Theratechnologies Announces New Positive Results For Two Investigational Peptide-Drug Conjugates Targeting Sortilin Positive Ovarian Cancer. The stock looks very, very interesting. It is a small, $200mn company with a strong pipeline and multiple approved products.
Theratechnologies Inc. (THTX), a commercial-stage biopharmaceutical company, today announced that new positive results about its two investigational peptide-drug conjugates (PDC) TH1902 and TH1904 will be presented tomorrow during an oral presentation at a virtual session of the Annual Meeting of the American Association for Cancer Research (AACR).
The development of personalized therapies against ovarian cancer remains highly challenging even in current modern oncology. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to peptide ligands that selectively target receptors abundantly and/or exclusively expressed in these tumor cells. Increased expression of Sortilin (SORT1), a scavenging receptor also known as neurotensin receptor-3, has been observed in invasive ovarian cancer biopsies. In addition, increased SORT1 expression correlated with breast tumor grades.
In light of these observations, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. As a proof-of-concept, doxorubicin and docetaxel were conjugated to a Sortilin-binding proprietary peptide (TH19P01).
In vitro, significant intracellular delivery of the doxorubicin-TH19P01 conjugate (TH1904) and docetaxel-TH19P01 conjugate (TH1902) were observed in a ES-2 ovarian cancer cell line model while preserving efficient doxorubicin or docetaxel cytotoxic mechanism. TH19P01 and drug conjugate uptake in ovarian cancer cells assays were reduced when SORT1 expression was specifically silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Importantly, drug-TH19P01 conjugates were found to bypass the P-glycoprotein (P-gp) efflux pump in MDCK-MDR1 cells overexpressing P-gp as the uptake of conjugates was unaffected by the P-gp inhibitor Cyclosporin A.
In vivo, TH1904 and TH1902 caused a more potent inhibition of human ovarian tumor xenografts grown in mice and were better tolerated than their unconjugated parent drugs.
In vivo results obtained with TH1902 and TH1904 demonstrate a high accumulation of the conjugates in ovarian tumors with low accumulation in healthy ovary tissue. Compared to treatments using doxorubicin or docetaxel, two commonly used treatments for ovarian cancer, TH1902 and TH1904 were both found to have better efficacy, at equivalent dose, while not inducing weight loss nor decreasing lymphocytes, two common side effects observed with current treatments.
These results strongly support future clinical development of this targeted technology platform to generate redacted personalized therapeutics with specific indications in Sortilin-positive cancers.
“This data is particularly interesting as it shows that TH1902 has significant activity in more than one type of cancer, thus opening the door to making TH1902 our lead PDC and to test it in a number of SORT1+ cancers. TH1902 has already demonstrated activity in vivo for the treatment of triple-negative breast cancer. We now realize that it could become a potent and well-tolerated weapon in the fight against ovarian cancer as much as TH1904,” said Dr. Christian Marsolais, Senior Vice President and Chief Medical Officer, Theratechnologies.
“These new results further support the great potential of our PDCs as a unique and effective vehicle for the treatment of many types of cancers in which SORT1 receptors are overexpressed. The high specificity of our PDCs could translate to significantly better efficacy and tolerability,” added Dr. Marsolais.
The neurotensin receptor-3 also known as sortilin was the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) discovered two decades ago in the human brain. The expression of sortilin is not confined to the nervous system but sortilin is ubiquitously expressed in many tissues. Sortilin has multiple roles in the cell as a receptor or a co-receptor, in protein transport of many interacting partners to the plasma membrane, to the endocytic pathway and to the lysosomes for protein degradation. Sortilin could be considered as the cells own shuttle system. In many human diseases including neurological diseases and cancer, sortilin expression has been shown to be deregulated. In addition, some studies have highlighted that the extracellular domain of sortilin is shedded into the culture media by an unknown mechanism. Sortilin can be released in exosomes and appears to control some mechanisms of exosome biogenesis. In lung cancer cells, sortilin can associate with two receptor tyrosine kinase receptors called the TES complex found in exosomes. Exosomes carrying the TES complex can convey a microenvironment control through the activation of ErbB signaling pathways and the release of angiogenic factors. Deregulation of sortilin function is now emerging to be implicated in four major human diseases- cardiovascular disease, Type 2 diabetes mellitus, Alzheimer disease and cancer.
source – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802778/
About Theratechnologies’ SORT1+ technology
Theratechnologies has developed a peptide which specifically targets Sortilin 1 (SORT1) receptor. It was discovered that SORT1 is overexpressed in ovarian, triple-negative breast, skin, lung, colorectal and pancreatic cancers, among others. SORT1 plays a significant role in protein internalization, sorting and trafficking, making it an attractive target for drug development.
Commercially available anticancer drugs, like docetaxel, doxorubicin or tyrosine kinase inhibitors are linked to our investigational redacted peptide to specifically target the Sortilin receptor. This could potentially improve the efficacy and safety of those agents.
Theratechnologies intends to initiate, by the end of 2020, a first-in-human clinical trial with TH1902 in cancer patients.
THTX looks very, very interesting. It is a small, $200mn company with a strong pipeline and multiple approved products.