady and slowly growing source of revenue. (After failure on any 2nd-gen drug, pona should be the only real option).
So putting my risk-averse big pharma hat on, it's a pretty tempting morsel for a sales and marketing oriented pharma looking for product to sell.
>CD47
I discussed that article on SI a week or two back.
Basically suggests that AE's (particularly anemia-related) might be dependent on the level of pre-existing inflammation.
Basically macrophages need both a positive ("eat-me") signal and the absence of a negative ("don't eat-me") signal to become active. Inflammation appears to provide an eat-me signal, so adding CD47 blockade is going to make for busy macrophages. So a patient with say rheumatoid arthritis (where SYK is upregulated) might end up with much more anemia than one without.
Cancer cells are thought to generally have an eat-me signal already.
Peter
Not seen a triptan and seizure link discussed anywhere.
But migraine and epilepsy share some features like being induced by flickering lights, and many of the anti-epileptics (notably Topamax) have also found use in migraine prophylaxis.
I'll amend that to "bad signal." :)
With a microcap, and when the big company has lots of money, I think it is a fairly significant signal.
I recall LGND not participating in an offering by their microcap spin-off - I certainly took that as a very negative sign.
They pretty much have to participate in new offerings given their big holding - not doing so would be a very bad signal.
This paper strongly suggests cardiac SAEs have not been observed with triptans (HR=0.86):
ww.ncbi.nlm.nih.gov/pubmed/25246519
Over the last few decades I've at scanned virtually all migraine-related abstracts. The big worry I've seen discussed with triptans is overuse (very likely leading to more migraines) rather than cardiac issues.
>>Then why did the FDA announcement on the VRBAC cancelation explicitly mention the possibility of a rescheduled meeting
Because the FDA is wants to keep their options open in this situation in case something unexpected comes up.
Difference between a formal FDA announcement and their informal communications with a company. So my take is that it's not 100%, but there is a strong likelihood that no AC meeting will be required. (Can still have other hitches like CMC of course).
Not considering the diabetes indication right now is a short-term negative though.
>>DVAX
My own read of this:
Agreed. But the key here has always been efficacy rather than safety. Compared to the mabs, I always expected better safety but possibly less efficacy. Of course those are related - if dosing of mabs is limited by safety, the TRIL's drug could easily have better efficacy too.
When I get back I'll comment on the recent PNAS paper on inflammation and CD47.
>>TRIL just tipped their hand to some safety
I doubt if they have enough data to know for sure yet. But if they had seen bad anemia they presumably wouldn't have made this change.
I'm currently travelling so will comment more when I return in a few days.
Can't imagine anti-cd47 mabs would have a good enough safety profile (because of induced anemia) to allow use in atherosclerosis.
Not clear to me either how they will avoid these issues.
The CD47 agonist effect combined with blocking SIRPa apparently causes apoptosis, so if anything this approach would be stronger on efficacy but more problematic on safety.
>TRIL
Recent strength probably related to a big round of funding (including big pharma) for a private CD47 company based on mabs that are CD47 agonists - effective market cap probably higher than TRIL even though not yet in clinic. So space as a whole is clearly heating up.
Here some Chinese researchers examine a SIRPa-Fc fusion protein in a model of autoimmune encephalitis (the standard MS preclinical model):
Format: AbstractSend to
J Autoimmun. 2016 May;69:74-85. doi: 10.1016/j.jaut.2016.03.002. Epub 2016 Mar 16.
Blockade of CD47 ameliorates autoimmune inflammation in CNS by suppressing IL-1-triggered infiltration of pathogenic Th17 cells.
Gao Q1, Zhang Y2, Han C2, Hu X3, Zhang H2, Xu X2, Tian J4, Liu Y4, Ding Y4, Liu J2, Wang C3, Guo Z2, Yang Y5, Cao X6.
Author information
1National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China; Department of Cell Biology, Third Military Medical University, Chongqing, 400038, China. Electronic address: qiangguogao@163.com.
2National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
3National Key Laboratory of Medical Molecular Biology & Department of Immunology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
4Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
5First Hospital of Jilin University, Changchun, 130012, China.
6National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China; National Key Laboratory of Medical Molecular Biology & Department of Immunology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China. Electronic address: caoxt@immunol.org.
Abstract
The migration of Th17 cells into central nervous system (CNS) tissue is the key pathogenic step in experimental autoimmune encephalomyelitis (EAE) model. However, the mechanism underlying the pathogenic Th17 cell migration remains elusive. Here we report that blockade of CD47 with CD47-Fc fusion protein is effective in preventing and curing EAE by impairing infiltration of Th17 cells into CNS. However, CD47 deficiency does not directly impair the migration of Th17 cells. Mechanistic studies showed that CD47 deficiency inhibited degradation of inducible nitric oxide synthase (iNOS) in proteasome of macrophages by Src activation and led to the increased nitric oxide (NO) production. Then NO suppressed inflammasome activation-induced IL-1ß production. This lower IL-1ß reduces the expression of IL-1R1 and migration-related chemokine receptors on CD47(-/-) Th17 cells, inhibiting the ability of Th17 cells to infiltrate into the CNS of CD47(-/-) mice and therefore suppressing EAE development. In vivo administration of exogenous IL-1ß indeed promoted the infiltration CD47(-/-) Th17 cells into CNS and antagonized the protective role of CD47 deficiency in EAE pathogenesis. Our results demonstrate a potential preventive and therapeutic application of CD47 blockade in controlling EAE development.
Copyright © 2016 Elsevier Ltd. All rights reserved.
