Macrocycle goes full Circle

The private US biotech Circle Pharma just became a clinical-stage company. The group’s lead project, a molecule coded CID-078 that inhibits cyclin A/B-RxL, has started its first-in-human study in solid tumours, the latest listings on clinicaltrials.gov reveal.

The registry also features new entries for Lamassu’s MDM2 inhibitor – a mechanism linked with the p53 “guardian of the genome” – Abogen’s KRAS neoantigen mRNA therapy, and a cytokine Pfizer hadn’t highlighted at February’s R&D day. For Circle the clinical trial start will be a key test of its approach to develop therapeutics based on macrocyclic peptides.

A lot is riding on this approach, with Circle having raised $160m so far from investors including the Column Group, Nextech, Pfizer and Lilly, but only generating preclinical data so far. Circle argues that macrocycles share some of the characteristics of small molecules and biologicals; other companies known to have been active here include Spexis and Vilya, both preclinically.

As for CID-078 specifically, Circle says this inhibits RxL-mediated binding of substrates to cyclins A and B, and could be “synthetically lethal” in retinoblastoma-dysregulated cancers. The company is also working on a cyclin E/CDK2 inhibitor, as well as molecules that hit cyclin A and cyclin D; all three are at the preclinical stage.

Guardian of the genome

Meanwhile, malfunctioning of the p53 protein is thought to lie behind numerous cancers, but it has proved extremely hard to target on a molecular basis, as PVM found last year with its p53 “reactivator” PC14586.

A notable player still involved here clinically is Boehringer Ingelheim with the MDM2-p53 antagonist brigimadlin, and now the ranks have been swelled by the entry of Lamassu’s SA53-OS into phase 1. SA53-OS is similar to brigimadlin in blocking MDM2 and thus inhibiting its interaction with p53, whose activity is thus supposedly restored; like the Boehringer molecule this will be tested in p53 wild-type patients.

Given the continued crowding of KRAS-targeting therapies Abogen’s ABO2102 might be of interest given that this is not a small molecule but an mRNA neoantigen therapy. However, its Chinese phase 1 study, in KRAS-mutated pancreatic cancer, is investigator sponsored. 

Abogen also has a clinical-stage mRNA immunotherapy generating IL-12, but the latest phase 1 entrant here is Pfizer, with PF-07921585, an IL-12 mutein. The latter asset has led a rather low-key existence, with Pfizer opting at its R&D day in February to highlight other novel molecules such as the Seagen-derived anti-PD-L1 ADC PF-08046054.

Perhaps one reason for this is the largely disappointing track record of cytokine-based therapies, including those trying to harness IL-12-mediated tumour suppression. In 2020 Bristol Myers Squibb paid $475m in near-term up-fronts for rights to Dragonfly’s extended half-life IL-12 therapy DF6002, but ended this deal three years later.

In February Xencor said it was pausing development of its IL-12/Fc fusion protein XmAb662, whose phase 1 trial has now been terminated on clinicaltrials.gov.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 27 and 30 Aug; **available on Chinese clinical trial registry and OncologyPipeline since May 2024.