Executive Summary / Key Takeaways

• Plus Therapeutics is a clinical-stage biotechnology company focused on developing targeted radiotherapeutics, led by REYOBIQ, and a novel diagnostic platform, CNSide, for difficult-to-treat Central Nervous System (CNS) cancers like glioblastoma and leptomeningeal metastases.
• The company's differentiated technology, utilizing Rhenium-186 nanoliposomes for precise, high-dose radiation delivery and the CNSide platform for enhanced CSF diagnostics, offers potential advantages over existing therapies and diagnostics, supported by promising early clinical data showing favorable safety profiles and efficacy signals.
• Recent significant financing ($15 million gross proceeds) and substantial non-dilutive grant funding (including $17.6 million from CPRIT and $3 million from the DoD) have bolstered the balance sheet, providing anticipated cash runway into mid-2026 to advance key clinical trials and support the commercial launch of CNSide.
• Key upcoming catalysts include potential FDA alignment on pivotal trial pathways for REYOBIQ in LM and GBM, initiation of multi-dose LM and pediatric brain cancer trials, the phased commercial launch of the CNSide diagnostic platform, and further clinical data presentations.
• Despite clinical and strategic progress, the company faces significant financial risks, including ongoing operating losses, a substantial accumulated deficit, and multiple critical Nasdaq listing compliance challenges (minimum stockholders' equity, minimum bid price, timely filing) that pose a material threat to its listing status and future capital-raising ability.

A Focused Mission: Targeting CNS Cancers

Plus Therapeutics, Inc. is a clinical-stage pharmaceutical company dedicated to addressing the significant unmet needs in Central Nervous System (CNS) cancers. Evolving from its origins as Cytori Therapeutics, Inc., the company underwent a strategic transformation, culminating in its name change in 2019 and a sharpened focus on developing targeted radiotherapeutics. A pivotal moment in this journey was the 2020 acquisition of the REYOBIQ technology from NanoTx, Corp., forming the cornerstone of its lead therapeutic pipeline. This was further complemented by the strategic acquisition of the CNSide diagnostic platform from Biocept, Inc. (BIOC) in 2024, adding a synergistic diagnostic capability aimed at improving patient management and expanding the market for its therapeutic candidates.

The company's core strategy revolves around leveraging innovative platform technologies to deliver radiation precisely to tumor sites while minimizing exposure to healthy tissues. This approach seeks to overcome the limitations of traditional treatments, particularly external beam radiation therapy (EBRT), which often struggle to deliver sufficient therapeutic doses to CNS tumors without causing significant damage to surrounding healthy brain tissue. By focusing on high-need indications like recurrent glioblastoma (GBM), leptomeningeal metastases (LM), and pediatric brain cancers (PBC), Plus Therapeutics aims to offer potentially safer, more effective, and more convenient treatment options.

The Technological Edge: Precision Radiotherapy and Novel Diagnostics

At the heart of Plus Therapeutics' therapeutic strategy is REYOBIQ (rhenium 186 Re obisbemeda), a novel injectable radiotherapy. This technology encapsulates the radionuclide Rhenium-186 within nanoliposomes, designed for targeted delivery via convection-enhanced delivery (CED) or intraventricular catheters (like Ommaya reservoirs) directly into brain tumors or the cerebrospinal fluid (CSF). This localized delivery method is intended to bypass the blood-brain barrier and concentrate the radiation dose where it is needed most.

The Rhenium-186 isotope is strategically chosen for its properties: a short half-life suitable for localized treatment, beta energy for destroying cancerous tissue, and gamma energy that allows for real-time imaging during administration. This real-time visualization is a key differentiator, potentially giving clinicians better control over dosing and distribution compared to traditional methods. The company highlights that REYOBIQ has the potential to deliver radiation doses up to 20 times greater than what is typically possible with standard EBRT while significantly sparing normal tissue. Preclinical studies in LM animal models showed tolerance to doses as high as 1075 Gy. In the ReSPECT-GBM Phase 2 trial, an average absorbed dose of 300 Gy to the tumor was observed (n=18), with doses >100 Gy correlating with improved overall survival compared to standard care. For LM, Phase 1 PK/PD analysis demonstrated impressive target-to-off-target radiation absorbed dose ratios, exceeding 100:1 in Cohort 5, indicating highly localized delivery. Furthermore, studies suggest Rhenium-186 largely spares the spinal cord compared to other beta emitters, supporting its suitability for CNS applications.

