north, two things (KITE, JUNO, NOVARTIS and PPHM).
Indeed that question to Dr. Wolchok was PS related in general: a treatment + PtdSer-targeting, whereby a treatment can be anything and CAR-T was certainly not at the top of our minds at that time. Actually it might well be we weren't even assuming PtdSer-targeting could play a role in CAR-T at that moment as this surfaced only with Dr. Wolchok's CAR-T+PtdSer test results.
So reminding Wolchok about that question brings PtdSer-Targeting to his mind, then moving into the CAR-T topic (he just presented and named KITE/GILD) IMO brings the context to PtdSer-Targeting+CAR-T a topic on which he and his lab had, I think we may call it that, a break through in pre-clinical CAR-T Solid Cancers.
But, we are not just playing an international chess match here :) Actually I am only interested in my investment. And your reply mentioning JUNO had some reaction behind the screens as I received mail on the subject saying that actually there are indeed JUNO+MSK CAR-T ties. And that is in-line with what you wrote.
So we make advancement here. Let's include JUNO (CELGENE backed) in the picture with KITE/GILD and even Novartis. I'll give the complete detailed mix of facts and reasoning:
1) FACT: MSK+Party X has done a pre-clinical trial with CAR-T + PtdSer-Targeting (Party PPHM) replacing OX40 as immuno modulator.
2) FACT: Dr. Wolchok's Lab at Memorial Sloan Kettering had the lead in that pre-clinical trial.
3) FACT: Dr. Wolchok said last year that research results pointed indeed to the fact that PtdSer-targeting would be a COMBO substance of which immuno-therapy can profit. The question was placed in the context of "response foot-print increase" as the value proposition for traditional IO such as PD-1.
4) FACT: Dr Wolchok said that an experimental clinical trial on humans has been designed and is READY to be run by MSKCC.
5) FACT: Dr. Wolchok has NOT explicitly named the technology (IO vs IO CAR-T), nor the type of cancer, but has explicitly said that the start of that trial 'depends on the company'.
6) Dr. Wolchok has NOT named the company but since there is NO DOUBT that the clinical trial in question does AT LEAST contain PtdSer-Targeting since the complete conversation was in the context of last years question and his more recent CAR-T presentation and hence BOTH are about PtdSer-Targeting as immuno-modulator we may for sure say that PPHM is AT LEAST one company that fits the 'depends on the company'. Till here there is NOTHING we can say about any other company.
7) FACT: We know that no-one can run a clinical trial without the 'GO' of the underlying vendors who have control during the complete trial including their say over the publication of the results. (SPECULATION: possibly the reason why we don't have Yervoy results as they might not fit BMY's shoe - bad = not good for Yervoy, good = may make others jump on PtdSer-targeting, saying nothing may create doubt about PtdSer which could fit any form of acquisition strategy.).
8) FACT: We know PtdSer-Targeting came from PPHM in MSK's CAR-T. We may speculate about KITE, JUNO or NOVARTIS as being that other company. Dr. Wolchok mentioned KITE-Gilead acquisition in his presentation.
9) FACT: PtdSer-Targeting is clearly the potential differentiator in CAR-T for solid cancers that for KITE, JUNO or NOVARTIS will make the difference with OX40. Given the public nature of the presentation (e.g. ASCO) it is IMPOSSIBLE that those 3 main players in CAR-T would NOT be aware of a breakthrough pre-clinical trial of someone with the reputations of Dr. Wolchok.
10) FACT: PPHM has made some, and possibly via Sard Verbinnen much (speculation), publicity about selling R&D (incl. IP & pipelines of PtdSer-targeting). An example are the mentioning in Q/CC, a few PRs and in the ASM material. Bavituximab has been mentioned EXPLICITLY. Here also I refuse to believe that the 3 main CAR-T players would not have been aware or not have been contacted as they represent serious candidates with clear incentives.
11) REASONING: There is no way that ALL 3 (KITE, JUNO and NOVARTIS, where applicable with their big brothers Gillead and Celgene) have not been aware of that and would not have had at least one phone call with PPHM on the subject. FACT: Novartis wants CONTROL of its cocktails in order not to have to share profits (CNBC, CEO statement), Gillead needed a new cornerstone molecule (statement CEO) and is known for excellent D&D and to go 1000% or not go at all, and JUNO is in a more peculiar situation certainly when it comes to pocket depth compared with the two others as Celgene did not acquire JUNO (yet). But ALL 3 have CAR-T on there TOP MENU.
12) FACT: On the scientific side, in order to understand the value of the pre-clinical results that were not on humans and of which one says that human trials often deviate, the following. CAR-T has show to work, in general on non-solid and solid cancers. However a solid cancer CAR-T treatment including the OX40 as immune modulator has shown to undo the benefits. One could say that CAR-T performed as expected but that another element, the toxicity of OX40, while providing immuno modulation also caused the side effects harming the patient more then the CAR-T did good. Hence NO FDA approvals in solid cancers.
