On April 8, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported preclinical data that highlight the versatility and flexibility of the Company’s SORT1+ Technology platform (Press release, Theratechnologies, APR 8, 2024, View Source [SID1234641884]). In a poster session at the 2024 annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in San Diego, Calif., researchers reported that Theratechnologies’ investigational camptothecin-peptide conjugates are well tolerated and associated with significant tumor regression in colorectal cancer (CRC) and triple-negative breast cancer (TNBC) xenograft models. The study also demonstrated synergistic anti-tumor efficacy and good tolerability with the combination of two peptide drug conjugates with different payloads.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"The preclinical data presented at AACR (Free AACR Whitepaper) add to the sizeable body of evidence supporting the potential utility of the SORT1+ Technology platform as an engine for the development of novel peptide-drug conjugates to treat various types of cancer," said Christian Marsolais Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "In addition to our lead peptide-drug conjugate, sudocetaxel zendusortide, these latest data highlight the promising tolerability and anti-tumor effects of our investigational camptothecin-peptide conjugates, further demonstrating the versatility and flexibility of the platform. We welcome discussions with potential partners who are interested in the further development of these innovative therapies."
The SORT1+ Technology platform relies on the use of a novel, proprietary peptide called TH19P01, which can be conjugated (attached) to numerous well-characterized anticancer drugs. Theratechnologies designed TH19P01 to interact with and be transported by the scavenger receptor sortilin (SORT1), which is involved in protein internalization, sorting, and trafficking, and is expressed in multiple tumor types. Targeting SORT1 with platform-derived peptide-drug conjugates (PDCs) leads to receptor-mediated internalization (endocytosis) of anticancer agents. Once inside cancer cells, active drug is released from the peptide and exerts its cytotoxic effect directly on the cancer cell.
In the poster presented at AACR (Free AACR Whitepaper), the investigators noted that SORT1 gene silencing inhibits camptothecin-conjugate uptake in human HT-29 colorectal adenocarcinoma cells. This observation suggests that these PDCs enter cancer cells via a SORT1-mediated internalization process.
The investigators also described the preclinical effects of three PDCs – TH2101, TH2205, and TH2310 – that have a cytotoxic payload of SN-38, the active metabolite of irinotecan, an anticancer agent that is derived from the Chinese tree Camptotheca acuminate. In addition, the poster summarized the activity of another PDC, TH2303, which carries an exatecan payload, a structural analog of camptothecin. Compared to unconjugated irinotecan, the exatecan- and SN-38-conjugates exerted greater anti-proliferative activities against CRC cells in mice. In two different CRC xenograft models, as well as in the TNBC xenograft model, TH2303 was associated with increased tumor growth inhibition and greater tolerability compared to unconjugated exatecan or irinotecan.
In another experiment described in the poster, the combination of two SORT1-targeting PDCs – sudocetaxel zendusortide (TH1902) and TH2101, which have a synergistic anti-tumor effect at reduced doses, led to increased tumor growth inhibition and some complete responses in the HT-29 xenograft model, compared to either PDC administered alone. The combination also was well tolerated.
"The significant tumor regression following combination therapy is notable because the HT-29 xenograft model is known for its resistance to multiple cytotoxic drugs," commented Prof. Borhane Annabi, Chair in Cancer Prevention and Treatment in the Chemistry Department at the Université du Québec à Montréal. "That observation, along with the impressive anticancer efficacy of the camptothecin-peptide conjugates when administered alone, underscores the potential feasibility of this approach in treating various tumor types."
A copy of the AACR (Free AACR Whitepaper) poster, as well as a second poster presented at the conference, which reinforces existing data for the Company’s lead investigational PDC sudocetaxel zendusortide (TH1902) in activating anti-PD-L1 immunotherapy tumor cell-killing in SORT+1 cancers, can be found at the Theratechnologies website.
About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology
Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Company’s broader licensed oncology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial.
Theratechnologies has established the SORT1+ TechnologyTM platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.