Drug Trials Research Articles

Ultrasound Patterns of Vitiligo at High Frequency and Ultra-High-Frequency.

To detect ultrasonographic anatomical alterations in all the skin layers in patients with vitiligo. A prospective observational color Doppler ultrasound study was performed in nonsegmental face and/or neck vitiligo patients without a history of previous treatments. Two sites, a lesional area and a contralateral clinically healthy region, were ultrasonographically studied and compared in the same patient. All cases were studied in high-frequency (24 MHz) and ultra-high-frequency (70 MHz) ultrasound devices with the highest axial spatial resolution available in the market. Demographic data of the sample, ultrasound grayscale, and color Doppler features were recorded and analyzed. Ten patients met the study criteria (60% females; mean age 49 years). All cases presented ultrasonographic undulation of the epidermis in the affected zones vs 50% in the healthy control regions, being more prominent in the vitiligo areas. Eighty percent demonstrated intense hypoechoic thin plaques in the upper dermis (subepidermal). All vitiligo areas presented thickening and hypoechogenicity of the regional hair follicles and/or pilosebaceous units. Ninety percent showed prominent sebaceous glands, and 20% demonstrated a hypoechoic cap surrounding the sebaceous glands in the lesional areas. Dermal hypervascularity was detected in 100% of the affected regions and 40% of the clinically healthy areas. Ultrasound can identify subclinical inflammatory cutaneous patterns in the epidermis, dermis, hair follicles, pilosebaceous units, and sebaceous glands in vitiligo. This noninvasive information can support early detection, monitoring, and research, including the clinical trials of drugs used to manage this devastating disease.

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates.

Lysine specific demethylase-1 (LSD1) serves as a regulator of transcription and represents a promising epigenetic target for anticancer treatment. LSD1 inhibitors are in clinical trials for the treatment of Ewing's sarcoma (EWS), acute myeloid leukemia, and small cell lung cancer, and the development of robust inhibitors requires accurate methods for probing demethylation, potency, and selectivity. Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. Inhibitors were also subject to viability studies in three human cell lines and Western blot assays to monitor H3K4me2 nucleosome levels in EWS (TC-32) cells, enabling a correlation of drug potency, inhibition in vitro, and cell-based studies. For example, SP-2577, a drug in clinical trials for EWS, inhibits activity on small peptide substrates (Ki = 60 ± 20 nM) using an indirect coupled assay but does not inhibit demethylation on H3K4me2 peptides or nucleosomes using direct Western blot approaches. In addition, the drug has no effect on H3K4me2 levels in TC-32 cells. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1.

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.

The cortical neurophysiological signature of amyotrophic lateral sclerosis

Abstract The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterise the cortical oscillatory signature of amyotrophic lateral sclerosis for potential as a pharmacodynamic biomarker. Eight-ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n=36) and healthy age-matched controls (n=51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutations-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a Random Forest Regression model was trained and evaluated using nested Leave-One-Out Cross-Validation. Amyotrophic lateral sclerosis was characterised by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta, and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The Random Forest model achieved a coefficient of determination (R2) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.

Animal models for the treatment of human diseases

Abstract Currently, studies conducted on animal models provide new insight into the aetiology and course of various pathological conditions in humans. Due to the cause of disease, animal models can be divided into two categories: natural models, such as nude mice, and induced models, such as transgenic pigs. This article discusses several examples of animal models and their contributions to the development of effective therapies for human diseases such as muscular dystrophy, cystic fibrosis, and atherosclerosis. In addition, we presented the latest news on gene therapy, xenotransplantation, and drug trials in humans and animals.

Complete Remission with Partial Hematological Recovery as a Palliative Endpoint for Treatment of Acute Myeloid Leukemia

Complete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. In comparison to patients with no response (NR), those with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (92.3% vs 22.3%, p < 0.0001) or TI for at least 112 days (63.5% vs 8.7%, p < 0.0001), a reduced risk over time for severe infection (HR 0.43, p = 0.0007) or severe bleeding (HR 0.17, p = 0.01), and a longer overall survival (OS) (HR 0.31, p < 0.0001). The effects were consistent across drugs. In comparison to patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.

