Exscientia, the Oxford-based pioneer in artificial intelligence (AI)-based drug development, has advanced the first of three candidates planned for first-in-human studies this year—an immunology and inflammation (I&I) small molecule designed by the company and licensed to Bristol Myers Squibb (BMS).

EXS4318, a potentially first-in-class selective Protein kinase C (PKC) theta inhibitor, is the first clinical candidate to emerge from the initial small molecule AI-based discovery collaboration launched by Exscientia and Celgene in March 2019. At the time, Celgene agreed to pay Exscientia $25 million upfront plus undisclosed payments tied to achieving milestones, and tiered royalties on net product sales.

Later that year, BMS completed its $74 billion acquisition of Celgene. BMS and Exscientia expanded the collaboration two years later to I&I as well as oncology candidates. In return, BMS multiplied what it agreed to pay Exscientia to potentially more than $1.3 billion in clinical, regulatory and commercial payments—including up to $50 million upfront, up to $125 million in “near to mid-term” milestones, and tiered royalties on net sales.

BMS will oversee the clinical and commercial development of EXS4318, with Exscientia eligible for undisclosed milestones and tiered royalties from the pharma giant. BMS opted to in-license the PKC theta inhibitor in August 2021, triggering a $20 million milestone payment to Exscientia.

“We want to be as innovative in the clinic as we have been in development,” Exscientia CEO Andrew Hopkins, DPhil, told GEN Edge. “It’s not just a case of building an AI discovery engine and then throw in the molecule over the wall, say, into a traditional drug development paradigm. We want to change the drug development paradigm as well.”

Hopkins elaborated on Exscientia’s desire to disrupt drug development on GEN’s CEO interview series “Close to the Edge.” “We think of ourselves as a tech company that develops drugs. AI has been the core to what we do,” Hopkins said last year, before adding: “Some people have called us a pharma tech, how we combine technology and pharma together. But we are just starting the journey.”

During the first three quarters of 2022, BMS paid Exscientia $15 million, according to Exscientia’s third quarter 2022 regulatory filing. BMS paid a $10 million upfront payment relating to the fifth target in the companies’ collaboration, and a $5 million payment relating to a six-month extension of Exscientia’s first collaboration with BMS, in order to generate additional translational data about various collaboration compounds using Exscientia’s precision medicine platform. For Q1-Q3 2022, Exscientia received $117.3 million in cash inflows from all its collaborations.

Designed through Exscientia’s AI generative design platform, EXS4318 was identified within 11 months after the start of design, and was the 150th novel compound synthesized in the PKC theta program pursued as part of the collaboration with BMS.

PKC theta is structurally similar to several related kinases, making it difficult to achieve the levels of selectivity required to avoid off-target effects. According to Exscientia, the target product profile for EXS4318 was especially challenging due to the needs for sustained, high levels of target inhibition to drive efficacy, as well as for low daily dose in humans.

EXS4318 is one of three I&I candidates Exscientia has partnered with BMS; the other two are in the early discovery phase. The companies also have five partnered oncology candidates—of which two are in IND-enabling phases with their targets expected to be disclosed in the first half of this year; and the other three, early discovery.

Two Phase I/II candidates

EXS4318 is one of two Exscientia candidates in Phase I/II trials. The other is EXS21546, a majority-owned A2A receptor antagonist co-invented and being developed with Evotec as an anti-cancer immunotherapy. EXS-21546 is under study in the Phase I/II IGNITE-AI trial assessing the A2A receptor antagonist plus anti-PD-1 therapy in up to 110 patients with immunotherapy relapsed or refractory renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC).

“We are now recruiting in Europe for that trial, and hopefully the first patients going through the door will be in this half of the year. So that’s moving forward,” Hopkins said.

Designed to combat adenosine related immunosuppressive effects through activation of T-cells, EXS21546 showed targeted A2A receptor signaling inhibition in healthy volunteers in a Phase Ia study (NCT04727138)  whose results were published in June 2022.

EXS21546 is one of 17 candidates in Exscientia’s pipeline that have oncology indications. Next furthest along is GTAEXS-617, a cyclin dependent kinase 7 (CDK7) inhibitor indicated for transcriptionally addicted cancers and co-owned with China-based GT Apeiron.

GTAEXS-617 is in the IND-enabling phase, with a Phase I/II trial set to enroll its first patient in the first half of this year in ovarian cancer among multiple solid tumor indications. At the 34th EORTC-NCI-AACR (ENA) Annual Symposium, last year, Exscientia presented biomarker data and novel patient stratification methods that it said support development of GTAEXS-617.

Exscientia is also targeting ENPP1 through an oncology candidate in late discovery phase co-owned with Rallybio; and has 12 early discovery oncology candidates—the three partnered with BMS, two partnered with Sanofi (with which Exscientia has an up to $5.2 billion oncology and immunology collaboration launched last year), one co-owned with GT Apeiron, one co-owned with EQRx, one co-owned with Huandong, and four candidates wholly owned by Exscientia.

Another seven candidates are for I&I—a wholly-owned inhibitor of the NLRP3 inflammasome in late discovery phase; and six early discovery candidates. In addition to the two BMS I&I candidates, Exscientia is also developing a bispecific small molecule and an unspecified molecule, both partnered with Sanofi; as well as a selective PARP1 inhibitor and an unspecified molecule, both co-owned with EQRx.

Also in Exscientia’s pipeline:

  • Hypophosphatasia—A late discovery phase candidate targeting ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), co-owned with Rallybio.
  • Coronavirus—A wholly-owned late discovery candidate targeting the main protease (Mpro) of SARS-CoV-2, developed under a $70 million collaboration with the Bill and Melinda Gates Foundation.
  • Anti-infective—An early discovery phase candidate also developed with the Gates Foundation, which gave the company a $4.2 million grant in 2020 to identify new innovative treatments for malaria and tuberculosis as well as for non-hormonal contraception.
  • Psychiatry—A late discovery candidate co-owned with Blue Oak Pharmaceuticals, through a collaboration to co-discover and develop treatments for brain disorders.

Exscientia has also worked to co-develop a Phase I clinical candidate with Sumitomo Pharma (formerly Sumitomo Dainippon Pharma), DSP-0038 for Alzheimer’s disease psychosis, a “design-as-service” candidate now overseen by Sumitomo. The companies also co-developed DSP-1181 for obsessive-compulsive disorder and brought it into the clinic, until Sumitomo quietly ended its development after disappointing Phase I results.

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