Lisbon, Portugal – November 6, 2023 – Mondego Bio, a pioneering Portuguese biopharmaceutical company, has announced a significant milestone with the initiation of its first-in-human Phase Ia clinical trial for MB-388, an innovative oral small-molecule inhibitor targeting protein tyrosine phosphatases PTPN2 and PTPN1. This groundbreaking therapy is engineered to enhance the efficacy of cancer immunotherapies by addressing key mechanisms of resistance, potentially offering new hope to patients with advanced solid tumors.
The Phase Ia trial is a meticulously designed, placebo-controlled, randomized, and double-blind study that will evaluate the safety, tolerability, and pharmacokinetic profile of MB-388 in healthy volunteers. The study will assess both single and multiple ascending doses, a critical step in determining the optimal and safest dosage for future patient populations. Early results from this initial human study are anticipated in December 2026, providing crucial insights into how MB-388 is absorbed, distributed, metabolized, and excreted by the body, and importantly, how it engages its molecular targets.
Understanding MB-388: A Dual-Action Approach to Overcoming Immunotherapy Resistance
MB-388’s therapeutic potential lies in its novel mechanism of action. It acts as a dual inhibitor of protein tyrosine phosphatases, specifically PTPN2 and PTPN1. These enzymes play a crucial role in regulating cellular signaling pathways, and their dysregulation can contribute to the development of resistance to cancer immunotherapies. By inhibiting both PTPN2 and PTPN1, MB-388 is designed to exert its effects within both tumor cells and immune cells.
In tumor cells, the inhibition of these phosphatases can lead to enhanced antigen presentation, making the cancer cells more recognizable to the immune system. Simultaneously, in immune cells, particularly T cells, MB-388 aims to restore the effectiveness of interferon-gamma (IFN-γ) signaling. This crucial pathway is often suppressed in the tumor microenvironment, hindering the anti-cancer activity of T cells. By reactivating IFN-γ signaling, MB-388 can bolster the cytotoxic capabilities of CD8-positive T cells and natural killer (NK) cells, thereby promoting a more robust anti-tumor immune response.
This dual-action strategy is particularly relevant in overcoming resistance to current immunotherapies, such as checkpoint inhibitors (e.g., PD-1/PD-L1 blockers). While these therapies have revolutionized cancer treatment for many, a significant proportion of patients do not respond or develop resistance over time. MB-388’s ability to modulate the tumor microenvironment and enhance immune cell function holds the promise of converting non-responders into responders and re-sensitizing patients who have become resistant to existing treatments.
A Phased Clinical Development Strategy: From Healthy Volunteers to Advanced Cancer Patients
The initiation of the Phase Ia trial marks the first step in a comprehensive clinical development plan for MB-388. Following the assessment in healthy volunteers, Mondego Bio has a clear roadmap for advancing the therapy into patient studies.
Key Milestones in the Clinical Development Plan:
- December 2026: Anticipated release of initial human pharmacokinetic (PK) and pharmacodynamic (PD) results from the Phase Ia trial. This data will be critical for dose selection and understanding the drug’s behavior in humans.
- January 2027: Commencement of a Phase Ib clinical trial. This study will be conducted in patients with advanced solid tumors who have either progressed on or are refractory to standard treatments, including established checkpoint inhibitor therapies.
- Combination Study Design: The Phase Ib trial will initially focus on monotherapy dose escalation to establish safety and tolerability. Subsequently, it will incorporate a combination run-in phase with programmed cell death ligand 1 (PD-(L)1) blockade. This combination approach will be evaluated in both checkpoint-naive and checkpoint-refractory patient populations, aiming to identify synergistic effects.
- December 2027: Expected readout from the combination dose escalation portion of the Phase Ib trial. This will provide crucial efficacy signals and further inform the path forward for MB-388.
This carefully staged approach ensures that MB-388 is rigorously evaluated for safety and efficacy at each step, maximizing the potential for a successful development pathway and ultimately benefiting patients.
