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I mentioned that Lux appears to be active against IDH1mut AML. TUSP may be also but so far we only have one PR. What I found interesting was a connection between IDH1mutation and the up-regulation of PDGFRalpha (a target of LUX). Here is a new paper discussing this possible connection in AML. It may partially explain why Lux is active agains IDH1mut AML-i.e. via PDGFalpha direct inhibition. Authors suggest possible use of desatinib (a PDGFRalphai) in IDH1mut AML. Lux is also a PDGFRalpha inhibitor.
https://www.nature.com/articles/s41375-022-01751-6
ACUTE MYELOID LEUKEMIA
Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)
Sophie Steinhäuser, Patricia Silva, Lennart Lenk, Thomas Beder, Alina Hartmann, Sonja Hänzelmann, Lars Fransecky, Martin Neumann, Lorenz Bastian, Simone Lipinski, Kathrin Richter, Miriam Bultmann, Emely Hübner, Shuli Xia, Christoph Röllig, Fotini Vogiatzi, Denis Martin Schewe, Veronica Yumiceba, Kristin Schultz, Malte Spielmann & Claudia Dorothea Baldus
Leukemia volume 37, pages134–142 (2023)
Abstract
Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML.
I thought I responded to both. I provided data to support the concept of-sub-saturating synergy-at least it does in my opinion. If you don't accept that, it's fine. I added an argument that we do not have sufficient data to suppot a dose inhibiting effect-yet. I only addressed this because you used it to support your position on the sub-saturating synergy effect.
BTW: I never take our exchanges in a negative way. I believe they help me think through these issues. My hope is that is your experience also.
Brian Druker has a library of AML plasma samples that he uses for in vitro IC50 evaluations of potential drug compounds. Years ago he evaluated the IC50s for Lux (806) in these AML plasma samples. In the trials the plasma level of Lux G1 has plateaued at approximately 1 microM per the recent reported data. If you look at Drukers data, approximately 15% of the AML in a panel of over 200 plasma samples had an IC50 at or over 1 micoM. To my knowledge Druker's library is a general collection of AML patient plasma samples-i.e. it is NOT SKEWED to the hard to treat r/r patients. On the other hand APTO targeting only hard to treat AML patients. My belief is that virtually all of the AML patients treated with G1 AML are in the category represented by the 15%. i.e. 1 microM G1 Lux is not enough. That is what we have seen in the scale up.
One approach is the new G3. If they can get the plasma level up to 4 or 5 microM, we may see some AML CRs. In the one patient that achieved 4-5 microM, we DID see a CR.
But here is why I am hammering on the combinations. Druker also did a assessment of Lux (806) IC50 in combinations with Venetoclax. He used approximately 95-100 AML plasma samples (hard to count them on the graph). ONLY TWO had an IC50 above 0.7 microM. i.e. if APTO had done the dose escalation of G1 in combination with Venetoclax we may have see many CRs.
The good news is that there are similar synergies expected with Tusp + venetoclax. That combination will initiate early next year. I am focused on that.
The 80mg data was generated by Hanmi (Korea). The 120, 160 by APTO. 160 ORR higher than 120 ORR. Are the patient populations the same. Who knows. What about the fine print. PR versus CRi, CRh, CR etc. We just don't have enough data to know yet.
There is not enough data to argue that TUSP is less effective at the higher doses. Is it possible? Yes. I am not too concerned either way. We have active doses.
Regarding the sub-saturationl dose (hypothesis), it is not proven, but makes the most sense. Over the past years I have done literature searches on the individual TK's that Lux and TUSP inhibit. You can find papers that talk about syk, Jak, aurora, met, PDGFalpha, flt and other targets having roles in AML. Hitting multiple pathways or MOA's simultaneously is the premise behind drug combinations. Having multiple targets within one molecule is fortuitous. It is not a big leap to imagine that hitting several of these simultaneously my have synergistic effects.
If you look at the Lux IC50 AML plasma cell dot plots in vitro you can clearly see that the addition of venetoclax lowers the median IC50 of Lux significantly. Without checking, I recall the the median Lux IC50 alone was around 1 microM (for the plasma samples tested). With venetoclax the median Lux IC50 was around 0.6 microM.
Totally agree. My biggest criticism is the lack of urgency. He is so focused on dotting the "i"s and crossing the "t"s for monotherapy that we are facing financial/dilution risks. APTO is finally getting to initial combination studies.
I believe that G1 Lux + venetoclax would have shown significant ORR results at the 750/900mg levels and that would have helped market perception. I agree with movement to G3 as the final formulation, but that doesn't mean we could not have had some combination data.
