Theratechnologies (Canada)

Abstract Background People with HIV (PWH) are at an increased risk of cardiovascular disease (CVD), even after accounting for traditional risk factors like diabetes and dyslipidemia. Metabolic syndrome, a component of which is central adiposity, is also increasingly prevalent in PWH. Yet, there are few data on the contribution of excess visceral abdominal fat (EVAF) to increased CVD risk in PWH in the modern ART era. Methods We used the Visceral Adiposity Measurement and Observation Study (VAMOS) to investigate how EVAF impacts traditional CVD risk factors and overall CV risk in PWH. VAMOS is a cross-sectional, multi-center observational study in PWH, virologically suppressed for ≥1 year, with BMI ranging from 20 to 40 kg/m2. Participants completed study visits, labs, and an abdominal computed tomography scan in the overnight fasting state. Visceral fat was quantified by a single slice at L4-L5. Growth hormone (GH) levels, HOMA-IR and triglyceride:high-density lipoprotein (TG:HDL) ratios (an alternative measure of insulin resistance, IR) were also analyzed. Relationships with EVAF were assessed by Spearman correlation coefficients and Wilcoxon Two-Sample Tests (EVAF defined as ≥130 cm2). Results Of the 170 participants studied, the majority were white and male with an average age of 54 years. Median visceral fat area was 148 cm2 (94, 218) with an EVAF prevalence of 58%. Participants with EVAF had higher HOMA-IR values (p≤.0001) and higher TG:HDL ratios (p=0.0013) than those without EVAF. There was also a positive correlation between EVAF and HOMA-IR (ρ=0.43, p≤0.0001) and TG:HDL ratio (ρ=0.33, p≤0.0001). Importantly, greater visceral fat area was associated with higher 10-year ASCVD risk (p< 0.0001). To understand a potential driver behind this relationship between EVAF and CV risk, GH levels were explored. Increasing visceral fat surface area was inversely correlated with GH levels (ρ=-0.17, p=0.03); moreover, there were lower GH levels in subjects with EVAF (p=0.05). Conclusion Increased levels of visceral fat relate to increased CV risk scores, as well as the traditional risk factors of IR and lipid levels, which contributes to the heightened risk of CVD in PWH on modern ART regimens. The dynamics between decreased GH levels and EVAF found here support targeting EVAF reduction via the GH axis. Disclosures Karam Mounzer, MD, Epividian: Board Member|Epividian: Honoraria|GS: Advisor/Consultant|GS: Grant/Research Support|GS: Honoraria|Merck: Advisor/Consultant|THERA Technologies: Grant/Research Support|ViiV healthcare: Advisor/Consultant|ViiV healthcare: Grant/Research Support|ViiV healthcare: Honoraria John R. Koethe, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Merck & Co.: Advisor/Consultant|Merck & Co.: Grant/Research Support Jordan Lake, MD, Merck: Advisor/Consultant|Theratechnologies: Advisor/Consultant Mohammed Zogheib, PharmD, MPH, Theratechnologies: Employee Colleen McGary, PhD, Theratechnologies: Employee R Brandon Cash, PharmD, Theratechnologies: Employee

Abstract Sortilin (SORT1), or neurotensin receptor-3, is a scavenging receptor in the Vacuolar Protein Sorting 10 protein (Vps10p) family. SORT1 is involved in the internalization and trafficking of its ligands through an endocytic process and is associated with cancer cell survival and progression, making SORT1 a candidate for novel drug delivery. We recently reported on the pattern and prevalence of SORT1 expression in endometrial, breast, ovarian, colorectal, pancreas cancers, and skin melanoma. To better understand SORT1 expression, we screened tissues from different cancer types using the same immunohistochemistry (IHC) method. A total of 19 cancer tissue microarrays (TMAs) with 1394 evaluable cancer cores were screened. Each cancer core was scored using an H-score ranging from 0 to 300, where 0 corresponds to no cell stained for SORT1, while 300 corresponds to strong SORT1 staining in all cells. The table below summarizes the % of cores with moderate to high SORT1 expression (defined as H-score ≥100) as well as the average H-Score for each cancer type evaluated. Sub-analyses of SORT1 expression by tumor histological sub-type, stage and grade are also being performed. A total of 234 healthy or normal adjacent tissues cores were also assessed. Weak or null staining was observed in these tissues. Moderate staining was observed in specific cell types in kidney tubules and glomeruli, colonic mucosa, splenic sinusoidal spaces in red pulp, blood vessels in smooth muscle of spleen and colon, dendritic and axonal extensions of pyramidal-type neurons in brain, and testicular seminiferous tubules. SORT1 is currently being studied as a cancer target in a first-in-human (FIH) study of a peptide-drug conjugate (clinicaltrial.gov: NCT04706962). These results suggest that SORT1 is highly expressed in multiple tumors and is a promising target for the delivery and internalization of cancer therapeutic agents. Table 1. Cancer Type No. evaluable cores % of indication with H-score ≥ 100 Average H-Score Endometrial 94 90 197 Thyroid 108 92 188 Melanoma 155 83 184 Lung 152 58 112 SCLC 44 95 183 NSCLC 108 43 82 Bladder 118 81 156 Testis 40 100 116 Small intestine 54 63 102 Eye 26 46 83 Cervix 376 38 75 Prostate 150 39 71 Liver 121 23 52 Citation Format: Guylaine Roy, Pratik Kadekar, Lynn Marie Douglas, Maude Frappier, Jean-Christophe Currie, Jess Dhillon, Gregory Cesarone, Richard Siderits, Karen Kirchner, Michel Demeule, Christian Marsolais. Differential expression of a novel transport receptor, SORT1 (sortilin), in cancer versus healthy tissues that can be utilized for targeted delivery of anti-cancer drugs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3942.