Incorporating transgender and nonbinary participants in phase 1 clinical drug trials: Current knowledge gaps and considerations.

Phase 1 clinical drug trials critically depend on the participation of healthy volunteers to evaluate the safety and pharmacokinetics of new medicinal products. Current selection criteria and health definitions often overlook the unique health profiles of transgender and nonbinary individuals, potentially excluding them from participating in these essential early-stage studies. This review aims to identify and discuss current knowledge gaps and considerations regarding the inclusion of transgender and nonbinary participants in phase 1 clinical drug trials. We highlight the need for research on how gender-affirming hormone therapy may affect drug pharmacokinetics and call for the development of inclusive biological reference ranges that account for the physiological effects of hormone therapies.

Improved clinical data imputation via classical and quantum determinantal point processes

Imputing data is a critical issue for machine learning practitioners, including in the life sciences domain, where missing clinical data is a typical situation and the reliability of the imputation is of great importance. Currently, there is no canonical approach for imputation of clinical data and widely used algorithms introduce variance in the downstream classification. Here we propose novel imputation methods based on determinantal point processes (DPP) that enhance popular techniques such as the multivariate imputation by chained equations and MissForest. Their advantages are twofold: improving the quality of the imputed data demonstrated by increased accuracy of the downstream classification and providing deterministic and reliable imputations that remove the variance from the classification results. We experimentally demonstrate the advantages of our methods by performing extensive imputations on synthetic and real clinical data. We also perform quantum hardware experiments by applying the quantum circuits for DPP sampling since such quantum algorithms provide a computational advantage with respect to classical ones. We demonstrate competitive results with up to 10 qubits for small-scale imputation tasks on a state-of-the-art IBM quantum processor. Our classical and quantum methods improve the effectiveness and robustness of clinical data prediction modeling by providing better and more reliable data imputations. These improvements can add significant value in settings demanding high precision, such as in pharmaceutical drug trials where our approach can provide higher confidence in the predictions made.

Current immunotherapeutic approaches to diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6–7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, versus approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG.

Transgender people in clinical trials of drugs and biologics: An analysis of ClinicalTrials.gov from 2007 to 2023.

Transgender people have unmet health needs related to chronic conditions such as dementia, osteoporosis and hypertension. Community-driven advocacy increased transgender representation in phase III trials for pharmacological prevention of HIV, but the extent to which drug trials for other conditions have included transgender people is unknown. We investigated the extent to which trials of drugs and biologics represented transgender people across therapeutic areas on ClinicalTrials.gov. Cross-sectional analysis of trials of drugs and biologics registered on ClinicalTrials.gov from 2007-2023. We included efficacy and effectiveness trials (phase II-IV) with transgender-related terms (e.g. 'transgend*'). We labelled trials as Inclusive or Exclusive of transgender people using the trial eligibility criteria. We compared trials (therapeutic area, trial design, enrolment), summarized trials registered from 2008 onward and characterized participant enrolment for Inclusive trials with primary trial publications. We summarized continuous data using median (range), categorical data using frequencies and percentages and compared trial characteristics using Fisher's exact test. Ninety-seven trials represented transgender people. Characteristics were similar between 85 Inclusive and 12 Exclusive trials. Among Inclusive trials, 58% focused on infectious diseases (e.g. treatment or prevention of HIV and COVID-19), 15% on mental health (e.g. post-traumatic stress disorder, substance use-related disorders), and the remainder focused on endocrine (9%), pain (5%), digestive system disorders (1%) and neoplasms (1%). Twenty (of 25) trials reported enrolment of transgender participants in primary trial publications or reported results. Transgender-inclusive trials have increased since 2008. Most trials focused on infectious diseases and mental health. Investigators should increase opportunities to include of transgender people in trials of drugs and biologics for chronic diseases.

Women's health and kidney protective medications.

