Sitting down with… Neil Dhawan

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Reece Armstrong speaks to Neil Dhawan, the Co-founder and CEO of Totus Medicines about the company’s approach to drug discovery using fundamental technologies in chemistry, biology and artificial intelligence (AI).

RA: How is Totus Medicines attempting to target untreatable or undruggable diseases?

ND: Discovering a highly effective drug is like winning the lottery. If you can buy 100,000 times the number of tickets – or screen 100,000 times as many therapeutic molecules – you’re going to win a lot more and a lot faster. Totus has enabled cellular search across vast chemical space at massive scale to deliver effective medicines at an unprecedented pace. Totus has been able to identify the first highly-effective covalent molecule against the most mutated oncogene, PI3K-alpha, in four months and moved this molecule into clinical trial in two years.

RA: Could you discuss how Totus uses high-throughput cell-based screening, AI/ML & covalent chemistry to improve its drug discovery processes?

ND: Totus has innovated three interdependent and fundamental technologies in chemistry, biology, and AI to enable screening of billions of candidate molecules against hundreds of targets in parallel. First, we have built a technology to rapidly synthesise billions of highly drug-like compounds. Second, we have created a novel DNA-tracking technology to analyse billions of molecular interaction in a cellular setting. Third, we have created a 3D-AI platform to analyse all of this data and rapidly design highly-effective drug candidates.

RA: How have advancements in technology enabled companies like Totus to begin to target previously untreatable diseases?

ND: For many untreatable diseases like cancer, there are an array of drug targets that we know are driving the disease. However, current technologies have not been able to yield effective molecules to impact these drug targets. Effectively drugging all of these undrugged targets would lead to enormous patient benefit and potentially produce curative options. By enabling a million-fold improvement in drug screening, Totus is rapidly unearthing effective candidate molecules in months against targets that have plagued current technology for decades.

RA: You’ve recently dosed the first patient in a clinical trial of TOS-358, your first-in-class covalent PI3Kα inhibitor for the treatment of numerous cancers. Could you tell us about the trial and TOS-358?

ND: TOS-358 is an orally available, highly selective covalent inhibitor of PI3Kα designed to achieve deep and durable inhibition of PI3K-AKT signalling with no off-target effects. TOS-358 consistently demonstrated efficacy superior to non-covalent PI3Kα inhibitors (ATP competitive and allosteric) in patient-derived and cell line-derived xenograft models with no significant toxicities. The TOS-358-001 study is a multicentre dose escalation Phase I), dose expansion (Phase Ib) clinical study evaluating the safety, tolerability, and preliminary efficacy of TOS-358. Eligible subjects are adults with PI3Kα-mutant tumours. The study is currently enrolling in the US with European sites planned to open later in 2023.

RA: How impactful could TOS-358 be across a range of cancers?

ND: Based on our preclinical studies, TOS-358 is highly effective across PI3Kα-mutant tumours, including breast, colorectal, lung, gastric, head and neck, and ovarian tumours. Our Phase I study (NCT05683418) tests TOS-358 as a monotherapy in cohorts of patients with a range of tumour types.

RA: What have been some of the long-term challenges in targeting harder to treat diseases?

ND: Many hard-to-treat diseases are driven by hard-to-drug targets. While reliable targets may be unclear in certain disease, the genetics revolution has unearthed central and critical targets in a variety of diseases. However, even when we know the important drug targets, finding effective molecules to intervene with that drug target has proved challenging. Totus’ platform is seeking to solve this critical challenge by enabling cellular screening on a million-fold improve scale versus current technologies.

RA: Could you talk more about Totus Medicines’ goal of identifying molecules for every gene in the human genome? How can this impact drug discovery?

ND: It’s impossible to overstate the potential of Totus’ work. If you can screen the whole human genome, you can attempt to drug any relevant target with highly effective and specific drugs. By understanding how your drug is interacting with the full array of human proteins at the same time, we can rapidly deduce safe, effective drugs for almost any target.

RA: With such large volumes of data generated through screening approaches, is data analysis a challenge for Totus?

ND: The Totus platform innovation is especially timely with the emergence of ML, which are very data hungry. At Totus we say, “The more data, the better!”

RA: What’s the future outlook for Totus Medicines?

ND: In 2023 at Totus, we have the opportunity to prove the power of our platform with the most important form of data – clinical data. Through the Totus platform, we have discovered and advanced TOS-358 into the clinic to achieve efficacy for patients with PI3Kα-mutant tumours. 15% of all cancer patients have PI3Kα- mutant tumours, representing one of the most significant unmet needs in all of oncology. Importantly, TOS-358 is just the beginning for Totus. We are building an array of drug programmes targeting other incredibly important targets in oncology.

DDW Volume 24 – Issue 3, Summer 2023

Neil DhawanBiography:

Neil Dhawan is the Co-founder and CEO of Totus Medicines, where he focuses on combining small molecule design, structural biology, genetics, biochemistry, and cell biology to design new classes of drugs to target untreatable diseases.

 

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