Many CEOs never waste time trying to get a monotherapy approval. I think he believes it's the fastest path to approval, but that's a risk. Combinations are much more likely to show clear efficacy-IMO.
Thanks for the links. Helps a lot. I want to do some extra reading on the MGMT subgroup. I have seen some other work in the area of DNA damaging agents that focus on MGMT. Need to refresh my memory in this area.
While you are hiking I will be getting a knee replacement, so my posting may slow significantly for a few weeks.
It's a company with one product and no pipeline. Run by a salesman. I don't know if they will be bought out or at what price. For me that's not a good reason to own it. It's boring.
Yes I posted on SPPI boards for over 20 years. I sold out several years ago when I realized that the Amgen boys didn't know what they were doing.
Thanks for the further clarification. I actually popped in here mainly to say hello to Antihama. I've had many productive exchanges with him over the years. Among the best posters on these boards.
I'm a bit curious about the NWBO story especially as it relates to a true unmet need with GBM. The uncertainty about the phase III data coupled with the relatively high market cap are a bit off-putting for me at least at this point.
Antihama, thank you for the quick update. It's good to hear from you. I was astonished to see that NWBO has 1B shares outstanding. That can't be helpful.
Do you believe that NWBO can sort out the psPD and mixed OS data to the satisfaction of the FDA or is there pushback?
1. "80 mg dose works better than 120 mg and 160 mg." Not sure we have enough data to support that. APTO has most complete picture and chose 120mg as the monotherapy starting dose with flexibility to go up or down. What's important to me at this point is the size of the therapeutic window.
2. Agree!
3. You jest! I am not yet convince about TP53mut. I would like to see at least a couple more. I think NRAS and NPM1 responses are pretty well established.
The data is what it is, encouraging, but not yet convincing.
I consider the montherapy data as an appetizer. I want to see combination data.
Two observations from todays PR. First the 40mg response was in Wild Type Flt-3 patient. A triple combination in Wild-Type Flt-3 first line AML would be a major market. So this is very encouraging. It would not compete with the Flt-3mut triplet combinations. Second. APTO believes that Tuspetinib is active in sub-saturating doses because of it multi-kinase profile. This is key to its activity at these low doses and makes TUSP a very good combination partner.
Agree. I still have no idea what they are doing. I think they have a terrible algorithm and they offer no recourse to challenge. I wrote some analysis summaries purely on topic and could not post them. In any event I plan to stay on Ihub and build a community here. In fact I may start paying for message board services so that I have more posting options and control.
Several years ago I was part of a private messaging board where a number of serious posters could have meaningful discussions. That is possible here, but not necessary unless we are invaded by scammers.
Welcome to Ihub.
No. It is interesting that they are getting response at this lower level.
Hello. First I would like to say hi to my old posting friend Antihama. It has been a while.
Question for the board. What is it about NWBO that makes this board so incredibly active? I've been on boards like this in the past, but am amazed by the level of interest in NWBO. I am also amazed that a small biotech has over a billion shares outstanding.
APTO announced the initiation of the APTIVATE trial today. I thought they initiated dosing in December. New response at 40mg is good news. The therapeutic window for Tuspetinib is very large which bodes well for combination studies. My only complaint is the slow pace.
In addition to the progress with avutometinib + defactinib in LGSOC ONCT is moving two KRAS-G12C projects forward: avutometinib + sotorasib and avutometinib + adagrasib in KRAS-(G12C) NSCLC. Preclinical data suggests that we should see synergy with these combinations. I believe that the avuto + soto initial readout should happen at any time and this will be a big deal if the data is encouraging. In the preclinical data VSTM demonstrated that the synergistic effect of avutometinib + a G12C inhibitor was further enhanced with the addition of defactinib. I hope that they advance this G12C program with both the doublet and the triplet approach.
Clinical progress with the LGSOC program and the KRAS-G12C programs justify a much higher market cap than we have now. Any success with pancreatic cancer would be a total game-changer. The LGSOC and KRAS-G12C programs and low market cap provide a low risk opportunity to be in on the big prize which is Pancreatic cancer.
This is a very inactive board, but IKNA is worth keeping an eye on. I currently do not own any but am interested enough to follow it. Right now my biggest interest is in IKNA's new molecule IK-595- the RAF:MEK clamp. They intend to file and IND application in 2H2023. I see very big future potential for IK-595 and want to see how IKNA develops it's early clinical plan.
I am not too familiar with there lead drug so I am neutral regarding it.
I'm well aware of Zilovertamab Vedotin. ONCT spun that out as the only product of Velos bio and then sold the company for $2.5B. They kept the ROR1-monoclonals and the ROR1-CAR-T program. They are just now initiating the CAR-T program in B-cell malignancies. I am very excited about that. Nemtabrutinib + Zilo(V) is worth watching. Need to also consider the side effects with ADCs. Is the Nem +Zilo(V) combination a pivotal for rrMCL?
