PI3Kα: SABCS 2022 Axel Hoos STX-478 Xenograft Models Breast Cancer
How can a PI3Kα inhibitor help patients suffering with breast cancer? The company that I represent is Scorpion Therapeutics, our focus is on elevating the entire game for precision oncology, so using targeted molecules that go after mutations and cancer and optimize outcomes for patients.
So we call that Precision Oncology 2.0, now what we’re presenting here at SABCS is basically data on our lead compound, a PI3Kα inhibitor that is mutation selective. We call it STX-478, that has shown very high level, a selectivity against specific (oncogenic) mutations in the helical and kinase domain of the PI3Kα pathway and has shown new data that is indicating synergy with other agents, standards of care like Palbociclib or Fulvestrant, and allow us to develop this molecule now that it’s about to enter the clinic in settings of first line, second line, and eventually a last line of treatment estrogen receptor positive HER2 negative breast cancer.
What is the next step for this research on PI3Kα?
There’s still a lot of treatment options available for patients in ER positive, HER2 negative breast cancer space, but there’s also a lot of toxicity and still an unmet medical need for all lines of therapy. So we have seen CDK inhibitors to be successful. We have seen some good data here at the meeting indicating progress in that space.
We have seen oral certs become successful. There have been two randomized clinical trials that showed very encouraging data that will likely lead to drug approvals in the oral cert space. And these are drugs that potentially a mutation selective PI3Kα inhibitor can combine with. So we expect that once you get select a mutation selective can create a clean compound that has certain clinical features that are attractive for patients.
We can add additional value to the existing therapies that are available, even the ones that are at the horizon, be that in the Fulvestrant or oral cert space, be that in the CDK4/6 space. We believe we can still add value by adding a compound to these existing therapies.
What are the key takeaways from this research and data on PI3Kα Clinical Trial?
We’re actually not in the clinic yet, so there’s no ongoing trial, but we are expecting to file our IND in the first quarter of next year. So we will be in the clinic soon. It would be a first in human study that will aim to identify a therapeutic window for the drug. Find the right dose, so we eliminate the toxicity that is still uncomfortable for many patients that are getting earlier generation drugs in the PI3Kα space.
And then we will look at combination data so we can actually combine with the certs or eventually the CDK inhibitors to ensure we have all the data to launch registrational programs once we have the drug profile defined. Now, one thing I would like to say is, in order to understand why the compound might be of clinical interest to patients and physicians are five critical features for which the drug was designed.
So it first has a low molecular weight that makes it easy to handle. That leads to a very good PI3Kα profile, so very low peak-to-trough, which means you can dose it once a day, dose it steadily, and have steady coverage of the target. In addition to that, it is brain penetrant, so it allows us to even address brain metastases that patients might have at a rate of like 20 to 30%, at least in these breast cancer patients.
And it will also have the ability to combine well with other agents because it has a good safety profile. So our expectation is that one of the dominant toxicities that exist in the pediatric alpha space, which is hyperglycemia, can be dialed out. By finding the right therapeutic window for this molecule. So there are significant improvements over existing therapies and we hope we can deliver that in our first inhuman trial already.
What is STX-478?
A small molecule called STX-478, which was formerly known as ST-814, is highly differentiated, allosteric, and designed to penetrate the central nervous system (“CNS”). Its purpose is to inhibit the H1047X-mutant form of phosphoinositide 3-kinase alpha (“PI3K pathway”), which is one of the most common variants of PI3K pathway and a validated oncogenic disease driver across a range of solid tumors.
What are the most common questions you’re asked for this research?
What oncologists usually want to know is the clinical profile of the molecule. What will this mean for my patients? As I just said in terms of the features that we anticipate is critically, the molecule is brain penetrant. The molecule has a very good PI3Kα profile. It’s easy to administer, it has a likely a low dose, so it has low protein binding, therefore you can give, have to give less of the molecule in order to reach the pathway and inhibit the pathway. So we think it will be easy to use clinically, we’ll have a good safety profile and then can be given longer before toxicity occurs. That will be dose limiting and that could lead to vastly improved clinical efficacy.
Read and Share the Article Here: https://oncologytube.com/v/41700
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Is there anything you would like to leave oncologists with about PI3Kα?
So besides what I have already said critical thing is we believe this is a best in class profile for the molecule. Up to the point that we’re at. We have to now translate this best in class profile into a clinical profile from the preclinical data that we have presented here and then develop it in the right patient population. So we will aim for helical domain mutated patient populations in the ER positive HER2 negative breast cancer space. And we will also look at the helical domain mutated solid tumors as a separate cohort to ensure that we can deliver some value in that setting too. The drug was originally designed for helical domain mutations.
Now we have learned, and that’s part of the data shown here, that we can also have activity against helical domain mutation that means more patients that could have benefit from this agent after we identified a right dose in clinical development, which might be different between the two, but ultimately both pathway components can be addressed.
Final thoughts on PI3Kα
You can only say that you know now that we are able with advanced medicinal chemistry and a significant number of new tools to make better small molecules for cancer patients, we have really reached a level of Precision Oncology 2.0. We are elevating the game and we are making better molecules that can replace existing molecules and deliver more value for patients. I think that’s a key takeaway. Physicians should be selective in the molecules that they use to treat their patients, and we now are at a new level, we can actually deliver better molecules. And Scorpion Therapeutics is aiming to do exactly that with our platform position Oncology 2.0 is the name of the game as we go forward.
