RE:RE:RE:RE:RE:Novel Format Conjugates February 2023This was the interview with Christian last year prior to the presentation, there is no transcript but the interview itself gives a good idea what was addressed last time. It was an introduction to the technology backed by the preclinical findings, future opportunities for their PDC and a bit about the trial at the time (the trial started on March 4). I have highlighted the points which were discussed also the part about SN38 “actively exploring”!
Compared to this year highlighted below one can presume there should be more about the more current trial compared to the previous year as at the time the basket trial has been going on for some 10 months.
2023:
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• Sortilin is a novel receptor overexpressed in cancer, whose normal function as a scavenger receptor can be exploited to rapidly transport cytotoxic drugs into cancer cells • Learn about the validation of the unique MoA and kinetics of internalization of TH1902 into the cancer cells • Gain insight into the status of the Phase I Study (Part I Dose Escalation, Part II basket trial in multiple tumor types) including study design, dosing, safety and early signs of efficacy” Interview 2022:
“Can you give us an insight on the work you are doing at Theratechnologies & why you decided to focus on peptide drug conjugates? I am the CMO and VP of Medical Affairs at Theratechnologies and am responsible for the oversight of both the R&D and Medical Affairs functions. Right now, we have two commercial products approved by the FDA in the U.S. and one in Europe. So we are involved in both commercial revenue-generating activities as well as in pipeline research and development of novel drugs. We are really focused on increasing the Theratechnologies pipeline and based on my previous experience in Oncology at Pfizer. I believe our team, from management down to bench scientists, are really up to the task and well suited to optimizing this unique technology platform to treat cancer and contribute to Theratechnologies growth. The history behind our conjugate platform is that we had been interested in a small company, Katana, for about 2 years. They were developing this interesting PDC targeting the sortilin receptor, which is a novel target expressed in many different cancers. We decided to bring this technology in house by acquiring Katana in 2018. Since then, Theratechnologies has been driving the research and development of this SORT1+ TechnologyTM platform and have moved it from the lab to the clinic all within an 18-mo period from the time Katana was acquired. I would love to hear more about your SORT1+ Technology™ and why you are targeting SORT1+ cancers? We have made significant advances in demonstrating proof-of-concept around our novel SORT1+ TechnologyTM. It’s an extremely interesting and flexible platform which targets a receptor in cancer that is involved in the trafficking and internalization of large molecules across the cell membrane, delivering them directly into tumor cells via endocytosis. The Sortilin or SORT1 receptor is highly expressed in many different solid tumors and is an important receptor that is just now being investigated for cancer drug development. So far, we have been able to identify a small 17 amino acid peptide that interacts with the sortilin receptor in a similar fashion to the natural binding ligands, which are progranulin and neurotensin. In tumors that overexpress sortilin, this is an opportunity to precisely target and ferry cytotoxic drugs to cancer cells and avoid targeting normal cells for a precision medicine approach to cancer therapy. What is most interesting is the potential of this platform, which is very flexible and can be used to attach to a variety of other anti-cancer drugs and other molecules to the peptide. Talk us through your pipeline of peptide drug conjugates. Originally, Theratechnologies developed a peptide drug conjugate (PDC) with doxorubicin as the cytotoxic payload (TH1904), shortly after a second PDC was also developed using docetaxel as the cytotoxic payload (TH1902). After many in vivo experiments in animal models, we realized that TH1902 has the broader activity across a wider range of tumors and therefore became our lead candidate for further cancer drug development. We were then able to bring this compound from basic research to the “first in human” (FIH) trial in an 18-month period. Now, due to success of this first PDC,