Abstract Tumor-infiltrating immune cells are involved in the control of cancer and are closely related to clinical outcomes. 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. Melanomas express elevated levels of SORT1 and are considered as one of the most immunogenic tumors where immune checkpoint inhibitors are among the standard of care treatment used. Here, we first questioned whether TH1902 anti-cancer effects involved infiltration of immune cells in a murine SORT1-positive syngeneic, non-immunogenic and highly aggressive B16-F10 melanoma model in C57BL/6 mice. Weekly administration of docetaxel reduced by half the growth of B16-F10 tumor allografts, while administration of TH1902 as a single agent and at equivalent docetaxel doses, was well tolerated and resulted in tumor regression after only 2 treatments. Surprisingly, in this immunologically cold tumor, immunohistochemistry analysis of tumors for immune cell infiltration showed a net increase in total leukocytes (CD45+) infiltration within TH1902-treated tumors compared with docetaxel-treated tumors, especially with for tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Furthermore, the increased staining intensities for Perforin and Granzyme B were indicative of the elevated cytotoxic T and natural killer (NK) cells activity in TH1902-treated tumors. This corroborated with increased caspase-3 apoptotic activity. TH1902 and docetaxel doses were next halved and combined with the checkpoint inhibitor anti-PD-L1. In a first study, the TH1902/anti-PD-L1 combination resulted in increased tumor growth inhibition when compared with both agents alone. Interestingly, TH1902 as a single agent showed better tumor growth inhibition than docetaxel or docetaxel/anti-PD-L1 combination. In a second study, the TH1902/anti-PD-L1 combination significantly increased animal survival over either anti-PD-L1 or TH1902 as single agents (21 days increased median survival compared to 2.5 and 12.5 days respectively). We conclude that the superiority of TH1902 anticancer activity over docetaxel involves, in part, the modulation of infiltrating immune cells within the tumor microenvironment. 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. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Zgheib, Isabelle Cousineau, Richard Béliveau, Christian Marsolais, Borhane Annabi. The peptide-drug conjugate sudocetaxel zendusortide (TH1902) potentiates anti-tumoral activity of the anti-PD-L1 checkpoint inhibitor and induces immune cell infiltration in a B16-F10 syngeneic melanoma model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4499.

Background: Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemoresistance phenotype of human triple-negative breast CSC (hTNBCSC) and ovarian CSC (hOvCSC) is unknown. Methods and Results: Immunophenotyping of hTNBCSC and hOvCSC was performed by flow cytometry and confirmed the expression of SORT1, and of CSC markers CD133, NANOG, and SOX2. Western blotting demonstrated the expression of the drug efflux pumps from the P-gp family members, ABCB1 and ABCB5. The cellular uptake of the fluorescent Alexa488-peptide from TH1902 was inhibited upon siRNA-mediated repression of SORT1 or upon competition with SORT1 ligands. In contrast to docetaxel, TH1902 inhibited in vitro migration, induced cell apoptosis and lead to G2/M cell cycle arrest of the hTNBCSC. These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. In vivo, using immunosuppressed nude mice xenografts, TH1902 significantly inhibited the growth of hTNBCSC and hOvCSC xenografts (~80% vs. ~35% for docetaxel) when administered weekly as intravenous bolus for three cycles at 15 mg/kg, a dose equivalent to the maximal tolerated dose of docetaxel. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. Conclusions: 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.