We will see interim data from the r/rMCL registrational trial in about 2 years.
Back to Lux. Right now I am most interested in them getting G3 to RP2D and getting it into combinations in AML population. I don't see B-cell as the leading indications for early value creators. APTO is pretty focused on AML for the near future.
Not very impressive. I suggest you look at ONCT presentation slides. They have an r/rMCL trial underway with zilovertamab + Ibrutinib. In r/r MCL they have ORR of 89% and CR of 43%. Median PFS not reached yet at 19.5 months follow-up.
Pirtobrutinib may be better than Ibrutinib monotherapy, but I don't think it will out perform Zilo + Ibrutinib combination.
I hold as much ONCT as I do APTO because of the potential of Zilovertamab in these B-cell malignancies. Also look at the combination efficacy for CLL. It's knock-out data. Happy to discuss this on the ONCT board if you are interested.
Yes the growth rate, month over month, quarter over quarter, will be the real tell. Not sure how $45M in 2023 will be perceived for a company with no pipeline. I think they need to identify a new pipeline drug in a hurry.
I am anxiously waiting for ONCT to initiate patient dosing in the CAR-T program. I am expecting some exciting results by mid-year.
I ran into the YMB's new woke algorithm..
Or you could say only one out of 30 met the required sales incentive threshold. Assuming this is a sales target reward rather than an incentive award. Just don't read too much into it. SPPI should report sales in the quarterly.
A grant of this type is used to entice a new hire or retain a current hire. It only signals SPPI is willing or needs to use stock as an incentive for non-executive employee. I don't think you can interpret it as indicative of good or bad sales at this time.
BTW: I am a new victim of Yahoo message board WOKE activism and can no longer post on their boards. You will find me posting on Ihub boards going forward.
The RAMP201 and FRAME data for LGSOC is excellent so far. We should have final data readout in about 18 months (IMO). This data is expected to support an AA filing with the FDA for LGSOC. The current PPS does not reflect the significance of this. In addition, we have near term pending data on RAMP203 for RAS(G12C) NSCLC. Positive results with RAMP203 will further enhance value and help establish Avutometinib as a valid approach to RAS pathway cancers.
As an aside, I have my eyes on Akena's RAF:MEK clamp which may be even better than Avutometinib. The only problem is that Akena's molecule is several years behind Avuto in development.
Ivosidenib and olutasidenib target various isoforms of IDH1 and will compete in a relatively small market. Both cause differentiation syndrome. Ivo causes QT elongation and Olut causes liver toxicity (both manageable). Tusp and Lux are NOT targeting the IDH1/2 enzymes. Never-the-less Tusp seems to be active against at least some IDH2 patients and possibly IDH1 patients. Lux has shown high sensitivity of IDH1mut versus wild-type in vitro. TUSP and LUX are broad multi-kinase inhibitors that individually hit many proven AML targets. They do not directly inhibit IDH 1 or 2, but they may be indifferent to these mutations in efficacy especially in first and second line use. If TUSP is successful for first line use it will not compete with any individual IDH inhibitor but it may dramatically reduce their need.
I think that the ability of TUSP and LUX (eventually) to inhibit AML cells with TP53 loss of function and RAS activation are the most significant breakthroughs. But both drugs do much more than that.
Ivosidenib side effects include differentiation syndrome and QTc elongation.
I think that anyone interested needs to follow-up reading this PR by listening to the webcast presentation. It provides a more granular and encouraging overview than the PR alone does. I felt much more encouraged after hearing the overview and seeing the slides.
For instance the 28% ORR is interim data, not fully matured data. If one includes the 3 unconfirmed PRs the ORR is 38%. That's very good. If approved there will be TWO drugs approved.
I already one a nice chunk. Listened to the webcast. Data looks very impressive. Open to discussing it.
They are focused on AA for monotherapy in Flt3muti failures and or TP53/NPM1/Ras if warranted after expansion studies. That is the fastest path to approvals. That said I am extremely interested in the combination studies. I think that in view of how active TUSP is alone we will see very significant increase in CRs with TUSP + Ven.
APTO need some big clinical hits to ramp up its current valuation. Obviously that won't come from approvals. I think it could come from TUSP + Ven data.
I believe that few people understand where this is going. I am thinking way ahead of where APTO is, but I am also aware of the current situation and what needs to happen.
I don't think of TUSP and LUX as Flt3mut inhibitors. I look at them as multi-TKIs. I look at the potential in the context of the full range of TKI activity as it relates to AML heterogeneity.
