Orphan Drug Research Articles

Revision of pharmaceutical legislation in the context of antimicrobial resistance and challenges facing the introduction of innovative antimicrobial medical products in Europe

The presented article provides a systematic review of the pharmaceutical legislation (EU Pharmaceutical Package) – the current proposal of the European Commission for a new Directive, repealing and replacing Directives and modifying Regulations of the European Parliament and of the Council, incorporating the relevant parts of the Regulation concerning medicinal products for pediatrics, Regulation for orphan drugs and others, aiming at revision of the pharmaceutical legislation in the context of antimicrobial resistance and challenges facing the introduction of innovative antimicrobial medicines in Europe. It outlines a critical analysis on the impact of the changes in the context of introduction of innovative antimicrobial medicinal products with an emphasis on unsatisfied medical demands of the European population. The revision of the pharmaceutical legislation provides an argument to consider that the proposed Pharmaceutical Package could resolve some of the issues associated with the access to novel antibiotic medicines. It is necessary to find a consensus and a balance between, on the one hand, meeting the need for antibiotics for the citizens of the European Union and, on the other hand, providing timely access to generic medicines to meet the needs of the population.

Societal preferences for granting orphan drugs special status in reimbursement decisions

BackgroundOrphan drugs, for patients with a rare disease, are increasingly available but often do not meet standard cost-effectiveness criteria for reimbursement. Consequently, policymakers regularly face the dilemma whether to relax these criteria for reimbursing orphan drugs. We examined whether—and why—there would be societal support for such differential treatment of orphan drugs. MethodsWe conducted a labelled discrete choice experiment in a sample of the adult population (n = 1,172) in the Netherlands. Respondents were presented with ten choices on whether to reimburse an orphan drug given that a non-orphan drug with similar characteristics would not be reimbursed, because it was not cost-effective, and asked to explain their choices. We used random-intercept logit regression models and inductive coding for analysing the quantitative and qualitative data. ResultsOf the respondents, 36.4% consistently chose for reimbursing the orphan drug, mostly because “everyone is entitled to live a healthy life and good quality healthcare”, and 17.3% consistently for not reimbursing the orphan drug, mostly because “[this] is unfair to patients with a common disease”. The remaining 46.3% made alternating choices and were more likely to choose for reimbursing orphan drugs when patients were aged between 1 and 70 years, had moderate disease severity, and considerable health gain from treatment. ConclusionsThis study finds considerable support but also strong preference heterogeneity amongst members of the public in the Netherlands for differential treatment of orphan drugs in reimbursement decisions, when these drugs do not meet common cost-effectiveness criteria. However, a substantial minority opposes differential treatment, mostly on moral grounds.

LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency.

New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing.

An update on management of rare diseases in India

Rare diseases, characterized by their prevalence in smaller segments of the population, pose significant challenges globally. While definitions may vary across nations based on prevalence rates, these conditions are often life-threatening despite affecting fewer individuals. Genetics play a prominent role, contributing to approximately 80% of rare disorders, with treatments often categorized as ‘orphan drugs’. Regardless of a country's economic status or development level, rare diseases impose substantial burdens on healthcare systems and national economies. In India, rare diseases represent a pressing public health concern, yet they often receive inadequate attention and resources. Factors such as insufficient diagnosis, limited awareness, sparse epidemiological data, high treatment costs, and scant research and development exacerbate the challenges faced by patients and healthcare providers. Despite their significant impact, rare diseases remain a neglected area within the healthcare landscape. The aim of this review was to shed light on the rare disease landscape in India by examining available secondary data from published sources. By comprehensively assessing the existing literature, researchers seek to gain insights into the prevalence, management, and challenges surrounding rare diseases in the Indian context. This endeavor is crucial for informing policymakers, healthcare professionals, and stakeholders about the urgent need for improved strategies and resources to address the complex issues associated with rare diseases in India.

The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report.

In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher-project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key.

Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure

Serious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients.