Beyond REYOBIQ, the company is also developing Rhenium-188 NanoLiposome Biodegradable Alginate Microsphere (RNL-BAM) for solid organ cancers, regulated by the FDA as a medical device.

Complementing its therapeutic pipeline is the CNSide platform, a cerebrospinal fluid cancer diagnostic portfolio. Acquired in 2024, CNSide offers laboratory developed tests (LDTs) for tumor cell enumeration (CSF01), cellular biomarker identification (CSF02 - FISH), and molecular biomarker identification (CSF03 - NGS). This platform addresses a critical diagnostic gap in LM, where standard methods like cytology lack sensitivity. The FORESEE clinical trial demonstrated CNSide's enhanced sensitivity, detecting tumor cells in CSF with 80% accuracy compared to just 29% for cytology. Crucially, the trial showed CNSide influenced over 90% of clinical management decisions and identified actionable mutations influencing 24% of therapeutic selections, highlighting its potential to improve patient care and treatment selection. For investors, these technological differentiators represent the core competitive moat, offering the potential for superior clinical outcomes, which could translate into market share gains and pricing power if regulatory approvals are achieved.

Clinical Progress: Advancing Key Programs

Plus Therapeutics is actively advancing its lead therapeutic candidate, REYOBIQ, across multiple CNS cancer indications through its ReSPECT clinical trial program.

The ReSPECT-LM program, substantially funded by a nearly $18 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT), focuses on leptomeningeal metastases, a devastating complication of advanced cancers. The Phase 1 single-dose escalation trial was completed on February 26, 2025, successfully determining the recommended Phase 2 dose (RP2D) as 44.10 mCi. Interim data from this trial has shown promising signals, including a median overall survival of 9 months compared to historical consensus of approximately 4 months, and high clinical benefit rates across radiographic (75%), clinical (86%), and CSF tumor cell count (93%) assessments. Based on these positive results, the company plans to conduct an end-of-Phase 1 meeting with the FDA to discuss an expedited path to approval, potentially involving a single-dose expansion trial at the RP2D, initially focusing on LM from breast cancer (for which REYOBIQ has Orphan Drug Designation). In parallel, a Phase 1 multiple-dose escalation trial is anticipated to begin enrollment in the first half of 2025, aiming to optimize dosing regimens for potentially longer-term benefit, building on positive observations from compassionate use cases. The FDA has granted both Fast Track and Orphan Drug Designation (for LM from breast cancer and lung cancer), underscoring the high unmet need and potentially facilitating regulatory review.

In ReSPECT-GBM, evaluating REYOBIQ for recurrent glioblastoma, enrollment continues in the Phase 2 portion for smaller tumors (<20 mL). Phase 1 results were recently published in the prestigious journal Nature Communications, highlighting promising safety and efficacy, including a median overall survival of 17 months for patients receiving >100 Gy, significantly exceeding the historical standard of care survival of around 8 months. The trial is supported by an NIH grant covering approximately 90% of costs and is expected to complete enrollment of the final patients by the end of 2025. To accelerate enrollment and prepare for a potential pivotal trial, the company has added new clinical sites, including Ohio State University and North Shore/Lenox Hill Hospitals. Discussions with the FDA regarding a pivotal trial design are planned for later this year.

The ReSPECT-PBC program targets pediatric brain cancers, specifically high-grade glioma and ependymoma. This initiative is significantly supported by a $3.0 million award from the U.S. Department of Defense. Following positive prior interactions with the FDA, the company anticipates obtaining IND approval in 2025 and aims to initiate the Phase 1 trial this year at Lurie Children's Hospital in Chicago.

Building the Commercial Engine: The CNSide Opportunity

Recognizing the critical need for improved diagnostics in CNS cancers, particularly LM, Plus Therapeutics strategically acquired the CNSide platform from Biocept, Inc. in April 2024. This acquisition was driven by the understanding that better diagnosis could significantly expand the addressable market for REYOBIQ and that CNSide holds substantial value as a standalone commercial product.

