Executive Summary / Key Takeaways

• Lisata Therapeutics is advancing Certepetide, a novel peptide designed to enhance drug penetration and modify the tumor microenvironment in solid tumors, positioning it as a potential backbone therapy across multiple cancer types and therapeutic modalities.
• The company anticipates a data-rich 12-18 months, with key readouts expected from multiple Phase 2 trials, including the final analysis of the ASCEND trial in pancreatic cancer (Cohort B data in July 2025, final analysis thereafter) and top-line data from the BOLSTER trial in cholangiocarcinoma (mid-2025).
• Strategic collaborations with partners like Kuva Labs, Catalent (CTLT), Valo Therapeutics, and GATC Health (GATC) are exploring Certepetide's potential in imaging, antibody-drug conjugates, oncolytic viruses, and leveraging AI for development, broadening its applicability beyond traditional chemotherapy combinations.
• Lisata maintains a focus on prudent capital management, with cash, cash equivalents, and marketable securities of $25.8 million as of March 31, 2025, projected to fund operations into the third quarter of 2026, supported by expense controls and non-dilutive funding efforts like NOL sales.
• Despite clinical progress and a diversified pipeline strategy, management has expressed frustration with the current market valuation, believing upcoming data catalysts will better reflect the company's intrinsic value and potential.

Unlocking the Tumor Fortress: Certepetide's Promise in Solid Tumors

Lisata Therapeutics is a clinical-stage pharmaceutical company dedicated to overcoming one of the most formidable challenges in cancer treatment: the dense, protective barrier surrounding solid tumors. Many aggressive cancers, such as pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, and glioblastoma multiforme (GBM), are encased in a fibrotic stroma and harbor an immunosuppressive tumor microenvironment (TME). These factors severely limit the ability of conventional and even cutting-edge therapies, including chemotherapeutics and immunotherapies, to reach and effectively kill cancer cells. Lisata's core strategy revolves around its lead investigational product, certepetide (formerly LSTA1 or CEND-1), designed to breach this tumor fortress and fundamentally alter the treatment landscape for these difficult-to-treat diseases.

The company's journey to this focus was significantly shaped by its acquisition of Cend Therapeutics in September 2022, which brought the promising Certepetide asset into its pipeline. This strategic move built upon Cend's foundational research and existing partnerships, including a long-standing license agreement with Sanford Burnham Prebys and a key collaboration with Qilu Pharmaceutical for the Greater China market. Since the merger, Lisata has centered its efforts on leveraging Certepetide's unique mechanism of action to enhance drug delivery and improve patient outcomes across a growing portfolio of clinical and preclinical programs.

The CendR Pathway: A Technological Moat

At the heart of Lisata's approach is Certepetide's ability to activate the C-end rule (CendR) active transport mechanism. Certepetide is a nine-amino acid cyclic peptide that selectively targets alpha-v beta-3 and alpha-v beta-5 integrins, which are highly upregulated on tumor vasculature, endothelial cells, tumor cells, and certain immunosuppressive cells within the TME, but are minimally expressed on healthy tissues. Upon binding to these integrins, certepetide undergoes proteolytic cleavage, releasing a linear peptide fragment. This fragment then binds to neuropilin-1, another receptor upregulated in solid tumors, triggering the CendR pathway.

This activation leads to the formation of microvesicles that can encapsulate co-administered drugs circulating in the bloodstream and ferry them through the tumor stroma and into the tumor cells. This tumor-specific active transport system is designed to result in systemically co-administered anti-cancer drugs more efficiently penetrating and accumulating within the tumor, while potentially leaving normal tissues unaffected. The tangible benefit is the potential for enhanced anti-cancer activity without a corresponding increase in systemic adverse side effects, a critical advantage in combination therapies.

Beyond drug delivery, Certepetide has demonstrated in preclinical models its ability to modify the TME by reducing T-regulatory cells and augmenting cytotoxic T cells. This modification is intended to make tumors more susceptible to attack by the patient's own immune system and co-administered immunotherapies, while also inhibiting the metastatic cascade.

The versatility of Certepetide's mechanism is a key differentiator. It is modality-agnostic, meaning it can potentially enhance the delivery and efficacy of a wide range of therapeutic agents, including chemotherapeutics, immunotherapies, RNA-based therapeutics, and even imaging agents or cell therapies. This broad applicability provides a significant strategic advantage, allowing Lisata to explore numerous combination opportunities and potentially position Certepetide as a backbone therapy across diverse solid tumor types.

