iCo Therapeutics (Canada)

Thyroid function laboratory testing is often overused. Tailored de-implementation interventions require an understanding of underlying barriers and facilitators contributing to overuse. We performed a mixed-methods study exploring barriers and facilitators of appropriate thyroid function testing using surveys and focus groups conducted between June and October 2023 in British Columbia, Canada. Quantitative survey data were summarised using simple statistics, and open-ended survey questions were summarised using summative content analysis. Focus group transcripts were analysed using thematic analysis. Key themes were mapped onto the combined Theoretical Domains Framework and Capability, Opportunity, Motivation-Behaviour model. 230 practitioners completed the survey (1.4% response rate), and 53 practitioners attended a total of six focus groups. Three themes emerged around barriers from synthesising the results: patient expectations, practitioner knowledge gaps and health system factors. Patient expectations were linked to non-specific symptoms, recommendations from alternate care providers, increased interest in hormone testing and internet searches, leading to patient requests for more testing and/or referrals to specialists. Knowledge gaps included use of specialised tests, interpretation of free hormone results, frequency of thyroid testing and screening in asymptomatic, pregnant and postpartum patients. Health system barriers included lack of practitioner time, lack of family doctors leading more patients to seek care from alternative providers, existing order sets and ordering processes, and existing culture of ordering practices. Identified facilitators of behaviour change towards appropriate thyroid testing included educational resources for practitioners and patients, leveraging of health information systems for seamless viewing of prior test results, reflexive testing and provision of personalised practitioner feedback. Interventions to reduce overutilisation of thyroid testing should include easily accessible physician educational and feedback resources, patient educational materials and changes to laboratory ordering processes and information systems. Future studies should develop and evaluate the use of these intervention elements in British Columbia.

<h3>Objectives</h3> The terms ‘prediabetes’ (6.0% ≤ A1c ≤ 6.4%) and ‘mild diabetes’ (6.5% ≤ A1c ≤ 7.0%) describe conditions where blood sugar levels are elevated but still fall within the treatment targets set by national guidelines and specialty societies for type 2 diabetes. While some view these diagnostic labels as offering opportunities for early intervention and delaying disease progression, there are concerns regarding overdiagnosis, with potential consequences including over-testing and overtreatment. Currently, there is limited understanding of patient experiences and priorities regarding the diagnosis and management of pre- or mild diabetes. <h3>Method</h3> We conducted a qualitative study engaging individuals recently diagnosed with pre- or mild diabetes, in collaboration with health services researchers, healthcare professionals, and patient research partners. Following the Patient Engagement Framework from the Strategy for Patient Oriented Research (SPOR), we worked with three patient research partners from British Columbia, Alberta, and Ontario, Canada. Together, we obtained funding, designed and conducted pre-interview surveys and interviews, and analyzed data to better understand patient experiences and priorities. We used reflexive thematic analysis, following Braun and Clarke’s approach, to develop meaning-based themes. <h3>Results</h3> Twelve adults have participated in this study so far, with four to eight more anticipated. Of all participants 66.7% had prediabetes and 33.3% had mild diabetes. The majority (58.3%) of participants were in the 40–60 years age range. We developed three main themes: i) While experiencing a range of negative emotions following initial diagnosis, participants often expressed gratitude for early detection and symptom awareness, ii) valued receiving information and education early on, and iii) desired individualized treatment approaches that aligned with their priorities, taking health equity factors into account. As an important subtheme under the third theme, while lifestyle modification was often preferred as the initial approach, many participants also acknowledged pharmacotherapy as a viable option when lifestyle changes had been maximized or could no longer be further optimized. <h3>Conclusions</h3> This study focuses on the balance between the perceived benefits of early intervention and the risks of overdiagnosis and its consequences. Understanding patient experiences and perspectives in early-stage diabetes highlights the need for shared decision-making and individualized care. Insights will guide the development of tools and resources to help both patients and clinicians shape and navigate informed, patient-centered care. Future work is needed to clarify the evidence for early diagnosis or treatment of people with pre- or mild diabetes to avoid overdiagnosis and overtreatment.

