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Market cap of Aptose is less than $20M. I wonder why any larger biotech company don't buy Aptose for $40 or $60M. 100% or 200% premium looks attractive. And Tusp would be a nice addition to any hematologic oncology pipeline, especially for this steal price. Or is it that nobody see a value in Tusp?
As I can see, David Epstein is a CEO of PairX Bio since Sep 2023. He is also a founder of this company. It can explain why did he leave BDTX.
https://www.linkedin.com/in/david-m-epstein-8836593/
I think, recent SP decline is related to three factors. 1. World Conference of Lung Cancer in September where several studies on drugs targeting EGFR mutations in lung cancer were presented, including 4th generation TKIs. It showed that market is relatively crowded. 2. Outcome of Janssen Landmark Phase 3 MARIPOSA Study where RYBREVANT plus lazertinib beat Osimertinib in 1st line EGFRmut NSCLC. It should affect BDTX strategy for 1535 development. Placing it post Osimertinib might became not so relevant. 3. CEO employment termination without cause.
Guess, all eyes are on data readout in GBM this quarter.
From what Rice said at today's Cantor conference:
1. Already reported Tusp/Ven data with 15 patients. Will have data with around 30 and 45 patients at ESH and ASH, respectively. At ASH, will focus on durability.
2. Cash enough to the end of Q1 2024.
3. Lux was not even mentioned.
Without knowing why did it happened, I don't have clear opinion. But it could be either negative or neutral. I don't see how it can be positive. Hope, it is not clinical data related.
Interesting from bio of Philippe Ledru. "At Merck, he also provided leadership on all licensing and M&A activities, including the Peloton Therapeutics and Arqule acquisitions in 2019".
Titles of BDTX presentations at triple meeting:
1. Oral presentation, Oct 8, 2023, "BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases".
2. Poster, "Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers".
3. Poster, "Discovery and characterization of selective, FGFR1 sparing, inhibitors of FGFR2/3 oncogenic mutations for the treatment of cancers".
I didn't hear anything new in what Rice said. According to slide 26, they won't start a registrational trial until 3Q24. They don't have money to run their business one more year. Dilution is not an option. I think, their last chance is to demonstrate something spectacular at ASH in December and then license Tusp or sell the company.
Listened to David Epstein presentation at Morgan Stanley Healthcare Conference two days ago. He said that measurement of clinical activity in GBM is more complicated than in NSCLC. It has to be done by RANO criteria, not by measuring ORR by Recist 1.1 criteria. They need to demonstrate increase in PFS and ultimately, in OS. Their goal is to achieve six months PFS in 25% patients. Possibly, it is a reason why they already reported NSCLC data but still waiting to release GBM data in 4thQ. Measuring PFS at 6 months takes longer then ORR.
New Aptose Corporate presentation is posted.
https://d1io3yog0oux5.cloudfront.net/_40124f64f3e3cedf7965f5988141e281/aptose/db/776/7466/pdf/Aptose+Corporate+Presentation+September+2023.pdf
On a last slide, under Key Activities and Upcoming Events, highest priority is "Advancing partnering discussions". Good sign? I couldn't find a word Luxeptinib in this presentation.
QT prolongation is irregular heart rhythm. If a drug has side effect of prolonging the QT interval on electrocardiogram, it most likely won't be approved. So far, you don't see it. But it might show up with higher plasma level of Lux which you expect to reach by using G3 formulation.
Here is Luxeptinib information page from NIH.
https://drugs.ncats.io/substance/TQ6PBX1JU0
I didn't know that Luxeptinib inhibits POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY H MEMBER 2 with IC50 100 nM. Found that KCNH2 blockers cause drug-induced QT prolongation. Should watch it with new formulation.
From VA Formulary Advisor.
Projected Place in Therapy/Conclusions
• In 2 phase III clinical trials in patients with early breast cancer receiving myelosuppressive chemotherapy for 4
cycles in the adjuvant setting, eflapegrastim was non-inferior to pegfilgrastim in reducing the duration of severe
neutropenia during cycle 1 (primary endpoint) and during cycles 2-4 (secondary endpoint). Pooled rates of febrile
neutropenia for this chemotherapy combination without G-CSF prophylaxis are 29.1%.
• Safety during the clinical trial (adverse reactions in ≥20%) was similar between eflapegrastim and pegfilgrastim
despite the fact that eflapegrastim provides a lower dose of G-CSF compared to pegfilgrastim. The package
labeling for both products contains the same contraindication and Warnings and Precautions.
• There is no clear place in therapy for eflapegrastim instead of pegfilgrastim.
https://www.va.gov/formularyadvisor/DOC/466
Yes, he was a contact person for one site, not a PI for entire study. First author doesn't mean a PI. It means, he is presenting data.