The CNSide platform's ability to provide highly sensitive tumor cell detection (80% vs. 29% for cytology) and valuable biomarker information (influencing 24% of therapeutic selections in the FORESEE trial) positions it as a potential game-changer for physicians managing patients with suspected or diagnosed LM. The company has established CNSide Diagnostics, LLC as a wholly-owned subsidiary and is actively preparing for commercial launch. Key steps include setting up a centralized laboratory in Houston, obtaining necessary certifications (CLIA registration secured, compliance anticipated Q1 2025), securing reimbursement codes (Z-Code, PLA code applications underway), negotiating agreements with commercial payers and medical systems, and building a dedicated team.

The CNSide tumor cell enumeration test is on track for a full commercial launch this year, starting with a geographically limited introduction in Q2 2025 and expanding as market access objectives are met. The company estimates the total addressable market in the U.S. for CNSide could exceed 0.5 million tests annually. While specific financial guidance for the diagnostic business is expected later in 2025 as visibility improves, the strategic intent is clear: CNSide is designed to be a valuable revenue-generating product that also enhances the clinical utility and market potential of REYOBIQ.

Navigating the Competitive Terrain

Plus Therapeutics operates within the highly competitive landscape of oncology, specifically targeting CNS cancers and radiotherapeutics. Its direct competitors include established players with approved therapies and pipelines in related areas, such as Novocure Ltd. (NVCR) with its Tumor Treating Fields for glioblastoma, and large pharmaceutical companies like Lantheus Holdings, Inc. (LNTH), Bayer AG (BAYRY), and Bristol-Myers Squibb Co. (BMY) with broader oncology and radiopharmaceutical portfolios.

Compared to Novocure's device-based TTFields therapy, PSTV's REYOBIQ offers a drug-based, single-infusion approach with the potential for significantly higher, more targeted radiation doses delivered directly to the tumor or CSF. While NVCR has an established, FDA-approved product and revenue stream, PSTV is still in clinical development, facing the inherent risks and longer timelines associated with drug approval.

Against broader radiopharmaceutical companies like Lantheus and Bayer, PSTV's technological differentiation lies in its specialized nanoliposome carrier and the use of Rhenium-186 for precise CNS delivery. This targeted approach aims for better tumor retention and reduced systemic exposure compared to some systemically delivered radiotherapies. However, these larger competitors benefit from established manufacturing scale, global commercial infrastructure, and diverse pipelines.

Compared to standard treatments like external beam radiation therapy (EBRT) and systemic chemotherapies or biologics (like those from BMY), REYOBIQ's direct delivery and high-dose potential represent a significant technological advantage, aiming to improve efficacy while reducing systemic toxicity and patient burden (single treatment vs. multi-week regimens).

The CNSide platform also competes with existing diagnostic methods, primarily CSF cytology. The FORESEE trial data showing 80% sensitivity for CNSide versus 29% for cytology demonstrates a clear technical superiority that could drive adoption if market access and reimbursement are secured.

PSTV's competitive advantages, or moats, are primarily rooted in its proprietary nanoliposome technology, the specific properties of Rhenium-186 for CNS applications, its growing intellectual property portfolio, and its success in securing significant non-dilutive grant funding. These grants provide a crucial financial buffer that many smaller biotechs lack, allowing it to advance its pipeline without solely relying on dilutive equity financing.

However, PSTV faces significant competitive disadvantages due to its clinical-stage status, lack of commercial revenue, negative profitability, and smaller scale compared to large pharmaceutical companies. Its high cash burn rate and reliance on external funding make it vulnerable to market conditions and financing risks, potentially hindering its ability to compete effectively in later-stage development and commercialization against better-capitalized rivals. Barriers to entry in the targeted radiotherapeutics and CNS diagnostics markets are high, primarily due to the significant R&D costs, complex manufacturing requirements, and stringent regulatory pathways, which can favor larger, more experienced players.

Financial Snapshot: Performance, Liquidity, and Funding Strategy

Plus Therapeutics continues to operate at a significant loss as it invests heavily in research and development. For the three months ended March 31, 2025, the company reported a net loss of $17.40 million, contributing to a substantial accumulated deficit of $510.90 million as of that date. Operating expenses totaled $4.60 million in Q1 2025, down from $4.98 million in Q1 2024, primarily due to reduced R&D spending ($1.76 million vs $2.76 million), partially offset by increased general and administrative costs ($2.84 million vs $2.21 million).

