RE:RE:RE:RE:RE:RE:RE:Tarveda TherapeuticsJeff - am I right in saying that what matters is the amount of sortilin receptors on the cell surface and not the amount of sortilin within a cell? And that late stage cancer cells have shown to have more sortilin receptors at the surface of the cell? If this is correct, do the results you noted below matter much? If it is more about sortilin expression on the cell's surface than about the total amount within a cell, is there any data on that? I suspect not but perhaps you have seen something.
jeffm34 wrote: The amount of off target accumulation of TH1902 will likely be higher than those therapeutics that targeted NTSR1. You can see the expression of sortilin(NTSR3) is higher in the cancer cells but also much higher in non cancer cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464404/
The proportion of cancer tissue which stained positively for NTSR1 (H-score > 0) was significantly higher than the proportion of normal epithelium which expressed NTSR1 (70.7% vs 10.7% respectively, p < 0.01, Fisher’s exact test). Similarly, the proportion of CRC tissue which stained positively for NTSR3 was significantly higher than normal epithelium (96.5% vs 80.4% respectively, p < 0.01, Fisher’s exact test).
SPCEO1 wrote: My understanding is that the sortilin receptors that are contained within the cells are not going to attract TH-1902, only those that are expressed on the cell surface. Is that correct? It also has sounded to me based on earlier discussions here that most sortilin receptors are contained within the cell and that more are expressed in late stage cancer cells. If there are sortilin receptors in healthy cells, they are most often contained inside the cell - is that a correct assumption? Or does no one relly know yet?
Who knows what TH will share with us about the findings in the phase 1a trial? But I am assuming that whether they share info with us or not, there will be issues that arise in the trial that will be of some concern. That almost always is the case in any drug trial. The question is are those concerning issues ones that can be dealt with in some manner or do they represent something that seriously undermines TH-1902 either medically or commercially. Given the signals coming from the company's words and actions thus far, whatever they have seen in the phase 1a that is concerning does not appear to be a debilitating issue for TH-1902 program.
jeffm34 wrote: Actually there are significant comparisons and implications for TH1902. Both receptors are over expressed in some cancer cells and both are present in other non cancer tissues as well. In the studies targeting NTSR1 they found
"Nontumoral uptake was high in several organs" This was always going to be the ibiggest ssue to overcome with TH`902. This is also why your guess as to what the MTD of TH1902 was going to be was so ridiculous. jfm1330 wrote: Even though they share similar names and a common ligand (neurotensin), NTSR1 and NTSR3 are very different. NTSR1 is a G protein with seven transmembrane segments, while NTSR3 (sortilin) is a single transmenbrane segment (domain) and is not a specific receptor of neurotensin. So little comparisons to be made.
jeffm34 wrote: What's more relevant is the work they've done targeting the NT receptor NTSR1. Sortilin(NTSR3) and NTSR1 are both overexpressed in some types of cancer cells.
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There have been broad disclosures from Tarveda Therapeutics involving conjugates comprising of a neurotensin analog and an active agent through a linker. For active agents, different payloads like bortezomib, cabazitaxel, DM1, doxorubicin, monomethyl auristatin E (MMAE), SN-38, and its analogs were used. For the targeting moiety, neurotensin analogs, and even the β-arrestin biased agonist ML314 were proposed [177]. Many of the conjugates include the linkers cathepsin B peptide or di-sulfide bonds. Conjugates of the present invention were studied in various in vitro assays. Tumor cell proliferation was reduced by conjugates of the present invention. Close to 100 conjugates were synthesized using different ligands and payloads. Conjugates were assessed for receptor-dependent cytotoxicity by the difference between an NTSR1-targeting conjugate, and the corresponding conjugate with the same linker moiety and an active agent where the NTSR1-targeting domain has been scrambled. Conjugates were assessed in an in vitro assay evaluating inhibition of cell proliferation in HT-29 cells (human colon cancer cells) with NTSR1 targeting compounds showing better IC50 values than NTSR1 scrambled compound (61 and 63) in some cases for e.g 6.2 nM vs 110 nM. Conjugates were also assessed in an in vitro assay evaluating inhibition of cell proliferation in SW48 (human colon cancer cells), IC50 = 79 nM. Many of the synthesized conjugates had subnanomolar Kd for NTSR1 (for e.g. compound 13 (62) and 14 (64) in the patent had Kd of 0.48, and 0.78, respectively)" jfm1330 wrote: We spoke about this company here before. Their first candidate PEN-866 with SN38 went through a dose escalation phase I. It is interesting to read the results. They claim to be able to determine tumor accumulation of the drug through tissue pharmacokinetic (I am not sure exactly what it means and how they can do that). On the efficacy front, out of 26 evaluable patients, 11 had stable disease at 8 weeks of which seven lasted 12-58 weeks. One partial respose (tumor shrinkage higher than 30%), and decreased target lesion size in six patients. So as we can see, nothing spectacular on the efficacy front. Patients were selected based on cancer type, not HSP90 expression. They have extended this trial to a phase IIa on multiple cancer types. They plan to enroll more than 300 patients.
It is hard to compare two very different drug conjugate/receptor concepts with two different cytotoxic drugs involved, and PEN-866 is not a PDC, it is a small molecule ligand conjugated to SN38. But we can see that efficacy results are modest in phase I, and Thera will not have stable diseases on many patients, because they treated a very limited number, and obviously not for as long as 58 weeks, not even close. All that being said, PEN-866 is in phase IIa even though it had so little efficacy data in phase I. But they claim to have proof of tumor accumulation of the drug, which is proof of concept.
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.3515