DSP-0390: A Comprehensive Analysis of an Investigational Emopamil-Binding Protein Inhibitor for the Treatment of High-Grade Glioma

Executive Summary

This report provides a comprehensive analysis of the investigational therapeutic agent DSP-0390, a novel, orally administered small molecule being developed by Sumitomo Pharma Oncology, Inc. An initial query for "EBP-22" was determined to refer to this specific drug, an Emopamil-Binding Protein (EBP) inhibitor that received significant regulatory attention in 2022. DSP-0390 is being evaluated for the treatment of high-grade glioma (HGG), a group of aggressive brain tumors with a dire prognosis and a profound unmet medical need, particularly in the recurrent setting where no standard of care exists.

The therapeutic rationale for DSP-0390 is predicated on a unique and compelling biological vulnerability. The central nervous system (CNS) is isolated from peripheral cholesterol by the blood-brain barrier, making brain cells entirely dependent on de novo cholesterol biosynthesis. Glioblastoma (GBM), the most aggressive HGG, exhibits a metabolic reprogramming characterized by an "addiction" to cholesterol, which is required for rapid cell proliferation. DSP-0390 targets EBP, a critical enzyme in this biosynthesis pathway. By inhibiting EBP, the drug is hypothesized to selectively induce cytotoxicity in hyperproliferative glioma cells by starving them of essential cholesterol, while potentially sparing peripheral tissues that can source cholesterol from circulation.

Preclinical studies have demonstrated significant antitumor activity for DSP-0390 in relevant orthotopic xenograft models of human GBM. This has led to a robust clinical development program, spearheaded by the first-in-human Phase 1/2 trial, NCT05023551. Preliminary results from this study are highly encouraging, indicating that DSP-0390 is well-tolerated, with no dose-limiting toxicities reported and only a single Grade 3 related adverse event observed across multiple dose-escalation cohorts. Furthermore, early efficacy signals have emerged, including durable tumor reduction in two patients with IDH-mutant grade 3 glioma. This finding has prompted a sophisticated, hypothesis-driven "window of opportunity" study (NCT06636162) to mechanistically investigate the link between IDH-mutation status and sensitivity to EBP inhibition.

In July 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to DSP-0390 for the treatment of brain cancer, a significant regulatory milestone that validates the therapeutic rationale and provides incentives to expedite its development. While the path to approval for any HGG therapy is challenging, with historically high attrition rates, the combination of a strong biological premise, a favorable early safety profile, and a scientifically rigorous, biomarker-informed clinical strategy positions DSP-0390 as a promising and noteworthy candidate in the neuro-oncology pipeline. Its continued development warrants close observation by clinicians, researchers, and industry stakeholders.

Introduction: The Unmet Need in Recurrent High-Grade Glioma and the Emergence of Novel Therapeutic Strategies

Deconstructing the "EBP-22" Query: Focusing on the True Subject, DSP-0390

An inquiry into the pharmaceutical agent "EBP-22" requires an initial clarification, as the term is ambiguous and corresponds to several distinct concepts within the biomedical and commercial landscapes. A systematic evaluation of available information reveals that the most relevant and specific subject of this query is the investigational drug DSP-0390, an inhibitor of the Emopamil-binding protein (EBP), which achieved a key regulatory milestone in 2022.[1]

Other potential interpretations of the "EBP" acronym are demonstrably unrelated to a specific therapeutic compound. A substantial body of literature uses "EBP" to refer to Evidence-Based Practice or Evidence-Based Medicine.[3] This is a well-established methodological framework for integrating clinical expertise with the best available research evidence to guide patient care decisions; it is a process, not a product.[4] Similarly, within the pharmaceutical industry and financial analysis sectors, "EBP" is a common acronym for

Emerging Biopharma companies—typically defined as smaller organizations with R&D spending below $200 million or revenues under $500 million.[8] While the developer of DSP-0390, Sumitomo Pharma Oncology, can be analyzed within this industry context, this classification does not refer to the drug itself.[10]

Further searches yield other irrelevant results, including "Enhanced Barrier Precautions," an infection control protocol used in nursing homes [12], and various commercial products such as EBP-22 branded batteries for Alinco two-way radios.[15] The lack of a unique identifier for the target protein highlights a potential communication challenge for the developer. As the drug progresses through clinical trials, a clear emphasis on the compound name, DSP-0390, will be essential to build a distinct brand and avoid confusion with these other widespread uses of the "EBP" acronym.

Therefore, this report will focus exclusively on the investigational drug DSP-0390, an Emopamil-binding protein inhibitor, for which "EBP-22" serves as an informal descriptor referencing its target and a pivotal year in its development.