The IDH1/IDH2 inhibitors are limited. Yes they generate CRs, but most AML patients have multiple mutations, not just IDH1 or IDH2. They are very susceptible to relapse. I believe that TUSP will be much more effective in first line AML if it proves to be safe with HMA + Ven (which I expect). I expect the range of AML patients that will respond to the triplet to include the IDH2 and possible the IDH1mut patients.
I believe that financial uncertainty is the primary factor holding APTO PPS down. Fear of dilution. Sometime within the next 6 months APTO needs to address this. I see several potential scenarios.
1. A dilution at the current PPS. That would likely be a major hit to current shareholders.
2. A dilution on positive news. Possible.
2. A non-dilutive loan tied to milestones. Several companies have taken this route.
3. Out-licensing of Lux, preferably for inflammation or other non-cancer indications. This may be possible if they get the G3 dosage data needed.
4. Help from Hanmi. Hanmi has helped SPPI and I see no reason why they might not help APTO. Especially since they have a huge vested interest in TUSP being successful.
One of these or combinations of these may be in play.
Some interesting learnings. In vitro IDH1mut cells are more sensitive to Lux than are IDH1wt cells. In vivo, we see that TUSP is active against IDH2mut cells (at least in some combinations). TUSP showed a PR (not a CR) with an IDH1 patient. IDH1mut has been linked to the upregulation of PDGFRalpha. PDGFRalpha is a target kinase of Lux. There are reasons to think that TUSP and LUX together would be very effective against IDH1mut/IDH2mut. Of course there is not enough data to prove this, but there is enough to pay attention to it.
The kinomes inhibited by TUSP and LUX overlap to some degree, but they also each have unique targets. Together they cover an impressive array of valid kinase targets (i.e. targets shown in the literature to be relevant). Also impressive is the fact that both TUSP and LUX have good safety profiles at plasma levels up to 1 microM minimum.
As I said. I don't know why APTO put that 6 month DoR target on the slide. Based on all I have read and heard from them I believe the duration requirement will involve HSCT. I just don't see any scenario where CRs will not go to HSCT long before 6 months if they qualify. Those patients that get a CR and are not qualified for an HSCT are likely extremely sick and or fragile. APTO will request a post HSCT maintenance use of TUSP. In that situation I can see a 6 month DoR.
My hope is that as this monotherapy strategy unfolds we will see some combination data. I think combination data will be the real value driver starting around mid-year and going forward.
TUSP in first and second line is the prize.
Are you asking about Tuspetinib or Luxeptinib? The G3 dosing of Luxeptinib is ongoing.
They saw one dose limiting event at 200mg. Based on Pd and Pk data they decided that 120mg was a good level to pursue with the option to go up to 160mg as warranted. Based on all the data we can see 120mg makes sense. Well within the efficacy range with plenty of safety. One of TUSPs greatest values is it's high tolerability without sacrificing it's efficacy. This is what makes it a potential best-in-class for AML.
Yes dosage is pretty well established. They have a wide therapeutic window with TUSP-40mg up to 160mg. They will initiate patients on monotherapy expansion at 120mg and adjust up or down if warranted. They will use the results of the expansion phase to decide what to propose to the FDA for any AA trial. They will initiate the combination trial dose exploration at 80mg.
My objective for listing them is to recognize that they do not a priori prevent a CR with TUSP. Of course the context and co-mutations probably affect the outcome. "Tusp targets NPM1 mutations only in patients with Flt3 co-mutations." I don't think that is a valid assumption. We don't have any data, just the absence of a Fltwt, Npm1 co-mutation among the current CRs. Future patients with Fltwt, NPM1 may show a CR (we'll see). Whether the monotherapy strategy will settle on previous Flt3i failures, TP53mut, RASmut, or NPM1mut is yet to be determined. That is the main goal of the expansion phase. Regarding DoR. I think APTO should not have posted that six month goal for several reasons. First these AMLr/r patients have an average survival of only a few months. Second they are going into HSCT ASAP if they qualify. I don't believe that any CR patient that qualifies will stay on TUSP for six months prior to HSCT. APTO knows this. That's why they discussed the strategy of treat with TUSP, achieve a CR, expect HSCT, then follow with TUSP for maintenance. This is the strategy they discussed in the Dec 6 webcast and this is the strategy I expect them to propose to the FDA. All of this is fine as part of the AA monotherapy plan, but I still believe the big breakthrough CRs will be seen in combinations and that the real benefits will be first and second line use.
I also expect Lux to re-emerge in a big way in 2023. 1 microM plasma levels may be a bit too low for monotherapy efficacy. I do not believe it is too low for combinations. We already know we can achieve 1 microM levels.