Solving the puzzle of 2-hydroxypropyl β-cyclodextrin: Detailed assignment of the substituent distribution by NMR spectroscopy

2-Hydroxypropyl-β-cyclodextrin (HPBCD) is one of the most important cyclodextrin derivatives, finding extensive applications in the pharmaceutical sector. Beyond its role as an excipient, HPBCD achieved orphan drug status in 2015 for Niemann-Pick type C disease treatment, prompting research into its therapeutic potential for various disorders. However, the acceptance of HPBCD as an active pharmaceutical ingredient may be impeded by its complex nature. Indeed, HPBCD is not a single entity with a well-defined structure, instead, it is a complex mixture of isomers varying in substituent positions and the degree of hydroxypropylation, posing several challenges for unambiguous characterization. Pharmacopoeias' methods only address the average hydroxypropylation extent, lacking a rapid approach to characterize the substituent positions on the CD scaffold. Recognizing that the distribution of substituents significantly influences the complexation ability and overall activity of the derivative, primarily by altering cavity dimensions, we present a straightforward and non-destructive method based on liquid state NMR spectroscopy to analyze the positions of the hydroxypropyl sidechains. This method relies on a single set of routine experiments to establish quantitative assignment and it provides a simple yet effective tool to disclose the substitution pattern of this complex material, utilizing easily accessible (400 MHz NMR) instrumentation.

[Translated article] Current situation and evolution of the availability of drugs in the pediatric population in Spain

ObjectiveTo analyze the characteristics of the new medicines approved in the pediatric population in the last 3 years, both those with studies only in the pediatric population and those that extend their indication in this population group, as well as the current situation in relation to their marketing and financing. MethodsDescriptive observational study of all drugs that include an indication in the pediatric population in Spain (by extension of the indications of drugs already authorized or because they are new drugs that already include an indication in this population group), from January 2019 to March 2022. ResultsDuring the study period, 129 drugs included their indication in the pediatric population. 13.9% of them are not marketed, 46.5% are in a situation of non-financing, under study or without a request for financing, and 4.6% are financed for a specific pediatric subpopulation. 52.7% are original drugs, 4.7% are generic, 38.8% are biological, 3.8% are biosimilar, and 17.8% are orphan drugs. 57.36% of these medicines obtain the pediatric indication due to extension of the indication and 42.64% obtain it because they are new medicines that already include their studies in the pediatric population. ConclusionsDrugs with authorized indications are increasingly available in the pediatric population and the trend is to extend the indication of authorized drugs to the adult population. However, barriers in terms of financing and marketing need to be expedite and overcome to facilitate access to them.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

Availability and Access to Orphan Drugs for Rare Cancers in Bulgaria: Analysis of Delays and Public Expenditures.

Rare cancers are defined by an annual incidence of fewer than 6 per 100,000. Bearing similarities to rare diseases, they are associated with substantial health inequalities due to diagnostic complexity and delayed access to innovative therapies. This situation is further aggravated in Southeastern European countries like Bulgaria, where limited public resources and expertise underscore the need for additional policy and translational research on rare cancers. This study aimed to explore the availability and access to orphan drugs for rare cancers in Bulgaria for the period of 2020-2023. We cross-compared data from both the European Union and national public sources to evaluate the number of available and accessible orphan drugs for rare cancers, the delay from market authorization to reimbursement, the dynamics of public expenditures, and regional disparities in access across the country. We juxtaposed the main characteristics of oncological and non-oncological orphan drugs as well. Only 15 out of 50 oncological orphan drugs that were authorized by the European Medicine Agency were accessible for rare cancer patients in Bulgaria. The median delay between market authorization and inclusion in the Bulgarian Positive Drug List was 760 days. The total expenditures for all orphan drugs for rare cancers amounted to EUR 74,353,493 from 2020 to 2023. The budgetary impact of this group rose from 0.24% to 3.77% of total public medicinal product expenditures for the study period. Rare cancer patients represent a vulnerable population that often faces limited to no access to treatment. We call for targeted European and national policies to address this major inequality.

Pozelimab, a human monoclonal immunoglobulin for the treatment of CHAPLE disease.