Lisata is also exploring the potential to molecularly bind or tether Certepetide to anti-cancer agents. While co-administration offers a faster path to market by avoiding the complexities of developing a new chemical entity (NCE), tethering could represent an attractive life-cycle management strategy, creating novel NCEs with potential for distinct patent protection. A recent research license with Catalent to evaluate Certepetide as a payload on their SMARTag antibody-drug conjugate (ADC) platform represents a significant step into this area, with Catalent assuming R&D expenses.

The company's intellectual property portfolio, covering composition of matter, method of use, indication, and formulation, provides protection into the 2030s, with potential extensions into the early 2040s through pending applications and market exclusivity benefits from orphan drug designations (7-10 years depending on geography).

Navigating the Competitive Landscape

The battle against solid tumors is fiercely competitive, involving large pharmaceutical companies with established oncology portfolios (like Amgen (AMGN) and Gilead Sciences (GILD)), as well as innovative biotech firms developing novel approaches such as gene editing (CRISPR Therapeutics (CRSP)) and gene therapies (Bluebird Bio (BLUE)). These competitors offer therapies with varying mechanisms, efficacy profiles, and cost structures.

Amgen and Gilead, with their vast resources and broad portfolios, command significant market share in oncology biologics and viral therapies, respectively. Their products often demonstrate high efficacy in certain cancers but come with premium pricing. CRISPR Therapeutics and Bluebird Bio are at the forefront of gene and cell therapies, offering potentially transformative, highly precise treatments, but often facing manufacturing challenges, high upfront costs, and complex regulatory pathways.

Lisata's strategic positioning leverages Certepetide's unique drug delivery and TME modification mechanism to carve out a niche, particularly in cancers where stroma and TME barriers are major impediments. While direct, precise market share figures for LSTA's specific niche indications compared to these large players are not publicly detailed, the company's focus on enhancing existing standard-of-care therapies offers a potentially more cost-efficient approach compared to the high development and manufacturing costs associated with some cell and gene therapies. Preliminary clinical data suggesting improved response rates and survival trends in combination with standard chemotherapy, without significantly increasing adverse events, points to a potential value proposition that could be attractive in cost-sensitive healthcare environments.

Lisata's strategy of pursuing multiple combination studies with various modalities (chemo, immuno, ADC, imaging) and in different tumor types allows it to explore the broadest potential market for Certepetide. Collaborations like the one with Kuva Labs to explore Certepetide with imaging technology highlight a move towards personalized medicine, aiming to identify patients most likely to benefit, a strategic response to the need for targeted therapies in the competitive landscape. The partnership with GATC Health to use AI in drug development is another strategic move aimed at increasing efficiency and derisking the development process, potentially accelerating its competitive timeline.

However, Lisata's smaller scale compared to large pharma giants means it faces challenges in terms of R&D bandwidth and the ability to fund large, global Phase 3 trials independently. This necessitates reliance on partnerships and careful capital management. While its niche focus provides a degree of protection from direct competition with broad-spectrum drugs, it also means targeting smaller patient populations initially. The company's ability to secure non-dilutive funding and enter into collaborations where partners bear development costs is crucial for mitigating these scale-related disadvantages and advancing its pipeline against larger, better-funded competitors.

Clinical Momentum and Upcoming Catalysts

Lisata's development pipeline is actively generating data, with several key readouts anticipated in the near term. The ASCEND trial, an investigator-initiated Phase 2 study in first-line metastatic pancreatic cancer combining Certepetide with gemcitabine and nab-paclitaxel, is a central focus. Preliminary data from Cohort A (single dose) presented in January 2025 showed encouraging trends, including a median overall survival of 12.68 months for the Certepetide group versus 9.72 months for placebo, an ORR of 46% versus 28%, and notably, 6.2% complete responses in the treatment arm versus none in the placebo arm. While median PFS was similar (5.50 months), these signals of improved response and survival are promising for a disease with such poor prognosis. Preliminary data from Cohort B (double dose) has been accepted for presentation at ESMO-GI in July 2025, with the final analysis of both cohorts expected thereafter. These data are critical for informing the design of a potential global Phase 3 registration trial, which the company is actively planning.

The BOLSTER trial in cholangiocarcinoma is also progressing rapidly. Enrollment in the first-line cohort was completed ahead of schedule, and top-line data are expected in mid-2025. Based on investigator enthusiasm and the high unmet need, a second cohort for second-line cholangiocarcinoma was added, with enrollment capped at approximately 20 patients to expedite data analysis and conserve capital.