13) REASONING: It has been observed that OX40 has the SAME toxicity problems on animals as on humans. That is NOT specific to the PtdSer-Targeting pre-clinical trial findings but was known BEFORE from many trials for CAR-T in solid cancers (currently clinicaltrial.gov has about 1400 clinical trials on C19 alone of which many show the immuno modulator problems in their results. If you google the subject it becomes clear very fast that that toxicity is the main problem in CAR-T solid cancers for everyone).
14) REASONING: Under #13 there is no doubt possible that solving the toxicity by removing immuno-modulators as OX40 (and alikes) from the equation would be a MAJOR BREAKTHROUGH but at the same time there is no doubt that CAR-T would no longer work for solid cancers as immune modulation is needed.
15) FACT: PtdSer-Targeting has been proven safe and not toxic and with no side effects of its own on more then 1000 human patients and that in combination with a wide range of other substances.
16) FACT: Dr. Wolchok proved that on animals PtdSer-Targeting in combination with CAR-T does not have ANY off-target toxicity (the target being the T-Cells). But that does not suffice on its own!
17) FACT: Dr Wolchok proved that on animals PtdSer-Targeting performs the needed role of immuno-modulator to make CAR-T work on solid cancers and this in total absence of other immuno-modulators such as OX40.
18) REASONING: From ALL the above we can conclude that the step that remains to be proven is that the combination of CAR-T with PtdSer in HUMANS has the same effect. For that to be true we need:
- PtdSer-Targeting NOT to have the side effects of its own as does OX40 and alikes. We know that is so for a fact on 1000 humans.
- That PtdSer-Targeting if combined with CAR-T does not create a toxicity that PtdSer-targeting doesn't have when alone or combined with other substances then CAR-T. We know that for sure in animals BUT have no prove of that for humans.
19) REASONING: In absence of prove in humans the complete problem now boils down to one single question: Is there some substance in humans that is not present in the animals used for the pre-clinical test, that can make the combination of CAR-T+PtdSer-targeting toxic? And it negative variant, is there an absence of a substance in humans that the animals had that prevented toxicity. This is actually ONE question with two facets.
20) FACT: For OX40 the above question could be answered by saying that all forms of toxicity seen in animal tests have been observed in humans too (solid cancers). While side effects resulting of this toxicity where partially of different nature (in animals a number of observations are different because animals do not have the communication abilities as do humans and hence everything has to come from scans, blood-work, physical observation, etc). However, as far as I know no NEW forms of toxicity (such as the sudden appearance of new substances in the blood) have been observed letting to believe, and actually more, that the CAR-T+PtdSer on their OWN do not create such toxic substances. AND THAT is 90% of the solution. The remaining 25% is the risk that humans do have a trigger for those to to produce a toxic substance that animals did not/could not produce by lack of that trigger.
21) REASONING; It is IMPOSSIBLE, IMO, for professional BP's to not have come to that same scientific risk assessment. The workings of CAR-T are not at questions, purely the spoiling factor in solid cancers by means of toxicity of OX40 replacement is. And given the facts mentioned about, incl. Bavituximab's safety profile and track record, that risk will probably be MUCH smaller then the 10% (100-90) that I assigned it above. This last reasoning is of MAJOR importance for what comes next if we go to the CORE of the problem at hand.
OVERALL REASONING
The clinical trial on humans involving PtdSer-targeting that makes the most sense, given PPHM steps out and MSK is not busy with chemo and radio in the PtdSer arena, is an IO+PtdSer-Targeting trial. Given the history of Q&A with Dr. Wolchok this boils down to either PD-1/CTLA-4+PtdSer-targeting or CAR-T+PtdSer-targeting. Both area's in which Dr. Wolchok has been looking at PtdSer-targeting.
Dr. Wolchok for sure knows that a Pembrolizumab (=Keytruda)+PtdSer-targeting (=Bavituximab) is a trial in the NCCN series sponsored by PPHM (Johns Hopkins , "Phase II Study of Pembrolizumab and Bavituximab for Progressive Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck".) And Dr. Wolchok may know the Yervoy+Bavituximab results (it was melanoma and Dr. Wolchok in the melanoma world is His Royal Highness Dr. WOLCHOK).
We can EXCLUDE (to be complete) that the clinical trial on humans that Dr. Wolchok was be talking about would have been the one of NCCN mentioned above that hasn't started yet. Under NCCN agreements they run there trials and PPHM is not involved, except by PPHM own statement for biomarking consultancy. So NCCN does not "depends on the company" and it is not an MSKCC ran clinical trial so Wolchok would not be in that loop waiting. The other NCCN PtdSer clinical trials are excluded as already recruiting.