BackgroundThe principal goal of antiretroviral therapy (ART) is durable suppression of HIV RNA. In treatment-experienced (TE) patients, ongoing viremia can lead to further accumulation of drug resistance, increased morbidity and mortality. ART efficacy often depends on HIV disease severity; therefore, we sought to assess its impact on long-term virologic suppression in patients treated with Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved for multi-drug resistant (MDR) HIV-1 treatment.MethodsIn TMB-301, a Phase 3 study, 40 TE patients with viral load (VL) >1000 copies/mL (c/mL) received an intravenous (IV) loading dose of IBA (2000mg) followed by maintenance doses (800mg IV) every 2 weeks combined with an optimized background regimen. Patients who completed TMB-301 in the US (n=27) continued to an expanded access protocol TMB-311. To determine the impact of baseline (BL) disease on long-term virologic response, we conducted an on-treatment analysis stratified by BL VL and CD4 count up to week 96. Differences in the proportion of suppressed (< 50 c/mL) individuals among the strata were assessed by Fisher’s exact test.ResultsMedian BL VL and CD4 count were 35,350 c/mL and 73 cells/mL, respectively. The number of patients in the VL strata were 11, 17 and 12 for VL < 10,000, 10,000-70,000, and >70,000 c/mL, respectively. There were 12, 10, 5 and 13 patients in the subgroups with CD4 count < 10, 10-100, >100-200 and >200 cells/µL. Population disease severity was reflected by four deaths (unrelated to study drug). Overall, the proportion of suppressed patients increased from 55% at week 24 (n=31) to 75% for patients remaining on treatment for 96 weeks (n=20). Median VL decrease was 2.9 log10 c/mL. Notably, no statistically significant differences were found across groups. Among patients with advanced HIV disease, 66.7% with CD4 count < 10 cells/mL and 71.4% with VL >70,000 c/mL at BL remained fully suppressed at week 96.ConclusionIn TE patients with advanced HIV disease, maximal viral suppression with IBA was observed regardless of BL CD4 or VL strata if patients remained on treatment. This demonstrates that TE patients across the spectrum of HIV disease, can achieve viral suppression by using drugs with a new mechanism of action.DisclosuresPrincy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Jason Leider, MD, PhD, THERA (Speaker’s Bureau) Jihad Slim, MD, Abbvie (Speaker’s Bureau)Gilead (Speaker’s Bureau)Jansen (Speaker’s Bureau)Merck (Speaker’s Bureau)ViiV (Speaker’s Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Maurice Leonard, PhD, Theratechnologies Europe Ltd (Employee, Shareholder) R Brandon Cash, PharmD, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

Supernumerary robotic limbs are emerging to augment human function. Unlike exoskeletons, these robots provide additional kinematic structures to the user that enable novel human-robot interactions. To assist walking, a supernumerary leg should be compliant to impacts, minimize efforts on users, move quickly when swinging and exert large assistive forces on the ground. Here, we study the potential of a supernumerary leg powered by delocalized magnetorheological clutches (MR leg) to assist walking with three different gaits. Simulations show that the MR leg's low actuation inertia reduces the impact impulse by a factor 4 compared to geared motors and that delocalizing the clutches reduces by half the inertial forces transmitted to the user during swing. An impedance controller receives a reference trajectory based on each ankle's position to move the MR leg in synchrony with the gait cycle. Experiments show that the MR leg can comfortably contact the ground and swing at 3.9 m/s for a 1.4 m/s walk. The MR leg tracks the ankle within 5% of the gait cycle for the leader-follower gait, alternately tracks both ankles for the double gait and contacts the ground in between each step for the three-legged gait. A theoretical upper limit suggests that the average transmitted power in a gait cycle could be 84 W for the leader-follower gait, which is 4 times higher than autonomous ankle exoskeletons.