The Therapeutic Challenge of Recurrent High-Grade Glioma (HGG)

High-grade gliomas (HGG) represent the most common and malignant primary brain tumors in adults, with glioblastoma (GBM, WHO Grade IV) being the most aggressive subtype.[18] The prognosis for patients with HGG remains exceptionally poor despite decades of research and a multimodal treatment approach for newly diagnosed disease.[20] The current standard of care for newly diagnosed GBM consists of maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide chemotherapy.[21] This regimen provides a modest survival benefit, but recurrence is a near-certainty, with a median progression-free survival of approximately seven months.[18]

The clinical landscape for recurrent HGG is defined by a profound and persistent unmet medical need. Crucially, there is no established standard of care for recurrent or progressive GBM.[18] This therapeutic vacuum forces clinicians to consider a limited and often ineffective set of options on a case-by-case basis. These may include re-operation for a minority of eligible patients, re-irradiation, or systemic therapies such as nitrosoureas (e.g., lomustine), alternative dosing schedules of temozolomide, or the anti-angiogenic agent bevacizumab.[21] However, these treatments offer only marginal benefits, and combination regimens have generally failed to demonstrate superior activity while often increasing toxicity.[21] The identification of effective therapies has been hampered by numerous challenges, including the molecular heterogeneity of the tumors, the protective nature of the blood-brain barrier, and the difficulty of designing controlled clinical trials in this setting.[23] This stark clinical reality creates a clear and urgent imperative for the development of mechanistically novel therapeutic strategies, such as the targeted metabolic inhibition offered by DSP-0390.

The Molecular Basis for EBP Inhibition in Glioma: A Targeted Attack on Tumor Metabolism

The scientific rationale for investigating DSP-0390 in high-grade glioma is rooted in the convergence of two fundamental biological principles: the unique metabolic environment of the brain and the specific metabolic dependencies acquired by malignant glioma cells. This combination creates a compelling and potentially exploitable therapeutic vulnerability.

The Brain's Unique Cholesterol Economy

The central nervous system (CNS) possesses a distinct and isolated cholesterol metabolism. The brain is the most cholesterol-rich organ in the body, containing approximately 20% of the body's total cholesterol, where it serves as an indispensable component of cell membranes, myelin sheaths, and signaling pathways.[26] However, this vital pool of cholesterol is almost entirely synthesized locally, or

de novo, within the brain itself.[26] The blood-brain barrier (BBB), a highly selective semipermeable border of endothelial cells, effectively prevents the uptake of cholesterol from peripheral circulation.[26] Consequently, brain cells, including astrocytes and oligodendrocytes, are completely reliant on their own internal machinery for cholesterol production to meet their structural and functional needs.[27] This metabolic isolation from the rest of the body is the central pillar upon which the therapeutic strategy of DSP-0390 is built. A systemic therapy that inhibits

de novo cholesterol synthesis could, in theory, exert a profound effect on cells within the CNS while having a minimal impact on peripheral tissues, which can readily compensate by sourcing cholesterol from dietary intake. This establishes a potentially wide therapeutic window, a highly desirable feature for any novel anti-cancer agent.

Emopamil-Binding Protein (EBP): The Gatekeeper of Sterol Synthesis

Emopamil-binding protein (EBP), also known by its enzymatic name 3β-hydroxysteroid-Δ8,Δ7-isomerase, is the specific molecular target of DSP-0390.[1] EBP is an integral membrane protein located in the endoplasmic reticulum.[32] Its primary biological function is to catalyze a critical isomerization step in the later stages of the cholesterol biosynthesis pathway (the Kandutsch-Russell pathway). Specifically, EBP converts Δ8-sterols, such as 8(9)-cholestenol and zymosterol, into their corresponding Δ7-isomers, such as lathosterol.[32] This reaction is essential for the production of mature cholesterol.

The importance of EBP is underscored by human genetics; inactivating mutations in the EBP gene cause Conradi-Hünermann-Happle syndrome, an X-linked dominant form of chondrodysplasia punctata characterized by skeletal abnormalities, skin changes, and cataracts.[32] Structurally, human EBP consists of a five-transmembrane-helix fold that creates a cavity within the membrane, allowing it to bind a variety of ligands.[34] This binding promiscuity is notable, as EBP has been shown to be a component of the microsomal anti-estrogen-binding site (AEBS) and can bind pharmacologically diverse compounds, including the anti-breast cancer drug tamoxifen, potentially contributing to drug resistance by sequestering the active agent.[34]

Glioblastoma's Metabolic Addiction to Cholesterol

While normal brain cells carefully regulate their cholesterol levels, malignant glioma cells develop a profound dependency—often described as an "addiction"—to cholesterol to fuel their hallmark characteristic of uncontrolled proliferation.[27] The rapid synthesis of new cell membranes required for tumor growth creates an immense demand for cholesterol.[37]

Studies have shown that glioblastoma cells fundamentally reprogram their metabolic pathways to satisfy this demand. There is a clear clinical correlation between this pathway and patient outcomes, as the upregulation of cholesterol synthesis genes is strongly associated with decreased survival in GBM patients.[29] This observation is not merely prognostic; it suggests that the tumors most reliant on this pathway—and thus with the worst prognosis—may also be the most sensitive to its inhibition. This insight provides a direct line of reasoning for a biomarker-driven therapeutic strategy, where patients whose tumors exhibit the highest expression of EBP or other pathway enzymes could be selected as most likely to benefit from DSP-0390.