The complement is a crucial factor of the innate immune system. However, its activation can lead to various diseases, so it needs to be controlled. In mammals, surface-bound complement regulatory proteins safeguard cells from uncontrolled complement-mediated lysis. One of the human complement regulators is CD55, also known as the decay-accelerating factor (DAF), a single-chain, type I cell surface protein anchored to glycosylphosphatidylinositol (GPI). The genetic loss of the complement regulatory protein CD55 leads to a fatal illness known as CHAPLE disease. The complement and innate immunity become hyperactive in this disease, causing angiopathic thrombosis and protein-losing enteropathy. Patients with CHAPLE disease experience abdominal pain, nausea, vomiting, diarrhea, loss of appetite, weight loss, impaired growth, and swelling. This genetic condition has no known cure, and managing its symptoms can be challenging. Pozelimab, a human monoclonal immunoglobulin IgG4 antibody, is a drug that targets the terminal complement protein C5. The drug has a high affinity for both wild-type and variant human C5. Pozelimab has received designations such as fast track, orphan drug, and rare pediatric disease, making it a significant medical breakthrough. It is currently the only available treatment for this disease. In this review, we have summarized the preclinical and clinical data on pozelimab.

Preisregulierung durch Nutzenbewertung bei seltenen Erkrankungen

The aim of the study is a detailed investigation of the population-normalized treatment costs of orphan drugs. For this purpose, a study was already conducted in 2022 to examine the treatment costs of orphan drugs for the years 2005 to 2021. The calculations have now been validated as part of a study update, using the identical sample size. The update enabled an inflation adjustment based on the price index of the year 2022, as well as complete treatment costs after AMNOG assessment and price negotiation for all orphan drugs. The analysis shows that the AMNOG also fulfills its function as a price regulation instrument for orphan drugs. Since the introduction of AMNOG, the inflation-adjusted normalized treatment costs for orphan drugs have fallen both in terms of the launch price (minus 25%) and the reimbursement amount (minus 6%).

Abstract CT105: Early clinical experience with a novel first-in-class G-quadruplex experimental anti-cancer drug

Abstract The human genome contains G-rich regions that are over-represented in many cancer gene promoters. These can form higher-order G-quadruplex arrangements under the influence of an appropriate and selective small molecule compound. The resulting ligand-G-quadruplex complex may be resistant to polymerase read-through and thus results in transcriptional down-regulation of target genes. QN-302, based on a tetra-substituted naphthalene diimide chemotype, is a potent and selective G-quadruplex-binding compound that has been designed and initially developed at University College London. It displays single-digit cell growth inhibition in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. RNA-seq analysis shows that it is a pan-quadruplex agent, down-regulating the expression of multiple G-quadruplex-promoter cancer genes and pathways in PDAC. It also shows in vivo anti-tumor activity in several animal models for PDAC, with low toxicity observed at therapeutic doses. QN-302 was licensed to Qualigen Therapeutics Inc in January 2022. It was granted Orphan Drug designation by the FDA in December 2022 for PDAC. This was followed by extensive regulatory toxicological and pharmacological studies together with successful scale-up synthesis, purification and formulation. QN-302 was granted IND clearance in August 2023 by the FDA for phase 1 clinical trials in advanced or metastatic solid tumors. This Phase 1a clinical trial is being conducted in two USA cancer centers (START Midwest, Grand Rapids, MI and Honor Health, Scottsdale, AZ) using a protocol based on 28-day once-weekly dose escalation and evaluation of three potential biomarkers, two of which have been suggested by transcriptomic analysis as being indicative of G-quadruplex-induced drug response and accompanying decrease of anti-tumor activity. So far 1 Cohort (3 patients) has been dosed at the lowest dose of 1.62 mg of QN-302 as part of this Phase 1a clinical trial. Patient #1, a male patient of metastatic pancreatic cancer, is currently in Cycle 4 of therapy showing Stable Disease and no AEs or SAEs reported. Patient #2, a female patient of metastatic colorectal cancer, completed Cycle 2 after which she showed progression upon CT Scan before entering Cycle 3 and was taken off study. Patient #3, a male patient of metastatic PDAC, is currently ending Cycle 2, about to enter Cycle 3, showing Stable Disease upon CT scan. All patients dosed showed no AEs, SAEs or side effects. They were also clinically observed to have improved QOL compared to prior SOC while on therapy with QN-302, This presentation will outline this unique approach and summarize safety, tolerability, PK/PD data and any early clinical data as described above including preliminary biomarker data now that clinical evaluation has commenced. The advantages and challenges of QN-302 will also be discussed. Citation Format: Tariq Arshad, Stephen Neidle, Sreenivasa Chandana, Erkut Borazanci. Early clinical experience with a novel first-in-class G-quadruplex experimental anti-cancer drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT105.