we initiated a follow up research project on an SN38 conjugate for colorectal cancer (CRC). Although TH1902 demonstrated preclinical activity in CRC, docetaxel is not the preferred cytotoxic agent of choice in the clinical setting. Irinotecan and its metabolite, SN38, may be a better choice of payload for this new PDC for CRC patients expressing SORT1 receptor, and we are actively exploring this new candidate drug. We are also considering other novel approaches using the SORT1+ TechnologyTM platform to develop additional novel drugs. For example, this could be a very good platform to develop a siRNA PDC to target cancer cells, resulting in either silencing a specific receptor or producing a protein that could impact cancer growth. What do you believe to be the biggest challenge within the novel format conjugate space and how are you addressing this challenge? ADCs are very well established anticancer therapies and proof of concept (POC) has been demonstrated across multiple ADCs. However, ADCs have their own challenges in terms of drug delivery and toxicity profiles. Our PDCs are unique chemical entities with different MOA and PK/PD profiles from that of ADCs. The rapid internalization of the cytotoxic agent inside the cancer cell and the precision in which it is delivered can potentially increase the safety profile and the efficacy of well-established anti-cancer drugs, such as docetaxel or other cytotoxics. We are also striving to help the scientific community and pharma better understand the differences of our unique platform from ADCs and the commercial potential of this novel platform. In our case, an ADC is not required, due to its rapid internalisation by the targeted receptor. The PDCs are tailored to be specifically internalized by the sortilin receptor to deliver the cytotoxic agent rapidly and precisely inside the cancer cell, without the need for the highly cytotoxic drugs that are used with ADCs. What would you say then has been the most exciting breakthrough in Novel Format Conjugate space? The multiple new cancer targets recently identified in past few years have been breakthroughs for the development of highly effective new treatments for this deadly disease. The versatility of this PDC platform can have significant impact on the development of these new targets. Why is it important for everyone to come together at the Novel Format Conjugates Summit? Scientific meetings are very important to share new ideas in drug development and this venue reinforces the fact that we are stronger together. It also provides an excellent opportunity for collaboration and the chance to meet again with old friends and colleagues. What are your highlights on the Novel Format Conjugate Summit agenda and what are you most looking forward to? I look forward most to the exchange of ideas and obtaining feedback on our development process in this new forum to help our PDC drug approval process moving forward while, at the same time, raising awareness of our novel technology. Can you give us a sneak peek into your presentation? The topic will be “SORT1+ TechnologyTM Platform and Novel Peptide Drug Conjugates (PDCs) Targeting Sortilin (SORT1). In the presentation, the following points will be discussed: •
Sortilin receptor, and its role in the normal cell and how its role and function change in cancer. • Why sortilin is an important biomarker/target in cancer, its expression levels in solid tumors, how it can be used for novel drug delivery and why it is an ideal candidate for internalization of novel peptide drug conjugates (PDCs). • Sortilin’s unique structure and MOA, leading to rapid internalization into cancer cells and delivery of less toxic payloads with better efficacy and safety profiles. • Preclinical data will be also discussed in order to demonstrate the efficacy and safety of Theratechnologies’ lead PDC candidate, TH1902, across multiple solid tumors. • The ongoing clinical FIH trial will also be discussed. Finally, we want to go into some detail around the potential of this novel SORT1+ TechnologyTM platform for future development. " 2nd Next-Generation Conjugates Summit | Boston, MA | February 21-23 2023 (next-gen-conjugates.com) Wino115 wrote: I'm hoping given the overall theme is from "...lab bench to bedside" -- so pre-clinical to in-humans --that he'll want to at least give some glimpses into whatever they've been able to understand in humans with the data they've collected. Unfortunately, it doesn't look like they will provide a transcript or anything from that meeting so we'll never know. I suspect we'll be a little in-the-know on some of that by the time the conf comes around.
qwerty22 wrote: I wondered about that but it's probably preclinical, like the paper they just published that was largely about engaging Sortilin.
Wino115 wrote: It's interesting that, if accurate, the wording seems to also suggst a bit more detail on some of the MOA issues. Maybe it's just all the 2 years of studying it, but perhaps they'd be more inclined to discuss the detailed science PK/PD data learned in 1a and 1b in that kind of setting. Maybe the "validation" is both pre-clinical and some of what they've seen so far.
"...
validation of the unique MoA and kinetics of internalization of TH1902 into the cancer cells..."
qwerty22 wrote: "Gain insight into the status of the Phase I Study"
Erm, yes please!