Furthermore, GBM cells dismantle the normal homeostatic feedback mechanisms that control cholesterol levels.[27] In healthy cells, excess cholesterol is converted to oxysterols, which then activate the Liver X Receptor (LXR) to halt further cholesterol uptake and promote its efflux from the cell. Research has shown that GBMs actively suppress the production of these oxysterols, thereby keeping LXR inactive and ensuring that the "off switch" for cholesterol accumulation is disabled.[27] This allows the tumor to continuously import and synthesize cholesterol, unchecked.

This combination of factors—the brain's reliance on de novo synthesis, the critical role of EBP in this pathway, and the acquired addiction of GBM cells to the pathway's end product—makes EBP an exceptionally rational and compelling target for therapeutic intervention in HGG.

Profile of DSP-0390: A Novel, Investigational EBP Inhibitor

Developer and Drug Classification

DSP-0390 is an investigational therapeutic agent under development by Sumitomo Pharma Oncology, Inc., a clinical-stage company that operates as a wholly-owned subsidiary of the Japan-based Sumitomo Pharma Co., Ltd..[2] The organization maintains a global presence with teams in both the United States and Japan and has a stated commitment to advancing novel cancer therapeutics, with a pipeline that includes programs in both oncology and neurology.[2] The development of a neuro-oncology asset like DSP-0390 sits squarely at the intersection of these core competencies, suggesting a strong strategic alignment and the presence of relevant internal expertise, which can be a positive indicator for the long-term prospects of a development program.

DSP-0390 is classified as an orally administered small molecule and a new chemical entity.[29] It is identified by the Chemical Abstracts Service (CAS) number 2376765-57-8 and the FDA Unique Ingredient Identifier (UNII) RB55ZW48XG.[41] Its systematic chemical name is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b'-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c]benzopyran].[42]

Mechanism of Action

DSP-0390 functions as a potent and selective inhibitor of the Emopamil-binding protein (EBP).[1] As detailed previously, EBP is a key enzyme that catalyzes one of the final steps in the

de novo biosynthesis of cholesterol.[29] By binding to and inhibiting the function of EBP, DSP-0390 effectively blocks this metabolic pathway.

The central therapeutic hypothesis is that this inhibition will lead to a state of cholesterol starvation within the tumor cells. Given the demonstrated dependence of hyperproliferative glioblastoma cells on a continuous supply of newly synthesized cholesterol to build cell membranes and support aberrant growth, this disruption is expected to induce selective cytotoxicity and, ultimately, tumor cell death.[1]

Preclinical Evidence

The advancement of DSP-0390 into human clinical trials was supported by a foundation of compelling preclinical data. Preclinical studies have demonstrated that DSP-0390 exhibits significant antitumor activity in orthotopic xenograft models of human glioblastoma.[1] These models, in which human tumor cells are implanted into the brains of immunodeficient mice, are considered a relevant system for evaluating the potential efficacy of CNS-penetrant drugs.

In addition to its effects in GBM models, in vitro experiments have shown that DSP-0390 possesses cytotoxic activity against other cancer cell lines, including those derived from colorectal cancer and triple-negative breast cancer.[2] While the primary development focus is currently on HGG, these findings suggest that the therapeutic principle of targeting cholesterol synthesis via EBP inhibition may have potential for broader applications in oncology, particularly in other tumor types known to have altered cholesterol metabolism.

The Clinical Development Program for DSP-0390

The clinical evaluation of DSP-0390 is a multi-faceted program designed to rigorously assess its safety, pharmacokinetics, and antitumor activity. The strategy is notable for its scientifically driven approach, using early data to inform and refine the development path. The program is currently composed of two key studies, summarized in Table 1.

Trial ID	Phase	Title	Indication(s)	Status (as of early 2024)	Sponsor	Key Objectives
NCT05023551	Phase 1/2	A Study of DSP-0390 in Patients with Recurrent High-Grade Glioma	Recurrent WHO Grade III/IV Glioma (GBM, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma)	Active, Not Recruiting	Sumitomo Pharma Oncology, Inc.	Determine safety, MTD/RDE; Characterize PK; Assess preliminary antitumor activity (ORR, PFS, OS) 46
NCT06636162	Early Phase 1	Early Phase 1 Window of Opportunity Study of Oral DSP-0390 in Grade II and III Gliomas	IDH-mutant WHO Grade II/III Glioma (candidates for surgery)	Recruiting	Washington University School of Medicine	Determine PK/PD effect in brain tumor tissue; Test hypothesis of increased susceptibility in IDH-mutant tumors 49

The First-in-Human, Dose-Escalation Study (NCT05023551)

The cornerstone of the clinical program is NCT05023551, a first-in-human, open-label, Phase 1/2 study initiated in September 2021 and conducted at sites in the United States and Japan.[1]

Trial Design

The study employs a two-part design common for early-stage oncology trials:

• Part 1 (Dose Escalation): This initial phase was designed to enroll approximately 21-30 patients with recurrent WHO grade III or IV malignant glioma who had progressed after at least one line of prior therapy. The primary goal was to establish the safety profile of DSP-0390 and to identify the Maximum Tolerated Dose (MTD) and/or a Recommended Dose for Expansion (RDE). Dose escalation was guided by a sophisticated Bayesian Logistic Regression Model to optimize patient safety and efficiently identify the appropriate dose level.[29]
• Part 2 (Dose Expansion): Following the determination of the RDE, a dose expansion cohort is planned. This part will function as a Phase 2a signal-seeking study, enrolling an additional 20-40 patients, specifically with recurrent WHO grade IV GBM with measurable disease. The objective of this phase is to gather more robust data on the preliminary antitumor activity and safety of DSP-0390 at the selected dose.[1]

Key Eligibility Criteria and Endpoints

Key inclusion criteria for the trial include adult patients (≥18 years) with a Karnofsky Performance Status (KPS) score of ≥70% and adequate renal, hepatic, and hematologic function. Major exclusion criteria are multifocal disease, leptomeningeal or extracranial metastasis, and significant cardiovascular disease.[29]

The primary endpoints for the dose-escalation phase are safety-focused, including the incidence of treatment-emergent adverse events (AEs), serious AEs (SAEs), dose-limiting toxicities (DLTs), and the determination of the MTD/RDE. Secondary endpoints include characterization of the pharmacokinetic (PK) profile and preliminary efficacy measures such as 6-month Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), and 12-month Overall Survival (OS).[29]

Preliminary Results from NCT05023551 (as of May 2023)

Preliminary data from the dose-escalation portion of the trial were presented in late 2023 and provide the first glimpse into the drug's behavior in humans. As of May 9, 2023, 24 patients had been treated across six dose levels, ranging from 20 mg to 240 mg once daily.[45] The patient population was representative of HGG, including individuals with GBM (70.8%), anaplastic astrocytoma (12.5%), and anaplastic oligodendroglioma (8.3%). A notable characteristic of the cohort was that 10 patients (41.7%) had tumors with an isocitrate dehydrogenase (IDH) mutation.[45]

The emerging safety and efficacy profile from these preliminary data is summarized in Table 2.

Parameter	Finding	Source(s)
Dose Levels Studied	20 mg QD to 240 mg QD	45
Patients Enrolled	24	45
Dose-Limiting Toxicities (DLTs)	None reported	45
Most Common Treatment-Related AEs (Grade 1/2)	Nausea (29.2%), Alanine aminotransferase (ALT) increased (25.0%)	45
Grade ≥3 Related AEs	One patient with Grade 3 dry skin (4.2%)	45
Reported Efficacy Signals	Two patients with IDH-mutant grade 3 glioma experienced tumor reduction and remained on treatment for ≥9 months.	45
Pharmacodynamics	Dose-dependent changes observed in PK and PD biomarkers.	45

The safety findings from this initial cohort are particularly significant. The absence of any DLTs and the very low rate of high-grade toxicity are highly encouraging for a CNS-penetrant drug targeting a fundamental metabolic pathway. In a field where Phase 1 trials are often defined by toxicity challenges, the ability of DSP-0390 to escalate through multiple dose levels without hitting a toxicity ceiling represents a major de-risking event for the program. This early clinical experience appears to validate the preclinical hypothesis that targeting a brain-specific metabolic process can create a favorable therapeutic window.

The "Window of Opportunity" Study (NCT06636162)

The second key component of the clinical program is an investigator-initiated, early Phase 1 "window of opportunity" study. This type of trial involves administering an investigational drug to patients for a short period between their cancer diagnosis and their scheduled surgery. It provides an invaluable chance to study the drug's effects directly within human tumor tissue.

This study, sponsored by the Washington University School of Medicine, is designed to enroll patients with IDH-mutant WHO grade II or III glioma who are already candidates for surgical resection.[49] Patients receive oral DSP-0390 for approximately two weeks prior to their surgery.[49] The primary objective is to measure the concentration of DSP-0390 in both the resected tumor tissue and the patient's plasma, providing direct evidence of the drug's ability to reach its target in the brain.[49]

Crucially, this study is designed to test a specific, data-driven hypothesis. Following the observation of tumor reduction in two IDH-mutant patients in the main Phase 1 trial, this study explicitly aims to investigate whether the altered cholesterol metabolism known to be driven by the IDH mutation increases the tumor's susceptibility to DSP-0390.[49] The existence of this trial demonstrates a highly sophisticated and agile development strategy. Rather than waiting for later-phase trials, the sponsor and investigators are proactively using early clinical signals to conduct rigorous mechanistic studies. This approach seeks to define a responsive patient population early, which could significantly increase the probability of success in larger, more definitive trials by enriching for patients most likely to benefit. This represents a hallmark of a well-conceived translational medicine plan.