Diversity Plans and Postmarketing Studies: First Impressions of Anticipated Diversity Requirements in the United States.

Recent Food and Drug Administration (FDA) draft guidelines are intended to improve representation and formalize the assessment of race and ethnicity in drug development, but how regulators and industry stakeholders plan to implement and enforce new requirements is still being determined. Here, a 10-question survey was developed to assess the experiences of industry stakeholders in developing diversity plans. These survey results informed an analysis of postmarketing studies to understand how diversity requirements have been enforced to date. Among 13 survey responders, experience submitting and receiving feedback on diversity plans was limited. A variety of challenges have been associated with developing these plans, including questions regarding regulatory guidance. Sponsors have utilized several data sources, including real-world datasets, to define enrollment goals. Diversity-related postmarketing studies most commonly related to oncologic diseases, and endpoints frequently related to efficacy. Most marketing applications associated with diversity-related postmarketing studies received Orphan drug designation (ODD) and Accelerated Approval. These results show that industry experience with diversity plans remains limited in the absence of finalized regulatory guidance. Sponsors are beginning to develop strategies for submitting diversity plans, which include identifying key functions and data sources to support enrollment goals, although definitive conclusions were difficult to draw from the small responder pool. In the postmarketing setting, studies are already underway to improve the understanding of racial and ethnic differences in responses to approved drugs. Development programs relating to oncology, which has historically suffered from a lack of diverse representation, have been a primary focus of such studies thus far.

Feasibility and practicability of routine pactice data collection and evaluations (AbD) – Experiences, analyses and suggestions for further development

With the instrument of Routine Practice Data Collection and Evaluations (German: AbD) introduced in 2019, the legislator has created the possibility of collecting comparative data in routine care. The AbD serves to generate evidence and the purpose of benefit assessment in accordance with the AMNOG (German Act on the Reform of the Market for Medicinal Products) as the basis for new reimbursement negotiations. A central point for the feasibility of an AbD are the current requirements for the proof of a quantifiable additional benefit. In a simulation study, the rigid effect thresholds currently stipulated in IQWiG‘s methods paper, but also modified requirements, were analysed. All completed orphan drug procedures since the introduction of the early benefit assessment in 2011 were included. The study shows that the procedure currently proposed by IQWiG for the AbD requires relatively large numbers of patients, which are often difficult to achieve, especially for orphan drugs. Based on the simulated, modified criteria, an alternative procedure is proposed that could do justice to the special situation of an AbD as an adjusted but non-randomised comparison.

Zilucoplan: A Newly Approved Macrocyclic Peptide for Treatment of Anti-Acetylcholine Receptor Positive Myasthenia Gravis

Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual mechanism of action preventing the formation of the membrane attack complex (MAC) and the destruction of the neuromuscular junction. This drug has been demonstrated to be able to treat the generalized myasthenia gravis without significant adverse effects, with good efficacy, safety, and tolerability profile. Zilucoplan is not only innovative and promising in the therapeutics of generalized myasthenia gravis, but it could also be beneficial for the treatment of other diseases as well as a model for synthesis of analogues to improve pharmacological profile.

