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It is what it is. Another option.
Pirtobrutinib was approved for MCL in January. I think this is the reason.
Most of the market and analyst reports are a joke. I ignore them all.
Update: Arbitration decision likely in April.
I think that ONCT has huge potential, but the data is slow in coming. I'm hoping that the ROR1-Car-T data is positive, but that won't come until later in the year.
No one can credibly advise you on timing. This is a micro-cap stock that can and will swing wildly in price.
I cannot understand how the ROR1-drug conjugate could be worth $2.8B, and the ROR1-CAR-T have no value. It should be comparable in value IMO.
I'm more interested in them getting to the next dose of Lux. I really hope they are not slow walking Lux. The FDA meeting on TUS monotherapy is not critical at this moment since we are early in the Aptivate expansion trail. I'm fine if they get it done within the next few months.
Major arbitration decision imminent.
I think it will depend on how strong the expansion data they take to the FDA is. I think anything over 20% ORR would argue against a salvage therapy arm. We just need to wait for the data.
In the case of TUSP monotherapy I am not sure there is an "alternative therapy" to compare with. The patients in the expansion arm have exhausted all currently available therapies and have an average of 3-4 months to live. It will be interesting to see guidance from FDA on this.
That's my point. The design and targets will be negotiated. Sounds like they want to include an interim analysis for fast approval if data warrants. We need to wait until after they meet with the FDA on this. I don't expect an FDA meeting regarding combinations until late this year or early next year.
Getting a first look at the population that responds to Tus/Ven double will be highly informative, especially versus Tus alone. Furthermore the big question right now is how myleo-suppressive is the combination. The design of a registrational double trial will become clear AFTER they meet with the FDA. They need this initial data for that meeting.
I think a ven only arm in this patient population will be judged unethical. It won't happen.
I don't know how many sites are open but I expect the rate of enrollment in the Aptivate trial to be high, especially as they open up sites that can do the Tusp/Ven combination. Expect oncologist to steer their patients towards the chance of getting into the Tusp/ven arm. This is a very big deal.
I will listen to the call again today, but I don't believe Rice was talking about Ven when he mentioned big pharma interest. I think any deal regarding TUSP would be for regional rights or co-marketing. I can't see them giving up the whole of TUSP. Rice is finally talking about combinations.
I hope they are not slow walking Lux.
APTO Quarterly:
Reported a second response with TP53 patient (at 40mg)
Aptivate recruiting progressing rapidly; initiated the Tusp + Ven combo this week.
Activity with RAS mutated patients looks encouraging.
Thinking about Lux in B-cell and inflammation combinations.
Rice teased about big pharma interest in TUSP (stay tuned)
Significant data read-out in last quarter of 2023.
They will need some form of financing within the next six months (my opinion).
Summary: Science looks great, but bumpy road ahead.
Totally agree.
We’ll see. I want an update on lux dosing. It has been over three months since initiation at 50mg. I hope they are not dragging their feet on lux. I also want to know if any combination with tusp has been initiated.
Major event pending within 20 days.
Lux should not be thought of as just a BTK or Flt3 inhibitor.
TUSP should not be thought of as just a Flt3 inhibitor.
Each molecule needs to be assessed in the context of all of its kinase inhibitory targets at the mechanistic level for the target disease and indication.
As you just posted, Lux is being looked at as a SYK inhibitor in context of auto-immune disease.
Lux inhibits PDGFa and CSF1R. Why is that important in AML? There is a rational. When and where does AURA/B inhibition potentially play a role. There is a rational.
I think it would be very smart for APTO of out-license LUX for non-cancer indications once they get the dosing set. That said, I see huge synergy with combinations of LUX and TUSP in AML based on the complementary kinome inhibition profiles. Further LUX is likely to find a space in NHL, perhaps DLBCL, especially in combinations.
You need to get past thinking about the proteins as Flt3 inhibitors or BTK inhibitors. Those functions are subsets of their activities.
No. Flt3i may be "A" driver mutation, but there are likely many others. NPM1c takes the brakes off of the pTEFb transcription elongation factor which is used my many, many transcription factors. I am reading a paper right now where NPM1c contributes to the upregulation of HOX9a and MEIS1 proteins which by the way are driven by MLL-fusions (another AML lesion). NRAS is liked to the upregulation of mcl-1 (which helps the cell overcome venetoclax).
The bigger point is that those alterations that affect epigenetics combined with NPM1c effect on transcription machinery make the AML cells susceptible to a wide range of drivers.
NPM1 is mutated in approximately 35% of AML cells. Unmutated NPM1 shuffles between the nuceolus and the cytoplasm. Mutated NPM1 is predominantly found in the cytoplasm because of the loss of nucleolus localization signal. NPM1 binds a protein call HEXIM1. Mutated NPM1 can sequester most of the HEXIM1 in the cytoplasm.