We discuss the sex-based differences in the pharmacokinetics and pharmacodynamics of kidney protective medications and their implications on women's health. A critical examination of adverse drug reactions highlights the underrepresentation of women in clinical trials for kidney and cardiovascular protective drugs, such as SGLT2 inhibitors, ACE inhibitors, and endothelin receptor antagonists. This underscores the need for sex-specific analyses in clinical studies to accurately assess medication efficacy and safety. The research demonstrates that women are more likely to experience adverse events and less likely to benefit from certain treatments, emphasizing the urgent need for healthcare providers to adopt a sex-informed approach in prescribing practices. Future research should prioritize sex differences from the outset to enhance understanding and improve clinical outcomes for women with chronic kidney disease and cardiovascular conditions.

Long-term outcomes of peripheral blood stem cell unrelated donors mobilized with filgrastim

AbstractAllogeneic hematopoietic cell transplantation is a life-saving procedure used to treat a variety of devastating diseases. It requires hematopoietic stem cells collected via filgrastim-mobilized peripheral blood stem cells (PBSCs) or bone marrow (BM) harvest from volunteer unrelated donors (URDs). There is a paucity of safety data regarding donors’ long-term adverse events. This prospective, observational study combined PBSC donors enrolled in the NMDP Investigational New Drug trial and BM donors between 1 July 1999 and 30 September 2015. The primary objective was to describe the long-term incidence of myeloid malignancies. The secondary objectives included describing the long-term incidence of lymphoid malignancies, nonhematologic malignancies, autoimmune disorders, and thrombotic events. A total of 21 643 donors (14 530 PBSCs and 7123 BM) were included. The incidence rate of myeloid disorders per 100 000 person-years in donors of PBSCs was 2.53 (95% confidence interval [CI], 0.82-7.84) and in donors of BM, it was 4.13 (95% CI, 1.33-12.8). The incidence rate ratio of PBSCs/BM donors was 0.61 (95% CI, 0.12-3.03; P = .55). The incidence of other malignancies, autoimmunity, and thrombosis did not differ between the donor types. This comprehensive study of the long-term effects of filgrastim in URDs of PBSCs provides strong evidence that donors who receive filgrastim are not at an increased risk of these events compared with BM donors. It also provides reassurance to current donors undergoing stem cell mobilization as well as individuals considering joining stem cell registries, such as NMDP.

Senolytics and cell senescence: historical and evolutionary perspectives

Abstract Senolytics are a new class of anti-aging drugs developed to selectively kill ‘senescent’ cells that are considered harmful in normal aging. More than twenty drug trials are ongoing with diverse ‘senolytic cocktails’. This commentary on recent reviews of senolytics gives historical context of mammalian cell senescence that enabled these new drugs. While cell senescence is considered harmful to aging tissues, many studies show its essential role in some regenerative and developmental processes for which senolytic drugs may interfere. Longer-term studies of side effects are needed before senolytics are considered for general clinical practice. The wide occurrence of cell senescence in eukaryotes, yeast to fish to humans, and suggests an ancient eukaryotic process that evolved multiple phenotypes.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura

BackgroundCongenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.MethodsIn this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.ResultsA total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.ConclusionsDuring prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)

Abstract PO4-14-08: A gene expression-based classifier for HER2-low breast cancer