Regulatory and Commercial Landscape

Regulatory Status: FDA Orphan Drug Designation

A pivotal milestone in the development of DSP-0390 was achieved on July 18, 2022, when Sumitomo Pharma Oncology announced that the U.S. Food and Drug Administration (FDA) had granted Orphan Drug Designation (ODD) to the compound for the treatment of brain cancer.[1] This designation is a formal recognition by the FDA that the therapy is intended for a rare disease or condition affecting fewer than 200,000 people in the United States.[2]

The granting of ODD is a significant validation and de-risking event for an investigational drug program. It signals that the regulatory agency acknowledges the serious and life-threatening nature of the condition and the profound unmet medical need for new treatments. It also indicates that the agency finds the drug's scientific rationale and preliminary data sufficiently plausible to warrant incentives designed to facilitate and expedite its development and review. These incentives are substantial and include a potential seven years of market exclusivity upon approval, tax credits for qualified clinical trials, and the waiver of certain FDA fees, such as the Prescription Drug User Fee Act (PDUFA) fee for a New Drug Application (NDA). The ODD for DSP-0390 was granted based on the data and design of the ongoing Phase 1 trial (NCT05023551), underscoring the perceived promise of the program even at an early stage.[48]

It is important to note that while some sources discuss orphan designations from the European Medicines Agency (EMA) for other glioma therapies [56], the provided research contains no evidence that DSP-0390 has received a similar designation in Europe. An EMA orphan designation for glioma (EU/3/21/2434) was granted to a different compound sponsored by Ipsen Pharma, not Sumitomo.[56]

Future Development and Commercial Trajectory

DSP-0390 is advancing through the clinical pipeline, with some sources listing its current status as Phase 2 for the treatment of Anaplastic Astrocytoma.[38] This likely refers to the dose-expansion cohort of the NCT05023551 study, which functions as a Phase 2a component to gather initial efficacy data in a more defined patient population. The drug is also being tracked by industry observers as a notable emerging therapy in the high-grade glioma pipeline.[58]

The path forward, however, is fraught with statistical and clinical challenges. According to an analysis by the business intelligence firm GlobalData, the historical benchmark for the Phase Transition Success Rate (PTSR)—the probability of a drug successfully moving from one phase to the next—for an oncology drug in Phase 2 for Anaplastic Astrocytoma to advance to Phase 3 is only 19%.[38] This stark figure quantifies the immense difficulty of developing effective treatments for HGG and means that, historically, more than four out of every five drugs that show promise in Phase 2 ultimately fail to demonstrate sufficient benefit in larger, pivotal trials.

The ability of DSP-0390 to overcome this daunting "19% hurdle" will depend entirely on its capacity to generate a compelling and clinically meaningful efficacy signal in the ongoing Phase 2 expansion cohort. The key question for the program is what makes it different from the many that have failed before. The answer may lie in its targeted approach. By identifying and focusing on a potential biomarker-defined subpopulation—such as IDH-mutant gliomas, where its mechanism of action may be most relevant—the developer may be able to demonstrate a much stronger treatment effect than the historical average seen in "all-comer" HGG trials. This precision medicine strategy represents the program's most logical path to defying the historical odds and reaching late-stage development.

Synthesis, Critical Analysis, and Strategic Recommendations

Integrated Analysis: A Promising Strategy Facing High Hurdles

The investigational agent DSP-0390 represents a scientifically elegant and potentially transformative approach to treating high-grade glioma. The program's foundational strength is its compelling biological rationale: targeting the unique and isolated cholesterol metabolism of the brain provides a clear, mechanistically-driven strategy to attack a fundamental vulnerability of glioma cells. This is not a repurposed therapy but a purpose-built molecule designed to exploit a specific metabolic addiction.

This strong rationale is substantiated by several key factors. First, preclinical data demonstrated significant antitumor activity in relevant animal models, providing the necessary proof-of-concept to proceed to the clinic.[29] Second, and perhaps most critically at this stage, the emerging clinical safety profile is exceptionally favorable. The absence of dose-limiting toxicities and the low incidence of high-grade adverse events in the initial dose-escalation cohorts suggest that the hypothesized therapeutic window is translating from theory into practice, a major de-risking event for the program.[45] Finally, the early but intriguing efficacy signal in patients with IDH-mutant tumors provides a tangible, data-driven path forward.[45] The fact that this observation is already being pursued with a dedicated, hypothesis-testing window-of-opportunity study speaks to a sophisticated and scientifically rigorous development plan.[50]

Despite these strengths, the program faces the formidable challenge inherent to all neuro-oncology drug development: the historically high bar for demonstrating a clinically meaningful benefit in recurrent HGG. A clean safety profile is necessary but not sufficient. To alter the treatment paradigm and achieve regulatory approval, DSP-0390 must ultimately demonstrate a clear and robust improvement in patient-oriented outcomes, such as progression-free or overall survival, against a backdrop of numerous past failures in the field.