Other ongoing studies include CENDIFOX, evaluating Certepetide with FOLFIRINOX in pancreatic, colon, and appendiceal cancers (enrollment completed December 2024, data awaited), the Qilu Pharmaceutical Phase 2 trial in China (enrollment completed, data expected in the next 12-18 months, potentially triggering a $10 million milestone upon Phase 3 initiation), the iLSTA trial combining Certepetide with chemotherapy and immunotherapy in locally advanced pancreatic cancer (enrollment nearing completion, preliminary data suggests improved outcomes and TME effects), and a Phase 2a study in glioblastoma multiforme (GBM) with temozolomide (actively enrolling, enrollment completion now expected in 2026). The planned FORTIFIDE study in second-line pancreatic cancer is on hold as the company explores faster, more cost-effective approaches, potentially leveraging imaging endpoints from the Kuva Labs collaboration.

These multiple data catalysts over the next 12-18 months represent significant potential inflection points for Lisata, offering opportunities to validate Certepetide's broad applicability and therapeutic potential across different tumor types and combinations.

Financial Health and Capital Strategy

As of March 31, 2025, Lisata held $20.2 million in cash and cash equivalents and $5.6 million in marketable securities, totaling $25.8 million. This represents a decrease from $31.2 million in cash, cash equivalents, and marketable securities at December 31, 2024.

The net loss for the three months ended March 31, 2025, was $4.7 million, an improvement from the $5.4 million net loss in the same period of 2024. Operating expenses totaled $5.8 million in Q1 2025, down from $6.6 million in Q1 2024, reflecting reduced R&D spend ($2.6M vs $3.2M) primarily due to lower CRO/site costs and CMC spend, and slightly lower G&A ($3.2M vs $3.4M).

Net cash used in operating activities was $5.4 million for the three months ended March 31, 2025, compared to $7.0 million for the same period in 2024. Investing activities provided $9.4 million in Q1 2025, primarily from net sales of marketable securities, compared to $6.4 million provided in Q1 2024. Financing activities used $23 thousand in Q1 2025, mainly due to tax withholding payments on equity awards, partially offset by proceeds from ATM issuances ($0.2 million).

The company believes its current cash position is sufficient to fund operations into the third quarter of 2026. This projection is based on existing and planned activities and reflects a continued focus on prudent capital management, including delaying certain Phase 3 CMC activities and exploring cost-effective alternatives for studies like FORTIFIDE. Lisata also utilizes its At The Market (ATM) offering agreement for capital, subject to limitations based on its public float, and has successfully generated non-dilutive funds through the sale of New Jersey NOLs ($0.9 million net proceeds in January 2025).

While the current cash runway provides near-term stability to reach key data milestones, the company acknowledges the need for additional financing to meet long-term liquidity needs, particularly for advancing programs into larger, more expensive trials like a potential Phase 3 study. The ability to raise capital on favorable terms remains a risk, dependent on market conditions and the success of its clinical programs.

Risks and Challenges

Investing in a clinical-stage biopharmaceutical company like Lisata carries inherent risks. The success of Certepetide is uncertain and dependent on positive results from ongoing and planned clinical trials, which can be subject to delays, unforeseen safety issues, or failure to meet endpoints. Regulatory approvals are not guaranteed, even with positive data. The competitive landscape is intense, and larger companies with greater resources could develop more effective or cost-efficient therapies. Reliance on investigator-initiated trials means Lisata has limited control over timelines and data dissemination. The need for significant future financing poses a risk of dilution to existing shareholders or the inability to fully pursue development opportunities if capital is unavailable on acceptable terms.

Conclusion

Lisata Therapeutics stands at a pivotal juncture, armed with a differentiated technology designed to address fundamental barriers in solid tumor treatment. Certepetide's ability to enhance drug delivery and modify the tumor microenvironment offers a compelling value proposition, potentially improving the efficacy of a wide range of anti-cancer therapies without adding significant toxicity. The company has strategically built a diverse pipeline of clinical and preclinical studies, exploring Certepetide's potential across multiple tumor types and therapeutic modalities, supported by a network of collaborations.

With a series of key data readouts anticipated over the next 12-18 months, including critical results from the ASCEND and BOLSTER trials, Lisata is entering a period of significant catalysts that could validate its approach and illuminate the path forward, particularly towards a potential Phase 3 study in pancreatic cancer. The company's focus on prudent capital management provides a runway to reach these near-term milestones, although future financing will be necessary for broader development. While challenges remain in a competitive and capital-intensive industry, the upcoming data has the potential to demonstrate Certepetide's value, potentially leading to a re-evaluation by the market and advancing Lisata's mission to transform the treatment of solid tumors.