Hexim1 is a key suppressor of pTEFb and a stabilizer of p53 in the nucleous. Loss of Hexim1 from the nucleous leads to activation of pTEFb (leading to gene transcription) and destabilization of p53 ( a gene expression repressor). i.e. in simplistic terms loss of control over gene transcription and malignancy.
Of course this is a very simplistic summary. You can read relevant articles that give much greater details. Try googling; MPM1 HEXIM1; or HEXIM1 AML, or NPM1 pTEFb.
AML cells with the common DNMT3A and NPM1 mutants are generally pre-AML. Once additional mutations such as Flt3 come into play the AML becomes more aggressive. ie. DNMT3a and NPM1mutations set the stage for the signaling pathways.
I have been trying to understand how mutations in NPM1 contribute to disease progression in AML. I finally found a mechanism that is believed to play a significant role. Anyone interested?
Could also be news on lux dosing or initiation of tusp/ven combination cohort, or some financing strategy.
Correction: in my mention of IKNA and VSTM drugs I call them RAS:RAF clamps. They are actually RAF:MEK clamps. I've been sleep deprived since my surgery.
IKNA saw a nice PPS jump today. Looks like it was in response to IK-595 data presentation at the Plenary Session at AACR Special Conference on RAS Targeting. This is the RAS:RAF clamp that I mentioned previously. At first look IK-595 may be even better than VSTM's RAS:RAF clamp. That said VSTM is about two years ahead of IKNA and their drug VS-6766 (in combination with a FAK inhibitor) is showing very strong (breakthrough rated) data in LGSOC.
That's very interesting. I did a quick check and it appears that in the Ven/Gilt and Ven/Quiz combinations VEN is used in the 400mg+range. If we see efficacy with Ven at 50 or 100mg with TUSP I would expect a significant reduction in myelo-suppression. There must be a reason APTO is testing with this significantly lower Ven dose. Naval Daver is in the thick of all this.
I listened to BDTX presentation. Nice story. May pay a little more attention to it as they generate data. I haven't been too focused on EGFR lately, but I am interested in the RAS program as it compares to some other RAS pathway strategies. I currently have quite a bit of VSTM and am watching IKNA. Both have RAS/RAF clamps in development.
I am hoping they have some meaningful data by mid-year, but I'm not confident of that. Depends on how rapidly they are recruiting into the expansion arms. We have not had any updates on that since they announced trial initiation on Jan 30th.
They have been at dose level, 50mg, for Lux for three months now. I hope that they announce something about that very soon. i.e. did they clear that level; what's the pK/pD data look like, any responses?
I believe you are correct that Ven is the main driver of myelosuppression in the Flt3/Ven combos. That said we don't know if lower doses of Ven may be effective in a TUSP/Ven combo. We don't know the dose titration plans for TUSP/Ven yet.
In any event, Gilteritinib and Quizartinib bring other toxicities such as QTc elongation and DS into the combination picture.
A huge open question is whether we will see myelosuppression when TUSP is combined with Venetoclax. If we don't see it it will be a huge positive development. As I understand it the biggest hurdle doctor's are facing with using Quizartinib or Gilteritinib in combinations with VEN is myelosuppression.
The more I read the scientific literature and the more I understand the muti-faceted aspects of AML the more convinced I become that TKIs with muti-kinase activity are the most valuable approach. Whether LUX or TUSP has the optimal multi-TKI profile or not is certainly open to debate, but many of the targets hit by these agents are involved in AML.
We do not have a lot of data yet but I find it interesting that TUSP seems to be active against NPM1 and MLL-fusion driven AMLs. These two drivers are being targeted by the new Menin inhibitors. The menin inhibitors and TUSP seem to have similar ORRs. The mechanism of the menin inhibitors is understood, not so much for TUSP in these specific populations. So far, TUSP seems to have less side effects.
"My view is that all combo phase 3 trials don't belong here." I did not say that. What I have been saying is that the market needs to see the potential of combinations. I believe that the efficacy of combinations will be far more compelling than the efficacy of TUSP monotherapy. That will drive market value.
The APTIVATE expansion trial is NOT just a monotherapy trial. It will look at both monotherapy AND combinations. The monotherapy and combination cohorts are to run in PARALLEL with first readout of efficacy from BOTH expected around mid-year.
My comments are not about strategy. That is set with the APTIVATE trial. They are about expectations of what will move the PPS. I think that will be positive surprise combinations data. If the monotherapy cohort moves the PPS up fine, but my bet is on combinations.
I do agree that APTO may never take either Lux or Tusp through to full approvals. If the potential of these drugs is as I expect APTO will be acquired, but not within the next two years. IMO
We should get the quarterly update around March 22, 2023. Don't know if they will give any milestone updates before that. The next nine months are going to be touch and go because of the financial concerns. I'm playing the long game.
This quizartinib NDA targets first line "fit" FLT3-ITD positive AML patients. The potential first line Tuspetinib (combination) target population is much larger than this. It may ultimately include both fit and unfit AML patients with and without AML-flt3 mutations. AND it has a much better safety profile. The market will not recognize this until APTO posts clinical results with various combination such as Tusp+Ven and Tusp+Ven+hypometh agents. It will take another year to get enough data for the market to begin to see this potential.
