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Step Pharma
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Trailblazing a new concept for treating cancer

Over the years, there have been a number of significant advances in the treatment and management of cancer.

 

However, cancer has been, and continues to be, one of the most challenging diseases to solve. Despite decades of research dedicated to the search for cures, cancer is currently the world’s biggest killer, responsible for the deaths of around 10 million people globally, young and old, every year. For this reason, there is a need to explore new ideas and new concepts.

With 18 million new cases of cancer worldwide reported in 2020, and 10 million deaths, there is a need to explore new ideas and new concepts.

Cancer is caused by faults, called mutations, in the DNA of cancer cells that causes them to grow uncontrollably. These cancer cells have a frustrating capability to outsmart attack by our immune system, the first line of defence. In addition, response to chemotherapy and targeted therapy is frequently not long-lasting due to the development of resistance. To add further fuel to the fire, because of the large variety of different mutations, a treatment that works for one individual might not have the same result in another. Because of this complexity, scientists across the globe are searching for different approaches to target cancer in new ways.

One of the new approaches being applied by scientists is to precisely target a vulnerability of cancer cells. This includes important concepts such as synthetical and collateral lethality, whereby DNA mutations found in cancer cells render them highly sensitive to precision cancer treatments. A potential advantage of this approach is maximising the effects of the drug against cancer cells whilst sparing normal tissues. Challenges include identifying the right cancers, which often requires the development of new assays based on genomics or protein expression.

Having overseen the development of many new cancer drugs across a career in pharma and biotech spanning close to 30 years, Brian Schwartz was in search of a company pursuing science that no-one has applied. In 2022, he joined Step Pharma as its CMO. Brian and the team at Step Pharma are homing in their efforts on targeting an enzyme called cytidine triphosphate synthase (CTPS) 1.

 

But why is CTPS1 so important?

Dividing cancer cells require a continual supply of nucleotides to replicate their DNA. Pyrimidines, one of the essential classes of nucleotide, are supplied by the de novo pyrimidine synthesis pathway. Every step in this pathway is catalysed by a single enzyme, except the final step where two enzymes, CTPS1 and CTPS2, can catalyse the conversion of UTP to CTP.  Recent studies have shown that cancer cells are addicted to CTPS1 in order to keep dividing, whereas CTPS2 is sufficient for the proliferation of healthy cells. This is why the Step Pharma team believes that selectively targeting CTPS1 is so important.

“What gets me up in the morning is working for a company that is trailblazing a new journey to improve outcomes for those living with cancer.  Our concept selectively targets an Achilles’ heel of cancer cells which we hope will stop cancer in its tracks.”

Brian Schwartz, CMO, Step Pharma

 

Targeting the key pathways on which cancer cells depend has the potential to improve outcomes for those living with cancer. In addition, the development of highly selective drugs has the potential to decrease unwanted effects on normal cells. The net result is treatments that are more effective at killing cancer cells but with fewer unwanted side effects.

“Whilst the ultimate wish of those living with cancer is to be cured of their disease, freedom from treatment associated side effects is also very important. Through the development of highly selective drugs targeting key cancer pathways, we are aiming to improve both survival and quality of life.”

Brian Schwartz, CMO, Step Pharma

Step Pharma
In Blog

Bringing precision into cancer treatment with genomic testing

Philip Beer, Chief Scientific Officer at Step Pharma, who is also the Chair of the Genomics Working Group of the British In Vitro Diagnostics Association (BIVDA), provides his perspectives on the recently published report titled “Leveraging partnerships to realise the UK’s potential in genomics” which focuses on the UK genomics landscape and patient access to genomic testing. Philip details the reasons he got involved in BIVDA’s Genomics Working Group and the difference genomic testing can make in cancer treatment.

Genetic testing to identify DNA changes in cancer samples has the potential to match the right patient with the right drug at the right time, thus improving outcomes and making a significant difference to the lives of those living with cancer. The findings of this report highlight ways forward to improve access to genomic medicines for the benefits of patients.

 

Why are you involved with the British In Vitro Diagnostics Association and what is your role there?

I have a longstanding interest in the use of biomarkers, genomics in particular, as a means to power oncology drug development. Biomarker profiling is the process of analysing biological samples, including cancer DNA, to better understand how patients are likely to respond to different treatments. An optimal approach is to embed comprehensive biomarker profiling into routine clinical care pathways. The NHS has articulated an ambitious vision to do this, but we still have some work to do to make this a reality.

I got involved with BIVDA to find out how the organisation engaged emerging and existing technologies for genomic testing, as many of the barriers to implementation relate to technological pathways and processes. This led to my taking up the Chair of the newly convened Genomics Working Group. The report that was just published, in collaboration with Charles River Associates, is the first fruits of the labour of this working group.

 

How can biomarkers be utilised in the process of developing novel cancer treatments at Step Pharma and the industry as a whole?

New cancer drugs that enter clinical development with a selection biomarker are far more likely to succeed. This reflects a better understanding of both the mechanism of action of the drug and the selection of the right cancer types to target. The majority of cancer types are not single entities. What we call colorectal cancer, for example, is a complex mixture of different disease types. By breaking down a complex disease into smaller, molecularly defined entities, we can increase success rates for the therapeutic targeting of specific pathways. At Step Pharma we have plans for biomarker selected studies in solid tumour patients that we believe will have increased sensitivity to inhibition of CTPS1.

 

What is your hope for the future regarding the role of biomarkers in cancer treatment?

