A Prelude to a Lilly duel

Lilly signalled its interest in SMARCA2 inhibition in February when it chose Foghorn’s FHD-909 for clinical development. Now it has been revealed that this project will start human testing at around the same time as another selective oral contender, Prelude’s PRT7732.

The companies are ahead of the SMARCA2 pack, which currently doesn’t involve any other big pharma players. Meanwhile, the popular targets B7-H3 and folate receptor alpha also feature in first-in-human trial intiations, according to the latest listings on the clinicaltrials.gov registry.

Looking SMARC

FDH-909 (now known as LY4050784) and PRT7732 aren’t quite the first SMARCA2 inhibitors to hit the clinic: that honour goes to Foghorn’s oral SMARCA2/4 inhibitor FHD-286 and Prelude’s intravenous SMARCA2 degrader PRT3789. Data on the latter will be presented at the upcoming ESMO meeting.

Still, Prelude could be looking for a more convenient option with its oral degrader, and FHD-286 has suffered a (now lifted) clinical hold in AML, following deaths thought to be due to differentiation syndrome.

The latest trials could give an insight into whether the degrader or inhibition approach has an edge in patients with solid tumours and SMARCA4 mutations.

B7-H3 x PD-L1

While SMARCA2 is still fairly niche, B7-H3 is crowded with over 40 assets against this target in the clinic, according to OncologyPipeline.

ADCs represent a popular approach, and DualityBio has become the latest clinical-stage contender here with DB-1419. Uniquely, the asset also hits PD-L1, although it’s unclear what this might add. DualityBio’s broader ADC approach has received validation from BioNTech, which has licensed its HER2, TROP2 and straight B7-H3 projects.

Indeed, B7-H3 has been a hotbed of activity, with Merck & Co last year licensing ifinatamab deruxtecan from Daiichi as part of a megabucks deal, while GSK turned to Hansoh Pharma to get HS-20093, now dubbed GSK5764227. A global GSK-sponsored phase 1 study of that asset is set to begin on 30 August.

The lead B7-H3-targeting ADC, Macrogenics’ vobramitamab duocarmazine (vobra-duo), has run into problems with toxicity; however, this uses a DNA alkylating agent payload while the aforementioned assets, including DualityBio’s DB-1419, employ a currently more fashionable topoisomerase 1 inhibitor.

Folate receptor alpha

Folate receptor alpha (FRα) is another popular target for ADC development. The poster child here is Elahere, the drug that drove AbbVie’s $10bn takeout of ImmunoGen. Sutro is also gunning for approval of its contender, luveltamab tazevibulin, with a pivotal ovarian cancer trial under way, but Bristol recently handed farletuzumab ecteribulin rights back to Eisai.

The latest entrant here is Zymeworks, with ZW191. Unlike Elahere, luvelta-T and farletu-E, which use tubulin inhibitor payloads, ZW191 features a topoisomerase 1 inhibitor. This makes it look more similar to Lilly’s recent entrant, LY4170156.

Of the 10 FRα ADCs in clinical development, six are based around topoisomerase 1 inhibitors, including Genmab’s rinatabart sesutecan (via ProfoundBio) and AstraZeneca’s AZD5335.

Pol theta

The synthetic lethality target Pol theta is less crowded, but interest seems to be growing – Moma Therapeutics’ MOMA-313 was recently unveiled as a new clinical entrant, and now Repare will soon join the fray, with RP-3467 due to start phase 1 in October. The study, called Polar, will evaluate RP-3467 with and without the PARP inhibitor Lynparza in advanced solid tumours.

Repare’s Pol theta inhibitor programme was previously partnered with Ono Pharmaceutical, but the Japanese group handed back rights last year. This isn’t the first attempt Repare has had at Pol theta inhibition; its first-generation project, RP-2119, was discontinued at the preclinical stage.

Other companies in Pol theta inhibition include GSK, via a deal with Ideaya, Artios Pharma and Varsity Pharmaceuticals. 

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 14 and 20 Aug 2024.