The Q1 2025 net loss was significantly impacted by non-cash charges totaling $13.87 million related to financing activities, including interest expense, financing expenses, warrant issuance costs, and changes in the fair value of derivative instruments.

Cash flow from operations remains negative, with $6.17 million used in operating activities during Q1 2025.

As of March 31, 2025, the company held $9.87 million in cash and cash equivalents and $3.53 million in investments, totaling $13.40 million in liquid assets.

Current assets were $10.87 million, while current liabilities stood at $10.56 million, resulting in positive working capital of $0.31 million.

The company's financial strategy heavily relies on securing non-dilutive grant funding and raising capital through equity and debt financing. This approach is necessitated by the ongoing operating losses and the substantial cash requirements for clinical development and commercialization. Management explicitly states an ongoing need to raise additional cash and that these factors raise substantial doubt about the company's ability to continue as a going concern.

Recent financing efforts have provided a crucial lifeline. In early March 2025, the company closed a private placement that generated approximately $15.0 million in gross proceeds. This financing involved the issuance of common stock, prefunded warrants, and warrants (Series A and Series B) that could lead to significant future dilution, with up to 473.81 million shares potentially issuable upon exercise of outstanding warrants and prefunded warrants as of March 31, 2025, compared to 32.72 million shares outstanding as of May 27, 2025.

Grant funding continues to be a significant source of capital. The CPRIT grant for the ReSPECT-LM program provides up to $17.6 million over three years, with $12.4 million received as of March 31, 2025, and approximately $7.2 million remaining at the start of 2025, with further advances expected throughout 2025. The DoD award for the pediatric brain cancer trial provides $3.0 million, with just over $2.0 million remaining and $1.1 million anticipated in 2025. The NIH grant continues to support the ReSPECT-GBM trial. Management guides for 2025 grant revenue to be in the range of $6 million to $8 million.

Combined with the recent financing, these anticipated grant funds are expected to provide cash runway through key milestones into mid-2026. Operational efficiencies, such as consolidating operations into the Houston CNSide facility in Q1 2025, are also aimed at managing costs.

Outlook and Key Catalysts

The outlook for Plus Therapeutics is centered on advancing its lead clinical programs, launching its diagnostic platform, and securing the necessary funding and regulatory approvals to bring its technologies to market. Management has outlined several key catalysts anticipated in the near to medium term:

• Regulatory Interactions: A critical near-term focus is the planned end-of-Phase 1 meeting with the FDA for the ReSPECT-LM program. The goal is to align on an expedited path to approval, potentially involving a single-dose expansion trial designed to support registration. The company also anticipates obtaining IND approval for the ReSPECT-PBC trial in 2025 and plans to meet with the FDA later this year to discuss the ReSPECT-GBM Phase 2 data and align on a pivotal trial design.
• Clinical Trial Progress: Enrollment is expected to complete in the ReSPECT-GBM Phase 2 trial by the end of 2025. Enrollment for the ReSPECT-LM Multi-Dose trial is anticipated to begin in the first half of 2025, and the company aims to initiate enrollment for the ReSPECT-PBC trial in 2025.
• Data Presentations: The company plans to present updated clinical data from its ReSPECT trials at key medical conferences throughout 2025, including comprehensive LM data at the Nuclear Medicine and Neurooncology Symposium in May, and further updates at SNO/ASCO in August and SNO in November.
• CNSide Commercialization: The CNSide tumor cell enumeration test is on track for a full commercial launch this year, starting with a geographically limited introduction in Q2 2025 and expanding throughout the year as market access objectives (CLIA compliance, coding, payer agreements) are met. Additional CNSide testing capabilities are expected to be rolled out in 2025.
• Supply Chain Expansion: Efforts to build supply chain redundancy and commercial readiness, including contracting with additional manufacturing partners, are ongoing and expected to yield updates in the near future.
• Grant Funding: The company continues to pursue non-dilutive funding, targeting at least $10 million in new grant applications annually, in addition to receiving anticipated advances from existing grants.

These milestones, if achieved, could significantly de-risk the pipeline and provide potential inflection points for the stock, demonstrating progress towards regulatory approval and commercialization.