Supporting Preclinical Data: A Strong Foundation for Clinical Success
The decision to advance MB-388 into human trials is underpinned by compelling preclinical data. In rigorous laboratory and animal model studies, MB-388 has demonstrated significant anti-tumor activity.
Key Preclinical Findings:
- Activity in Resistant Models: Preclinical tumor models that were either responsive or resistant to PD-1 blockade showed a positive response to MB-388. This suggests that the drug can overcome common mechanisms of resistance observed with existing immunotherapies.
- Enhanced Immune Infiltration: Treatment with MB-388 resulted in an increase in intratumoral CD8-positive T cells, a critical type of immune cell responsible for killing cancer cells. Furthermore, it led to increased levels of granzyme B, an enzyme that plays a key role in T cell-mediated cytotoxicity. This indicates that MB-388 effectively primes the tumor microenvironment for immune attack.
- Combination Efficacy: MB-388 demonstrated synergistic activity when combined with anti-PD-1 therapy in preclinical models, further validating its potential as a combination agent.
- Superior Profile to Competitors: When compared to osunprotafib, another clinical-stage PTPN2/PTPN1 inhibitor, MB-388 exhibited a more favorable profile. It demonstrated higher oral exposure, prolonged target engagement, and a substantially higher unbound fraction in human plasma, suggesting better bioavailability and potential for greater therapeutic effect.
These preclinical results provide a strong scientific rationale for MB-388’s potential to enhance cancer immunotherapy and underscore the importance of the ongoing clinical trials.
Official Statements: Optimism and Strategic Vision from Mondego Bio Leadership
The commencement of the Phase Ia trial has been met with enthusiasm and optimism from Mondego Bio’s leadership team. Nikolay Savchuk, CEO of Mondego Bio, articulated the significance of this milestone:
"Starting the first clinical study of MB-388 is an important milestone for Mondego," Savchuk stated. "The Phase Ia study will define the relationship between exposure, pathway engagement and tolerability, giving us the data to move efficiently into our planned study in patients with cancer. We are confident that MB-388 has the potential to significantly impact the treatment landscape for patients facing difficult-to-treat cancers."
Savchuk’s remarks highlight the strategic importance of the Phase Ia trial in generating essential data that will guide subsequent clinical development. The focus on the "relationship between exposure, pathway engagement and tolerability" underscores a data-driven approach to drug development, ensuring that MB-388 is advanced responsibly and effectively.
Wider Implications: Advancing the Frontier of Cancer Immunotherapy
The development of MB-388 by Mondego Bio is indicative of a broader trend in oncology: the pursuit of combination therapies and novel mechanisms to overcome the limitations of current treatments. As the field of cancer immunotherapy matures, the focus is shifting towards strategies that can broaden patient access, enhance response rates, and prolong survival for those with advanced and refractory diseases.
MB-388’s dual PTPN2/PTPN1 inhibition represents a sophisticated approach to modulating the complex tumor-immune cell interactions that dictate therapeutic success. By targeting key regulators of immune signaling and antigen presentation, the drug has the potential to:
- Expand the reach of immunotherapy: Enable a greater number of patients to benefit from checkpoint inhibitors and other immunotherapies.
- Resensitize resistant tumors: Provide a viable treatment option for patients whose cancers have stopped responding to existing therapies.
- Improve overall survival and quality of life: Offer new hope and improved outcomes for individuals with advanced solid tumors.
Mondego Bio, a company founded with the backing of prominent investors including Biovance Capital, OrbiMed, and Torrey Pines Investment, and supported by the Fundo de Capital e Quase Capital managed by Banco Português de Fomento with InvestEU Fund backing, is strategically positioned to advance this promising therapeutic candidate. Their focus on developing small-molecule therapies that restore critical immune functions aligns with the evolving needs of cancer patients and the scientific community’s drive to conquer complex oncological challenges. The successful progression of MB-388 through its clinical trials could mark a significant advancement in the fight against cancer, offering a new paradigm for immunotherapy enhancement.
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