Abstract Background: The definition of HER2-low breast cancer from clinical trials of antibody-conjugated drugs (ADCs) relies on immunohistochemistry scoring (IHC). However, in daily-practice the accuracy of IHC is hindered by inter-observer variability in assessing HER2 non-overexpressing status. Here, we aimed to identify breast cancer primary tumors with low HER2 expression by leveraging gene expression profiling. Materials and methods: A discovery approach was applied to gene expression profile of internal INT1 (n= 125) and INT2 (n= 84) datasets. We identified specific differently expressed genes (DEGs) according to HER2 IHC categories 0, 1+, 2+ and 3+. Principal Component Analysis (PCA) was used to generate a HER2-low signature whose performance was confirmed in the independent INT3 (n= 95), and TCGA and GSE20194 publicly available datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by non-parametric Kruskal-Wallis (KW) test with post hoc pair wise comparisons (i.e. contrasts); the HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC) with its corresponding 95% Confidence Interval (CI). Gene Ontology and KEGG analyses were performed to enrich the DEGs for functional information. Results: A 20-gene HER2-low signature, consisting of both up-regulated (n=11) and down-regulated (n=9) genes, was computed based on the DEGs according to HER2 IHC categories as follows: 11 genes specific for the 1+ category, 8 genes for the 2+ category, and 1 gene for the HER2-low category. HER2-low signature genes were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature levels demonstrated a significant association with HER2 IHC categories (KW p-value &amp;lt; 0.001) and were distributed in a bell-shaped pattern across IHC categories (low values 0 and 3+; high values 1+ and 2+), effectively distinguishing HER2-low from 0 (contrast p-value &amp;lt; 0.001) and 3+ (contrast p-value &amp;lt; 0.001). Notably, the signature levels were significantly higher in tumors scored with 1+ as compared to 0 (contrast p =0.002). The HER2-low signature association with IHC categories and discriminatory capability was confirmed in the independent INT3 and TCGA datasets with higher values in HER2-low compared to both 0 and 3+. The HER2-low signature achieved an AUC value of 0.72 (95%CI 0.62-0.83) in differentiating HER2 0/3+ from HER2 1+/2+ categories, which is worth noting in light of the individual ERBB2 mRNA AUC value of 0.48 (95%CI 0.34-0.62). Conclusions: The 20-gene HER2-low signature was generated by maximizing the differences in gene expression between tumors with different HER2 status according to IHC. In contrast to the previously published single ERBB2 gene expression assessment, our data presents compelling evidence for effectively distinguishing HER2-low tumors, including those scored as 1+ from HER2-0 tumors. Our signature holds potential in selecting novel candidates for ADC therapy. Citation Format: Serena Di Cosimo, Sara Pizzamiglio, Chiara Maura Ciniselli, Valeria Duroni, Vera Cappelletti, Loris de Cecco, Maria Carmen De Santis, Rosaria Orlandi, Marilena Iorio, Marco Silvestri, Giancarlo Pruneri, Paolo Verderio. A gene expression-based classifier for HER2-low breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-08.

Abstract PO5-14-06: Transcriptomics-based drug screening in 3D ex vivo patient-drived breast cancer model and patient biopsy for personalized therapy

Abstract Breast cancer is a leading cause of cancer-related mortality for women worldwide. Hormone receptor-positive (HR+) breast tumors, which represent 70% of all breast cancer cases, are treated with endocrine therapy. However, not all patients benefit from this treatment regimen because of patient-to-patient variation. Therefore, high throughput drug screening system is warranted to enable personalized medicine. Patient-derived organoids, which serve as a screening platform, lose their hormone receptors and response upon ex vivo culturing, and may not be adequate models for HR+ breast tumors. Moreover, unidentified biological components in the widely-used basement membrane matrix, Matrigel, result in high batch-to-batch variations and poor reproducibility in organoid cultures. Here, we propose a hydrogel-based 3D ex vivo model with defined structural and chemical properties to test hormone and drug sensitivity of HR+ breast tumors from patient-derived xenografts (PDXs) and patient tumor biopsies using microfluidics. Our data demonstrate the feasibility of this model to preserve cell proliferation and hormone receptor expression over 7 days. We also demonstrate that responses to hormones and FDA-approved drugs are faithfully maintained in this model. Finally, to establish a high throughput hormone and drug testing workflow with transcriptomic readout, we multiplexed barcoded- and drug-treated tumor samples in a single experiment with bulk RNA-sequencing. Our preliminary data demonstrate patient-specific responses to hormones and drugs that correspond to patient genetic mutation profiles, treatment history, disease stages and subtypes. This platform also enables testing of drugs in clinical trials that shows promising therapeutic outcomes for breast cancer, such as CDK4/6i, AKTi, PARPi, mTORi and their combination with endocrine therapy, thanks to the high throughput of the screening system and the low consumption of patient-derived or patient tissue. Given the capability of combining this physiologically-relevant 3D ex vivo model with RNA-seq for HR+ breast tumors, this platform holds potential for high throughput compound testing and transcriptomic profiling of patient biopsies for personalized medicine. Citation Format: Yueyun Zhang, Carlos Henrique Venturi Ronchi, Giovanna Ambrosini, Yuanlong Liu, Patrick Aouad, Daria Matvienko, Christoph Merten, Cathrin Brisken. Transcriptomics-based drug screening in 3D ex vivo patient-drived breast cancer model and patient biopsy for personalized therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-06.