Key Questions and Future Research Directions

As the DSP-0390 program advances, several critical questions must be addressed to fully define its potential and guide its future development:

• Biomarker Validation: The most pressing question is whether the window-of-opportunity study (NCT06636162) will confirm that IDH-mutation status is a robust predictive biomarker for response to DSP-0390. Further investigation into other potential markers, such as the baseline expression level of EBP or other cholesterol synthesis enzymes, could help further refine patient selection and maximize the treatment effect in a pivotal trial.
• Durability of Response: The early tumor reductions observed are promising, but their durability is unknown. Long-term follow-up from the NCT05023551 expansion cohort will be essential to determine if these responses are transient or can provide sustained clinical benefit.
• Mechanisms of Resistance: As with all targeted therapies, acquired resistance is an anticipated challenge. Preclinical research should be initiated to explore potential mechanisms of resistance to EBP inhibition. This could involve upregulation of cholesterol import pathways, activation of bypass metabolic routes, or mutations in the EBP target itself. Understanding these mechanisms is crucial for developing next-generation inhibitors or rational combination strategies.
• Combination Strategies: The potential of DSP-0390 in combination with other therapies should be explored. Could it act synergistically with the standard-of-care, temozolomide, by stressing tumor cells metabolically? Could it be combined with other metabolic inhibitors to create a more profound blockade? These questions should be addressed in preclinical models to inform future clinical trial designs.
• Long-Term CNS Safety: While short-term safety appears favorable, the long-term neurological consequences of chronically inhibiting a key enzyme in the brain's cholesterol pathway must be carefully monitored. Research has linked EBP to oligodendrocyte formation and myelination.[34] Therefore, long-term follow-up in clinical trials should proactively assess for any subtle or delayed neurological or cognitive effects.

Strategic Recommendations for Key Stakeholders

For the Developer (Sumitomo Pharma Oncology)

1. Prioritize the Biomarker-Driven Strategy: The data from the window-of-opportunity study should be the primary driver of the Phase 3 trial design. If the IDH-mutant hypothesis is validated, the pivotal trial should be designed to enroll this enriched population to maximize the probability of demonstrating a statistically significant and clinically meaningful benefit, thereby increasing the overall probability of success.
2. Initiate Preclinical Combination Studies: To build a life cycle management plan and address potential resistance, preclinical studies investigating DSP-0390 in combination with standard-of-care agents (temozolomide, radiation) and other novel therapies should be initiated in parallel with the current clinical program.
3. Maximize Data Dissemination: Upon completion of the dose-expansion and window-of-opportunity studies, the full PK/PD and efficacy data, including the biomarker analyses, should be presented at a major international scientific conference (e.g., ASCO, SNO). This will be critical for building confidence in the drug's mechanism and clinical potential among key opinion leaders, clinicians, and the investment community.

For Clinicians and Researchers

1. Support Clinical Trial Enrollment: The neuro-oncology community should prioritize the enrollment of eligible patients into ongoing and future trials of DSP-0390. The window-of-opportunity study, in particular, offers a unique chance to answer fundamental mechanistic questions and should be strongly supported.
2. Incorporate Long-Term Neurological Follow-Up: Investigators involved in DSP-0390 trials should ensure that study protocols include comprehensive and long-term neurological and neurocognitive assessments to proactively monitor for any unforeseen toxicities related to chronic EBP inhibition in the CNS.

For Investors and Industry Analysts

1. Identify Key Value Inflection Points: DSP-0390 should be viewed as a high-risk, high-reward asset, typical for the neuro-oncology space. The primary near-term value inflection point will be the release of efficacy data (e.g., ORR, 6-month PFS) from the Phase 2 expansion cohort of NCT05023551.
2. Evaluate the Strength of the Translational Strategy: The value of the DSP-0390 program lies not just in the molecule itself, but in the sophisticated, biomarker-driven clinical strategy being employed. The favorable early safety profile and the proactive investigation of the IDH-mutant hypothesis are significant de-risking factors. The results from the window-of-opportunity study should be viewed as a key leading indicator of mechanistic validation and the potential for success in a biomarker-selected pivotal trial.