My dream scenario would be if they can combine TUSP and LUX into combinations. I don't look at these as two Flt-3 inhibitors; I see them as two multi-kinase inhibitors with complementary profiles.
You and I disagree on a key point. You seem to see the need for an approval before APTO gets any street credibility for Tuspetinib. I think they need to see the potential of Tuspetinib in combinations.
You may recall that Argule got a $2B buyout on surprise RT data long before any potential approvals were envisioned. I think APTO will eventually see multi-billion valuation-perhaps within the next 2-3 years.
I hope this helps to enlighten you to why I am so fixated on seeing the combination data. I expect the TUSP + Venetoclax efficacy data to be even stronger than this AND I expect a much better safety profile.
Daver himself believes that TUSP is well suited as a combination partner. TUSP has been shown in vitro to be synergistic with other drugs beyond Venetoclax.
APTO needs to get to first line triple therapy with TUSP ASAP. Keep in mind that TUSP also shows significant activity in Flt3-wt.
I did not say develop lux now. I said do not abandon it. I want to see the dose escalation data, which is NOT phase II. I am as acutely aware of the history and the current cash problems as anyone. I have outlined at least twice now possible financing routes to carry the work forward to significant PPS moving data.
I believe that in the TUSP dose expansion monotherapy trial we will be fortunate to see an ORR for r/rAML that failed flt3i in the 25% range. That is likely sufficient to get us into a fast track registrational trial, but I do not think it will have great impact on the PPS. On the other hand I believe that the TUSP + Venetoclax r/rAML cohort can generate an ORR of 40%+ (this is based on in vitro synergies). The combination arm is to run in parallel with the monotherapy arm for r/rAML, so I am hoping for the first combination readout to occur in 3rd quarter (possibly 4th quarter) of this year.
No one else is talking about this, so I believe that an ORR of 40%+ in r/rAML which has no approved therapies will be seen as a surprise breakthrough by the street. This is what will move the stock much higher. If I am correct, APTO needs to find enough cash (with minimal dilution) to get us into the late 2023 data readouts.
It is premature to focus on the costs of developing either drug to approval. We need to prove the value of the drugs which I believe lies in there use in combinations.
"We are facing dilution and a reverse split, at best. Bankruptcy at worst." If you believe this I do not understand why you don't sell what you have and move on. Of course that's your personal choice and I am making no suggestion either way. I just find it odd.
I fear that we will undergo some dilution, but I also expect that there will be significant positive news that can mitigate the impact. I have a substantial core position that I plan to hold and if what I expect to happen happens I plan to add more shares. I believe APTO has TWO huge drug candidates in the works.
If they abandon Lux (which I don't expect) I would seriously reconsider my position here. To me that would be an unforgiveable sin.
I will repeat until proven wrong: Combinations will completely change the picture here. The first combination trial initiation is imminent. I will be here to see the reveal.
APTO has several potential short term financing options to get to real PPS moving data.
1. Outl-icensing of Lux for non-cancer indications.
2. Partnering of Lux for NHL indications.
2. Non-dilutive milestone driven loan tranches.
3. Possible Hanmi equity investment as they did to help SPPI.
4. Near term (positive surprise data); I believe that the initial combo data will be such.
Currently we have an ORR for r/rAmL in the range of 20% with TUSP monotherapy. I believe that the ORR for r/rAML will be in the 40%+ range with TUSP + Venetoclax. That will be a positive surprise and I expect such data around the third quarter.
My take away from this is that "CG-806 downmodulated the anti-apoptotic proteins Mcl-1 and Bcl-xL,"
"Resistance of BCR-stimulated CLL cells from ABT-199 mediated apoptosis directly correlated with induction of the antiapoptotic Bcl-2 family protein Mcl-1"
https://doi.org/10.1182/blood.V126.23.489.489
These data suggest that 806 helps knock down the Mcl-1 and Bcl-xl, whereas Venetoclax knocks down Bcl-2. Together that's a very strong approach to defeating the cells anti-apoptotic tricks.
This is likely a contributor to the synergy between 806 and venetoclax and the synergy between Tuspetinib and venetoclax.
It' why I am so anxious to see some combination data. I truly believe this will be a game-changer.
"Olutasinedib is not a multi-kinase inhibitor" Have you seen data supporting this?
I had knee replacement surgery last Thursday, so my responses here will be shorter and less frequent over the next few months. Please keep posting.
The initiation of the APTIVATE trial raises a serious question. The r/rAML patients are in desperate straits. Given a choice between an RP2D dose of LUXP (which has shown multiple CRs) and a finding dose of G3 Lux which would you choose. I believe that both need to be offered for ethical reasons. i.e. is APTO going to have trouble establishing an RP2D for G3 Lux?
We should have cleared the G3 Lux 50mg dose by now.