Successes and pitfalls in orphan drug development for sickle cell disease

AbstractSickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

Abstract 6644: aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy

Abstract Background: Recurrence and progression rate following surgical treatment of locally advanced urothelial cancer is high, underscoring the unmet need to develop an effective, well tolerated treatment strategies, particularly for high grade upper tract urothelial cancer (HG-UTUC). The treatment success of low grade UTUC by vascular targeted photodynamic therapy (VTP) with WST11 (Padeliporfin) in phase I clinical trials led the FDA to approve Phase 3 trial in a fast track, orphan drug designation for low grade UTUC (ENLIGHT). Recently, treatment with immune checkpoint inhibitor (ICIs) of the PD1/PD-L1 axis has been approved for treatment of HG-UTUC. Yet, the failure rate of aPD1 therapy in HG-UTUC is high.We hypothesized that immune checkpoint inhibition needs to be complemented by the massive priming and accrual of newly activated anti-tumor immune cells through tumor immunogenic cell death. Early evidence indicated that WST11 VTP promotes anti-tumor immunity suggesting that VTP/aPD1 combinations may significantly improve the treatment success of HG-UTUC. Methods: Mice bearing s.c. MB49-Luc, were subjected to WST11 VTP at 14d post implantation at suboptimal dose of drug or partial area of illumination. 4 or 5 doses of aPD1 were intraperitonealy administrated every 3 days starting at 1d post VTP (aPD1+1), or every 3 days till 10 days post-treatment starting at 2 days before VTP (aPD1-2). Tumor progression was followed up to 90 days post treatment using IVIS. Hematoxylin-eosin staining, and multiplex immunohistochemistry (mIHC) were performed on controls and treated animals. Results: WST11 VTP with suboptimal drug dose, aPD1+1, and aPD1-2 resulted in 17%, 23% and 43% cure at day 90 post VTP. VTP at suboptimal drug dose combined with aPD1+1 or aPD1-2, resulted in 50% and 77% cure rate at 90 days, respectively. VTP with optimal drug dose (5mg/kg) but partial illumination resulted in 20% cure rate while combining this treatment modality with aPD1-2 resulted in 90% animal cure rate at day 90.At 24h post VTP mIHC showed a 2-3 fold increase of cytotoxic T cells, dendritic and NK cells, and a ~4 folds overexpression of PD1 and PD-L1 in the treated tumor tissue. At 2 days post aPD1-2 initiation, PD1 and PD-L1 apparent expression dropped to 0 and 2 folds higher than control, respectively. Following the combined VTP and aPD1-2 treatment, both PD1 and PDL-1 contents dropped down to zero and the CD8 content reached 3 folds enhancement compared to control. Conclusions: These observations indicate that elevating the content of anti-tumor immune cells in the tumor microenvironment by VTP in combination with ICI synergistically enhances the therapeutic effect providing a much higher complete cure compared with the individual therapies. The cure rate extent strongly depends on the synchronization of the two modalities providing guidelines for the clinical management of HG-UTUC treatment. Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Rachel Hamri, Raz Robas, David Kain, Avigdor Scherz. aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy [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 6644.