Abstract PO4-10-12: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023

Abstract Title: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 Background: The number of FDA-approved genome-targeted cancer drugs for metastatic breast cancer has increased, providing the potential for personalized therapy. To help physicians, patients, and policymakers differentiate meaningful from trivial innovation in this field, we assessed the validity of the targets and value of the outcomes used in the pivotal trials supporting approval. Methods: We analyzed trials supporting genome-targeted breast cancer drugs FDA-approved between 2006-2023, defined as those using a genomic test in which the drug targeted a given genomic alteration. From FDA drug labels and trial reports, we extracted characteristics of pivotal trials. For Accelerated Approvals—a special FDA program allowing approval based on unvalidated surrogate measures—if the drug later received traditional approval based on a confirmatory trial, only the latter was analyzed. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for approved indications was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets qualifying for ESCAT category level I-A or I-B associated with ESMO-MCBS grade 4 or 5 were rated as high-benefit genomic-targeted breast cancer treatments. Results: Fifteen genome-targeted drugs covered 17 indications and targeted 8 driver alterations. Among the 17 pivotal trials supporting these indications, most were randomized (11, 65%), phase 3 (11, 65%) and open-label (14, 82%). The most common primary endpoint leading to approval (10, 59%) was progression-free survival. Eleven trials (65%) had a I-A ESCAT targetability, 5 (29%) had a I-C targetability score and 1 (6%) was categorized as II-A. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were classified as tier I-A due to randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. RET fusions, NTRK fusions, and microsatellite instability were classified as tier I-C, while high-tumor mutational burden was categorized as tier II-A. Eighteen percent of trials (3/17) demonstrated ESMO-MCBS grades 4-5. Overall, 3 of 17 (18%) indications had high-benefit genomic-based cancer treatments. Conclusions: Among molecular-targeted cancer therapies approved for metastatic breast cancer, fewer than a fifth demonstrated substantial patient benefits at approval. Benefit frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Consolacion Molto Valiente, Jerry Avorn, Aaron Kesselheim. Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-12.

Potential therapeutic strategies to halt viral neuroinvasion.

The viral infection of the central nervous system is a significant public health concern. So far, most clinical cases of viral neuroinvasion are dealt with supportive and/or symptomatic treatments due to the unavailability of specific treatments. Thus, developing specific therapies is required to alleviate neurological symptoms and disorders. In this review, we shed light on molecular aspects of viruses' entry into the brain which upon targeting with specific drugs have shown promising efficacy in vitro and in preclinical in vivo model systems. Further assessing the therapeutic potential of these drugs in clinical trials may offer opportunities to halt viral neuroinvasion in humans.

Pre-treatment bone mineral density (BMD) and the benefit of pharmacologic treatment on fracture risk and BMD change: analysis from the FNIH-ASBMR SABRE project.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). This study used data from a large set of randomised controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into femoral neck (FN) BMD T-score subgroups (≤ -2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all fracture outcome reached statistical significance (interaction p = 0.001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all and all clinical fractures in the lower BMD quintiles (all interaction p ≤ 0.03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

Facilitators and barriers to adolescent participation in a TB clinical trial.

<sec id="st1"><title>BACKGROUND</title>The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.</sec><sec id="st2"><title>METHODS</title>Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.</sec><sec id="st3"><title>RESULTS</title>Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.</sec><sec id="st4"><title>CONCLUSION</title>Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial.</sec>.