Embedding comprehensive biomarker profiling into routine clinical practice has the potential to accelerate oncology drug development. In an ideal world, all patients would have access to biomarker profiling at the time of diagnosis with advanced cancer. Genomic and clinical outcome data from all patients could then be collated and made available to industry and academic researchers. Large, high quality clinico-genomic datasets have the potential to power all stages of drug development, from target discovery to patient selection.

Step Pharma
In Blog

Driving a step change in the treatment of cancer

Blog

April 2023

There are over a hundred different types of blood cancer with the forms of leukemia, lymphoma and myeloma being the most common. Every 3 minutes someone in the US is diagnosed with a blood cancer.

For solid tumours, the most common cancers include breast, lung, colon and prostate.

Andrew Parker, CEO of Step Pharma, discusses his motivation to lead the Company to focus on a novel target, CTPS1, which is considered to be an Achilles Heel of cancer, in the search for highly selective, safe and effective treatments for both blood cancers and solid tumours.

 

What was your motivation to join Step Pharma?

I have always been intrigued by how a single mutation in our DNA can be irreversibly disruptive, leading to the transition of a normal cell into a cancerous cell. The human genetic story of how a mutation resulting in the loss of CTPS1, a key enzyme that is required for the synthesis of DNA and RNA, leads to the understanding that this could be a novel approach to treat lymphoma exemplifies this concept.

Humans with CTPS1 deficiency demonstrated an impaired capacity to proliferate lymphocytes but importantly have no other negative consequences. This highlighted that inhibiting CTPS1 could be a targeted approach to treat lymphoproliferative disorders such as leukemia and lymphoma without the side effects often seen with cancer drugs. This level of genetic validation is very compelling and quite unusual in drug discovery. The Company’s deep understanding of CTPS1 biology and chemistry has ultimately led to the discovery of STP938, a selective CTPS1 inhibitor with excellent pharmaceutical properties.

Consequently, I was convinced by the scientific concept, coupled with the belief and passion of the founding scientists and the enthusiasm of the investors.

In joining Step Pharma in 2019, I had the opportunity to lead and build a team of like-minded drug developers who are focussed on bringing about highly selective cancers treatments without the significant side effects associated with current and emerging cancer therapies.

You’ve previously worked in senior roles in pharma across other disease areas. How are you applying this experience as CEO of a cancer biotechnology company?

I have had many different roles across big pharma, biotech and VC, each of which has always taught me something new. Drug development requires deep knowledge of the disease area so it is essential to have the right minds engaged. The team at Step Pharma is a perfect balance of deep understanding of oncology, in particular blood cancers, as well as the organisational and drug development skills required to successfully advance a small molecule program.

The biotech CEO role is focused on the bigger picture, building the right team, setting the strategic direction, ensuring we have enough money to succeed, but the most important thing I have learned is to never allow this to disconnect you from the science and the detail of the preclinical and clinical data.

What is the issue you are trying to solve with current treatments for T cell and B cell malignancies? 

The successful treatment of lymphoma, which develops from white blood cells called lymphocytes, is quite different when comparing T cell with B cell lymphoma. In all cases the frontline therapy is chemotherapy which brings a successful outcome for many patients but is associated with significant side effects. However, a significant number of patients treated with chemotherapy will relapse.

For B cell lymphomas there are a range of second-line and third-line drugs which offer limited benefit for these patients and a significant number will still relapse. In T cell lymphomas there are very few second line agents and none of them are particularly effective.

We aim to bring forward treatments that will add to the armoury of options for B cell lymphoma patients and transform the way T cell lymphoma is treated.

 

Why is CTPS1 inhibition going to address this need?

Targeting the pathways that make nucleotides, which are required for the synthesis of DNA and RNA, is a well explored and validated concept in oncology. However, until now this has been achieved through non-selective drugs, which cause unacceptable side effects.

Human genetics and the identification of a handful of individuals that lack CTPS1 demonstrated the crucial role that CTPS1 plays in allowing lymphocytes, T and B cells, to proliferate. Importantly, the lack of CTPS1 in these individuals had no other effects. This means that selective inhibition of CTPS1 should block proliferation of cancerous T and B cells and not bring unexpected side effects. The reason this can be achieved is due to the related enzyme CTPS2 which is able to maintain nucleotide synthesis in healthy cells, something unique to this step in the pathway and a key differentiation for our approach.

 

Targeted therapies for cancer is a crowded and challenging space, what makes Step Pharma stand out from others in the field and why do you believe you will succeed?

We believe that our investigational therapy, STP938, has the potential to transform the way lymphomas are treated. T cell lymphoma patients have no good options following relapse and there are few alternative drugs in development. The high unmet need for novel therapies brings the potential for the accelerated approval of STP938 following successful Phase II clinical studies.

B cell lymphoma treatment is complex and, despite the recent success seen with CAR-T therapies, many patients are not fit enough to withstand the trauma of a CAR-T therapy.  As more data accumulates, it is becoming clear that the majority of CAR-T patients will also relapse. The future of cancer treatment lies in moving away from chemotherapy and towards the use of appropriate combinations of targeted therapies to maximise the benefit to patients. These combinations should be driven by science, and we have spent considerable time developing an understanding of the most appropriate drugs that could ultimately combine with STP938.

We also believe that inhibition of CTPS1 will be successful in the treatment of some solid tumours. We are developing a biomarker that will enable selection of patients sensitive to CTPS1 inhibition, with an initial focus on ovarian and lung cancer, aiming to start clinical studies next year. In addition, the combination of STP938 with drugs that inhibit the DNA Damage Response pathway has shown incredible synergy in pre-clinical experiments across a range of solid tumours.

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