Critical Risks on the Path Forward

Despite the promising technology and strategic initiatives, Plus Therapeutics faces significant risks that could materially impact its ability to execute its plans and continue as a going concern.

The most pressing risk is the company's financial health. It has a history of substantial operating losses and a large accumulated deficit ($510.90 million as of March 31, 2025). Net cash used in operations remains high ($6.17 million in Q1 2025). While the recent $15 million financing and anticipated grant funds provide an expected runway into mid-2026, the company explicitly states an ongoing need for additional capital. There is no guarantee that future financing will be available on favorable terms, or at all, which could force the company to delay, scale back, or abandon its development programs and commercialization plans. This financial uncertainty raises substantial doubt about its ability to continue as a going concern.

Compounding the financial risk are multiple critical Nasdaq listing compliance challenges. Although the company regained compliance with the Minimum Stockholders Equity Requirement on March 7, 2025, it was again below the requirement as of March 31, 2025, and is subject to a Mandatory Panel Monitor until March 7, 2026, meaning any further non-compliance before that date could lead to an immediate delisting determination. Furthermore, on May 16, 2025, the company received notice of non-compliance with the Minimum Bid Requirement ($1.00 minimum closing bid price) and has until November 12, 2025, to regain compliance. A reverse stock split, while approved by stockholders, may be necessary but does not guarantee long-term compliance or stock price stability. On May 21, 2025, the company also received a notice of deficiency for the delayed filing of its Q1 2025 Form 10-Q, requiring a compliance plan by July 21, 2025. Failure to resolve these listing deficiencies could result in the delisting of the company's common stock from Nasdaq, severely impacting its liquidity, market visibility, and ability to raise future capital.

The terms of the March 2025 private placement warrants, particularly the price reset and the 3x cashless exercise multiplier for Series B warrants, introduce significant potential for future dilution. As of March 31, 2025, the number of shares potentially issuable upon exercise of these warrants and prefunded warrants is substantial relative to the current outstanding share count. This could depress the stock price and may also pose a risk under Nasdaq Listing Rule 5101, which grants Nasdaq broad discretionary authority to delist securities if it determines continued listing is not in the public interest, potentially due to the highly dilutive nature of a transaction.

Clinical trial risk is inherent for any biotech company. While early data is promising, there is no guarantee that later-stage trials will demonstrate sufficient safety and efficacy to support regulatory approval. The success of the LM program hinges on FDA alignment on an expedited pathway and positive results from planned expansion and multi-dose trials. The GBM program's future depends on successful completion of Phase 2 enrollment and positive pivotal trial data.

Finally, the successful commercialization of CNSide depends on achieving CLIA compliance, securing favorable reimbursement, and executing a successful market launch against existing diagnostic methods.

Conclusion

Plus Therapeutics is charting a course through the challenging landscape of CNS cancers with a differentiated approach centered on its REYOBIQ targeted radiotherapeutic and the newly acquired CNSide diagnostic platform. The core investment thesis rests on the potential of these technologies to offer superior outcomes for patients with devastating conditions like LM and GBM, leveraging precise, high-dose radiation delivery and enhanced diagnostic capabilities. Promising early clinical data and the strategic synergy between the therapeutic and diagnostic assets provide a compelling narrative for potential value creation.

The company has demonstrated an ability to attract significant non-dilutive funding through government and state grants, a crucial advantage that helps offset the substantial costs of clinical development. The recent equity financing further strengthens the balance sheet, providing a runway to reach key clinical and commercial milestones over the next 18-24 months. Upcoming catalysts, including regulatory interactions, trial advancements, and the commercial launch of CNSide, offer potential inflection points for investors to monitor.

However, the path forward is fraught with significant financial and operational risks. The company's history of losses and ongoing cash burn necessitate continuous access to capital, while multiple, simultaneous Nasdaq listing deficiencies pose a material threat to its market access and visibility. The potential for substantial dilution from recent financings also remains a key consideration. For investors, the story of Plus Therapeutics is one of high potential tempered by high risk. The success of the investment thesis will ultimately depend on the company's ability to translate promising early data into regulatory approvals, execute its commercial strategy for CNSide, and navigate its critical financial and listing challenges while effectively leveraging its technological advantages in a competitive market.