FIRST CONCLUSION: We are talking about a NEW clinical trial on humans with MSKCC/Wolchok involvement that is already designed and depends on the company for WHEN it may start.
SECOND CONCLUSION: We can, given the PtdSer involvement, with certainty say that PPHM is at least one of the companies this depend on and that, at the moment of writing, no GO has been given by a or the companies that need to give it.
So our 1st educated speculation must be: Is the trial on humans for traditional IO or CAR-T, not yet thinking about who the other Biotech company might be.
FIRST SPECULATIVE CONCLUSION: MSKCC is going to run a CAR-T+PtdSer clinical trial on humans of they get the go, because:
1) Dr. Wolchok's findings are BREAKTHROUGH-grade for CAR-T as a viable solid cancer treatment. This is PRESTIGE, something nothing to under-estimate in those scientist mids.
2) CAR-T is a MUCH better treatment then IO in the presented circumstances without toxicity. We are talking CURE possibilities and much less burden on the patients during treatment.
3) CAR-T, if it works for Solid Cancers, would be a short-circuit for all current traditional IO (PD-1, CTLA-4, etc) because of #2 above and extends the % of patients that would go for a treatment compared to pain-management in a palliative scenario.
4) The word "experimental", highlighted all at the top, emphasised, IMO, the pioneering character of this clinical trial on humans compared to IO+PtdSer that has already be done (Yervoy+Bavituximab) and of which another is designed and waiting for starting at NCCN, then CAR-T/PtdSer were we are really in the ROOT Clinical Trial for Car-T+PtdSer-targeting on humans in solid cancers.
5) That is the clinical trial would have been PD-1+PtdSer it would have been done by UTSW where Dr. Brekken came up with the amazing mice results and the dying of old age, proving the lasting immune response. However, the patients would still have to go through the burden of side effects and many treatments compared to CAR-T.
FIRST SPECULATIVE CONCLUSION: The other party in the MSKCC human clinical trial for CAR-T+PtdSer is KITE/GILD because:
1) GILD has the deepest pockets and determination to be #1 in their field once they go for it. They can outbid Novartis and JUNO/Celgene easily and have a strong share price to bargain with too. Even if MSK used JUNO in the pre-clinical test, it will be easily replaced by KITE/GILD certainly know that they have a first FDA approval.
2) Dr. Wolchok did mention GILD/KITE in his presentation but there has been no clear indication (although it is probably the case) that the pre-clinical was JUNO based. Dr. Wolchok, when waiting and depending on the company is to important to not give a reason why the delay and waiting on a breakthrough clinical trial in which he has already put the effort of designing it. SO he will probably be under some non-disclosure and mentioning that GILD acquired KITE doesn't look like any violation of that, probably just his subconciense at work.
3) Although JUNO's drug might have been the one used by MSKCC in the pre-clinical, I think JUNO is kind of out of the game because Novartis has Kymriah approved in the CAR-T field and GILD/KITE has Yescarta approved. Two leaders with deeper pockets and approved CAR-T drugs, IMO, blow a party as JUNO of the table whether JUNO was or was not the manufacturer of the CAR-T because the findings were not about CAR-T but about the eliminations of OX40 toxicity side effects.
4) As per the above 1 to 3, KITE/GILD and NOVARTIS remain as the ONLY two contenders in this CAR-T+PtdSer scenario. But NOVARTIS's CEO has made a statement on CNBC that the IO companies that remain for acquisition are expensive and that they prefer to WAIT. That was BEFORE KITE got CAR-T approved too and BEFORE GILD acquired KITE and BEFORE MSK Dr. Wolchok's pre-clinical results were available. The Gillead CEO also made a statement before all that was known, namely, that they were searching for a new cornerstone molecule. I thing they found that with KITE and that PtdSer for them may just be the cement they need to seal that cornerstone to the ground and make it better then other cornerstones. And GILD is the company that will spare no expenses to get there while Novartis is much more conservative.
FINAL CONCLUSION (partly based on fact partly on educated speculation)
MSKCC is waiting to run an already designed experimental clinical trial on humans for CAR-T+PtdSer-Targeting in a solid cancer (possibly all solid cancers given the 'experimental') and needs a GO (at the time of writing) of PPHM.
PPHM is negotiating final terms with GILD and when finalised GILD/KITE will be the company that will have to give the GO to MSKCC.
Novartis is second runner up and only would have stand a chance if they drop the conservative approaches of acquisition because against GILD they don't stand a chance that way.
JUNO became an outsider by lack of CAR-T approval, only a 10-year agreement will Celgene vs acquisition and by lack of sufficient own pocket depth to compete with the others.
All 3 companies have not meaningfully invested in traditional anti-PD-1, anti-CTLA-4, etc and CAR-T is their chance to short-circuit that with a better solution. This is THEIR chance to win a WAR they didn't even participate in.
AIMO