Abstract Targeted radiotherapies represent an emerging treatment modality for aggressive cancers with limited treatment options, such as small cell lung cancer (SCLC). ABD147 is a Delta Ligand 3 (DLL3)-targeted antibody conjugate designed to carry and deliver cytotoxic radioactive isotopes to DLL3-expressing tumor cells. DLL3 is commonly expressed on the cell surface of neuroendocrine cancer cells, including SCLC, but has limited and predominantly intracellular expression in non-malignant tissues. The ABD147 antibody specifically binds human DLL3 with high affinity and is internalized by DLL3-expressing cancer cells. To minimize radiation exposure to normal tissue, ABD147 has been engineered to clear quickly from the blood compartment. Using indium-111 to determine ABD147 pharmacokinetics and biodistribution in mice, we demonstrate rapid blood and normal tissue clearance of 111In-ABD147, as designed, following a single intravenous dose administration. However, 111In-ABD147 retains high tumor accumulation (activity concentration of up to 30% ID/g) in xenograft mouse models of SCLC despite low DLL3 surface antigen expression on tumor cells (≤ 3000 copies). 111In-ABD147 shows a favorable tumor-to-normal tissue distribution with predominant liver clearance. Following ABD147 therapeutic radioisotope delivery of actinium-225 or lutetium-177 (225Ac-ABD147, 177Lu-ABD147), we demonstrate single-dose tumor regression and dose-dependent sustained anti-tumor efficacy, corresponding to an extension of survival out to 84 days in multiple SCLC xenograft models. In summary, ABD147 can preferentially deliver radionuclides to DLL3-expressing tumor tissue while substantially reducing the systemic radioactive exposure typical of conventional IgG radioconjugates. Following promising results in preclinical models, including potent anti-tumor activity, 225Ac-ABD147 is now progressing into clinical development. Citation Format: Iva Kulic, Etienne S. Melese, Emma Cummins, Alex Mandel, Raja Viswas, Michael Abrams, Adam Judge. Preferential tumor-to-normal tissue biodistribution and single-dose efficacy with ABD147, a DLL3-targeted engineered antibody-based radiotherapeutic, in preclinical small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6028.

Over 25% of older adults live with type 2 diabetes (T2DM).1 Current guidelines discourage intensive T2DM treatment in older adults with functional limitations, dementia, and/or frailty, such as those living in long-term care (LTC). Intensive T2DM treatment has unclear benefit in this population, increases risk of harm, and may have a deleterious effect on quality of life.1, 2 Diabetes Canada guidelines recommend moderate control in this population (e.g., HbA1c targets 7.1%–8.5% or higher), and to avoid sulfonylureas (SUs) or insulin.3 Despite unclear benefit and increased risk of harm, older adults in LTC may be overtreated for T2DM.4-8 People that are overtreated may benefit from stopping or reducing the dose of antihyperglycemics (“deprescribing”).9, 10 This examined rates of overtreatment and deprescribing of antihyperglycemics at urban LTC facilities in British Columbia, Canada. Residents with an HbA1c available at baseline were categorized as overtreated if they had a baseline HbA1c of <7% (on any antihyperglycemic[s]) or if they had a baseline HbA1c of <7.5% on a SU or insulin. Deprescribing was defined as having an antihyperglycemic stopped or the dose reduced without having another antihyperglycemic medication started or increased. We captured the proportion of antihyperglycemic medications that were changed as well as the proportion of individual residents that had an antihyperglycemic change during the follow up period. We used descriptive statistics to summarize the data. The study was approved by the University of British Columbia (UBC) Research Ethics Board (REB) and received Providence Health Care Institutional Approval (UBC REB # H22-01575). Of 630 residents in the five LTC homes, 120 residents met inclusion criteria (Table 1). Among residents with an HbA1c available (n = 85), 34/85 residents (40%) met the criteria for being overtreated. We found that 17/34 (50%) residents in the overtreated group had an antihyperglycemic stopped during follow-up and <5 had a dose reduced, while 9/51 (18%) of the not overtreated group had an antihyperglycemic stopped and 5/51 (10%) had a dose reduced. This corresponded to a deprescribing rate of 50% in the overtreated group and 27% in the not overtreated group, over 6 months (Figure 1). In the overtreated group, <5 residents had a dose increased or a new antihyperglycemic started over the study period. In the not overtreated group, the dose was increased for 6/69 (9%) of antihyperglycemics used at baseline and at least one new antihyperglycemic was started over the study period in 17/51 (33%) residents. Antihyperglycemics were started and subsequently stopped over the study period for 5/34 (15%) residents in the overtreated group compared to 10/51 (19%) residents in the not overtreated group. Medications were stopped and subsequently restarted in <5 residents in the overtreated group and <5 residents in the not overtreated group. Our results suggest that overtreatment of T2DM continues to occur in LTC. The rates of overtreatment we observed are consistent with other published studies among LTC residents in Canada and the United States.4-8 We found higher rates of deprescribing compared to a recent study in US LTC homes, which may be explained by our longer follow-up period.8 Limitations included missing HbA1c data for around 30% of residents with diabetes. We did not capture ethnicity, socioeconomic factors, and other factors that could affect T2DM management. Data collection was limited to urban Vancouver area LTC homes. Deprescribing of antihyperglycemics in LTC appears to be safe, with a 2022 US cohort study finding deintensification was not associated with an increased risk of adverse events (ED visits, hospitalizations, death) at 60 days.10 However, scaling back T2DM care can be challenging for both healthcare providers and people with T2DM.11 Most healthcare providers and people with T2DM are open to considering antihyperglycemic deprescribing but require support, tools, and guidance to do so.11, 12 Efforts that promote individualizing T2DM care in LTC continue to be warranted. This may include knowledge translation efforts for existing guidance and/or quality improvement or implementation strategies.1, 3 Concept and design: Wade Thompson, Aaron Tejani. Acquisition of data: Wade Thompson, Aaron Tejani, Isla Drummond, Jeffrey Pan, Alixandra Logan, AmirHossein Moradi, Maric Son, Heather Brodoway, Kanika Khosla, Kruti Shukla. Analysis and interpretation of data: All. Manuscript preparation: All. The authors would like to acknowledge Anthony Tung for his assistance with drug utilization data. None to declare. This article did not receive any financial support and thus no sponsor had a role in the study. No sources of funding.

