Expanding A Single Mechanism Through Genetic Logic And Clinical Observation

By Andrew Parker, Ph.D., CEO, Step Pharma

In oncology drug development, the assumption has often been that success comes from breadth: multiple assets, multiple targets. But our experience at Step Pharma suggests a different path is possible: with the right biology, a single mechanism can open multiple clinically meaningful avenues. Our lead molecule, dencatistat, is a selective cytidine triphosphate synthase 1 (CTPS1) inhibitor that now forms the basis of clinical development programs spanning three distinct indications. This has not come from strategic ambition alone but from following the data — genetic, biochemical, and clinical — wherever it has led.

Targeting CTPS1 In Haematological Disorders

The rationale for CTPS1 inhibition stems from human genetics. CTPS1 is an enzyme involved in the synthesis of nucleotides, the building blocks of DNA and phospholipids required for cell membrane synthesis. Loss-of-function mutations in CTPS1 are known to cause severe immunodeficiency due to impaired lymphocyte proliferation, highlighting CTPS1’s non-redundant role in this cell type. In contrast, most other tissues appear able to compensate through CTPS2, its paralogue enzyme. This cell type-specific selectivity offered a compelling opportunity: a chance to specifically target aberrant lymphocyte proliferation in lymphoid malignancies while sparing normal tissues.

We developed our lead asset with that goal in mind. Our first clinical studies in relapsed and refractory T cell and B cell lymphomas were informed by this biology. These early studies confirmed on-mechanism clinical activity but also revealed an unexpected, yet consistent, reduction in platelet counts: a pharmacodynamic effect we now understand to be directly linked to the drug’s mechanism of action.

Rather than treating this as an obstacle, we saw it as a prompt to look deeper. Could the platelet effect itself be therapeutic? Essential thrombocythaemia (ET), a myeloproliferative neoplasm characterized by elevated platelet levels and increased thrombotic risk, seemed a natural next step. With over 60 lymphoma patients now dosed and a clean safety profile established, we initiated a Phase 1b study in high-risk ET patients who are resistant or intolerant to existing therapies. This was not a preordained direction for the program but one that emerged from the data. Subsequently, we have shown that mature human megakaryocytes do not express CTPS2, explaining the dependence on CTPS1 for phospholipid synthesis and platelet production.

CTPS1, CTPS2, And Solid Tumors

At the same time, we were also investigating CTPS1 dependency in solid tumors. Detailed analysis of tumor genomics highlighted that a subset of cancers harbor deletions encompassing the CTPS2 gene, making them reliant on CTPS1 for nucleotide synthesis. This sets up a classic synthetic lethal scenario: by inhibiting CTPS1, we may be able to selectively target tumors that have lost CTPS2 expression. We have developed a CTPS2 assay to guide patient selection and are enrolling individuals with advanced solid tumors into Phase 1b expansion cohorts focused initially on ovarian, lung, and endometrial cancer, where the prevalence of CTPS2 loss is greater than 15%, in the belief that one in 10 of all solid tumors have deleted the CTPS2 gene.

The evolution of dencatistat — from lymphoma to CTPS2-null solid tumors to ET — has not been driven by a desire for breadth alone but by a consistent thread of biological logic. Each indication reflects a different aspect of the same underlying mechanism — whether informed by human genetics, observed pharmacology, or tumor-specific vulnerabilities. This is the essence of our pipeline-in-a-product approach: a development strategy determined by following the science.

Building Multiple Indications

grows. Building multiple indications from a single mechanism allowed us to apply early learnings — whether in regulatory engagement, clinical trial design, or trial management — across different programs. There are efficiencies in that continuity, both operationally and financially. Success in one setting also helps reinforce confidence in the underlying biology, which can support decision-making around subsequent studies.

Nonetheless, we are also conscious of the demands this approach places on focus and execution. Running parallel programs, even if they stem from a common mechanism, stretches resources and requires clear prioritization. Platform-based strategies may appear to diversify risk, but they also concentrate it — if a core assumption falters, the impact can be far-reaching. It is a model that can be capital efficient but not capital light. While we believe in the scientific coherence of our programs, we recognize that each indication will ultimately be judged on its own merits.

Expanding Dencatistat

Of course, translating this kind of scientific strategy into real clinical progress depends on more than the biology. Expanding dencatistat into multiple indications has required coordination across different regulatory environments, operational timelines, and clinical strategies. We have had to think carefully about how to structure our trials so that they are both indication specific and adaptable, particularly as requirements evolve across regions. Tools like the EU Clinical Trials Information System (CTIS) have helped streamline some of this complexity, but ultimately, it is the underlying development framework and the ability to stay responsive to new data that determines whether such a model can work in practice.

There is no question that oncology drug development is fraught with complexity; however, our experience with dencatistat suggests that when a mechanism is biologically sound, thoughtfully developed, and clinically observed with curiosity, it can take us further than we might have first imagined.

We will continue to follow the science and the data wherever it leads.

About The Author

Andrew Parker has more than 20 years of experience from senior leadership and managerial positions in international pharmaceutical, biotech, and start-up companies. Parker took up leadership of Step Pharma in September 2019. Prior to joining Step, he was CSO at Zealand Pharma, Denmark. Prior experience, covering scientific strategy and business development, was garnered from leadership roles with Shire Pharmaceuticals, Opsona Therapeutics, and AstraZeneca. He has also acquired venture capital experience as general partner and scientific director for the Life Sciences Investment Fund Eclosion2. Parker was awarded a Ph.D. in molecular biology from the National Institute for Medical Research at Mill Hill, London, which he followed with post-doctoral research at Johns Hopkins Medical School, Baltimore, USA. He has an MBA from the University of Warwick Business School, UK.