He became a PI of the study around Apr 26, 2023. You don't see him as PI on Jan 27, 2023 and before.
https://classic.clinicaltrials.gov/ct2/history/NCT03850574?A=8&B=11&C=Side-by-Side#StudyPageTop
I thought he is unbiased KOL. As for trial, see "Study design" or "Arms and Interventions".
Four new study sites were added to APTIVATE trial in August, two from CA, one from Australia and one from Spain. It is interesting that Naval Daver, MD, from M.D. Anderson Cancer Center is listed as Principal Investigator.
https://classic.clinicaltrials.gov/ct2/history/NCT03850574?A=10&B=11&C=merged#StudyPageTop
Somewhat positive. Short interest is in steady decline since R/S on Jun 6, 2023.
https://www.nasdaq.com/market-activity/stocks/apto/short-interest
Ha ha. Good job. Posted by Defense World Staff on Aug 25th, 2023. Equities research analysts at StockNews.com began coverage on shares of Spectrum Pharmaceuticals (NASDAQ:SPPI – Get Free Report) in a note issued to investors on Friday. The firm set a “hold” rating on the biotechnology company’s stock.
First time I see announcement of participation in investment conference which includes recent clinical data. Guess, they might give a fresh update on their data on September 11.
Out licensing for non cancer indication will not bring substantial money to Aptose. They don't have any clinical data. Who is going to pay upfront? For Aptose, licensing would make sense only for all indications.
During an earnings call two weeks ago, Rice said to expect more definitive comments about LUX with the G3 formulation in the coming weeks. I can see three possibilities, 1) New positive data only; 2) New positive data and out licensing; 3) New negative data and discontinuation. What outcome you expect? I think, out-licensing.
Not yet. They have encouraging data but they don't have money. Fixing funding problem would be a major turning point. And I would like to know what FDA thinks about path forward. How Tusp registrational trial should look like? And WHO will run it?
Rolvedon vs biosimilars cost.
The final 2 articles highlighted in this issue of the Medical Letter address the question of cost. The first notes the recent approval of the new bone marrow stimulatory agent eflapegrastim-xnst (Rolvedon) for the prevention of chemotherapy-induced febrile neutropenia. The agent was FDA approved based on the results of 2 randomized trials in which it demonstrated noninferiority in one trial and possible superiority in the other trial vs pegfilgrastim (Neulasta).
Although there should always be interest in discovering novel, increasingly effective, less toxic approaches to supportive care measures in cancer management, the question here is the value of such agents vs less expensive biosimilar agents employed for this purpose. One dose of eflapegrastim is said to cost $4500 compared with pegfilgrastim biosimilar costing approximately $2500. This sum is not insignificant considering the common use of bone marrow stimulatory agents by oncology practices and health care systems, as well as the financial impact on third-party payers or as increasingly mandated insurance co-pay for individual patients.
https://www.onclive.com/view/unresolved-issues-in-antineoplastic-drug-therapy-is-it-finally-time-to-address-
I don't deny anything. My point is that for best outcome of combo trial it is desirable that both drugs have meaningful mono activity.
Lack of activity as monotherapy revealed yesterday is not encouraging and lowers my expectations for combo. What are they going to use as control arm? Ven is not good because many patients are R/R to Ven. Tusp is not good because it doesn't work.
Something is wrong with their mono arm of APTIVATE trial. Only 1 response in 7 patients (14%, and they didn't say whether it is a PR or CR) is not what you would expect based on their dose escalation part where CRc rate with 80 mg dose was 30%. Looks like that as a single agent Tusp has no chance. No other choice but to run a combo. As for combo, they said it will be a randomized trial. It means, they will have a control arm. Not sure what drug is appropriate as control.
Most important message from yesterday call: We are in desperate need for partner(s).
Wonder whether they will present new data today. And does any new data from Aptose matter?
Not sure. Mobo is for EGFR Ex20ins and Pozi is for HER2 Ex20ins. I think Takeda was too ambitious studying Mobo against Platinum doublet. They would better run a study of Mobo+Platinum against Platinum. On the other hand, they might consider high toxicity of combo.
From today's Takeda earning call. "Following a planned interim analysis, the Phase 3 EXCLAIM-2 trial was stopped for futility. The trial compared EXKIVITY monotherapy to chemotherapy in first line, non-small cell lung cancer with exon 20 insertion mutations. We will be engaging with regulators required regarding these data and determining next steps for the program." So, mobocertinib doesn't work better than chemo.
Yes, maybe not worth it. Wonder why they are still presenting data. Here is a title of oral presentation at WCLC 2023 meeting in September: "Efficacy and Safety of Poziotinib in HER2 Exon 20 Insertion NSCLC Patients who Received at Least 2 Previous Systemic Therapies". Authors: X. Le, A. Prelaj, C. Baik, N. Tchekmedyian, S. Leu, G. Bhat, J.V. Heymach, R. Cornelissen.
Experts opinion on Poziotinib. Just published, "Poziotinib for HER2 Exon 20-Mutated NSCLC: Addition or Burden to the Therapeutic Arsenal?"