Works cited

1. FDA Grants Orphan Drug Designation to DSP-0390 for Brain Cancer - OncLive, accessed June 19, 2025, https://www.onclive.com/view/fda-grants-orphan-drug-designation-to-dsp-0390-for-brain-cancer
2. Sumitomo Pharma Oncology Receives Orphan Drug Designation for DSP-0390, an Investigational Emopamil-binding Protein (EBP) Inhibitor for the Treatment of Brain Cancer - PR Newswire, accessed June 19, 2025, https://www.prnewswire.com/news-releases/sumitomo-pharma-oncology-receives-orphan-drug-designation-for-dsp-0390-an-investigational-emopamil-binding-protein-ebp-inhibitor-for-the-treatment-of-brain-cancer-301587648.html
3. The Evidence for Evidence-Based Practice Implementation - Patient Safety and Quality - NCBI Bookshelf, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/books/NBK2659/
4. Evidence-based medicine - Wikipedia, accessed June 19, 2025, https://en.wikipedia.org/wiki/Evidence-based_medicine
5. The Essential Guide to Evidence-Based Practice - The Oxford Review, accessed June 19, 2025, https://oxford-review.com/evidence-based-practice-essential-guide/
6. Evidence-based practice in clinical psychology: What it is, why it matters; what you need to know, accessed June 19, 2025, https://gsapp.rutgers.edu/sites/default/files/2023-04/spring_2007_article.pdf
7. Evidence Based Practice (EBP) - Physiopedia, accessed June 19, 2025, https://www.physio-pedia.com/Evidence_Based_Practice_(EBP)
8. 5 things to understand about pharmaceutical R&D - Brookings Institution, accessed June 19, 2025, https://www.brookings.edu/articles/five-things-to-understand-about-pharmaceutical-rd/
9. Emerging Biopharma's Contribution to Innovation - IQVIA, accessed June 19, 2025, https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/emerging-biopharmas-contribution-to-innovation
10. Emerging Biopharma's Contribution to Innovation - IQVIA, accessed June 19, 2025, https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/emerging-biopharma-contribution-to-innovation
11. Outsourcing & Emerging Biopharma - Contract Pharma, accessed June 19, 2025, https://www.contractpharma.com/exclusives/outsourcing-emerging-biopharma/
12. Enhanced Barrier Precautions (EBP) Frequently Asked Questions (FAQ) - | WA.gov, accessed June 19, 2025, https://doh.wa.gov/sites/default/files/2022-11/420446-EnhancedBarrierPrecautions.pdf
13. Frequently Asked Questions (FAQs) about Enhanced Barrier Precautions in Nursing Homes, accessed June 19, 2025, https://www.cdc.gov/long-term-care-facilities/hcp/prevent-mdro/faqs.html
14. Enhanced Barrier Precautions in the Long-Term Care (LTC) Setting, accessed June 19, 2025, https://www.dshs.texas.gov/sites/default/files/IDCU/health/Healthcare-Safety/Conferences/2022/051922-1LTC-Enhanced-Barrier-Precautions-Healthcare-Safety.pdf
15. 12V 1650mAh NiMh Radio Battery for Alinco EBP-22 EBP-22N EBP-22N EBP-28 EBP-28N | eBay, accessed June 19, 2025, https://www.ebay.com/itm/263680121183
16. 2x 12V 1650mAh NiMh Radio Battery for Alinco EBP-22 EBP-22N EBP-22N EBP-28 | eBay, accessed June 19, 2025, https://www.ebay.com/itm/401437361366
17. EBP-22h - Batteries America, accessed June 19, 2025, https://batteriesamerica.com/products/ebp-22h
18. Recurrent Glioblastoma: A Review of the Treatment Options - MDPI, accessed June 19, 2025, https://www.mdpi.com/2072-6694/15/17/4279
19. Treatment advances in high-grade gliomas - Frontiers, accessed June 19, 2025, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1287725/full
20. Brain Cancer Glioma (NCCN Guidelines for Patients), accessed June 19, 2025, https://www.nccn.org/patients/guidelines/content/PDF/brain-gliomas-patient.pdf
21. Standards of care for treatment of recurrent glioblastoma—are we there yet? - PMC, accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3534423/
22. Establishing the Standard of Care for Patients with Newly Diagnosed and Recurrent Glioblastoma - ASCO Publications, accessed June 19, 2025, https://ascopubs.org/doi/10.14694/EdBook_AM.2012.32.197
23. www.ncbi.nlm.nih.gov, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/books/NBK469987/#:~:text=Currently%2C%20no%20standard%20of%20care,and%20disease%20heterogeneity%20(10).
24. Standards of care for treatment of recurrent glioblastoma—are we there yet? | Neuro-Oncology | Oxford Academic, accessed June 19, 2025, https://academic.oup.com/neuro-oncology/article-abstract/15/1/4/1373604
25. Current Standards of Care in Glioblastoma Therapy - NCBI, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/books/NBK469987/
26. Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma - PMC, accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6406281/
27. Glioblastomas Are Addicted to Cholesterol – Can Breaking Their Dependency Stop These Tumors?, accessed June 19, 2025, https://braintumor.org/news/glioblastomas-are-addicted-to-cholesterol-can-breaking-their-dependency-stop-these-tumors/
28. Cholesterol metabolism and its implication in glioblastoma therapy ..., accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8990433/
29. DSP-0390, an oral emopamil binding protein (EBP) inhibitor, in patients with recurrent high-grade glioma: A first-in-human, phase 1 study. - ASCO Publications, accessed June 19, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS2077
30. DSP-0390, an oral emopamil binding protein (EBP) inhibitor, in patients with recurrent high-grade glioma: A first-in-human, phase 1 study. - ASCO, accessed June 19, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT363620