Abstract Background: Triple-negative breast cancer (TNBC) still lacks defined molecular biomarkers. Thus, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the cell surface receptor Sortilin was reported in tumors from patients with TNBC. Given Sortilin’s functions in protein internalization and trafficking; we developed a new Sortilin-targeted peptide-anticancer drug conjugate to treat Sortilin-positive breast cancer. The conjugate consists of 2 molecules of Docetaxel linked to a 17 amino acids peptide (TH-1902) which enables specific binding to Sortilin and subsequent internalization of TH-1902. Methods: MDA-MB-231 breast cancer cells were used as a TNBC model for in vitro and in vivo xenograft assays. Female CD-1 nude mice (Crl:NU-Foxn1nu) were used for xenograft tumor models, female athymic nude mice (Crl:NU(NCr)-Foxn1nu) were used in hematotoxicology and female Crl: CD-1 mice were used for pharmacokinetic evaluation. In vitro cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. The microtubule polymerization and depolymerization assay was performed by spectrofluorimetry, whereas fluorescent TH-peptide uptake was assessed by flow cytometry. Tissue microarrays included 9 normal adjacent tissues, 35 infiltrating ductal carcinomas (IDC), and 10 lymph nodes metastatic (LNM) carcinomas. Hematotoxicity assay allowed for blood neutrophil counts analysis in plasma samples. Results: Fluorescent Alexa488-labeled TH-peptide was found to be internalized in MDA-MB-231 cells and reduced by 72% upon transient SORT1 gene silencing. Alexa488-labeled TH-peptide uptake was inhibited by 65% in the presence of an excess of unlabeled TH-peptide and by the Sortilin ligands Neurotensin and Progranulin. TH-1902 exerted potent anti-proliferative and anti-migratory activities in vitro. TH-1902, like Docetaxel alone, triggered cell death mechanisms. The apoptotic and anti-migratory effects were reversed upon siRNA-mediated gene silencing of SORT1. Conjugation of Docetaxel to TH-peptide did not affect its capacity to alter microtubule stabilization, once internalized and cleaved from the TH-peptide within the cells. This further triggered the down-regulation of IL-6, Bcl-xL and mutant p53 pro-survival biomarkers. Sortilin immunolabeling showed very low levels in normal adjacent tissues, whereas high levels of Sortilin labeling were scored in IDC and LNM. In vivo, TH-1902 exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Hematotoxic assays revealed that neutrophils count decreased significantly in Docetaxel-treated mice at MTD after 3 cycles, whereas they remained within normal limits in TH-1902-treated mice at an equivalent dose of Docetaxel even after six injections of TH-1902. Preliminary assessment of TH-1902 in normal CD-1 mice revealed that most Docetaxel remained associated with the peptide over the time course analyzed after a single IV bolus injection at 50 mg/kg. Absence of neutropenia in the presence of TH-1902 may be explained by the low levels of free Docetaxel in mouse plasma. Conclusions: The results demonstrate that Sortilin can be used as a target for treatment of TNBC. In addition, TH-1902 specifically internalized Docetaxel through a receptor-mediated mechanism exploiting Sortilin’s functions and significantly decreased the concentration of Docetaxel in normal cells. Overall, TH-1902 improved the efficacy and safety profiles compared to Docetaxel, which makes it a promising novel therapy for the treatment of TNBC. Citation Format: Michel Demeule, Cyndia Charfi, Jean-Christophe C Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau, Borhane Annabi. Receptor-mediated chemotherapy using a new Docetaxel-peptide conjugate for Sortilin-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-07.

Haptic joysticks for man-machine interaction used in aerospace flight control have highly demanding requirements of reliability, force density, and high dynamics that can hardly be met with conventional electromagnetic actuators. This work explores the potential of using an alternative actuation strategy based on hyper-redundant MR clutches that modulate the force of a tendon-driven 2-degree-of-freedom spherical gimbal. A system design and its closed-loop force control scheme are proposed. Experimental results for an open-loop characterization, static force control and dynamic force control are set out and compared with typical requirements for such devices from the literature. Results show that the proposed architecture leads to one of the lightest systems reported in the literature that has the potential to meet reliability requirements by providing ajam-free design with duplex fault tolerance, and yet, can generate high force levels while providing enough force resolution. The approach is promising and can extend to high-performance collaborative robot applications.

The recent embedding of electroencephalographic (EEG) electrodes in wearable devices raises the problem of the quality of the data recorded in such uncontrolled environments. These recordings are often obtained with dry single-channel EEG devices, and may be contaminated by many sources of noise which can compromise the detection and characterization of the brain state studied. In this paper, we propose a classification-based approach to effectively quantify artefact contamination in EEG segments, and discriminate muscular artefacts. The performance of our method were assessed on different databases containing either artificially contaminated or real artefacts recorded with different type of sensors, including wet and dry EEG electrodes. Furthermore, the quality of unlabelled databases was evaluated. For all the studied databases, the proposed method is able to rapidly assess the quality of the EEG signals with an accuracy higher than 90%. The obtained performance suggests that our approach provide an efficient, fast and automated quality assessment of EEG signals from low-cost wearable devices typically composed of a dry single EEG channel.