sudocetaxel zendusortide (TH 1902)

A weekly administration of TH1902 as a single agent in a murine B16-F10 melanoma syngeneic tumor model demonstrated superior tumor growth inhibition than did docetaxel. TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.

P1, N=70, Recruiting, Theratechnologies | Active, not recruiting --> Recruiting

P1, N=70, Active, not recruiting, Theratechnologies | Trial completion date: Mar 2023 --> Dec 2024 | Trial primary completion date: Mar 2023 --> Dec 2024

TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962.

Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate (PDC) of the sortilin (SORT1)-binding peptide TH19P01 ester-linked to two docetaxel moieties, has been shown to exert superior anti-cancer activities in multiple cancer models including melanoma syngeneic and xenograft murine models. This is the first demonstration that immune cell infiltration patterns play a pivotal role in the TH1902-associated anti-tumoral response. Combination of TH1902 with checkpoint inhibitors (anti-PD-L1) further reveals that this may lead to improved clinical outcomes in future immunotherapy translational approaches.

P1, N=70, Active, not recruiting, Theratechnologies | Recruiting --> Active, not recruiting

Synopsis Understanding why the normal function of a scavenger receptor, SORT1, can be exploited to rapidly transport novel peptide drug conjugates (PDCs) into cancer cells Discussing the over expression of SORT1 in many solid tumours Learn about Thera’s lead PDC candidate, TH1902, across multiple solid tumours Review the potential of this novel SORT1+ platform for future developments

These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC.

Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin.

P1, N=70, Recruiting, Theratechnologies | Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Mar 2022 --> Mar 2023

Mice bearing A-2780 xenograft tumors were treated with TH1902, paclitaxel or docetaxel alone, as well as with each in combination with carboplatin. Moreover, TH1902 combined with carboplatin also demonstrated better efficacy than did either of the taxane-carboplatin combinations. Overall, the results indicate that TH1902 possesses an in vivo efficacy superior to those of docetaxel against ovarian and endometrial cancers in the animal models tested, and that TH1902 could be safely combined with carboplatin to reach optimal inhibition of tumor growth.

Moreover, considerable weight loss was associated with docetaxel treatment over 24 days while TH1902 treatments resulted in no net change in mouse body weights. In this syngeneic model, TH1902 is more tolerated and effective than docetaxel at inhibiting both melanoma xenograft growth and metastatic formation.

In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.

Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel.

P1, N=65, Recruiting, Theratechnologies | Not yet recruiting --> Recruiting

In all cases, TH1902 showed more potent inhibition than Docetaxel. These results strongly support future clinical development of TH1902 as novel therapeutics in SORT1+ cancers.