31. TP-0390 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 19, 2025, https://synapse.patsnap.com/drug/331bfe85c4b2419db245a2580c39adbc
32. EBP gene: MedlinePlus Genetics, accessed June 19, 2025, https://medlineplus.gov/genetics/gene/ebp/
33. 10682 - Gene ResultEBP EBP cholestenol delta-isomerase [ (human)] - NCBI, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/gene/10682
34. Structural basis for human sterol isomerase in cholesterol ..., accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6549186/
35. Evolution, Expression Profile, Regulatory Mechanism, and Functional Verification of EBP-Like Gene in Cholesterol Biosynthetic Process in Chickens (Gallus Gallus) - Frontiers, accessed June 19, 2025, https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.587546/full
36. Identification and Pharmacological Characterization of SRBP-2: A Novel SR31747A-binding Protein - AACR Journals, accessed June 19, 2025, https://aacrjournals.org/cancerres/article/63/16/4809/510237/Identification-and-Pharmacological
37. The role of cholesterol metabolism in tumor therapy, from bench to bed - Frontiers, accessed June 19, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.928821/full
38. DSP-0390 by Sumitomo Pharma for Anaplastic Astrocytoma ..., accessed June 19, 2025, https://www.pharmaceutical-technology.com/data-insights/dsp-0390-sumitomo-pharma-anaplastic-astrocytoma-likelihood-of-approval/
39. Development Pipeline - Sumitomo Pharma, accessed June 19, 2025, https://www.sumitomo-pharma.com/rd/pipeline_new-medicine/pipeline.html
40. ・ This table shows clinical studies on indications for which the Sumitomo Pharma Group aims to obtain approval in Japan, U.S.,, accessed June 19, 2025, https://www.sumitomo-pharma.com/rd/pipeline_new-medicine/assets/pdf/epip.pdf
41. DSP-0390 | CAS#2376765-57-8 | EBP inhibitor | MedKoo, accessed June 19, 2025, https://www.medkoo.com/products/58631
42. DSP-0390 - GSRS, accessed June 19, 2025, https://gsrs.ncats.nih.gov/ginas/app/ui/substances/50545576-bdc6-432e-aea7-ad53283636e1
43. DSP-0390 - precisionFDA, accessed June 19, 2025, https://precision.fda.gov/ginas/app/ui/substances/50545576-bdc6-432e-aea7-ad53283636e1
44. 10007-act-2 first in human study of dsp-0390, an oral emopamil binding protein (ebp) inhibitor, in recurrent high-grade glioma (hgg): preliminary results - ResearchGate, accessed June 19, 2025, https://www.researchgate.net/publication/376405071_10007-ACT-2_FIRST_IN_HUMAN_STUDY_OF_DSP-0390_AN_ORAL_EMOPAMIL_BINDING_PROTEIN_EBP_INHIBITOR_IN_RECURRENT_HIGH-GRADE_GLIOMA_HGG_PRELIMINARY_RESULTS
45. 10007-ACT-2 FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS, accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10710592/
46. DSP-0390, an oral emopamil binding protein (EBP) inhibitor, in patients with recurrent high-grade glioma, accessed June 19, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2022.40.16_suppl.TPS2077
47. Study of DSP-0390 in Patients with Recurrent High-Grade Glioma - NCI, accessed June 19, 2025, https://www.cancer.gov/clinicaltrials/NCI-2022-01926
48. FDA Grants Orphan Drug Designation to DSP-0390 in Brain Cancer - Targeted Oncology, accessed June 19, 2025, https://www.targetedonc.com/view/fda-grants-orphan-drug-designation-to-dsp-0390-in-brain-cancer
49. Window of Opportunity Study of DSP-0390 in Gliomas - PAN Foundation Trial Finder, accessed June 19, 2025, https://trialfinder.panfoundation.org/en-US/trial/listing/543315
50. 202412002 - Siteman Cancer Center, accessed June 19, 2025, https://siteman.wustl.edu/clinical-trial/202412002/
51. Study of DSP-0390 in Patients with Recurrent High-Grade Glioma - UCSF Clinical Trials, accessed June 19, 2025, https://clinicaltrials.ucsf.edu/trial/NCT05023551
52. Sumitomo Dainippon Pharma Oncology Announces First Patient Dosed - BioUtah, accessed June 19, 2025, https://bioutah.org/wp-content/uploads/2021/11/SDP-Oncology-DSP-0390-Press-Release_10.20.21-FINAL.pdf
53. ACT-13 DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA: A FIRST-IN-HUMAN, PHASE 1 STUDY | Neuro-Oncology Advances, accessed June 19, 2025, https://academic.oup.com/noa/article/4/Supplement_3/iii8/6869017
54. CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS - PMC, accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10639673/
55. Sumitomo Pharma Oncology Receives Orphan Drug Designation for DSP-0390, an Investigational Emopamil-binding Protein (EBP) Inhibitor for the Treatment of Brain Cancer - BioUtah, accessed June 19, 2025, https://bioutah.org/sumitomo-pharma-oncology-receives-orphan-drug-designation-for-dsp-0390-an-investigational-emopamil-binding-protein-ebp-inhibitor-for-the-treatment-of-brain-cancer/
56. EU/3/21/2434 - orphan designation for treatment of glioma - European Medicines Agency, accessed June 19, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-21-2434
57. Glioma - Patient Worthy, accessed June 19, 2025, https://patientworthy.com/category/glioma/
58. High-Grade Glioma Pipeline 2024: Latest FDA Approvals, Clinical Trials, and Emerging Therapies Assessment by Delveinsight - openPR.com, accessed June 19, 2025, https://www.openpr.com/news/3899898/high-grade-glioma-pipeline-2024-latest-fda-approvals
59. Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation | Request PDF - ResearchGate, accessed June 19, 2025, https://www.researchgate.net/publication/378906079_Discovery_and_Optimization_of_Selective_Brain-Penetrant_EBP_Inhibitors_that_Enhance_Oligodendrocyte_Formation