Axel Hoos, MD, PhD – About The Author, Credentials, and Affiliations
Axel Hoos, MD, PhD, is the chief executive officer of Scorpion Therapeutics, a Boston-based biotechnology business that focuses on Precision Oncology 2.0 to maximize small molecule quality and provide transformative cancer medications.
Dr. Hoos is also a Trustee on the Board of the Sabin Vaccine Institute (SVI), a global health organization; a Director on the Board of TCR2, a cell therapy company; a Co-founder and Director on the Board of Imugene, a biotechnology company; a Co-Director of the Cancer Immunotherapy Consortium; and a SAB member of the Cancer Research Institute (CRI).
Previously, Dr. Hoos served at GlaxoSmithKline Pharmaceuticals as Senior Vice President, R&D Governance Chair, and Therapeutic Area (TA) Head for Oncology (GSK). At GSK, he was in charge of technical and financing choices in R&D and Discovery and Development in Oncology, with a focus on immuno-oncology, cancer cell therapy, synthetic lethality, epicenetics, and tumor-cells (cancer-cells) targeting. After the sale of marketed medications to Novartis in 2015, he returned GSK to Oncology with a new pipeline focus on innovation that can offer transformative value to patients. Tesaro, Merck-Serono, Adaptimmune, Lyell, Immatics, Ideaya, Surface Oncology, and iTeos were involved in recent acquisitions, licensing transactions, and commercial collaborations.
Dr. Hoos was the Global Medical Lead in Immunology/Oncology at Bristol-Myers Squibb (BMS), where he created the first checkpoint inhibitor in Immuno-Oncology, Yervoy (Ipilimumab). The 2018 Nobel Prize in Medicine was awarded to Dr. James Allison for the scientific mechanism of ipilimumab. Under the guidance of Dr. Hoos, a new paradigm for the discovery of cancer immunotherapies was established, which contributed to birth the discipline of Immuno-Oncology (Nat. Rev. Drug Discovery 2016, 15(4):, 235-47).
Dr. Hoos was Senior Director of Clinical Development at Agenus Bio prior to joining BMS (former Antigenics).
Dr. Hoos received his medical degree from Ruprecht-Karls-University and his doctorate in molecular oncology from the German Cancer Research Center (DKFZ) in Heidelberg, Germany. He received additional education at the Technical University of Munich and the Memorial Sloan-Kettering Cancer Center in New York. He is a graduate of the Leadership Development Program at Harvard Business School. Dr. Axel Hoos is the chief executive officer of Scorpion Therapeutics, a Boston-based biotechnology business that focuses on Precision Oncology 2.0 to maximize small molecule quality and provide transformative cancer medications. Dr. Hoos is also a Trustee on the Board of the Sabin Vaccine Institute (SVI), a global health organization; a Director on the Board of TCR2, a cell therapy company; a Co-founder and Director on the Board of Imugene, a biotechnology company; a Co-Director of the Cancer Immunotherapy Consortium; and a SAB member of the cancer Research Institute (CRI). Previously, Dr. Hoos served at GlaxoSmithKline Pharmaceuticals as Senior Vice President, R&D Governance Chair, and Therapeutic Area (TA) Head for Oncology (GSK). At GSK, he was in charge of technical and financing choices in R&D and Discovery and Development in Oncology, with a focus on immuno-oncology, cell therapy, synthetic lethality, epicenetics, and tumor-cell targeting. After the sale of marketed medications to Novartis in 2015, he returned GSK to Oncology with a new pipeline focus on innovation that can offer transformative value to patients. Tesaro, Merck-Serono, Adaptimmune, Lyell, Immatics, Ideaya, Surface Oncology, and iTeos were involved in recent acquisitions, licensing transactions, and commercial collaborations. Dr. Hoos was the Global Medical Lead in Immunology/Oncology at Bristol-Myers Squibb (BMS), where he created the first checkpoint inhibitor in Immuno-Oncology, Yervoy (Ipilimumab). The 2018 Nobel Prize in Medicine was awarded to Dr. James Allison for the scientific mechanism of ipilimumab. Under the guidance of Dr. Hoos, a new paradigm for the discovery of cancer immunotherapies was established, which contributed to birth the discipline of Immuno-Oncology (Nat. Rev. Drug Discovery 2016, 15(4):, 235-47). Dr. Hoos was Senior Director of Clinical Development at Agenus Bio prior to joining BMS (former Antigenics). Dr. Hoos received his medical degree from Ruprecht-Karls-University and his doctorate in molecular oncology from the German Cancer Research Center (DKFZ) in Heidelberg, Germany. He received additional education at the Technical University of Munich and the Memorial Sloan-Kettering Cancer Center in New York. He is a graduate of the Leadership Development Program at Harvard Business School.
Scorpion Therapeutic – Scorpion addresses recognized drivers of cancer genesis and disease progression that are commonly regarded as drug-resistant.
Their elite team includes specialists in cancer biology, medicinal chemistry, next-generation chemical proteomics, computational chemistry and molecular biophysics, machine learning, and drug development.
Its completely integrated discovery platform is based on the most advanced available tools for drug discovery, small molecule design, and target identification, which we believe will allow us to swiftly produce highly selective small molecule compounds against an unprecedented spectrum of targets.
Reference
Scorpion Therapeutic – Scorpion Therapeutics Presents Preclinical Proof-of-Concept Data Supporting the Development of Its Potentially Best-in-Class Mutant-Selective PI3Kα Inhibitor for the Treatment of Solid Tumors at the AACR Annual Meeting 2022. Scorpion Therapeutic, April 8, 2022