From the paper: "In accordance with the National Comprehensive Cancer Network, the current optimal treatment for patients with metastatic HER2 exon 20 insertion mutation, in second line, T-DXd, seems to be most appropriate. Nevertheless, HER2-specific TKIs with better selectivity and reduced toxicity are expected to yield at least similar outcomes in the near future. In the interim, poziotinib presents a treatment option that should not be disregarded entirely. It is crucial to explore the patient population and dosages for which this strategy can offer a beneficial effect while maintaining an acceptable quality of life."
https://www.jto.org/article/S1556-0864(23)00548-8/fulltext
Should ASRT work on Pozi?
Tried to refresh my memory on Lux G3 and noticed something weird. Look at slide 31 of EHA presentation. It shows time course of Lux plasma concentration in cycle 1 at different drug doses. First, Look at 900 mg dose curve. Lux level reaches almost 1 uM on day 15 and then it drops to ~0.15 uM at the end of cycle. Second, how to explain a sudden plunge in plasma Lux on day 15 with 750 mg G1 and 50 mg G3? And why so many measurements on day 15? Third, why to compare 50 mg G3 with 900 mg G1, a worst PK dose, and not with 600 mg G1? Fourth, why do you see plasma Lux decline with 50 mg G3 from day 8 to day 15 and day 22? Where is data for day 29?
Nothing to compare. As you know, easiest and fastest way to bring Tusp to the market is accelerated approval for use in patients progressed on Flt3 inhibitors. Aptose already demonstrated that Tusp is active in some patients after Gilteritinib or Midostaurine treatment. But we don't know whether Tusp is active after Quizartinib or not. Quiz works by a different mechanism as compared to Gilt and it can inhibit other TKs, like Tusp. Keep in mind that Quiz is now approved in 1st line. Expect many patients pre-treated with Quiz before they are eligible for Tusp.
The US FDA has approved Daiichi Sankyo's Vanflyta (quizartinib) for acute myeloid leukemia (AML) that is positive for FLT3-ITD. Approval was based on the results of the phase 3 QuANTUM-First trial that showed Vanflyta met its primary endpoint of overall survival. Vanflyta in combination with chemotherapy as well as a maintenance monotherapy treatment, cut the risk of death by 22% compared to chemo alone.
It is not easy to follow an evolving story of EGFR mutations in NSCLC and other cancers. Most common are mutations called the exon 19 deletions and exon 21 L858R mutation. Other mutations including exon 20 insertion mutations are less common. To treat patients with most common mutations, two drugs, Iressa and Tarceva were developed. BTW, David Epstein and Elizabeth Buck, were involved in the development of Tarceva. They know this field. Patients treated with Iressa or Tarceva sooner or later progress. One of the reasons for disease progression is the emergence of an additional mutation, called a resistant mutation, T790M. Tarceva or Iressa are ineffective against T790M. AstraZeneca found the way to overcome this resistance by inventing Osimertinib (Tagrisso). It turned out to be such a great drug that oncologists started using it as a first line treatment instead of chemotherapy, Iressa or Tarceva. Osimertinib is less toxic and more effective. And as David Epstein mentioned, patients treated with Osimertinib never develop T790M mutation. However, after some years on Osimertinib, patients become resistant to this drug as well. Why? Because new mutations emerge. Some of them are in EGFR again, some are in other proteins. Most common mutation in EGFR causing resistance to Osmertinib, is C797S. In addition, several less common Osimertinib resistance mutations were identified. To make EGFR mutation landscape more complicated, these Osimertinib resistance mutations can co-exist with other so-called intrinsic mutations. Now, how BDTX-1535 can help? It can block activation of EGFR caused by Osimertinib-resistant mutations and EGFR intrinsic mutations. Possibly it doesn’t work so good against T780M, but after Osimertinib you don’t have it. In GBM, EGFR mutations are different and one of the reasons why Osimertinib doesn’t work in GBM could be low brain penetrance.
BDTX-1535 profile already separates it from other agents in EGFRmut NSCLC.
Somewhat positive. From recently published paper, "Deciphering the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FMS-like tyrosine kinase 3".
FMS-like tyrosine kinase (FLT3) has become the legitimate molecular therapeutic target for acute myeloid leukemia therapy. Though FLT3 inhibitors have impact on disease progression, drug resistance induced by secondary point mutations is the primary mechanism and urgent to overcome. Herein, we sought to decipher the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FLT3. A series of molecular modeling studies, including molecular dynamics (MD) simulation, dynamic cross-correlation (DCC) analysis, binding free energy (MM-GBSA) and docking study were explored to elucidate the differential tolerance mechanisms of two inhibitors to the same mutant. The F691L mutation had relatively larger effect on gilteritinib than HM43239, which showed as the changed and fixed conformation, respectively. These observations rationalized that the binding affinity of gilteritinib decreased more than that of HM43239 in the F691L mutant.
https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2229447