A second shot at PARP1 from Eikon

Eikon's second PARP1 inhibitor, a PRMT5 blocker Bayer licensed from Puhe BioPharma last month, and a new contender in the p53 reactivation game from GeneScience are all heading into first-in-human studies, new listings on clinicaltrials.gov reveal.

PRMT5 is a target that's yet to deliver on its promise, but despite this companies including Tango, Amgen, BeiGene, and now Bayer, continue betting on it. Meanwhile, privately held Eikon is notable for having raised significant funds from venture capitalists, and took its first PARP1 inhibitor, EIK1003, into phase 1 in 2023; its second PARP1 project, EIK1004, is said to be brain-penetrant.

Both molecules are the result of a tie-up Eikon struck in mid-2023 with China's Impact Therapeutics, granting the private US biotech global ex-China rights to IMP1734 and other PARP1-selective inhibitors. IMP1734 is now coded EIK1003 at Eikon, while EIK1004 is known as IMP1707 at Impact; as of this month both will be in phase 1 solid tumour studies.

As is to be expected, one of the most advanced players in PARP1-selective inhibition is AstraZeneca, with saruparib, the promise being reduced toxicity versus broad PARP inhibition. However, this isn't the lead focus for Eikon, which became a pivotal-stage company when it took the TLR7/8 agonist EIK1001 into phase 2/3 last December.

Synthetic lethality

Given Astra's involvement in synthetic lethality mechanisms like PARP, it's no surprise that this company also has a presence in PRMT5 inhibition, in the early-stage molecule AZD3470.

However, this mechanism has largely disappointed; Amgen's AMG 193 produced lacklustre results at last year's ESMO, and shortly afterwards Tango discontinued TNG908. But the latter has taken two more PRMT5 inhibitors, TNG462 and TNG456, into the clinic, and last month Bayer paid an undisclosed amount for rights to Puhe's PH020, now coded BAY 3713372.

At the time that deal was struck Bayer said it had enrolled the first patient in the project's first-in-human dose-escalation study, and this has now been listed on clinicaltrials.gov. While any remaining promise for PRMT5 inhibition now likely lies in combination with MAT2A inhibition, Bayer's phase 1 is a monotherapy study.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 30 Mar and 6 Apr 2025.

The p53 protein is sometimes called the guardian of the genome, and its malfunctioning is thought to lie behind numerous cancers, though it has proved extremely hard to target on a molecular basis, as PVM found with its p53 “reactivator” rezatopopt.

Now GeneScience has taken its p53 Y220C reactivator GenSci128 into phase 1 in TP53 Y220C mutated solid tumours. Similar approaches have seen Boehringer Ingelheim fail in the phase 3 Brightline-1 study with the MDM2-p53 antagonist brigimadlin, which appears to have quietly been discontinued after being talked up last year; other phase 3 MDM2-p53 antagonists include Ascentage's alrizomadlin and Kartos's navtemadlin.

A final notable new entrant into phase 1 is Avelos's MASTL inhibitor AVS1001. MASTL inhibition is said to disrupt mitosis by activating the tumour suppressor PP2A, but according to OncologyPipeline there's only one other similarly acting project, at Pfizer, which had a preclinical poster at last year's AACR.