Fenretinide is a synthetic retinoid pharmaceutical linked to ceramide build-up in vivo. Saposin D is an intralysosomal protein necessary for ceramide binding/degradation. We show, via electronic absorption spectroscopy, fluorescence spectroscopy, and ceramide hydrolysis assays, that fenretinide is bound by saposin D {K a = (1.45 ± 0.49) × 105 M-1}, and affects ceramide solubilization/degradation.

Visceral leishmaniasis is a deadly parasitic disease caused by obligate intramacrophage protozoans of the Leishmania genus. The World Health Organization estimates the annual death toll to be 50,000, with 500,000 new cases each year. Without treatment, visceral leishmaniasis is inevitably fatal. For the last 70 years, the first line of defense has been pentavalent antimonials; however, increased resistance has brought amphotericin B to the forefront of treatment options. Unfortunately, the difficult route of drug administration, toxicity issues, and cost prevent amphotericin B from reaching the infected population, and mortality continues to rise. Our reformulation of amphotericin B for oral administration has resulted in a highly efficacious antileishmanial treatment that significantly reduces or eradicates liver parasitemia in a murine model of visceral leishmaniasis. This formulation has overcome amphotericin B's significant physicochemical barriers to absorption and holds promise for the development of a self-administered oral therapy for the treatment of visceral leishmaniasis.

Diabetic retinopathy is one of the leading causes of blindness in the United States and other parts of the world. Historically, laser photocoagulation and vitrectomy surgery have been used for the treatment of diabetic retinopathy, including diabetic macular edema. Both procedures have proven to be useful under certain conditions but have their limitations. New pathways and processes that promote diabetic retinopathy have been identified, and several new therapeutic approaches are under investigation. These new therapies may be beneficial in the treatment of diabetic retinopathy and include antivascular endothelial growth factor agents, corticosteroids, and therapies that may potentially target a number of additional diabetic retinopathy-related factors and processes, including antisense oligonucleotides. Second-generation antisense oligonucleotides, such as iCo-007, may offer a significant advantage in the treatment of diabetic retinopathy by downregulating the signal pathways of multiple growth factors that seem to play a critical role in the process of ocular angiogenesis and vascular leakage. Benefits of such molecules are expected to include the specificity of the kinase target and an extended half-life, resulting in less frequent intravitreal drug administration, resistance to molecule degradation, and a good safety profile.