Abstract 5908: Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate

Abstract Rare cancers are defined as cancers with an annual incidence rate lower than 15/100,000 by the National Cancer Institute. Despite what the terminology may suggest, rare cancers collectively are neither very rare, accounting for about a quarter of all cancers, nor less deadly than other forms of cancer. In fact, the comparative lack of research and case studies of rare cancers compared to other forms of cancer provides both an obstacle and a unique opportunity when it comes to drug development. While finding adequate animal models and cell lines to study the disease may be more difficult, the development of innovative treatment options for rare cancers is often incentivized by the Orphan Drug Act, accelerating approval from the FDA and acting as a gateway to approval for other indications. One such rare cancer is angiosarcoma, a rare cancer that originates from the endothelium. Angiosarcoma represents about 1% of total sarcomas and can develop anywhere in the body but occurs mainly in the breast, liver, or skin of the head and neck area. Angiosarcoma is characterized by a high metastasis rate of 16% to 44%, which results in a dismal prognosis, with overall survival ranging from 6 to 16 months. Considering the high reoccurrence rate and high metastatic potential of angiosarcoma, chemotherapeutic options seem to be the obvious choice. However, mainstream chemotherapies have failed to have long-term therapeutic effects. Another approach is the use of anti-angiogenic therapy, which proved effective but was unable to lead to a complete response. Herein, we describe a novel endothelial cell-targeting therapy option for the treatment of angiosarcoma. Previously, we have discovered Doppel, a 23 kDa GPI-anchored protein that is expressed specifically in the endothelium of tumor-associated blood vessels, except for the testis. Considering the fact that angiosarcoma is a rapidly growing tumor of endothelial origin, we hypothesized that Doppel might be a viable target for both the detection and treatment of angiosarcoma. We subsequently developed an antibody-drug conjugate to Doppel by conjugating a human antibody to MMAE using a unique linker, KGDEVD. When tested on xenografts of the angiosarcoma cell lines KU-CAS3 and KU-CAS5, the tumors responded extremely well to anti-Doppel ADC treatment. Most surprisingly, even tumors exceeding 1 cm^3 went into complete remission after 6 doses of the ADC. Thus, we delved deeper into the mechanism of action behind the ADC. ADC internalization was demonstrated using confocal microscopy. Apoptosis assays show that the ADC is capable of inducing apoptosis and caspase 3 expression in angiosarcoma cells, a crucial step in the activation of the KGDEVD linker. In-vitro toxicity assays of the ADC against KU-CAS3 show an IC50 value of 7.94 nM, much lower compared to normal endothelial cell lines. Citation Format: Byoungmo Kim, Ha Kyeong Lee, Youngro Byun, Yoon Gun Ko, Sang Yoon Kim. Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate [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 5908.

Abstract 4729: Incorporation of the antitumor compound 2OHOA and its metabolite into cell membranes

Abstract The compound 2-hydroxyoleic (2OHOA) is a bioactive lipid molecule that has demonstrated an anti-tumor effect and high safety in cellular and animal models of glioblastoma multiform (GBM), considered the most aggressive and lethal of primary tumors of the central nervous system. Due to the poor prognosis of patients, with a median survival of 15 months, it is of great importance to develop new therapeutic strategies that improve the efficacy and safety of treatments to achieve complete remission of GBM. Granted orphan designation for the treatment of glioma in both the European Union and the United States, 2OHOA completed a phase I/IIA study on advanced solid tumors in adults (NCT01792310) showing pharmacological efficacy and safety. It is currently undergoing a phase IIB/III clinical trial on glioma patients (NCT04250922) in combination with the standard of care for glioma and a pediatric study on glioma and other solid tumors (NCT04299191).Here, we seek to define the mechanism of action of 2OHOA which is based on Membrane Lipid Therapy, an innovative approach that proposes the use of new molecules designed to modify the composition and lipid structure of the membrane and reverse a pathological lipid state. Therefore, we further investigated the effect of 2OHOA on membrane lipid composition when applied to human glioblastoma cell line by gas chromatography. In addition, we defined the 2OHOA’s effect on different components of the cell signaling pathway by Western Blot and PK in glioma patients.Our results demonstrated that 2OHOA is mostly incorporated in glioma cell membranes and poorly integrated in non-tumor cells, which would explain its specific effects and low side effects in GBM treatment. Moreover, we observed that after its incorporation, 2OHOA is metabolized to produce the compound C17:1n-9 by α-oxidation pathway, a key process for its anti-tumor effect in glioma cells. In addition, the C17:1n-9 metabolite impairs cell growth, reinforcing the 2OHOA activity. Finally, we examined this metabolite as a biomarker to predict and trace 2OHOA treatment, studying the pharmacokinetics of glioma patients treated with the drug in phase I/IIA and its accumulation in mice xenograft tumors. In conclusion, 2OHOA shows a different incorporation into cell membranes between tumor cells and non-tumor cells. Moreover, both 2OHOA and its metabolite C17:1n-9 have an antiproliferative effect and exhibit an appealing potential in the treatment of patients that develop GBM with unmet effective therapy. Citation Format: Roberto Beteta-Göbel, Raquel Rodríguez-Lorca, Paula Fernández-García, Pablo V. Escribá, Victoria Lladó. Incorporation of the antitumor compound 2OHOA and its metabolite into cell membranes [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 4729.