It's worth noting that the CD47 on RBCs apparently changes its conformation some over time as it gets oxidized to some degree, and this potentially changes its binding to these drugs. Just an added complication to the whole picture.
Nanoscale. 2014 Sep 7;6(17):9951-4. doi: 10.1039/c4nr02889a.
Studying the mechanism of CD47-SIRPa interactions on red blood cells by single molecule force spectroscopy.
Pan Y1, Wang F, Liu Y, Jiang J, Yang YG, Wang H.
Author information
Abstract
The interaction forces and binding kinetics between SIRPa and CD47 were investigated by single-molecule force spectroscopy (SMFS) on both fresh and experimentally aged human red blood cells (hRBCs). We found that CD47 experienced a conformation change after oxidation, which influenced the interaction force and the position of the energy barrier between SIRPa and CD47. Our results are significant for understanding the mechanism of phagocytosis of red blood cells at the single molecule level.
Ah yes, I now recall that presentation.
>>Safe levels were established for each fusion protein; tolerability was inversely correlated with Fc effector activity (i.e., mutated IgG4 > IgG4 > IgG1)<<
So why are they now emphasizing this aspect in a PR? Preparation for partnering the safer but less potent candidate? Or because they worry that other competitors might not show efficacy?
I agree that the extension to solid tumors is at least a soft signal of manageable tox.
Peter
There are always going to be challenges to a patent if the drug is successful. But pretty close to zero chance that someone can just copy their drug before the patent expires - this is a complex large molecule.
So all that is likely at issue is whether others might find freedom to operate in the same space. If others desperately want to do so, that would be very good news. Perhaps analogous to the patent fight over PD1 - there BMY and ONO claim that Merck and others are infringing and they are due a royalty.
Digging deeper, looks like TRIL also has a IgG4 candidate (TTI-622) in their pipeline. Their patent refers to both IgG1 and IgG4.
You would expect IGg1 to have greater effector function but also perhaps more potential for toxicity. So maybe the IgG4 is destined for combination therapy.
>>This will be the first human data with a potent IgG1-containing protein targeting CD47
This is the first time I've noticed them highlighting the IgG1 aspect - I assume it is to provide a differentiation from IgG4 as used by Forty Seven.
Sometimes these subtle changes in accent in a PR can be revealing. Of course many times they are just noise or an attempt at a smokescreen.
Peter
>>is the pk of the drug so tricky?
Once it binds to the target it gets rapidly degraded - so called "target mediated drug disposition." That's pretty unusual and likely inherent in this target.
Most proteins that are present at low concentration are that way because they are both made slowly and also degraded slowly. CTGF seems to be different - it seems to be both made and then degraded fairly rapidly.
http://link.springer.com/article/10.1007%2Fs11095-016-1918-0
In practical terms, if someone is making abnormally large amounts on a continuing basis, then you will have to dose that person at higher levels (or more frequently) to get the same free drug levels.
Now maybe the higher doses they now use have taken care of the issue - I just don't know. Or it might be that for some patients you have to individualize the dose.
>>moved extremely slow from initial pilot results too
Yes, agonizingly slowly. If I recall correctly they originally couldn't agree with the FDA on an endpoint so they tried some other indication that looked quicker.
Fibrosis is pretty much always going to have difficult endpoints, and the tricky PK of the drug also has slowed things.
>>mention survival advantage at therapeutic dose
Part of what I suspect is going on here is that the required dose is patient-dependent. Patients with higher circulating CTGF likely need higher (or more frequent doses) to achieve similar blood levels of the drug. So that likely would have muddied the results considerably. Sounds like they just took the advice of their pancreatic expert to go for this resection trial.
But for me, the ca19-9 responses they show in this trial suggest that adding this drug to SOC in all cases might makes sense.
Some of my thoughts on FGEN call here:
http://www.siliconinvestor.com/readmsg.aspx?msgid=30695255
>> Helsinn
Reputable cancer-care company - MGI Pharma (MOGN) originally licensed Aloxi from them.
It was noted by JQ on twitter yesterday that the proposed regimen for this patient excludes Abraxane.
Quoting the clinical trials listing "it is felt that she cannot tolerate more aggressive chemotherapy."
So not too significant for FGEN one way or another.
So a new familial ALS gene was just discovered:
http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3626.html
For me, the key insight here is that the five genes now known to be associated with familial ALS are all fairly disparate. That suggests that ALS is ultimately multiple diseases, although there is a final common pathway producing symptoms that are largely indistinguishable from each other. (Some specific genetic mutations are admittedly associated with faster progression).
My strong feeling is that this paradigm actually applies to a lot of different diseases. From a drug development standpoint, if you intervene at a late enough stage you may not care what the actual driver is. But intervening at a late stage pathway is very likely to be inferior to intervening nearer the root cause of the disease. But intervening at an early stage without being able to identify which patients you should be treating is also going to cause problems - some patients in your trial simply won't respond.
Peter
(This is a copy of a post I made on SI - figured it would be of interest here too)
>>Seems hard to believe.
Key maybe whether this was a true "intent to treat" result or not. Any time you say that people who had a follow-up training did better, you are potentially reporting a confounded result.
Peter
CD47 outside cancer is indeed interesting. Not just heart disease but also maybe some long-last infections like TB and malaria (basically the bug fooling the immune system).
The mabs aren't likely to be useful in atherosclerosis - the AEs just too significant. Some modest chance that TRIL's approach might work though. I did ask about this stuff some time back - they said (not unreasonably) that they keep an eye on it but are focused on cancer.
Here are a couple of abstracts:
Malaria:
http://www.pnas.org/content/112/10/3062.abstract
TB and SIRP:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006414
(can't say I understand the implications of this particular article)
Peter